Nouveautés dans la prise en charge des patients avec

Lausanne, 10 octobre 2013
Nouveautés 2013
1.  Qui traiter
Nouveautés dans la prise en
charge des patients avec
ostéoporose
Service des maladies osseuses
Hôpitaux universitaires et Faculté de médecine de Genève
Osteoporosis:
Operational Definition
(Ordonance du 1er janvier 2003)!
T - Score
- 1.0 and above
OSTEOPOROSIS
- 1.0 to - 2.5
- 2.5 and below
Established Osteoporosis: + Fracture
1994
5.  Rôle du laboratoire
Ostéodensitométrie : indications remboursées !
The T-score compares an individual’s BMD with the mean value for young
normals and expresses the difference as a standard deviation score.
OSTEOPENIA
3.  Fractures atypiques
4.  Combien de temps traiter
René Rizzoli
NORMAL
2.  Calcium-Vitamine D
Kanis JA et al, J Bone Miner Res 1994;9:1137-1141
Remboursement
1. Ostéoporose clinique manifeste & fracture
2. Hypogonadisme
3. Traitement par glucocorticoïdes
4. Hyperparathyroïdie primitive
5. Ostéogenèse imparfaite
6. Maladies digestives & malabsorption
7. Porteurs du VIH (juillet 2012)
7. Au maximum une fois tous les 2 ans
DXA seulement : colonne et/ou hanche
Remboursement: état actuel
Substance
Alendronate
Ibandronate
Risedronate
Zoledronate
« Limitatio »
Cp hebdomadaire : pas de limite
Cp quotidien : - 2.5 T-Score ou fracture
- 2.5 T-Score ou fracture
- 2.0 T-Score ou fracture
- 2.5 T-Score ou fracture
Raloxifene
Basedoxifene
- 1.0 T-Score ou fracture
- 1.0 T-Score ou fracture
Calcitonine
Teriparatide
Retiré
Fracture après traitement ≥ 6 mois par
antirésorbant, ≤ 24 mois, spécialiste
Denosumab
- 2.5 T-Score ou fracture
Ten-Year Fracture Probability
-> Indication to Treatment
2008
www.SVGO.ch
www.shef.ac.uk/FRAX
Intervention Threshold
www.iofbonehealth.org
ASSESSMENT WITH BMD
10 year fracture probability (%)
10 Year Fracture Probability (%)
For Major Fractures:
30 % (eg Germany)
20 % (eg US, Canada)
OR
40
Consider
treatment
30
20
e
Int
-> 70 % Women 75-85 Years
-> 9-13 % Men 75-85 Years
in Switzerland
rve
n
n
tio
10
0
thr
ho
es
ld
No
treatment
40
50
60
70
80
Age (years)
Theshold: Fixed
Age-Dependent
90
www.SVGO.ch
Age
50
60
70
80
Association suisse contre l’ostéoporose
(ASCO)
Traitement
1.  Fracture vertébrale ou de hanche
√
2.  ≤ - 2.5 T-Score
√
3.  Risque absolu de fracture (OMS-FRAX-Suisse)
√
- Seuil variable en fonction de l’âge
(-> risque équivalent à celui associé à une fracture prévalente
vertébrale ou de hanche)
%
10
15
30
40
JUGEMENT CLINIQUE !
Recommandations 2010
Institute of Medicine 2011
Bolland et al BMJ 2010
Causes of Vitamin D Deficiency
1. Reduced Skin Synthesis
Sunscreen, Veel, Aging, Season, Skin Pigment
2. Decreased Availability
Malabsorption, Obesity
Spontaneous Calcium Intake
< 805 mg/d
≥ 805 mg/d
Risk
0.98 [0.69-1.38]
1.85 [1.28-2.67]
3. Increased Catabolism / Loss
Anticonvulsants, HAART, Nephrotic Syndrom
4. Breast-feeding
5. Decreased 25-OH-D Synthesis
Liver Failure
6. Decreased 1,25-(OH)2-D Synthesis
CKD, Vitamin D-dependent Rickets
X-Linked Hypophosphatemia,
AD Hypophosphatemia, Oncogenic Osteomalacia
Bolland et al BMJ 2010
25-OH-D Levels: Definitions
1.  Deficiency (< 25 nmol/l) -> Mineralization Defect
2.  Insufficiency (< 50 nmol/l) -> Increased Bone Turnover
and/or PTH
3.  Sufficiency (Suboptimal) (50-75 nmol/l) -> Neutral Effect
(General Population)
4.  Optimal (> 75 nmol/l) -> Desiderable Benefits on Falls
& Fracture (Osteoporotic Patients)
http://www.bag.admin.ch/themen/ernaehrung_bewegung/05207/13246/index.html?lang=de
Summary
Vitamine D : une bonne à tout faire ?
1.  25-Hydroxyvitamin D Levels > 50 nmol/l are Sufficient to
Normalize Calcium and Bone Homeostasis
2.  Extraskeletal Systems: Modest Reduction of Falls are
Observed with ≥ 800 IU / day (RCT)
3.  From Association Studies, Colon Cancer, Infections,
Cardiovascular and Metabolic Diseases are more Likely in
Subjects with 25-Hydroxyvitamin D Levels < 50 nmol/l
->Target : 25-Hydroxyvitamin D Levels > 50 nmol/l
Osteoporosis Pathogenesis and Management
Falls
Osteoporosis
Mechanical Overload
Mechanical Incompetence
Fracture
Treatment -> Fracture Repair
Rehabilitation
-> To Restore Independence
-> To Reduce Disabilities
Prevention Subsequent Fracture
Anti-fracture Efficacy (RR ± 95% CI)
Changes of gait Variability under Dual-Task from
Baseline to 6 Months With Music-based Multitask
Exercise
Vertebral Fx
Non-Vertebral Fx
RLX 60 (MORE)*
RLX 60, 120
(MORE)***
RLX 60 (MORE)**
ALN 5/10 (FIT1)*
ALN 5/10 (FIT1)*
ALN 5/10 (FIT2)**
ALN 5/10 (FIT2)**
RIS 5 (VERT-NA)*
RIS 5 (VERT-NA)*
RIS 5 (VERT-MN)*
RIS 5 (VERT-MN)*
IBAN 2.5 ***
IBAN inter
ZOL
Stride Length
Variability
Under Dual Task
Condition
RIS 2.5/5 (Hip Study)***
IBAN
ZOL
CT 200 (PROOF)*
CT 200 (PROOF)*
Denosumab ***
Denosumab ***
Teriparatide 20µg*
Teriparatide 20µg*
Strontium ranelate
Strontium ranelate
(SOTI)*
Strontium ranelate
(TROPOS)***
0.2
(SOTI)*
Strontium ranelate
(SOTI +TROPOS)**
Subject with ≥ 1 Fall: 0.46
Trombetti et al Arch Int Med 2010
0.2
Hip Fx
Relative Risk
ALN 5/10 (FIT2)**
RIS 5 (VERT-NA)*
* with prev vert
1.0
(Clinical or Symptomatic)
ALN 5/10 (FIT1)*
RIS 5 (VERT-MN)*
RIS 2.5/5 (Hip Study)***
IBAN
ZOL
CT 200 (PROOF)*
Denosumab ***
Teriparatide 20µg*
Strontium ranelate
(SOTI)*
Strontium ranelate
(TROPOS)***
0.2
0.6
*** with or without prev vert fractures
Early (≤ 1 Year) Changes
in Vertebral Fracture Risk
RLX 60, 120
(MORE)***
Only studies with preplanned
analysis:
RIS 2.5/5 (Hip Study)
ZOL 5 mg (Horizon Study)
Denosumab (Freedom
Study)
1.0
Update from Delmas 2002
Anti-fracture Efficacy (RR ± 95% CI)
Significant hip fracture risk
Reduction: 5 studies
0.6
* with prev vert fracture(s) ** without prev vert fractures
0.6
*** with or without prev vert fractures
1.0
Post-hoc
• Alendronate
- 59 %
Black et al 2000
• Raloxifene
- 68 %
Maricic et al 2002
• Risedronate
- 69 %
Roux et al 2004
• Strontium Ranelate
- 52 %
Meunier et al 2004
• Zoledronate
- 60 %
Black et al 2007
• Denosumab
- 61 %
Cummings et al 2009
Osteonecrosis of the Jaw
Definition of Osteonecrosis of the Jaw
•  ‘Exposed bone in the mandible,
maxilla or both that persists for at
least 8 weeks, in the absence of
previous radiation and of
metastases in the jaws’1
•  Many reports of ONJ involved
patients with signs of local
infection including osteomyelitis
Osteoporosis
1 / 110’000 patient-year (german registry)
1 / 20’000 patients (Australia 2007)
1 / 20’000 - 100’000 (1/13’800)
- Yearly Zoledronate 1 case out of 3’800 over 3 years
(+ 1 case placebo group)
Cancer
1.4 vs 2.0 % Zoledronate vs Denosumab over 2 years
Doses:
ZOL
Denosumab
4 mg/4 weeks vs 5 mg/year in Cancer vs OP
120 mg/4 weeks vs 60 mg/6 months
1. Rizzoli et al. Bone. 2008. 2. Khosla et al. J Bone Miner Res. 2007 3. Stopeck et al JCO 2010
1. Rizzoli R, et al. Bone. 2008;42(5):841–847. 2. Khosla S, et al. J Bone Miner Res. 2007:22:1479–1491.
Atypical Fractures under Alendronate Therapy
Atypical Femoral Fracture
1.  Odvina, JCEM 2005 -> 9 Spontanenous Non-vertebral
Fractures with Retarded Healing
2.  Schneider, Geriatrics 2006 -> 1 Case of 2 Spontaneous
Fractures Preceded by Pain and X-ray abnormalities
3.  280 entries on PubMed (October 2013)
- Transverse Fracture
- Cortical Thickening
- Prodromal Pain (73%)
- Bilateral Stress Fractures (29%)
Rizzoli et al, Osteoporos Int 2011
Sept 2003
Jan 2008
Increasing Occurrrence of Atypical Femoral
Fractures Associated with Bisphosphonate Use
R Meier et al, Arch Int Med 2012
• 477 X-ray Examinations of
Subtrochanteric Fractures
1999-2010 (out of 5453 Hip Fr over
12 Yrs)
-  1.4%/Yr
(p = 0.02)
-> 9.6%
• 39 Atraumatic Transverse
Fractures with Cortex Thickening
+ 10%/Yr
(p= 0.034)
-> 0.7% of all proximal femur
fractures
-> 28%: bilateral (vs 0.9 %)
Non-Atypical fractures
• 32 with Long-term Bisphosphonate
Treatment (4.1 Yrs)
Histomorphométrie :
biopsie transiliaque non décalcifiée
Indications à la biospie transiliaque
PRIMARY
MEASUREMENTS
T.Ar.
• Suspicion d’ostéomalacie
B.Ar.
B.Pm
.
1,2,3.. N.Bf.
Ct.Ar.
1
2
• Suspicion de maladie héréditaire
Vd.Ar.
Ct.Wi
3
• Ostédystrophie rénale
• Ostéoporose chez des sujets jeunes
DERIVED
PARAMETERS
BV/TV, Tb.Th., Th.N.
N.Bf./B.Ar., Por,....
Adapted from Eriksen et al. 1994
Epitopes dans le collagène de type I
et sites de scission par la cathépsine K
NTX
ICTP
CK
a2 (I) JYDGKGVG
CTX
CK
CK
CK
GPP-SAGFDFSFLPQPPQ EKAHDGGR a 1
N
C
CK
CK
Deoxypyridinoline
Pyridinolines
Garnero et al., JBC, 1998
Sassi et al., Bone, 2000
Marqueurs biochimiques
du remodelage osseux
Risque des fractures de hanche
Odds-ratio
5
Influencés par:
25
o 
Pre-analytical Conditions
o  Sample Storage
o  Diurnal Variation
o  Food Intake
Mean / SEM
PreMP
Early MP
15
DPyd/Cerat
o 
20
Individual Variation
3
5
0
-5
2
-10
-15
-20
o 
Assay Variation & Performance
4
Late MP
10
17
20
23
2
5
8
11
14
17
Time (Hours)
o  Renal Function
1
Low hip
BMD
high
U-CTX
Low BMD
+
high CTX
A.Schlemmer et al. J Bone Miner Res 1994;9:1883
Garnero et al., 1996
Hormone parathyroïdienne
CTX-I & P1NP sériques
Alendronate
P1NP
*
6
*
9
STAND2
* *
12 BL 1 3
*
6
*
9
DECIDE1
70
*
12
Serum PINP (µg/L)
Serum CTX-I (ng/mL)
DECIDE1
84
1
Denosumab
sCTX I
0.9
0.8
0.7
0.6 *
0.5
0.4
0.3
0.2
0.1
0 * *
BL1 3
Site de scissionSite: 33-34 + 36-37
Dans le foie et le rein
Epitope:
STAND2
60
Demi vie:
• N-terminal
< 4 min
• C-terminal
>90 min
50 *
40
30
20
*
10
• Mid-molecule
*
*
*
0
BL1 3
6
9
Study Month
*
*
*
*
*
*
12 BL1 3
6
9
12
Study Month
Dotted line is lower limit of the premenopausal reference range (The University of Sheffield Bone Marker Laboratory)
Values are medians; error bars represent the interquartile range; *P ≤ 0.01
4 min
• Intact
• Intact «bioactive»
2-
7-
1. Brown JP, et al. J Bone Miner Res. 2009;24:153;. 2. Kendler DL, et al. J Bone Miner Res. 2010;25:72
Interprétation des valeurs de PTH
en fonction de la calcémie
JCEM 90:6370-2,2005
PTH
[pM]
4
2
7.0
1
1.0
Bioactive vs « Intacte »
°
°
3
°
6
°
°
2.25
2.60
Plasma Calcium [mM]
5
°
Contribution du laboratoire :
Evaluation minimale
1.  Calcémie corrigée par l’albumine
2.  PTH intacte
3.  25-OH-D (D3 + D2)
4.  CTX (Cross-Laps) sérique
5.  (Phosphatase alcaline spécifique de l’os,
P1NP)
Contribution of Biochemical Laboratory
1.  Differential Diagnosis
2.  Mechanisms -> Bone Loss, Fracture Risk
3.  Treatment Efficacy
4.  Compliance Verification