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Medicographia
Vol 35, No. 2, 2013
115
A
Ser vier
publication
Osteoarthritis: a story of
close relationship between
bone and cartilage
E DITORIAL
139
Osteoarthritis: new approaches
Arthrose : nouvelles approches
M. C. Hochberg, USA
T HEMED
145
ARTICLES
Epidemiology of osteoarthritis
C. Cooper, E. Dennison, M. Edwards, A. Litwic, United Kingdom
152
Osteoarthritis and comorbidities
L. I. Alekseeva, E. L. Nasonov, Russia
158
Osteoarthritis pathophysiology: similarities and dissimilarities with other
rheumatological diseases and the role of subchondral bone
J. A. Roman-Blas, G. Herrero-Beaumont, Spain
164
Role of imaging in osteoarthritis: diagnosis, prognosis, and follow-up
A. Guermazi, F. W. Roemer, H. K. Genant, USA and Germany
172
Osteoarthritis treatments: where do we stand at the moment?
C. Roubille, J. Martel-Pelletier, J. P. Pelletier, Canada
181
Knee replacement for osteoarthritis: facts, hopes, and fears
L. S. Lohmander, Sweden and Denmark
189
Disease-modifying osteoarthritis drugs (DMOADs): what are they and
what can we expect from them?
A. J. Barr, P. G. Conaghan, United Kingdom
197
The economic weight of osteoarthritis in Europe
M. Hiligsmann, J. Y. Reginster, The Netherlands and Belgium
Contents continued on next page
Medicographia
Vol 35, No. 2, 2013
115
A
C ONTROVERSIAL
Ser vier
publication
QUESTION
203 Can normal age-related changes in cartilage be distinguished from early
osteoarthritic changes?
L. A. Alekseeva, Russia - J. P. A. Arokoski, Finland - F. N. Birrell, United
Kingdom - S. Bölükbaş i, Turkey - O. P. Bortkevych, Ukraine - P. Horák,
Czech Republic - A. El Maghraoui, Morocco - A. Mahmoud Ali Elsayed,
Egypt - A. Migliore, Italy - T. Pap, Germany - J. del Pino-Montes, Spain C. A. F. Zerbini, Brazil
I NTERVIEW
216 Nonpharmacological treatments in osteoarthritis
E. Kon, Italy
F OCUS
221 Long overlooked: the role of subchondral bone in osteoarthritis
pathophysiology and pain
D. M. Findlay, Australia
U PDATE
228 Clinical research in osteoarthritis: what’s new?
X. Chevalier, F. Eymard, France
A
TOUCH OF
F RANCE
237 Cinema, science, and medicine in France
C. Régnier, France
246 Children of the Cinémathèque
I. Spaak, France
EDITORIAL
‘‘
In early phases of OA, there
are anabolic changes in both articular cartilage and subchondral
bone. In the former, there is increased synthesis of matrix molecules while, in the latter, there is
activation of the bone remodeling cycle. With progression of OA,
catabolic changes dominate in the
articular cartilage with increased
synthesis of tissue-destructive enzymes including matrix metalloproteases (MMPs), and disintegrins
and MMPs with thrombospondin
motifs.”
Osteoarthritis:
new approaches
by M. C. Hochberg, USA
steoarthritis (OA) is a disease of the total joint, not just the articular cartilage. The Osteoarthritis Research Society International Disease State
Working Group defined OA as “a progressive disease representing the
failed repair of joint damage that, in the preponderance of cases, has
been triggered by abnormal intra-articular stress.”1 They noted that all tissues of the
joint are involved, including not only the articular cartilage, but also the subchondral
bone, ligaments, periarticular structures, and menisci, when present. The results of
the OA process are cartilage degradation and bone remodeling; these features are
associated with the development of symptoms of pain, stiffness, and functional disability. In this current concept of OA, the structural changes represent the disease
while the symptoms of aching, discomfort, pain, and stiffness represent the illness
for which patients seek medical care. This concept has profound implications for
treatment: while there are drugs currently approved for treating the illness of OA,
there are none currently approved for slowing the structural progression of OA.
O
Marc C. HOCHBERG, MD, MPH
Professor of Medicine and
Epidemiology and Public Health
University of Maryland School
of Medicine, Baltimore
Maryland, USA
Osteoarthritis (OA) is the most common form of arthritis, and is a major cause of
morbidity, activity limitation, physical disability, excess health care utilization and reduced health-related quality of life, especially in people aged 45 and above in developed countries.2 The incidence (risk of developing the disease) and prevalence
(proportion of persons with the disease) of OA increase with advancing age in both
sexes. In general, women have a higher incidence and prevalence of symptomatic
radiographic OA, particularly in the hands and knees. There are ethnic and racial
differences in the occurrence of OA that may be due to genetic and/or lifestyle factors; these include the lower prevalence of hand and hip OA in Chinese and the
higher prevalence of hip and knee OA in African Americans compared with whites.3
Address for correspondence:
Professor Marc C. Hochberg,
MD, MPH, c/o Division of
Rheumatology, University of Maryland
School of Medicine, 10 S. Pine St.,
MSTF 8-34, Baltimore, Maryland
21201, USA (e-mail: mhochber@
medicine.umaryland.edu)
Medicographia. 2013;35:139-144.
www.medicographia.com
Osteoarthritis: new approaches – Hochberg
It is now recognized that OA is not only a cause of pain and physical dysfunction,
but is also associated with excess mortality.4,5 Losina and colleagues reported that
the presence of knee OA, especially when combined with the presence of obesity, was associated with the loss of 3 to 4 quality-adjusted years of life.4 Neusch
and colleagues, in analyzing data from a 15-year prospective cohort study in the
United Kingdom, reported that persons with symptomatic hip and/or knee OA had
a 50% increase in all-cause mortality compared with that expected based on their
age and gender distribution.5 Risk factors for all-cause mortality included not only
the presence of comorbid conditions such as cardiovascular disease, cancer, and
diabetes, but also the presence of walking disability. This suggests that an approach
to reducing walking disability in patients with symptomatic lower limb OA might not
only improve quality of life, but also prolong survival.
MEDICOGRAPHIA, Vol 35, No. 2, 2013
139
EDITORIAL
Much research has focused on the role of obesity, joint injury,
and genetic predisposition as risk factors for the development
of OA.6-8 Metabolic syndrome—the phenotype characterized
by abdominal obesity, dyslipidemia, hypertension, and type 2
diabetes mellitus due to insulin resistance—is associated with
OA; this association may be mediated by the production of
circulating adipokines and accumulation of age-related glycation end products in articular cartilage.6 While the heritability
of OA has been recognized for over 60 years, only in the past
decade, with the development of commercially available genotyping platforms, have scientists been able to perform genomewide association studies examining the association of single nucleotide polymorphisms (SNPs) with OA.8 The largest
consortium to investigate the association of SNPs with radiographic and clinical OA is Translational Research in Europe
Applied Technologies for OsteoArthritis (TreatOA); indeed, the
TreatOA website (http://www.treatoa.eu/publications.html)
currently lists more than 50 peer-reviewed articles on the results of genetic studies in OA.
The interplay between the articular cartilage and subchondral
bone in the pathophysiology of OA has been increasingly recognized over the past decade and is a major focus for current
research into the development and progression of OA.9-11 In
early phases of OA, there are anabolic changes in both articular cartilage and subchondral bone. In the former, there is increased synthesis of matrix molecules while, in the latter, there
is activation of the bone remodeling cycle. With progression
of OA, catabolic changes dominate in the articular cartilage
with increased synthesis of tissue-destructive enzymes including matrix metalloproteases (MMPs), and disintegrins and
MMPs with thrombospondin motifs. Accompanying changes
in the subchondral bone include trabecular thinning leading to
relative osteopenia below areas of sclerosis due to thickening
of the cortical plate. These changes are mediated, in part, by
the diffusion of small molecules between bone and cartilage,
including cytokines, angiogenic growth factors, and MMPs.
Another component of the OA process that has received increasing recognition is the role of synovitis.12,13 Studies have
demonstrated increased expression of genes that encode cytokines (such as interleukin-1 and 15), chemokines, and MMPs
in synovial fibroblasts. Synovitis, as measured on magnetic resonance imaging (MRI) and/or ultrasound, is associated with
both pain and structural progression; it is not known, however, whether specific anti-inflammatory therapy is more efficacious in patients with synovitis than in those without it.
Synovitis is but one feature of OA that is associated with pain;
others include the presence of moderate-to-large bone marrow lesions and joint effusions. Studies of the mechanisms of
pain in OA have increasingly explored the nature of OA pain
and the role of peripheral and central sensitization superimposed on peripheral nociception.14,15 Peripheral sensitization
has a spinal component with signal amplification in neurons
140
of the spinal cord underlying both primary and secondary hyperalgesia. In addition, there is central sensitization, manifested by lower pressure pain thresholds and higher pain summation scores. The mechanisms of central sensitization in OA
may be due to spinal hyperexcitability coupled with defective
descending inhibitory noxious control pathways. Functional
MRI studies in patients with chronic OA pain have demonstrated atrophy in the thalamus and gray matter of pain-related cortical areas, which is partially reversible after total joint
arthroplasty.
The management of patients with OA continues to evolve with
more evidence supporting the efficacy of nonpharmacologic
modalities as well as the approval and study of newer pharmacological modalities, including biologic agents.16 The American College of Rheumatology published new recommendations for the medical management of OA of the hand, hip, and
knee in 2012.17 Nonsteroidal anti-inflammatory drugs (NSAIDs)
remain the cornerstone of oral therapy for pain in patients with
OA, despite their association with potential serious adverse
events including gastrointestinal bleeding from complicated
ulcers and small and large bowel lesions, and cardiovascular
thrombotic events, especially myocardial infarction. Patients
who have an inadequate response to or are unable to tolerate oral NSAIDs may be treated with intra-articular agents
such as glucocorticoids and hyaluronates and/or centrally acting analgesics such as tramadol, duloxetine, and opioids. The
efficacy of duloxetine—a serotonin norepinephrine reuptake
inhibitor that can be used either alone or as an adjunct to acetaminophen or NSAIDs—supports the observations summarized above that demonstrate the role of central sensitization
in chronic OA pain due to loss of diffuse inhibitory noxious
control.
There remains an unmet need for both more efficacious treatments for pain and agents that are capable of modifying the
rate of structural progression in OA. Tanezumab, a monoclonal antibody directed against nerve growth factor, has demonstrated efficacy in patients with hip and knee OA with moderate-to-severe pain.18 However, the development of this agent,
and of other compounds in its class, has been placed under
clinical hold by the US Food and Drug Administration (FDA)
because of reports of osteonecrosis adverse events that were
eventually adjudicated to be rapidly destructive OA involving
not only index joints such as the hip and knee, but also nonindex joints such as the shoulder. Further studies of the mechSELECTED
MMP
MRI
NSAID
OA
SNP
ABBREVIATIONS AND ACRONYMS
matrix metalloprotease
magnetic resonance imaging
nonsteroidal anti-inflammatory drug
osteoarthritis
single nucleotide polymorphism
EDITORIAL
anism underlying these joint-related serious adverse events
are needed to assess the risk-benefit relationship of this promising treatment for pain in patients with OA.
There have been many studies involving potential diseasemodifying OA drugs (DMOADs); however, there are no agents
that are approved at this time by either the FDA or European
Medicines Agency (EMA) for this indication. Recent data suggest that oral strontium ranelate, at doses of either 1 or 2 g
per day, significantly reduced the rate of decline in joint space
width compared with placebo in subjects with knee OA followed for a mean of 30 months.19 Similar results were noted
when subjects were classified as “progressors” based on a
decline in joint space width of at least 0.5 mm.20 Another approach to disease modification is the application of principles
of regenerative medicine with endogenous stem cells.21 It is
hoped that the results of basic biomedical, clinical, and translational research will provide new approaches to the management of patients with OA during the remaining years of this
and future decades. I
References
1. Lane N, Brandt K, Hawker G, et al. OARSI-FDA initiative: defining the disease
state of osteoarthritis. Osteoarthritis Cartilage. 2011;19:478-482.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of
arthritis and other rheumatic conditions in the United States. Arthritis Rheum.
2008;58:26-35.
3. Jordan JM: Impact of race/ethnicity in OA treatment. HSS J. 2012;8:39-41.
4. Losina E, Walensky RP, Reichmann WM, et al. Impact of obesity and knee
osteoarthritis on morbidity and mortality in older Americans. Ann Intern Med.
2011;154:217-226.
5. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and disease specific mortality in patients with knee osteoarthritis: population based
cohort study. BMJ. 2011;342:d1165.
6. Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis.
Nat Rev Rheumatol. 2012;8:729-737.
7. Muthuri SG, McWilliams DF, Doherty M, Zhang W. History of knee injuries and
knee osteoarthritis: a meta-analysis of observational studies. Osteoarthritis
Cartilage. 2011;19:1286-1293.
8. Hochberg MC, Yerges-Armstrong L, Mitchell BM. Osteoarthritis susceptibility
genes continue trickling in. Lancet. 2012;380:785-787.
9. Lories RJ, Luyten FP. The bone-cartilage unit in osteoarthritis. Nat Rev Rheumatol. 2011;7:43-49.
10. Goldring MB. Articular cartilage degradation in osteoarthritis. HSS J. 2012;8:7-9.
11. Weinans H. Periarticular bone changes in osteoarthritis. HSS J. 2012;8:10-12.
12. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical
symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625-635.
13. Scanzello CR. Pathologic and pathogenic processes in osteoarthritis: the effects of synovitis. HSS J. 2012;8:20-22.
14. Mease PJ, Hanna S, Frakes EP, Altman RD. Pain mechanisms in osteoarthritis:
understanding the role of central pain and current approaches to its treatment.
J Rheumatol. 2011;38:1546-1551.
15. Schaible HG. Mechanisms of chronic pain in osteoarthritis. Curr Rheumatol
Rep. 2012; 14:549-556.
16. Hochberg MC. Osteoarthritis year 2012 in review: clinical. Osteoarthritis Cartilage. 2012. 20:1465-1469.
17. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology
2012 recommendations for the use of nonpharmacologic and pharmacologic
therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;
64:455-474.
18. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain
from osteoarthritis of the knee. N Engl J Med. 2010;363:1521-1531.
19. Reginster JY, Chapurlat R, Christiansen C, et al. Structure modifying effects of
strontium ranelate in knee osteoarthritis. Osteoporos Int. 2012;23(suppl 2):
S58-S59.
20. Reginster JY, Chapurlat R, Christiansen C, et al. Strontium ranelate reduces the
number of radiological or radioclinical progressors in patients with primary knee
osteoarthritis. Osteoporos Int. 2012;23(suppl 2):S366-S367.
21. Marini JC, Forlino A. Replenishing cartilage from endogenous stem cells. N Engl
J Med. 2012;366:2522-2524.
Keywords: osteoarthritis, pathophysiology, risk factors, treatment
141
ÉDITORIAL
‘‘
Dans les phases précoces de
l’arthrose, des changements anaboliques interviennent aussi bien
dans le cartilage articulaire que
dans l’os sous-chondral. Dans le
premier type de tissu se produit
une augmentation de la synthèse
des molécules de la matrice tandis
que dans le second se déroule une
activation du cycle du remodelage
osseux. Au fur et à mesure de la
progression de l’arthrose, les changements cataboliques dominent
dans le cartilage articulaire, avec
une augmentation de la synthèse
d’enzymes destructrices des tissus.”
Arthrose :
nouvelles approches
par M. C. Hochberg, États-Unis
L’
arthose est une maladie qui affecte la totalité de l’articulation, et non pas
seulement le cartilage articulaire. Le Groupe de travail de l’OARSI (Osteoarthritis Research Society International, la Société internationale de recherche
sur l’arthrose) a défini l’arthrose de la façon suivante : « maladie progressive correspondant à une incapacité de réparation des lésions articulaires qui, dans
la majorité des cas, ont été déclenchées par des stress intra-articulaires anormaux ».1
Il a été observé que tous les tissus de l’articulation sont touchés, non seulement le
cartilage articulaire, mais également l’os sous-chondral, les ligaments, les structures
périarticulaires et les ménisques lorsqu’ils sont présents. Le processus arthrosique
conduit à une dégradation du cartilage et à un remodelage osseux ; ces caractéristiques sont associées au développement de symptômes douloureux, de raideur
et d’incapacité fonctionnelle. Dans ce concept actuel de l’arthrose, les altérations
structurelles représentent la maladie, tandis que les symptômes à type de douleur
sourde, gêne, douleur et raideur constituent la pathologie pour laquelle les patients
consultent un médecin. Ce concept a d’importantes répercussions sur le traitement :
alors que certains médicaments sont actuellement autorisés pour le traitement de
la pathologie de l’arthrose, il n’existe actuellement aucun traitement approuvé ralentissant la progression structurelle de l’arthrose.
L’arthrose, la forme la plus fréquente d’arthropathie, est une cause importante de
morbidité, de limitation des activités, d’incapacité physique, de surutilisation des soins
de santé et de réduction de la qualité de vie liée à la santé, et ce plus particulièrement chez les personnes âgées de 45 ans et plus dans les pays développés.2 L’incidence (le risque de développer la maladie) et la prévalence (proportion de personnes
atteintes de la maladie) de l’arthrose augmentent avec l’âge dans les deux sexes.
D’une manière générale, les femmes présentent une incidence et une prévalence
supérieures d’arthrose symptomatique radiographique, en particulier au niveau des
mains et des genoux. Il existe des différences ethniques et raciales dans la survenue de l’arthrose, principalement liées à des facteurs génétiques et/ou relatifs au
style de vie ; notamment une prévalence plus faible de l’arthrose des mains et de
la hanche chez les Chinois, et une prévalence supérieure de l’arthrose de la hanche
et du genou chez les Afro-Américains par rapport aux blancs.3
Il est désormais établi que l’arthrose provoque non seulement une douleur et un dysfonctionnement physique, mais qu’elle est également associée à un excès de mortalité.4,5 Losina et coll. ont indiqué que la présence d’une arthrose du genou, en
particulier en cas d’obésité concomitante, était associée à une perte de 3 à 4 années de vie ajustées sur la qualité de vie.4 Neusch et coll., qui ont analysé les don-
142
Arthrose : nouvelles approches – Hochberg
ÉDITORIAL
nées d’une étude de cohorte prospective de 15 ans menée
au Royaume-Uni, ont montré que les personnes présentant
une arthrose symptomatique de la hanche et/ou du genou
présentaient une augmentation de 50 % de la mortalité de
toute cause par rapport à celle prévue sur la base d’une distribution par tranche d’âge et sexe.5 Les facteurs de risque
de mortalité de toute cause comprennent la présence de comorbidités, notamment les maladies cardio-vasculaires, le cancer et le diabète, mais également la présence d’une incapacité à la marche. Cela suggère qu’une approche permettant
de réduire l’incapacité à la marche chez les patients atteints
d’arthrose symptomatique des membres inférieurs pourrait
non seulement améliorer leur qualité de vie, mais également
prolonger leur durée de vie.
Un grand nombre de recherches ont porté sur le rôle de l’obésité, des lésions articulaires et de la prédisposition génétique
comme facteurs de risque du développement de l’arthrose.6-8
Le syndrome métabolique – un phénotype caractérisé par une
obésité abdominale, une dyslipidémie, une hypertension et un
diabète de type 2 dû à une insulinorésistance – est associé
à l’arthrose ; cette association pourrait être due à la production d’adipokines circulantes et l’accumulation de produits terminaux de glycation liés à l’âge dans le cartilage articulaire.6
Si la transmission héréditaire de l’arthrose est reconnue depuis plus de 60 ans, ce n’est qu’au cours de la dernière décennie que les scientifiques, grâce à la disponibilité dans le
commerce de plates-formes de génotypage, ont été en mesure d’effectuer de larges études d’association sur l’ensemble
du génome, en examinant l’association des polymorphismes
nucléotidiques (single nucleotide polymorphisms, SNP) avec
l’arthrose.8 Le plus large consortium ayant exploré l’association des SNP avec les preuves radiographiques et cliniques
d’arthrose est TreatOA (Translational Research in Europe Applied Technologies for OsteoArthritis) ; en effet, le site Internet
de TreatOA (http://www.treatoa.eu/publications.html) comporte actuellement une liste de plus de 50 articles évalués par
des pairs sur les résultats d’études génétiques dans l’arthrose.
L’interconnexion entre le cartilage articulaire et l’os sous-chondral dans la physiopathologie de l’arthrose a été confirmée au
cours de la dernière décennie, et constitue l’un des sujets majeurs des recherches actuelles sur le développement et la progression de l’arthrose.9-11 Dans les phases précoces de l’arthrose, des changements anaboliques interviennent aussi bien
dans le cartilage articulaire que dans l’os sous-chondral. Dans
ABRÉVIATIONS
ET ACRONYMES
MMP matrix metalloprotease (métalloprotéinases de la matrice)
IRM
Imagerie par résonance magnétique
le premier type de tissu se produit une augmentation de la
synthèse des molécules de la matrice tandis que dans le second se déroule une activation du cycle du remodelage osseux. Au fur et à mesure de la progression de l’arthrose, les
changements cataboliques dominent dans le cartilage articulaire, avec une augmentation de la synthèse d’enzymes destructrices des tissus, notamment les métalloprotéinases de la
matrice (MMP), ainsi que des désintégrines et des MMP munies de motifs thrombospondines. Les changements concomitants dans l’os sous-chondral comprennent un amincissement trabéculaire provoquant une ostéopénie relative sous
les zones de sclérose, liée à l’épaississement de la plaque corticale. Ces changements sont assurés en partie par la diffusion de petites molécules entre l’os et le cartilage, notamment
des cytokines, des facteurs de croissance angiogéniques et
des MMP.
Un autre composant du processus arthrosique de mieux en
mieux identifié est le rôle de la synovite.12,13 Des études ont
démontré une augmentation de l’expression des gènes codant pour les cytokines (notamment les interleukines 1 et 15),
les chimiokines et les MMP dans les fibroblastes synoviaux.
La synovite, mesurée par imagerie par résonance magnétique
(IRM) et/ou échographie, est associée à la fois à la présence
de douleurs et à une progression structurelle ; il n’a cependant pas été établi si un traitement anti-inflammatoire spécifique était plus efficace chez les patients atteints de synovite que chez ceux qui ne l’étaient pas.
La synovite est l’une des caractéristiques de l’arthrose associée à la douleur ; les autres comprennent la présence de
lésions modérées à importantes de la moelle osseuse et
d’épanchements articulaires. Les études des mécanismes de
la douleur dans l’arthrose explorent de plus en plus souvent
la nature de la douleur arthrosique et le rôle de la sensibilisation périphérique et centrale associée à la nociception périphérique.14,15 La sensibilisation périphérique a une composante rachidienne s’accompagnant d’une amplification des
signaux dans les neurones de la moelle épinière, qui sous-tend
une hyperalgie primitive et secondaire. En outre, il existe une
sensibilisation centrale, qui se manifeste par l’abaissement
des seuils de douleur à la pression et une augmentation des
scores totaux de douleur. Les mécanismes de la sensibilisation centrale dans l’arthrose peuvent être dus à une hyperexcitabilité rachidienne couplée à un déficit des voies de contrôle
descendantes inhibitrices des stimuli nociceptifs. Des études
d’IRM fonctionnelle menées chez des patients présentant une
douleur arthrosique chronique ont mis en évidence l’atrophie
des zones corticales liées à la douleur dans le thalamus et la
substance grise, partiellement réversible après une arthroplastie articulaire totale.
AINS Anti-inflammatoires non stéroïdiens
SNP single nucleotide polymorphism (polymorphisme nucléotidique)
La prise en charge des patients atteints d’arthrose ne cesse
d’évoluer au fur et à mesure que les preuves confirmant l’efficacité des modalités non pharmacoépidémiologiques s’ac-
143
ÉDITORIAL
cumulent, mais également avec l’autorisation de nouvelles modalités pharmacologiques, notamment les agents biologiques,
et les études qui sont menées dessus.16 L’ Académie américaine de rhumatologie (American College of Rheumatology)
a publié en 2012 de nouvelles recommandations sur la prise
en charge médicale de l’arthrose de la main, de la hanche et
du genou.17 Les anti-inflammatoires non stéroïdiens (AINS)
restent la base du traitement oral de la douleur chez les patients arthrosiques, malgré leur association à des effets indésirables potentiellement graves, notamment des hémorragies
gastro-intestinales provenant d’ulcères compliqués et de lésions de l’intestin grêle et du gros intestin, ainsi que des événements cardio-vasculaires thrombotiques, en particulier l’infarctus du myocarde. Les patients présentant une réponse
inadéquate ou n’étant pas en mesure de tolérer les AINS
oraux peuvent être traités par des agents intra-articulaires,
notamment les glucocorticoïdes et les hyaluronates et/ou des
analgésiques centraux, par exemple le tramadol, la duloxétine et les opiacés. L’efficacité de la duloxétine – un inhibiteur
de la recapture de la sérotonine et de la noradrénaline pouvant être utilisé seul ou en complément du paracétamol ou
des AINS – confirme les observations résumées ci-dessus,
démontrant le rôle de la sensibilisation centrale dans la douleur arthrosique chronique provoquée par la perte du contrôle
inhibiteur diffus induit par la nociception.
Il reste sur ce plan un besoin non satisfait de traitements plus
efficaces de la douleur et d’agents capables de modifier la vitesse de progression structurelle de l’arthrose. Le tanézumab,
un anticorps monoclonal dirigé contre le facteur de croissance
nerveuse, a démontré son efficacité chez les patients atteints
d’arthrose de la hanche et du genou présentant une douleur
144
modérée à sévère.18 Cependant, le développement de cet
agent et des autres composés de sa classe a fait l’objet d’une
suspension clinique de la part de la Food and Drug Administration (FDA), à cause d’événements indésirables à type d’ostéonécrose finalement confirmés comme constituant une arthrose rapidement destructrice affectant non seulement les
articulations de référence comme la hanche et le genou, mais
également d’autres articulations, notamment l’épaule. D’autres études sur le mécanisme lié à ces événements indésirables articulaires graves sont nécessaires pour évaluer le
rapport bénéfice-risque de ces traitements prometteurs de
la douleur chez les patients atteints d’arthrose.
De nombreuses études ont été menées sur les traitements de
fond de l’arthrose ; cependant, aucun médicament n’a jusqu’à
présent été approuvé par la FDA ou l’Agence européenne
des médicaments (EMA) dans cette indication. De récentes
données suggèrent que le ranélate de strontium par voie orale,
à des posologies de 1 ou 2 g par jour, réduit de manière significative le taux de déclin de l’épaisseur de l’interligne articulaire par rapport à un placebo chez des sujets présentant une
arthrose du genou suivis pendant une durée moyenne de 30
mois.19 Des résultats similaires ont été recueillis lorsque les sujets ont été classés comme « progresseurs » sur la base d’une
diminution de l’interligne articulaire d’au moins 0,5 mm.20 Une
autre approche de l’évolution de la maladie est l’application
des principes de la médecine régénérative avec des cellules
souches endogènes.21 Les résultats de recherches biomédicales fondamentales, cliniques et translationnelles suscitent
l’espoir de fournir de nouvelles approches pour la prise en
charge des patients atteints d’arthrose vers la fin de cette décennie et dans les décennies à venir. I
OSTEOARTHRITIS:
‘‘
A
STORY
OF
BETWEEN
A systematic review and
meta-analysis of the risk factors
for the onset of knee osteoarthritis in older adults has shown that
there is a consistent strong association between increased bone
mineral density and the onset of
knee osteoarthritis… Although a
definite molecular basis and common pathophysiology have not
been identified to explain the inverse relationship between osteoarthritis and osteoporosis, a shared
genetic component may explain
why they seldom coexist.”
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Epidemiology of
osteoarthritis
b y C . C o o p e r, E . D e n n i s o n , M . E d wa rd s ,
and A. Litwic, United Kingdom
O
L
Cyrus COOPER,a,b MA, DM,
FRCP, FFPH, FMedSci
Elaine DENNISON,b MB BChir,
MA, MSc, FRCP, PhD
Mark EDWARDS,b BSc, MBChB,
MRCP
Anna LITWICb
a
IHR Musculoskeletal Biomedical
Research Unit
University of Oxford, UK
b
MRC Lifecourse Epidemiology
Unit, (University of Southampton)
Southampton General Hospital
Southampton, UK
Professor Cyrus Cooper, Director
and Professor of Rheumatology,
MRC Lifecourse Epidemiology Unit,
(University of Southampton),
Southampton General Hospital,
Southampton SO16 6YD, UK
(e-mail: [email protected])
steoarthritis is a global degenerative joint disease involving the cartilage and many of its surrounding tissues. Prevalence and incidence
estimates of osteoarthritis in different populations may vary considerably due to different diagnostic classifications; in general, radiographic case
definition produces the highest estimates, with self-reported and symptomatic
osteoarthritis definitions producing similar estimates. The World Health Organization’s Scientific Group on Rheumatic Diseases estimates that 10% of the
world’s population aged 60 years or older have significant clinical problems
that could be attributed to osteoarthritis. The highest osteoarthritis prevalence
estimates are found in the hand joints, with women more commonly affected
than men.
Medicographia. 2013;35:145-151 (see French abstract on page 151)
Definition and classification
steoarthritis (OA) is a degenerative joint disease involving the cartilage and
many of its surrounding tissues. In addition to damage and loss of articular cartilage, there is remodeling of subarticular bone, osteophyte formation,
ligamentous laxity, weakening of periarticular muscles, and, in some cases, synovial
inflammation.1 These changes may occur as a result of an imbalance in the equilibrium between the breakdown and repair of joint tissue. Primary symptoms of OA include joint pain, stiffness, and limitation of movement. Disease progression is usually
slow but can ultimately lead to joint failure with pain and disability.
O
There have been many attempts to accurately identify and grade radiographic disease in OA. Of these, the classification by Kellgren and Lawrence (K&L) is the most
widely accepted and used. Overall, grades of severity are determined from 0 to 4
and are related to the presumed sequential appearance of osteophytes, joint space
loss, sclerosis, and cysts.2 The World Health Organization (WHO) adopted these
criteria as the standard for epidemiological studies on OA. Cross-sectional imaging
methods, such as magnetic resonance imaging (MRI), can visualize joint structures
in more detail and continue to undergo evaluation to determine if they will provide
a means by which the definition of OA can be refined.
Many studies now report the prevalence of self-reported or symptomatic OA; these
differing approaches may go some way toward explaining part of the heterogeneity
in OA estimates.3 A recent systematic review3 attempted to understand the differences in prevalence and incidence of OA according to case definition in knee, hip,
Epidemiology of osteoarthritis – Cooper and others
145
OSTEOARTHRITIS:
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OF
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SELECTED
Self-reported
OA
Symptomatic
OA
BMI
body mass index
COPCORD Community Oriented Program for the Control of
Rheumatic Disorders
DIP
distal interphalangeal
NHANES
National Health And Nutrition Examination Survey
OA
osteoarthritis
WHO
World Health Organization
Radiographic OA
Figure 1. Relationships between osteoarthritis (OA) classifications.
After reference 3: Pereira et al. 2011;19:1270-1285. © 2011, Elsevier Ltd.
and hand joints and concluded that radiographic case definition afforded the highest estimates, while self-reported and
symptomatic OA definitions presented similar estimates. The
interrelationship between the different classifications used is
shown in Figure 1.
age of 50 years. A leveling off or decline occurs at all joint sites
around the age of 80 years. For example, the age- and sexstandardized incidence rate from the Fallon Community Health
Plan in Massachusetts (USA) was highest for knee OA (240/
100 000 person-years), with intermediate rates for hand OA
(100/100 000 person-years), and lowest observed rates for
hip OA (88/100 000 person-years) (Figure 3).6 The incidence
rates found by the Dutch Institute for Public Health (RIVM)
in 2000 were similar. For hip OA, the reported prevalence was
0.9 and 1.6 per 1000 per year in men and women, respectively, and for knee OA the corresponding figures were 1.18
and 2.8 per 1000 per year in men and women, respectively
(Figure 4).7
N Hand OA
The prevalence of radiographic hand OA varies greatly and
has been reported to range from 27% to over 80%.8,9 In a
Epidemiology
OA may develop in any joint, but most commonly affects the study from the Netherlands, 75% of women aged between
knee, hip, hand, spine, and foot. In 2005, it was estimated that 60 and 70 years had evidence of OA in the distal interphaover 26 million people in the USA had some form of OA.4 langeal (DIP) joints, and 10% to 20% of subjects aged below
Self-reported physician-diagnosed OA data from the 2004- 40 years were reported to have OA radiological changes in
2005 Australian National Health Survey is shown in Figure 2.5 their hands or feet.7 In a rural sample from the former Soviet
The incidence of hand, hip, and knee OA increases with age, Republic of Turkmenia,10 all males over the age of 65 years had
and women have higher rates than men, especially after the at least one affected hand joint. Symptomatic hand OA, as
defined by the American College of Rheumatology (ACR) criteria, is, however, far less common. Its prevalence was found to be 8% in
35%
the US National Health and Nutrition ExamMales
30%
ination Survey (NHANES III).11 Data from the
Females
25%
Framingham cohort demonstrated a prevalence of 13.2% in men and 26.2% in women
20%
aged ⱖ70 years, with at least one hand joint
15%
with symptomatic OA.8 A study from Teheran
showed that the prevalence of hand OA in
10%
people aged 40 to 50 years was 2.2%, ris5%
ing with age to 22.5% in people aged >70
years.12 As with many studies, including the
0%
0-14
15-24
25-34
35-44
45-54
55-64
65-74
75+
Framingham cohort, differentiation by sex in
Age group (years)
this population showed that women were
more frequently affected than men.12 InterestFigure 2. Age-specific prevalence of osteoarthritis in Australia in 2004-2005 (Ausingly, data from China based on thirteen surtralian Institute of Health and Welfare analysis of the Australian Bureau of Statistics’
veys involving 29 621 adults demonstrated
2004-2005 National Health Survey).
that symptomatic OA of the hand was rarely
After reference 5: Australian Institute of Health and Welfare. 2007. Arthritis series no 5. Cat no. PHE
observed, irrespective of age or sex.13
93. Canberra: AIHW. © 2007, Australian Institute of Health and Welfare.
146
OSTEOARTHRITIS:
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Incidence (per 10 –5 patient-years)
Men
CLOSE
BONE
1200
1000
1000
800
800
Knee
600
600
Hip
400
Hand
Knee
400
Hip
200
Hand
200
0
0
30
40
50
60
70
80
20
30
40
Age (years)
50
60
70
80
Age (years)
Men
80
Prevalence of osteoarthritis (%)
DIP
60
60
DIP
40
40
Knee
Knee
20
20
Hip
0
Hip
0
30
40
50
Figure 3.
Incidence of
clinical osteoarthritis of
the hand,
knee, and
hip among
participants
in the Fallon
Health Plan.
After reference
6: Oliveria SA
et al. Arthritis
Rheum. 1995;
38:1134-1141.
© 1995, American College of
Rheumatology.
Women
80
20
CARTILAGE
Women
1200
20
AND
60
70
80
Age (years)
N Knee OA
Knee involvement occurs less frequently than hand OA, although, similarly, it is more common in women, with femaleto-male ratios varying between 1.5:1 and 4:1. Prevalence rates
for knee OA, based on population studies in the USA, are comparable to those in Europe. These studies report that severe
radiographic changes affect 1% of people aged between 25
and 34 years and this figure increases to nearly 50% in those
75 years and above.14 Few studies have reported secular trends
in knee pain; a recent report from the Framingham Study
found that the age- and BMI-adjusted prevalence of knee
pain and symptomatic knee OA approximately doubled in
women and tripled in men over 20 years (Figure 5, page 148);
no such trend was observed in the prevalence of radiographic
knee OA.15 Similarly, using questionnaire data enquiring about
pain in and around the knee, the same researchers found
that the age- and BMI-adjusted prevalence of knee pain increased by about 65% in NHANES from 1974 to 1994 among
non-Hispanic white and Mexican American men and women
and among African American women.15 These secular trends
20
30
40
50
60
Age (years)
70
80
Figure 4.
Prevalence
of clinical
osteoarthritis
of the hand,
knee, and hip
in a Dutch
population.
Reproduced
with permission
from reference
7: van Saase
JL et al. Ann
Rheum Dis.
1989;48:271280. © 1989,
BMJ Publishing
Group Ltd.
could not be fully explained by increasing obesity. According
to data produced by the Dutch Institute for Public Health,
the prevalence of knee OA in those aged 55 and above was
15.6% in men and 30.5% in women.7
Geographical variation in OA epidemiology also exists. Studies from China, which used similar methods and definitions
to those used in the Framingham Study, found that the prevalence of bilateral knee OA and lateral compartment disease
were two to three times higher in Chinese cohorts compared
with estimates from the Framingham OA Study.16 Data on clinically diagnosed knee OA in the Community Oriented Program
for the Control of Rheumatic Disorders studies (COPCORD) in
Asia showed that the prevalence within this area ranged from
1.4% in urban Filipinos to 19.3% in rural communities in Iran.17
Part of the reason for this difference may be explained by the
physical and socioeconomic environment. The COPCORD
studies conducted in India, Bangladesh, and Pakistan looked
specifically into differences between rural and urban populations. In India, it showed a significantly higher prevalence of
147
OSTEOARTHRITIS:
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Age- and BMI-adjusted prevalence of
radiographic and symptomatic knee OA (%)
50
Radiographic knee OA
41.9
39.7
40
35.1
36.5
Women
Men
20
16.7
16.1
11.8
10.4
10
7.8
5.7
1992-1995
Original
Examination period
knee pain in rural (13.0%) than in urban (8.1%) communities.17
Furthermore, in China, men aged 60 years and above from a
rural community had approximately double the prevalence of
symptomatic knee OA than their urban counterparts.16
N Hip OA
Hip OA is less common than either hand or knee OA. The
mean prevalence of primary radiographic hip OA in studies
from Asia and Africa is 1.4% and 2.8%, respectively.17 These
levels are much lower than those seen in Europe and North
America. In the Study of Osteoporotic Fractures, the prevalence of radiographic hip OA was analyzed in women over the
age of 65, using eleven different definitions. Excluding the definition of minimum joint space of less than 2.5 mm, the prevalence ranged from 1.0% to 6.2%, depending on the definition used.18
Risk factors
OA is referred to as “primary” in the absence of an extrinsic
cause. The proportion of individuals with primary OA within a
specific OA population varies greatly. As age increases, the
likelihood of an individual having primary OA increases. There
are also differences by sex; in the Queensland Aboriginal communities it was found that 88% of women had primary OA,
whereas 82% of men had secondary OA.19
The risk of developing OA is determined by both systemic and
local factors. Several systemic factors have been identified;
these may act by increasing the susceptibility of the joints to
injury, by direct damage to joint tissues, or by impairing the
process of repair in damaged joint tissue. Local factors are
most commonly biomechanical in nature and adversely af-
148
fect the forces applied to the joint. Risk
factors are discussed individually below;
the varying prevalence of some, such as
obesity and nutritional factors, may partly explain the differing rates of OA seen
in different populations.
N Age
The prevalence and incidence of radiographic and symptomatic OA considerably increase with age. The relation2002-2005
Offspring and
ship between age and the risk of OA is
community
likely multifactorial and is probably the
consequence of numerous individual factors that may include oxidative damage,
thinning of cartilage, muscle weakening, and a reduction in
proprioception. Furthermore, the basic cellular mechanisms
that maintain tissue homeostasis decline with age, leading to
an inadequate response to stress or joint injury and resultant
joint tissue destruction and loss.
Symptomatic knee OA
0
1983-1985
Original
Abbreviations: BMI, body mass index; OA, osteoarthritis.
Reproduced with permission from reference 15:
Nguyen US et al. Ann Intern Med. 2011;155:725-732.
© 2011, American College of Physicians.
35.4
32.5
30
Figure 5. Varying prevalence of radiographic
and symptomatic knee osteoarthritis over
a 20-year period among participants in the
Framingham Osteoarthritis Study.
N Sex
The incidence of knee, hip, and hand OA is higher in women
than men and in women it increases dramatically around the
time of menopause. The latter finding has led investigators to
hypothesize that hormonal factors may play a role in the development of OA, but the results of clinical and epidemiologic studies have not universally corroborated this.20-22 A recent
systematic review of 17 studies found that there was no clear
association between sex hormones and hand, knee, or hip
OA in women, although single analysis of the studies was not
possible due to study heterogeneity.23
N Ethnicity and race
The prevalence of OA and patterns of joint involvement vary
among different racial and ethnic groups. Both hip and hand
OA were much less frequent among Chinese in the Beijing
Osteoarthritis Study than in whites in the Framingham Study,
but interestingly, Chinese women had a higher prevalence of
knee OA, which may be explained by excessive knee loading
from squatting.24 Indeed, prolonged squatting and kneeling
has been associated with an increased risk of moderate to severe radiographic knee OA.24 Results from the Johnston County Osteoarthritis Project have shown that the prevalence of
hip OA in African American women was similar to that in white
women, but that the prevalence was slightly higher in African
American men (21%) than in white men (17%).25
OSTEOARTHRITIS:
A
STORY
OF
BETWEEN
N Genetics
Strong evidence from family clustering and twin studies indicates that the risk of OA has an inherited component. Classic
twin studies have shown that the influence of genetic factors
is between 39% and 65% in radiographic OA of the hand
and knee in women, about 60% in OA of the hip, and about
70% in OA of the spine.26 Although specific genes have been
identified, the individual effects are relatively small; for example, Kerkhof et al27 reported a genome-wide association study
showing that the C allele of rs3815148 on chromosome 7q22
was associated with a 1.14-fold increased prevalence of knee
and/or hand OA and also with a 30% increased risk of knee
OA progression.
N Nutrition (including vitamin D)
Dietary factors are the subject of considerable interest in
OA.28,29 Protection against knee OA progression has been reported in older men and women with high dietary vitamin D
intakes, and for those with high serum levels of vitamin D.28
The Rotterdam Study reported that low vitamin D intake increased the risk of progression of knee OA.30 The Osteoporotic Fractures in Men study found that men with vitamin D deficiency were twice as likely to have prevalent radiographic
OA,31 but a recent longitudinal study of Finnish participants
failed to find associations between low vitamin D status and
risk of incident hip or knee OA.32 Although the results are inconsistent, a biologically plausible mechanism for the effect of
vitamin D on OA could be postulated, through its important
role in bone metabolism, which may modulate periarticular
bone responses to excess loading and joint damage. The
results of further studies are awaited.
Low vitamin C dietary intake has also been associated with an
increased risk of OA progression among participants in the
Framingham Study.33 A role for selenium has also been postulated.34
N Osteoporosis
Osteoporosis is, like OA, a common age-related skeletal disorder. While early results indicated that reduced bone mineral density might be protective against OA, further studies have
been inconsistent with this finding. A systematic review and
meta-analysis of the risk factors for the onset of knee OA in
older adults has shown that there is a consistent strong association between increased bone mineral density and the
onset of knee OA in the three studies that investigated this risk
factor in women.35 Although a definite molecular basis and common pathophysiology have not been identified to explain the
inverse relationship between OA and osteoporosis, a shared
genetic component may explain why they seldom coexist.
N Smoking
There have been conflicting reports on the role of smoking in
OA. Some studies have reported a protective association between smoking and OA, but others in contrast, report that
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smoking may be associated with a greater risk of both cartilage loss and knee pain in OA. A recent meta-analysis of
observational studies concluded that the observed protective
effect of smoking in OA is likely to be false.35 It may be caused
by selection bias, as many studies have been conducted in a
hospital setting where control subjects have smoking-related conditions, and subjects were recruited as part of studies
that were not primarily designed to investigate smoking.36
N Obesity and metabolic disease
Obesity is one of the strongest and best-established risk factors of OA. The current literature suggests that, although both
show significant associations, the relationship between obesity and hip OA is weaker than with knee OA.37 Recent data
suggest that OA is associated with the metabolic syndrome,
suggesting a possible common pathogenic mechanism involving metabolic abnormalities and systemic inflammation.38
Studies have specifically suggested significant associations
between OA and cardiovascular risk factors, such as hypertension and hypercholesterolemia. However, clinical evidence
of an association between diabetes and OA is inconsistent.
Several studies did find an association between diabetes and
OA39 and fascinating hypotheses explaining this association
have been suggested, including that high glucose concentrations produce reactive oxygen species (ROS) and advanced
glycation end products, which induce cartilage degeneration
and degradation. Other studies have failed to confirm the association and further research is required.
N Sarcopenia
Muscle weakness may be an important risk factor for knee OA.
Men and women with pre-existing radiographic evidence of
knee OA have been identified as having weaker quadriceps
than those without OA, particularly when the joints are symptomatic.40 One consequence of quadriceps weakness is that
the knee becomes less stable during physical activity. Quadriceps exercises may therefore offer some protective advantage to patients involved in activities that are known to be associated with a high risk of OA development. Greater muscle
strength is not, however, always protective as it corresponds
to higher forces and thus increased joint loading during activity. It has been shown that higher grip strength in men is
associated with a greater risk of developing OA in the proximal interphalangeal, metacarpophalangeal, and first carpometacarpal joints—the joints subjected to the largest forces
during grip.41
N Local mechanical risk factors
A traumatic knee injury is one of the strongest risk factors for
the development of knee OA. Acute injuries, including meniscal and cruciate tears, fractures, and dislocations, can result
in an increased risk of OA development and musculoskeletal
symptoms. In addition to the direct trauma-induced damage
to local tissues, disruption of normal biomechanics and altered
load distribution within the joint also contribute to the subse-
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load is transmitted through the medial compartment. Any shift
in either a valgus or varus direction affects load distribution.
Abnormal increases in compartmental loading are thought
to increase stress on the articular cartilage—and other joint
structures—subsequently leading to degenerative change.
A systematic review has confirmed that knee malalignment is
an independent risk factor for the progression of knee OA.45
quent increased OA risk. This risk is greater still if the subject has OA in another joint. The repetitive and excessive joint
loading that accompanies specific physical activities increases the risk of developing OA in the involved joints. Workers
whose jobs require repeated pincer grip have an increased
risk of hand OA, particularly in the DIP joint.42 Similarly, prolonged squatting and kneeling stresses the larger joints and
is consequently associated with increased risk of moderate
to severe radiographic knee OA.
Conclusion
There have been conflicting results in studies examining the
relationship between sporting activities and subsequent OA.
There is some evidence that elite long-distance runners are
at high risk of developing knee and hip OA.43 Other studies
suggest that in the absence of joint injury, moderate recreational running and sports participation do not appear to increase
the risk of hip or knee OA.44 The mechanical alignment of the
knee influences load distribution across the articular surfaces.
In a normally aligned knee, 60% to 70% of the weight-bearing
OA is the commonest joint disease worldwide and mainly
occurs in later life. It tends to be slowly progressive and can
cause significant pain and disability. Symptoms and radiographic changes are poorly correlated and thus defining OA
for research purposes is challenging. Established risk factors
include obesity, local trauma, and occupation. These, in addition to genetic factors, may partly explain geographic variations in OA prevalence. There is conflicting evidence regarding the roles of nutrition, smoking, and sarcopenia, with the
results of further studies awaited. I
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Scand J Rheumatol. 2012;41:124-131.
33. McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996;39:648-656.
34. Jordan JM, Fang F, Arab L, et al. Low selenium levels are associated with increased risk for osteoarthritis of the knee. Arthritis Rheum. 2005;52:s455.
35. Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2010;18:24-33.
36. Hui M, Doherty M, Zhang W. Does smoking protect against osteoarthritis?
Meta-analysis of observational studies Ann Rheum Dis. 2011;70:1231-1237.
37. Grotle M, Hagen KB, Natvig B, et al. Obesity and osteoarthritis in knee, hip and/
or hand: An epidemiological study in the general population with 10 years follow-up. BMC Musculoskelet Disord. 2008;9:132.
38. Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in
individuals with osteoarthritis: an analysis of NHANES III data. Postgrad Med.
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2009;121:9-20.
39. Frey MI, Barrett-Conner E, Sledge PA, et al. The effect of noninsulin dependent
diabetes on the prevalence of clinical osteoarthritis. A population based study.
J Rheumatol. 1996;23:716-722.
40. Slemenda C, Brandt KD, Heilman DK, et al. Quadriceps weakness and osteoarthritis of the knee. Ann Intern Med. 1997;127:97-104.
41. Chaisson CE, Zhang Y, Sharma L, Kannel W, Felson DT. Grip strength and the
risk of developing radiographic hand osteoarthritis: results from the Framingham
Study. Arthritis Rheum. 1999;42:33-38.
42. Hadler NM, Gillings DB, Imbus HR, et al. Hand structure and function in an
industrial setting. Arthritis Rheum. 1978;21:210-220.
43. Buckwalter JA, Lane NE. Athletics and osteoarthritis. Am J Sports Med. 1997;
25:873-881.
44. Spector TD, Harris PA, Hart DJ, et al. Risk of osteoarthritis associated with longterm weight-bearing sports: a radiologic survey of the hips and knees in female
ex-athletes and population controls. Arthritis Rheum. 1996;39:988-995.
45. Tanamas S, Hanna FS, Cicuttini FM, Wluka AE, Berry P, Urquhart DM. Does
knee malalignment increase the risk of development and progression of knee
osteoarthritis? A systematic review. Arthritis Rheum. 2009;61:459-467.
Keywords: burden; epidemiology; osteoarthritis; risk factor
EPIDÉMIOLOGIE
DE L’ARTHROSE
L’arthrose est une maladie dégénérative articulaire mondiale touchant le cartilage et la plupart des tissus environnants. Sa prévalence et son incidence varient considérablement d’une population à l’autre selon les classifications
diagnostiques utilisées pour les estimer; la définition radiologique de l’arthrose donne généralement les estimations
les plus élevées, tandis que les définitions symptomatiques et auto-rapportées donnent des estimations à peu près
équivalentes entre elles. D’après le groupe scientifique des maladies rhumatologiques de l’OMS, 10% des gens âgés
de 60 ans ou plus ont des problèmes cliniques significatifs pouvant être attribués à l’arthrose. L’arthrose a une plus
forte prévalence au niveau des articulations de la main, et touche plus volontiers les femmes que les hommes.
151
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Adipose tissue is an active
metabolic and endocrine organ
producing hormones and bioactive substances, such as adipokines (also known as adipocytokines), that have various biological
effects and underlie the association of obesity with concomitant
diseases… Adipokines, including
leptin, are involved in the local
modulation of articular cartilage
metabolism. Patients with OA were
found to have elevated levels of
leptin in both synovial fluid and
subchondral bone.”
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Osteoarthritis
and comorbidities
b y L . I . A l e k s e e va
a n d E . L . N a s o n ov, R u s s i a
O
L
Eugeny L. NASONOV, MD, PhD
Director, National Scientific
Research Institute of Rheumatology
(Russian Academy of Medical
Sciences), Moscow
RUSSIA
Lyudmila I. ALEKSEEVA,
MD, FACPh
(Russian Academy of Medical
Sciences), Chief of Department
Department of Metabolic Disorders
of the Musculoskeletal System and
Osteoarthritis and Osteoporosis
Laboratories, Moscow
RUSSIA
steoarthritis (OA) is the most common disorder of the musculoskeletal system and the leading cause of functional incapacity and disability in adults. A significant number of studies have demonstrated that
patients with OA are at significantly higher risk of developing comorbid conditions than people without the disease. OA is most commonly associated with
cardiovascular diseases, including arterial hypertension, as well as obesity,
diabetes mellitus, and pulmonary diseases. The combination of various chronic diseases with diseases of the musculoskeletal system, especially with OA,
will be observed more and more frequently, and will affect not only health care
systems, but also the quality of life. The relation between OA and comorbid disorders may be explained, to some extent, by common etiologic and pathogenetic mechanisms, or may be related to the biological processes of aging,
which can lead not only to the development, but possibly also to the maintenance of comorbidities. The data presented in this article suggest that OA is
a disease that is pathogenetically related to cardiovascular diseases, obesity,
and other metabolic conditions. As a consequence, the examination of OA
patients should not be limited to the assessment of their articular disorder, but
rather should be comprehensive, with particular attention paid to the state of
their cardiovascular system. This article highlights the importance of using
an integrated approach when considering treatment options.
steoarthritis (OA) is the most common disorder of the musculoskeletal
system: about 15% of the world population suffers from OA and 65% of
them are aged 60 years and over. Osteoarthritis is the leading cause of functional incapacity and disability in adults1 and reduces the quality of life of patients.
Moreover, patients with OA were found to have higher all-cause mortality rates than
the general population.2 The analysis of 617 lethal outcomes in osteoarthritic patients, compared with a population of similar age and sex, has shown that almost
40% of deaths were caused by atherosclerotic coronary artery disease (CAD) and
gastrointestinal tract disorders.3
O
Professor Eugeny L. Nasonov,
Institute of Rheumatology, Russian
Academy of Medical Sciences,
34 A Kashirskoye shosse,
115522 Moscow, Russia
152
In 1990, in a study of 2384 people aged 55 to 74 years, Lawrence et al showed that
patients with radiographic evidence of knee OA had higher mortality rates than subjects without radiographic abnormalities (38.9% vs 31.6% in men; 30% vs 17.7%
in women, respectively).4 Haara et al found an association between the presence
of OA in any finger joint and increased cardiovascular mortality, and in women the
Osteoarthritis and comorbidities – Alekseeva and Nasonov
OSTEOARTHRITIS:
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risk of death was higher in the presence of radiographic evidence of OA of the distal interphalangeal joints of both hands.5
Although there is a discrepancy between the presence of pain
and the radiographic signs of OA, which are observed together in 15% to 76% of cases,6 higher mortality rates are found
both in patients with symptomatic OA and in those with only
radiographic evidence of the disease.5 This suggests that OA
is not only the most common disease of the joints, but also
the most urgent problem in general practice. Osteoarthritis—
along with cardiovascular diseases (CVD), degenerative diseases of the nervous system, and osteoporosis—is an agerelated disorder. Moreover, joint dysfunction and pain and the
resulting reduction in physical activity are destabilizing factors
in the course of various somatic disorders. In patients with underestimated concomitant somatic diseases, OA is associated with a high rate of drug-related complications, especially
when nonsteroidal anti-inflammatory drugs (NSAIDs) are used.7
Many studies have demonstrated that patients with OA are
at significantly higher risk of developing comorbid conditions
than people without the disease. In their 18-month follow-up
study of 1026 patients with OA, Kadam et al revealed a clear
correlation between the number of concomitant conditions
(“morbidity count”) and a patient’s physical function. Almost
half of the patients with OA (49%) were diagnosed with more
than 5 conditions other than OA (high morbidity count), 28%
had 3 or 4 conditions (medium morbidity count), 25% had 1
or 2 conditions (low morbidity count), and only 3.7% of the
patients had OA alone.8 In osteoarthritic patients, high morbidity counts were associated with reduced physical function
(after adjusting for age, sex, and socioeconomic parameters).
Osteoarthritis and cardiovascular disease
OA is most commonly associated with CVD, including arterial hypertension (AH), as well as obesity, diabetes mellitus, and
pulmonary diseases.8-10 An analysis of publications in Medline
SELECTED
AGE
AH
AMICA
BMI
CAD
CVD
ICAM-1
IGF-1
IL
MMP
NSAID
OA
PAI
TGF-β1
advanced glycation end-product
arterial hypertension
Atrial fibrillation Management In Congestive heart
failure with Ablation
body mass index
coronary artery disease
cardiovascular diseases
intracellular adhesion molecule-1
insulin-like growth factor
interleukin
matrix metalloproteinase
osteoarthritis
plasminogen activator inhibitor
transforming growth factor-β1
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in the period from 1966 to July 2004 revealed that hypertension is present in 48% to 65% of patients with OA and in more
than 65% of patients over 80 years of age with OA requiring
knee arthroplasty.11 Rosemann et al showed that osteoarthritic patients of both sexes have similar rates of hypertension
(53%), high cholesterol (36%), heart failure (19%), diabetes
mellitus (17%), and CAD (13%).12 Women with OA were found
to have a lower quality of life and lower mood (P<0.01), a higher degree of disability (P<0.01), and to feel more pain (P<0.01).
In the large-scale AMICA study (Atrial Fibrillation Management
in Congestive Heart Failure With Ablation) in Italy, which involved 3080 physicians and 29132 patients with OA, hypertension was found in 53% of study participants, type 2 diabetes in 15%, and history of myocardial infarction or angina in
6%. The degree of hypertension correlated with pain intensity, joint dysfunction, and worsening quality of life.9 Danish
researchers found CVD in 54% patients with hip OA aged between 50 and 85 years.1 In Russia, a 1-year study of the rates
of concomitant diseases associated with knee OA in an outpatient clinic also revealed twice higher rates of CAD, AH, and
obesity, compared with patients without OA from the same
clinic.13
The increase in life expectancy has resulted in an aging population. Therefore, the combination of various chronic diseases
with diseases of the musculoskeletal system, especially with
OA, will be observed more and more frequently, and will affect
not only health care systems, but also the quality of life. The relation between OA and comorbid disorders may be explained,
to some extent, by common etiologic and pathogenetic mechanisms, or may be related to the biological processes of aging, which become more prevalent with age (such as cartilage
degeneration, insulin resistance, weight gain, dyslipidemia, etc),
and lead not only to the development, but possibly also to the
maintenance of comorbidities.
OA and CVD are both considered to be age-related diseases.
With aging, various human tissues accumulate advanced glycation end-products (AGEs), which play an important role in
the pathogenesis of both atherosclerosis and OA.14-16 The formation of AGEs on the basement membrane of vascular walls
leads to wall thickening, a narrowing of the lumen of capillaries, and reduced vascular wall elasticity, which can accelerate
the development of the atherosclerotic process. AGEs also
accumulate in human cartilage tissue,16 where they bind with
long-lived proteins—mainly collagen—and subsequently damage and deteriorate their functional properties. AGEs are supposed to adversely affect the metabolic activity of chondrocytes and can stimulate the formation of proinflammatory
cytokines.17,18
Metabolic disturbances and nonspecific inflammation also play
an important role in the pathogenesis of atherosclerosis and
OA. Traditionally, OA has been considered to be a degenera-
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tive disease of the joints, but accumulating evidence suggests
that nonspecific inflammation is also important in its pathogenesis.19,20 In OA, there are no classical macroscopic signs
of inflammation and no severe infiltration by inflammatory cells
in joint tissues. However, elevated levels of proinflammatory
cytokines, interleukins (IL)-1, and tumor necrosis factor α
(TNF-α) are observed in the synovial fluid of osteoarthritic patients. IL-1 stimulates the chondrocytes, thereby increasing
the production of matrix metalloproteinases (MMPs)—proteolytic enzymes that degrade collagen and cartilage proteoglycans. Increased levels of MMP-3 were found in the synovial fluid and blood of patients with OA of the knee and hip
joints. Moreover, serum levels of MMP-3 and MMP-9 were
significantly higher in patients with hip OA compared with
those with less severe OA.21 Therefore, MMP-3 and MMP-9
levels can serve as diagnostic markers of rapidly progressive
OA. In addition, the chondrocytes of osteoarthritic individuals
overexpress COX-2; this induces the synthesis of proinflammatory prostaglandins and the inducible form of nitric oxide
synthase (iNOS), an enzyme that regulates the formation of
nitric oxide and exerts a toxic action on the cartilage.
Epidemiological and immunopathological data suggest that
inflammation is the major manifestation of atherosclerosis and
is associated with dyslipidemia and chronic immune dysregulation.22,23 Proinflammatory cytokines and cell adhesion molecules expressed by vascular and blood cells play an important role in the pathophysiology of atherosclerosis. Prospective
epidemiological studies have shown an association between
the clinical manifestations of atherothrombotic disease and
systemic markers of inflammation, including white blood cell
count and various hemostatic proteins that reflect acute inflammation, such as fibrinogen, plasminogen activator inhibitor
(PAI), and von Willebrand factor.20,24 C-reactive protein is directly involved in the pathogenesis of atherothrombosis and
stimulates the production of tissue factor by the macrophages.
capsule of atherosclerotic plaques, and elevated levels of
inhibitor of plasminogen activator-1 (PAI-1) are implicated in
the process of thrombogenesis.28
Another aspect of the association of vascular disease with OA
relates to changes in the blood vessels of subchondral bone.
The occurrence of OA and its subsequent progression are
thought to be a consequence of atheromatous disease in
these vessels.29,30 Bone is a highly vascularized tissue, and its
vasculature is involved in all aspects of the growth, recovery,
and metabolism of bone tissue. It is possible that in the context of vascular disease, episodic circulatory disorders take
place in the subchondral bone, resulting in the development
of OA. Subchondral bone ischemia, on the one hand, may
lead to impaired nutrition and gas exchange in the articular
cartilage, and thus trigger degenerative changes; on the other
hand, it may promote osteocyte apoptosis in the subchondral bone, thereby inducing osteoclastic resorption.31,32
The association of OA with CVD is probably determined not
only by common pathogenetic mechanisms, but also by other external factors. Thus, the limitation of physical activity in
patients with OA is a significant aggravating factor for cardiovascular disease. By inducing a neuroendocrine response,
chronic pain is often the cause of complications in CVD patients. Pincus and Sokka have found that reduction in life expectancy in older people is determined, to a great extent, by
the severity of pain.33 They assessed the survival rates of 1525
patients, of which 24% (370 patients) had OA, 16% (246 patients) had CVD, and 7.1% (109 patients) had OA and CVD.
The results showed that the relative risk of death among patients with OA and a pain intensity of more than 40 mm on the
visual analog scale (VAS) was higher than in patients with a
pain intensity of less than 40 mm, without any significant differences according to age or sex.
Osteoarthritis and obesity
Tissue factor is the main inductor of coagulation in vivo and
its local concentration in the arterial wall is associated with
the development of events resulting in coronary thrombosis.25
In patients with a high risk of vascular complications, elevated
levels of other markers of inflammation, such as IL-6, intracellular adhesion molecule-1 (ICAM-1), macrophage inhibitory
cytokine-1 (MIC-1), and soluble CD40 ligand are also observed. Experimental studies have shown that the vascular
endothelium and the smooth muscle cells of the arteries produce IL-6. At the same time, the IL-6 gene is expressed in
areas of atherosclerotic lesions in man; therefore, IL-6 may
also have procoagulant properties.25,26 Metalloproteinases
take part in the remodeling of blood vessels and increase the
rigidity of the arteries with age.27 Matrix metalloproteinase-3
(MMP-3) has been associated with lipid structures in arteriosclerotic plaques and MMP-3 genotype may be an important determinant of age-related vascular remodeling and arterial stiffness.27 MMP-9 is involved in the rupture of the fibrous
154
Obesity is among the most urgent health care and social
problems of contemporary society. It is a risk factor not only
for OA, but also for many other diseases associated with metabolic disturbances. OA, in turn, through the dysfunction and
limitation of physical activity leads to an increase in body mass
index (BMI) that can result in the development of CVD and
diabetes. The risk of developing these conditions increases
progressively with increasing BMI. In overweight patients with
a 40% excess in body mass, the risk of premature death is
twice that of people of average weight. In Russia, a study of
298 patients with overt OA of the knee and hip joints showed
a marked increase in the prevalence of CVD and diabetes
with increasing BMI.34
Many studies have demonstrated an association between
obesity (BMI >30) and OA of the knee, for both symptomatic
and radiographic OA.35,36 Moreover, the risk of OA of the knee
increases progressively with increasing BMI. Prospective stud-
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ies have revealed that excess body mass contributes to the
progression of the radiographic manifestations of knee OA.37
In a prospective cohort study, Wang et al found that both
central obesity and the amount of fat mass represent risk
factors for arthroplasty of the knee and hip joints.38 Interestingly, not only is increased body weight associated with an
increased risk of OA, but it was also shown that weight loss
causes a decrease in the risk of OA. A 2-kg/m2 decrease in
BMI was shown to reduce the risk of OA development by more
than 50% at 10 years.39
There is also some evidence of an association between obesity and OA of the joints of the hand. A study in female twins
has shown that obesity is an important risk factor for the
development of OA of the knee and carpometacarpal joints,
with a significant 9% to 13% increase in the risk of OA per
each additional kilogram of body weight.40 A recently published systematic review confirms the existence of a positive association between body weight and OA development
in the hands.41
There is some controversy in the data published on the relationship between obesity and OA of the hip. Some researchers
identified a clear correlation between BMI and the risk of hip
OA,42 while others did not find any correlation at all.43
However, a majority of studies have demonstrated an association between OA and obesity. Excess weight increases the
load on the skeleton and causes lesions in bone and muscle tissue. Pressure-sensitive mechanoreceptors capable of
triggering a signaling cascade were found on the surface of
chondrocytes.17 Activation of these mechanoreceptors can
lead to the expression of cytokines, metalloproteinases, prostaglandins, and nitric oxide.19 Experimental data show that,
under certain conditions, overload can trigger the inhibition
of matrix synthesis and degradation of cartilage.44 Obesity can
potentially induce cartilage damage through activation of the
mechanoreceptors.
Available data not only suggest an effect of overweight on
the development of OA in the knee joints, but also confirm
the existence of other mechanisms related to obesity that can
change the metabolism of cartilage and bone tissue and lead
to the development of OA. Adipose tissue is an active metabolic and endocrine organ producing hormones and bioactive substances, such as adipokines (also known as adipocytokines), that have various biological effects and underlie
the association of obesity with concomitant diseases. Thus,
leptin and adiponectin can have an influence on cartilage,
bone tissue, and vascular walls. Adipokines, including leptin, are involved in the local modulation of articular cartilage
metabolism.45 Elevated levels of leptin were found in both the
synovial fluid and subchondral bone of osteoarthritic patients.
Mainard et al demonstrated the importance of leptin in the
pathogenesis of OA by showing its impact on the synthesis
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of insulin-like growth factor (IGF-1) and transforming growth
factor-β1 (TGF-β1).46 Leptin, IGF-1, and TGF-β1 can be found
in the cartilage of osteoarthritic patients (in osteophytes), but
not in the cartilage of disease-free patients.47 Moreover, osteophytes are associated with increased TGFβ1 expression.
TGFβ1 induces fibrotic changes in the synovial membrane,
bone sclerosis, and the differentiation of stem cells from the
periosteal layer, resulting in the formation of osteophytes.48
An experimental study showed that injections of leptin into
the joints of healthy rats caused symptoms of OA.45 In addition, Miller et al showed that a decrease in serum leptin levels
may be one of the mechanisms by which weight loss slows
down the progression of OA.49
Treatment of OA
The data presented above suggest that we can consider OA
as a disease that is pathogenetically related to cardiovascular
diseases, obesity, and other metabolic conditions. As a result,
the examination of OA patients should not be limited to the
assessment of their articular disorder, but rather should be
comprehensive, with particular attention paid to the state of
their cardiovascular system. This highlights the importance of
having an integrated approach when choosing a treatment,
which should ideally combine nonpharmacological and pharmacological therapy. Patients should be informed about their
condition, its main symptoms, and what may cause its progression. Patient education is, therefore, required in order to
teach patients to follow an exercise regimen at work and at
home and to perform regular aerobic exercise. Physical exercise regimens should be individualized, taking into account
the presence of comorbidities and their severity. Patients should
clearly understand that overweight, especially of the visceral type, is a confounding factor for the disease and, therefore, the target is not only to prevent weight gain, but also to
reduce it. In addition, information should be provided on the
use of orthopedic devices that facilitate the reduction of the
load applied to the joints.
The main goals of pharmacological therapy in OA are effective pain relief, suppression of inflammation in the joint, improvement in functional capacity, and prevention of disease
progression. When treating the clinical manifestations of OA
in patients with obesity and other metabolic diseases (AH,
CAD, etc)—or who are at high risk of their development—
doctors should thoroughly think through their choice of therapy. In the presence of comorbidities, the excessive and unreasonable prescribing of drugs without first considering the
particularities of their interactions can lead to a sharp increase
in the risk of adverse effects and a worsening of the disease.
NSAIDs are commonly used to relieve pain in osteoarthritic
patients, in accordance with the European League Against
Rheumatism (EULAR), Osteoarthritis Research International
(OARSI), and American College of Rheumatology (ACR) treatment guidelines. However, despite their being the most com-
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monly prescribed drugs for the treatment of OA, NSAIDs were
shown to cause a significant proportion of side effects in pharmaco-epidemiological studies, especially due to their improper use in elderly patients with comorbidities. Both selective
and nonselective NSAIDs have pronounced anti-inflammatory and analgesic effects, but in patients with OA and metabolic diseases (obesity, AH, CAD, etc), or at high risk of developing them, they may cause a number of side effects that can
aggravate the course of cardiovascular conditions. An increased risk of cardiovascular accidents (myocardial infarction, stroke, and sudden cardiac death) can be considered to
be a class-specific side effect for all NSAIDs.50 NSAIDs can
cause the destabilization of AH and progression of heart failure and it was found that NSAID treatment in patients with a
history of heart disease increases the likelihood of hospitalization due to heart failure by 10 times (odds ratio=10.5), compared with patients not taking NSAIDs (odds ratio=1.6).51 Fi-
nally, it should also be borne in mind that NSAIDs can reduce
the efficacy of drugs used in the conventional therapy of CVD
(β-blockers, diuretics, angiotensin-converting enzyme inhibitors, and, to a lesser extent, calcium channel blockers).
Conclusion
Current data suggest that OA is a disease that is pathogenetically related to cardiovascular diseases and other metabolic conditions. The problem of comorbidity in patients with OA
has clear prognostic significance. Early recognition of the
comorbid conditions associated with OA and their comprehensive treatment with well-evidenced therapies will substantially reduce cardiovascular risks and improve patient prognosis. I
Acknowledgements. Professor Eugeny L. Nasonov is chief editor of
Scientific-Practical Rheumatology (Russia) and on the editorial board of
Clinical Rheumatology (EULAR).
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33. Pincus T, Sokka T. Mortality in rheumatic diseases. Clin Exp Rheum. 2008;26
(suppl 51):S1-S4.
34. Denisov LN, Nasonova VA, Koreshkov EG, Kashevarova NG. Obesity in the development of osteoarthritis and concomitant diseases. Ther Arch. 2010;10:
34-37.
35. Gelber AC, Hochberg MC, Mead LA, et al. Body mass index in young men and
the risk of subsequent knee and hip osteoarthritis. Am J Med. 1999;107:542548.
36. Manek Nisha J, Hart D, Spector TD, MacGregor AJ. The association of body
mass index and osteoarthritis of the knee joint: an examination of genetic and
environmental influences. Arthritis Rheum. 2003;48:4:1024-1029
37. Reijman M, Pols HA, Bergink AP, et al. Body mass index associated with onset
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and progression of osteoarthritis of the knee but not of the hip. The Rotterdam
Study. Ann Rheum Dis. 2007;66:158-162
38. Wang Y, Simpson JA, Wluka AE, et al. Relationship between body adiposity
measures and risk of primary knee and hip replacement for osteoarthritis: a
prospective cohort study. Arthritis Res Ther. 2009;11:R31.
39. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in
obese patients diagnosed with knee osteoarthritis: a systematic review and
meta-analysis. Ann Rheum Dis. 2007;66:4:433-439.
40. Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthritis of the hand and knee in women: a twin study. J Rheumatol. 1996;23:12211226.
41. Yusuf E, Nelissen RG, Ioan-Facsinay A, et al. Association between weight or
body mass index and hand osteoarthritis: a systematic review. Ann Rheum Dis.
2010;69:761-765
42. Liu B, Balkwil A, Cooper C, et al; Million Women Study Collaborators. Reproductive history, hormonal factors and the incidence of hip and knee replacement for
osteoarthritis in middle-aged women. Ann Rheumat Dis. 2009;68:1165-1170.
43. Tepper S, Hochberg MC. Factors associated with hip osteoarthritis: data from
the First National Health and Nutrition Examination Survey (NHANES-I). Am J
Epidemiol. 1993;137:1081-1088.
44. Pottie P, Presle N, Terlain B, et al. Obesity and osteoarthritis: more complex than
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predicted. Ann Rheum Dis. 2006;65:1403-1405.
45. Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthrit Rheumat. 2003;48:11:3118-3129.
46. Mainard D, Dumont H, Presle N, et al. Role of leptin in the pathogenesis of osteoarthritis: a clinical and experimental study. J Bone Joint Surg Br Proc. 2008;
90:254-255.
47. Lajeunesse D, Delalandre A, Fernandes JC. Subchondral osteoblasts from osteoarthritic patients show abnormal expression and production of leptin: Possible role in cartilage degradation. J Bone Min Res. 2004;19(suppl 1):S149.
48. Chevalier X, Tyler JA. Production of binding proteins and role of the insulinlike growth factor I binding protein 3 in human articular cartilage explants. Br J
Rheumatol. 1996;35:6:515-522.
49. Miller GD, Nicklas BJ, Loeser RF. Inflammatory biomarkers and physical function in older, obese adults with knee pain and self-reported osteoarthritis after
intensive weight-loss therapy. J Am Geriatr Soc. 2008;56:644-651.
50. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: A scientific statement from the American
Heart Association. Circulation. 2007;115:1634-1642.
51. Page J, Henry D. Consumption of NSAIDs and the development of congestive
heart failure in elderly patient: an unrecognized public health problem. Arch Int
Med. 2000;160:777-784.
Keywords: arterial hypertension; cardiovascular system; comorbidity; metabolic disorder; obesity; osteoarthritis; pathogenesis; treatment goal
ARTHROSE
ET COMORBIDITÉS
L’arthrose est la pathologie la plus courante du système musculosquelettique et la cause principale de handicap et
d’incapacité fonctionnelle chez l’adulte. D’après un nombre significatif d’études, les patients arthrosiques ont un
risque nettement plus important de développer des comorbidités que ceux qui n’ont pas d’arthrose. L’arthrose se retrouve le plus souvent associée aux maladies cardiovasculaires, dont l’hypertension artérielle, à l’obésité, au diabète
et aux maladies pulmonaires. L‘association de diverses maladies chroniques avec des pathologies du système musculosquelettique, en particulier l’arthrose, va devenir de plus en plus fréquente et cela aura des conséquences non
seulement sur les systèmes de soins de santé, mais aussi sur la qualité de vie. Les liens entre l’arthrose et les troubles comorbides peuvent s’expliquer, en partie, par des mécanismes étiologiques et pathogénétiques communs, ou
peuvent être liés aux processus biologiques du vieillissement, qui peuvent conduire non seulement au développement, mais peut-être aussi au maintien des comorbidités. Les données présentées dans cet article suggèrent que
l’arthrose est liée pathogénétiquement aux maladies cardiovasculaires, à l’obésité et à d’autres troubles métaboliques. Ainsi, l’examen des patients arthrosiques ne devrait pas se limiter à l’évaluation de leur pathologie articulaire,
mais devrait être plus complet, en faisant particulièrement attention à leur système cardiovasculaire. Ceci souligne
l’importance de l’usage d’une approche globale lors du choix des traitements dans l’arthrose.
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A complex and paradoxical
relationship seems to exist between osteoarthritis and osteoporosis, although there is increasing evidence to support a close
biomolecular and mechanical association between subchondral
bone and cartilage. Indeed, microarray profiles have identified a
number of genes differentially expressed in osteoarthritic bone that
are key players in the structure and
function of both bone and cartilage.”
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Osteoarthritis pathophysiology:
similarities and dissimilarities with
other rheumatological diseases
and the role of subchondral bone
by J. A. Roman-Blas
a n d G . H e r re ro - B e a u m o n t , S p a i n
O
L
Gabriel HERRERO-BEAUMONT, MD
Jorge A. ROMAN-BLAS, MD
Bone and Joint Research Unit
Rheumatology Service
IIS Fundación Jiménez Díaz
Universidad Autónoma
Madrid, SPAIN
steoarthritis (OA) is a disease not only of the cartilage, but also of the
whole joint. In osteoarthritis and chronic inflammatory arthritides, the
intensity of the inflammatory response of the joint determines juxtaarticular bone loss. Thus, in rheumatoid arthritis, the intense synovial and cartilage inflammation, pannus formation, and systemic bone loss induce increased subchondral bone turnover with subsequent juxta-articular bone loss.
By contrast, the mild and patchy synovitis seen in osteoarthritis results in lower subchondral bone turnover and less subsequent bone loss than in rheumatoid arthritis–like conditions. Angiogenesis and sensory nerve growth also
contribute to joint damage to different extents in these arthropathies. However, the main underlying pathogenic mechanisms may be common among
these joint diseases. A better understanding of the biological events involved
in inflammation-induced bone loss in these diseases could lead to the identification of novel therapeutic strategies for the prevention of bone loss and
also potentially progression of joint damage.
steoarthritis (OA) is a multifactorial disease that affects not only articular
cartilage, but also the whole joint. The involvement of subchondral bone in
OA is of great relevance and interest, as are changes that occur in the synovial membrane, tidemarks, and periarticular structures in the course of the disease.1,2 Thus, acquired or genetically conditioned biomechanical and biochemical
alterations affecting any joint tissue may cause anomalous intra-articular stresses
and subsequent tissue damage associated with a failure of repair.3 OA is characterized by pain, stiffness, and functional impairment ultimately resulting in chronic
disability and significant economic burden, especially in the elderly.
O
Subchondral bone
Professor Gabriel Herrero-Beaumont,
Bone and Joint Research Unit,
Fundación Jiménez Díaz,
Avenida Reyes Católicos, 2,
28040 Madrid, Spain
158
The bone underlying joint cartilage is composed of several specific anatomical regions, including the subchondral cortical plate, subchondral trabecular bone, and
subarticular bone.4 Each region is likely to contribute to cartilage pathology in a distinct manner. Current imaging techniques show unclear anatomical boundaries between these tissues, generating some confusion with regard to their study.5 Bone at
the joint margins is markedly active and is frequently the site of osteophyte development in primary OA or bone erosion in inflammatory arthritis. The close relationship
between subchondral bone and joint cartilage, two tissues that are adjacent to one
another as well as mechanically and biologically intertwined, makes them a function-
OA pathophysiology vs other rheumatological diseases – Roman-Blas and Herrero-Beaumont
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al unit that contributes significantly to normal joint function.
Changes to either the mechanical or biological properties of
subchondral bone may alter the corresponding state of articular cartilage, and vice versa.6 When both tissues are damaged,
the relationship between them changes, thereby posing an asyet-unanswered question that has valuable therapeutic implications in the setting of chronic joint diseases.
Effect of systemic osteoporosis on subchondral
bone structure and remodeling
Systemic osteoporosis (OP) alters the microstructural and biological properties of subchondral bone. Compared with normal and osteoarthritic femoral heads, the femoral heads of
patients with OP show the least stiff and dense subchondral
bone plates (OA femoral heads show values in between normal and OP femoral heads). Although osteoporotic bone has
been found to contain less mineral, its organic and water contents have been found to be proportionally higher, suggesting
no change in the relative amount of organic matrix.7 Studies in
different animal models have reported that OP has a negative
effect on subchondral bone integrity.8-10 In an experimental
model of OP in rabbits, which was induced by glucocorticoid
administration and ovariectomy, subchondral bone mineral
density was significantly lower compared with controls.8 This
experimental model also showed a decrease in subchondral
plate thickness and only a negative tendency in bone area
fraction and trabecular thickness values, while the microarchitecture index fractal dimension was increased. The decrease in subchondral plate thickness would indicate that
this experimental model of OP exhibits a much more profound
effect on subchondral cortical bone than subchondral trabecular bone. Increased remodeling in favor of subchondral
bone resorption has also been reported in osteoporotic rabbits, as determined by reduced alkaline phosphatase expression and increased matrix metalloproteinase (MMP)–9 expression, also supported by a decrease in the osteoprotegerin
(OPG)/receptor activator of nuclear factor-κB ligand (RANKL)
ratio compared with healthy controls.9 In ovariectomized sheep,
bone volume fraction was found to be reduced in subchondral bone compared with controls. Trabeculae were also significantly thinner in these animals, with reduced connectivity
density, and significant alterations observed in the trabecular architecture under the tibial plateau following 12 months
SELECTED
ACLT
AIA
BML
MMP
OA
OP
OPG
RANKL
anterior cruciate ligament transection
antigen-induced arthritis
bone marrow lesion
osteoarthritis
osteoporosis
osteoprotegerin
receptor activator of nuclear factor-kB ligand
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of estrogen deficiency.10 Lastly, in an ovariectomized mouse
model, use of either estrogen supplementation or bisphosphonate treatment resulted in inhibition of tibial and patellar
subchondral cortical thinning.11 Taken together, these studies
demonstrate a relevant and negative effect of systemic OP on
the structure and metabolism of subchondral bone.
Influence of osteoporosis in the remodeling of
subchondral bone in osteoarthritis
It is increasingly acknowledged that articular cartilage homeostasis is dependent on the integrity of the underlying bone.12-15
Several studies have identified specific changes that occur to
the architecture and turnover of subchondral bone in OA.16,17
The study of the influence of OP on subchondral bone remodeling could reveal relevant mechanisms involved in the development of OA. Thus, our group developed a rabbit model of
surgically-induced OA preceded by OP, and demonstrated
that microstructure impairment in subchondral bone associated with increased remodeling increases cartilage damage.9 Indeed, compared with control and OA knees, OPOA
knees demonstrated diminished subchondral bone area/tissue
area, trabecular thickness, and polar moment of inertia, as
well as a pronounced decline in subchondral plate thickness.
Compared with controls, the subchondral bone of OA, OP,
and OPOA knees showed a decrease in alkaline phosphatase
expression and OPG/RANKL ratio as well as an increase in
the fractal dimension and MMP-9 expression. In addition, the
severity of cartilage damage was increased in OPOA knees
versus controls. Remarkably, good correlations were observed
between structural and remodeling parameters in subchondral bone, and furthermore, between subchondral structural
parameters and cartilage Mankin score.
In line with our results, a decrease in subchondral plate thickness was also reported in an ovariectomized murine model
of intra-articular iodoacetate-induced knee OA,11 as well as
in experimental models of OA evaluating the early disease
stage.13,14,18-20 Thinning and porosity of the subchondral plate
were only present in the medial compartment and were related to superjacent cartilage damage, while in the canine anterior cruciate ligament transection (ACLT)–medial meniscectomy
model of OA,20 trabecular bone changes were mostly found in
the lateral compartment and were related to mechanical unloading. Thickening of the subchondral plate has, however,
been described in animal models of surgically-induced OA corresponding to late-stage disease.13,19,21 Remarkably, in some
of these studies, the early decrease in subchondral plate thickness was followed by late plate thickening.13,19 Furthermore,
in the rat ACLT and meniscectomy models of OA, increased
mRNA levels of cathepsin K and tartrate-resistant acid phosphatase were found in subchondral bone at week 2 postsurgery, as well as invasion of cathepsin K+ osteoclasts into the
articular cartilage from the subchondral region. These events
thus confirm that bone resorption is an early event in the disease course of OA. Upregulation of the osteoanabolic mark-
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ers runx2 and osterix was observed from week 4 to 6 postsurgery, which is thought to constitute the pathophysiological basis for late events in the disease course of OA such as
subchondral sclerosis and osteophyte formation. Local and
temporal regulation of matrix degradation, differentiation, and
vascular invasion markers was seen in articular cartilage in a
manner consistent with the aforementioned changes in subchondral bone.22
In human knee OA, cartilage damage is frequently associated with thickening of the subchondral plate and osteophyte
development.16,23 Aside from this hypertrophic OA, some authors consider that there is another variant, the atrophic form,
which is characterized by a lack of osteophytes and loss of
subchondral bone volume in OA patients with compromised
hip and knee.24 This atrophic form probably shares several
etiopathogenic mechanisms and phenotypic features with OA
associated with OP (Table). Furthermore, the correlation observed in hypertrophic OA between serum levels of C-propeptide and type II collagenase has been found to be lost in atrophic OA, the latter showing reduced type II collagen synthesis.25
This could contribute to the absence of osteophyte formation
as well as the increased subchondral bone turnover seen in
rapidly progressive hip and knee OA. Of note, the presence
Effects of systemic osteoporosis in osteoarthritis
A complex and paradoxical relationship seems to exist between OA and OP, although there is increasing evidence to
support a close biomolecular and mechanical association between subchondral bone and cartilage.15 Indeed, microarray
profiles have identified a number of genes differentially expressed in osteoarthritic bone that are key players in the structure and function of both bone and cartilage. These include
genes involved in the Wingless-type mouse mammary tumor
virus/β-catenin (Wnt/β-catenin) and transforming growth factor–β/mothers against decapentaplegic (TGF-β/SMAD) signaling pathways and their targets.30 Furthermore, aggrecan
production, as well as SOX9, type II collagen, and parathyroid
hormone–related protein mRNA expression, were inhibited in
sclerotic but not nonsclerotic osteoblasts, while expression
of MMP-3, MMP-13, and osteoblast-specific factor 1 by human OA chondrocytes was augmented in a coculture system.
Thus, sclerotic osteoarthritic subchondral osteoblasts may
contribute to cartilage degradation and chondrocyte hypertrophy.31 In addition, in our animal model of OA preceded by
OP, improvement in subchondral bone integrity was shown
to reduce the progression of cartilage damage, suggesting a
direct relationship between these two conditions.32 On the other hand, several cross-sectional studies have demonstrated
Disease mechanism/phenotypic feature
Role of osteoporosis
in disease progression
(cartilage degradation)
Disease type
Subchondral
bone remodeling
Systemic
osteoporosis
Cartilage
inflammation
Atrophic OA*
++ (toward resorption)
++ ?
++
++ (predominantly joint
space narrowing)
Hypertrophic OA
++ (toward formation)
+/–
––
––
+++ ?
+++
+++
++
Rheumatoid arthritis
* Atrophic OA probably shares common development events with OA associated with osteoporosis.
+/– presence or absence; + mild; ++ moderate; +++ severe.
of subchondral bone attrition in knee OA, defined as flattening or depression of the osseous articular surface, is strongly associated with subchondral bone marrow lesions (BMLs)
on magnetic resonance imaging. In turn, BMLs reflect the presence of active remodeling processes due to chronic overload.26
Cartilage loss occurs in the same knee subregions as subchondral bone attrition.27 In addition, it is possible that in posttraumatic OA, trabecular microarchitecture changes differ from
those in primary OA. Indeed it has been proposed that during
the early postoperative period in the canine ACL-deficient knee,
disuse osteopenia can potentially occur due to decreased
loadbearing.28 Likewise, subchondral bone in animal models of
OA with early stages of the disease has shown both decreased
volume and stiffness and increased remodeling.29 The impact
of these subchondral bone changes in OA is still a matter for
debate, in part due to the heterogeneity of the disease.
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Table.
Etiopathogenic
mechanisms
and phenotypic
features of
atrophic osteoarthritis (OA),
hypertrophic OA,
and rheumatoid
arthritis, and the
involvement of
osteoporosis.
an inverse relationship between OP and OA,33,34 although others have produced opposite results.35 Confounding variables
such as race, obesity, and physical activity could explain the
mutually exclusive relationship between OA and OP, whereby
overweight individuals and/or those who undertake excessive physical activity could have a higher risk of developing
OA and having a higher bone mass.
Recently, we proposed that high as well as low bone mass
conditions can result in OA induction and/or progression.5
Thus, both bone mass phenotypes may be considered risk
factors for OA initiation. The presence of other risk factors such
as skeletal shape abnormalities, joint overload, or obesity may
have a synergistic effect regarding OA initiation. In addition,
inflammatory mediators released by the articular cartilage in
OA may lead to subchondral bone loss through increased
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bone remodeling. Accordingly, treatment goals for OA must
consider improvement of subchondral bone integrity. This
therapeutic approach should be individualized according to
the patient’s bone mineral density status and OA phenotype, and the use of drugs should also subsequently be individualized for each patient. Recent findings suggest that
the same drugs could be useful for treating both processes
simultaneously, at least in a subgroup of patients with OA and
concomitant OP.32
Effect of chronic synovitis on subchondral
bone remodeling
Juxta-articular bone loss is related to the intensity of the inflammatory response in the affected joint.36,37 This fact is observed not only in rheumatoid arthritis, but also in other arthritides associated with a high degree of inflammation.38,39 Juvenile
idiopathic arthritis, seronegative spondyloarthropathies, systemic lupus erythematosus, as well as septic arthritis, are all
rheumatic diseases in which intense inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or
the axial or appendicular skeleton.39
Various hormones, cytokines, and chemokines produced by
the inflamed synovial membrane have been reported to be
involved in juxta-articular osteoporosis in these diseases.36
The inflammatory mediators modulate the expression of the
crucial factor RANKL, in whose presence macrophages differentiate into bone-resorbing osteoclasts in zones of contact
between the inflamed synovium and subchondral bone, as
described in rheumatoid arthritis.40 In addition to membranebound RANKL in osteoblasts, RANKL secreted by synovial
cells actively promotes bone destruction in chronic inflammatory arthritis.37 Hence, high local RANKL concentrations lead
to increased osteoclastogenesis at the bone-pannus interface.
We have recently described that RANKL expressed by chondrocytes also contributes significantly to the pathogenesis of
the juxta-articular bone loss associated with chronic arthritis
in a rabbit model that develops a more intense and destructive version of the well-established antigen-induced arthritis
(AIA).41 This experimental arthritis was found to be accompanied by severe juxta-articular bone loss, as estimated by
x-ray and bone mineral density measurement. The increase in
RANKL expression in the cartilage of AIA rabbits was linked
to the particular presence of extracellular RANKL in the calcified cartilage. Previous results from our group have also
shown that RANKL is localized in the extracellular matrix of
human OA cartilage and could reach the subchondral bone
through the calcified cartilage.42 These results indicate that
chondrocyte-synthesized RANKL acts on subchondral bone
cells, stimulating juxta-articular bone loss. Other studies have
demonstrated that soluble RANKL produced by hypertrophic
chondrocytes is a biologically active molecule during bone
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growth,43 acting in a paracrine manner on the subchondral
bone plate. We have also shown that RANKL synthesized by
prostaglandin E2–stimulated mature articular chondrocytes
is also biologically active and is responsible for the mononuclear cell differentiation into osteoclast in the absence of exogenous RANKL.41
By contrast, in OA, mild synovial hyperplasia is predominantly present, with proliferation and activation of lining cells associated with fibrosis-related changes.44-46 Synovial inflammatory infiltrates are composed of mononuclear cells that appear
in far less abundance than in the synovium in rheumatoid arthritis, and they are distributed in a patchy pattern, mostly confined to areas adjacent to sites of damaged cartilage, thereby increasing OA severity throughout the disease course.47,48
The inflammatory synovial changes are associated with increased production of proinflammatory cytokines and mediators of OA joint damage.49 The Krenn synovitis score was
found to be well correlated with subchondral bone structural
parameters in an experimental model of OA preceded by OP.46
Furthermore, rabbits with surgery-induced knee OA showed
a lower synovial inflammatory response and less subchondral
bone loss than rabbits with AIA.41 Remarkably, RANKL expression in OA cartilage—particularly in calcified cartilage—
was less than in AIA cartilage, suggesting that the relevant
involvement of this osteoclastogenic molecule in subchondral
bone loss in OA is smaller in degree than in chronic inflammatory arthritis.41
In addition, inflammation drives synovial angiogenesis through
macrophage activation, which in turn perpetuates inflammation and synovial hyperplasia, inducing pannus formation to
variable extents. This is a well-recognized pathogenic mechanism in the rheumatoid arthritis joint. Novel studies, however, have identified the presence of increased angiogenesis in
the synovium, osteophytes, menisci, and osteochondral junction in OA patients.50 Channels extending from subchondral
bone into noncalcified articular cartilage provide the anatomical basis for angiogenesis and sensory nerve growth through
the osteochondral junction. Thus, to different extents, angiogenesis also contributes to structural damage in chronic joint
diseases.50
In summary, the intensity of the inflammatory response of the
joint determines the juxta-articular bone loss in OA and
chronic inflammatory arthritides. In articular conditions such
as rheumatoid arthritis, the intense synovial and cartilage inflammation, pannus formation, and systemic bone loss will
lead to high production of key biological mediators such as
RANKL, which are involved in increased subchondral bone
turnover with subsequent juxta-articular bone loss. By contrast, during the OA disease process, mild and patchy synovitis will occur with less RANKL expression in cartilage, resulting
in lower subchondral bone turnover and subsequent bone
loss than in rheumatoid arthritis–like conditions. In addition,
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angiogenesis and sensory nerve growth also contribute to
joint damage to varying extents in these arthropathies. However, the main underlying pathogenic mechanisms may be
common among these joint diseases. Further elucidation of
the biological events involved in inflammation-induced bone
loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss, and potentially joint damage progression, in these diseases. I
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24. Conrozier T, Merle-Vincent F, Mathieu P, et al. Epidemiological, clinical and radiological differences between atrophic and hypertrophic patterns of hip osteoarthritis: a case-control study. Clin Exp Rheumatol. 2004;22:403-408.
25. Conrozier T, Ferrand F, Poole AR, et al. Differences in biomarkers of type II
collagen in atrophic and hypertrophic osteoarthritis of the hip: implications for
the differing pathobiologies. Osteoarthritis Cartilage. 2007;15:462-467.
26. Roemer FW, Neogi T, Nevitt MC, et al. Subchondral bone marrow lesions are
highly associated with, and predict subchondral bone attrition longitudinally: the
MOST study. Osteoarthritis Cartilage. 2010;18:47-53.
27. Neogi T, Felson D, Niu J, et al. Cartilage loss occurs in the same subregions as
subchondral bone attrition: a within-knee subregion matched approach from
the multicenter osteoarthritis study. Arthritis Rheum. 2009;61:1539-1544.
28. Boyd SK, Muller R, Matyas JR, Wohl GR, Zernicke RF. Early morphometric and
anisotropic change in periarticular cancellous bone in a model of experimental knee osteoarthritis quantified using microcomputed tomography. Clin Biomech (Bristol, Avon). 2000;15:624-631.
29. Lavigne P, Benderdour M, Lajeunesse D, et al. Subchondral and trabecular
bone metabolism regulation in canine experimental knee osteoarthritis. Osteoarthritis Cartilage. 2005;13:310-317.
30. Hopwood B, Tsykin A, Findlay DM, Fazzalari NL. Microarray gene expression
profiling of osteoarthritic bone suggests altered bone remodelling, WNT and
transforming growth factor beta/bone morphogenic protein signalling. Arthritis
Res Ther. 2007;9:R100.
31. Sanchez C, Deberg MA, Piccardi N, Msika P, Reginster JY, Henrotin YE. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked
by interleukin-6, -1 beta and oncostatin M pre-treated non-sclerotic osteoblasts.
32. Bellido M, Lugo L, Roman-Blas JA, et al. Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis
preceded by osteoporosis. Osteoarthritis Cartilage. 2011;19:1228-1236.
33. Stewart A, Black A. Bone mineral density in osteoarthritis. Curr Opin Rheumatol. 2000;12:464-467.
34. Dequeker J, Aerssens J, Luyten FP. Osteoarthritis and osteoporosis: clinical and
research evidence of inverse relationship. Aging Clin Exp Res. 2003;15:426-439.
35. Ng MC, Revell PA, Beer M, Boucher BJ, Cohen RD, Currey LF. Incidence of
metabolic bone disease in rheumatoid arthritis and osteoarthritis. Ann Rheum
Dis. 1984;43:370-377.
36. Goldring SR, Gravallese EM. Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications. Arthritis Research. 2000;2:33-37.
37. Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS. Mechanisms of disease:
the link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol.
2005;1:47-54.
38. Nade S. Septic arthritis. Best Pract Res Clin Rheumatol. 2003;17:183-200.
39. Walsh NC, Crotti TN, Goldring SR, Gravallese EM. Rheumatic diseases: the effects of inflammation on bone. Immunol Rev. 2005;208:228-251.
40. Udagawa N, Kotake S, Kamatani N, Takahashi N, Suda T. The molecular mechanism of osteoclastogenesis in rheumatoid arthritis. Arthritis Research. 2002;4:
281-289.
41. Martínez-Calatrava MJ, Prieto-Potín I, Roman-Blas JA, Tardio L, Largo R, Herrero-Beaumont G. RANKL synthesized by articular chondrocytes contributes
to juxta-articular bone loss in chronic arthritis. Arthritis Res Ther. 2012;14:
R149.
42. Moreno-Rubio J, Herrero-Beaumont G, Tardio L, Alvarez-Soria MA, Largo R.
Nonsteroidal antiinflammatory drugs and prostaglandin E(2) modulate the synthesis of osteoprotegerin and RANKL in the cartilage of patients with severe
knee osteoarthritis. Arthritis Rheum. 2010;62:478-488.
43. Usui M, Drissi H, Zuscik M, O’Keefe R, Chen D, Boyce BF. Murine and chicken
chondrocytes regulate osteoclastogenesis by producing RANKL in response
to BMP2. J Bone Miner Res. 2008;23:314-325.
44. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical
symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625-635.
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45. Oehler S, Neureiter D, Meyer-Scholten C, Aigner T. Subtyping of osteoarthritic
synoviopathy. Clin Exp Rheumatol. 2002;20:633-640.
46. Lugo L, Villalvilla A, Gómez R, et al. Effects of PTH[1-34] on synoviopathy in an
experimental model of osteoarthritis preceded by osteoporosis. Osteoarthritis Cartilage. 2012;20:1619-1630.
47. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis:
a potential predictive factor of structural progression of medial tibiofemoral
knee osteoarthritis—results of a 1 year longitudinal arthroscopic study in 422
patients. Osteoarthritis Cartilage. 2005;13:361-367.
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48. Loeuille D, Chary-Valckenaere I, Champigneulle J, et al. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee:
correlating magnetic resonance imaging findings with disease severity. Arthritis Rheum. 2005;52:3492-3501.
49. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial
tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64:
1263-1267.
50. Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth
in osteoarthritis. Nat Rev Rheumatol. 2012;8:390-398.
Keywords: inflammatory arthritis; osteoarthritis; subchondral bone
PHYSIOPATHOLOGIE DE L’ARTHROSE : RESSEMBLANCES ET DIFFÉRENCES AVEC
D ’AUTRES PATHOLOGIES RHUMATOLOGIQUES ; LE RÔLE DE L’ OS SOUS - CHONDRAL
L’arthrose est non seulement une pathologie du cartilage mais aussi de toute l’articulation. Dans l’arthrose et les arthrites inflammatoires chroniques, l’intensité de la réponse inflammatoire de l’articulation détermine la perte osseuse
juxta-articulaire. Ainsi, dans la polyarthrite rhumatoïde, l’inflammation intense du cartilage et de la synovie, la formation de pannus et la perte osseuse généralisée provoquent une augmentation du renouvellement osseux sous-chondral entraînant une perte osseuse juxta-articulaire. À l’inverse, la synovite modérée et clairsemée de type arthrosique
conduit à un renouvellement osseux sous-chondral plus faible et à une perte osseuse ultérieure moins importante
que dans la polyarthrite rhumatoïde. L’angiogenèse et la croissance des nerfs sensoriels contribuent également à causer des lésions articulaires de sévérité différente dans ces arthropathies. Toutefois, les principaux mécanismes pathogènes sous-jacents sont probablement communs à ces maladies articulaires. De nouvelles stratégies thérapeutiques pour prévenir la perte osseuse et, éventuellement, l’évolution des lésions articulaires pourraient être élaborées
si les phénomènes impliqués dans la perte osseuse provoquée par l’inflammation au cours de ces maladies étaient
mieux compris.
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Radiography is the only EMAand FDA-recommended imaging
modality for defining the inclusion
criteria and efficacy end points of
a clinical trial. However, it has its
limitations and well-defined MRIbased diagnostic criteria of OA are
needed. MRI plays a crucial role in
understanding the natural history
of the disease and in guiding future therapies due to its ability to
image the knee as a whole organ
and to directly and three-dimensionally assess cartilage morphology and composition.”
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Role of imaging in
osteoarthritis: diagnosis,
prognosis, and follow-up
b y A . G u e r m a z i , F. W. R o e m e r,
and H. K. Genant, USA and Germany
O
L
Ali GUERMAZI,a MD, PhD
Frank W. ROEMER,b MD
a,b
Quantitative Imaging Center
Department of Radiology
Boston University School of
Medicine, Boston, USA
b
Klinikum Augsburg
Augsburg, GERMANY
steoarthritis is a highly prevalent joint disorder primarily affecting elderly people worldwide. The importance of imaging for assessment
of all the structures of the joint such as cartilage, meniscus, subarticular bone marrow, and synovium for diagnosis, prognostication, and followup has been well recognized over the past decade. Conventional radiography
is still the most commonly used imaging technique for evaluation of a patient
with a known or suspected diagnosis of osteoarthritis. However, recent MRIbased knee osteoarthritis studies have begun to reveal the limitations of radiography. The ability of MRI to image the knee as a whole organ and to directly and three-dimensionally assess cartilage morphology and composition
plays a crucial role in understanding the natural history of the disease and in
the search for new therapies. Use of the appropriate MRI pulse sequences is
crucial to assess the various features of osteoarthritis, and support from experienced musculoskeletal radiologists is necessary for study design, image
acquisition, and interpretation. This article describes the roles and limitations
of conventional radiography and MRI in osteoarthritis imaging, and also provides some insight into the use of other modalities such as ultrasound, nuclear
medicine, computed tomography, and computed tomography arthrography
in clinical practice and research in osteoarthritis, with a particular emphasis
on the assessment of knee osteoarthritis in the tibiofemoral joint.
steoarthritis (OA) is a highly prevalent joint disorder and is becoming increasingly common, posing major health and economic challenges for aging industrialized societies. Despite various surgical and symptom-oriented
approaches, there is still no definitive disease-modifying therapy, other than total
joint replacement, for this complex and heterogeneous disease.
O
Harry K. GENANT, MD
University of California
San Francisco, USA
Professor Ali Guermazi, Department
of Radiology, Boston University
School of Medicine, 820 Harrison
Avenue, FGH Building, 3rd Floor,
Boston, MA 02118, USA
164
Most research studies of knee OA involve acquisition of conventional radiographs
and magnetic resonance images, including the Osteoarthritis Initiative (OAI,
http://www.oai.ucsf.edu/datarelease/), one of the largest epidemiological OA studies.1 The OAI is an ongoing 4-year observational study of approximately 4800 participants, sponsored by the National Institutes of Health, and targeted at identifying the most reliable and sensitive biomarkers for evaluating the development and
progression of symptomatic knee OA. Data from baseline through the 48-month
follow-up visit for the entire cohort were made publically available in 2011. This article aims to describe the current role of radiography and magnetic resonance im-
Imaging of osteoarthritis – Guermazi and others
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aging (MRI) in OA imaging, and also
to give some insight into the use of
other modalities: ultrasound, nuclear
medicine, and computed tomography (CT). Current research tends to
focus on the knee due to the high
prevalence of knee OA and the relative ease of use of MRI compared
with other central appendicular joints.
This nonsystematic review article will
focus primarily on the assessment
of OA in the tibiofemoral joint of the
knee.
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B
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D
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Conventional radiography
Radiography is the simplest and least
expensive imaging technique. It can
detect OA-associated bony features
including marginal osteophytes, subchondral sclerosis, and subchondral
cysts.2 Radiography can also deter- Figure 1. Multitissue contribution to joint space narrowing.
(A) Baseline anterior-posterior radiograph showing doubtful joint space narrowing in the medial tibiofemoral commine joint space width (JSW), an in- partment (arrowheads). (B) Follow-up image at 24 months showing a definite increase in joint space loss medially
direct surrogate of cartilage thickness (arrows).(C) Corresponding baseline intermediate-weighted magnetic resonance imaging (MRI) showing normal
and meniscal integrity, but precise cartilaginous tibiofemoral surface and no relevant meniscal extrusion. (D) MRI at 24 months showing definite meniscal extrusion (arrows) likely to be responsible for the joint space narrowing on the radiograph.
measurement of each of these articular structures is not possible by x-ray.3 Despite this, slowing The severity of OA can be estimated using semiquantitative
of radiographically detected joint space narrowing (JSN) is the scoring systems. Published atlases provide images that repreonly structural end point currently recommended by the reg- sent specific grades.2 The most widely used system, the Kellulatory bodies in the United States (US Food and Drug Ad- gren and Lawrence (K&L) classification,5 has limitations, espeministration [FDA]) and in Europe (European Medicines Agency cially as K&L grade 3 includes all degrees of JSN, regardless
[EMA]) to prove the efficacy of disease-modifying OA drugs of the actual extent. In contrast, the Osteoarthritis Research
in phase-3 clinical trials. OA is defined radiographically by the Society International (OARSI) atlas2 classification grades tibiopresence of osteophytes.4 Progression of JSN is the most femoral JSW and osteophytes separately for each compartcommonly used criterion for the assessment of OA progres- ment of the knee. Compartmental scoring appears to be more
sion and the complete loss of JSW characterized by bone- sensitive to longitudinal radiographic changes than K&L grading.
on-bone contact is one of the indicators for joint replacement.
Methods of JSW measurement can be manual or semiautomated using computer software. However, previously held beSELECTED ABBREVIATIONS AND ACRONYMS
liefs that JSN and its changes are the only visible evidence of
cartilage damage have been shown to be incorrect. Recent
BML
bone marrow lesion
studies have demonstrated that alterations in the meniscus,
CE-MRI
contrast-enhanced MRI
such as meniscal extrusion or subluxation, also contribute to
CT
computed tomography
JSN (Figure 1).3 The lack of sensitivity and specificity of radiDESS
double-echo steady state
ography for the detection of the pathologic features associdGEMRIC delayed gadolinium-enhanced MRI of cartilage
ated with OA, and the poor sensitivity to change at follow-up
FLASH
fast low-angle shot
imaging, are inherent limitations of radiography.
GRE
gradient-recalled echo
JSN
JSW
K&L
MRI
OA
OAI
PET
SPGR
joint space narrowing
joint space width
Kellgren and Lawrence
osteoarthritis
Osteoarthritis Initiative
positron emission tomography
spoiled gradient echo
Interestingly, an older method—digital tomosynthesis—has
lately experienced a revival. Tomosynthesis generates an arbitrary number of section images from a single pass of the xray tube. Using 3T MRI as a reference, Hayashi et al found
that tomosynthesis depicted more osteophytes and subchondral cysts than radiography.6 The clinical availability of these
systems is currently limited, but the potential of this technique for OA research may be worth exploring.
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Magnetic resonance imaging
MRI offers a number of advantages for OA imaging.
First, MRI has a tomographic viewing perspective
and thus provides cross-sectional images of the
anatomy free of the projectional limitations of radiography. Second, MRI is uniquely able to directly depict all the components of the joint and their pathologies, including the articular cartilage, menisci, intraarticular ligaments, synovium, effusion, bone attrition,
bone marrow lesions (BMLs), subchondral cysts,
and intra- and periarticular cystic lesions (Figure 2).
The joint can be evaluated as a whole organ, providing a much more detailed picture of the changes
associated with OA than is possible with other techniques.7 Third, MRI can detect the pathology of preradiographic OA and possible complications of the disease at a much
earlier stage than radiography.8
N Technical considerations
Several MRI systems are commercially available but 1.5T systems are the most widely used in clinical and research settings. Examination times vary depending on the purpose of
the exam, but usually last between 20 and 40 minutes, including patient positioning. High-field 3T MRI was introduced
for clinical application several years ago. A higher signal-tonoise ratio is a definitive advantage, but disadvantages include
increased susceptibility artifacts, high costs, and the limited
commercial availability of coils. Most OA studies that include
MRI use 1.5T MRI systems because of their wide availability
and reliable image quality. The OAI is one of the few large studies to have used a 3T system (Figure 3).
So far, 7T MRI in humans has only been applied in research.9
In the future, 7T systems may be able to produce higher-resolution images with a shorter scan time than 3T systems. So
far, however, the available 7T protocols have not been any
better than 3T for knee cartilage evaluation.10
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Figure 2. Osteoarthritis is a
whole-joint disease process that
can only be completely visualized
by magnetic resonance imaging.
This sagittal intermediate-weighted fatsaturated image shows diffuse cartilage
loss in the medial tibio-femoral joint.
A horizontal-oblique tear extending to
the superior surface is seen in the posterior horn of the medial meniscus
(arrowhead) and a small subchondral
cyst appears in the medial weight bearing part of the femoral condyle (arrow).
There is also joint effusion and a popliteal
cyst (asterisk) and a small osteophyte
at the posterior medial femoral condyle
(no arrow).
The role of contrast-enhanced MRI (CE-MRI) in the clinical and
research environment remains to be fully established. Visualization of synovitis in OA is superior on contrast-enhanced
scans using the intravenous paramagnetic agent gadolinium
with histological correlation,11 and recent studies have shown
that CE-MRI-detected synovitis is associated with knee pain
(Figure 4).12
Since different tissues are involved in OA and both morphologic and quantitative analyses are needed, a variety of different sequences have been developed for “whole-organ”
assessment of OA. Selecting the appropriate MR pulse sequences to study specific features of OA is essential for success. In general, fluid-sensitive fat-suppressed sequences
(eg, T2-weighted, proton-density-weighted, or intermediateweighted fast spin-echo sequences) are useful for evaluation
of cartilage, bone marrow, ligaments, menisci, and tendons.13
It is particularly important to use these sequences to assess focal cartilage defects and BMLs. Gradient-recalled echo (GRE)type sequences (eg, 3D-spoiled gradient echo at steady state
[SPGR], double-echo steady state [DESS], and fast low-angle shot [FLASH]) are not suitable for marrow or focal defect
assessment. They are prone to susceptibility artifacts, which
C
Figure 3. Development of a focal cartilage defect over two years as visualized with 3T magnetic resonance imaging (MRI).
(A) Coronal intermediate-weighted image showing a small superficial cartilage defect in the weight-bearing part of the medial femoral condyle (arrow). (B) Follow-up
MRI at 12 months reveals extension of defect to the subchondral bone, now representing a full-thickness focal lesion (arrow). (C) MRI image at 24 months showing
a slight increase in the size of the focal full thickness defect.
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Figure 4. Visualization of synovitis on
contrast-enhanced
magnetic resonance
imaging (MRI).
Sagittal T1-weighted fatsaturated image showing
severe synovitis in the
suprapatellar recess (arrowheads), at the Hoffa fat
pad (small arrow) and especially posterior to the
posterior cruciate ligament,
the most common location
of synovitis in osteoarthritic knees (large arrow). Synovitis cannot be visualized
with nonenhanced MRI.
hinder accurate interpretation of images.14 GRE-type sequences also usually require long imaging times, and motion
artifacts can degrade image quality.15 A recent study demonstrated that focal cartilage lesions were more conspicuous
and larger on the intermediate-weighted fast spin-echo sequence with fat suppression compared with the DESS sequence.16 It was also shown that GREtype sequences have limited sensitivity
A
to BMLs compared with fast spin-echo
sequences (Figure 5).17 For synovitis,
CE-MRI is preferable to non–CE-MRI,
but if only non–CE-MRI is available, gradient-echo type sequences should again
be avoided because they are prone to
chemical shift artifacts, making accurate assessment difficult.18
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Knee Score (MOAKS).22 MOAKS is a recent effort to combine
the strengths of existing systems, but little information on its
use has been published to date. In addition to these scoring
systems based on non-enhanced MRI, semiquantitative scoring systems for synovitis using contrast-enhanced MRI have
been proposed.12,23 In particular, the system proposed by Guermazi et al enables comprehensive assessment of synovitis
in the whole knee joint,12 rather than being restricted to the
peripatellar regions.23 These contrast-enhanced MRI–based
scoring systems will enable longitudinal assessment of synovitis in future clinical trials.12
Recently, MRI-based semiquantitative scoring systems for
hand OA (Oslo Hand OA MRI score [OHOA-MRI]) and hip
OA (Hip OA MRI Scoring system [HOAMS]) have been proposed.24,25 However, further validation, evaluation of responsiveness, and iterative refinement of these new systems are
needed to assess their utility in clinical trials and epidemiological studies. To the authors’ knowledge, no semiquantitative
scoring systems enabling evaluation of other joints, such as
B
On the other hand, GRE-type sequences
do provide high spatial resolution and
excellent contrast of cartilage to subchondral bone, and are well suited for
quantitative measurement of volume Figure 5. Sequence selection for visualizing specific osteoarthritis features.
and thickness.15 MRI is a powerful tool (A) Coronal proton-density-weighted fat-saturated image showing a large bone marrow lesion (BML) in the
central part of the medial femur (ill-defined area of hyperintensity indicated by arrows). A large BML is also
for OA research, but it is also complex depicted in the medial tibial plateau (asterisk). (B) Fast low-angle shot (FLASH) image. Although commonly
and how it is used is largely determined used for cartilage segmentation due to the excellent contrast between cartilage and subchondral bone and
resolution acquisition, the FLASH image depicts the femoral BML poorly compared with the protonby the goal of the research. Clinicians high
density-weighted image (arrow). The large tibial BML can barely be distinguished on the FLASH image.
planning clinical OA research using MRIderived data should seek expert advice from trained and ex- the shoulder, elbow, and ankle, as a “whole joint” have been
perienced musculoskeletal radiologists on which pulse se- published. A limited number of small studies have been published recently involving cartilage repair techniques or novel
quences are best suited to their purpose.
imaging methodologies for these joints.26
N Semiquantitative MRI whole-organ scoring
Semiquantitative whole-organ scoring has been applied to N Compositional imaging of cartilage
a multitude of OA studies.7,19 Analyses based on semiquan- Compositional MRI can assess the biochemical properties of
titative scoring have added greatly to our understanding of different joint tissues and is thus very sensitive to early prethe pathophysiology and natural history of OA as well as to morphologic changes. The vast majority of studies applying
the clinical implications of structural changes. A short list of compositional MRI have focused on cartilage, although the
semiquantitative scoring systems includes the Whole-ORgan technique can also be used to assess other tissues such as
Magnetic resonance imaging Score (WORMS),7 the Knee Os- the meniscus or ligaments.27 T2 mapping has been used to
teoarthritis Scoring System (KOSS),20 the Boston Leeds Os- describe the molecular composition of hyaline cartilage in the
teoarthritis Knee Score (BLOKS),21 and the MRI OsteoArthritis knee on the basis of collagen structure and hydration.
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In healthy cartilage, T2 values increase from deep to superficial cartilage layers.28 It has been shown that T2 values are
related to age and activity levels and that they are associated
with OA severity.29,30 T2* relaxation measures have also been
tested for their ability to depict the collagen matrix. T2* mapping was shown to be a reproducible process that can differentiate between OA and non-OA subjects.31
T1rho is also sensitive to the interactions of water with macromolecules. It has been shown to correlate with the proteoglycan concentration in cartilage,32 and is also sensitive to collagen.33 Although T1rho has been shown to have a larger
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B
index over 12 months in the medial but not in the lateral tibiofemoral compartment. This finding supports the notion that
body weight affects disease progression and emphasizes the
role of weight loss in clinical and structural improvement.38
Novel compositional techniques have been reported. Raya et
al studied the feasibility of in vivo diffusion tensor imaging at
7T MRI and demonstrated better discrimination of OA versus non-OA knees than with T2 mapping.39 Although this technique shows promise, it will have to be more practical and
widely available for use with standard MRI systems before it
can be applied in broader clinical research settings.
C
Figure 6. Biochemical magnetic resonance imaging.
(A) Sagittal intermediate-weighted fat-saturated image depicts a horizontal-oblique tear of the posterior horn of the medial meniscus (arrow). (B) Corresponding baseline
color-coded T1-weighted image showing normal delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) map of femoro-tibial cartilage. (C) At 24 months there is
a marked decrease in the dGEMRIC index in the medial femoral cartilage (coded in red - arrowheads). An incidental partial meniscal maceration is also seen (arrow).
dynamic range than T2,34 it is more complex to implement,
and is limited by radiofrequency power deposition. It has been
reported that T1rho and T2 values show different spatial distributions and may provide complementary information on cartilage degeneration.35
Sodium MRI and the delayed gadolinium-enhanced MRI of
cartilage technique (dGEMRIC) are designed to measure fixed
charge densities in cartilage and, by implication, its proteoglycan content (Figure 6).36 These techniques are based on
the premise that mobile ions will distribute themselves in cartilage in relation to the concentration of the charged proteoglycan molecules; in MRI, the mobile ions are the naturally
abundant sodium, or the negatively charged MRI contrast
agent Gd(DTPA)2– (Magnevist, Berlex, NJ, USA).
In the dGEMRIC technique, Gd(DTPA)2– is injected intravenously, and images are acquired typically around 90 minutes after injection. The negative charge on the Gd(DTPA)2– molecule
causes it to disperse into the cartilage in inverse relation to
the negatively charged glycosaminoglycan molecular concentration.37 A recent interventional study evaluating the effect
of weight loss on articular cartilage showed an improvement
in cartilage quality reflected by an increase in the dGEMRIC
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N Quantitative cartilage morphometry
Quantitative analysis of knee OA features has been applied
mainly to cartilage morphology, where the three-dimensional
nature of MRI data can be exploited to assess tissue parameters such as volume, thickness, or other continuous variables. The real strength of quantitative measurements is that
they are more objective and less observer-dependent than
semiquantitative scoring methods and that relatively small
changes in cartilage thickness or volume can be detected over
time.40 Correctly segmenting the cartilage requires well-trained
users, working either manually or with segmentation software.
Most investigations have focused on measuring cartilage volume, but volume has its limitations. Discrimination of patients
with OA from healthy subjects is limited because men in
general, and anybody with large bones, will have larger joint
surfaces and more cartilage volume, so there is a wide overlap between groups.41 While this problem can be mostly overcome by adjusting the analysis for the bone surface area in
each subject, a new analytic strategy called “extended ordered
values” has been proposed.42 The extended ordered values
approach sorts changes in subregional thickness in the medial and lateral tibial and femoral cartilage plates in ascending
order. This analytic method enables more efficient measurement of changes in cartilage thickness, independently of their
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anatomical locations, and shows better sensitivity for detecting differences in longitudinal rates of cartilage loss than
anatomical subregions and radiography.42
Ultrasound
Ultrasound is a technique that enables multiplanar and realtime imaging at a relatively low cost, without radiation exposure. It has the ability to image soft tissue and to detect synovial pathology without the need for contrast administration.
Limitations of ultrasound are primarily that it is an operator-dependent technique and that the physical properties of sound
hinder its application to deeper articular structures and the
subchondral bone. The ability to detect synovial pathology is
perhaps the major advantage of ultrasound over radiography.
Ultrasound-detected grey-scale synovitis has been validated
against arthroscopy, MRI, and histology in large-joint OA, and
ultrasound has been demonstrated to be more sensitive than
clinical examination in detecting synovial hypertrophy and joint
effusion.43 Additionally, color-coded Doppler signal has been
validated as an indirect measure of histological synovial vascularity in large-joint OA.44 Tissues other than synovium have
also been studied using ultrasound. Saarakkala et al compared knee ultrasonography to arthroscopic grading for detecting degenerative changes in articular cartilage.45,46 The authors concluded that positive findings on ultrasound are strong
indicators of degenerative changes in cartilage, but also stated that negative findings do not rule out degenerative cartilage
alterations. A study by Kawaguchi et al used ultrasound to
look at medial radial displacement of the meniscus in the
supine and weight-bearing positions and showed that the
medial meniscus was significantly displaced radially by weight
bearing in control knees and in knees with K&L grades 1-3.46
Its use with dynamic and weight-bearing conditions is one
of the inherent strengths of ultrasound and warrants further
exploration.
Computed tomography
CT is a valuable tool for the characterization of OA, particularly when imaging of osseous changes or detailed presurgical
planning is required. Helical multidetector (MD) CT systems
enable acquisition of isotropic voxels and multiplanar reconstructions in any given plane with quality equal to the original
plane. Cortical bone and soft tissue calcifications are better
depicted than on MRI. CT has an established clinical role in
assessing facet joint OA of the spine.47 Drawbacks are its low
soft-tissue contrast and the relatively high dose of radiation it
delivers. CT arthrography is an alternative method for indirect
visualization of cartilage and other intrinsic joint structures,
especially in the knee joint. CT arthrography may be relevant
especially where access to MRI facilities is limited or when
MRI is contraindicated. Spiral CT arthrography of the knee
and shoulder enables excellent imaging of the articular surface.48 Penetration of contrast medium into the deeper layers
of the cartilage surface indicates an articular-side defect of the
chondral surface. The high spatial resolution and the high at-
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tenuation difference between the cartilage and the contrast
medium within the joint make focal morphologic changes conspicuous. Limitations of the technique are its insensitivity to
changes of the deep layers of cartilage without surface alterations and its invasive nature.
Nuclear medicine
Scintigraphy uses radiopharmaceuticals to visualize skeletal
metabolism, to contribute to the localization of disease, and
to assess the severity of pathologic changes in OA. 99mTC-hydroxymethane diphosphate scintigraphy shows increased
activity during the bone phase in the subchondral region in
nodal hand OA.49 This finding can be observed before the typical radiographic changes and reflects the osteoblastic activity of early cartilage loss. A study comparing MRI with scintigraphy in patients with chronic knee pain demonstrated good
agreement between MRI-detected subchondral BMLs and
radionuclide uptake, but generally poor agreement between
increased bone uptake and cartilage defects or osteophytes.50
A prospective study showed that a normal bone scan at baseline was highly predictive of a lack of progression of knee OA
over a 5-year period.51 Two other recent studies showed that
scintigraphy may predict JSN, but no better than baseline radiographic or pain status.52,53
Positron emission tomography (PET) demonstrates metabolic changes in target tissues and can detect foci of inflammation, infection, and tumors. PET utilizes 2-18F-fluoro-2-deoxy–
D-glucose (FDG) and reflects glucose metabolism. A recent
pilot study in knees with medial OA showed increased uptake
in periarticular regions, the intercondylar notch, and also in
areas of subchondral bone marrow corresponding to MRI-detected BMLs.54 A recent animal study showed increased uptake of FDG after experimentally induced knee OA in rats,
suggesting that PET could be useful for early detection of OA
changes.55 However, whether FDG-PET will have a role in the
assessment of OA in a clinical and research setting remains
to be seen. Limitations of PET include its limited availability,
high radiation exposure, and costs.
Conclusion
Conventional radiography is still the first and most widely used
imaging technique for evaluation of a patient with a known or
suspected diagnosis of OA. In research and clinical trials it is
the only EMA- and FDA-recommended imaging modality for
defining the inclusion criteria and efficacy end points of a clinical trial. However, radiography has its limitations and well-defined MRI-based diagnostic criteria of OA are needed. MRI
plays a crucial role in understanding the natural history of the
disease and in guiding future therapies due to its ability to
image the knee as a whole organ and to directly and threedimensionally assess cartilage morphology and composition.
Ultrasound and contrast-enhanced MRI play important subsidiary roles in the diagnosis and follow-up of treatment of OArelated synovitis. I
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3. Hunter DJ, Zhang YQ, Tu X, et al. Change in joint space width: hyaline articular
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11. Loeuille D, Sauliere N, Champigneulle J, Rat AC, Blum A, Chary-Valckenaere I.
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12. Guermazi A, Roemer FW, Hayashi D, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum
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14. Roemer FW, Guermazi A. MR imaging-based semiquantitative assessment in
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16. Roemer FW, Kwoh CK, Hannon MJ, et al. Semiquantitative assessment of focal cartilage damage at 3T MRI: A comparative study of dual echo at steady
state (DESS) and intermediate-weighted (IW) fat suppressed fast spin echo sequences. Eur J Radiol. 2011;80:e126-e131.
17. Hayashi D, Guermazi A, Kwoh CK, et al. Semiquantitative assessment of subchondral bone marrow edema-like lesions and subchondral cysts of the knee
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echo and Dual Echo Steady State sequences. BMC Musculoskelet Disord.
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18. Roemer FW, Hunter DJ, Guermazi A. Semiquantitative assessment of synovitis
in osteoarthritis on non contrast-enhanced MRI. Osteoarthritis Cartilage. 2009;
17:820-821; author reply 822-824.
19. Roemer FW, Crema MD, Trattnig S, Guermazi A. Advances in imaging of osteoarthritis and cartilage. Radiology. 2011;260:332-354.
20. Kornaat PR, Ceulemans RY, Kroon HM, et al. MRI assessment of knee osteoarthritis: Knee Osteoarthritis Scoring System (KOSS)—inter-observer and intra-observer reproducibility of a compartment-based scoring system. Skeletal
Radiol. 2005;34:95-102.
21. Hunter DJ, Lo GH, Gale D, Grainger AJ, Guermazi A, Conaghan PG. The reliability of a new scoring system for knee osteoarthritis MRI and the validity of
bone marrow lesion assessment: BLOKS (Boston Leeds Osteoarthritis Knee
Score). Ann Rheum Dis. 2008;67:206-211.
22. Hunter DJ, Guermazi A, Lo GH, et al. Evolution of semi-quantitative whole joint
assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score). Osteoarthritis Cartilage. 2011;19:990-1002.
23. Baker K, Grainger A, Niu J, et al. Relation of synovitis to knee pain using contrast-enhanced MRIs. Ann Rheum Dis. 2010;69:1779-1783.
24. Haugen IK, Lillegraven S, Slatkowsky-Christensen B, et al. Hand osteoarthritis
and MRI: development and first validation step of the proposed Oslo Hand Osteoarthritis MRI score. Ann Rheum Dis. 2011;70:1033-1038.
25. Roemer FW, Hunter DJ, Winterstein A, et al. Hip Osteoarthritis MRI Scoring
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System (HOAMS): reliability and associations with radiographic and clinical findings. Osteoarthritis Cartilage. 2011;19:946-962.
26. Apprich S, Trattnig S, Welsch GH, et al. Assessment of articular cartilage repair
tissue after matrix-associated autologous chondrocyte transplantation or the
microfracture technique in the ankle joint using diffusion-weighted imaging at
3 Tesla. Osteoarthritis Cartilage. 2012;20:703-711.
27. Mayerhoefer ME, Mamisch TC, Riegler G, et al. Gadolinium diethylenetriaminepentaacetate enhancement kinetics in the menisci of asymptomatic subjects:
a first step towards a dedicated dGEMRIC (delayed gadolinium-enhanced MRI
of cartilage)-like protocol for biochemical imaging of the menisci. NMR Biomed.
2011;24:1210-1215.
28. Smith HE, Mosher TJ, Dardzinski BJ, et al. Spatial variation in cartilage T2 of the
knee. J Magn Reson Imaging. 2001;14:50-55.
29. Dunn TC, Lu Y, Jin H, Ries MD, Majumdar S. T2 relaxation time of cartilage at
MR imaging: comparison with severity of knee osteoarthritis. Radiology. 2004;
232:592-598.
30. Hovis KK, Stehling C, Souza RB, et al. Physical activity is associated with magnetic resonance imaging-based knee cartilage T2 measurements in asymptomatic subjects with and those without osteoarthritis risk factors. Arthritis Rheum.
2011;63:2248-2256.
31. Newbould RD, Miller SR, Toms LD, et al. T2* measurement of the knee articular
cartilage in osteoarthritis at 3T. J Magn Reson Imaging. 2012;35:1422-1429.
32. Borthakur A, Mellon E, Niyogi S, Witschey W, Kneeland JB, Reddy R. Sodium
and T1rho MRI for molecular and diagnostic imaging of articular cartilage. NMR
Biomed. 2006;19:781-821.
33. Menezes NM, Gray ML, Hartke JR, Burstein D. T2 and T1rho MRI in articular
cartilage systems. Magn Reson Med. 2004;51:503-509.
34. Li X, Benjamin Ma C, Link TM, et al. In vivo T(1rho) and T(2) mapping of articular cartilage in osteoarthritis of the knee using 3 T MRI. Osteoarthritis Cartilage.
2007;15:789-797.
35. Li X, Pai A, Blumenkrantz G, et al. Spatial distribution and relationship of T1rho
and T2 relaxation times in knee cartilage with osteoarthritis. Magn Reson Med.
2009;61:1310-1318.
36. Gray ML, Burstein D, Kim YJ, Maroudas A. Magnetic resonance imaging of cartilage glycosaminoglycan: basic principles, imaging technique, and clinical applications. J Orthop Res. 2008;26:281-291.
37. Burstein D, Gray M, Mosher T, Dardzinski B. Measures of molecular composition and structure in osteoarthritis. Radiol Clin North Am. 2009;47:675-686.
38. Anandacoomarasamy A, Leibman S, Smith G, et al. Weight loss in obese people has structure-modifying effects on medial but not on lateral knee articular
cartilage. Ann Rheum Dis. 2012;71:26-32.
39. Raya JG, Horng A, Dietrich O, et al. Articular cartilage: in vivo diffusion-tensor
imaging. Radiology. 2012;262:550-559.
40. Eckstein F, Guermazi A, Roemer FW. Quantitative MR imaging of cartilage and
trabecular bone in osteoarthritis. Radiol Clin North Am. 2009;47:655-673.
41. Otterness IG, Eckstein F. Women have thinner cartilage and smaller joint surfaces than men after adjustment for body height and weight. Osteoarthritis Cartilage. 2007;15:666-672.
42. Wirth W, Buck R, Nevitt M, et al. MRI-based extended ordered values more efficiently differentiate cartilage loss in knees with and without joint space narrowing than region-specific approaches using MRI or radiography—data from the
OA initiative. Osteoarthritis Cartilage. 2011;19:689-699.
43. Karim Z, Wakefield RJ, Quinn M, et al. Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: a comparison with arthroscopy and clinical examination. Arthritis Rheum. 2004;50:387-394.
44. Walther M, Harms H, Krenn V, Radke S, Faehndrich TP, Gohlke F. Correlation of
power Doppler sonography with vascularity of the synovial tissue of the knee
joint in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum.
2001;44:331-338.
45. Saarakkala S, Waris P, Waris V, et al. Diagnostic performance of knee ultrasonography for detecting degenerative changes of articular cartilage. Osteoarthritis
Cartilage. 2012;20:376-381.
46. Kawaguchi K, Enokida M, Otsuki R, Teshima R. Ultrasonographic evaluation of
medial radial displacement of the medial meniscus in knee osteoarthritis. Arthritis Rheum. 2012.64:173-180.
47. Hechelhammer L, Pfirmann CW, Zanetti M, Hodler J, Boos N, Schmid MR. Imaging findings predicting the outcome of cervical facet joint blocks. Eur Radiol.
2007;17:959-964.
48. Vande Berg BC, Lecouvet FE, Poilvache P, et al. Assessment of knee cartilage
in cadavers with dual-detector spiral CT arthrography and MR imaging. Radiology. 2002;222:430-436.
49. Hutton CW, Higgs ER, Jackson PC, Watt I, Dieppe PA. 99mTc HMDP bone
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scanning in generalised nodal osteoarthritis. II. The four hour bone scan image
predicts radiographic change. Ann Rheum Dis. 1986;45:622-626.
50. Boegard T, Rudling O, Dhalstrom J, Dirksen H, Petersson IF, Jonsson K. Bone
scintigraphy in chronic knee pain: comparison with magnetic resonance imaging. Ann Rheum Dis. 1999;58:20-26.
51. Dieppe P, Cushnaghan J, Young P, Kirwan J. Prediction of the progression of
joint space narrowing in osteoarthritis of the knee by bone scintigraphy. Ann
Rheum Dis. 1993;52:557-563.
52. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Bone scintigraphy is not a
better predictor of progression of knee osteoarthritis than Kellgren and Lawrence
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grade. J Rheumatol. 2004;31:329-332.
53. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Severity of joint pain and
Kellgren-Lawrence grade at baseline are better predictors of joint space narrowing than bone scintigraphy in obese women with knee osteoarthritis. J Rheumatol. 2005;32:1540-1546.
54. Nakamura H, Masuko K, Yudoh K, et al. Positron emission tomography with 18FFDG in osteoarthritic knee. Osteoarthritis Cartilage. 2007;15:673-681.
55. Umemoto Y, Oka T, Inoue T, Saito T. Imaging of a rat osteoarthritis model using (18)F-fluoride positron emission tomography. Ann Nucl Med. 2010;24:663669.
Keywords: magnetic resonance imaging, osteoarthritis, radiography, ultrasound
RÔLE
DE L’ IMAGERIE DANS L’ARTHROSE
:
DIAGNOSTIC , PRONOSTIC , ET SUIVI
L’arthrose est une maladie articulaire à la prévalence élevée touchant essentiellement les sujets âgés du monde entier. Les dix dernières années ont reconnu l’importance de l’imagerie dans l’évaluation des structures articulaires (cartilage, ménisque, moelle osseuse sous-chondrale, synovie) pour le diagnostic, le pronostic et le suivi. La radiographie
conventionnelle est toujours la technique la plus couramment utilisée dans l’évaluation d’un patient pour lequel l’arthrose est connue ou suspectée. Ses limites ont néanmoins été mises en évidence par des études récentes sur l’arthrose du genou utilisant l’IRM. La capacité de l’IRM à représenter le genou comme un organe à part entière et à
évaluer la morphologie et la composition du cartilage directement et en trois dimensions joue donc un rôle essentiel dans la compréhension de l’histoire naturelle de la maladie et dans la recherche de nouveaux traitements. L’évaluation des différentes caractéristiques de l’arthrose nécessite des séquences IRM adéquates et la compétence de
radiologues expérimentés dans la pathologie musculosquelettique est indispensable pour la conception des études,
ainsi que pour l’acquisition et l’interprétation des images. Cet article présente les rôles et limites de la radiographie
conventionnelle et de l’IRM dans l’imagerie de l’arthrose et aborde également l’utilisation d’autres techniques comme
l’échographie, la médecine nucléaire, la tomodensitométrie et l’arthro-scanner en pratique clinique et dans la recherche sur l’arthrose, en insistant plus particulièrement sur l’évaluation de l’arthrose du genou au niveau de l’articulation tibio-fémorale.
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Guidelines for the medical
management of osteoarthritis focus on controlling pain and improving function and quality of
life while minimizing therapeutic
toxicity… Clinicians managing osteoarthritis are able to draw upon a
wide spectrum of therapeutic options, combining nonpharmacological approaches and pharmacological treatments both to relieve
pain and to attempt to delay disease progression… The current
therapeutic options, however, are
neither exclusive nor sufficient.”
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Osteoarthritis treatments:
where do we stand
at the moment?
b y C . R o u b i l l e , J . M a r t e l - Pe l l e t i e r,
a n d J . P. Pe l l e t i e r, C a n a d a
O
Camille ROUBILLE, MD
L
Johanne MARTEL-PELLETIER, PhD
Jean-Pierre PELLETIER, MD
Osteoarthritis Research Unit
University of Montreal Hospital
Research Centre
University of Montreal
Montreal, Quebec, CANADA
Professor Jean-Pierre Pelletier,
Osteoarthritis Research Unit,
University of Montreal Hospital
Research Centre (CRCHUM),
Notre-Dame Hospital,
1560 Sherbrooke Street East,
Montreal, Quebec H2L 4M1,
Canada (e-mail: [email protected])
172
steoarthritis is the most common form of arthritis and results in pain
and reduced quality of life. Although a structure-modifying treatment
remains the greatest unmet need in osteoarthritis, several symptomatic treatments are available. This article will review the nonpharmacological approaches and pharmacological treatments currently available for osteoarthritis management, as well as the surgical treatments available for the
condition. At present, a multimodal approach combining nonpharmacological and pharmacological treatments is still the best option for the management of osteoarthritis, as recommended in the guidelines of Osteoarthritis
Research Society International and the American College of Rheumatology.
Nonpharmacological management mainly relies on patient education, exercise, prevention of injuries, weight loss in overweight patients, and use of orthotic devices. Pharmacological symptomatic treatments include a number
of analgesic options such as acetaminophen, nonsteroidal anti-inflammatory
drugs (NSAIDs), opioids, duloxetine, topical NSAIDs, capsaicin, lidocaine patches, intra-articular corticosteroids and hyaluronic acid injections, and slowacting drugs including glucosamine and chondroitin sulfate, diacerein, and
avocado soybean unsaponifiables. When the combination of nonpharmacological and pharmacological approaches becomes unsuccessful at managing
symptoms, surgical treatment may be considered.
Nonpharmacological management
he combination of patient education, improved muscle strength, and reduced
body mass index has been reported to be joint protective. Recent guidelines
from the American College of Rheumatology (ACR) strongly recommend weight
loss for overweight patients with knee or hip osteoarthritis, as well as cardiovascular and/or resistance land-based exercises and aquatic exercise.1 No preference
is made regarding aquatic versus land-based exercise, as the choice will depend
on individual ability. As to date there have been very few high-quality randomized
controlled trials reported in the literature, the ACR conditionally recommends selfmanagement programs, manual therapy in combination with supervised exercise,
psychosocial interventions, use of thermal agents, walking aids if needed, tai chi,
Chinese acupuncture, and transcutaneous electrical stimulation. For hand osteoarthritis, assistive devices, joint protection techniques, thermal modalities, and
trapeziometacarpal joint splints are also conditionally recommended by the ACR
guidelines.1
T
Osteoarthritis treatments: where do we stand at the moment? – Roubille and others
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N Patient education
Patient education should form the cornerstone of nonpharmacological management for osteoarthritis,2,3 and patients
should be involved in the management of their condition as
much as possible.3 Indeed, as with other chronic diseases, patients should know about their condition’s evolution over time
as well as its management and any associated investigations,
and this can be achieved through use of books, regular telephone calls, and education groups. It has been suggested
that education contributes to pain reduction and optimization
of health care resource usage.4
N Exercise programs
Physical activity involving aerobic and/or resistance land-based
exercises and/or aquatic exercises, including local muscle
strengthening and general fitness, is recommended for osteoarthritis patients.1 Strengthening exercises, especially for the
quadriceps femoris muscle, may improve muscular balance,
decrease impact loads, and support function, and they have
also been reported to reduce pain and disability in hip5 and
knee osteoarthritis.6 Water-based exercises have been shown
to have short-term effects on pain relief for patients with hip
and/or knee osteoarthritis.7 In addition, contrary to popular belief, running—even long distances—as part of normal nonprofessional conditioning does not accelerate the development
of osteoarthritis of the knee.8 However, the risk of osteoarthritis development may be different for middle-intensity levels of
running compared with high or competitive levels: moderate
regular running may be safe, whereas professional runners
may have an increased risk for osteoarthritis.9,10
N Prevention of injuries
Prevention of injuries is necessary in contact sports such as
soccer.11 Increased joint traumatisms such as anterior cruciate ligament lesions or meniscal lesions increase the risk of
developing osteoarthritis. Effective treatment such as postoperative rehabilitation should decrease this risk.
N Weight loss
Does weight loss reduce osteoarthritis symptoms and prevent overall progression of structural damage? This is a most
important and relevant question in the management of osteoarthritis. In obese patients, weight loss and maintenance
SELECTED
ACR
ASU
COX
NSAID
OARSI
TKA
UKA
WOMAC
American College of Rheumatology
avocado soybean unsaponifiables
cyclooxygenase
Osteoarthritis Research Society International
total knee arthroplasty
unicondylar knee arthroplasty
Western Ontario and McMaster Universities Arthritis
index
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of weight at a lower level seems to reduce osteoarthritis-related pain.12 Weight loss in obese people was reported to improve the content of the macromolecule proteoglycan in the
cartilage, as well as the cartilage thickness in the medial, but
not lateral, compartment of the knee.13 Interestingly, obesity increases the risk of progressive osteoarthritis in neutrally aligned
knees or those in valgus alignment, but not in patients with
varus alignment.14 Thus, overload alone across the joints does
not seem to be sufficient to induce the development of osteoarthritis. As obese individuals also have a higher incidence
of osteoarthritis in non–weight-bearing areas, including finger
joints, it has been suggested that factors such as adipokines,
one representative of this family being leptin, could promote
cartilage damage, thus inducing osteoarthritis.15,16 Therefore,
although mechanical factors may be one element favoring the
development of osteoarthritis in obese patients, inflammatory
mediators also appear to be important contributing factors.
Thus, in addition to weight loss, additional treatments may
eventually be required for optimal therapeutic intervention.
N Orthotic devices
Orthotic devices such as special footwear, insoles, knee bracing, and canes are recommended for patients with hip and/or
knee osteoarthritis.2,17 The latest ACR guidelines recommend
medially-directed patellar taping, as well as medially-wedged
insoles for patients with lateral compartment knee osteoarthritis, and laterally-wedged subtalar strapped insoles for
those with medial compartment knee osteoarthritis.1 Canes
held in the contralateral hand as a walking aid can reduce pain
in patients with hip and knee osteoarthritis. In knee osteoarthritis, use of braces1 and sleeves was shown to have beneficial effects compared with medical treatment alone (acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]),
as assessed by the Western Ontario and McMaster Universities Arthritis index (WOMAC) and function tests.18 Moreover,
braces seem to be more effective than sleeves, and laterallywedged insoles may decrease NSAID intake compared with
neutral insoles.18
N Alternative therapies
Acupuncture3 and transcutaneous electrical stimulation17 have
been reported to show some short-term pain relief efficacy,
and they are considered alternative strategies for the management of osteoarthritis. These strategies are conditionally
recommended by the ACR guidelines for those patients with
knee osteoarthritis who are candidates for total knee arthroplasty but are unwilling or unable to undergo surgery because
of comorbidities or concomitant medications contraindicating
such surgery.1
Pharmacological treatment
The prescribing habits of physicians have changed over time.
Because osteoarthritis is a chronic disease and is more common in people aged over 60 years, safety remains critical.
Guidelines for the medical management of osteoarthritis fo-
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Treatment type
Oral
Symptomatic
drugs
Topical
Adverse effect/safety profile
Acetaminophen
GI discomfort, bleeding; renal failure; hypertension; hepatotoxicity
NSAIDs; coxibs
GI ulcer/bleeding; cardiovascular events; renal events
Opioids
Constipation; vomiting; somnolence; increased risk of fracture,
morbidity, and mortality in elderly
Duloxetine
Constipation; nausea; hyperhidrosis
Topical NSAIDs
Skin reactions; Gl events
Capsaicin
Skin burning sensation; long-term skin desensitization?
Lidocaine patches
Injectable
Slow-acting
symptomatic
drugs
Intra-articular corticosteroids
Local infection, systemic effects
Intra-articular hyaluronic acid
or viscosupplementation
Local reactions at the site of injection, swelling, flares of pain
Glucosamine and chondroitin
sulfate
Oral
Diacerein
Lower GI effects
Avocado soybean
unsaponifiables
Table I. Adverse effects of different pharmacological options for the treatment of osteoarthritis.
Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.
cus on controlling pain and improving function and quality
of life while minimizing therapeutic toxicity (see Table I for an
overview of the adverse effects of the different pharmacological treatments available).2,3,17 For hand osteoarthritis, the recent ACR guidelines recommend topical capsaicin, topical
NSAIDs, oral NSAIDs including cyclooxygenase (COX)-2 inhibitors, and tramadol.1 They also advise against the use of
opioids or intra-articular treatments for this condition. For knee
and hip osteoarthritis, acetaminophen, oral NSAIDs, topical
NSAIDs (except for hip osteoarthritis), tramadol, and intra-articular steroid injections are recommended.1
N Symptomatic treatments
N Oral analgesics
Acetaminophen remains the first-line therapeutic agent for
mild-to-moderate pain2,3,17 because of its low cost and its efficacy and safety profile for doses not exceeding 4 g per day
(although a maximum of 3 g is more advisable, in line with US
Food and Drug Administration recommendations). If found to
be successful at alleviating pain, it is recommended that acetaminophen be the preferred long-term oral analgesic.2 It has
been reported that acetaminophen is less effective at relieving osteoarthritis pain than NSAIDs19 but more effective than
placebo.20 However, this result was not confirmed by a study
using WOMAC and the Lequesne index to assess efficacy.20
The use of analgesics in osteoarthritis should take into account
the clinical context, however. Significant adverse effects have
been reported with acetaminophen, including gastric ulcerations and bleeding, increased risk of mild loss of renal function
with long-term consumption, and hypertension with doses of
up to 3 g per day.21-23 Furthermore, even at therapeutic dos-
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es, acetaminophen can cause asymptomatic elevation of liver
enzymes in healthy people.24 The implications of this remain
unclear, but it is recommended that acetaminophen should
not be used in patients with existing liver dysfunction or related risk factors. On the basis of the aforementioned information, it is recommended that the lowest effective dose of
acetaminophen be used for pain relief.
NSAIDs are generally recommended for patients who are unresponsive to appropriate dosages of acetaminophen. These
should be prescribed at the lowest dose and for the shortest
possible duration,17 and preferentially for inflammatory flares.
According to the new ACR guidelines,1 NSAIDs should be
used for the initial management of hand, hip, and knee osteoarthritis, as with acetaminophen and tramadol. Moreover,
for patients aged over 75 years, rather than prescribing oral
NSAIDs, guidelines recommend the use of topical NSAIDs,
duloxetine, tramadol, or intra-articular hyaluronan injections.
In patients suffering from upper gastrointestinal ulcers without any gastrointestinal bleeding in the prior year, for cases
where the physician chooses to prescribe an NSAID, the ACR
and Osteoarthritis Research Society International (OARSI)
guidelines recommend the use of either a COX-2 inhibitor
rather than a nonselective NSAID, or a nonselective NSAID
combined with a proton-pump inhibitor.1,17 For patients with
reports of gastrointestinal bleeding within the past year, the
use of a COX-2 inhibitor in association with a proton-pump
inhibitor is recommended.1 Although NSAIDs are known to
be superior to acetaminophen for pain relief,19 their use is limited by a number of adverse effects, including gastrointestinal,
renal, and cardiovascular adverse effects, which increase with
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age.25-27 The risk level varies according to the drug and dosage.
COX-2 inhibitors were shown to be as effective as conventional NSAIDs for pain relief, with fewer gastrointestinal complications,28 but with a potential cardiovascular risk27—which is
also shared by conventional NSAIDs. Physicians should therefore take into account their patients’ comorbidities and assess their individual global risk before prescribing NSAIDs.
In recent years, opioids have become a widely prescribed
class of drugs, especially for osteoarthritic patients who either
have contraindications or an intolerance to NSAIDs or who
have failed to respond to both acetaminophen and NSAID
treatment.2,17 Opioids are recommended by the new ACR
guidelines for patients with symptomatic knee osteoarthritis
who have not had an adequate response to nonpharmacological or pharmacological modalities and are either unwilling
to undergo or are not candidates for total joint arthroplasty.1
However, opioids are not recommended for the management
of hand osteoarthritis–related pain.1 It is common to start with
a weak opioid such as codeine or tramadol, often in combination with acetaminophen, and if ineffective or not tolerated,
to use a stronger opioid like hydrocodone, oxycodone, morphine, or transdermal fentanyl. However, adverse events are
frequent and significant, and include sedation, constipation,
urinary retention, nausea and vomiting, respiratory depression,
and confusion. Impaired coordination and judgment can lead
to falls, particularly in older adults who are more susceptible
to opioid-related effects as a result of renal insufficiency and/or
lower lean body mass. In elderly people, opioids may cause
severe injuries from falls, such as hip fractures, or even death.
Fracture risk appears to be greater with opioids than with
NSAIDs in older people, and the risk increases with higher opioid dosage, especially during the first 2 weeks after initiating
short-term opioid therapy.29 Moreover, it seems that opioids
do not improve patient functioning30 or quality of life.
Patients with osteoarthritis have been shown to have higher
mortality than the general population, particularly because of
cardiovascular events. This appears to be strongly related to
walking disability and reduced physical activity.31 Thus, immobility resulting from osteoarthritis may shorten lifespan. One
may wonder if opioids, by reducing patient mobility, may reduce life expectancy by increasing cardiovascular risk. However, this relationship has not yet been established.31 The use
of opioids in a chronic and painful disease such as osteoarthritis is still controversial for many reasons. It is recommended
that opioid treatment be started at a low dose and gradually
adjusted upwards, taking into account renal function, age, and
other relevant risk factors. Long-term opioid use should be
avoided or at least regularly reevaluated.32 The benefits of using opioids should be weighed as judiciously as possible.
For the past few years, antidepressants have been used in
chronic pain management because of their reported analgesic
action, which is independent of their antidepressive effect. In
recent years, the chronic pain often observed in osteoarthritis
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has been shown to involve centrally-mediated pain pathway
dysfunction, which has led to the study of drugs that have a
centrally-mediated action. Duloxetine is a selective serotonin
and norepinephrine reuptake inhibitor with central nervous system activity that is already used in three chronic pain conditions: diabetic peripheral neuropathic pain, fibromyalgia, and
chronic low back pain. Recently, duloxetine was found to improve pain as well as function in knee osteoarthritis, as evaluated by clinically relevant outcomes in two 13-week trials.33
The drug’s effect is related to a direct analgesic effect, independent of improvement of depression and anxiety. The main
adverse events reported included nausea, constipation, and
hyperhidrosis. Duloxetine is recommended by the ACR guidelines as an alternative treatment for patients with symptomatic
knee osteoarthritis who have failed to respond to both pharmacological and nonpharmacological options.1 Controlled
trials to compare duloxetine with other interventions in osteoarthritis and to evaluate its efficacy in combination with
other therapies may be useful to potentially enhance treatment options.
N Topical treatments
Adjuvant topical therapies are interesting treatments that can
be used to decrease the consumption of analgesics. Topical
NSAIDs, such as diclofenac and ketoprofen, seem to be as
effective as oral NSAIDs34,35 but with a lower risk of systemic
exposure and gastrointestinal complications. Their principal
reported adverse effect is local skin reactions. They are recommended as alternative or adjuvant therapy,17 although ACR
guidelines recommend them for the initial management of knee
osteoarthritis and prefer them to oral NSAIDs for patients older than 75 years of age.1
Capsaicin, the active principle ingredient of hot chili peppers,
can cause depletion of substance P from sensory nerve endings and reduce or abolish the transmission of painful stimuli.
However, its effectiveness and safety in pain relief remains controversial.36 A burning sensation is the most common adverse
effect, particularly during the first week of application.36 It is
still unclear if long-term capsaicin treatment can cause persistent desensitization of the skin that may not be totally reversible. Capsaicin is recommended by guidelines for the
initial management of hand osteoarthritis, but not knee osteoarthritis.1,2
Lidocaine patches, which are approved for postherpetic neuralgia, have also been reported to reduce neuropathic pain associated with moderate to severe osteoarthritis of the knee,
without any reported treatment-related adverse effects.37
N Injectable therapies
Intra-articular injection of a long-acting corticosteroid is recommended for relief of pain from osteoarthritic flares, especially if accompanied by effusion and when NSAIDs are ineffec-
175
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tive.2,17 The ACR guidelines recommend intra-articular corticosteroid injections for the initial management of knee and hip
osteoarthritis.1 Short-term pain reduction in knee osteoarthritis occurs after 2 to 3 weeks, but has no significant effect on
function. The Cochrane Database of Systematic Reviews reported that after 4 weeks, there was no effect on pain, physical function, or stiffness.38 However, repeated injections of intra-articular corticosteroids every 3 months for 2 years showed
pain relief efficacy after 1 year but not after 2 years.38 The longterm safety of repeated intra-articular steroid injections in
symptomatic knee osteoarthritis has been demonstrated, with
improvement of osteoarthritis symptoms for up to 2 years.39
Comparisons between corticosteroids have revealed that triamcinolone hexacetonide is superior to beta-methasone.38
Viscosupplementation could have a significant benefit for knee
osteoarthritis, despite some reported local acute reactions
such as transient pain and swelling at the injection site.40 Viscosupplementation is recommended by guidelines for knee
osteoarthritis,2 and compared with intra-articular corticosteroids, it shows delayed but prolonged efficacy.40 The OARSI
guidelines consider that intra-articular hyaluronate injections
may be useful for the treatment of knee osteoarthritis and have
a beneficial symptomatic effect.17 Moreover, the ACR guidelines conditionally recommend viscosupplementation for patients who have had an inadequate response to initial therapy.1 By contrast, a single injection of hyaluronic acid in hip
osteoarthritis seems to be no more effective than placebo.41
More data are needed on the structural effect of viscosupplementation.
N Symptomatic slow-acting drugs for osteoarthritis
Disease-modifying agents that not only reduce joint pain but
also slow progression of the disease are of interest for alleviation of the manifestations of osteoarthritis over the long term.
For the past 10 years, chondroitin sulfate and glucosamine
sulfate have been widely prescribed and used by osteoarthritis patients for symptom relief. They are safe, and have possible structure-modifying effects.17 Glucosamine is a naturally
occurring amino monosaccharide, and chondroitin sulfate belongs to the group of glycosaminoglycans and is a major component of the articular cartilage.
In osteoarthritis clinical trials, the symptomatic effect size of
glucosamine varies and is considered controversial. However, the results of studies have greatly depended on the different products used, the study population, and study design and
quality.42-45 Formulations of glucosamine that result in lower
plasma concentrations and potential low bioavailability, as well
as study populations with a low baseline level of pain, may
have contributed to the controversy.45 Glucosamine sulfate
and chondroitin sulfate have been approved as drugs for the
treatment of osteoarthritis in Europe, but not in North America,
where they are regulated not as drugs but as nutraceuticals.
As a consequence, substantial variation in their content is pos-
176
sible.43 This explains why in the latest ACR guidelines, these
agents were not recommended for treatment of osteoarthritis.1
Glucosamine sulfate was found to be effective as an osteoarthritic pain relief treatment and for improvement of function.42 Recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)
system concluded that glucosamine sulfate demonstrated
pain reduction and improvement in physical function with very
low toxicity and with moderate-to-high–quality evidence.44 The
latest OARSI guidelines recommend the use of glucosamine
sulfate and chondroitin sulfate for osteoarthritis treatment, as
they demonstrated pain relief with a moderate to large effect
size (0.58 and 0.75, respectively).3 When a purified preparation
of glucosamine sulfate is used, it appears to be safe—in particular, with no induction of glucose intolerance in healthy adults.46
The protective effect of glucosamine sulfate on structural progression of knee osteoarthritis was reported in two studies exploring the radiological progression of knee osteoarthritis after daily administration of glucosamine sulfate for 3 years.47-51
Chondroitin sulfate has been shown to improve knee joint
swelling and delay radiographic progression in patients with
knee osteoarthritis evaluated by x-rays,51,52 and more recently a magnetic resonance imaging study reported that chondroitin decreases cartilage loss and the progression of bone
marrow lesions.53 A recent post-hoc analysis of an osteoarthritis clinical trial reported a trend favoring chondroitin sulfate
versus placebo for delayed occurrence of total knee replacement at 4 years.54 However, the structural effects of glucosamine and chondroitin sulfate remain under debate, and these
treatments are not registered as structure-modifying agents.
Diacerein, an inhibitor of interleukin-1β, is a slow-acting agent
with pain-relieving symptomatic effects in patients with knee
osteoarthritis,55 and which also reduces the progression of
hip osteoarthritis.56,57 Diacerein provides sustained pain relief
for several weeks after discontinuation, suggesting a long carry-over effect,55 and an analgesic-sparing effect. Moreover,
the effect of diacerein has been found to be additive to that
of NSAIDs. Interestingly, it does not inhibit cyclooxygenase
or prostaglandin E2. Loose stools and diarrhea are the most
frequent adverse events. It is safer for the upper gastrointestinal system than NSAIDs55 and has a good overall safety profile, and it is therefore an alternative option to NSAIDs for the
treatment of osteoarthritis.
Avocado soybean unsaponifiables (ASU) are fractions of unsaponifiable avocado and soybean oils. The symptomatic
efficacy of ASU has been assessed in patients with hip and
knee osteoarthritis.58 ASU seems to be effective at pain reduction and has shown some beneficial effects on clinical symptoms of knee and hip osteoarthritis, with a carry-over effect
that persists after treatment discontinuation.59 A recent study
reported that in hip osteoarthritis, a 3-year treatment with ASU
reduced the percentage of joint space width progressors, indicating a potential structure-modifying effect.60
OSTEOARTHRITIS:
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Nonpharmacological
treatment
Education
Exercises
Prevention of injuries
Weight loss
Orthotic devices
Surgery
Arthroscopic
lavage
Cartilage repair
Osteotomy
Arthroplasty
Pharmacological
treatment
Oral
Acetaminophen
NSAIDs and COX-2
inhibitors
SYSADOA
Duloxetine
Opioids
Topical
NSAIDs
Capsaicin
Lidocain patches
Intra-articular
Corticosteroids
Hyaluronic acid
Intra-articular
Corticosteroids,
hyaluronic acid
Oral
Acetaminophen, NSAIDs,
SYSADOA, opioids, duloxetine
Topical
NSAIDs, capsaicin, lidocaine patches
Surgical treatment
Initial treatment of osteoarthritis should be conservative. However, when pain and loss of function persist after the use of
appropriate nonpharmacological and pharmacological treatments, surgery should be considered to reduce disease morbidity. Surgical options for knee osteoarthritis are arthroscopy,
including lavage and debridement (the efficacy of which is
controversial), cartilage repair surgery (bone marrow stimulating techniques, transplantation of osteochondral grafts), osteotomy with axis correction, and arthroplasty (unicondylar knee
Treatment type
Nonpharmacological
Education, exercise, prevention of injuries,
weight loss, orthotic devices
Figure 2. Multimodal management of osteoarthritis: initiate with nonpharmacological approaches (blue), follow with pharmacological
treatments (pink), and if ineffective, culminate in surgery (green).
Abbreviations: NSAID, nonsteroidal anti-inflammatory drug;
SYSADOA, symptomatic slow-acting drugs for osteoarthritis.
Component
Education; exercise; injury prevention; weight loss; orthotic devices
Acetaminophen
NSAIDs and COX-2 inhibitors
Oral
Opioids
Duloxetine
Symptomatic
drugs
Topical NSAIDs
Topical
Capsaicin
Lidocaine patches
Injectable
Slow-acting
symptomatic
drugs
Surgical
CARTILAGE
Surgery
Abbreviations: COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory
drug; SYSADOA, symptomatic slow-acting drugs for osteoarthritis.
Pharmacological
AND
arthroplasty [UKA] and total joint replacement).61 Arthroscopy
is a minimally invasive surgical technique used for chondral
surface debridement, lavage of joints, removal of torn meniscal fragments, and repair of menisci and cruciate ligament injuries. It remains controversial because it usually provides a
short-term benefit and does not seem to delay progression
to joint replacement.62 Arthroscopy should be of interest for
selected patients such as those with symptomatic meniscal
Figure 1. Multimodal management of osteoarthritis.
Nonpharmacological
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Intra-articular hyaluronic acid or
viscosupplementation
Glucosamine and chondroitin sulfate
Oral
Diacerein
Avocado soybean unsaponifiables
Arthroscopic lavage and debridement; cartilage repair; osteotomy with axis
correction; arthroplasty (UKA, TKR, THR)
Table II.
Multimodal
approach to
osteoarthritis
management
involving
nonpharmacological,
pharmacological, and
surgical
treatment
options.
Abbreviations:
COX, cyclooxygenase; NSAID,
nonsteroidal
anti-inflammatory drug; THR,
total hip replacement; TKR, total
knee replacement; UKA, unicondylar knee
arthroplasty.
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Treatment type
Nonpharmacological
Intervention
Education
Exercise
Strengthening for knee
Aerobic for knee
Exercises for hip
In water for hip and knee
Prevention of injuries
Weight loss
Orthotic devices
Oral
OARSI effect size*
(95% CI)
0.06 (0.03, 0.10)
0.32
0.52
0.38
0.19
(0.23,
(0.34,
(0.08,
(0.04,
0.42)
0.70)
0.68)
0.35)
0.20 (0.00, 0.39)
Acetaminophen
0.14 (0.05, 0.22)
NSAIDs and COX-2 inhibitors
0.29 (0.22, 0.35)
Opioids
0.78 (0.59, 0.98)
Duloxetine
Topical NSAIDs
Pharmacological
Symptomatic
drugs
Topical
0.44 (0.27, 0.62)
Capsaicin
Lidocaine patches
Injectable
Symptomatic
slow-acting
osteoarthritis
drugs
Surgical
0.58 (0.34, 0.75)
Intra-articular hyaluronic acid or
viscosupplementation
0.60 (0.37, 0.83)
Glucosamine sulfate
0.58 (0.30, 0.87)
Glucosamine hydrochloride
Oral
–0.02 (–0.15, 0.11)
Chondroitin sulfate
0.75 (0.50, 1.01)
Diacerein
0.24 (0.08, 0.39)
Avocado soybean unsaponifiables
0.38 (0.01, 0.76)
Arthroscopic lavage and debridement
Osteotomy with axis correction
Arthroplasty (UKA, TKR, THR)
0.21 (–0.12, 0.54)
*An effect size of 0.2 is considered small, while 0.5 is considered moderate, and >0.8 is considered large.
Table III. Multimodal management of osteoarthritis and effect size of the different components of the 2010 guidelines from Osteoarthritis
Research Society International (OARSI).
Abbreviations: CI, confidence interval; COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; THR, total hip replacement; TKR, total knee replacement;
UKA, unicondylar knee arthroplasty.
Based on data from reference 3: Zhang et al. Osteoarthritis Cartilage. 2010;18:476-499. © 2010, Osteoarthritis Research Society International.
tears, in whom it can be used to remove the degenerative
fragments and alleviate mechanical symptoms. Bone marrow stimulation through the use of a microfracture technique
induces subchondral injury and bleeding that may promote
chondrogenesis by mesenchymal stem cells in the defective
area. Its efficacy is uncertain, however, because of variability
in the volume of cartilage repair that has been achieved, as
well as possible functional deterioration.62
Patients with unicompartmental osteoarthritis of the knee can
be treated with a correction osteotomy17 or unicondylar or total knee arthroplasty (TKA). Osteotomy can be considered
178
when knee osteoarthritis is associated with valgus or varus
deformation. It transfers load-bearing from the pathological
compartment of the knee to the normal compartment in order to reduce pain and delay joint replacement. Nevertheless,
its longevity is limited, and conversion to total knee replacement often occurs within the following few years. UKA seems
to be as safe and effective for pain relief and functional improvement as TKA, as well as high tibial osteotomy in patients
with unicompartmental knee osteoarthritis.63 Long-term survival rates with UKA are variable but are reported to be around
90% at 10 years, which is less than for TKA (up to 98% at 15
years), except in younger patients.61 TKA remains a success-
OSTEOARTHRITIS:
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BETWEEN
ful treatment for end-stage symptomatic knee osteoarthritis,
especially in elderly patients. The main complications are persistent postoperative pain (especially in the femoropatellar
compartment), infections, and stiffness of the knee. In order
to improve outcomes with TKA, computer-assisted navigation and minimally invasive techniques are being developed.
The choice of surgical treatment may be based on level of pain
and physical function, disease stage, patient age, and comorbidities. No specific cut-off point defining the requirement for
joint replacement currently exists.64 However, the aim of a
surgical intervention for osteoarthritis such as joint replacement should be to restore patient mobility and give the patient enough capacity to perform the level of activity required
to help prevent cardiovascular diseases.
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Conclusion
Clinicians managing osteoarthritis are able to draw upon a
wide spectrum of therapeutic options, combining nonpharmacological approaches and pharmacological treatments
both to relieve pain and to attempt to delay disease progression (Figures 1 and 2; Table II, page 177), as recommended
by the OARSI (Table III) and ACR guidelines. The trade-off between benefits and adverse effects should always be considered when choosing an appropriate treatment from among
the available agents. The current therapeutic options, however, are neither exclusive nor sufficient. Thus, the focus is
moving toward developing disease-modifying osteoarthritis
drugs that can be taken in association with conventional
therapeutic strategies to provide more effective treatment of
osteoarthritis. I
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outcome: predictors derived from a 4-year observation following a randomized
clinical trial using chondroitin sulfate. Submitted.
55. Pelletier JP, Yaron M, Haraoui B, et al. Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study
Group. Arthritis Rheum. 2000;43:2339-2348.
56. Dougados M, Nguyen M, Berdah L, Mazieres B, Vignon E, Lequesne M. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539-2547.
57. Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies
with diacerein in the treatment of osteoarthritis. Arch Intern Med. 2006;166:18991906.
58. Christensen R, Bartels EM, Astrup A, Bliddal H. Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2008;16:399-408.
59. Maheu E, Mazieres B, Valat JP, et al. Symptomatic efficacy of avocado/soybean
unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with
a six-month treatment period and a two-month follow-up demonstrating a persistent effect. Arthritis Rheum. 1998;41:81-91.
60. Maheu E, Cadet C, Marty M, et al. Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: the ERADIAS study. Ann Rheum Dis. 2013 Jan 23. Epub ahead of print.
61. Ronn K, Reischl N, Gautier E, Jacobi M. Current surgical treatment of knee osteoarthritis. Arthritis. 2011;2011:454873.
62. Choong PF, Dowsey MM. Update in surgery for osteoarthritis of the knee. Int
J Rheum Dis. 2011;14:167-174.
63. Griffin T, Rowden N, Morgan D, Atkinson R, Woodruff P, Maddern G. Unicompartmental knee arthroplasty for the treatment of unicompartmental osteoarthritis: a systematic study. ANZ J Surg. 2007;77:214-221.
64. Gossec L, Paternotte S, Bingham CO 3rd, et al. OARSI/OMERACT initiative to
define states of severity and indication for joint replacement in hip and knee
osteoarthritis. An OMERACT 10 Special Interest Group. J Rheumatol. 2011;38:
1765-1769.
Keywords: analgesic; chondroitin sulfate; exercise; glucosamine sulfate; guideline; intra-articular; osteoarthritis; weight loss;
surgery
TRAITEMENTS
DE L’ARTHROSE
:
OÙ EN SOMMES - NOUS ACTUELLEMENT
?
L’arthrose, la forme la plus courante des pathologies articulaires, entraîne douleur et diminution de la qualité de vie.
Actuellement, pour cette maladie, plusieurs médicaments symptomatiques sont commercialisés. Cependant, il n’existe
à ce jour aucun traitement prévenant la détérioration articulaire. Dans cet article seront décrits les traitements non pharmacologiques et pharmacologiques disponibles dans la prise en charge de l’arthrose, ainsi que les traitements chirurgicaux possibles. Les recommandations actuelles de l’Osteoarthritis Research Society International et de l’American
College of Rheumatology suggèrent une approche multidimensionnelle, associant des traitements non pharmacologiques et pharmacologiques. La prise en charge non pharmacologique de l’arthrose repose essentiellement sur
l’éducation du patient, l’exercice physique, la prévention des blessures, la perte de poids lorsqu’elle est nécessaire
et l’utilisation d’orthèses. Les traitements pharmacologiques axés sur la réduction des symptômes comprennent les
analgésiques tels que l’acétaminophène, les anti-inflammatoires non stéroïdiens (AINS), les opioïdes, la duloxétine,
les AINS locaux, la capsaïcine, les patchs de lidocaïne, les injections intra-articulaires de corticoïdes et d’acide hyaluronique, et les médicaments d’action lente comme la glucosamine et la chondroïtine sulfate, la diacerhéine et les
insaponifiables d’avocat et de soja. Le traitement chirurgical est envisagé lorsque les approches non pharmacologiques et pharmacologiques visant à réduire les symptômes ont échoué.
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Rates of total knee replacement (TKR) are increasing worldwide, and in 2010, more than
600 000 procedures were carried
out in the US alone, with rates
tripling over the last decade in
those aged between 45 and 64.
At over $20 000 per procedure, the
annual cost of TKR in the US now
exceeds $13 billion… The reasons
for this increase are most certainly
multifactorial. Population growth,
the increasing number of elderly
people, and the increase in average body mass index (BMI) are, no
doubt, important factors.”
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Knee replacement
for osteoarthritis: facts,
hopes, and fears
b y L . S . Lo h m a n d e r,
Sweden and Denmark
O
L. Stefan LOHMANDER, MD, PhD
Department of Orthopedics
Clinical Sciences Lund
Lund University, SWEDEN
Research Unit for Musculoskeletal
Function and Physiotherapy
and Traumatology
University of Southern Denmark
DENMARK
steoarthritis (OA) affects hundreds of millions of people worldwide and
is responsible for a huge burden of pain, functional limitations, and
loss of quality-adjusted life expectancy. OA of the knee accounts for
more than 90% of total knee replacements (TKR). By 2030, the incidence of
TKR in the US is expected to increase by more than 6-fold. Pain and difficulty
walking limiting participation in daily activities are the primary reasons for undergoing TKR. However, among patients with disabling OA, only a minority are
willing to consider TKR. Reduced willingness to undergo TKR is associated
with increasing age, being black (in the US), overestimation of the pain and
disability needed to warrant TKR, and rejection of the medicalization of OA.
The perception of the benefits of TKR is less positive among women and those
of lower socioeconomic status. TKR is one of the most cost-effective medical
interventions. Data from joint registries show that the 10-year reoperation rate
for TKR is less than 5%. However, between 10% and 30% of patients undergoing TKR report little or no improvement following surgery, or are not satisfied. Patients’ expectations of joint replacement are relief of pain and improved
mobility. Following TKR, the expectations regarding pain relief, walking ability, and the ability to perform daily activities are fulfilled to a greater extent
than the expectations of being able to perform more physically demanding activities. To ensure optimal patient satisfaction, health professionals should
provide sufficient information so that patients have realistic expectations of
the results of TKR.
steoarthritis (OA) affects hundreds of millions of people worldwide and accounts for a huge burden of pain, functional limitations, loss of productivity, disability, and loss of quality-adjusted life expectancy.1,2 Any estimate of
the burden of OA is strongly dependent on the criteria used, and the population
and age group studied. The most recent estimates of the World Health Organization
(WHO) Global Burden of Disease Study 2010 reported that OA of the knee and hip
is now ranked as the 11th leading cause of years lived with disability (YLD [prevalence of a condition multiplied by the disability weight associated with that condition]),
up from the 15th position in 1990. There was an estimated 64% increase in the global burden of OA-related YLD between the years 1990 and 2010. OA of the knee is
responsible for four-fifths of the OA-related YLDs of the lower extremities. In the US,
it is estimated that the direct and indirect costs of OA exceed US $100 billion per
year.3-5 Excess mortality is observed in patients with OA and this is related to increas-
O
Professor L. Stefan Lohmander,
Department of Orthopedics, Lund
University Hospital, 221 85 Lund,
Sweden
Knee replacement for osteoarthritis: facts, hopes, and fears – Lohmander
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ing functional impairment in those patients.6 OA most commonly affects the knees, hips, and hands, but may affect other joints as well, such as the shoulders, elbows, ankles, feet,
and spine. The prevalence rises steeply between the ages of
50 and 60 for both women and men, so that the majority of
patients with symptomatic OA are aged between 60 and 80
years. However, OA also occurs in younger and middle-aged
patients. In fact, effective treatment of OA represents a particularly difficult challenge in patients aged between 30 and 60
years.
Few
Surgery
Some
Drugs,
walking aids
All
OA of the knee represents a major share of the OA disease
burden, and OA is by far the most common reason for total
knee replacement (TKR), usually accounting for more than
90% of knee replacement procedures. The incidence of TKR
for OA is rising steeply, and should continue to rise dramatically, with a more than 6-fold increase expected by 2030 in
the US.7 The following discussion will focus on knee replacements for OA, but will also, where appropriate, use evidence
gathered from the study of hip replacement for OA.
Risk factors for knee OA
OA of the knee shares the same general risk factors as OA
of the other joints in that each patient and each joint carries
its own mix of genetic and environmental factors responsible
for the development of OA. For the knee, individual genetic
variability is thought to account for about 40% of the risk, with
environmental factors accounting for the remaining 60%. Genetic variability may, for example, be expressed as individual
differences in the quality of the cartilage matrix, reactivity of
inflammation pathways, growth and repair pathways, and joint
shape. Environmental risks are mostly biomechanical, affecting the dynamic loading of the joints and increasing stress on
joint tissues. This in turn will result in the activation of inflammation and tissue degradation. Leading examples of such environmental “joint stressors” are overweight and obesity, joint
injury, and occupational overload. Genetically determined variations in joint shape may also influence the risk of OA by increasing joint stress.
Information, exercise,
weight loss, self-management
Figure 1. A stepwise approach to the management of osteoarthritic
patients.
justed years of life lost, and almost 1 million hospital admissions per year.2,9,10 Although knee OA is usually perceived as
a disease of the elderly, the mean age at diagnosis is actually
56 years.11 The prevalence of knee OA is rising due to the aging of the population and increasing rates of joint injury and,
most importantly, obesity.
Management options for knee OA
A wide range of treatments are used for knee OA, including
nonpharmacological, pharmacological, and surgical approaches.12-14 OA management strategies are determined by disease
severity, patient preferences, local resources, and established
treatment modalities.
A stepwise approach to the management of osteoarthritis is
widely recommended, starting with patient empowerment and
self-management, and, if these simple approaches are unsuccessful, the addition of specific medical or surgical interventions (Figure 1). With the exception of knee replacement,
the effect size for most therapeutic interventions in knee OA
is only small to moderate.
Epidemiology of knee OA
As already stated, the disease burden of OA is enormous. It
is the most common form of progressive joint disease, and
affects 50 million adults in the US and Europe,1,8 with OA of
the knee representing a major share of this burden. In the
US, knee OA accounts for more than 10 million quality-adSELECTED
BMI
NSAID
OA
TKR
YLD
182
body mass index
osteoarthritis
total knee replacement
year lived with disability
Basic management of osteoarthritis includes education, exercise, and weight loss (for overweight people), which can be
complemented as needed by simple analgesics, and, for hand
and knee joints, topical nonsteroidal anti-inflammatory drugs
(NSAIDs). Additional studies are needed to tailor the different
programs to different patients. Common sense suggests that
a combination of treatments benefits most patients.
Oral NSAIDs and paracetamol (acetaminophen) are often used
by patients with OA. However, gastrointestinal, renal, and cardiovascular side effects are of particular concern with NSAIDs,
since many patients with OA are elderly and have comorbidities, and thus are at increased risk of some or all of these side
effects. These concerns add complexity to the task of pre-
OSTEOARTHRITIS:
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scribing pain relievers for patients with OA. The utility of opioids for OA is limited by their side effects. Corticosteroid injections are frequently used, but their benefit is short-lived (1
to 4 weeks). In addition to these treatments, patients with knee
OA use a wide range of alternative therapies.
The surgical management of knee OA commonly includes
arthroscopic surgery of the knee upon suspicion of a meniscus tear or cartilage derangement amenable to surgical treat-
14 000
12 000
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Practice variations in the use of knee replacement
and future projections for TKR use
Joint replacement for OA of the knee may be the only intervention with a large effect size, but it is only appropriate for
patients with advanced disease or substantial symptoms that
do not respond to other treatments. This group is but a minority of all those with knee OA, but still represents a very substantial number of patients. Rates of TKR are increasing worldwide, and in 2010, more than 600 000 procedures were carried
A
180
160
OA
RA
Posttraumatic
B
Females
Males
140
Yearly incidence of knee
arthroplasty/100 000
10 000
Number
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8000
6000
4000
120
100
80
60
40
2000
0
1975
20
1980
1985
1990
1995
2000
2005
2010
Year of operation
0
1975
1980
1985
1990
1995
2000
2005
2010
Year of operation
Figure 2. (A) Annual number of knee replacements in Sweden for osteoarthritis (OA), rheumatoid arthritis (RA), and posttraumatic osteoarthritis between the years 1975 and 2010. (B) Annual incidence of knee replacements (all replacements) for men and women.
Reproduced with permission from reference 24: Annual report 2011. www.knee.nko.se. © 2011, Swedish Knee Arthroplasty Register.
ment. However, high-quality trials comparing arthroscopic surgical debridement (including meniscus resection) with sham
surgery, medical care as usual, or exercise programs found no
difference between the groups compared,15-18 thereby showing that arthroscopic surgery is of no added benefit for these
patients. Over the age of 35, meniscus lesions are often part
of the early stages of the osteoarthritic process, and the diagnosis of a meniscus tear by magnetic resonance imaging
(MRI) of the osteoarthritic knee does not correlate with the
presence of symptoms.19
Valgus osteotomy of the tibia can provide long-lasting pain
relief and functional improvement in physically active patients of less than 60 years of age in whom OA is mainly limited to the medial knee compartment. If and when needed,
the osteotomy can later be converted to a knee replacement.
In a large national Swedish series of about 3000 patients who
had undergone tibial osteotomy for knee OA at a mean age of
52 years, the 10-year “conversion rate” to TKR was 30%.20
This suggests that osteotomy should remain a viable option for
patients in this group, thereby delaying or obviating the need
for knee replacement by more than 10 years in most cases.
out in the US alone, with rates tripling over the last decade in
those aged between 45 and 64.9,21 At over $20 000 per procedure, the annual cost of TKR in the US now exceeds $13
billion.5,22,23
National knee replacement registry data from the Scandinavian countries, UK, and Australia also confirm the continuous
and rapid increase in the incidence of knee replacement for
OA. For example, results from the Swedish Knee Arthroplasty Register show that the annual rate of primary TKR for OA in
Sweden doubled between 2000 and 2010 (Figure 2), while
the annual rate of TKR in those younger than 55 increased
5-fold.24,25 The dramatic increase seen in younger patients may
in part reflect a change in surgical practice from the use of osteotomy and unicompartmental knee replacement to TKR
in younger patients.25
The mean age for TKR has changed over time, and in Sweden it now shows a decreasing trend, being about 69 years
for both women and men (Figure 3, page 184).24 Reflecting
the current routine widespread use of TKR as a procedure to
treat severe knee OA, 1 in 14 elderly women in Sweden has
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72
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A
110
100
Females
Males
Females 2010
Males 2010
Females 2000
Males 2000
90
80
Prevalence /1000
70
Mean age
B
68
66
64
70
60
50
40
30
20
62
10
60
1975
0
1980
1985
1990
1995
2000
2005
2010
Year of operation
50
60
70
80
90
100+
Age
Figure 3. (A) Temporal shifts in the mean age at primary total knee replacement surgery for women and men in Sweden between 1975
and 2010. (B) Comparison of the 2000 and 2010 prevalence rates of knee replacement according to age for women and men in Sweden.
Reproduced with permission from reference 24: Annual report 2011. www.knee.nko.se. © 2011, Swedish Knee Arthroplasty Register.
now had a TKR.24 Similarly, nearly 1 in 20 Americans over 50
years of age have had knee replacement surgery, which represents more than 4 million people.9,21
tifactorial. Population growth, the increasing number of elderly people, and the increase in average body mass index (BMI)
are, no doubt, important factors.
Direct comparisons of the rates of TKR for OA between different countries are hindered by the limited availability of highquality specific data for OA procedures, as well as by differences in population structure. The 2007-2009 estimated rates
of primary TKR for all diagnoses per 100 000 people varied
between 9 for Romania and 213 for the USA.26 Even between
countries with seemingly similar socioeconomic conditions,
national health care systems, and population structures, the
TKR rates per 100 000 varied greatly, ranging from 188 for
Germany, 178 for Finland, 112 for Sweden, to 98 for France.26
The reasons for these wide variations in usage are not clear,
but are likely to be due to differences on both the “supply side”
(health care services) and the “demand side” (patients).
The increase in the age-standardized prevalence of knee OA
(for which there is limited evidence) may be driven by the
now global epidemic of overweight and obesity (for which
there is strong evidence), and by an increase in joint injury
rates. These two “environmental” risk factors may together
be responsible for up to 50% of knee OA cases in some societies.21 The importance of overweight and obesity in the risk
of severe knee OA leading to TKR was investigated in a prospective population-based cohort study (Figure 4); a mean BMI
of 30 was associated with an 8-fold increase in TKR risk when
compared with a “normal” BMI of about 22.28 Even an increase
in BMI from 21-22 to 24-25 (ie, within a BMI range that is considered normal) was associated with a 3-fold risk increase in
the rate of TKR for OA. In fact, in this large population-based
study, very few TKR procedures were carried out on patients
in the lowest BMI quartile (Figure 4). In the US, the major impact of obesity on the risk of knee OA and TKR can also be
illustrated by estimating the number of TKRs averted by “reversing” the prevalence of obesity to the levels of 10 years ago.
This would correspond to a mean BMI reduction of 0.6 or a
reduction in body weight of less than 2 kg for a person of average height. This means that more than 100 000 TKRs would
be averted over the remaining life span of this population.2
Time-related trends in TKR use
The projections for future TKR rates have regularly been outdone by reality. In the US, the demand for primary TKR was,
in 2005, expected to grow by more than 600%, to reach 3.48
million procedures by 2030.27 The growth of total knee revision surgeries was projected to be proportional, with the demand for revision procedures expected to double between
2005 and 2015. If these predictions hold true, both health
care infrastructures and the training of orthopedic surgeons
will need to expand accordingly. The dramatic increase in TKR
rates inevitably leads to questions about financial feasibility in
the future: who will pay? So what are the possible reasons
for the steeply increasing demand for TKR seen over the last
decade? The reasons for this increase are most certainly mul-
184
Population growth, aging, and an increase in BMI all seem
to result in an increase in the demand for TKR, even if these
factors do not fully explain the recent steep increase in demand.21 However, increased availability on the “supply side”
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among women than men, and among those of lower socioeconomic status.36 Although blacks suffer from more severe
OA than whites in the US, they are less likely to consider surgery as a solution to their problem, and this is associated
with less positive beliefs about the benefits of surgical procedures.37 A person’s knowledge and beliefs regarding TKR
appears to be largely shaped by his or her interactions with
family and friends. The differences summarized here may at
least in part explain the inequities observed in joint disease
care.38,39
1.00
0.99
Fraction of the study population
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0.97
0.96
0.95
0.94
0
2
4
6
8
10
12
14
Years of follow-up
Figure 4. Kaplan-Meier survival analysis of population fraction
without total knee replacement (TKR) or osteotomy for knee osteoarthritis.
The graph shows the fraction of the population studied who did not undergo
TKR or osteotomy for knee osteoarthritis. Individual survival plots show body
mass index (BMI) quartiles (population, n=11026 [men] + 16934 [women]), with
a statistically significant difference between each of the four survival curves.
Each BMI quartile consisted of 2756 men and 4233 women on average. The
median BMI values of the population quartiles were 22.5/21.1 (men/women)
(green), 25.0/23.6 (gray), 27.0/26.0 (blue), and 30.1/30.1 (red), respectively, for
BMI quartiles 1 to 4.
Modified from reference 28 with permission: Lohmander et al. Ann Rheum
Dis. 2009;68:490-496. © 2008, BMJ Publishing Group Ltd & European League
Against Rheumatism.
is a further important and possible reason for the increase
in the incidence of TKR surgery, as total joint replacements
have changed from the early days of being “boutique” procedures to now being a generally available “commodity” in many
settings.29,30
What determines patient demand for TKR?
Pain and difficulty walking limiting mobility and participation
in normal daily activities are the primary reasons for undergoing TKR for OA. However, several studies have indicated that
among patients with a marked need for joint replacement, ie,
those with disabling OA, only a minority (around one-third)
were willing to consider joint replacement as a treatment option.31-33 Patients’ willingness to undergo total joint replacement is, therefore, a critical predictor in determining the demand for this procedure.34,35
Reduced willingness to consider joint replacement was shown
to be associated with increasing age, being black rather than
white (in the US), overestimation of the levels of pain and disability needed to warrant joint replacement, and rejection of
the medicalization of OA—ie, considering OA as a natural
and inevitable part of aging.34,35 The perception of the benefits of joint replacement for OA was shown to be less positive
Given the low proportion of patients with OA in whom TKR is
indicated who are actually willing to undergo the procedure,
changes in willingness to undergo TKR seem to be an important contributing factor in driving the recent increase in the
incidence of TKR, and also in driving a future increase in the
demand for TKR. Increased expectations regarding the maintenance of an active lifestyle into older age may influence willingness, as may direct-to-consumer advertising, which is now
common in many countries. Studies investigating temporal
changes and changes in willingness to undergo TKR in different settings would be of considerable interest.
Indications for TKR as perceived by health
professionals and patients
Several attempts have been made to develop consensus criteria for TKR indications. As in all such efforts, the composition of the group and the method used to form the consensus
determine the result. Well-known examples of such criteria are
those developed in New Zealand and Canada.40,41 Components of these scores include pain, functional impairment,
problems in care giving, and radiographic severity. However,
attempts to determine cut-off points leading to an “appropriate” indication for TKR by correlating preoperative patientreported symptoms with recommendations for placement on
a TKR waiting list have not been successful.42 This suggests
that these more easily measured components explain only a
minor proportion of the decisions to place patients on waiting
lists for surgery.
Most TKR criteria have been dominated by the views of health
professionals, often orthopedic surgeons. The views of patients on the appropriateness of TKR have been explored to
some extent, and suggest that they do not always agree with
the views of health professionals. The concept of the “capacity to benefit” from TKR suggests that the benefits should outweigh any likely risks or unintended consequences by a considerable margin for TKR to be indicated.43,44
Effectiveness of knee replacement: what
determines outcome and patient satisfaction
after TKR for OA?
It has been said that total joint replacement “doesn’t bring
years to life, but brings life to years.” This is true in the sense
that patient-reported outcomes of joint replacement are on
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average “good to excellent,” and it is particularly pertinent in
comparison with most nonsurgical treatments for severe OA.
The Scandinavian national joint registries have for many years
reported on the continuous improvement of outcomes over
time as a result of improved surgical, anesthesiological, and
care procedures and materials.45 In Sweden, the 10-year revision (reoperation) rate is now estimated to be less than 5%
for patients operated with TKR for OA at the beginning of this
century.24 This means that for more than 95 out of 100 patients
undergoing TKR for OA, the patient will be survived by the implant. Reoperation rates from other countries have generally been somewhat higher, perhaps because of the choice of
implants, surgical techniques, and other factors.26 However, it
is well-known that the risk of reoperation is considerably higher for younger patients operated with TKR, than for older patients.24 Higher revision rates for younger patients operated
with TKR are expected in light of the changing demographics of TKR surgery, with rapidly increasing numbers of younger
patients undergoing joint replacement.46 The Swedish national registry reports no difference in revision rates between men
and women operated with TKR for OA in the 2000s.24
When considering these excellent results, it should be noted
that they represent reoperation rates, not patient-reported outcomes. In fact, between 10% and 30% of patients undergoing joint replacement report little or no improvement following surgery, or are not satisfied with the outcome.47-50
Factors associated with a less than optimal patient-reported
outcome of TKR at 6 months include worse preoperative
pain and function, increased anxiety/depression, and living
in poorer areas.51 Multiple joint involvement negatively influences the outcome after TKR,52 while severe obesity results
in slower recovery after surgery, but with no difference at 3
years.53 It should be noted that the determinants of pain or
function following TKR may not be the same in all studies.51,54
The most important expectations of patients undergoing joint
replacement surgery are pain relief and improved mobility. It
appears that at 5 years following TKR, patients’ expectations
of pain relief, walking ability, and ability to perform the activities of daily living are fulfilled to a greater extent than their expectations of being able to perform more physically demanding activities.50 For example, 41% of patients expected to be
able to perform activities such as golfing and dancing following TKR, while only 14% were in fact able to perform these
activities 5 years after undergoing TKR. To ensure optimal patient satisfaction, it is important that health care professionals provide adequate information before surgery so that patients have realistic expectations of the results of TKR.
Conclusion
The expectations, results, and patient satisfaction with TKR
surgery for OA summarized above reflect the current “case
mix” of patients with regard to disease severity, expectations
of outcome, age, and active life expectancy. TKR stands out
as one of the most effective and cost-effective medical interventions. However, whether this outstanding record will be upheld or not given the changing demographics of patients undergoing this type of procedure, with those aged between 45
and 64 years being the most rapidly increasing group, remains
to be seen. Innovations and new implant designs have at times
been introduced before evidence of their efficacy and safety
could be established. Improved regulatory and clinical processes for the introduction of new devices are badly needed.
Another pressing question is that of health economics. The
projected dramatic increase in TKR use, if it becomes a reality, will demand increased orthopedic and hospital resources,
among others, and this will result in sharply increased costs
for patients and society. I
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6. Nüesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Jüni P. All cause and
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11. Burbine SA, Weinstein AM, Reichmann WM, et al. Projecting the future public
health impact of the trend toward earlier onset of knee osteoarthritis in the past
20 years. Oral presentation at: American College of Rheumatology Annual Scientific Meeting; November 5-9, 2011. Chicago, IL. Abstract 2510.
12. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert
consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-162.
13. Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following
systematic cumulative update of research published through January 2009.
therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;
64:465-474.
15. Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic
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surgery for osteoarthritis of the knee. N Engl J Med. 2002;347:81-88.
16. Kirkley A, Birmingham TB, Litchfield RB, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2008;359:1097-1107.
17. Herrlin S, Hållander M, Wange P, Weidenhielm L, Werner S. Arthroscopic or conservative treatment of degenerative medial meniscal tears: a prospective randomised trial. Knee Surg Sports Traumatol Arthrosc. 2007;15:393-401.
18. Herrlin SV, Wange PO, Lapidus G, Hållander M, Werner S, Weidenhielm L. Is
arthroscopic surgery beneficial in treating non-traumatic, degenerative medial
meniscal tears? A five year follow-up. Knee Surg Sports Traumatol Arthrosc.
2013;21:358-364.
19. Englund M, Guermazi A, Gale D, et al. Incidental Meniscal Findings on Knee
MRI in Middle-Aged and Elderly Persons. N Engl J Med. 2008;359:1108-1115.
20. W-Dahl A, Robertsson O, Lohmander LS. High tibial osteotomy in Sweden
1998-2007. A population-based study of the use and rate of revision to knee
arthroplasty. Acta Orthop. 2012;83:244-248.
21. Losina E, Thornhill TS, Rome BN, Wright J, Katz JN. The dramatic increase in
total knee replacement utilization rates in the United States cannot be fully explained by growth in population size and the obesity epidemic. J Bone Joint
Surg Am. 2012;94:201-207.
22. Medicare Fee Schedules. Centers for Medicare & Medicaid Services; 2010.
http://www.cms.gov/home/medicare.asp. Accessed October 22, 2012.
23. Medicare Hospital Inpatient Prospective Payment System. Centers for Medicare
& Medicaid Services; 2010. http://www.cms.gov/MedicareFeeforSvcPartsAB/
03_MEDPAR.asp. Accessed October 22, 2012.
24. Swedish Knee Arthroplasty Register. Annual report 2011. http://www.knee.
nko.se/english/online/thePages/publication.php. Accessed October 22, 2012.
25. W-Dahl A, Robertsson O, Lidgren L. Surgery for knee osteoarthritis in younger
patients. A Swedish Register Study. Acta Orthopaedica. 2010; 81:161-164.
26. Kurtz SM, Ong KL, Lau E, et al. International survey of primary and revision total knee replacement. Int Orthop. 2011;35:1783-1789.
27. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision
hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint
Surg Am. 2007;89:780-785.
28. Lohmander LS, Gerhardsson M, Rollof J, Nilsson PM, Engström G. Incidence
of severe knee and hip osteoarthritis in relation to different measures of body
mass. A population-based prospective cohort study. Ann Rheum Dis. 2009;
68:490-496.
29. Katz JN, Martin TL. Clinical Pathways and the commodification of total joint
replacement. Osteoarthritis Cartilage. 2012;20:1057-1058.
30. Gooch K, Marshall DA, Faris PD, et al. Comparative effectiveness of alternative
clinical pathways for primary hip and knee joint replacement patients: a pragmatic, randomized, controlled trial. Osteoarthritis Cartilage. 2012;20:10861094.
31. Frankel S, Eachus J, Pearson N, et al. Population requirement for primary hipreplacement surgery: a cross-sectional study. Lancet. 1999;353:1304-1309.
32. Hawker GA, Wright JG, Coyte PC, Williams JI, Harvey B, Glazier R, Wilkins A,
Badley EM. Determining the need for hip and knee arthroplasty: the role of clinical severity and patients’ preferences. Medical Care. 2001;39:206-216.
33. Hawker GA, Wright JG, Badley EM, Coyte PC, for the Toronto arthroplasty
health services research consortium. Perceptions of, and willingness to consider, total joint arthroplasty in a population-based cohort of individuals with
disabling hip and knee osteoarthritis. Arthritis Care Res. 2004;51:635-641.
34. Hawker GA, Guan J, Croxford R, Coyte PC, Glazier RH, Harvey BJ, Wright JG,
Williams JI, Badley EM. A prospective population-based study of the predictors
of undergoing total joint arthroplasty. Arthritis Rheum. 2006;54:3212-3220.
35. Frankel L, Sanmartin C, Conner-Spady B, et al. Osteoarthritis patients’ percep-
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tions of “appropriateness” for total joint replacement surgery. Osteoarthritis Cartilage. 2012;20:967-973.
36. Ibrahim SA, Siminoff LA, Burant CJ, Kwoh CK. Differences in expectations of
outcome mediate African American/white patient differences in ‘willingness’ to
consider joint replacement. Arthritis Rheum. 2002;46:2429-2435.
37. Suarez-Almazor ME, Souchek J, Kelly PA, O'Malley K, Byrne M, Richardson M,
Pak C. Ethnic variation in knee replacement: patient preferences or uninformed
disparity? Arch Intern Med. 2005;165:1117-1124.
38. Jüni P, Lowy N, Reichenbach S, Villiger PM, Williams S, Dieppe PA. Gender inequity in the provision of care for hip disease: population-based cross-sectional study. Osteoarthritis Cartilage. 2010;18:640-645.
39. Mujica-Mota RE, Tarricone R, Ciani O, Bridges JFP, Drummond M. Determinants for total hip and knee arthroplasty: a systematic literature review. BMC
Health Services Res. 2012;12:225.
40. Hadorn DC, Holmes AC. The New Zealand priority criteria project. Part 1: Overview. BMJ. 1997;314:131-134.
41. Naylor CD, Williams JI. Primary hip and knee replacement surgery: Ontario criteria for case selection and surgical priority. Qual Health Care. 1996;5:20-30.
42. Gossec L, Paternotte S, Maillefert JF, et al; OARSI-OMERACT task force total
“articular replacement as outcome measure in OA”. The role of pain and functional impairment in the decision to perform total joint replacement in hip and
knee osteoarthritis: an international cross-sectional study of 1909 patients.
Report of the OARSI-OMERACT Task Force on total joint replacement. Osteoarthritis Cartilage. 2011;19:147-154.
43. Petrou S, Wolstenholme J. A review of alternative approaches to healthcare resource allocation. Pharmacoeconomics. 2000;18:33-43.
44. Dieppe P, Lim K, Lohmander S. Who should have knee joint replacement surgery for osteoarthritis? Int J Rheum Dis. 2011;14:175-180.
45. Swedish Knee Arthoplasty Register. http://www.knee.nko.se/english/online/
thePages/publication.php. Accessed October 22, 2012.
46. Ravi B, Croxford R, Reichmann WM, Losina E, Katz JN, Hawker GA. The changing demographics of total joint arthroplasty recipients in the United States and
Ontario from 2001 to 2007. Best Pract Res Clin Rheumatol. 2012;26:637-647.
47. Dickstein R, Heffes Y, Shabtai EI, Markowitz E. Total knee arthroplasty in the elderly: patients’ self-appraisal 6 and 12 months postoperatively. Gerontology. 1998;
44:204-210.
48. Jones CA, Voaklander DC, Johnston DW, Suarez-Almazor ME. Health related
quality of life outcomes after total hip and knee arthroplasties in a community
based population. J Rheumatol. 2000;27:1745-1752.
49. Nilsdotter AK, Petersson IF, Roos EM, Lohmander LS. Predictors of patient-relevant outcome after total hip replacement for osteoarthritis—a prospective study.
Ann Rheum Dis. 2003;62:923-930.
50. Nilsdotter AK, Toksvig-Larsen S, Roos EM. Knee arthroplasty: are patients’ expectations fulfilled? A prospective study of pain and function in 102 patients with
5-year follow-up. Acta Orthopaedica. 2009;80:55-61.
51. Judge A, Arden NK, Cooper C, et al. Predictors of outcomes of total knee replacement surgery. Rheumatology. 2012;51:1804-1813.
52. Perrucio AV, Power JD, Evans MK, et al. Multiple joint involvement in total knee
replacement for osteoarthritis: effects on patient-reported outcomes. Arthritis
Care Res (Hoboken). 2012;64:838-846.
53. Jones CA, Cox V, Jhangri GS, Suarez-Almazor ME. Delineating the impact of
obesity and its relationship on recovery after total joint arthroplasties. Osteoarthritis Cartilage. 2012;20:511-518.
54. Dowsey MM, Nikpour M, Dieppe P, Choong PF. Associations between preoperative radiographic changes and outcomes after total knee joint replacement for osteoarthritis. Osteoarthritis Cartilage. 2012;20:1095-1102.
Keywords: indication; osteoarthritis; total joint replacement; willingness
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PROTHÈSES
DE GENOU POUR L’ARTHROSE
:
RÉALITÉ , ESPOIRS ET CRAINTES
L’arthrose touche des centaines de millions de personnes dans le monde. Elle est responsable de douleurs, de restrictions fonctionnelles et de perte d’espérance de vie ajustée sur la qualité. L’arthrose du genou est la cause de plus
de 90% des prothèses totales de genou (PTG). D’ici à 2030, l’incidence des PTG aux États-Unis devrait être multipliée par 6. Les principales raisons pour la pose d’une PTG sont la présence de douleur et une difficulté à la marche
limitant les activités de la vie quotidienne. Toutefois, seule une minorité de patients ayant une arthrose invalidante
sont prêts à envisager la PTG. Ce faible engouement pour la pose d’une PTG est lié au vieillissement, au fait d’être
Noir (aux États-Unis), à la surestimation de la douleur et du handicap nécessaires pour justifier une PTG et à un rejet
de la médicalisation de l’arthrose. Les femmes et les personnes dont le statut socio-économique est bas ont une perception des bénéfices d’une PTG moins positive que les autres. Le rapport coût-efficacité de la chirurgie pour PTG
est l’un des meilleurs. Les données issues des registres sur les articulations montrent que le taux de réintervention
à 10 ans pour PTG est inférieur à 5%. Cependant, de 10% à 30% des patients ayant eu une PTG ne sont pas satisfaits de l’intervention, ou n’ont perçu, au mieux, qu’une amélioration modérée. Ce qu’attendent les patients d’une prothèse, c’est le soulagement de leur douleur et une mobilité améliorée. Après la pose d’une PTG, les attentes concernant le soulagement de la douleur, l’aptitude à la marche et la capacité à effectuer les activités de la vie quotidienne
sont satisfaites dans une plus grande mesure que celles concernant la possibilité de pratiquer des activités plus physiques. Les professionnels de santé devraient informer les patients de façon à ce que leurs attentes soient réalistes,
ce qui leur assurerait une meilleure satisfaction.
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There may be some lessons
to be learned from the management of rheumatoid arthritis, although the disease-modifying osteoarthritis drugs (DMOADs) that
are used in the treatment of established osteoarthritis (OA) are likely
to differ from disease-modifying
antirheumatic drugs (DMARDs) in
some respects. DMARDs are typically used in a younger population
where toxicity may be better tolerated and the absence of comorbidities and their concurrent therapies permits the use of agents
with greater potential toxicity.”
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Disease-modifying osteoarthritis drugs (DMOADs):
what are they and what can
we expect from them?
b y A . J . B a r r a n d P. G . C o n a g h a n ,
United Kingdom
O
Andrew J. BARR, MBBS, MRCP
Philip G. CONAGHAN
MBBS, PhD, FRACP, FRCP
Division of Rheumatic and
Musculoskeletal Disease
University of Leeds and NIHR
Leeds Musculoskeletal
Biomedical Research Unit, UK
Professor Philip G. Conaghan,
Division of Rheumatic and
Musculoskeletal Disease, Chapel
Allerton Hospital, Chapeltown Road,
Leeds LS7 4SA, UK
steoarthritis (OA) is the most common form of arthritis and represents
a huge burden on individuals and health economies. The mainstay
of current therapy involves a combination of nonpharmacological and
pharmacological interventions aimed at reducing pain and improving function. Current treatments do not inhibit structural deterioration of the OA joint;
yet, the unmet need for this type of treatment is immense. The current definition of a disease-modifying OA drug (DMOAD) is that of a drug that inhibits
structural disease progression and ideally also improves symptoms and/or
function. There are currently no licensed DMOADs but there are many prospective agents under investigation. The challenges of DMOAD development include the establishment of appropriate preclinical animal models that reflect
human OA, the limitations of the current radiographic standard for structural
assessment, and the lack of stratification of patients in trials by phenotype or
tissue involvement. Furthermore, DMOADs should probably be used in early
disease before irreversible molecular and biomechanical pathology is established, as is commonly present at the time of diagnosis. DMOADs are likely
to be prescribed for long periods in this chronic illness of an aging population, which demands excellent safety data in a target population with multiple comorbidities and the potential for drug interactions. Issues in DMOAD
development, potential DMOADs, magnetic resonance imaging biomarkers,
and lessons learned from the treatment of rheumatoid arthritis are briefly discussed in this review.
steoarthritis (OA) is the most common form of arthritis and represents a
huge burden on both individuals and health economies. It is characterized by changes involving all the joint tissues. Affected individuals suffer
pain, functional limitation, and poor quality of life. We can predict a dramatic increase in the burden of OA in aging and increasingly obese Western populations.
O
OA represents whole joint failure and occurs when the homeostatic equilibrium of
joint tissue repair and breakdown becomes unbalanced. Risk factors for disease
initiation and progression vary according to anatomical site and include age, obesity,1,2 anthropometric and anatomical characteristics, joint malalignment, and trauma.3 A genetic predisposition also contributes to OA risk; OA is a polygenic disease
whose susceptibility results from the interaction of many genes.4,5 The mainstay of
current therapy involves a combination of nonpharmacological and pharmacologi-
DMOADs: what are they and what can we expect from them? – Barr and Conaghan
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cal interventions aimed at reducing pain and improving function. The pharmacological interventions include paracetamol,
nonsteroidal anti-inflammatory drugs, and opiate analgesics.
Their utility is limited by—at best—moderate effect size,6 or by
significant toxicities, especially as OA is most prevalent in the
elderly where comorbidities are more common. Current treatments do not appear to inhibit the structural deterioration of the
OA joint; the unmet need for such a treatment is immense.
What are disease-modifying osteoarthritis drugs?
A disease-modifying osteoarthritis drug (DMOAD) is a drug
that inhibits the structural disease progression of OA and
ideally also improves symptoms and/or function. There are
currently no licensed DMOADs. There are draft guidelines from
the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both requiring that a DMOAD
should not only slow or halt radiographic structural disease
progression, but also achieve patient-reported long-term clinical benefit.7,8 Historically, attempts at developing DMOADs
have focused primarily on preventing hyaline cartilage loss,
thereby providing putative “chondroprotective” agents. However, and perhaps appropriately, as typical clinical OA involves
multiple tissues, more recent attempts have been made at targeting other tissues including the subchondral bone, which
plays an important role in OA pathogenesis.
There are a number of issues to consider in developing therapies that modify structural disease progression.
order to adequately power a clinical study. Furthermore, the
sensitivity of this measure to change may be reduced by knee
repositioning variability in serial radiographic measurement of
JSW, so great care must be taken in repositioning methods.12
Conventional radiography does not detect early (preradiographic) OA changes in the subchondral bone, cartilage, or menisci.13 Typically, inclusion criteria for research trials have included patients with radiographically detectable JSN (Kellgren and
Lawrence grade ⱖ2). While this selects a group of patients
who no doubt have OA, multiple large MRI studies suggest
that these patients have complex multiple tissue pathologies,
with gait studies suggesting a high probability of abnormal
biomechanical features, meaning that these may be patients
in whom pharmacological intervention alone and aimed at a
single tissue would be unlikely to modify structural deterioration. A preradiographic patient cohort with milder disease
may be more likely to respond. Treatment of rheumatoid arthritis according to the concept of early disease has certainly revolutionized the management of rheumatoid arthritis.
N Magnetic resonance imaging as a potential end point
Conventional radiography cannot capture the extent of the
multi-tissue involvement in OA joints. Typically, patients with
Kellgren-Lawrence grade ⱖ2 are recruited for DMOAD trials,
but these patients may lack uniformity in terms of joint tissue
involvement, and this is clinically indistinguishable. Stratifying
and monitoring these tissue changes among patients would
require MRI.
Challenges in DMOAD development
N The current standard for structural assessment:
conventional radiography
Conventional radiography is widely available and radiographic joint space width (JSW) is the traditionally used surrogate
for assessing cartilage thickness. JSW can be used for both
defining and measuring structural disease progression. Manual and semiautomated methods can be used to quantify JSW
from a conventional radiographic image, providing different
measures such as minimum, mean, or location-specific JSW.
Joint space narrowing (JSN) is used as the primary end point
in DMOAD trials in OA. Although JSN is a predictor of total
joint replacement,9 the limitations of radiographic JSN should
be appreciated. Indeed, while JSN is used to define cartilage
loss in knee OA, magnetic resonance imaging (MRI) studies
have shown that it measures a complex construct including
meniscal degeneration, meniscal extrusion, and hyaline cartilage loss.10
The annual rate and variability of JSN in the natural history of
OA is well described, which facilitates powering in clinical trials.11,12 However, the average annual change in JSN is approximately 0.1 to 0.2 mm per annum, with change occurring in a
small group of “progressors.” The relative insensitivity to change
of this surrogate measure of hyaline cartilage loss means
that long trials with large numbers of patients are needed in
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The advantages of MRI include the ability to examine the presence and extent of pathology in all of the individual joint tissues in OA.14 There is good evidence of the reliability and responsiveness of MRI cartilage morphometry in knee OA and
there is some evidence of its predictive and construct validity.15,16 This includes quantitative loss of cartilage volume being a potential predictor of total knee replacement. The assessment of subchondral bone marrow lesions and synovitis in
knee OA has also demonstrated good responsiveness for
SELECTED
BMP-7
DMOAD
DMARD
iNOS
IL-1
JSW
JSN
MRI
MMP
MSS
OA
TIMP
human bone morphogenetic protein 7
disease-modifying osteoarthritis drug
disease-modifying anti-rheumatic drug
inducible nitric oxide synthase
interleukin 1
joint space width
joint space narrowing
musculoskeletal syndrome
osteoarthritis
tissue inhibitor of metalloproteinases
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semiquantitative MRI assessment.16 Further work is required
to investigate the predictive validity and quantification of these
noncartilage MRI pathologies. While MRI acquisition is, of
course, more expensive and time-consuming than plain radiography, there are trade-offs in that increased responsiveness
should result in fewer patients being required to demonstrate
a structure-modifying effect.
MRI-based joint tissue measures of OA have not been routinely used as clinical outcome measures in structure-modification DMOAD trials. However, following the last decade
of MRI-OA cohort studies and trials, a recent Osteoarthritis Research Society International (OARSI) working group recommended that MRI cartilage morphology assessment be used
as a primary structural end point in clinical trials and noted
the rapid evolution of quantitative MRI assessments of subchondral bone and synovium.17
N Novel end points: joint arthroplasty and virtual joint
arthroplasty
While pain and function outcomes are common outcomes
that may be adapted for DMOAD studies from symptom-modifying trials, less frequently used measures such as quality of
life and delay in time to joint replacement may also provide
important information about the value of a putative agent. Rate
of joint arthroplasty has been used as an end point reflecting
the severity of symptoms and structural damage, but many
variables influence both the decision to perform and the timing of this outcome measure. These include the surgeon’s or
physician’s opinion and the patient’s comorbidities and willingness to undergo surgery, in addition to local and national
health system variations in surgical waiting lists. In an attempt
to overcome these confounding factors influencing the “time
to total joint replacement” end point, an alternative has been
proposed. This is “time to fulfilling criteria for total joint replacement” or “virtual total joint replacement,” which could be used
to evaluate treatment response to DMOADs in clinical trials.18
The criteria consist of a composite index of three domains:
physical function, pain, and structure19; its validity is currently
being assessed in an international study although provisional reports indicate that large patient numbers would be required to detect differences between groups in DMOAD randomized control trials.20
N Symptomatic improvement
The current regulatory approval standard for DMOADs requires
that structural disease modification be linked with some clinical benefit. However, in observational studies in OA there is
generally a weak relation between pain and/or function and
JSN and radiographic structural change.21 Furthermore, cartilage is not directly attributable as the cause of the typical OA
symptoms, including pain and stiffness.22 Importantly, most
trials of symptom-modifying drugs have been of short duration, often only 3 months long. DMOAD trials need to monitor
pain over long periods of time (1 to 2 years), where the effi-
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cacy of existing analgesics has often not been clearly demonstrated. Such long-duration trials are often associated with
patient drop-out, especially in an elderly population, and robust statistical modeling will be required to cope with missing data.
N DMOAD safety profile
Prospective DMOADs for use in established OA are likely to
require long-term administration in an aging population with
significant comorbidities, and will thus be prescribed alongside a variety of medications. For that reason, prospective
DMOADs will be required to demonstrate a good safety profile with respect to both patient tolerance and drug interactions. Long-duration trials will therefore be needed to achieve
this.
N Preclinical models
Animal models can mimic certain aspects of human disease.
However, there is no single model that reflects all of the phenotypes and components of human OA. The marked differences between animal models and human disease may result
in dismissing drugs that may be viable DMOADs in humans
due to preclinical failure in animal models. Existing models
include primary idiopathic and secondary experimentally induced disease. Small animal models may provide us with a
clearer understanding of the molecular pathways involved in
the pathogenesis of OA and the effects of prospective
DMOADs on these pathways.23 Although large weight-bearing models may be more relevant, they are less frequently
used. Animal models generally achieve adequate severity of
OA but some may exceed that seen in humans. There is a
general consensus of opinion that animal models of less severe OA will be better placed to establish the efficacy of prospective human DMOADs. Furthermore, establishing animal
models with relevance to human OA will require standardization of experimental techniques, disease severity, and treatment responses.24
Are there candidate DMOADs?
A number of prospective DMOADs are under investigation
and some of those more advanced in development are summarized in Table I (page 192). The degradation of cartilage
and that of subchondral bone are closely linked in OA. Table I describes the mechanism of action of the prospective
DMOADs on cartilage, although they may also structurally
modify subchondral bone.
N Calcitonin
Calcitonin is responsible for regulating calcium homeostasis
and promotes osteoblastic bone formation. It inhibits bone
resorption by binding to calcitonin receptors on osteoclasts.
Calcitonin is indicated for the prevention of osteoporosis in
postmenopausal women. It can be administered orally, intranasally, or subcutaneously. Its inhibition of subchondral bone
turnover may be chondroprotective and, therefore, it may in-
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Mechanism of action
Prospective DMOAD
Anticatabolic
Systemic therapy
Calcitonin
Bisphosphonates
Strontium ranelate
iNOS inhibitors
MMP-13 inhibitors
Aggrecanase inhibitors
Anti-IL-1β
Doxycycline
Cathepsin K inhibitors
Local therapy
BMP-7
MMP-13 inhibitors
TIMP-3
FGF-18
Anti-IL-1β
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
Anabolic
✓
✓
✓
Table I. Prospective disease-modifying osteoarthritis drugs
(DMOADs) and their mechanisms of action on cartilage.
hibit the structural disease progression of OA.25 In a human
trial, bone resorption and cartilage degradation markers were
significantly lower in the oral salmon calcitonin group compared with placebo.26 In a 2-year phase 3 trial of knee OA,
oral calcitonin modified symptoms and increased cartilage
volume but did not have an effect on JSW.27
N Bisphosphonates
Bisphosphonates are frequently used for treating conditions
with osteoclastic bone resorption, especially osteoporosis.
Increased subchondral bone turnover in OA is integral to the
pathogenic process of OA,28 and may be associated with progressive cartilage loss.29 This disease-specific pathogenic
process can be targeted using antiresorptive agents such as
bisphosphonates, which hinder the bone remodeling process
and could be chondroprotective. Animal models identified a
beneficial effect of bisphosphonates in OA through their impact on subchondral bone, which includes inhibition of remodeling and osteophyte formation along with decreased
vascular invasion of calcified cartilage.30
Initially, a phase 2 study of risedronate31 reported promising
findings with a trend toward inhibition of JSN in knee OA. However, a subsequent phase 3 study of risedronate in knee OA
reported no significant change in JSN or symptom severity.32
As yet, no study has accounted for the heterogeneity of the
OA population regarding subchondral bone abnormalities
when selecting patients. The insensitivity to change of conventional radiography used as an outcome measure (vide
supra) for structural change suggests that the above-mentioned studies were significantly underpowered to show a re-
192
sponse.33 Some potentially beneficial effects have nonetheless been observed. A reduction in biomarkers of cartilage
degradation at 6 months of therapy was noted, along with
slower knee OA progression.34
Zoledronic acid is a long-acting bisphosphonate that is licensed for postmenopausal osteoporosis. Along with other
bisphosphonates, zoledronic acid has demonstrated chondroprotective effects in animal models of OA35 in conjunction
with its impact on subchondral bone. In a 1-year randomized placebo controlled trial of zoledronic acid in patients with
knee OA, zoledronic acid demonstrated a reduction in bone
marrow edema (a marker associated with structural disease
progression) and knee pain.36 As it improves symptoms and a
marker of structural disease progression at the same time,
zoledronic acid represents an important prospective DMOAD.
N Strontium ranelate
Strontium ranelate is a drug used in the treatment of osteoporosis with antiresorptive and anabolic effects on the subchondral bone. Strontium ranelate influences bone remodeling through calcium-sensing receptors on osteoclasts and
osteoblasts in subchondral bone and by an antiresorptive action via inhibition of osteoclastogenesis.37 In vitro studies suggest that strontium ranelate has anabolic effects on cartilage
by directly promoting the formation of human cartilage matrix.38 In studies of human osteoporosis, strontium ranelate
reduces cartilage degradation markers and inhibits clinical
symptoms and radiographic features of spinal OA, indicating
its potential as a DMOAD.39 A double-blind, placebo-controlled, randomized, international 3-year study of knee OA
demonstrated a chondroprotective effect and symptomatic
improvement in WOMAC (Western Ontario and McMaster
Universities) index scoring.40
N Bone morphogenetic protein
Human bone morphogenetic protein-7 (BMP-7)—also known
as osteogenic protein-1 (OP-1)—is a transforming growth factor with a broad range of effects on a variety of cells, including
cartilage. It signals through transmembrane serine-threonine
kinase receptors, and is involved in cartilage homeostasis and
repair via anticatabolic and anabolic properties.41 In animal
models, BMP-7 demonstrated reparative effects on cartilage
lesions.42 Human chondrocytes also promote cartilage formation in response to BMP-7 treatment.43 Clinical trials investigating the efficacy of BMP-7 in human knee OA have commenced.
N Inducible nitric oxide synthase
Nitric oxide is considered to play a pathogenic role in cartilage degradation and pain in OA.44 Nitric oxide—along with its
metabolites—induces cartilage degradation and cytotoxic tissue damage via inhibition of proteoglycan and collagen synthesis, apoptosis of chondrocytes, and activation of matrix
metalloproteinases (MMPs).
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In animal models, selective inhibition of one isoform of nitric
oxide synthase (iNOS) significantly reduces articular cartilage
degradation and the number of osteophytes.45 There is also
a significant reduction in the severity and incidence of OA in
iNOS knock-out mice, indicating a potential role of iNOS in
human OA. However, in a recent 2-year randomized, double-blind, placebo-controlled trial of an oral selective iNOS inhibitor, cindunistat, there was only a transient slowing of JSN
in Kellgren-Lawrence grade 2 OA, which was not sustained
at 2 years, and no significant evidence of inhibition of structural progression was seen in OA of greater radiographic
severity.46
N Matrix metalloproteinase inhibitors
MMPs are collagenases that cleave type II collagen and result
in loss of biomechanical integrity of normal human articular
cartilage. This important pathogenic process in OA can be inhibited using MMP inhibitors. However, these MMP inhibitors
have failed early clinical trials due to the frequent development
of a painful musculoskeletal syndrome (MSS). This has been
attributed to the broad spectrum of MMP inhibition. MMP-13
appears to be an important collagenase in human OA and
specific inhibitors targeting it are in development.47 This more
targeted approach will, hopefully, avoid MSS.
N Tissue inhibitors of metalloproteinases
Aggrecan is an important protein found in articular cartilage
that is degraded as part of the pathogenesis of OA. This
process occurs as a result of the action of a variety of different aggrecanases, including a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). Endogenous
inhibitors of MMPs include the tissue inhibitor of metalloproteinase TIMP-3, which can inhibit the action of these aggrecanases.48 Greater cartilage degradation was noted in TIMP-3
knockout mice compared with wild-type mice.49 Therefore, tissue inhibitors of metalloproteinases represent a prospective
DMOAD target.
N Vitamin D
Vitamin D is required for normal cartilage and bone metabolism. It regulates the expression of MMPs by chondrocytes.50
Vitamin D insufficiency is common and is associated with reduced osteoblast activity and reduced bone quality, which
may explain its association with structural progression of OA.51
Several clinical trials are investigating the effect of vitamin D
on structural disease progression
N Fibroblast growth factor 18
Fibroblast growth factor 18 (FGF-18) is involved in cartilage
and bone development during skeletal maturation.52 In animal models, it has been shown to promote chondrogenesis,
cartilage repair, and subchondral bone remodelling.53 It represents an important potential DMOAD and is currently undergoing phase 2 clinical trials examining changes in cartilage
volume.
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N Interleukin 1 inhibitors
Interleukin 1 (IL-1) has been proposed to be involved in the
degradation of articular hyaline cartilage based upon preclinical studies. Inhibition of the enzyme that activates the
proinflammatory cytokine IL-1β, interleukin-1 beta-converting enzyme (ICE), has been achieved with a highly selective
caspase-1 inhibitor called pralnacasan. In animal models, a
reduction in joint damage was demonstrated.54 However, in
human OA, monoclonal antibody IL-1 inhibitors have failed to
demonstrate an improvement in symptoms.55
N Neutraceuticals and supplements
Glucosamine, an amino sugar, is a substrate for the formation of glycosaminoglycans, and chondroitin sulfate is a sulfated glycosaminoglycan. Glycosaminoglycans are important
constituents of articular cartilage. The availability of these substrates may limit the formation of cartilage and therefore glucosamine and chondroitin were used in trials as prospective
DMOADs. A recent meta-analysis of glucosamine and chondroitin concluded that there is no structural modifying effect
of these agents based upon trials using JSN as a clinical end
point.56
Collagen hydrolysate is another dietary supplement. It is formed
as a result of collagen hydrolysis and has only demonstrated
small clinical improvement in OA. Phase 2/3 trials with collagen hydrolysate are yet to be published.
N Doxycycline
Although there is no evidence to support an infectious etiology in OA, doxycycline has demonstrated potential as a
DMOAD based on preclinical data. Possible mechanisms of
action include inhibition of type XI cartilage degradation, inhibition of collagenase activity and a decrease in iNOS mRNA
transcription. A randomized, placebo-controlled, double-blind
trial of doxycycline of over 30 months that included 431 obese
women with unilateral radiographic knee OA reported a small
reduction in the rate of JSN in knees with established OA.11
Doxycycline is not currently recommended for the treatment
of OA.
N Cathepsin K
Cathepsin K, a cysteine proteinase, appears to play a role in
the pathogenesis of OA.57 In preclinical models, cathepsin K
inhibition reduced evidence of cartilage degradation.58 It is,
therefore, a prospective DMOAD.
Can we learn lessons from disease modification
in rheumatoid arthritis?
There may be some lessons to be learned from the management of rheumatoid arthritis, although the DMOADs that are
used in the treatment of established OA are likely to differ from
disease-modifying anti-rheumatic drugs (DMARDs) in some
respects. DMARDs are typically used in a younger population
where toxicity may be better tolerated and the absence of co-
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morbidities and concurrent therapies to treat them permits the
use of agents with greater potential toxicity. DMOADs for established OA will require excellent toxicity profiles in light of the
greater prevalence of comorbidities and potential for drug
interactions. However, DMOADs, like DMARDs, are likely to require chronic administration. OA affects a significantly greater
proportion of the population than rheumatoid arthritis and,
therefore, its treatment may represent a significant burden to
health services. Ideally, DMOADs should be inexpensive, patient-administered, and require little or no monitoring in comparison with DMARDs such as tocilizumab and infliximab.
DMARDs are often prescribed in combination to improve the
efficacy of treatment in terms of symptoms and structural disease progression. Similarly, DMOADs may also need to be
prescribed in combination, particularly if a single joint tissue
is targeted by the DMOAD. It is important to recognize that
OA is a whole joint disease involving pathophysiological interactions between subchondral bone, cartilage, synovium,
and ligaments and it is likely that an individual DMOAD will
only target a single tissue, thereby increasing the need for
combination therapy.
The cornerstone of DMARD therapy has been effective targeting of synovitis. While the synovium is only one of the tissues involved in OA pathogenesis, synovitis may contribute to
disease progression.59 Therapies that modify synovitis could
therefore potentially modify OA structural progression. Studies in this area are ongoing.
Conclusion
OA is the most common form of arthritis and is a chronic and
progressive disease of the whole joint with only moderately
effective treatment options currently available. There are a
number of prospective targets for structural and symptomatic
disease modification in patients with established OA, early
OA, or at the time of acute joint injury, with a view to preventing structural progression, improving symptoms and function,
and avoiding the need for total joint replacement. DMOADs
are the highest unmet need in the field of OA and prospective
DMOADs will need to demonstrate excellent safety profiles in
view of their target population. However, DMOAD trials will
require improved biomarkers and clinical end points to appropriately demonstrate the construct of OA structure modification. I
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49. Sahebjam S, Khokha R, Mort JS. Increased collagen and aggrecan degradation with age in the joints of Timp3(-/-) mice. Arthritis Rheum. 2007;56(3):905909.
50. Tetlow LC, Woolley DE. Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro.
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levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996;125(5):353-359.
52. Haque T, Nakada S, Hamdy RC. A review of FGF18: Its expression, signaling
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53. Moore EE, Bendele AM, Thompson DL, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage. 2005;13(7):623-631.
54. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den Berg W. Pralnacasan,
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55. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of
AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther. 2011;13(4):R125.
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58. Hayami T, Zhuo Y, Wesolowski GA, Pickarski M, Duong le T. Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012;50(6):1250-1259.
59. Conaghan PG, D'Agostino MA, Le Bars M, et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large,
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Keywords: biomarker; cartilage; DMOAD; subchondral bone; structure
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MÉDICAMENTS CONTRE L’ARTHROSE MODIFIANT LA MALADIE
QUE SONT- ILS ET QUE PEUT- ON EN ATTENDRE ?
(DMOAD) :
L’arthrose, forme la plus courante des arthropathies, représente un lourd fardeau pour les individus et les économies
de la santé. Les traitements actuels reposent sur l’association d’interventions pharmacologiques et non pharmacologiques dans le but de réduire la douleur et d’améliorer la fonctionnalité. Ces traitements ne permettent pas d’éviter la détérioration structurale de l’articulation arthrosique ; les besoins pour ce type de traitement sont donc immenses. La définition actuelle d’un « médicament contre l’arthrose modifiant la maladie » (DMOAD) est celle d’un produit qui inhibe la progression structurale de la maladie et qui, idéalement, améliore aussi les symptômes et/ou la
fonctionnalité. À ce jour, aucun DMOAD n’a obtenu l’AMM, mais il existe de nombreux produits en cours de développement. Le développement des DMOAD est confronté à la mise en place de modèles animaux précliniques
adéquats reproduisant l’arthrose humaine, aux limites du standard radiographique utilisé actuellement pour l’évaluation structurale de la maladie et au manque de stratification des patients par atteinte tissulaire ou phénotypique dans
les études. De plus, il va probablement falloir utiliser les DMOAD dans les stades précoces de la maladie, avant l’établissement d’une pathologie irréversible, comme c’est fréquemment le cas au moment du diagnostic. Dans cette pathologie chronique d’une population vieillissante, les DMOAD vont vraisemblablement devoir être prescrits sur de
longues périodes, ce qui exige d’excellentes données de sécurité pour leur utilisation chez une population sujette à
de multiples comorbidités et donc, potentiellement, à de nombreuses interactions médicamenteuses. Dans cet article, nous passons brièvement en revue les questions relatives au développement des DMOAD, les DMOAD potentiels, les biomarqueurs utilisés en imagerie par résonance magnétique et les leçons tirées du traitement de la polyarthrite rhumatoïde.
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OA has a substantial effect
not only on health care budgets
but also on patients, their employers, and their caregivers. For example, in Belgium, the costs of OA
in active patients are distributed
among the employers (45%), the
health care system (41%), and the
patients themselves (14%). Therefore, in addition to pain and a
poorer quality of life, patients living with OA may face significant
personal expenses due to OA.”
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The economic weight of
osteoarthritis in Europe
b y M . H i l i g s m a n n a n d J . Y. R e g i n s t e r,
The Netherlands and Belgium
T
L
Mickaël HILIGSMANN,a,b PhD
Jean-Yves REGINSTER,b MD, PhD
a
Department of Health Services
Research, School for Public Health
and Primary Care (CAPHRI)
Maastricht University
THE NETHERLANDS
b
Department of Public Health
Epidemiology and Health Economics
University of Liège, BELGIUM
his article aims to describe the economic weight of osteoarthritis (OA)
in Europe based on published data and to underline the principal cost
headings and their respective weights for patients and governments.
This review suggests that OA has a significant economic effect not only on
health care budgets, but also on patients, their employers, and their caregivers. The average total annual cost of OA per patient in Europe ranges from
€1330 to €10 452. When considering only direct medical costs, the annual
cost of OA ranged from €534 to €1788. In active patients, the indirect costs
were found to be much higher than the direct costs. European studies are,
however, not directly comparable with each other because of differences in
the approach taken, in patient characteristics, in health care systems, and in
the calculation of productivity losses. Our review confirms the immense burden of OA in Europe, which is expected to rise substantially further in the future with demographic changes and increasing obesity. Developing effective
and efficient treatment programs for OA is becoming increasingly important
to reduce the clinical and economic consequences of this major public health
problem worldwide.
steoarthritis (OA), the most common form of arthritis, is a serious disease
affecting the joints.1,2 OA affects nearly 10% of the population worldwide.3
In the United Kingdom, the lifetime risk of developing symptomatic knee
and hip OA is estimated to be 44.7% and 25.3%, respectively.4,5 OA causes pain,
stiffness, and severe disability. In the United States, knee OA is one of the five leading causes of disability among noninstitutionalized people.6 Symptomatic hip and
knee OA are also associated with excess mortality7 and account for many hospitalizations, primarily related to knee and hip replacement surgery.8 Since OA is a
disease whose prevalence increases with age, its prevalence and burden are expected to increase substantially in the near future due to demographic changes.
In addition, obesity, which is rising worldwide, is a strong risk factor for knee and hip
replacement.9 An increased trend in the prevalence of symptomatic knee OA and
in the number of OA-related hospitalizations has already been observed recently.10
O
Dr Mickael Hiligsmann
Department of Health Services
Research, Maastricht University
PO Box 616. 6200 MD, Maastricht,
The Netherlands (e-mail:
[email protected])
The economic cost of OA is also particularly high, resulting from decreased quality
of life, hospitalizations, and loss of productivity. Cost-of-illness studies have become increasingly important to identify how much society is spending on a particular disease and thus help decision makers establish research and treatment prior-
The economic weight of osteoarthritis in Europe – Hiligsmann and Reginster
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ities. In the United States, the annual medical care expenditures for OA were estimated at $185.5 billion (in 2007 dollars), of which $149.4 billion were insurer expenditures and
$36.1 billion were paid directly by the patients. In Europe,
some data has been published over the last few years on the
economic impact of OA on individuals, including those in the
workplace. The goal of this article is to review these publications so as to clarify the economic weight of OA in Europe
based on available published data. Specific attention will be
devoted to describing the principal cost headings (visits to
health professionals, drugs, loss of productivity, etc.) and
their respective weights for patients and governments.
es attributable to the disease resulting from absence from
work and reduced effectiveness at work. These costs may
be related to the patients themselves or to their caregivers.
Cost of osteoarthritis in Europe
A literature review was conducted using PubMed to find articles assessing the burden of OA in European countries between January 2000 and July 2012. The bibliographies of the
papers included were also analyzed to search for additional
references. Published studies on the economic cost of OA
were found in Belgium, France, Germany, Italy, the Netherlands, and Spain. All of these studies, with the exception of the
French study, used a bottom-up approach.
Cost-of-illness evaluation
Burden-of-disease evaluation of OA aims to describe the impact of OA on society, including its impact on health care systems, patients, their caregivers, and their employers. Measuring the burden of disease can be very helpful in guiding the
setting of health research priorities.11
The burden of OA can be measured with epidemiological parameters (incidence, prevalence) or with the impact of the disease on mortality, morbidity, quality of life, or health care costs.
Cost-of-illness studies evaluate the direct and indirect health
care costs of a particular disease over a period of time. This
can be done using two different approaches: a prevalencebased approach and an incidence-based approach. While
the incidence-based approach estimates the costs of new
cases of the disease during the period of time considered,
the prevalence-based approach includes the costs of all the
patients affected by the disease. Prevalence-based studies
are far more common and are more suitable for the estimation
of the annual burden of a disease.12
The cost of a disease can be estimated using either a “topdown” or a “bottom-up” approach. The top-down approach
examines the costs in an aggregated form (such as national indicators) while in the bottom-up approach, the overall
cost is based on the costs for the individuals.11 Most costof-illness studies of OA in Europe have used the bottom-up
method to estimate the economic burden of OA (see below).
The cost of a disease can be categorized into direct and indirect costs. Direct costs are those directly related to the disease, including, for example, visits to health care professionals, medical examinations, drug therapy, hospital admissions,
and nonmedical costs. Indirect costs include productivity lossSELECTED
GNP
gross national product
OA
osteoarthritis
WOMAC Western Ontario and McMaster Universities Osteoarthritis index
198
Informal care
(2%)
Contact with
health care
professionals
(22%)
Medical
examinations
(8%)
Work
disability
(58%)
Hospital
stays
(6%)
Drugs
(4%)
Figure 1. Direct and indirect costs of osteoarthritis in Belgium.
Based on a sample of 1811 active subjects with a mean age of 51 years. Total
cost per year = €1330. Direct costs are represented in red and indirect costs
in blue.
Data from reference 13: Rabenda et al. J Rheumatol. 2006;33:1152-1158.
© 2006, The Journal of Rheumatology.
N Belgium
In Belgium, the cost of OA was assessed in 2004 in a sample of 1811 active subjects employed by the Liège City Council (mean age, 51 years) who were followed prospectively for
6 months.13 The self-reported prevalence of OA was 34%. The
burden of OA was measured comprehensively, taking into
account the direct medical costs (consultations with health
professionals and with alternative medicine professionals, the
number and type of medical examinations, the number of hospital stays and emergency department consultations, and all
drugs taken) and the indirect costs (the number of sick leave
days, and the number of days off work taken by active subjects helping relatives or friends with OA).
The mean total direct and indirect costs were estimated at
€44.50 and €66.30 per OA patient-month, respectively,
which, when extrapolated to 1 year, came to €1330 per OA
patient annually. The average distribution of costs is shown in
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Figure 1. Consultations with health professionals, medical examinations, drugs, and hospital stays accounted for €23.70,
€8.70, €6.70, and €4.90 per OA patient-month, respectively. Of all these direct costs, €29.10 (65%) was covered by the
Belgian health care system and €15.40 (35%) was paid out
of pocket by the patients. The average number of sick-leave
days was 0.8 per OA patient-month, yielding—from the payer’s perspective—a cost of €64.50 per OA patient-month. The
Belgian health care system covered 25.9% of all sick-leave
payments, with employers covering the remaining 74.1%. Informal care was estimated to cost employers €1.80 per active subject-month, based on a mean of 0.02 days off work
per active subject-month. Multiple regression analyses showed
that age was a significant predictor of direct medical costs
and that poorer quality of life was a major determinant of direct and indirect costs.
N Italy
In Italy, the direct and indirect costs of knee OA were assessed
retrospectively in a sample of 254 patients (mean age, 65
years) over a period of 12 months in 2000-2001.14 The cost
per patient per year was estimated at €2170, of which 43%
were direct costs—including medical (hospitalization, diagnosis, and therapies) and nonmedical costs (transport, temporary caregivers, and auxiliary devices)—and 57% were indirect costs (productivity losses and informal care).
The distribution of costs is shown in Figure 2. Hospitalization
represented the largest medical cost, absorbing 25% of the
direct resources (mean annual cost, €233). The annual cost
of therapy was €136, of which 42% was spent on drugs and
Loss of
productivity–
primary
caregiver
(34%)
Loss of productivity–
other caregivers
(5%)
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58% on physiotherapy. Nonmedical costs (which represent
37% of the total costs) were mainly driven by temporary caregivers. In contrast with the study of Rabenda et al in Belgium,13
which only included active patients, the indirect costs were
found to be mainly due to informal care provided by primary
caregivers, which accounted for around 60% of the total indirect costs. The remaining indirect costs were due to loss of
productivity (31%) and to other caregivers (9%). Sensitivity
analyses revealed higher costs for patients with comorbidities
and for women. Age was also shown to be a predictor of costs.
N Netherlands
In the Netherlands, the productivity and medical costs of working patients with knee OA were recently assessed by Hermans et al.15 Loss of productivity and health care consumption were assessed by questionnaires in a sample of 117 knee
OA patients participating in a randomized clinical trial investigating cost-effectiveness (mean age, 52 years). Interestingly, this study included the measurement of reduced work
productivity while present at work in addition to loss of productivity resulting from absence from work.
The average total monthly knee OA–related costs were estimated at €871 per patient. The productivity costs accounted for 83% (€722) and the medical costs accounted for 17%
(€149) of these costs. As observed in Figure 3, the medical
costs were primarily driven by visits to primary (€62) and secondary care (€33), and by imaging (€40). Reduced productivity while present at work accounted for the majority (62%)
of the productivity costs. The inclusion of loss of productivity
while being present at work, which represented around 50%
Hospitalization
(11%)
Medication
use (1%)
Diagnosis
(10%)
Imaging
(4%)
Visits
(11%)
Aids
(1%)
Loss of
productivity–
present at work
(51%)
Compensation
for work
in the
household
(9%)
Therapy
(7%)
Transport
(2%)
Auxillary
devices
(2%)
Loss of
productivity–
patient (17%)
Loss of
productivity–
absent from work
(23%)
Temporary
caregivers
(12%)
Figure 2. Direct and indirect costs of osteoarthritis in Italy.
Figure 3. Direct and indirect costs of osteoarthritis in the Netherlands.
Based on a sample of 254 patients with a mean age of 65 years. Total cost per
year = €2170. Direct costs are represented in red and indirect costs in blue.
Data from reference 14: Leonardi et al. Clin Exp Rheumatol. 2004;22:699-706.
© 2004, Clinical and Experimental Rheumatology.
Based on a sample of 117 active patients with a mean age of 51 years. Total cost
per year = €10 452. Direct costs are represented in red and indirect costs in blue.
Data from reference 15: Hermans et al. Arthritis Care Res. 2012;64:853-861.
© 2012, American College of Rheumatology.
199
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of the total costs (€448 per patient-month), could explain the
relatively high cost of OA found in this study. Logistic regression analyses reported that increased pain during activity and
performing physically intensive work were significantly associated with loss of productivity.
€4.7 billion, which represents 0.5% of the gross national product (GNP) of Spain. Using regression models, the authors also
found that higher costs were associated with comorbidity,
poorer health status, and lower WOMAC score (Western Ontario and McMaster Universities Osteoarthritis index).
N Spain
The direct and indirect costs of osteoarthritis in Spain were
estimated by Loza et al in 2007.16 Based on a sample of 1071
patients aged over 50 years (mean age, 71 years) with symptomatic and radiologic knee and/or hip OA who were seen
at primary care centers in all provinces of Spain, data related
to OA health resources utilization, patient and caregiver expenses, and time lost in the previous 6 months were collected in two separate interviews. The costs were divided into
direct costs, including medical costs (professional time [all
consultations], image, laboratory, and other tests, medications,
and hospital admissions); and nonmedical costs (help at work
and home, and self-care adaptive aids, devices, and assistive household equipment purchased), and indirect costs
including compensation payments for lost productivity and
housekeeping help costs if the patient was a homemaker.16
N France
In France, the direct and indirect costs of osteoarthritis were
estimated by Le Pen et al using the top-down approach with
nationwide data from 2001 to 2003.17 The direct costs of osteoarthritis were estimated at 1.6 billion Euros (€2002), representing approximately 1.7% of the expenses of the French
health insurance system. Hospitalization represented 50% of
the direct expenses. The costs of medication and physicians
were estimated at €574 million (34%) and €270 million (16%),
respectively. A 156% increase in direct medical costs was reported compared with 1993, which was related to an increase
in the number of OA patients (+54%). The authors mentioned
that the cost per patient increased by only 2.5% per year.
Lost labor/
productivity
(6%)
Help for housewives
at home (8%)
Transport
(0%)
Aid
devices
(9%)
Professional
time
(21%)
N Other European countries
For other European countries, no detailed estimations of the
cost of OA have been published in any of the journals included in the database we searched. In the United Kingdom, however, the National Institute for Clinical Excellence (NICE) has
reported that the burden of OA represents 1% of the GNP.19
Image and
laboratory
tests
(10%)
Drugs
(5%)
House/work/
self-care help
(28%)
Discussion
Hospital
admissions
(13%)
Figure 4. Direct and indirect costs of osteoarthritis in Spain.
Based on a sample of 1071 patients with a mean age of 71 years. Total cost
per year = €1502. Direct costs are represented in red and indirect costs in blue.
Data from reference 16: Loza et al. Arthritis Rheum. 2009;61:158-165. © 2009,
American College of Rheumatology.
The average total annual cost of osteoarthritis was estimated at €1502 per patient (€2007). Direct costs accounted for
86% of the total cost, mostly due to home, work, and selfcare help (29%), professional medical time (21%), and hospital admissions (13%) (Figure 4). Indirect costs represented
only 14% of the total cost, with the largest component related to providing help for housewives at home. Assuming a
prevalence of knee and hip OA of, respectively, 10% and 4%
in Spain, the authors estimated the national cost of OA at
200
N Germany
In a recent article, Sabariego et al aimed to determine the direct medical costs in patients with osteoporosis, osteoarthritis, back pain, or fibromyalgia in Germany.18 The mean direct
cost of OA was estimated at €1511 in a sample of 97 OA patients. Medication, outpatient physician visits, nonphysician
services, and inpatient services accounted for €699, €357,
€171, and €175, respectively.
This review suggests that OA represents a significant economic burden to patients and society in Europe. The annual
cost of OA per patient ranges from €1330 to €10 452, depending on the country and the approach taken (Table). When
considering only the direct medical costs, the annual cost
of OA ranges from €534 to €1788. Drug therapies represent between 5.3% and 24.8% of the total direct medical
costs,13-16 while hospitalizations and visits to health care professionals range from 15.2% to 39.6%,13,14,16 and from 35.5%
to 53.9%,13-16 respectively. Indirect costs range from €205 to
€8664 per year, depending on patient characteristics and
the mode of calculation of productivity losses.13-16 The direct
and indirect costs of OA were shown to increase with patient
age and with poorer quality of life in several studies.13,14,16
Our review highlights the importance of indirect costs on the
burden of OA. In particular, in studies assessing the burden of
OA in active patients, indirect costs were found to be greater
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Country
Total
costs
Direct medical
costs
Belgium13
€1330
€534
€796
Italy14
€2170
€588
€1237
€10 452
€1788
€8664
€1502
€724
€205
NR
€1511
NR
Netherlands15
Spain16
Germany18
Indirect
costs
Table. Annual total costs, direct medical costs, and indirect costs
of osteoarthritis per patient in Europe. NR, not reported.
than direct costs.13,15 Indirect costs are especially high in OA
as patients have to take days off work or early retirement, and/
or are less efficient at work.11 The analysis performed in the
Netherlands showed that the indirect costs related to reduced
work efficiency were considerable, representing more than
50% of the total cost of OA. 15 To adequately estimate the
burden of OA, it is therefore important to estimate not only the
indirect costs due to time off from work but also to reduced
work efficiency at work.
Cost variations were observed across the European studies.
These studies are, however, not directly comparable because
of differences in the approach taken, in patient characteristics,
and in health care systems. Moreover, there are methodological differences in the calculation of productivity losses and
no time adjustment was made for the costs. Despite such potential differences, the direct medical costs were very similar
in Belgium, Italy, and Spain.13,15,16
The burden of OA is considerable, both from a societal and
individual patient perspective. OA has a substantial effect not
only on health care budgets but also on patients, their employers, and their caregivers. For example, in Belgium, the
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costs of OA in active patients are distributed among the employers (45%), the health care system (41%), and the patients
themselves (14%). Therefore, in addition to pain and a poorer quality of life, patients living with OA may face significant
personal expenses due to OA.
Our review confirms the great magnitude and economic
impact of OA worldwide. Non-European countries have also
reported a substantial burden of OA. For example, in the
United States, the average direct cost of OA is approximately $2600 per year per person living with OA20, while in
Canada, the excess burden of OA was recently estimated
at Can$-1200.21
Cost-of-illness studies could be very useful in guiding health
care priorities but there are limitations to their use for health
care decision-making and they do not necessarily lead to more
efficient health care systems. Cost-effectiveness analyses are
potentially more interesting in order to assign health care resources more efficiently. By comparing the costs and effects
of health interventions, health economic evaluation is a powerful tool for decision makers.22 However, current economic
analyses in OA are limited and mainly pragmatic studies.23
Providing high-quality economic evaluations in OA would be
of major importance to help decision makers make rational
decisions and efficiently allocate health care resources dedicated to OA.
In summary, this review illustrates the immense burden of OA
to patients and society in Europe. Developing adequate treatment programs for OA is becoming increasingly important
to reduce the clinical and economic consequences of this
major public health problem worldwide. Establishing the most
effective treatments and determining the best use of resources
should also become a priority in this area. I
References
1. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights. Part 1:
the disease and its risk factors. Ann Intern Med. 2000;133:635-646.
2. Reginster JY. The prevalence and burden of arthritis. Rheumatology (Oxford).
2002;41(suppl 1):3-6.
3. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of
arthritis and other rheumatic conditions in the United States. Part I. Arthritis
Rheum. 2008;58:15-25.
4. Murphy L, Schwartz TA, Helmick CG, et al. Lifetime risk of symptomatic knee
osteoarthritis. Arthritis Rheum. 2008;59:1207-1213.
5. Murphy LB, Helmick CG, Schwartz TA, et al. One in four people may develop
symptomatic hip osteoarthritis in his or her lifetime. Osteoarthritis Cartilage.
2010;18:1372-1379.
6. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J
Public Health. 1994;84:351-358.
7. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and
8. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol. 2006;20:3-25.
9. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces
the risk for symptomatic knee osteoarthritis in women. The Framingham Study.
Ann Intern Med. 1992;116:535-539.
10. Nguyen US, Zhang Y, Zhu Y, Niu J, Zhang B, Felson DT. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data.
Ann Intern Med. 2011;155:725-732.
11. Hunsche E, Chancellor JV, Bruce N. The burden of arthritis and nonsteroidal
anti-inflammatory treatment. A European literature review. Pharmacoeconomics.
2001;19(suppl 1):1-15.
12. Segel J. Cost-of-Illness Studies - A primer. RTI-UNC Center of Excellence in
Health Promotion Economics. 2006.
13. Rabenda V, Manette C, Lemmens R, Mariani AM, Struvay N, Reginster JY. Direct and indirect costs attributable to osteoarthritis in active subjects. J Rheumatol. 2006;33:1152-1158.
14. Leardini G, Salaffi F, Caporali R, et al. Direct and indirect costs of osteoarthritis
of the knee. Clin Exp Rheumatol. 2004;22:699-706.
15. Hermans J, Koopmanschap MA, Bierma-Zeinstra SMA, et al. Productivity costs
and medical costs among working patients with knee osteoarthritis. Arthritis
Care Res. 2012;64:853-861.
16. Loza E, Lopez-Gomez JM, Abasolo L, et al. Economic burden of knee and hip
osteoarthritis in Spain. Arthritis Rheum. 2009;61:158-165.
17. Le Pen C, Reygrobellet C, Gérentes I. Financial cost of osteoarthritis in France.
The “COART” France study. Joint Bone Spine. 2005;72:567-570.
18. Sabariego C, Brach M, Stucki G. Determinants of major direct medical cost categories among patients with osteoporosis, osteoarthritis, back pain or fibromyalgia undergoing outpatient rehabilitation. J Rehabil Med. 2011;43:703-708.
201
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19. National Institute for Health and Clinical Excellence. Osteoarthritis: the care and
management of osteoarthritis in adults. Clinical Guideline 59. London, UK: NICE;
2008.
20. Gabriel SE, Crowson CS, Campion ME, OFallon WM. Direct medical costs
unique to people with arthritis. J Rheumatol. 1997;24:719-725.
21. Tarride JE, Haq M, O’Reilly DJ, et al. The excess burden of osteoarthritis in the
province of Ontario, Canada. Arthritis Rheum. 2012;64:1153-1161.
22. Drummond M, Sculpher M, O’Brien B, Stoddart G, Torrance G. Methods for
the economic evaluation of health care programmes. 3rd edition. New York, NY:
Oxford University Press; 2007.
23. Bruyère O, Reginster J. The need for economic evaluation in osteoarthritis. Aging
Health. 2009;5:591-594.
Keywords: burden, cost-of-illness, direct cost, economic, indirect cost, osteoarthritis
LE
POIDS ÉCONOMIQUE DE L’ARTHROSE EN
EUROPE
Cet article décrit, à l’aide de données publiées, le poids économique de l’arthrose en Europe et souligne les principaux coûts et leur poids respectif pour les patients et les gouvernements. Il montre que l’arthrose entraîne des
conséquences économiques significatives non seulement sur les budgets de soins de santé mais aussi sur les patients, leurs employeurs et leurs soignants. Le coût annuel total moyen de l’arthrose par patient en Europe varie de
1 330 € à 10 452 €. Si l’on ne prend en compte que les coûts médicaux directs, le coût annuel de l’arthrose varie de
534 € à 1 788 €. Chez les patients actifs, les coûts indirects sont beaucoup plus élevés que les coûts directs. Les
études européennes ne sont cependant pas directement comparables les unes avec les autres car les approches,
les caractéristiques du patient, les systèmes de soins et le calcul des pertes de productivité diffèrent. Notre article
confirme l’immense fardeau de l’arthrose en Europe, qui augmentera de façon importante dans le futur, avec les
changements démographiques et l’augmentation de l’obésité. Il devient donc crucial de développer des programmes
de traitement efficaces pour l’arthrose, afin de réduire les conséquences cliniques et économiques de ce problème
majeur de santé publique dans le monde entier.
202
THE QUESTION
CONTROVERSIAL
lthough the development
of secondary osteoarthritis
can readily be pinpointed,
the boundary between age-associated changes in articular cartilage and the pathogenetic changes
related to primary osteoarthritis is
not so easy to define. Changes in
cartilage with age are likely universal, but development of osteoarthritis is not. This article will discuss
the way to differentiate these two
fates of the joint.
QUESTION
A
Can normal age-related
changes in cartilage
be distinguished from early
osteoarthritic changes?
1.
L. A. Alekseeva, Russia
2.
J. P. A. Arokoski, Finland
3.
F. N. Birrell, United Kingdom
4.
S. Bölükbaşi,
çs Turkey
5.
O. P. Bortkevych, Ukraine
6.
P. Horák, Czech Republic
7.
A. El Maghraoui, Morocco
8.
A. Mahmoud Ali Elsayed, Egypt
9.
A. Migliore, Italy
10 .
T. Pap, Germany
11.
J. del Pino-Montes, Spain
12 .
C. A. F. Zerbini, Brazil
Can age-related cartilage changes be distinguished from early OA changes?
203
CONTROVERSIAL
QUESTION
1. L. A. Alekseeva, Russia
Lyudmila A. ALEKSEEVA, MD, PhD
Department of Metabolic Disorders of
Musculoskeletal System
Osteoarthritis and Osteoporosis Laboratories
(Russian Academy of Medical Sciences)
34 A, Kashirskoye shosse
115522 Moscow, RUSSIA
C
urrently, osteoarthritis (OA) is the most common of
all the musculoskeletal diseases, and this relates to
the general increase in life expectancy and the accumulation of risk factors. The main symptom of OA and immediate reason for seeking medical care is pain, and this remains a permanent symptom over time. Despite traditional use
of analgesic and anti-inflammatory drugs, most patients with
OA continue to experience pain.
There are many reasons for the occurrence of pain in OA and
many factors determining its severity. The proportion of patients with so-called “painful” or overtly symptomatic knee OA
increases with age and reaches almost 80% in the oldest age
group.1 Moreover, the individual perception of pain by each patient cannot be ignored, and may depend not only on changes
in the joint, but also on the emotional and social status of the
patient.
On the other hand, articular cartilage has no innervation and
cannot be a direct cause of pain, but the reduction in its thickness and volume with OA results in a higher load on the subchondral bone within the weight-bearing areas of the joint. Remodeling processes, which take place in these areas, lead to
the development of osteosclerosis, osteophytes, and microfractures, and eventually to an increase in the stiffness of subchondral bone that can cause significant syndromic pain. Another cause of pain is the formation of foci of bone marrow
edema and an increase in the intramedullary pressure.4
In recent years, evidence has accumulated about the role of
subchondral bone in the development of OA. Subchondral
bone has been found to be able to produce a large number
of proinflammatory cytokines and growth factors. Changes in
its microarchitecture can influence the intensity of pain, and
the bone mineral density value in subchondral areas of the
tibia can be considered as a predictor of OA progression.
All of this demonstrates the importance of investigating pain
in OA, especially given the available information that pain can
affect disease prognosis. As was described in the National
Health and Nutrition Examination Survey (NHANES)–1 and by
Mazzuca and colleagues,5,6 the initial level of pain in the knee
joint in OA is a risk factor for the development of functional
impairment and radiological progression in the future. I
References
The source of pain in OA can be almost any structure of the
joint: the synovial membrane, bone, or soft tissues.2 Mechanisms of pain perception may include activation and local release of pro-inflammatory mediators, such as prostaglandins
and cytokines. Clinically, however, there is often a disparity between the degree of pain perception and the extent of destructive changes in the joint. A study with functional magnetic resonance imaging revealed that numerous areas in the
brain are involved in the occurrence of pain in OA. This study
demonstrated that perception of pain in OA is a complex
mechanism involving local factors and the activation of central pain pathways.3
204
1. McAlindon TE, Cooper C, Kirwan JR, Dieppe PA. Knee pain and disability in the
community. Br J Rheumatol. 1992;31:189-192.
2. Creamer P, Hunt M, Dieppe P. Pain mechanisms in osteoarthritis of the knee: effect of intraarticular anesthetic. J Rheumatol. 1996;23:1031-1036.
3. Sofat N, Ejindu V, Kiely P. What makes osteoarthritis painful? The evidence for
local and central pain processing. Rheumatology. 2011;50:2157-2165.
4. Sowers MF, Hayes C, Jamadar D, et al. Magnetic resonance-detected subchondral bone marrow and cartilage defect characteristics associated with pain and
X-ray-defined knee osteoarthritis. Osteoarthr Cartil. 2003;11:387-393.
5. Hassan BS, Doherty SA, Doherty M. Effect of pain reduction on postural sway,
proprioception, and quadriceps strength in subjects with knee osteoarthritis. Ann
Rheum Dis. 2002;61:422-428.
6. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Severity of joint pain and Kellgren-Lawrence grade at baseline are better predictors of joint space narrowing
than bone scintigraphy in obese woman with knee osteoarthritis. J Rheumatol.
2005;32:1540-1546.
CONTROVERSIAL
QUESTION
2. J. P. A. Arokoski, Finland
Cartilage in osteoarthritis
Jari P. A. AROKOSKI, MD, PhD
Clinical Lecturer and Adjunct Professor
(docent) of Physical and Rehabilitation
Medicine, Department of Physical
and Rehabilitation Medicine
Kuopio University Hospital
P. O. B. 1777, FI-70211 Kuopio
FINLAND
T
he etiology of osteoarthritis (OA) is not fully understood,
but there are known to be several predisposing risk factors for the condition.1 These include obesity, injuries to
the joints, and—most importantly—old age. The prevalence
and incidence of OA increases with age.2 However, although
epidemiological studies seem to indicate that primary OA and
aging are interrelated, aging does not directly cause OA.3 Agerelated changes in the musculoskeletal system may contribute
to the development of OA by making the joints more susceptible to the effects of other OA risk factors.3 Several novel aging theories such as progressive apoptotic cell loss, mitochondrial degeneration, and cell senescence have been proposed
to account for the cartilage degeneration in OA.4
The pathogenetic changes in primary, and especially early, OA
are difficult to distinguish clinically from normal aging, but there
are some differences discernible between these two fates of
the joint. The current research in this area focuses on articular cartilage.
Age-related changes in cartilage
Articular cartilage undergoes significant structural and mechanical changes with age.2 Articular cartilage collagen and
proteoglycan metabolism are relatively active during growth
and adolescence, but in adult individuals, the metabolism within cartilage is more sluggish.5 There is evidence of an increasing prevalence of articular surface fibrillation with age,2 and cartilage also thins with age, suggesting a loss of the cartilage
matrix.3
OA is characterized by a deterioration and progressive loss
of articular cartilage, and it manifests clinically with pain that
does not occur in normal aged cartilage.1 In experimental models of OA, some of the first detectable abnormalities that can
be observed even before there is any deterioration visible on
the cartilage surface include a decrease in the superficial proteoglycan concentration, increased water content, and the
separation and disorganization of the superficial collagen fibrils.1 In early OA, the synthesis of both type II collagen and
proteoglycans is increased. Advanced OA with fibrillation is
accompanied by a net loss and damage to type II collagen
fibrils, as well as a loss of proteoglycans. The loss of proteoglycans and collagen results in diminished cartilage stiffness.
At the molecular level, OA is viewed as being a metabolically
active process, including both cartilage destruction and repair.5 This equilibrium is regulated by the complex interplay
between anabolic growth factors (especially TGFβ and IGF-1)
and catabolic proinflammatory cytokines (especially IL-1 and
TNFα ). In a normal joint, these mediators are present at low
levels to maintain the homeostasis of cartilage, but in OA,
these processes become imbalanced, with the increased proteolytic degradation being mediated by matrix metalloproteinases, ie, collagenases and stromelysins.
Early diagnosis of osteoarthritis
The traditional diagnostic techniques, plain X-ray imaging or
arthroscopic examination, can only detect late and major tissue changes in OA and are incapable of differentiating early
cartilage OA changes from age-associated changes. However, early diagnosis would be highly advantageous as initial
OA changes may still be reversible.6 Recent developments in
quantitative imaging techniques, including magnetic resonance
imaging and ultrasound methods, as well as more sensitive
biomarkers, mean that diagnostic evaluation of cartilage in early OA may in the future become reality.6 I
References
This might be due to the fact that chondrocytes become less
responsive to the proliferative and anabolic effects of growth
factors with increasing age.3 Aggrecan, the major cartilage proteoglycan, decreases in molecular size and content,5 and this
would be expected to reduce cartilage stiffness and hydration.3 There is no major change in the content of total collagen
and pyridinoline during aging, but there is a marked increase
in the formation of advanced glycation end products, including pentosidine crosslinks, making the cartilage more brittle.3
1. Arokoski JPA, Jurvelin J, Väätäinen U, Helminen HJ. Normal and pathological
adaptation of articular cartilage to joint loading. Scand J Med Sci Sports. 2000;
10:186-198.
2. Martin JA, Buckwalter JA. Roles of articular cartilage aging and chondrocyte
senescence in the pathogenesis of osteoarthritis. Iowa Orthop J. 2001;21:1-7.
3. Loeser RF. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
4. Aigner T, Richter W. OA in 2011: age-related OA—a concept emerging from infancy? Nat Rev Rheumatol. 2012;10:70-72.
5. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626-634.
6. Chu CR, Williams AA, Coyle CH, Bowers ME. Early diagnosis to enable early treatment of pre-osteoarthritis. Arthritis Res Ther. 2012;14:212.
205
CONTROVERSIAL
QUESTION
3. F. N. Birrell, United Kingdom
joint in early OA include synovitis and ligament/enthesis and
subchondral bone abnormalities: the importance of these
changes relates to their association with pain, which in clinical
studies has been of stronger importance than early joint space
narrowing (although advanced disease has a very strong relationship with radiographic change,3 in contrast to earlier assertions). Specific enzymes, such as matriptase, are upregulated in OA cartilage,4 which suggests potential relevance as
a target for treatment.
Fraser N. BIRRELL, MD, PhD, FRCP
Musculoskeletal Research Group
Institute of Cellular Medicine
4th Floor, Cookson
Framlington Place, Newcastle University
Newcastle NE2 4HH, UK
T
he short answer is yes. However, interest and a degree
of controversy derive from the techniques that are available to discriminate between the two and consideration of whether osteoarthritis (OA) is a disease restricted to
cartilage alone or should more correctly be considered a disease of the whole joint.
The main techniques used to investigate cartilage include imaging, histology, and gene expression profiling. Clinically, the
most useful test would be one that is noninvasive and readily available. Unfortunately, plain radiographs usually provide
no direct visualization of cartilage, unless chondrocalcinosis
is present, and the indirect evidence is limited by difficulties
in interpreting joint space, which is affected by positioning,
and the variable interposition of other low-density tissues such
as menisci. High-resolution musculoskeletal ultrasound and
magnetic resonance imaging can directly visualize cartilage, but
there is a lack of true population data on age-related changes,
even with magnetic resonance imaging. Large studies, for example Osteoarthritis Initiative, sponsored by the National Institutes of Health in the United States,1 have focused on a single joint (the knee) and used convenience sampling.
However, probably the most definitive current technique for
distinguishing OA from age-related change alone in cartilage
is gene expression profiling. A recent study by Loeser et al 5
has shown that there are quite different profiles in young versus aged mice, with 493 genes showing differential expression and an age-related decrease in matrix gene expression
and increase in immune and defense response gene expression. Thus, there is a characteristic aging gene profile signature in mice. Replication in humans will provide us with an invasive tool for discriminating age-related change: arguably
a controversial answer to the controversial question.
A growing appreciation of OA as a disease of the whole joint
suggests that a narrow focus on cartilage alone is, however,
probably counterproductive. Ongoing longitudinal studies will
allow us to define which changes in and around the joint are
associated with progression and response to treatment. We
should increasingly use these predictors and regard cartilage
changes as just one of several key outcomes of OA. I
References
Histological techniques include macroscopic examination of
cartilage sections for thinning and fibrillation and microscopic
examination with stains for proteoglycans (such as Safranin O).
While grading systems for cartilage are discriminating for advanced disease, early OA changes may be difficult to discriminate from age-related change using grading systems for cartilage alone.2 Three other approaches to discriminate early
OA changes are: microscopic examination of the whole joint,
measurement of specific enzymes upregulated in OA, and
gene expression profiling. Pathological changes around the
206
1. Osteoarthritis Initiative. Available at: http://oai.epi-ucsf.org/datarelease/. Accessed
November 21, 2012.
2. McNulty MA, Loeser RF, Davey C, Callahan MF, Ferguson CM, Carlson CS.
Histopathology of naturally occurring and surgically induced osteoarthritis in
mice. Osteoarthritis Cartilage. 2012;20:949-956.
3. Neogi T, Felson D, Niu J, et al. Association between radiographic features of
knee osteoarthritis and pain: results from two cohort studies. BMJ. 2009;339:
b2844.
4. Milner JM, Patel A, Davidson RK, et al. Matriptase is a novel initiator of cartilage
matrix degradation in osteoarthritis. Arthritis Rheum. 2010;62:1955-1966.
5. Loeser RF, Olex AL, McNulty MA, et al. Microarray analysis reveals age-related
differences in gene expression during the development of osteoarthritis in mice.
Arthritis Rheum. 2012;64:705-717.
CONTROVERSIAL
QUESTION
4. S. Bölükbaşi, Turkey
Selçuk BÖLÜKBAŞI, MD
and Traumatology
Gazi University School of Medicine
06500 Besevler
Ankara, TURKEY
C
urrently, it is not possible to give an exact answer to
this question. In order to begin to answer the question, one must first elucidate whether or not aging of
the cartilage is the same process as cartilage degradation.
As the role of mitochondria is known in degenerative diseases,
a study was conducted to investigate mitochondrial function
in healthy chondrocytes and osteoarthritic chondrocytes, as
well as age-related changes in mitochondria. The study showed
that mitochondrial mass was increased in osteoarthritic chondrocytes, but no correlation was found between mitochondrial function and age in normal and osteoarthritic chondrocytes.1 This result suggests that cartilage aging and cartilage
degradation are two separate processes.1
In another study, the matrix homeostasis of a healthy human
ankle was evaluated.2 Type I collagen synthesis and denaturation were found to be associated with the pericellular matrix, and the type II collagen (CII) and proteoglycan content in
the matrix were determined as remaining constant throughout life. Age had an important effect on the denaturation of CII,
which decreased as age increased, relative to collagenasemediated cleavage.2 These observations suggest that cartilage aging and the osteoarthritic process are two separate
processes, since the aging of the ankle cartilage bore no resemblance to the molecular degenerative changes of osteoarthritis.2 Thus, a clear difference emerges between aging and
osteoarthritis.
arthritis is a multifactorial disease and age is the major (but not
only) risk factor, it is difficult to determine whether cartilage
degradation and cartilage aging are different processes.
In an experimental study, the accumulation of advanced glycation end products (AGEs) was investigated in relation to osteoarthritis.3 AGEs adversely affect the formation of cartilage,
lead to the formation of osteoarthritis, and increase with aging.
In this study, the accumulation of AGEs was found to cause a
tendency to develop osteoarthritis. The results showed that
higher AGE levels in the cartilage increased the severity of osteoarthritis, and they provided the first in vivo molecular evidence to demonstrate the role of aging in the development of
osteoarthritis.3
With the development of microarray technology, studies have
emerged suggesting that gene expression analysis of subchondral bone can be conducted in early experimental osteoarthritis and can be used in its diagnosis and treatment.4
However, it is currently impossible to obtain suitable subchondral bone and cartilage samples from humans and animals
in order to study the beginning and early stages of osteoarthritis.4 Another study indicated that by measuring certain
biomarkers of bone, cartilage, and synovial metabolism (sC2C,
uCTX-II, sCPII, uNTx, and sHA), changes in cartilage matrix
and early structural changes in cartilage could be identified.5
This and many similar studies show that biomarkers may be
important indicators of early-stage osteoarthritis. With such
biomarkers, it could be possible to differentiate early osteoarthritis from cartilage aging.
To date, studies have not been able to clearly reveal the distinction between osteoarthritis and cartilage aging. It is therefore difficult to distinguish primary osteoarthritis in its early
stages from cartilage aging, hence the need for further studies in this area. I
References
On the basis of the two aforementioned studies, new investigative molecular studies could in the future be used routinely to help differentiate the early stage of osteoarthritis from cartilage aging. Currently, however, the results of studies such
as these are not completely clear and remain to be clarified.
Additionally, contrary to the aforementioned results, aging is
one of the most important risk factors in the development of
osteoarthritis, and more than 50% of the population over the
age of 60 years have osteoarthritic joints.3 Because osteo-
1. Manerio E, Martin MA, Andres MC, et al. Mitochondrial respiratory activity is altered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 2003;48:
700-708.
2. Aurich M, Poole R, Reiner A, et al. Matrix homeostasis in aging normal human
ankle cartilage. Arthritis Rheum. 2002;46:2903-2910.
3. De Groot J, Verzijl N, Wenting-van Wijk MJG, et al. Accumulation of advanced
glycation end products as a molecular mechanism for aging as a risk factor in
osteoarthritis. Arthritis Rheum. 2004;50:1207-1215.
4. Zhang Y, Fang H, Chen Y, et al. Gene expression analyses of subchondral bone
in early experimental osteoarthritis by microarray. PloS One. 2012;7:1-19.
5. Ishijima M, Watari T, Naito K, et al. Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins
of pain in early knee osteoarthritis. Arthritis Res Ther. 2011;13:R22.
207
CONTROVERSIAL
QUESTION
5. O. P. Bortkevych, Ukraine
Normal aging involves a marked increase in the formation of
advanced glycation end products, including pentosidine crosslinks. The resultant increased crosslinking of collagen molecules can alter the biomechanical properties of cartilage, resulting in increased stiffness and susceptibility to fatigue.
Oleg P. BORTKEVYCH, MD, PhD, DMedSc
Department of Clinical Rheumatology
National Scientific Centre M. D. Strazhesko
Institute of Cardiology
5, Narodnogo Opolcheniya St, 03151
UKRAINE
steoarthritis (OA) is a disease of the joint affecting all
joint tissues. Similarly, joint aging is systemic. Age is
the most prominent risk factor for OA, and although
the relationship between aging and OA is well known, its mechanisms are not fully understood.
A highly prevalent change in aging cartilage is deposition of
calcium-containing crystals due to increased pyrophosphate
production by chondrocytes. Calcium crystals may stimulate
chondrocyte production of inflammatory mediators and extracellular matrix–degrading enzymes, contributing to the onset
and progression of OA, and may play a role in erosive OA, a
more destructive form of OA most commonly seen in the distal interphalangeal joints in elderly women.
Joint changes that are both intrinsic and extrinsic (sarcopenia, altered bone remodeling, reduced proprioception) contribute to OA development. The concept that aging contributes
to, but does not directly cause OA, is consistent with the multifactorial nature of the condition and the joints most commonly affected. OA normally develops after long periods of
exposure to risk factors such as obesity, joint trauma, joint
malalignment, or abnormal shape and leg length inequality.
Age-related changes occur in the joint tissues of all individuals, most notably in articular cartilage. However, symptomatic,
radiographic, macroscopic, or microscopic signs of OA do not
manifest in all individuals, even at an advanced age. This suggests that aging does not necessarily cause OA, rather agerelated changes provide a basis upon which OA can develop.
Age-associated cellular changes in articular cartilage include
cell depletion and impaired responses to extracellular stimuli
resulting in abnormal gene expression and cell differentiation.
In full-thickness cartilage, cell density decreases with aging. In
OA-affected cartilage, chondrocyte proliferation in the form
of “cell clusters” or “cloning” has been observed in areas of
fibrillation. Cells in these clusters express progenitor cell markers and a wide spectrum of proteins associated with abnormal chondrocyte activation and differentiation. This represents
a tissue repair response of progenitor cells. The activation pattern of the cluster cells also underscores the notion that aging
does not uniformly affect all cells in cartilage and that certain
cell subsets in aging and OA-affected cartilage are capable
of proliferation and activation.
Individuals with OA risk factors may undergo an accelerated
rate of change similar to that associated with aging, consistent with the concept that aging results from an imbalance between stressors causing damage and mechanisms that repair or protect against damage.
With increasing age, chondrocytes become less responsive
to the proliferative and anabolic effects of growth factors,
which may contribute to an imbalance between anabolic and
catabolic activity. Altered cell signaling in response to growth
factors may also account for the reduced anabolic response
with age.
O
In both aging and OA, changes occur in the total amount and
composition of articular cartilage extracellular matrix, which
also undergoes proteolysis and other modifications. The superficial zone is where the earliest age-related changes occur
in human articular cartilage. In OA, increased proteolytic activity in cartilage and synovial fluid causes cartilage matrix
changes and increased degradation of collagen molecules.
There is also a decrease in fixed charge density due to degradation and loss of aggrecan.
208
Conceptually, age-related pathologies originate from limitations
in the maintenance and repair mechanisms of DNA, anomalies in the antioxidant mechanisms that contribute to the detoxification of reactive oxygen species, or abnormalities in
mechanisms for removal of abnormal proteins and organelles.
A clear distinction between aging and OA has not always been
provided, so that it can be difficult to differentiate primary agerelated changes from those that are part of the OA process. I
CONTROVERSIAL
QUESTION
6. P. Horák, Czech Republic
Pavel HORÁK, MD, PhD
Department of Internal Medicine
Nephrology, Rheumatology, Endocrinology
Faculty of Medicine and Dentistry
Palacký University of Olomouc
I. P. Pavlova 6
772 00 Olomouc
CZECH REPUBLIC
O
steoarthritis (OA) is a slow-developing disease of the
diarthrodial joints associated with progressive cartilage damage, soft tissue and subchondral bone
changes, bony osteophytes, and joint inflammation. OA is most
common in the hands, causing significant pain and functional loss, but involvement of the knees or hips is usually more
disabling. Aging is the most important risk factor, followed
by obesity, previous joint injury, female sex, and genetic disposition. Two fundamental mechanisms lead to OA: normal
load on abnormal cartilage (primary OA) or abnormal load on
normal cartilage (secondary OA). Although cartilage aging is
universal, OA is not found in all elderly people; a proportion of
them are free of symptomatic and radiographic OA, indicating the presence of additional risk and/or protective factors.
There are several theories explaining the pathogenesis of primary OA. The oldest theory, wear and tear of the cartilage matrix, emphasizes the effect of mechanical load over a lifetime.
The extracellular matrix theory links OA to intrinsic changes
in proteoglycans, the collagen network, and chondrocyte biology that are caused by advanced glycation end products
and oxidative stress. The apoptotic theory views OA as the
result of chondrocyte apoptosis or other types of cell death.
The mitochondrial theory emphasizes the role of mitochondrial DNA damage, which may be advanced by inflammatory cytokines, contributing to chondrocyte energy failure and
death. A recent theory on cell senescence describes OA as
the increasing inability of the chondrocytes to keep up with
mechanical or inflammatory attacks leading to failure in maintaining cartilage integrity.
The causes of cell aging remain unclear, but it is increasingly
accepted that there are a limited number of cell replication
cycles, culminating in replicative senescence. Replication is
limited by telomere exhaustion. Telomeres are eroded by each
division cycle, eventually down to the minimum length for DNA
replication, resulting in cycle arrest.
In adults, subchondral bone isolates cartilage from the vascular system, resulting in no influx of progenitor cells into cartilage. Chondrocytes are postmitotic, with little or no cell turn-
over, and are among the oldest cells in the body. They accumulate age-related changes and are also unable to move
from damaged regions due to the constraint of the extracellular matrix. Aside from aging, repeated injuries (joint instability) increase the requirements for replication and damage
repair and thus contribute to the exhaustion of mitotic potential. As a result of the specific local environment, oxidatively damaged molecules can accumulate in chondrocytes,
leading to a decreased ability to maintain matrix synthesis and
homeostasis. Chondrocyte senescence reduces the ability
to respond to growth factor stimulation, contributing to an
imbalance in cartilage formation and degradation, as well as
decreased chondrocyte anabolic activity. Furthermore, senescence-associated secretory phenotype (SASP) may negatively affect the local environment. Cells exhibiting SASP produce proinflammatory cytokines and matrix metalloproteinases
very similar to those in OA. Another cell senescence factor,
high-mobility group box protein 2, regulates gene transcription and decline in the superficial zone of aging chondrocytes and is associated with increased chondrocyte death in
OA models.
Current findings support the view that cartilage aging usually
occurs before overt primary OA. In many cases, it is impossible to distinguish the senescent chondrocyte from the osteoarthritic chondrocyte because cell senescence is the number
one precondition for OA. There is some evidence of increased
chondrocyte proliferation during the development of OA, and
chondrocyte death has also been observed, with reduced
numbers particularly in the superficial regions of cartilage.
However, it is not clear if the cell damage and reactivity represent changes associated with the aging process, early OA,
or a continuum from aging to OA.
A better understanding of the role of senescence biology in OA
development may translate practically into the development
of new strategies to delay the onset of chondrocyte senescence and prevent the development or progression of OA. I
Further reading
1. Aigner T, Richter W. Age related OA—a concept emerging from infancy? Nat
Rev Rheumatol. 2012;8:70-72.
2. Horton Jr WE, Bennion P, Yang L. Cellular, molecular, and matrix changes in
cartilage during aging and osteoarthritis. J Musculoskelet Neuronal Interact.
2006;6:379-381.
3. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
4. Anderson AS, Loeser RF. Why is osteoarthritis an age-related disease? Best
Pract Res Clin Rheumatol. 2010;24:15-26.
5. Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence
and osteoarthritis. Biogerontology. 2002;3:257-264.
209
CONTROVERSIAL
QUESTION
7. A. El Maghraoui, Morocco
Abdellah El MAGHRAOUI, MD
Professor of Rheumatology
Rheumatology Department
Military Hospital Mohammed V
Rabat
MOROCCO
O
steoarthritis (OA) is a common age-related disorder,
often described as a chronic degenerative disease
and thought by many to be an inevitable consequence of growing old. Epidemiological studies show that age
remains the most prominent risk factor for the initiation and
progression of primary OA in susceptible joints.1 The prevalence of OA increases with age: radiographic surveys of multiple joints (hands, spine, hips, and knees) reveal the presence of OA in at least one joint in over 80% of older adults.2
However, not all older adults with symptoms of joint pain have
radiographic evidence of OA in the painful joint, and only about
half of people with radiographic OA experience significant
symptoms. Moreover, it is well-known that not all older adults
develop OA and not all joints in the body are affected to the
same degree. It is also well-known that radiographic OA
changes, particularly osteophytes, are common in the aged
population, but symptoms of joint pain are frequently independent of radiographic severity. Consequently, due to the discrepancies between osteoarthritic pain and radiographic evidence of OA, most current epidemiological studies define OA
through a combination of clinical and radiographic criteria.
The current concept is that OA is a disease of the “whole joint,”
which involves a complex series of molecular changes at the
cell, matrix, and tissue levels and complex interactions between the tissues that make up the joint. Aging is the major
risk factor, and it contributes to, but does not directly cause
OA. This is consistent with the multifactorial nature of the condition and the differing joints most commonly affected. Besides age, the common risk factors for OA include obesity,
previous joint injury, genetics, and anatomical factors including joint alignment. These risk factors appear to interact with
age to determine which joints are affected by OA and how
severe the condition will be. Thus, there are important differences between an aged joint and one with OA. Age-related
210
mechanical stress on joint cartilage (arising from a number of
factors, including altered gait, muscle weakness, degeneration of ligaments, changes in proprioception, and changes in
body weight), and changes within the joint (including cell and
matrix changes in joint tissues, thickening of the subchondral
bone, variable degrees of synovial inflammation, loss of meniscal tissue, and hypertrophy of the joint capsule contributing
to joint enlargement) contribute to the development of OA
when other OA risk factors are also present.3 The pathological changes noted in the other joint tissues also contribute
to the loss of normal joint function, and because, unlike cartilage, they contain pain fibers, these tissues are responsible
for the pain experienced by people with OA.
Thus, it is very important to question how to distinguish normal age-related changes in cartilage that do not progress to
OA from early changes that reliably do progress to OA. In this
regard, magnetic resonance imaging (MRI) studies have shown
promising results. New methodological approaches for quantitative assessment have been introduced, and an MRI-based
definition of OA has been suggested.4 A recent study using
MRI methods sensitive to cartilage matrix composition demonstrated that subjects at risk for OA have both higher and more
heterogeneous cartilage T2 values than controls, and that T2
parameters are associated with morphologic degeneration.5
One could speculate that the development of these kinds of
techniques could help to distinguish age-related changes in
cartilage that predispose patients to OA from those that do
not. More information is needed to better understand how
aging changes in the bone, meniscus, and ligaments contribute to the development of OA. I
References
1. Aigner T, Richter W. OA in 2011: age-related OA—a concept emerging from infancy? Nat Rev Rheumatol. 2012;8:70-72.
3. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the pathogenesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2012;
20:423-435.
4. Hunter DJ, Arden N, Conaghan PG, et al. Definition of osteoarthritis on MRI: results of a Delphi exercise. Osteoarthritis Cartilage. 2011;19:963-969.
5. Joseph GB, Baum T, Carballido-Gamio J, et al. Texture analysis of cartilage T2
maps: individuals with risk factors for OA have higher and more heterogeneous
knee cartilage MR T2 compared to normal controls—data from the osteoarthritis initiative. Arthritis Res Ther. 2011;13:R153.
CONTROVERSIAL
QUESTION
8. A. Mahmoud Ali Elsayed, Egypt
Adel Mahmoud ALI ELSAYED, MD
Professor of Internal Medicine
Head of Rheumatology Division
Ain Shams University
53 El Makrizy Street
Roxy, Cairo
EGYPT
A
rticular cartilage is a unique tissue from the perspective of aging, in that chondrocytes and the majority
of the extracellular matrix proteins experience little
turnover, thus resulting in a tissue that must withstand years
of use and can also accumulate years of aging-associated
changes. It has been known for a very long time that aging
is the most prominent risk factor for the initiation and progression of osteoarthritis. This might be related to continuous mechanical wear and tear and/or time/age-related modifications
of cartilage matrix components. In addition, a mere loss of viable cells over time due to apoptosis or any other mechanism
might contribute. More recent evidence, however, supports
the notion that stressful conditions for the cells might promote chondrocyte senescence and be particularly important
in the progression of the osteoarthritic disease process.1
In animal models, aging predisposes articular cartilage to
changes in viable cell density and to expression of specific proapoptotic genes. Also, fetal and young (but still skeletally mature) bovine chondrocytes behave similarly, while aged chondrocytes display diminished proliferation, slightly reduced
proteoglycan accumulation, and significantly less collagen accumulation per cell compared with the younger cells. Histological observations and mechanical properties support these
findings, and a particularly significant reduction in the tensile
stiffness produced by aged chondrocytes compared with
younger cells has been observed.2
In humans, chondrocytes from normal but aged subjects display biochemical properties closer to osteoarthritic-derived
cartilage than to normal young cartilage, as indicated by cell
morphology, cell proliferation rate, and patterns of protein secretion (in particular stromelysin-1 and interstitial collagenase).3
During aging, nonenzymatic glycation results in the accumulation of advanced glycation end products (AGEs) in cartilage
collagen. The highest AGE levels are found in tissues with
slow turnover, such as cartilage. AGEs exert their effects by adversely affecting the biomechanical, biochemical, and cellular characteristics of the tissue, as well as by modulating tissue turnover.
This ultimately increases cartilage stiffness and brittleness, increases chondrocyte-mediated proteoglycan degradation,
reduces resistance to matrix metalloproteinase–mediated degradation, and decreases proteoglycan synthesis by chondrocytes. Articular cartilage becomes more prone to damage
and development of osteoarthritis.4
In addition, an age-associated reduction in growth factor signaling and an increase in oxidative stress may also play an important role in the age-osteoarthritis connection.5
Although different studies have shown that age is inversely associated with cartilage volume, cartilage turnover, and aggrecan expression in healthy individuals, the exact differentiation
between aged cartilage and early osteoarthritic cartilage seems
difficult, and age-related changes leading to failure of human
articular cartilage to resist damage are considered to be OA. I
References
1. Aigner T, Haag J, Martin J, Buckwalter J. Osteoarthritis: aging of matrix and
cells—going for a remedy. Curr Drug Targets. 2007;8:325-331.
2. Tran-Khanh N, Hoemann CD, McKee MD, Henderson JE, Buschmann MD.
Aged bovine chondrocytes display a diminished capacity to produce a collagen-rich, mechanically functional cartilage extracellular matrix. J Orthop Res.
2005;23:1354-1362.
3. Dozin B, Malpeli M, Camardella L, Cancedda R, Pietrangelo A. Response of
young, aged and osteoarthritic human articular chondrocytes to inflammatory
cytokines: molecular and cellular aspects. Matrix Biol. 2002;21:449-459.
4. DeGroot J. The age of the matrix: chemistry, consequence and cure. Curr Opin
Pharmacol. 2004;4:301-305.
5. Loeser RF Jr. Aging cartilage and osteoarthritis—what's the link? Sci Aging
Knowledge Environ. 2004;pe31.
211
CONTROVERSIAL
QUESTION
9. A. Migliore, Italy
cretory phenotype has some features in common with the OA
chondrocyte phenotype, including increased production of
cytokines and matrix metalloproteinases.
Alberto MIGLIORE, MD
Director UOS of Rheumatology
Hospital Villa S. Pietro
Rome, ITALY
A
ging is the main risk factor for primary osteoarthritis
(OA) and OA is the disease most strongly correlated
with aging. Both in humans and other animals, OA
development seems to be not rigorously time-dependent, but
to hold pace with the aging process. Despite older age being
the greatest risk factor for OA, OA is not an unavoidable consequence of growing old. Moreover, radiographic changes indicative of OA—mainly osteophytes—are frequent in the aged
population, but symptoms of joint pain may not correlate with
the severity of radiographic findings in many older subjects.
OA is a degenerative disease characterized by structural
changes to joint tissues that include synovial inflammation,
catabolic destruction of articular cartilage, alterations in subchondral bone, and decreasing muscle strength.
This article will only address differences between cartilage
changes caused by OA and those caused by aging. The effects of aging involve the whole articular cartilage. Major extracellular matrix changes comprise reduced cartilage thickness, proteolysis, advanced glycation, and calcification. Cellular
changes consist of decreased cell density, cellular senescence with reduced chondrocyte survival, decreased mitotic
and anabolic activity, anomalous cytokine excretion, and impaired cellular resistance.
One of the most pronounced age-related changes in chondrocytes is a senescent phenotype, which is caused mainly
by the accumulation of reactive oxygen species (ROS) and
advanced glycation end products. Senescent chondrocytes
display an impaired ability to respond to many mechanical
and inflammatory insults. Protein secretion is also altered in
aging chondrocytes, as demonstrated by a decrease in anabolic activity and increased production of proinflammatory
cytokines and matrix-degrading enzymes. The senescent se-
212
The age-related increase in ROS levels could play an important role in OA. The various inflammatory mediators that are
increased in OA, including IL-1, IL-6, IL-8, TNF-α, and other
cytokines, can all stimulate additional production of ROS. Excess ROS production can directly damage intracellular proteins and DNA, as well as the extracellular matrix, by stimulating matrix metalloproteinase production and activity, thus
playing a significant role in stimulation of cartilage degradation in OA.
The extracellular and cellular changes in aging compound each
other, leading to biomechanical dysfunction and tissue destruction. Some of these changes differ from those seen in OA,
which is also characterized by cell activation with increased
proliferation and gene expression. Disruption of the articular surface or superficial zone (SZ) seems to be a key triggering event for the chronic and progressive extracellular matrix degradation process leading to OA. The SZ contains the
majority of mesenchymal stem cells in adult cartilage. The
presence of stem cells endows the SZ with the capacity for
self-renewal, which may be required to respond to mechanical stress. However, the SZ can be compromised by acute
or chronic mechanical stress and by age-related cellular dysfunction. Once the SZ is disrupted, cartilage cells are activated, and through the production of matrix-degrading enzymes, lesions enlarge causing joint inflammation, pain, and
dysfunction. Loss of cells (eg, via apoptosis) is among the major changes that occur in the SZ due to aging and exposure
to mechanical stress.
Cartilage degradation results in the production of fragments of
extracellular matrix molecules. Some of these molecules may
be detected in blood, serum, synovial fluid, and urine, and
can act as useful biomarkers. The ability to detect biomarkers
of cartilage degradation may enable clinicians to differentiate
the appearance of subclinical OA from natural joint aging. Biomarkers indicating early phases of degeneration would be
useful in detecting preradiographic OA changes. Proteomic
techniques have the potential to improve our understanding
of OA pathophysiology. I
CONTROVERSIAL
QUESTION
10. T. Pap, Germany
Thomas PAP, MD
Institute of Experimental
Musculoskeletal Medicine
University Hospital Münster
Domagkstrasse 3
D-48149 Münster
GERMANY
O
steoarthritis (OA) is the most frequent joint disease
and an important cause of disability in the Western
world. It involves all parts of articular joints and is
characterized primarily by the progressive, irreversible loss of
articular cartilage. Given that the incidence of osteoarthritic
changes increases with age, the question of whether OA is a
mere aging phenomenon or as with cardiovascular disorders,
cancer, or neurodegenerative diseases, becomes more frequent during aging because of the cumulative effects of pathogenic factors (which in principle can affect individuals at any
age), is a controversial, yet important, one.
One main reason for the difficulty in answering this question
is that the processes that lead to and characterize normal
cartilage aging remain largely unknown. While it is well accepted that the composition of the extracellular matrix changes
with aging, aside from the loss of proteoglycans, disease-specific alterations in osteoarthritic cartilage are poorly characterized and understood. Also, OA most likely does not constitute a uniform disease, but rather an initially complex yet
ultimately narrow path of how cartilage responds to different
types of stress. In this context, it has been suggested that inflammation is a distinguishing factor between normal aging
and OA.1 However, the role of inflammation as a trigger and
accelerating force of osteoarthritic changes remains controversial, and while some recent data suggest a key role for
inflammatory signals, the most recent studies have failed to
demonstrate a key role for IL-1–mediated inflammation in
murine models of OA.2 Of interest, several lines of evidence
indicate that osteoarthritic changes are linked to the reexpression in chondrocytes of molecules and pathways that
are characteristic of different stages of endochondral ossification during embryonic development.3
Members of the syndecan family of transmembrane heparin
sulfate proteoglycans, particularly syndecan-4, are prominent
examples in this respect.4 We were able to show that syndecan-4, which is expressed prominently in hypertrophic chondrocytes of developing joints in the embryo, is reexpressed
both in human OA and in animal models of the disease, and
its concentration correlates with disease severity.4 Interestingly, the loss of syndecan-4 in genetically modified mice, as
well as its inhibition by specific antibodies, was capable of
preventing the development of OA-like changes.4 These data
are also of interest because according to recent data, increased expression of syndecan-2 can compensate for the
loss of syndecan-4 during embryogenesis but not during OA,
due to differential regulation of these two syndecans. While
the exact mechanisms are not fully understood, these data
suggest that while the program appears to be similar, the
triggers and mechanisms of cartilage remodeling during endochondral ossification and OA may be distinct.
Given that during endochondral ossification, deposition of basic calcium phosphate crystals is an important part of bone
formation, calcification of articular cartilage during OA is another indication of similarities between both conditions. Our
group found that the calcification of hyaline cartilage is a regular event in human OA and is strongly associated with the
hypertrophic differentiation of chondrocytes.5 The mechanisms
involved in pathological cartilage calcification during OA, and
particularly the pathways that link chondrocyte differentiation
to the calcification of the surrounding matrix, are not completely understood. However, changes in the synthesis and
transport of inorganic pyrophosphate, as well as in extracellular pyrophosphate metabolism, have been found to be associated with this process.6
Collectively, these data indicate that while mechanistically similar and part of a rather uniform program, the developmental
processes that occur either during embryogenesis or during
aging can be distinguished from the pathological changes
seen in OA. Distinguishing factors appear to include the nature, strength, and duration of underlying stimuli. I
References
1. Furuzawa-Carballeda J, Macip-Rodriguez PM, Cabral AR. Osteoarthritis and
rheumatoid arthritis pannus have similar qualitative metabolic characteristics and
pro-inflammatory cytokine response. Clin Exp Rheumatol. 2008;26:554-560.
2. Bougault C, Gosset M, Houard X, et al. Stress-induced cartilage degradation does
not depend on NLRP3 inflammasome in osteoarthritis. Arthritis Rheum. 2012;64:
3972-3981
3. Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.
Nat Med. 2010;16:678-686.
4. Echtermeyer F, Bertrand J, Dreier R, et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med. 2009;15:1072-1076.
5. Fuerst M, Bertrand J, Lammers L, et al. Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum. 2009;60:2694-2703.
6. Bertrand J, Nitschke Y, Fuerst M, et al. Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice. Ann Rheum Dis. 2012;71:
1249-1253.
213
CONTROVERSIAL
QUESTION
11. J. del Pino-Montes, Spain
Javier DEL PINO-MONTES, MD, PhD
Professor of Medicine
University of Salamanca
Service of Rheumatology
University Hospital of Salamanca
Paseo San Vicente, 54
37007 Salamanca
SPAIN
O
steoarthritis (OA) is probably the most common
chronic joint disorder. It is defined by focal lesions
of the articular cartilage, a hypertrophic reaction in
the subchondral bone, and new bone formation. OA is often
considered a chronic degenerative disease, with degradation
of articular cartilage attributed to wear and tear. Although aging is a known risk factor for OA, the condition is not a consequence of growing old, but involves a destructive chronic
active inflammatory mechanism mediated by cells within the
articular cartilage.1
In OA, there is a change in the normal adult chondrocyte state
characterized by cell proliferation, cluster formation, and increased production of matrix proteins and matrix-degrading
enzymes. Chondrocytes in OA cartilage express cytokine and
chemokine receptors, matrix metalloproteinases (MMPs), and
other proteins that enhance or modulate inflammatory and
catabolic responses. MMPs such as aggrecanases and collagenases are found in the osteoarthritic joint. In early OA,
MMP-3 and ADMTS-5 degrade aggrecan.2 Next, collagenases degrade type II collagen and the collagen network. As the
articular cartilage matrix proteins are degraded, fragments
of matrix proteins such as fibronectin and small leucine-rich
proteoglycans are produced, which can feed back and stimulate further matrix destruction. This early stage may reflect an
effort by the hypertrophic chondrocytes to repair cartilage damage. As OA progresses, the proteoglycan level eventually
drops very low, causing cartilage to soften and lose elasticity, thereby further compromising joint surface integrity.
Besides these mechanisms, the chondrocyte anabolic response to growth factors decreases with age. Under such circumstances, the chondrocyte is unable to maintain cartilage
homeostasis. Cell death has also been related to aging, and
formation of advanced glycation end products (AGEs) increases with age.4 Modification of collagen by AGE formation
results in increased crosslinking of collagen molecules affecting the biochemical properties of cartilage and making it more
brittle. Moreover, there is an age-related increase in reactive
oxygen species, and this may contribute to cell death and
matrix degeneration.5
There is no clear frontier between the features of articular cartilage in aging and OA, and both share some common characteristics. Senescent and osteoarthritic chondrocytes share
a secretory phenotype. Cell death has been observed during
the development of OA as well as in aging cartilage. Age-related loss of autophagy, a protective mechanism for normal
chondrocytes that protects cells during the stress response,
is associated with cell death and OA development.6 Age-related changes in cartilage matrix could also be important in
contributing to the development of OA. The increased accumulation and expression of AGEs that occurs in aging
chondrocytes is associated with enhanced sensitivity to cytokines and chemokines, which trigger expression of MMPs.
The increased production of reactive oxygen species could
also play an important role in OA.
The relationship between aging and OA is well known, but
the mechanisms by which aging predisposes the joint to OA
development are not fully understood. Age-related changes
observed in cell and cartilage matrix may increase the susceptibility to OA, but they do not directly cause it in older
adults. More information is needed to better understand how
aging changes in the bone, meniscus, and ligaments contribute to the development of OA. I
References
Aging produces a gradual loss of cartilage matrix as well as
a decrease in cartilage hydration and cellularity. Aging cartilage is characterized by an age-related loss in the ability of cells
and tissues to maintain homeostasis. Normal aging chondrocytes are reduced in number, rarely divide, and exhibit no
cellular proliferation or hypertrophic cells. They show shortened telomeres characteristic of cellular senescence. However, aging chondrocytes can exhibit a senescence secretory
phenotype, characterized by increased production of cytokines, MMPs, and several growth factors.3 As a result, in the
elderly, there is increased age-related cartilage catabolism.
214
1. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases.
Arthritis Res Ther. 2009;11:224.
2. Wang M, Shen J, Jin H, Im HJ, Sandy J, Chen D. Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis.
Ann N Y Acad Sci. 2011;1240:61-69.
3. Leong DJ, Sun HB. Events in articular chondrocytes with aging. Curr Osteoporos Rep. 2011;9:196-201.
4. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum. 2004;50:1207-1215.
5. Del Carlo M Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep.
2008;10:37-42.
6. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012;
4:269-285.
CONTROVERSIAL
QUESTION
12. C. A. F. Zerbini, Brazil
Cristiano A. F. ZERBINI, MD
Rheumatology Department
Hospital Heliópolis
Rua Conego Xavier #276
04231-030, São Paulo, SP
BRAZIL
O
steoarthritis (OA) is considered a characteristic agerelated disease. Its prevalence increases with age, affecting 30% to 50% of adults aged over 65 years.1
Although it is the greatest risk factor for OA, older age alone
is not responsible for its development. Age, obesity, female
sex, previous trauma (knee injury), and hand OA were reported as consistent risk factors for knee OA in people aged 50
years and older.2 Risk factors for OA such as obesity, genetics, anatomical abnormalities, and joint injury are well known,
but how they interact with age to initiate and develop OA is
still unclear. Recent advances in molecular biology are starting to clarify the connection between cellular aging changes
and the propensity to develop OA.
Chondrocytes are the only cell type in articular cartilage, and
they particularly suffer during aging. They are responsible
for the synthesis and breakdown of the cartilaginous matrix
and are driven by signals from growth factors, cytokines, and
the matrix itself. The chondrocytes of older cartilage are the
same cells present in the cartilage during youth. Chondrocytes
rarely divide or die in normal adult articular cartilage, with the
same cells remaining active for many years. Chondrocytes
have a very long lifespan, but in older individuals they may express changes characteristic of cell senescence. Cell senescence found in chondrocytes is called stress-induced or
“extrinsic” senescence, as opposed to replicative or “intrinsic” senescence. Stress-induced senescence can develop
from stimuli including activated oncogenes, ultraviolet radiation, and chronic inflammation. Stress-induced senescence
is associated with oxidative DNA damage, which results in
telomere shortening (as in replicative senescence). Many agerelated changes in chondrocytes, particularly oxidative DNA
damage, may induce development of the senescence-associated secretory phenotype (SASP).3 This phenotype when
expressed in chondrocytes may link the articular aging process
with the development of OA. SASP is characterized by increased production of inflammatory mediators such as cytokines and matrix metalloproteinases, which may induce cartilaginous matrix degradation and joint impairment and may
also be found in osteoarthritic cartilage. SASP expression in
chondrocytes may be linked to the production of reactive oxygen species (ROS) by dysfunctional mitochondria, resulting in
mitochondrial and nuclear DNA damage. Mitochondrial DNA
damage can be observed in OA and is associated with increased matrix degradation and decreased matrix synthesis.
ROS production may be induced by inflammatory cytokines
such as IL-1β and TNF-α, and is also associated with mechanical injury to joints. An increase in ROS may contribute
to chondrocyte death.4
Thus, ROS, mitochondrial dysfunction, and DNA damage may
be features of chondrocyte senescence associated with development of SASP and may lead to cartilage matrix impairment and development of OA.
Aged and osteoarthritic chondrocytes have a reduced ability
to respond to transforming growth factor-β and insulin-like
growth factor-1 (IGF-1) stimulation. This leads to a reduced
capacity for matrix repair, and consequently, a degeneration
of the articular cartilage. The decrease in chondrocyte responsiveness to IGF-1 is associated with increased ROS levels.5
Autophagy is a mechanism used by the cell to degrade and
recycle dysfunctional proteins. It is an important mechanism
by which cells are protected against stress. Autophagy declines with age, and its loss has been associated with increased chondrocyte death. Recent studies in autophagy have
attempted to clarify the possible role of this process in senescence and OA.6
Thus, to answer the question, we must determine if and when
the aging process results in the development of SASP. Senescent chondrocytes developing this phenotype are very similar to chondrocytes found in osteoarthritic joint tissues. In
my opinion, development of this phenotype with its associated inflammatory cytokines, or lack of it, will determine how
much we can distinguish between normal age-related changes
in cartilage and early osteoarthritic changes. I
References
1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum.
2008;58:26-35.
2. Blagojevic M, Jinks C, Jeffery A, et al. Risk factors for onset of osteoarthritis of
the knee in older adults: a systematic review and meta-analysis. Osteoarthritis
Cartilage. 2010;18:24-33.
3. Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular
senescence: causes and consequences. Trends Mol Med. 2010;16:238-246.
4. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
5. Yin W, Park JI, Loeser RF. Oxidative stress inhibits insulin-like growth factor-I
induction of chondrocyte proteoglycan synthesis through differential regulation
of phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK signaling pathways.
J Biol Chem. 2009;284:31972–31981.
6. Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in
normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62:791-801.
215
INTERVIEW
‘‘
While noninvasive treatments
such as exercise and physical therapy should be started in the earlier
phases, injective treatments should
be considered for the management
of patients after noninvasive procedures have failed. Prosthetic replacement, which is an irreversible
procedure, should of course be reserved as a last option during the
advanced and debilitating phases of osteoarthritis refractory to
other treatments.”
Nonpharmacological
treatments in osteoarthritis
I n t e r v i e w w i t h E . Ko n , I t a l y
T
Elizaveta KON, MD
III Clinic, Biomechanics Laboratory
Rizzoli Orthopaedic Institute
Bologna, ITALY
he goal of this interview is to better understand the role of nonpharmacological treatments in osteoarthritis. A wide spectrum of treatment options is available, ranging from adaptation of activity levels, exercise,
and physiotherapy, to intra-articular injections, surgical unloading of the degenerated joint compartment, and knee replacement. While the aim of all treatments is to improve symptoms, function, and therefore quality of life, each has
its own advantages and disadvantages and is more suitable for certain specific phases of joint osteoarthritis. There is currently no agreement on the most
effective management of osteoarthritis, and none of the available treatment
options have been proven to produce better results over all others or have been
clearly shown to have disease-modifying properties. In general, the optimal
conservative management of knee osteoarthritis requires a combination of
pharmacological and nonpharmacological treatment modalities. Among nonpharmacological treatments, a combination of different approaches is also
recommended. Aside from considering the treatment to be applied, one must
also consider that osteoarthritis is a chronic condition and that long-term disease management can be cumbersome. Thus, therapeutic education of patients with osteoarthritis is of major importance. Finally, prostheses produce
a high percentage of good results but require adaptation to the activity level
of the patient and also carry some important risks related to the surgical implant. Thus, when treating a patient affected by osteoarthritis, it is important
to consider all the available options for improving the clinical condition of the
patient and keep prosthetic replacement as a last option for when functional
limitations and symptoms prove to be refractory to less invasive procedures.
When should nonpharmacological management of osteoarthritis
be started?
Dr Elizaveta Kon, Biomechanics
Laboratory, Rizzoli Orthopaedic
Institute, Via Di Barbiano, 1/10,
40136 Bologna, Italy
216
he etiology of osteoarthritis (OA) is multifactorial. Age is the major independent risk factor for OA; however, aging and OA are interrelated, not interdependent. It is becoming apparent that age-related changes in the musculoskeletal system contribute to the development of OA by working in conjunction with
other factors that are both intrinsic (eg, malalignment, overloading) and extrinsic (eg,
genetics) to the joint. Regardless of the initial cause, once started, osteoarthritic
alterations lead to progressive loss of hyaline cartilage, leading eventually to endstage OA.1
T
Nonpharmacological treatments in osteoarthritis – Kon
INTERVIEW
Thus, nonpharmacological OA management should be started even before the clinical onset of symptoms, with the aim
of treating the predisposing factors. Early OA should be detected. Clinical recurrence of pain and discomfort of the knee
and/or short periods of stiffness, in between long periods with
very few clinical manifestations, should set the stage for performing additional investigations such as radiographs, ultrasound, magnetic resonance imaging (MRI), or arthroscopy.2
Malalignment, loss of meniscal tissue, cartilage defects, and
joint instability or laxity should be evaluated, and treatment (including surgery if appropriate) should be discussed with the
patient, taking into consideration their activity level and expectations as well as the risks of failure and complications associated with every procedure.
In addition to its preventative use in the early phase, nonpharmacological management should also always be considered
when OA is clearly established. Of course, when considering
treatment options, one should also always take into consideration the disease phase and the invasiveness of the procedure.
Nonpharmacological management is a broad definition, ranging from physiotherapy to knee replacement. While noninvasive treatments such as exercise and physical therapy should
be started in the earlier phases, injective treatments should
be considered for the management of patients after noninvasive procedures have failed. Prosthetic replacement, which
is an irreversible procedure, should of course be reserved as
a last option during the advanced and debilitating phases of
OA refractory to other treatments.
What is the cornerstone of nonpharmacological
treatment?
here is no cornerstone of nonpharmacological treatment. As previously underlined, this is a broad definition, ranging from adaptation of activity levels to exercise, from physiotherapy to intra-articular injections, from
surgical unloading of the degenerated joint compartment to
knee replacement, and so on.3,4 While all treatments are aimed
at improving symptoms, function, and therefore quality of life,
every treatment presents its own advantages and disadvantages and is more appropriate for specific phases of joint OA.
One nonpharmacological approach that is probably indicated across different phases of articular degeneration with minimal contraindications is exercise.
T
SELECTED
MRI
OA
OARSI
osteoarthritis
International clinical guidelines recommend exercise as an effective approach in the management of knee OA. The aims of
exercise in these patients are to reduce pain, improve physical function and health status, and prevent progression of the
disease. While the optimal dosage (frequency, intensity, and
duration) has not yet been determined, good results have been
reported for different types of exercise.5 In general, physical
activity is beneficial, rather than detrimental, to joint health, and
an MRI study showed that moderate exercise may also improve the knee cartilage glycosaminoglycan content in patients at high risk of developing OA, but long-term effectiveness still needs to be clarified.6
As mentioned, injective treatments also play an important role
in the management of OA, ranging from corticosteroids to viscosupplementation and also to more innovative biological
procedures such as the use of blood derivatives to aid the
restoration of joint homeostasis and tissue regeneration.7
Moreover, although the degenerative OA environment is an obstacle to tissue regeneration, progress made in bioengineering and the development of new scaffolds seems to represent
a promising solution that may help to avoid, or at least delay,
the need for more sacrificing metal resurfacing procedures.8
How should cost, availability, or practicality
of delivery be taken into account?
ost, availability, and practicality of delivery should always be taken into account in the management of OA
patients, especially when one considers that there is
currently no agreement on the most effective management of
these patients and none of the available treatment options
have been proven to produce better results over all others or
have been clearly shown to have disease-modifying properties.
C
Luckily, one of the nonpharmacological treatments proven to
be comparatively more effective for OA patients is exercise.
Hydrotherapy was found to produce a small-to-moderate improvement in function and quality of life and a small reduction in pain in osteoarthritic patients. Hydrotherapy is not always available, however, but other exercise modalities have
also proven to be useful: strength and aerobic training, rangeof-motion exercises, and stretching have beneficial effects in
modulating pain, increasing range of motion, reducing or eliminating soft tissue inflammation, inducing relaxation, improving repair, extensibility, or stability of contractile and noncontractile tissues, facilitating movement, and improving function.
Tai-chi, a traditional Chinese exercise that enhances balance,
strength, and flexibility, has also been shown to be effective
in treating knee OA.
A special comment should be made about the cost, availability, and practicality of delivery of the new injective procedures.
Among these, platelet-rich plasma therapy, a procedure based
217
INTERVIEW
on the injection of platelet concentrate to encourage tissue
regeneration through the release of growth factors contained
in the platelet alpha-granules, has been recently gaining popularity as a promising therapeutic option for early OA. However, despite some promising clinical results, the beneficial
effect of this procedure is limited over time.9 Thus, it is important to consider that the high costs, the contraindications
for several comorbidities, and the need for specialist centers
are major limitations that favor more classic injective procedures. Among these, viscosupplementation seems to offer a
clinical benefit, albeit limited over time, without side effects on
the joint tissues. However, in patients where the joint has already degenerated, corticosteroid injections can be considered as a cheap option that is easily and widely accessible.
Other more invasive surgical procedures also present specific
limitations with regard to cost, availability, or practicality of delivery. Patient comorbidities should also be taken into consideration when contemplating more invasive surgical procedures,
as comorbidities can complicate treatment, and logistical problems and the need for assistance during the sometimes long
postoperative rehabilitation phase also need to be considered.
How important is therapeutic education
in osteoarthritis and why?
herapeutic education in OA is of major importance. OA
is a chronic condition, and long-term management of
a disease can be cumbersome. Aside from occasional
injections or other medical procedures, patients affected by
OA are required to undergo much more difficult changes in
their life. In fact, correct management of OA often involves lifestyle adaptation with continuous exercise, frequent physical
therapy, and diet modification. None of this is achievable without proper therapeutic education. Patients need to be aware
of their condition, of the factors affecting the disease, and of
their responsibility in following the correct lifestyle and prescribed therapies. In terms of pharmacological therapy, patients must follow the treatment indications to obtain optimal
results, and personal initiatives or treatment adaptations that
do not follow the physician’s indications can only lead to lesser benefits. A recent review of the role of exercise in OA management focused on the different methods of treatment delivery, which can entail individual treatment, treatment within
a supervised group, or exercise performed at home. No difference was found in terms of the beneficial effects of exercise when patients had received proper therapeutic education
and performed the prescribed exercise. However, regular supervision may improve adherence to exercise, which is required
to maintain the benefits over time, and a recent study reported that the effects of exercise were better when conducted
over more than 12 supervised sessions.5 Supervised sessions
allowed for more therapeutic education and more control over
patients, who as a consequence followed their therapies better and thus achieved better results.
T
218
Therapeutic education is also of fundamental importance after surgery in order to limit the risk of complications such as
infection, or even fatal events, and to optimize treatment. For
example, biological implants for tissue regeneration require a
maturation phase during which the healing structure has to
be protected, and even after metal resurfacing, therapeutic
education is mandatory to ensure adaptation of life activities
and preservation of the prosthetic joint over time.
How long can nonpharmacological management
put off surgical intervention?
onpharmacological management can put off the need
for surgical intervention, but in this regard every single case must be considered individually. First, it has
to be stressed that sometimes it can be counterproductive to
put off surgical intervention. This is particularly true when there
are clearly recognized predisposing factors that could be addressed surgically. A previous total meniscectomy, joint instability due to ligament rupture, incongruity of the articular
surface due to previous intra-articular fractures, misalignment
causing overload, and degeneration of an articular compartment are just some examples of clinical conditions for which
delaying surgical treatment would only result in a worsening
of the joint condition with a worse final outcome.
N
On the other hand, when there are no clear predisposing factors or when patients present with comorbidities that contraindicate surgical treatments, nonpharmacological management can be used to put off surgical intervention. Of course
every case is different, but it is possible to state that in the majority of cases, proper management of OA can delay the need
for prosthetic replacement for several years. Lifestyle adaptation with diet modification and exercise, together with other
medical treatments such as physical therapy or injections to
treat the acute inflammatory OA phases, can improve the clinical condition and delay the need for more invasive surgery.
It is important for the patient to have clear expectations about
all the treatment options. Surgery can sometimes be considered by the patient as an easy way to improve their clinical
condition, but knowledge of the limitations and risks of surgery can give them the correct perspective in understanding
the importance of properly applying nonsurgical management for major beneficial effects and the longest delay before surgical intervention.
Is there any randomized controlled study available
on the nonpharmacological approach?
ome randomized controlled studies are available on the
nonpharmacological approach, but results are still far
from conclusive. Controversial findings, as well as the
incredibly high number of variables differing between each
study, make comparison of the available studies difficult.
S
INTERVIEW
Surprisingly, the definition of OA has not changed since 1986.
The diagnosis of knee OA can usually be made from the patient history and physical examination, and includes signs/
symptoms of knee pain with stiffness, joint crepitus and functional limitations, and typically an age above 50 years. Diagnosis is confirmed by radiograph demonstrating changes such
as osteophytes and joint space narrowing, subchondral bone
sclerosis, and cysts, and is graded according to the classification of Kellgren and Lawrence (Kellgren & Laurence grades
II-IV). It appears clear that this definition of OA cannot distinguish between the pathological changes in different tissues.
Thus, study populations can be heterogeneous and can respond differently to different treatments, even though they apparently present in the same disease phase.
There is no agreement in the literature on the best treatment
option for OA, and this is reflected in clinical practice where
treatment is mainly empirical and based on the personal experience of the individual physician. Moreover, leaving aside
the contradictory findings of the different studies, it is also difficult to translate the study results into clinical practice because the selected study populations are often a specific category of patients that is rare in the normal population. Patients
in clinical practice typically present with more complex clinical
situations and with comorbidities and combined treatments.
New imaging techniques are required to better assess the
disease phase and to properly classify study populations,
and more randomized controlled trials are needed to prove
which treatment approach is more suitable for each of the
different phases of OA degeneration.
Can nonpharmacological treatment be combined
with pharmacological treatment?
hile it is true that properly applied nonpharmacological treatment can sometimes limit the need for
pharmacological treatment, it is also well accepted
that combined treatment can often offer a better clinical outcome. In general, the optimal conservative management of
knee OA requires a combination of pharmacological and nonpharmacological treatment modalities, and among the nonpharmacological treatments, a combination of different approaches is recommended.
W
Osteoarthritis Research Society International (OARSI) produced a list of 25 recommendations regarding the treatment
of OA. These cover the use of 12 nonpharmacological modalities: education and self-management, regular telephone contact, referral to a physical therapist, aerobic, muscle strengthening and water-based exercises, weight reduction, walking
aids, knee braces, footwear and insoles, thermal modalities,
transcutaneous electrical nerve stimulation, and acupuncture.
A further 8 recommendations cover pharmacological treatment modalities, and finally, 5 recommendations cover surgical modalities: total joint replacements, unicompartmental
knee replacement, osteotomy and joint-preserving surgical
procedures, joint lavage and arthroscopic debridement in
knee OA, and joint fusion as a salvage procedure when joint
replacement has failed.
These strategies can be combined according to the specific
requirements of the patient with the aim of producing tailored
treatment and thus more satisfactory clinical results.
What can you tell us about life after knee
replacement surgery?
any options are currently available for knee replacement, from focal metal resurfacing to total prosthetic replacement of the affected joint.10 Of course,
functional improvement and limitations will depend strictly
on the implant type as well as the specific characteristics of
the patient, and also eventually on the presence of any surgical complications.
M
In general, this procedure offers a dramatic improvement in
the clinical condition. Most patients have minimal pain by 3
months (or sooner) after surgery and return to their normal
daily activities. It is not unusual to have occasional muscle
aches and persistent (but usually slight) swelling of the knee
and extremity for several months, and some patients require
a longer time to achieve good and stable results. Depending
on numerous factors, a persistent limp is usually expected,
but results tend to improve over time.
Unfortunately, 5% of patients will be unsatisfied because of
the persistence of pain or the onset of complications. Moreover, it has to be remembered that despite the technological
improvements of the last decades, implants still have limited
longevity and may require revision surgery. Age is one of the
major factors in determining reduced longevity. Younger patients wear out their replacements more quickly than older
patients, and this has to be taken into consideration in the
management of a patient affected by OA.
In general, prostheses give good results, but they also require
adaptation to the activity level of the patient and there are some
important risks related to the surgical implant. Thus, when treating a patient affected by OA, it is important to consider all
the available options to improve their clinical condition and to
keep prosthetic replacement as a last option when functional limitations and symptoms prove to be refractory to less invasive procedures. I
The author declares that she has no conflict of interest.
219
INTERVIEW
References
1. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the pathogenesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc.
2012;20:423-435.
2. Luyten FP, Denti M, Filardo G, Kon E, Engebretsen L. Definition and classification of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc.
2012;20:401-406.
3. Gomoll AH, Filardo G, de Girolamo L, et al. Surgical treatment for early osteoarthritis. Part I: cartilage repair procedures. Knee Surg Sports Traumatol Arthrosc. 2012;20:450-466.
4. Gomoll AH, Filardo G, Almqvist FK, et al. Surgical treatment for early osteoarthritis. Part II: allografts and concurrent procedures. Knee Surg Sports Traumatol Arthrosc. 2012;20:468-486.
5. Kon E, Filardo G, Drobnic M, et al. Non-surgical management of early knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2012;20:436-449.
6. Roos EM, Dahlberg L. Positive effects of moderate exercise on glycosamino-
glycan content in knee cartilage: a four-month, randomized, controlled trial in
patients at risk of osteoarthritis. Arthritis Rheum. 2005;52:3507-3514.
7. Kon E, Filardo G, Di Martino A, Marcacci M. Platelet-rich plasma (PRP) to treat
sports injuries: evidence to support its use. Knee Surg Sports Traumatol Arthrosc. 2011;19:516-527.
8. Kon E, Delcogliano M, Filardo G, Altadonna G, Marcacci M. Novel nano-composite multi-layered biomaterial for the treatment of multifocal degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2009;17:1312-1315.
9. Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage
pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:14901501.
10. Marcacci M, Bruni D, Zaffagnini S, et al. Arthroscopic-assisted focal resurfacing of the knee: surgical technique and preliminary results of 13 patients at 2
years follow-up. Knee Surg Sports Traumatol Arthrosc. 2011;19:740-746.
Keywords: injective treatment; nonpharmacological management; osteoarthritis; replacement surgery
TRAITEMENTS
NON PHARMACOLOGIQUES DE L’ARTHROSE
Le but de cette interview est de mieux comprendre le rôle des traitements non pharmacologiques de l’arthrose. L’éventail de traitements est large : adaptation des niveaux d’activité, exercice physique, physiothérapie, injections intraarticulaires, déchargement chirurgical du compartiment articulaire abîmé et prothèse de genou. Tous les traitements
visent à améliorer les symptômes, le fonctionnement et donc la qualité de vie ; toutefois, chacun d’entre eux présente
ses propres avantages et inconvénients et convient mieux à certaines phases spécifiques de l’arthrose articulaire. Il
n’y a actuellement aucun consensus sur la prise en charge la plus efficace de l’arthrose, et aucun des traitements
disponibles n’a montré de meilleurs résultats que les autres ou n’a clairement manifesté des propriétés modifiant la
maladie. En général, la prise en charge conservatrice optimale de l’arthrose du genou nécessite une association de
traitements pharmacologiques et non pharmacologiques. Parmi les traitements non pharmacologiques, l’association
des différentes approches est également recommandée. Hormis les considérations sur le choix traitement, il faut
aussi tenir compte du fait que l’arthrose est une pathologie chronique et que sa prise en charge à long terme peut
être pesante. L’éducation thérapeutique des patients arthrosiques est donc d’une extrême importance. Enfin, les prothèses ont un fort pourcentage de bons résultats mais nécessitent d’être adaptées au niveau d’activité du patient et
présentent aussi des risques importants liés à la prothèse implantée. Lorsque l’on traite un patient atteint d’arthrose,
il est important de prendre en compte toutes les options disponibles pour améliorer son état clinique et garder la
pose d’une prothèse comme dernière solution, lorsque les symptômes et les limitations fonctionnelles ne répondent
pas à des procédures moins invasives.
220
FOCUS
‘‘
It is clear that changes in subchondral bone parallel the progression of osteoarthritis and may even
be causally involved. The subchondral compartment may therefore
be a treatment target to delay or
prevent progression of the disease.
Since this compartment is richly
innervated, and cartilage is devoid
of nerves, bone is also a legitimate
treatment target for joint pain. However, treatments designed to normalize the bone changes in osteoarthritis are controversial…”
Long overlooked:
the role of subchondral
bone in osteoarthritis
pathophysiology and pain
b y D . M . F i n d l a y, A u s t ra l i a
O
David M. FINDLAY, PhD
Discipline of Orthopaedics
and Trauma
University of Adelaide
Adelaide, South Australia
AUSTRALIA
steoarthritis was previously considered to be solely a disease of cartilage degeneration. However, it is now recognized that all structures
in the joint are affected by the disease, notably subchondral bone, in
which characteristic changes occur throughout disease progression. These
changes in the bone seem to parallel disease progression and are associated with joint pain. This article focuses on the role played by subchondral bone
remodeling in the pathogenesis of osteoarthritis and in the expression of pain
in this condition. It examines the evidence for altered osteoblast and osteoclast
function and the possible involvement of osteocytes in establishing changes
in the subchondral bone environment in osteoarthritis. It also explores the biomechanical and genetic influences that may lead to an altered interaction between bone and cartilage. A large number of genes have been found to be
differentially expressed in subchondral bone in osteoarthritis compared with
osteoporotic or normal bone, and many of these changes persist in osteoblasts
derived from osteoarthritic bone. Relevant questions include how the cellular
and molecular changes give rise to structural changes in subchondral bone,
including bone marrow lesions; what the evidence is that bone marrow lesions are predictive or even causal of disease progression; and whether treatments targeting the subchondral bone could have efficacy in delaying or reversing degeneration of the overlying articular cartilage.
steoarthritis (OA) is characterized by progressive degenerative damage to
articular cartilage, although it is also associated with weakened muscles,
synovial inflammation, joint stiffness, altered bone alignment, loss of joint
congruency, and structural changes in the subchondral bone.1,2 There are well-described changes observed in the subchondral bone in OA,1-4 which include sclerotic but less mineralized bone, the formation of osteophytes, and subchondral cysts.
In addition, the development of bone marrow lesions (BMLs) that can be visualized
by magnetic resonance imaging (MRI) is frequently seen in OA, and these lesions
seem to be predictive of degeneration in the overlying cartilage compartment.5 The
changes in bone structure and remodeling are due ultimately to changes in the activity of bone cells, osteoclasts, osteoblasts, and osteocytes, driven in turn by altered
expression of key regulatory genes. These changes are likely in response to altered
loading of the joint and/or systemic changes, and the way that these influences are
transduced to gene expression and cell activity needs to be understood in order to
find effective treatments for OA. Since there is evidence of important communica-
O
Professor David M. Findlay, Discipline
of Orthopaedics and Trauma,
University of Adelaide, Level 4 Bice
Building, Royal Adelaide Hospital,
Adelaide, South Australia, 5000,
Australia (e-mail:
[email protected])
The role of subchondral bone in osteoarthritis pathophysiology and pain – Findlay
221
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tion between articular cartilage and its underlying bone, altered events in the subchondral bone may have significant
implications for cartilage health, which validates attempts to
treat OA by directing treatment to the subchondral bone.
Bone shape and osteoarthritis
It is clear that shape deformities in bone are associated with
OA and may either predispose to the disease, or result from
it.6,7 Malalignment of the knee, with varus or valgus alignment,
has been thought to predispose individuals to knee OA. However, as reviewed by Hunter et al,8 it is unclear whether malalignment is a risk factor for OA or comes about as a result
of the disease, and more longitudinal data are required to determine the link. Congenital dysplasia or dislocation of the hip,
whether occurring as a result of perinatal dislocation or congenitally incorrect morphology of the acetabulum or femoral
head, can give rise to hip OA because of the lack of congruency of the joint and the concentration of load in a small region of the joint. Genetics may play an important role in OA
that has bone deformity as its underlying cause. Waarsing et
al9 have described a range of shape “modes” for the proximal
femur, several of which predispose to OA, but apparently only
in carriers of susceptibility alleles of genes that associate with
OA. Haverkamp et al10 have obtained similar data for the knee,
suggesting that a larger tibial plateau area associates with OA.
Pincer deformities of the acetabulum and cam deformities of
the femoral neck,11 which result in various degrees of impingement of the hip joint, are thought to lead to OA. Nicholls et
al12 examined the relationship between cam deformity and the
19-year risk of total hip arthroplasty (THA) for end-stage hip
OA. Their intriguing results showed that individuals with THA
had a higher prevalence of cam deformity than their respective controls, although the study was limited by small numbers of subjects after exclusions. Further studies in this area
are warranted given the prospect that it might be possible to
predict the risk of hip OA from hip shape. Two recent studies addressed the important question of whether such deformities are inevitable or whether they may be preventable. It
was found that cam deformity seemed to arise from vigorous
SELECTED
ACLT
BML
ES/BS
MRI
OA
OARSI
OPG
OS/BS
TGFβ
THA
WOMAC
anterior cruciate ligament transection
bone marrow lesion
eroded surface/bone surface ratio
osteoarthritis
osteoprotegerin
osteoid surface/bone surface ratio
transforming growth factor β
total hip arthroplasty
Western Ontario and McMaster Universities Osteoarthritis index
222
sporting activity, being more prevalent in elite young basketball players than in age-matched controls.13 Similarly, the prevalence of flattening of the femoral head-neck junction was significantly increased in young male soccer players compared
with controls, and the presence of a convex prominence (cam
deformity) was found only in the soccer players.14 These studies highlight the responsiveness of bone to influences such as
loading, which has already been well described as a mechanism by which bone strengthens in response to increased
demand.15,16 They are also a reminder that bone is a dynamic
tissue that is constantly undergoing remodeling,17 thereby perhaps contributing to OA, but also offering potential points of
intervention.
Microstructural changes in bone in osteoarthritis
The microstructure of subchondral bone differs in osteoarthritic bone compared with nonosteoarthritic bone, particularly
with respect to the subchondral plate and adjacent trabecular bone, but also in regions more distal from the affected
joint.18,19 For example, Kumarasinghe et al20 reported increased
bone volume fraction in cancellous bone from the intertrochanteric region in individuals with OA compared with those
with normal or osteoporotic bone, with increased trabecular
number and decreased trabecular spacing. Reduced hardness of trabecular bone from the femoral head was also noted in hip OA compared with normal subjects,21 probably due
to decreased mineralization of the bone in OA.22 These changes
combine to produce bone that is stiffer and stronger than
normal or osteoporotic bone.22 It is not known at which stage
of human disease these changes appear, and whether they
are, in some way, causative of the disease process or simply describe it. For the most part, animal models show that
changes in the subchondral bone occur in parallel with cartilage degradation.23 Longitudinal mouse studies that used highresolution imaging to investigate joints in a mouse strain that
spontaneously develops knee OA compared with one that
does not showed that susceptible mice developed more trabecular bone in a region-specific manner, and particularly in
the tibial compartment, in parallel with arthritic changes in the
articular cartilage.24
In addition to the generalized changes in subchondral bone in
OA, areas of subchondral bone that appear bright with MRI,
which are termed BMLs, are commonly observed in both established OA and early OA, but rarely in symptom-free individuals.25,26 BMLs have not been extensively characterized, but
they arise in regions of predicted high loading and contain abnormal bone with areas of osteocyte death and areas of bone
sclerosis with reduced mineral density.27 Subchondral bone
attrition28 and repair of fractured trabeculae have also been
observed.29 BMLs are interesting clinically due to the fact that
longitudinal studies have shown that their presence is a potent risk factor for structural deterioration in knee OA30-32 and
for future joint replacement.5 BMLs have been shown to be
dynamic, increasing and decreasing in size, and they have
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also been found to disappear over a 2-year period.33 In a community-based population of older males and females, similar
proportions of BMLs were found to worsen and improve (assessed by measuring maximal area).34 Importantly, a change
in BML size was associated with changes in pain, perhaps
linking fluctuating knee pain to BML changes, at least in individuals with early-stage disease. Enlargement of BMLs has
been strongly associated with increased cartilage loss.5,31 Subchondral cysts, which are characteristic of established and
severe OA, arise at the same sites as BMLs.35 A number of
studies have indicated possible causal factors for BMLs, including mechanical loading,36 dietary fatty acid intake,37 and
total serum cholesterol and triglycerides.38
Bone remodeling in osteoarthritis
As stated, bone is constantly being remodeled, and this may
have special significance in OA in ways that require more attention.17 Understanding bone remodeling in the particular
context of OA is complex. The topic was recently the subject
of an excellent review by Burr and Gallant,39 who cited evidence for increased remodeling, accompanied by increased
vascularity, in the subchondral bone in early OA. By contrast,
late-stage disease is characterized by reduced bone resorption, with a bias toward bone formation. In addition to these
temporal variations, it is likely that bone remodeling varies
spatially within the joint; for example, medially versus laterally in the knee. There is histological and biochemical evidence
of increased bone remodeling in subchondral bone containing BMLs.40 Increased subchondral bone remodeling as detected by bone scans has been described in established OA,
where it has been reported to predict joint space narrowing.41
In contrast, a report by Berry et al42 concluded that higher levels of bone remodeling (assessed by serum bone turnover
markers) is associated with reduced cartilage loss (assessed
by MRI). It is difficult to determine whether changes in bone
turnover are a cause or effect in human OA; however, work in
Hartley guinea pigs showed that subchondral cancellous bone
was fragile before the onset of cartilage degeneration.43 In the
rat anterior cruciate ligament transection model of OA, increased subchondral bone resorption was associated with
early development of cartilage lesions, which preceded significant cartilage thinning and subchondral bone sclerosis.44
At the level of the bone cell, remodeling is a function of the
actions of osteoclasts, which resorb bone, and osteoblasts,
which are the bone-forming cells. The activities of both of
these cell types are regulated by osteocytes embedded within the bone matrix.45 There is good evidence that osteocytes
detect damage within the mineralized bone matrix and direct its repair by initiating targeted osteoclastic resorption of
the affected bone,46 and in OA, there is evidence of increased
microdamage and microfractures in subchondral bone in overloaded areas of the joint.47 Recent evidence suggests that
osteocytes are the major source of the osteoclast differentiating cytokine, receptor activator of nuclear factor κ-B ligand
(RANKL), in mature bone.48,49 Osteocytes also produce sclerostin, a Wnt inhibitor that negatively regulates bone formation.50 Individuals and animals deficient in sclerostin show bone
overgrowth.51 Sclerostin appears to mediate the actions of a
number of factors that influence bone formation, so that loading of bone, a known anabolic influence, decreases sclerostin
expression in bone,52,53 and unloading of bone, which is catabolic for bone, increases its expression.52 Both of these conditions might apply at different times during the progression
of OA. Interestingly, increased sclerostin expression has been
observed in cartilage overlying sclerotic bone, while the latter
by contrast shows decreased sclerostin expression.54,55 Since
osteocytes have such a strong influence on bone metabolism
and turnover, it may be an important finding that in osteoarthritic subchondral bone, osteocyte morphology was altered,
showing rough and rounded cell bodies with fewer and disorganized dendrites compared with the osteocytes in control
samples.56 In addition, and this has been particularly noted
in BMLs, there is evidence of osteocyte apoptosis, which, as
stated, can be a stimulus for osteoclastic resorption and bone
turnover.46
Differential gene expression in osteoarthritic bone
The structural changes in osteoarthritic bone follow changes
in bone cell activity, which are in turn driven by, and evidenced
as, altered gene expression in osteoarthritic bone compared
with bone from age- and sex-matched controls or osteoporotic individuals. The opportunity to investigate bone in OA is
essentially limited to sampling during joint replacement surgery in end-stage disease, and the gene expression observed
at this time likely represents the decrease in remodeling described in late-stage OA. In fact, both the gene and protein
expression that have been described in human late-stage OA
are largely consistent with the reduced bone turnover, sclerosis, and lower bone mineralization that have been described
in OA bone tissue at this time.39 Kuliwaba et al57 measured RNA
extracted from the cancellous bone in the intertrochanteric
region of the proximal femur, a site distal from the articular surface of the femur, and compared patients with end-stage OA
with age-matched autopsy controls. Differential gene expression was found in OA bone, which had the hallmarks of reduced inflammatory cytokines and bone resorption markers
and increased bone formation. Messenger RNA species encoding interleukin (IL)-6 and IL-11 and RANKL were significantly less abundant in the OA group, while osteoprotegerin
(OPG) mRNA expression was no different from controls.58 In
a separate study, an additional increase in the anti-osteoclastogenic cytokine interferon gamma was also observed in OA.59
Both RANKL mRNA levels and the ratio of RANKL:OPG mRNA
were strongly associated with eroded surface/bone surface
ratio (ES/BS) and osteoid surface/bone surface ratio (OS/BS)
in trabecular bone from control individuals; the former would
be expected for this cytokine, which is a potent driver of bone
resorption, and the latter is likely due to the fact that bone resorption and formation are coupled in healthy adult bone.58
223
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Intriguingly, these relationships were not apparent in osteoarthritic bone, suggesting that bone turnover is regulated differently in OA. In terms of bone formation, osteocalcin mRNA
expression was significantly greater in OA and, curiously, increased significantly with age in the OA group but not in controls.57 In addition, there was a significant positive correlation
between the osteocalcin mRNA levels and OS/BS in OA bone,
which was not seen in the control cohort. Work by the same
group showed elevated alkaline phosphatase, osteocalcin, osteopontin, and COL1A1 (collagen, type I, alpha 1) and COL1A2
(collagen, type I, alpha 2) mRNA in osteoarthritic bone compared with control,60 which the authors suggested reflects an
increase in osteoblastic biosynthetic activity in OA.
Hopwood et al61,62 performed gene microarray analysis on
bone from the same region of the femur, and identified a large
number of differentially expressed genes in OA compared with
control or osteoporotic bone. A substantial number of the topranking differentially expressed genes are known to play roles
in bone formation, and many of these genes are targets of
either the Wnt or transforming growth factor β (TGFβ)/bone
morphogenetic protein signaling pathways. These findings are
consistent with the increased amounts of insulin-like growth
factor types I and II and TGFβ protein measured in osteoarthritic bone from the iliac crest.63 This latter result, and the findings
from bone derived from the intertrochanteric region, are consistent with both increased anabolic stimulus in osteoarthritic
bone and the notion that bone metabolism may be systemically disturbed in OA.
Osteoblasts from osteoarthritic bone
Gene expression has also been explored in osteoblasts taken
from osteoarthritic subchondral bone. Interestingly, these cells
appear to retain their phenotypic differences from control cells
in culture. Thus, one group showed that cultured OA osteoblasts produced a similar degree of mineralization to control
cells, but with dramatically variable calcium:phosphate ratios
compared with control osteoblasts and normal bone (approximately 1.6).20 A second group showed that mineralization by OA osteoblasts was reduced compared with control
osteoblasts, which they found to be due to a threefold higher
COL1A1:COL1A2 mRNA ratio in the OA cells.64 This finding in
cells was similar to the differential expression of these genes
in osteoarthritic bone.60 Alkaline phosphatase and osteocalcin levels were also found to be elevated in OA osteoblasts
compared with normal osteoblasts, whereas osteopontin levels were similar.64 In this study, the authors obtained evidence
that TGFβ1 levels are approximately fourfold higher in OA osteoblasts than in normal osteoblasts, and that inhibiting TGFβ1
in OA osteoblasts corrected the abnormal COL1A1:COL1A2
ratio and increased cell mineralization. It was subsequently
shown that the increased TGFβ in OA cells induces increased
Dickkopf-related protein 2 (DKK-2), and that silencing of either
TGFβ or DKK2 in these cells normalized the OA phenotype, including the decreased mineralization of OA osteoblasts.65
224
Massicotte et al66 performed measurements of conditioned
media from osteoblasts derived from osteoarthritic subchondral bone, and reported two subgroups of cells based on
production of IL-6 and prostaglandin E2, while TGFβ levels
were increased in all osteoarthritic osteoblasts compared
with normal osteoblasts. Kumarasinghe et al20 performed an
extensive analysis of gene expression in primary osteoblasts
derived from OA and control femoral bone. They found that
the dysregulated expression of TWIST1 (twist-related protein 1), TGFβ1, and SMAD3 (mothers against decapentaplegic
homolog 3) mRNA observed by Hopwood et al62 in OA bone
is also present in OA osteoblasts when these cells are cultured ex vivo, and they proposed that at least part of the etiology of OA is due to altered intrinsic properties of the osteoblasts.
Directing treatments for osteoarthritis to the
subchondral bone
It is clear that changes in subchondral bone parallel the progression of OA and may even be causally involved. The subchondral compartment may therefore be a treatment target to
delay or prevent progression of the disease. Since this compartment is richly innervated, and cartilage is devoid of nerves,
bone is also a legitimate treatment target for joint pain. However, treatments designed to normalize the bone changes in
OA are controversial, largely because the promise of efficacy
seen in animal models has not been matched by human studies. It would seem reasonable that treatment with antiresorptive agents in early disease might be effective, since this phase
of the disease is characterized by increased bone remodeling. Accordingly, in two rat models of knee OA, the bisphosphonate alendronate suppressed both subchondral bone
resorption and the later development of OA symptoms in the
knee joint.67 Similarly, calcitonin reduced the levels of circulating bone turnover markers and the severity of OA lesions
in the dog model of anterior cruciate ligament transection
(ACLT).68 Kadri et al69 used OPG to block RANKL-mediated
bone resorption and remodeling in a mouse menisectomy
model of OA, and observed protection from meniscectomyrelated bone loss, lower OA scores, and reduced ADAMTS-4
and ADAMTS-5 expression following meniscectomy. In a high
bone turnover version of the same mouse model, pamidronate
dramatically preserved the bone mass and reduced the Osteoarthritis Research Society International (OARSI) score
while at the same time almost normalizing the expression of
ADAMTS-4 and ADAMTS-5 in the overlying joint cartilage.70
Such marked effects of antiresorptive agents have not been
consistently observed in human trials of antiresorptive agents
in OA subjects, where symptom relief, radiographic joint space
narrowing, or Western Ontario and McMaster Universities
Arthritis index (WOMAC) were used as end points,71 and it
has been argued that such agents are unlikely to show efficacy in late-stage OA because bone resorption is already suppressed at this stage.39 Interestingly, results of a trial in which
FOCUS
postmenopausal women were treated with strontium ranelate
indicated that subjects with early OA (C-terminal crosslinked
telopeptide type II collagen [CTX-II] was used as a surrogate
marker of disease) obtained the greatest benefit, again in
terms of CTX-II reduction.72 It is thus clear that earlier definitive diagnosis of OA is required so that these treatments
might be applied during periods of high bone turnover.6 In addition, more informative outcome measures for human clinical trials will assist in determining efficacy. A recent trial of
zolendronic acid showed a reduction over 6 months in BML
area as well as in pain,73 showing the potential utility of BMLs
as informative markers. Although there are likely several sources
of pain in OA, it seems logical that antiresorptives should reduce bone pain caused by elevated levels of bone remodeling, since this is the case in the high bone turnover states
of Paget’s disease,74 osteogenesis imperfecta,75 and cancerinduced bone pain.76 The results of the trial by Laslett et al73
suggest that this is a possibility in OA.
Conclusion
Changes in the bone of articulating joints are apparent from
the time of the earliest symptoms of OA, and are due to altered bone structure, altered biochemistry, and altered biomechanics, which in turn cause altered gene expression in
bone. This altered bone remodeling needs to be better understood temporally, spatially, mechanistically, and molecularly,
so that informed treatments can be developed for application
at a time point when efficacy can be achieved, starting as
early in the disease course as possible. In the evaluation of approaches that target the bone in OA, end points will be required that are based on better imaging and that are much
more informative of all the compartments of the joint, cartilage, synovium, tendon and muscle, and bone. I
Acknowledgements. Funding from the National Health and Medical Research Council of Australia and the support of the Department of Orthopaedics and Trauma, Royal Adelaide Hospital and the University of
Adelaide, Adelaide, Australia is gratefully acknowledged.
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49. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrixembedded cells control osteoclast formation. Nat Med. 2011;17:1235-1241.
50. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone
formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22:62676276.
51. Balemans W, Patel N, Ebeling M, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet.
2002;39:91-97.
52. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in
vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:
5866-5875.
53. Moustafa A, Sugiyama T, Prasad J, et al. Mechanical loading-related changes
in osteocyte sclerostin expression in mice are more closely associated with
the subsequent osteogenic response than the peak strains engendered. Osteoporos Int. 2012;23:1225-1234.
54. Power J, Poole KE, van Bezooijen R, et al. Sclerostin and the regulation of
bone formation: effects in hip osteoarthritis and femoral neck fracture. J Bone
Miner Res. 2010;25:1867-1876.
55. Chan BY, Fuller ES, Russell AK, et al. Increased chondrocyte sclerostin may
protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage.
2011;19:874-885.
56. Jaiprakash A, Prasadam I, Feng JQ, Liu Y, Crawford R, Xiao Y. Phenotypic
characterization of osteoarthritic osteocytes from the sclerotic zones: a possible
pathological role in subchondral bone sclerosis. Int J Biol Sci. 2012;8:406-417.
57. Kuliwaba JS, Findlay DM, Atkins GJ, Forwood MR, Fazzalari NL. Enhanced
expression of osteocalcin mRNA in human osteoarthritic trabecular bone of the
proximal femur is associated with decreased expression of interleukin-6 and
interleukin-11 mRNA. J Bone Miner Res. 2000;15:332-341.
58. Fazzalari NL, Kuliwaba JS, Atkins GJ, Forwood MR, Findlay DM. The ratio of
messenger RNA levels of receptor activator of nuclear factor kappaB ligand to
osteoprotegerin correlates with bone remodeling indices in normal human cancellous bone but not in osteoarthritis. J Bone Miner Res. 2001;16:1015-1027.
59. Zupan J, Komadina R, Marc J. The relationship between osteoclastogenic and
anti-osteoclastogenic pro-inflammatory cytokines differs in human osteoporotic and osteoarthritic bone tissues. J Biomed Sci. 2012;19:28.
60. Truong LH, Kuliwaba JS, Tsangari H, Fazzalari NL. Differential gene expression
of bone anabolic factors and trabecular bone architectural changes in the proximal femoral shaft of primary hip osteoarthritis patients. Arthritis Res Ther. 2006;
8:R188.
61. Hopwood B, Gronthos S, Kuliwaba JS, Robey PG, Findlay DM, Fazzalari NL.
Identification of differentially expressed genes between osteoarthritic and normal trabecular bone from the intertrochanteric region of the proximal femur
using cDNA microarray analysis. Bone. 2005;36:635-644.
62. Hopwood B, Tsykin A, Findlay DM, Fazzalari NL. Microarray gene expression
profiling of osteoarthritic bone suggests altered bone remodelling, WNT and
transforming growth factor-beta/bone morphogenic protein signalling. Arthritis
Res Ther. 2007;9:R100.
63. Dequeker J, Mohan S, Finkelman RD, Aerssens J, Baylink DJ. Generalized osteoarthritis associated with increased insulin-like growth factor types I and II
and transforming growth factor beta in cortical bone from the iliac crest. Possible mechanism of increased bone density and protection against osteoporosis. Arthritis Rheum. 1993;36:1702-1708.
64. Couchourel D, Aubry I, Delalandre A, et al. Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production.
65. Chan TF, Couchourel D, Abed E, Delalandre A, Duval N, Lajeunesse D. Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J Bone Miner Res. 2011;26:1399-1410.
66. Massicotte F, Lajeunesse D, Benderdour M, et al. Can altered production of interleukin-1beta, interleukin-6, transforming growth factor-beta and prostaglandin
E(2) by isolated human subchondral osteoblasts identify two subgroups of
osteoarthritic patients. Osteoarthritis Cartilage. 2002;10:491-500.
67. Hayami T, Pickarski M, Wesolowski GA, et al. The role of subchondral bone
remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004;50:1193-1206.
68. Manicourt DH, Altman RD, Williams JM, et al. Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of
canine experimental osteoarthritis and significantly reduces the severity of the
cartilage lesions. Arthritis Rheum. 1999;42:1159-1167.
69. Kadri A, Ea HK, Bazille C, Hannouche D, Lioté F, Cohen-Solal ME. Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in
murine experimental osteoarthritis. Arthritis Rheum. 2008;58:2379-2386.
70. Funck-Brentano T, Lin H, Hay E, et al. Targeting bone alleviates osteoarthritis
in osteopenic mice and modulates cartilage catabolism. PLoS One. 2012;7:
e33543.
71. Saag KG. Bisphosphonates for osteoarthritis prevention: "Holy Grail" or not?
Ann Rheum Dis. 2008;67:1358-1359.
72. Alexandersen P, Karsdal MA, Byrjalsen I, Christiansen C. Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis. Climacteric. 2011;14:236-243.
73. Laslett LL, Doré DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and
bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis.
2012;71:1322-1328.
74. Reid IR. Pharmacotherapy of Paget's disease of bone. Expert Opin Pharmacother. 2012;13:637-646.
75. Glorieux FH. Experience with bisphosphonates in osteogenesis imperfecta. Pediatrics. 2007;119(suppl II):S163-S165.
76. Sittig HB. Pathogenesis and bisphosphonate treatment of skeletal events and
bone pain in metastatic cancer: focus on ibandronate. Onkologie. 2012;35:
380-387.
Keywords: antiresorptive; gene expression; osteoarthritis; remodeling; subchondral bone
226
FOCUS
UN GRAND OUBLIÉ : LE RÔLE DE L’OS SOUS-CHONDRAL
DANS LA PHYSIOPATHOLOGIE ET LA DOULEUR ARTHROSIQUES
L’arthrose a longtemps été considérée comme étant uniquement une pathologie de dégénérescence du cartilage.
Il est désormais reconnu que toutes les structures articulaires sont touchées par la maladie, et notamment l’os souschondral, qui subit des modifications caractéristiques tout au long de la maladie. Ces modifications osseuses
semblent suivre la progression de la maladie et s’associent à une douleur articulaire. Cet article porte sur le rôle joué
par le remodelage osseux sous-chondral dans la pathogenèse de l’arthrose et l’expression de la douleur dans cette
pathologie. Il examine les arguments en faveur de l’altération des fonctions ostéoblastique et ostéoclastique et l’implication probable des ostéocytes dans les modifications de l’environnement osseux sous-chondral dans l’arthrose.
Il explore aussi les influences biomécaniques et génétiques qui peuvent modifier l’interaction entre l’os et le cartilage.
De nombreux gènes s’expriment de façon différentielle dans l’os sous-chondral au cours de l’arthrose par rapport
à l’os normal ou ostéoporotique, et nombre de ces changements persistent dans les ostéoblastes issus de l’os arthrosique. On peut donc se poser les questions suivantes : comment les modifications cellulaires et moléculaires donnent-elles naissance aux changements structuraux dans l’os sous-chondral, y compris aux lésions médullaires ? Les
lésions médullaires sont-elles des signes avant-coureurs ou même la cause de la progression de la maladie ? Enfin,
les traitements ciblant l’os sous-chondral peuvent-ils être efficaces pour différer ou inverser la dégénérescence du
cartilage articulaire sous-jacent ?
227
U P DAT E
‘‘
The concept of osteoarthritis
as organ failure with multitissue
damage opens up novel therapeutic perspectives… Current treatments for osteoarthritis are essentially aimed at controlling the
painful symptoms, thereby reducing the disability that is essentially
related to the pain in osteoarthritis. The real therapeutic goal for
osteoarthritis in the coming years
will be to find a treatment that can
permanently reduce cartilage destruction.”
Clinical research in
osteoarthritis: what’s new?
by X. Chevalier and F. Eymard, France
N
L
Xavier CHEVALIER, MD, PhD
Florent EYMARD
Service de Rhumatologie
Hôpital Henri Mondor
Université Paris XII UPEC
Créteil, FRANCE
ew therapeutic perspectives in osteoarthritis are focused on blocking
the degradative process by inhibiting tissue remodeling in the bone
and cartilage and inflammation of the synovial membrane. None of the
so-called slow-acting drugs that are currently available for the management
of osteoarthritis can be considered to be targeted treatments. A great hope
surfaced after initial trials with anti–nerve growth factor therapy showed a dramatic effect on pain in patients with knee osteoarthritis. Unfortunately, trials
were later stopped because of unexplained rapidly destructive arthropathies.
Biotherapies involving interleukin-1 blockers have been used in knee osteoarthritis, but so far have shown no efficacy on pain. Biotherapy for hand osteoarthritis involving the use of tumor necrosis factor blockers to slow down disease progression has failed. Nitric oxide inhibitors also failed to demonstrate
a chondroprotective effect in a large trial involving patients with knee osteoarthritis. Inhibitors of enzymes involved in cartilage matrix degradation are in
a preclinical phase of development, but constitute an appealing approach.
Targeting of subchondral bone is also a promising approach. Although previous chondroprotective trials using bisphosphonates have produced negative results, a recent large trial with strontium ranelate showed diminished joint
space narrowing over 3 years of follow-up. Another therapeutic approach currently under consideration is stimulation of chondrocyte anabolism. Intra-articular injection of growth factors is in the initial development phase. Finally, a new
lubricant called lubricin has shown very attractive results in animal models.
steoarthritis is the most common form of joint disease, affecting millions of
people throughout the world, and it represents a major and recognized cause
of pain and disability, particularly in the elderly.1 The aim of this review is to
provide an update on potentially chondroprotective molecules, as well as diseasemodifying antirheumatic drugs in clinical trials. Other therapeutic approaches such
as chondrocyte transplantation, stem cells, gene therapy, and intra-articular injections of conditioned media or platelet concentrates are very interesting possibilities
for the future in terms of chondroprotection, but as they are still in the early stages
of clinical development, they will not be discussed in this article.
O
Professor Xavier Chevalier, Service
de Rhumatologie, Hôpital Henri
Mondor, Université Paris XII UPEC,
Créteil, France
228
Understanding the disease in order to treat it
Osteoarthritis is often wrongly considered to simply be the slow and inexorable
wear of cartilage, hence the term degenerative disease. Actually, it is a disease of a
Clinical research in osteoarthritis: what’s new? – Chevalier and Eymard
U P DAT E
whole organ, the joint.2,3 The tissue changes observed in osteoarthritis include not only cartilage degradation, but also
sclerosis of subchondral bone, osteophyte formation, and
to varying degrees over time and space, inflammation of the
synovial membrane.3 The concept of osteoarthritis as organ
failure with multitissue damage opens up novel therapeutic
perspectives whereby not only the cartilage damage can be
targeted, but also synovitis and remodeling of subchondral
bone, the latter two participating in a major way in the destruction of cartilage.4,5
Current treatments for osteoarthritis, as defined by the latest
international consensus conferences, are essentially aimed at
controlling the painful symptoms, thereby reducing the disability that is essentially related to the pain in osteoarthritis.6,7 The
real therapeutic goal for osteoarthritis in the coming years will
be to find a treatment that can permanently reduce cartilage
destruction.
Data on the currently available treatments
For the purposes of slowing down the progression of osteoarthritis, a therapeutic class of drugs known as slow-acting
anti-arthritic agents is used. These drugs include derivatives
of avocado and soya, diacerein, chondroitin sulfate and glucosamine sulfate, and hydroxychloride salts. The status of
some of these molecules is that of a nutrient rather than a true
medicine. These molecules have shown a favorable risk-benefit ratio in lower limb osteoarthritis, but their analgesic effectiveness remains modest and controversial.7,8 A recent trial
using 800 mg of chondroitin sulfate for osteoarthritis of the
fingers showed that it could significantly reduce the painful
symptoms over a period of 6 months.9 In terms of chondroprotection, these molecules have been shown in various trials
to slow the narrowing of the joint space by about 0.1 mm per
year, especially in osteoarthritis of the knee, and to reduce the
number of patients defined as rapid progressors.8 Such a minimal annual slowdown still needs to be translated in terms
of clinical relevance. The “end point” could be, for example,
whether this annual slowdown can delay the need for the implementation of a total prosthesis of the treated joint.10
SELECTED
DORA
FGF18
IL-1
MRI
NGF
NO
TIMP
TNF-α
TNZ
WOMAC
Digital Osteoarthritis in Refractory hand OA (study)
fibroblast growth factor 18
interleukin 1
nerve growth factor
nitric oxide
tissue inhibitor of metalloproteinase
tumor necrosis factor–α
tanezumab
Western Ontario and McMaster Universities Arthritis
index
Targeting proinflammatory mediators and other
players in osteoarthritis
N Biotherapy
Biotherapy involves specifically blocking a molecule (cytokine
or growth factor) involved in the inflammatory and/or painful
process in osteoarthritis.11
N Targeting pain by inhibiting nerve growth factor
Nerve growth factor (NGF) is a molecule directly involved in
the pathways responsible for pain transmission.12 This molecule was first described in the nervous system. It acts by
means of two tyrosine kinase–type receptors.12 By binding to
its receptor, it may modify the phosphorylation of vanilloidlike pain receptors (nociceptors).12
NGF has been identified in the joint, particularly the osteoarthritic joint, and it is present at detectable levels in synovial
fluid.13 It was therefore logical to investigate the use of an inhibitor of NGF as a potential treatment. Tanezumab (TNZ) is
a fully human monoclonal antibody directed against NGF; it
was used in a randomized trial versus placebo that involved
perfusions every 8 weeks at different doses in patients suffering from painful knee osteoarthritis (n=450). The results at 16
weeks were impressive, with a very substantial reduction in
pain of between 45% to 62% in the TNZ groups compared
with 21% in the placebo group.14 Unfortunately, in addition to
some adverse neurological side effects, phase 3 clinical trials
revealed an increased number of rapidly destructive arthropathies (similar to neurological arthropathies) that led to the
implementation of prostheses, resulting in the suspension of
trials with this type of antibody.14 Use of nonsteroidal anti-inflammatory drugs in conjunction with anti-NGF seems to increase this risk. Since the publication of a recent report by the
US Food and Drug Administration, however, the use of NGF
inhibitors under specific conditions and without the concomitant use of nonsteroidal anti-inflammatory drugs has again
been authorized.
N Biotherapies targeting proinflammatory cytokines
Osteoarthritis is in part an inflammatory disease, as indicated
by its name. The inflammation is localized mainly in the synovial
membrane, but also in the subchondral bone and cartilage,
and involves a cascade of proinflammatory mediators (fragments of the matrix, cytokines, complement components).15,16
These mediators not only contribute to the degradation of the
cartilage matrix during attacks of synovitis, but are also involved in pain transmission pathways.17,18
Two proinflammatory cytokines play a major role in osteoarthritis: interleukin 1β (soluble form of interleukin 1[IL-1]) and tumor
necrosis factor–α (TNF-α).2,3,15 Through in vitro studies, and
later with the use of animal models in vivo, it was demonstrated that IL-1 is a key molecule favoring cartilage degradation, inhibition of chondrocyte synthesis, and apoptosis.15
Use of an IL-1 inhibitor through local intra-articular adminis-
229
U P DAT E
tration in experimental animal models of osteoarthritis showed
a slowdown in chondrolysis.19-22 Two randomized trials have
been conducted on two different inhibitors of IL-1 versus placebo in patients with knee osteoarthritis. We conducted the
first biotherapy trial in osteoarthritis using an IL-1 antagonist
(anakinra) administered by a single intra-articular injection (dose
of 50 mg or 150 mg) versus a placebo injection of physiological saline.23 In this trial, there was no significant difference in
the Western Ontario and McMaster Universities Arthritis Index
(WOMAC) global score or level of pain at 1 month, 3 months,
and 6 months. However, at 4 days, there was a small but significant difference in the level of pain reported in the patient
group that received 150 mg of the IL-1 receptor antagonist.23
In fact, pharmacokinetic studies have shown a very short halflife of about 6 hours for IL-1 receptor antagonists in serum,
which is incompatible with having a residual effect on pain.23
The second randomized trial compared repeated systemic
injections (by subcutaneous injection) of a monoclonal antibody blocking the type 1 receptor of IL-1 with placebo.24 The
injections were administered monthly. Again, up to 3 months,
IL-1 inhibition demonstrated no significant analgesic effect.
In addition, constant neutropenia was reported and a case
of death from severe pneumonia was also observed.24 On
the other hand, functional magnetic resonance imaging (MRI)
demonstrated changes in the subgroup of patients showing
a beneficial effect from IL-1 inhibition.24
From these two trials, we can conclude that at present, inhibition of IL-1 has not enabled observation of an analgesic
effect in knee osteoarthritis. However, IL-1 seems to be a good
therapeutic target. Thus, in the future, it will be necessary to
think about modes of administration, including the intra-articular mode, which can prolong the action of this inhibitor,
and to see whether prolonged inhibition of this cytokine can
delay the progression of osteoarthritis.
no evidence of a decrease in the structural evolution of digital osteoarthritis compared with placebo over a period of 1
year.28 Only the subgroup of patients with clinically detectable
effusion at baseline at the interphalangeal joints showed a
lower incidence of new erosions.28 In other words, it seems
that anti-TNF may be active on the structural progression of
the disease in a subgroup of patients suffering clinically from
a more inflammatory disease. The French study, Digital Osteoarthritis in Refractory hand OA (DORA), aimed to assess
the symptomatic effect of two injections of a monoclonal antibody directed against TNF-α.
N Nitric oxide inhibition
Nitric oxide (NO) is a gas that plays many physiological roles,
particularly in terms of regulation of arterial vasodilation, but it
may also play a deleterious role when produced in excess.
It has been demonstrated that NO produced in excess during osteoarthritis could contribute to cartilage destruction
through protein nitrosylation, but could also favor apoptosis
of chondrocytes through combined action with free radicals.29
It was therefore logical to consider that inhibition of NO could
reduce the progression of osteoarthritis. A recent randomized
placebo-controlled trial used two doses of an inhibitor of NO
administered orally (50 mg and 200 mg). The trial investigated
chondroprotection in knee osteoarthritis, with the main outcome criterion being evolution of radiographic joint space narrowing observed at 2 years.30 This study showed no difference
in the overall study population at 2 years in terms of reducing
progression of radiographic joint space narrowing. There was
only a trend favoring the molecule in the subgroup of patients
with a Kellgren-Lawrence grade superior to 2 at 48 weeks.30
To sum up, this trial does not allow us to conclude on the efficacy of NO inhibition in reducing the progression of knee osteoarthritis.
TNF-α is mainly used as a target in digital osteoarthritis, which
can involve a more painful and inflammatory condition called
erosive osteoarthritis.27 Systemic administration of a TNF-α
inhibitor is logical in this polyarticular form of osteoarthritis.
Repeated subcutaneous injections of adalimumab produced
N Inhibition of metalloproteases and enzymes involved
in cartilage degradation
Degradation of the extracellular matrix of cartilage is due to
the increased activity of enzymes such as metalloproteases,
as well as aggrecanase enzymes and a number of serine proteases.3 These enzymes are activated in situ by the action of
proinflammatory mediators such as cytokines. It seems logical, therefore, to block these enzymes in order to slow the
progression of osteoarthritis. The first trials to be conducted
in this area used nonselective inhibitors with many side effects,
including skeletal muscle disorders and tendinitis, which led
to discontinuation of their production.31 Highly selective inhibitors are currently available, however, including matrix metalloproteinase (MMP)-13 inhibitor. The major role of MMP-13 has
been well demonstrated in knockout mouse models of osteoarthritis.32 In an experimental model of osteoarthritis in dogs,
a selective inhibitor of this enzyme showed a convincing chondroprotective effect.33 The use of these kinds of inhibitors could
thus be tested clinically in future.34 Similarly, one can consider
the use of natural inhibitors of these metalloproteases, which
230
The second potentially interesting molecule to target is TNF-α,
which has an important proinflammatory effect and whose
effect on cartilage degradation potentiates that of IL-1.15 A
recent study conducted in a rabbit model of osteoarthritis
involving cross-section of the medial meniscus showed that
monthly intra-articular injections of infliximab (10 mg/kg or
20 mg/kg) over a 3-month period significantly decreased cartilage lesions compared with saline injections.25 In a case report, repeated subcutaneous injections of a blocking monoclonal antibody against TNF (adalimumab) in a patient with
congestive knee osteoarthritis was able to reduce pain and decrease subchondral edema observed with MRI at 6 months.26
U P DAT E
are designed as tissue inhibitors of metalloproteinase (TIMPs).
Indeed, it has already been demonstrated that intra-articular
injections of TIMP3 could slow the evolution of degenerative
lesions in experimental animal models of osteoarthritis.35
Targeting subchondral bone
There are many arguments in favor of a major role for subchondral bone in the genesis and progression of degenerative joint
disease (see article by Professor David Findlay in this issue).
In animal models, there are early lesions of the subchondral
plate (microcracks) in vivo, with accelerated bone remodeling. In situ, there is a break in the bone-cartilage calcified dividing line, leading to neovascularization of the deep layers
of cartilage and a change in chondrocyte phenotype under
the influence of factors such as vascular endothelial growth
factor. In vivo, MRI has revealed subchondral bone lesions
(bone marrow lesions) in the form of a hypersignal next to the
affected cartilage, which can predict the progression of knee
osteoarthritis. Finally, radiographs reveal late subchondral sclerosis.36,37
The use of treatments designed to slow remodeling of the subchondral bone appears appropriate in order to preserve the
adjacent cartilage. The use of parathyroid hormone (either in
a curative or preventive capacity) in an experimental model of
osteoarthritis in mice has shown very promising results in terms
of chondroprotection.38 A few clinical trials have been conducted using various anti-osteoporotic drugs to examine their
possible chondroprotective effect.
N Use of bisphosphonates
The use of risedronate at different doses in a randomized trial versus placebo conducted over 2 years was not able to
demonstrate any chondroprotective effect.39 The poor progression in patients included in this study may account for
the failure of bisphosphonates. However, decreased urinary
levels of collagen CTX2 (Human C-telopeptide of Type II Collagen) were observed in this trial, perhaps indicating a reduction in joint remodeling.39
A recent randomized placebo-controlled trial used a single
perfusion of zoledronic acid in 30 patients with symptomatic
osteoarthritis of the knee and subchondral edema revealed
by MRI.40 At 6 months, there was a significant decrease in
pain and bone edema observed on MRI in the patients receiving zoledronic acid. However, at 12 months, there was no
longer any significant difference.40
N Use of oral calcitonin
A large-scale trial involving nearly 1200 patients with knee osteoarthritis compared the use of two doses of oral calcitonin
with placebo. Patients were followed up over a 2-year period.
The main purpose of the study was to assess the ability of
oral calcitonin to slow joint space narrowing as assessed by a
standard knee x-ray.41 On the basis of this criterion, the test
was negative; however, patients also underwent MRI. A significant difference in cartilage volume favoring calcitonin was
observed at 12 months compared with placebo. It is difficult
to interpret the observed effect solely on the basis of MRI data.
Moreover, the rate of side effects observed with calcitonin was
very high and led to patient discontinuation on the grounds
of intolerance in nearly 20% of cases.41
N Use of strontium ranelate
The use of strontium ranelate for OA treatment has two advantages; on the one hand, there is an indirect effect on bone,
but there is also a potential direct effect on cartilage. Indeed,
the use of strontium ranelate specifically (the same effect was
not observed with calcium ranelate) produced increased synthesis of proteoglycans in vitro, and a synergistic effect with
insulin-like growth factor-1 on the anabolism of chondrocytes
in vitro.42 On the basis of this observation, the largest-ever
chondroprotection study was conducted using two doses of
strontium ranelate (1 g and 2 g) compared with placebo over
a period of 3 years in patients with symptomatic knee osteoarthritis.43 Over 1600 patients were recruited. The proportion
of patients who completed the study was approximately 55%
and 60%, respectively, which is consistent with what has been
observed in previous trials.44 The results of this trial were positive, and showed an annual slowdown of 0.14 mm in the
group receiving 1 g of strontium ranelate and 0.10 mm in the
group receiving 2 g of strontium ranelate. In addition, the group
of patients defined as radiological progressors (ie, those with
a loss of more than 0.5 mm over the 3-year period) was significantly reduced in the strontium ranelate groups compared
with placebo: 33% in the placebo group compared with 22%
and 26% in the strontium ranelate groups, respectively.44
Finally, for the highest dose of 2 g, a combined effect on pain
was also observed, especially in patients experiencing a painful
condition as well as rapid progression of their disease.44 This
large-scale study opens up interesting perspectives, and could
eventually lead to the use of anti-osteoporotic agents such as
strontium ranelate for the prevention of cartilage loss.
Stimulating anabolism by the use of growth factors
There is another interesting therapeutic option whose aim is
not to limit the destruction of cartilage, but rather to favor cartilage repair, even when it is naturally weak. The possibility of
direct intra-articular injection of growth factors (bone morphogenetic protein-7 or fibroblast growth factor 18; FGF18)
is still in its early stages, and phase 1/2 trials are currently ongoing.45,46 One study, published only as an abstract, used intra-articular injections of FGF18 (either a single injection or
two cycles of three intra-articular injections) in knee osteoarthritis.46 There was no evidence of a slowdown in the narrowing of the joint space compared with placebo, but there
was a benefit in terms of cartilage volume gain as assessed by
MRI at 1 year.46 With regard to local injections of either plateletrich autologous plasma or autologous conditioned serum, the
231
U P DAT E
principle of which is to concentrate growth factors or contrainflammatory cytokines, clinical efficacy on pain still needs to
be validated in large-scale placebo-controlled trials, and no
chondroprotection study has been conducted thus far.47,48
Protecting the superficial layers of cartilage
Protection of the superficial layers of cartilage is the principle behind the use of hyaluronic acid, which serves as a protective gel. Lubricin is a glycoprotein present in the synovial
fluid, which acts by adhering to the most superficial layers of
cartilage. Animal tests have shown the ability of this molecule
to prevent cartilage degradation when it is administered by intra-articular injection.49 The future may involve combined therapy using lubricin and hyaluronic acid.
Conclusion
A better understanding of the physiopathogenesis of degenerative disease in osteoarthritis, particularly the involvement
of different tissues of the joint such as the synovial membrane
and the subchondral bone, has allowed us to consider some
very interesting prospective therapeutic options. Combination of different treatments may also eventually be considered, which at different time points could target the synovial
membrane, stem cell cartilage repair, and limitation of longterm remodeling of the subchondral bone. Nevertheless, it will
also be necessary to demonstrate that modulatory effects on
these structural components can also have an impact on and
a clinical relevance for a “hard” criterion, such as delaying the
need for total joint replacement surgery. I
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12. Wood JN. Nerve growth factor and pain. N Engl J Med. 2010;363:1572-1573.
13. Barthel C, Yeremenko N, Jacobs R, et al. Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res Ther. 2009;
11:R82.
14. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain
from osteoarthritis of the knee. N Engl J Med. 2010;363:1521-1531.
15. Pelletier JP, Martel-Pelletier J, Abramson SE. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis
Rheum. 2001;44:1237-1247.
16. Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis.
Bone. 2012;51:249-257.
17. Sachs D, Cunha FQ, Poole S, Ferreira SH. Tumour necrosis factor-alpha, interleukin-1beta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity. Pain. 2002;96:89-97.
18. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis:
a potential predictive factor of structural progression of medial tibiofemoral knee
osteoarthritis: results of a 1 year longitudinal arthroscopic study in 422 patients.
19. Chevalier X, Mugnier B, Bouvenot G. Targeted anti-cytokine therapies for osteoarthritis. Bull Acad Natl Med. 2006;190:1411-1420.
20. Chevalier X. Intraarticular treatments for osteoarthritis: new perspectives. Curr
Drug Targets. 2010;1:546-560.
21. Caron JP, Fernandes JC, Martel-Pelletier J, et al. Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum. 1996;39:
1535-1544.
22. Pelletier JP, Caron JP, Evans C, et al. In vivo suppression of early experimental
osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis
Rheum. 1997;40:1012-1019.
23. Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in
osteoarthritis of the knee: a multicenter, randomized, double-blind, placebocontrolled study. Arthritis Rheum. 2009;61:344-352.
24. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of
AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Therapy. 2011;13:R125.
25. Zhang Q, Lv H, Chen A, Liu F, Wu X. Efficacy of infliximab in a rabbit model of
osteoarthritis. Connect Tissue Res. 2012;53:355-358.
26. Grunke M, Schulze-Koops H. Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade. Ann Rheum Dis. 2006;65:555556.
27. Punzi L, Ramonda R, Sfriso P. Erosive osteoarthritis. Best Pract Res Clin Rheumatol. 2004;18:739-758.
28. Verbruggen G, Wittoek R, Cruyssen BV, Elewaut D. Tumour necrosis factor
blockade for the treatment of erosive osteoarthritis of the interphalangeal finger
joints: a double blind, randomised trial on structure modification. Ann Rheum
Dis. 2012;71:891-898.
29. Abramson SB. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther. 2008;10(suppl 2):S2.
30. Hellio Le Graverand MP, Clemmer R, Redifer P, et al. A 2-year randomized, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor,
cindunistat (5SD-6010), in patients with symptomatic osteoarthritis of the knee.
Ann Rheum Dis. 2013;72:187-195.
31. Krzeski P, Buckland-Wright C, Bálint G, et al. Development of musculoskeletal
toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12month, double-blind, placebo-controlled study. Arthritis Res Ther. 2007;9:R109.
32. Little CB, Barai A, Burkhardt D, et al. Matrix metalloproteinase 13-deficient mice
are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 2009;60:3723-3733.
33. Settle S, Vickery L, Nemirovskiy O, et al. Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in
a dog model of osteoarthritis: confirmation by multivariate analysis that modulation of type II collagen and aggrecan degradation peptides parallels pathologic changes. Arthritis Rheum. 2010;62:3006-3015.
34. Li H, Feng F, Bingham CO 3rd, Elisseeff JH. Matrix metalloproteinases and inhibitors in cartilage tissue engineering. J Tissue Eng Regen Med. 2012;6:144-154.
35. Black RA, Castner B, Slack J, Tocker J, Eisenman J. Injected TIMP-3 protects
cartilage in a rat meniscal tear model. Osteoarthritis Cartilage. 2006;14(suppl B S23):A14.
232
U P DAT E
36. Pesesse L, Sanchez C, Henrotin Y. Osteochondral plate angiogenesis: a new
treatment target in osteoarthritis. Joint Bone Spine. 2011;78:144-149.
37. Hunter DJ, Zhang W, Conaghan PG, et al. Systematic review of the concurrent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage.
2011;19:557-588.
38. Sampson ER, Hilton MJ, Tian Y, et al. Teriparatide as a chondroregenerative
therapy for injury-induced osteoarthritis. Sci Transl Med. 2011;3:101ra93.
39. Bingham CO 3rd, Buckland-Wright JC, Garnero P, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease
symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 2006;54:3494-3507.
40. Laslett LL, Doré DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and
bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum
Dis. 2012;71:1322-1328.
41. Karsdal MA, Alexandersen P, Dam EB, et al. Oral calcitonin demonstrated symptom-modifying efficacy and decreased cartilage volume loss: results from a 2
year phase 3 trial in patients with osteoarthritis of the knee. Presented at: American College of Rheumatology Scientific Meeting; November 8, 2011; Chicago,
IL. Late breaking abstract L9.
42. Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage
matrix formation. J Bone Miner Res. 2001;16:299-308.
43. Cooper C, Reginster JY, Chapurlat R, et al. Efficacy and safety of oral strontium
ranelate for the treatment of knee osteoarthritis: rationale and design of randomised,
double-blind, placebo-controlled trial. Curr Med Res Opin. 2012;28:231-239.
44. Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium
ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis. 20113;72:179-186.
45. Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety
and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord. 2010;11:232.
46. McPherson R, Flechenshar K, Hellot S, Eckstein F. A randomized, double blind,
placebo-controlled, multicenter study of RHFGF18 administered intraarticularly using single or multiple ascending doses in patients with primary knee osteoarthritis (OZA), not expected to require knee surgery within a year. Osteoarthritis Cartilage. 2011;19(suppl S35):65.
47. Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage
pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:
1490-1501.
48. Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum
(Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17:152-160.
49. Jay GD, Elsaid KA, Kelly KA, et al. Prevention of cartilage degeneration and gait
asymmetry by lubricin tribosupplementation in the rat following anterior cruciate ligament transection. Arthritis Rheum. 2012;64:1162-1171.
Keywords: anti-osteoporotic drug; biotherapy; cartilage; metalloprotease; nitric oxide; osteoarthritis; strontium ranelate
LA
RECHERCHE CLINIQUE DANS L’ARTHROSE
:
QUOI DE NEUF
?
Les nouvelles perspectives de traitement de l’arthrose se concentrent sur le blocage du processus de dégradation
en inhibant le remodelage tissulaire dans l’os et le cartilage, ainsi que l’inflammation de la membrane synoviale. Aucun des médicaments anti-arthrosiques d’action lente actuellement disponibles ne peut être considéré comme un
traitement ciblé. Les premières études sur le traitement par antagonisme du facteur de croissance du nerf ayant
montré un effet spectaculaire sur la douleur des patients souffrant d’arthrose du genou, ont soulevé un grand espoir. Malheureusement, ces études ont par la suite été arrêtées en raison de la survenue inexpliquée d’arthropathies
rapidement destructives. Des biothérapies utilisant des bloqueurs de l’interleukine 1 ont été utilisées dans l’arthrose
du genou mais se sont jusqu’à maintenant montrées inefficaces sur la douleur. La biothérapie de l’arthrose de la
main par blocage du facteur de nécrose tumorale pour ralentir la progression de la maladie, a également échoué. De
même, les inhibiteurs du monoxyde d’azote n’ont pas réussi à montrer d’effet protecteur du cartilage dans une large
étude sur des patients souffrant d’arthrose du genou. L’utilisation d’inhibiteurs des enzymes impliquées dans la dégradation de la matrice cartilagineuse est en phase préclinique et représente une approche intéressante. Cibler l’os
sous-chondral représente également une approche prometteuse. Alors que les résultats d’études antérieures sur
la protection du cartilage par les bisphosphonates ont été négatifs, une grande étude récente a montré une diminution du rétrécissement de l’espace interarticulaire après 3 ans de traitement par le ranélate de strontium. Le traitement par stimulation de l’anabolisme du chondrocyte est également à l’étude. L’injection intra-articulaire de facteurs
de croissance est en phase initiale de développement. Enfin, un nouveau lubrifiant appelé lubricine a montré des
résultats très intéressants dans des modèles animaux.
233
A TOUCH
OF FRANCE
y inventing the film camera,
and perforations to advance
the film through a camera
and a projector, France, through
the Lumière brothers, gave birth
to the cinema. On 19 March 1895,
they produced the first footage
ever made, albeit on an admittedly dull topic, that of workers
leaving a factory after their day’s
work. “Touch of France” looks at
the early history of the motion picture and its developments in the
fields of science and medicine
(Christian Régnier), and at the gigantic effort to preserve the legacy of the cinema, with the French
Cinémathèque founded by Henri
Langlois (Isabelle Spaak). And remember, the love affair between
France and the cinema is still alive
and kicking: do “The Artist” and Audrey Tautou mean anything to you?
B
Cinema, science, and
medicine in France
C . R é g n i e r, Fra n c e – Page 237
Children of the Cinémathèque
I . S p a a k , Fra n c e – Page 246
A TOUCH
ublic health propaganda using moving pictures spread
in France during World War I
after the setting up of an extraparliamentary commission to study
how to extend the use of cinematography to other areas of teaching.
Most films shown by the Rockefeller mission, some 150 in all,
were produced by Pathé and by
Gaumont. Their titles left little to
the imagination: Don’t Spit on the
Ground, Beware the Fly, Don’t Lick
your Fingers to Turn the Page, The
Slums Must be Vanquished, Fingernails in Mourning.
OF
FRANCE
P
Cinema, science, and
medicine in France
b y C . R é g n i e r, Fra n c e
© All rights reserved
I
Christian RÉGNIER, MD
Praticien Attaché Consultant
de l’Hôtel-Dieu de Paris
Société Internationale
d’Histoire de la Médecine
9 rue Bachaumont
75002 Paris
(e-mail:
[email protected])
n the 1870s, a forerunner of the motion picture settled a bothersome question. Does a galloping horse ever become airborne? More prosaically, are
all four of its hooves ever off the ground at the same time? It fell to the English photographer Eadweard Muybridge to find the answer. Hired by a former
governor of California and racehorse owner, Muybridge placed glass-plate
cameras along the edge of a race track. As the horse passed each camera it
broke a thread and triggered the shutter, thus generating a series of photographs. Muybridge copied these as silhouettes onto a disc and, using his invention the zoopraxiscope, showed that there was indeed “unsupported transit,” a fleeting moment when the horse was airborne. The zoopraxiscope later
came to be regarded as an early movie projector, and with it Muybridge wrote
a page in the history of early cinematography. So too did the French astronomer Jules Janssen, with his “photographic revolver,” which he used in Japan
in 1874 to record the transit of Venus across the face of the sun. And above
all there was Étienne-Jules Marey, a French doctor and physiologist who developed the chronophotograph and other instruments for pioneering analysis in humans and animals of locomotion and physiological processes like
blood flow, breathing, and the beating heart. These and other pioneers were
driven by their thirst for scientific understanding. Others, meanwhile, had their
eyes on the immense commercial and artistic potential of the new technique
of motion pictures. At the close of the 19th century, the American engineer
Thomas Edison, the French industrialists Louis and Auguste Lumière, and
the French illusionist Georges Méliès joined the adventure of the new cinematography. Industrial logic, the drive for profitability, and the lure of wealth
drove them, and led to clashes with scientists who saw cinematography purely as a research and educational tool. From its beginnings in the laboratories
of science, cinema had become a show, a leisure activity accessible to everyone. Dubbed the seventh art (after architecture, sculpture, painting, music,
poetry, and dance) by the Italian film theoretician Ricciotto Canudo, the motion
picture was able to portray all aspects of life whether scientific or fictional.
Left page: Louis Lumière,
inventor of the cinematograph
—together with his brother
Auguste—inspecting a film
(photo dated 1935).
© AKG-images/Walter Limot.
Cinema, science, and medicine in France – Régnier
237
A TOUCH
OF
FRANCE
oday’s cinemagoers, accustomed as they are to computer-generated three-dimensional images full of sound
and fury, would have scant regard for a 45-second silent
film with the humdrum title Workers Leaving the Lumière Factory. Yet motion pictures were born that March day in 1895,
when the Lumière brothers Louis and Auguste showed their
film to a gathering of scientists at the Grand Café on the Boulevard des Capucines in Paris. Sons of a manufacturer of photographic equipment, the Lumières screened the film using
T
their “cinematograph,” which combined a camera and projector to recreate movement. Not everyone present was thrilled.
Étienne-Jules Marey, the President of the Academy of Sciences, was sickened by what he saw: intellectual theft. The
Lumière brothers’ projector, he said, was his invention, the
chronophotograph, hijacked and poorly disguised by the addition of a cam for perforated films. Marey was interested solely in science and biology, and was hostile to the commercial
exploitation of moving pictures.1,2 As a pioneer of the analysis of movement, he developed a chronophotographic projector using unperforated film to record and study normal and
abnormal human gait, the beating of a perfused frog heart,
airborne birds and insects, swimming rays, even the movement of smoke trails.
Cinema, a godsend for showmen and
industrialists
The principle of moving images was not new and various animation devices were invented in the middle years of the 19th
century. The thaumatrope, beloved of every child, relies on the
persistence of vision to combine two separate images into
one: a bird on one side of a spinning card, its cage on the
Charles-Émile Reynaud’s praxinoscope projector (invented in
1877) and projection image (1887). © Bettmann/CORBIS.
Frames from Moving Horse, filmed by physiologist Étienne-Jules
Marey (left) and Workers Leaving the Lumière Factory, filmed by
the Lumière Brothers in 1895. © Album/Oronoz/akg-images.
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FRANCE
Left: Thomas Edison (1847-1931), inventor of the phonograph, the light bulb, and the motion picture camera, and holder of 1093
patents, in his laboratory, ca 1915. © Bettmann/CORBIS. Right: Thomas Edison’s first motion picture camera (1891). © CORBIS.
other. The phenakistiscope, zootrope, kinetiscope, and praxinoscope (the latter invented in France in 1877 by CharlesÉmile Reynaud) all created the illusion of movement, and in
1891 Thomas Edison patented his kinetoscope and a camera, the kinetograph, which used perforated 35-mm film. The
kinetoscope’s continuous lighting offered closed loop images
for one viewer at a time. This wealth of ideas and inventions
knew no limit; nor, it should be added, did intellectual property disputes or wrangling over patent applications (nearly 150
in France in 1896).1
In December 1895, the Lumière brothers screened what was probably the
first ever comedy film. L’Arroseur Arrosé (The Sprinkler Sprinkled) was
shown to an audience of 33 in the Indian Salon of the Grand Café, on the
boulevard des Capucines in Paris.
The entry charge was 1 franc—to put
this into context, the salon could be
rented for a whole year for 30 francs.
The success was immediate, and lasting as word of mouth ensured that
for weeks on end people came to the
film show at the Grand Café—between 2000 and 2500 every day. Emboldened by their triumph, the Lumière
brothers trained operators and sent
them on filming trips around the world,
while use of their cameras spread
among fairground cinemas. Among
those at the first screening of The
Sprinkler Sprinkled that December day was the illusionist
Georges Méliès. He quickly acquired a camera and in 1897
opened a film studio at Montreuil-sous-Bois, near Paris, where
he founded his company Star-Film. A pioneer in special effects,
Méliès made one thousand 125-meter (4-minute) films, and
won worldwide acclaim with his masterpiece Le Voyage Dans
la Lune (A Trip to the Moon). Méliès trod not the cinematic road
of the quest for knowledge, but that of a storyteller making
films for the general public.1
Poster for L’Arroseur Arrosé (The Sprinkler Sprinkled) screened in 1895 by the Lumière
Brothers. © Bettmann/CORBIS.
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FRANCE
Film still from A Trip to the Moon, a movie by Georges Méliès (1902), based on the novel From the Earth to the Moon, by Jules Verne.
Méliès directed 555 films between 1896 and 1914. © Bettmann/CORBIS.
Industrialists, too, sought to exploit the potential of moving
images. Georges Demenÿ, Marey’s assistant at the physiology annex of the Collège de France, started out studying the
movements of the mouth during speech. In May 1892, at
the first International Exhibition of Photography in Paris, he
presented thirty or so moving images mouthing the phrase
“je vous aime” (I love you). Demenÿ also invented the phonoscope, which recorded both images and sound, to teach
deaf-mutes how to speak. He soon recognized, though, the
commercial potential of his invention, changed tack, and set
up a company (Société Générale du Phonoscope) to focus
on the industrial exploitation of his process.3
Using an improved version of his phonoscope, Demenÿ then
filmed short photograms, “living portraits” of people uttering
a few words, and everyday scenes unrelated to his original scientific endeavors. The breach with Marey, who was opposed
to the commercial exploitation of moving pictures, was not
long in coming, and in 1894 Demenÿ was forced to resign from
the Collège de France. Unfazed, Demenÿ is believed to have
filmed the national funeral of Louis Pasteur on 5 October 1895
using 6-mm film, and two years later invented the 35-mm version of his camera. Unversed in the ways of business, Demenÿ
sought help from Léon Gaumont, the founder of the French
240
production company L. Gaumont et Cie, which manufactured
projection equipment and cameras. Demenÿ fared badly in
the venture and his process was bought by Gaumont, thus
bringing to an untimely end this first marriage between science and industry.1,3
Birth of the French scientific film
In 1898, Dr Eugène Doyen, a well-known surgeon, paid someone to film him performing a hysterectomy and a craniotomy
(his specialties) in his private clinic on the rue Piccini in Paris.
When his surgeon colleagues of the Academy of Medicine
balked at showing his films in public, Doyen himself paid for
their projection. They showed medium-close shots, with no
décor, and were intended for teaching purposes, though
Doyen did not hesitate to show them to an “impressionable”
public. The surgeon Jean-Louis Faure, another pioneer of surgical films, said of Doyen’s films that they were of great educational value, but tended to showiness, which, he felt, marred
the demonstration of the surgical technique.
A few years later Doyen hired a camera operator to film his
surgical separation of Doodica and Radica, conjoined twins
who starred in Barnum and Bailey’s touring cabinet of curiosities. The sober staging and style seemed to invite viewers to
A TOUCH
OF
FRANCE
forces with genuine laboratories with animal facilities, an aquarium, a vivarium, biology, chemistry, and physics departments,
their films acquired an educational purpose. Some 450 onereelers popularizing science were produced in the four years
before the war. To kindle the interest of younger viewers and
to overcome any mind-wandering, the films showed odd or
unfamiliar creatures and insects. The industrialist Charles Pathé
was convinced of their educational value, saying that “the
cinematograph will be the theater, newspaper, and school
of tomorrow.” Édouard Petit, the chief inspector of schools,
begged to differ, believing that in the cinema “the somewhat
rushed sequence of images deforms the slow and progressive work of nature.”7-9
The conjoined twins Doodica and Radica, joined at the chest
(xiphopagus twins), surgically separated by Eugène Doyen in 1902.
Although the operation itself was a success, Doodica died shortly
after the separation, and Radica succumbed to tuberculosis in
1903. © IAM/akg/World History Archive.
abandon their role as onlookers and become protagonists.
The resulting “scientific” film—La Séparation des Sœurs Siamoises Doodica et Radica—trespassed into the realm of show
business. Worse was to come. Negatives of the film were kept
by the camera operator and distributed in France and beyond for projection at cafés chantants. What had started life
as a medical demonstration, ended in ghoulishness. Tarnished
by this unseemly episode, and by the resulting legal tussles
and controversy, Doyen fell from grace.
Then there was the question of copyright. Who exactly owned
such films? The filmmaker or the surgeon? And what of the
patient, without whom there would be no film? The fifty or
so films of Doyen’s surgical procedures were leased to the
Éclipse company, later transferred to
Gaumont, and then acquired by Doyen’s
heirs, only to go up in smoke during a
bombing raid in World War II.4-6
To adapt to the large variations in the duration of natural or biological phenomena, the scientific film from the outset used
techniques that would later be adopted by those making films
for cinematic storytelling: slow motion and time-lapse photography. One of Marey’s collaborators, the photographer Lucien Bull, originated high-speed cameras which, in the early
1900s, filmed at 1200 and then 4000 images per second, and
over the years he refined them until by 1951 they could record
one million images per second. Bull also invented a camera for
microcinematography capable of 8- to 10-fold magnification.7,8
Interest in scientific films waned at the start of the First World
War and laboratories were dismantled and their staff laid off.
Scientific documentaries took their place, but were less popular and designed for a different purpose: the dissemination
of scientific knowledge to prepared minds and the creation
of audiences keen on this type of film.
Using itinerant film shows to teach public hygiene
In 1917, as the United States of America joined forces with
the Allies in World War I, the Rockefeller Foundation sent a
commission to France “to aid that country in organizing a fight
Up to the outbreak of war in 1914, industrial scientific films were highly popular in France. Most French production
companies—Pathé, Gaumont, Éclair,
Éclipse—opened studios to make short
films which in general were shown in cinemas, before the newsreel and the main
feature. When the production units joined
One of the Rockefeller Foundation’s traveling educational units (roulottes d’hygiene),
which crisscrossed France from 1917
to 1925 as part of a mission to fight tuberculosis. Photo published in Cinémagazine
No. 49, on 23 December 1921.
241
A TOUCH
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FRANCE
upon tuberculosis, by which under existing conditions the population was seriously menaced.”10 The Commission for
the Prevention of Tuberculosis in France
was solemnly welcomed by French President Raymond Poincaré on 9 August
1917. It was funded by The Rockefeller
Foundation to the tune of $522 459 (the
equivalent today of roughly 45 million euros), and included training courses for
doctors and health visitors, the running
of dispensaries throughout France (70%
of the population lived in rural areas),
and “a campaign of popular education
by means of traveling exhibits, lectures,
slides, moving pictures, posters, pamphlets, and press articles.”10 Five circulating educational units known as the
“roulottes d’hygiène” (hygiene caravans)
traveled the length and breadth of France.
Aboard each were an electrical generator, film projection equipment, films, documents, 42 exhibition posters, and five people: the (American) film director, a female lecturer, a male lecturer, a mailman, and a “driver-cinematographer.”
Public health propaganda using moving pictures spread in
France during World War I after the setting up of an extraparliamentary commission to study how to extend the use of
cinematography to other areas of teaching. Most films shown
by the Rockefeller mission, some 150 in all, were produced by
Pathé and by Gaumont. Their titles left little to the imagination:
Doctor Jean Comandon (1877-1970), a
precursor of medical and hygiene documentaries, with more than 400 films to his credit.
Don’t Spit on the Ground, Beware the
Fly, Don’t Lick your Fingers to Turn the
Page, The Slums Must be Vanquished,
Fingernails in Mourning.11 These and like
films were aimed at teachers and university lecturers, the middle classes, soldiers,
housewives, and workers. And above all
children, for whom the Rockefeller lecturers ran “health crusades” with the added
incentive of prizes. Between 1917 and
1922, the Rockefeller mission organized
6800 talks, distributed 15 million leaflets,
and launched extensive American-style
press campaigns. Close to three million
French people attended the talks and
lectures.11 After World War I, public health
education using films continued, notably in the fight against
tuberculosis through the National Committee for Defense
Against Tuberculosis (which took over the films of the Rockefeller mission). The task of making new films was entrusted
to Jean Benoît-Lévy, who between 1920 and 1944 made to
order for various governmental ministries almost 300 onereelers and 15 features. These scientific and educational films
were made in consultation with medical officers, notably Dr
Louis Devraigne, head of the maternity ward at the Lariboisière Hospital in Paris, who gave advice (and provided scripts).
In 1927 alone ten million French people attended these film
shows, which were the educational medium most popular with the working classes and rural populations.12,13
Designed to appeal to, and so to educate, the general public, Benoît-Lévy’s
films extolled the values of humanism and
of republican science. Produced by the
Société d’édition cinématographique
française, which Benoît-Lévy created in
1922, there were films on cancer, the prevention of syphilis, and alcoholism. The
first great film recounted the life and work
of Louis Pasteur. Others followed, like
The Mother-To-Be on infant care, The Sacred Veil on visiting nurses, and Maternity, which advocated a pro-birth policy.
Jean Painlevé (1902-1989) filming an aquarium for his documentary L’Hippocampe,
with a high-speed Debrie GV camera, in Port-Blanc, Brittany, around 1925.
© Les Documents cinématographiques, Paris.
242
In a December 1932 interview, BenoîtLévy spoke of his belief that educational films have much in common, and oftentimes are confused, with drama films,
from which they borrow ideas on how
to be more compelling. Benoît-Lévy felt
A TOUCH
that educational films fall into two clearly distinct genres:
those used to illustrate a talk and to transmit understanding,
and those shown in ordinary film theaters and intended to
appeal to heart and soul. Education, Benoît-Lévy believed,
speaks above all to the intellect in the first genre, and to the
sentiments in the second, provided, that is, mind and heart
can be partitioned so neatly.12,14
Making the transition to the talkies, Benoît-Lévy produced
two realistic films—Itto and Hélène—in which the image of the
rebellious woman, mistress of her own destiny, contrasted
sharply with the silent images of Maternity.12 He also made
films for the teaching of surgery, as part of a medical-surgical
cinematographic encyclopedia, a project curtailed by the outbreak of war in 1939.
OF
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er—the world of science scoffed at Painlevé’s eclecticism,
unconvinced that cinema was a tool of scientific research.
Painlevé was one of the founders of the Institut de Cinématographie Scientifique and of the Commission Supérieure de
l’Image et du Son, which allied science and cinema. He even
acted in the film The Unknown Woman of Six Days directed by René Sti to fund the anatomy and histology laboratory of the Sorbonne. He gave talks illustrated by films at the
French Academy of Sciences on the larvae of midges of the
Chironomidae family (which contains some 5000 species).
Also a diver, Painlevé made numerous scientific documentaries of aquatic animal life, like the landmark documentary on
sea horses L’Hippocampe ou “Cheval Marin” (filmed through
an aquarium!).
A new genre: the independent
science documentary
Dr Jean Comandon “filmed the invisible.”
A maker of scientific films before World
War I, Comandon later moved on to documentaries. His research on microcinematography at the Saint Louis Hospital
in Paris was given technical backup by
Pathé, which he joined in 1906 to work
its laboratory. There he made films like
Crystallization, The Curious Soldier Flies:
The Stratiomyidae, and The Movement
of Plants.
Beset by financial difficulties, Pathé
stopped producing scientific films in
1926 and closed the laboratory where
Comandon worked. Already the recipient of various distinctions and awards
for his work, Comandon set up a scientific cinematography lab at the Institut
Pasteur in Garches (near Paris) where
he made films like The Phagocytosis of
Trypanosomes by White Blood Cells and
The Circulation of Blood.15,16
In the 1920s, film clubs, educational cinema offices, and specialized projection
rooms ensured the survival of scientific
cinema in a new form where mostly documentary films were shown to the public. Jean Painlevé bestrode French scientific cinema of the 1920s. Biologist,
scriptwriter, friend of the surrealists, humanist, jewelry designer, racing car driv“Buste d'Hippocampe” (sea horse bust),
photographed by Jean Painlevé, around 1930.
© Les Documents cinématographiques, Paris.
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Painlevé was friends with renowned film
directors like Jacques Prévert, Henri Langlois, Georges Franju, Sergei Eisenstein,
Luis Buñuel, Jean Vigo, and Abel Gance.
He used musicians in the making of his
documentaries like L’Hippocampe, for
which Darius Milhaud wrote the music,
and in The Vampire, in which the life of a
vampire bat was illustrated by the music
of Duke Ellington, including Echoes of the
Jungle (Painlevé was a jazz pianist too!).
Doctor Albert Calmette (1863-1933), who,
together with his assistant Camille Guérin,
developed the BCG vaccine against tuberculosis. © Wellcome Library, London.
In all, Painlevé took part in the making of
almost 200 films, using the latest technologies: underwater filming, special effects, steadycam. In 1930, he made a
militant four-minute film in which he declared his support for the use of citrate in
anticoagulation to stem massive bleeding, as recommended by a physician with the rank of general in the French military, but recently refused by the French
Defense Health Service Authorities.17,18 Dr Pierre Thévenard
started his career as a film scientific director in 1934 by making 35-mm films on urologic surgery and followed this up with
“CINEMOPHTHALMIA,”
THE BANE OF EARLY CINEMAGOERS
In the early 20th century, a visit to the newfangled cinema
was a risky affair. Eighteen-year-old Miss R. of Bordeaux
paid for her cinematic passion with conjunctivitis after every
show. And M. C., a barber of that same French city, was
unable to read his newspaper for days after every visit to
a film theater. What was happening? In 1909, local ophthalmologist Dr Ginestous provided the answer when he
gave a paper on a new medical phenomenon he had discovered: “cinemophthalmia.”
In the early years of cinematography, the persistence of
luminous impressions on the retina was calculated to last
2/25 of a second, and so filmmakers adopted a projection
speed of 16 images/second for 35-mm film. To produce
the cinematographic illusion, the succeeding images must
remain superimposed on the retina for long enough to
give the impression of movement. Each projected image
requires an illumination phase and a phase during which
the film is advanced at a fixed speed by one frame. The
resulting scintillation of the image generated eye strain, particularly as knavish film theater directors tended to slow
the projection speed so as to lengthen the show: a 1000meter film lasted 54 minutes when projected at 16 images/
second and 62 minutes at 14 images/second. This new
ailment of cinemophthalmia discovered by Dr Ginestous
was believed to be triggered by the poor quality of films,
244
an uninterrupted series of science documentaries and films, some of which won
awards: Beware of Vipers, Ultrasound,
The Killer Mushroom, The True Culprit, a
drama commissioned by the French welfare system to warn of the dangers of induced abortion, The Question of Cancer,
an encyclopedic review in thirteen reels,
and The Adventures of a Bluebottle. A
good number of Thévenard’s films were
set to music by André Jolivet, while popular actors and members of the Comédie-Française did the voiceovers. After
Thévenard joined the scientific cinematography laboratory of the Institut Pasteur, he was commissioned to make a documentary on Albert Calmette, co-discoverer of the bacillus Calmette-Guérin, used in vaccination
against tuberculosis. This and other films brought Thévenard
international renown.8,19
which were stained and scratched, by celluloid of uneven
thickness and grain, by poor shots dotted with fuzzy and
indistinct details that force the viewer’s eye constantly to
change focus (accommodation), and by deterioration of
the film perforations resulting in slippage of the film.
Cinemophthalmia had several clinical variants: simple eye
watering with photophobia, inflammatory erythema of the
eyelids and of the conjunctiva, problems focusing, exhaustion of ocular reflexes, notably fatigue of the internal eye
muscles, and retinal asthenopia without loss of visual acuity or abnormal refraction. Despite this alarming list of disorders, Dr Ginestous sought to hearten, saying that in fact
ophthalmias of this type had a good prognosis and usually resolved quickly, even without treatment. As for prophylaxis, Dr Ginestous had the answers: choose a better
class of film theater where they use new reels of film (no slippage) and the correct projection speed; wear blue-tinted
glasses; peer at the screen through fanned fingers or fibrous palm leaves; use eyedrops containing cocaine or
adrenaline.
Cinemophthalmia receded after World War I, like a fading retinal image, pushed into a footnote on the history of
medicine by improvements in cinema projection equipment, filming techniques, and celluloid film.21-24
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Epilogue
Movies have long depicted stories of medical practitioners
in a bewildering array of guises: the hospital bigwig, a country doctor, a physician and humanist, the doomed hero, the
medic guilty of malpractice, a doctor in the colonies, murderers, cranks. Illness and the afflicted too have well served many
an intrigue on the silver screen: the Machiavellian gimp, the
fragile and vulnerable heart patient, the erratic mental patient,
the consumptive condemned to a slow death, loathsome misshapenness and disfigurement, the chilling diagnosis of cancer, traumatic childbirth. The sick and the lame have served
as a mirror, a conceit, a vehicle for a social conception of disease and suffering.20 I
References
1. Sicard M. L’Année 1895: l’Image Écartelée Entre Voir et Savoir. Paris, France:
Les Empêcheurs de Penser en Rond: 1994.
2. Leuba M. Marey, Pionnier de la Synthèse du Mouvement, Beaune: Musée Marey,
1995.
3. Drevon A. Les travaux de Georges Demenÿ In: Martinet A et al. Le Cinéma et
la Science; Paris, France: Éditions du CNRS; 1994.
4. Lefebvre T. La Chair et le Celluloïd—Le Cinéma Chirurgical du Docteur Doyen.
Brionne, France: Jean Doyen; 2004.
5. Doyen E. L’Enseignement de la Technique Opératoire par les Projections Animées. Paris, France: Société Générale des Cinématographes Éclipses; 1911.
6. Faure JL. Les films chirurgicaux. Bull Soc Fr Hist Med. 1937;31:245-248.
7. Lefebvre T. De la science à l’avant garde. In: Berthoz A et al. Images, Science,
Mouvement. Paris, France: L’Harmattan-SÉMIA; 2003.
8. Thévenard P, Tassel G. Le Cinéma Scientifique Français. Paris, France: La Jeune
Parque; 1948.
9. Petit E. L’école et le cinéma. Film-Revue. 1913;53:1-2.
10. The Rockefeller Foundation Annual Report 1920. www.rockefellerfoundation.org/
.../annual-reports.
11. Picard JF. La Fondation Rockefeller et la Recherche Médicale. Paris, France:
PUF; 1999.
12. Vignaux V. Jean Benoît-Lévy ou le Corps Comme Utopie, une Histoire du Cinéma Educateur Dans l’Entre-Deux-Guerres en France, Paris,France: AFRHC;
2007.
CINÉMA,
13. Viborel L. Éducation populaire et cinématographe. La Vie Saine. 1957;44.
14. Laot F et al. L’Image dans l’Histoire de la Formation des Adulte. Paris, France:
L’Harmattan; 2010.
15. Do O’Gomes I. L’œuvre de Jean Comandon In: Martinet A et al. Le Cinéma et
la Science; Paris, France: Éditions du CNRS; 1994.
16. Comandon J. Pierre de Fondbrune (1901-1963). Annales de l’Institut Pasteur.
1964;106(4):515-518.
17. Berg B. De charmants petits rien. In: Leuba M et al. Marey, Pionnier de la Synthèse du Mouvement. Beaune, France: Musée Marey; 1995.
18. Millet R. Jean Painlevé cinéaste. In: Martinet A et al. Le Cinéma et la Science;
Paris, France: Éditions du CNRS; 1994.
19. Raynal A. Le docteur Thévenard, cinéaste et scientifique. In: Martinet A et al.
Le Cinéma et la Science. Paris, France: Éditions du CNRS; 1994.
20. Broussouloux C. Cinéma et Médecine. Le Médecin à l’Écran. Paris, France:
Ellipses; 2001.
21. Cahan D. Hermann von Helmholtz and the Foundation of Nineteenth-Century
Science. Berkeley, CA: University of California; 1994.
22. Helmholtz H. Handbuch der Physiologischen Optik. Leipzig, Germany: Leopold
Voss; 1867.
23. Lefebvre T. Une maladie au tournant du siècle: la cinémaophtalmie. In: Marié
M et al. Cinéma des premiers temps: Nouvelles contributions françaises. Théorème. 1996;4:131-145.
24. Ginestous E. Hygiène Oculaire de la Première Enfance. Paris, France: Vigot; 1909.
SCIENCE ET MÉDECINE EN
FRANCE
Le cinéma demeure avant tout un procédé technique scientifique d’exploration des mouvements des êtres vivants.
C’est la capacité d’inventer des appareils capables de saisir des images à grande vitesse puis de les assembler
qui constitue l’image animée. Les grands découvreurs furent l’astronome français Jules Janssen, inventeur du revolver astronomique (1874), le photographe anglais Eadweard Muybridge qui mit au point le zoopraxiscope pour décomposer les mouvements du cheval (1879) et surtout le médecin français Étienne-Jules Marey qui développa le
chronophotographe et la pellicule souple non perforée (1882). Ces hommes demeurèrent des hommes de science
qui produisirent donc des films à visée exclusivement scientifique. D’un autre côté, l’ingénieur américain Thomas
Edison (1894), les industriels français Louis et Auguste Lumière (1895), le magicien français Georges Méliès (1895)
comprirent que cette nouvelle technique de l’image animée offrait des perspectives commerciales et artistiques
immenses. Ils se lancèrent alors dans le cinéma-spectacle qui connut immédiatement un immense succès. La logique industrielle, la rentabilité animaient ces pionniers qui s’opposèrent souvent aux savants. Le cinéma devint un
art, un spectacle, un loisir accessible à tous. Cet art nouveau, le septième ainsi désigné par le critique franco-italien
Ricciotto Canudo, intégrait toutes les composantes de la vie. La médecine, le médecin, la maladie et le malade figurent en bonne place dans la thématique des films français tant comme acteurs de fiction ou comme agents d’intrigues. Pour autant, le cinéma scientifique, le documentaire, le film de propagande hygiénique connurent aussi,
en France, de belles heures de gloire. Attachés à la propagation de la science, de la médecine, de l’hygiène par
l’image, ces faiseurs d’images bouleversèrent souvent la technique cinématographique au plus grand bénéfice du
film de fiction.
245
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ecause Langlois considered
film images as reflecting how
people dressed, moved, ate,
entertained themselves—in short
lived—at a particular time and
place, determining how those
coming after it would view it, he
viewed every frame as testimony.
His motto was “Everything must
be saved.” It was thanks to him
that the work of the Lumière brothers and Georges Méliès was rescued from oblivion, that pre-War
cinema has been handed down to
posterity, and that the French New
Wave was made possible.
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FRANCE
B
Children of
the Cinémathèque
b y I . S p a a k , Fra n c e
A
Isabelle SPAAK
Journalist
(e-mail:
[email protected])
s with film institutes or “cinematheques” the world over, the vocation
of the Cinémathèque, founded in Paris in 1936, was to preserve, restore, research, and show films, playing the same role for the moving
image as libraries for books or museums for paintings. That the Cinémathèque
is perhaps the best endowed of its kind, holding around 40 000 films, is largely down to one man, Henri Langlois. Born in Izmir in 1914 and a devotee of film
from childhood, Langlois founded a silent film preservation club in Paris in
1935. A year later, aged 22, he became the first director of the Cinémathèque,
which he and two friends set up to save and preserve every film wherever
made, whether masterpiece or middling. His ambition also extended to rescuing from oblivion anything related to film, including scenarios, sets, costumes,
and projectors. Larger than life, a law unto himself—the archetypal sacred
monster—Henri Langlois let nothing stand between himself and film. During
the Second World War and the Occupation, he saved the Cinémathèque’s
collection from destruction. His obsession was his strength. He forged close
friendships with Chaplin and Hitchcock, and encouraged New Wave directors
on both sides of the Atlantic. As the soul and archeologist of the moving image, he was for the poet Jean Cocteau the “dragon standing guard over our
treasure,” all of which is now on exhibition in the rejuvenated 12th arrondissement of Paris to the delectation of modern movie-lovers.
re cinephiles an extant species in the 21st century? Are there still people
who take moviegoing so seriously that they are prepared to spend whole
days in dark theaters watching endless reruns of grainy reels of celebrated
or often completely unknown films when they could be consuming avalanches of
technically superior images in the comfort of their own homes thanks to DVDs, the
Internet, social networking sites, and other forms of video on demand? And what
meaning does cinephilia—a word coined in the early 1950s by the philosophizing
champions of an art form touted as the equal of painting or literature—have in the
21st century? It was the young cinephiles of the 1950s grouped around the extravagant figure of Henri Langlois, cofounder (with Georges Franju, Jean Mitry, and
Paul-Auguste Harlé) of the Paris Cinémathèque in 1936, who went on to revitalize
French cinema. François Truffaut, Eric Rohmer, Claude Chabrol, Jacques Rivette,
Jean Rouch, and Jean-Luc Godard were all nurtured at the Cinémathèque: they
were each so entranced with cinema that they had to make films themselves. All
of them discovered gems at the Cinémathèque that they would never otherwise
A
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Children of the Cinémathèque – Spaak
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have seen had not Langlois, “driven” (Truffaut) by his monomaniacal obsession, spent his days, nights, and entire life attempting to preserve everything that had been filmed since
images were first made to move. Langlois was a larger than
life figure, a law unto himself—the archetypal sacred monster.
Had he not been obsessed by the urgent necessity of “saving
everything,” what would have become of the Lumière brothers’ archive or the cinemagic of Georges Méliès? Who, but for
him, would have seen Marlene Dietrich in The Blue Angel were
it not for its miraculous escape from destruction from German wartime censorship? How else would France have been
introduced to Soviet cinema, Hollywood epics, and Japanese masterpieces? Filmmakers the world over are indebted
to the “dragon,” as the poet Jean Cocteau called him, for
having been there to “stand guard” over the treasures of their
profession.
But Langlois was not content to track films down, identify
them, and show them. He also saw himself as an archeologist. His aim was to save everything and anything that was
related directly or indirectly to cinema, including scenarios, objects, costumes, sets, and projectors. His collection had more
than a hint of Ali Baba’s cave to it. But who else was able to
forge links of mutual respect and friendship so strong that
Charlie Chaplin himself donated part of the cogwheels from
Modern Times, Martine Carol the dresses she wore in Max
Ophuls’ Lola Montès, Louise Brooks the buckles from her
stage shoes, Fritz Lang the robot he dreamed up for Metropolis, or Alfred Hitchcock the death head of Anthony Perkins’
mother in Psycho, posted in a large cardboard box?
Henri Langlois (1914-1977): cofounder and iconic figure of the
French Cinémathèque. © Condé Nast Archive/Corbis.
“Our spiritual home”
When the Cinémathèque left the Palais de Chaillot and moved
to the new quarters in the 12th arrondissement, in a building designed by Frank Gehry, Martin Scorsese declared at
the opening: “Filmmakers the world over are familiar with the
French Cinémathèque, even if they have never been here.
It’s our spiritual home.”
The new
Cinémathèque
Française
building,
designed by
Frank Gehry
(the same
architect who
designed the
Guggenheim
Musem in
Bilbao) and
opened to
the public on
28 September 2005.
© Ginies/
epa/Corbis.
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Charlie
Chaplin in
the satire
of the dehumanizing industrialized
world, Modern Times
(1936).
© Bettmann/
CORBIS.
This moving testimony reflected the reputation of an institution brought into being in 1936 by three devotees of what
in France is commonly referred to as the seventh art: director Georges Franju (1912-1987), film critic Jean Mitry (19071988), and Henri Langlois (1914-1977).
Franju and Langlois had met in the early ’30s at a printer’s
where the young Langlois had been apprenticed by his father after failing his exams. Born in Izmir, ex-Smyrna, in 1914
to French parents forced to return to France after the Greek
city was taken by Turkey in 1922, Henri Langlois had only one
interest: cinema. It was the one and only passion in his life, to the extent that he chose to go
to the movies rather than sit for his baccalaureat, to the great despair of his father. Franju and
Langlois found themselves partners in the same
passion.
Together they borrowed 500 francs (equivalent
to 375 euros in 2013 [INSEE indicator]) from
Henri’s parents to set up a sort of film club, Le
Cercle du Cinéma (The Cinema Circle), where
they showed silent films, encouraged by the film
historian Jean Mitry who was convinced that
the advent of the talkies would condemn the
masterpieces of silent cinema to oblivion if nobody bothered to preserve the reels. There was
no institution of any kind devoted to the protecBrigitte Helm as the Robot Maria in Metropolis,
directed by Fritz Lang in 1926, in Germany.
© Bettmann/CORBIS
248
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tion or preservation of what was yet to be acknowledged as
the seventh art. The founding principle of the Cinémathèque
was the desire to preserve a heritage under threat. Barely 22,
yet already steeped in film history and culture, there was no
one more fitting to preside over such an institution than Henri
Langlois.
His ambition was to preserve everything: the good along with
the not so good, final cuts along with outtakes. He excluded
nothing: scale models, scenarios, stills, sets, costumes, projectors, etc. Langlois was the first to look beyond, or beneath,
the masterpieces of cinema and take an interest in all films.
He saved everything, even the stinkers. Bad films too are a
record of their time. That is what drove Langlois. “I wanted
the shades of the living to mingle with those of the dead,”
said Langlois in justifying his approach under the triple guise
of archeologist, sociologist, and historian, “because that is
what cinema is about.”
“Everything must be saved”
Because Langlois considered film images as reflecting how
people dressed, moved, ate, entertained themselves—in short
lived—at a particular time and place, determining how those
coming after it would view it, he viewed every frame as testimony. His motto was “Everything must be saved.” It was
thanks to him that the work of the Lumière brothers and
Georges Méliès was rescued from oblivion, that pre-War cinema has been handed down to posterity, and that the French
New Wave was made possible.
The Palais de Chaillot, which housed the Cinémathèque from
1963 to 2005. © Bettmann/CORBIS.
The Cinémathèque’s first home, like its current home, was
in the 12th arrondissement, but in the rue Marsoulan. From
the start it was designed as both museum and cinema. Langlois had the appetite of an ogre. He increased the Cinémathèque’s archive from ten films in 1936 to over 60 000 in 1970.
But if anything he was even keener to show them. Langlois
saved films by recovering them, but also by restoring them
when they had begun to decompose. Most were made of celluloid, a fragile material that disintegrates under adverse storage conditions.
Director
Abel Gance
and crew
filming scene
in Napoleon,
in 1927.
© Bettmann/
CORBIS
249
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The Cinémathèque was built on the donation of films by filmmakers and producers thanks to a relationship with Langlois
based on mutual gratitude and admiration. Langlois was able
to show the films without paying fees, but they remained the
property of those who entrusted them with him. Perhaps the
bulk of the collection belonged to Langlois himself, a compulsive collector and inspired flea-market trawler, who was
snapping up items long before governments recognized the
need to establish cinematographic archives.
reels around in the métro. It sounds funny now, but at the
time it was dangerous.” Without Langlois and his daring ingenuity, Robert Wiene’s The Cabinet of Dr Cagliari (1919), or
Georges Méliès’ Joan of Arc (1900), or Josef von Sternberg’s
The Blue Angel with Marlene Dietrich, to take but three examples, would have been lost to history. Many items in the
Cinémathèque archive were under threat during the Occupation, and Langlois managed to hide them by secreting his
films in any number of hiding places in Paris, burying some in
Marlene
Dietrich on
the set of The
Blue Angel,
directed by
Joseph von
Sternberg,
based on
Heinrich
Mann’s novel
Professor Unrat (Professor
Garbage).
© John
Springer
Collection/
CORBIS.
Americans in particular were grateful to the Cinémathèque’s
director for having preserved works that would no longer have
existed without his intervention. It is thanks to Langlois, for instance, that we still have Abel Gance’s magnificent Napoleon
(1927), one of the masterpieces of silent cinema.
The German Occupation deprived the Cinémathèque of a
home of its own. To get round the censor, Langlois organized
clandestine viewings at his mother’s, attended in particular by
Simone Signoret, who had no hesitation, despite her PolishJewish father, in crossing Paris under the Occupier’s nose
pushing a pram full of reels. “The first time I saw Battleship Potemkin,” remembered Signoret, “was in 1941, rue Troyon, in
the dining room at Langlois’ mother’s. All the Soviet films, and
all the films by Renoir or Prévert that were banned under the
Occupation, in fact the only great films that I saw during this
period, were shown to me by Langlois who used to carry his
250
Michel Simon’s garden, and hiding others—those by Chaplin
and Soviet directors—in a Bordeaux wine estate. By 1944,
Langlois had saved 40 000 films. As soon as the War ended
he set out to find a home for them.
The small theater on the rue de Messine
In 1948, he found premises at 8 rue de Messine, near the
Champs-Elysées. Keeping to the same fundamentals: “preserve and show,” he decided to show only once. The singleshowing idea was simple, and caught on. It was the key to his
success.
Hungry to catch the one-off showings of Langlois’ rare finds,
cinephiles were assiduous in their attendance, meeting up
for each week’s program of unmissable films that Langlois
used to stencil on a single sheet of paper. They included the
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young Claude Chabrol, François Truffaut,
Eric Rohmer, Jean-Luc Godard, Alain
Resnais, Jacques Rivette, and others,
all irrevocably committed to film, with
Langlois as their spiritual godfather. It’s
thanks to Langlois that they saw their
first undubbed Japanese film and their
first Buster Keaton (subtitled in Czech…).
It was Langlois who trained and sharpened their eye. “Enjoying cinema,” Langlois used to say, “means enjoying life.”
Competition was fierce for the sixty seats
of the little theater on the rue de Messine. Jean-Paul Sartre and Simone de
Beauvoir were regulars, as were André
Gide, Georges Braque, Fernand Léger,
and the future French president Georges
Pompidou. After each showing discussion would go on for hours in the street
outside as Langlois had no time for the
French director François Truffaut shooting La Sirène du Mississippi (Mississippi Mermaid)
staged dissection of films after they were in 1969. © Alain Dejean/Sygma/Corbis.
shown. Langlois did not only rescue riches from the past. He also celebrated, made known and en- That didn’t stop him being warm, provided you agreed to
couraged the directors of the future, such as the French New board the train of his conversation, which was more exactly
Wave, the violently controversial Rainer Werner Fassbinder, a conspiracy-centered monologue”—the conspiracy being
and Nicholas Ray, one of the leading post-War Hollywood di- the constant threat of a State stranglehold over his collection.
rectors (Johnny Guitar, 1954, and Rebel Without a Cause,
1955, with James Dean). “The work by the French Cinéma- Langlois was paranoid. But he was not mad. He knew that
thèque was without doubt the most important individual ef- the Cinémathèque had outgrown the era of heroic one-man
fort in cinema history,” said Ray in support of Langlois in Feb- effort. Its riches had become an incitement to State lust. Anruary ’68.
dré Malraux, the then Minister of Culture, made a first attempt
at modifying the status and management of the Cinémathèque
in 1963, more exactly to convert it from a private association
A man “driven”
Langlois was characterful to have only attracted admirers. His to a fully State-funded institution. In exchange for State supdetractors accused him of being muddle-headed, a hope- port, a theater in the Palais de Chaillot, and increased fundless manager, and a thief to boot. Langlois behaved like a ing, Malraux wanted a leading role on the board of directors
scavenger, with the ethics and clothing to match. He was ac- and the power to appoint a regular and dependable financial
cused of keeping negatives any old how, of letting reels rust officer. In February 1968, Malraux stopped beating about the
in his bath (a rumor which only compounded his unwashed bush: he dismissed Langlois.
image), and of alarming nontransparency as to both the precise methods by which he acquired some of the items in his World cinema takes to the street
collection or their exact location. He was shielded by a close The events of May ’68, when the country rose up against a
guard of volunteers who were prepared, like Langlois himself, deaf and authoritarian government, were only weeks away,
for any sacrifice that would enrich or protect his collection, and Malraux underestimated the stature and loyalty of the
especially as they were convinced that the whole world was troops at Langlois’ command. Indeed, so spontaneous was
out to wrest them from him. The renowned film critic Serge the loyalty that command was unnecessary. Within twentyDaney sketched a realistic portrait of the “poet of film”: “Like four hours, world cinema had taken to the street: Abel Gance,
all driven men, Henri Langlois divided the world, people and François Truffaut, Jean-Luc Godard, Jean Renoir, and Robert
events into two blocks: 1. Those that were good for the Ci- Bresson banned the State from showing their films. They were
némathèque. 2. Those that were not good for the Cinéma- joined by dozens of other filmmakers, including Charlie Chapthèque. Even if he’d known you for ten years, he didn’t waste lin, Roberto Rossellini, Fritz Lang, Richard Lester, Carl Dreyer,
time asking after your health or your family because the very Orson Welles, and Jerry Lewis. Three thousand people demonnotions of health or family only had meaning in terms of the strated outside the Palais de Chaillot. The police charged.
health of the Cinémathèque or the family of the Cinémathèque. Godard was wounded, and François Truffaut used scenes
251
A TOUCH
OF
FRANCE
Filmmakers demonstrating in the streets of Paris in February 1968to reinstate Henri Langlois who had just been fired by the French
Minister of Culture André Malraux. © Georges Pierre/Sygma/Corbis.
from the demonstration in Stolen Kisses, which he dedicated
to the Cinémathèque when it came out the following year.
There were riots outside the Cinémathèque offices in the rue
de Courcelles. A petition gathered 700 signatures from the
international cinematographic elite: the directors Michelangelo
Antonioni, Ingmar Bergman, Luis Buñuel, Peter Brook, Alfred
Hitchcock, Elia Kazan, Akira Kurosawa, Pier Paolo Pasolini,
Claude Berri, Satyajit Ray, and Andy Warhol; actors such as
Jean-Paul Belmondo, Brigitte Bardot, Catherine Deneuve,
Michel Simon, Simone Signoret, Marlene Dietrich, Jane Fonda,
Katharine Hepburn, Peter O’Toole, and Gloria Swanson; as well as writers, artists and philosophers, such
as Roland Barthes, Samuel Beckett, Alexander Calder,
Truman Capote, Max Ernst, Eugene Ionesco, Pablo
Picasso, Paul Ricoeur, Jean-Paul Sartre, Henri CartierBresson, and Norman Mailer. The power of this Who’s
Who of world culture was such that the government
climbed down and Langlois could only be reinstated.
He spent his remaining years on his singular creation,
leaving behind him a Cinémathèque envied by the rest
of the world.
French director and producer Caude Berri (left), actor Michel Simon
(middle), and screenwriter and producer Claude Chabrol (right) during a
demonstration at the Cinémathèque on 12 February 1968. © James
Andanson/Sygma/Corbis.
252
The Cinémathèque was duly rescued from the jaws of
the State, but paid for it by having its subsidies reduced
to a minimum. Langlois fought to the end of his life to
maintain his artistic ideal: a film museum designed to
turn people into filmmakers rather than to satisfy consumers. He always maintained that true cinema was
made by mauvais élèves, “bad pupils” who refuse to sit
dutifully at their desks swallowing the teacher’s curricu-
A TOUCH
OF
FRANCE
Ingrid
Bergman
handing reel
to Roberto
Rossellini
(left) in 1949.
© Bettmann/
CORBIS.
lum. Once an ardent defender of the sacred monster, Truffaut
eventually moved away, finding it increasingly difficult to tolerate Langlois’ ever more autocratic behavior and his tendency to show “commercial” films to bring in much-needed
cash. In 1974, Henri Langlois received an honorary Oscar for
his contribution to cinema. He and his wife Mary Meerson managed to keep the Cinémathèque afloat by dint of round-theclock work. After his death on January 13 1977, his friends
clubbed together to build a fitting monument over his grave in
the Montparnasse cemetery—a sloping slab that reproduces
scenes from iconic films.
From dormancy to rebirth
Bereft of its creator, the Cinémathèque and Museum of Cinema entered a dark period of semi-dormancy lasting two
decades compounded in 1997 by a fire and the subsequent
flood caused by the firemen’s hoses directed onto the roof
of the Palais de Chaillot. The collections were saved, but the
Cinémathèque found itself confined to a little theater on the
Grands Boulevards until it was reborn and rehoused in 2005
in the building designed by Frank Gehry.
Our turn now to push open the door of this reincarnation. We
find a Cinémathèque that has modern technologies to help
it fulfill its timeless mission: to preserve and put on films, run
Alfred Hitchcock receiving the French Legion of Honor from the
hands of Henri Langlois in 1971. © Michel Ginfray/Apis/Sygma/
Corbis.
the great classics, but also organize retrospectives and festivals dedicated to specific filmmakers, actors, producers, and
technicians, archive the collections, display some of the fabulous objects in the museum, mount temporary exhibitions to
give glimpses into the wealth of its holdings, and reinforce the
links between film and the other arts. The Cinémathèque
also has a library and archive at the disposal of students and
253
A TOUCH
OF
FRANCE
researchers. After its record 300 000 visitors in the summer of
2012 for the temporary exhibition on the director Tim Burton,
with over 500 drawings, photographs, and scale models, the
Cinémathèque staged an exhibition in honor of Marcel Carné,
another monument in the history of film. Generations of cinephiles were raised on Carné’s cult film, Children of Paradise
(1945), which has since been re-released in theaters and on
DVD. It was made under pressure during the German Occupation by those who—like the film’s writer Jacques Prévert and
the actors Jean-Louis Barrault, Arletty, and Pierre Brasseur—
were out to prove that the French spirit was still free even if
France itself was not, much as Langlois always remained a
free spirit even when his Cinémathèque appeared threatened
by chains. I
LA CINÉMATHÈQUE FRANÇAISE
51 rue de Bercy
75012 Paris
Monday to Saturday 12 AM to 7
Sunday 10 AM to 8 PM
PM
www.cinematheque.fr
Paris burning? Raging flames engulf
the Palais de Chaillot on 22 July 1997,
threatening to destruct the collections of
the Cinémathèque. © AFP.
LES
ENFANTS DE LA
C INÉMATHÈQUE
Comme toutes les cinémathèques au monde, la Cinémathèque française fondée en 1936 a pour vocation d’organiser un lieu de conservation et de découverte des films comme les bibliothèques le sont pour les livres ou les
musées pour les tableaux. Mais, si la Cinémathèque Française est l’une des plus riches qui existe avec quelque
40 000 films, elle le doit surtout à la volonté et l’énergie d’un seul homme : Henri Langlois (1914-1977). Fou de cinéma dès son plus jeune âge, ce natif de Smyrne se lance à partir de 1935 dans l’aventure d’un cinéclub consacré à la préservation des films muets. A vingt-deux ans, il devient le premier directeur de la Cinémathèque qu’il a
initiée avec deux amis. Son but : tout sauver, tout conserver. Les chefs-d’œuvre comme les films moins bons, les
français mais aussi les russes, les japonais. Il entend aussi préserver de l’oubli tout ce qui touche aux films : décors, scénarios, matériel de projection, costumes. Monstre sacré, Henri Langlois dédie sa vie à son projet. Durant
la seconde guerre mondiale et l’Occupation, il sauve les films de la destruction. La force de Langlois est son obsession. Il noue des amitiés fortes avec Charlie Chaplin ou Alfred Hitchcock, encourage les jeunes réalisateurs de
la Nouvelle Vague et du renouveau Hollywoodien. « Monstre sacré qui veille sur nos trésors » dira de lui le poète
Jean Cocteau, il est l’âme et l’archéologue de l’image animée. Ses trésors sont exposés à Paris dans le douzième
arrondissement et continuent d’enchanter les cinéphiles d’aujourd’hui.
254
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