Paget`s Disease - Medicines for Mankind

Paget’s Disease
What is Paget’s disease?
Paget’s Disease, or osteitis deformans, as Sir James Paget – a surgeon at St Bartholomew’s Hospital, London, UK – first described it in 1877, is a chronic bone disorder,
characterised by an uncontrolled process of skeletal remodelling. The parallel process
of excessive breakdown and abnormal regrowth results in the formation of abnormal-
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ly structured bone which makes affected bones dense but fragile. In addition, a high
level of newly formed blood vessels and an excess of fibrous connective tissue in the
marrow is characteristic for the remodelled bone.
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The initial abnormality in Paget’s disease is a dramatic increase in the rate of bone
resorption caused by bone-destructing cells which are known as osteoclasts. Osteoclasts
in people with Paget’s disease are approximately five times larger than normal adult
osteoclasts. Because bone resorption triggers bone formation, the rate of bone resorption is matched by a rapid rate of bone formation over time by bone restructuring cells
known as osteoblasts. However, the osteoblasts, though numerous, are not abnormal
in Paget’s disease.
The parallel processes of resorption and regrowth may occur in one or several parts of
the skeleton and can result in weakened and enlarged bones. The most commonly
involved bones are the pelvis, vertebrae, skull, femur and tibia. The new shape of the
bones may cause pain, they may press on neighbouring nerves or fracture easily.
Enlargement of the skull, with varying degrees of deafness caused by damage of the
cranial nerves, is common and when the long bones of the leg are involved, bowing
deformity may occur. Joints also become involved because of the unequal stresses
imposed by the bent bones. Paget’s disease has usually a slow progression. The exact
cause is unknown, but it is suggested to be due to a slow viral infection of bone and
may include a heredity factor.
Who does Paget’s disease affect?
The disease occurs worldwide and affects both genders, is rarely found in people
under the age of 40, and occurs in up to five per cent of the European population
beyond that age. Epidemiology has revealed that hereditary (genetic) factors are
important in Paget’s disease. This is reflected by the fact that up to 15 per cent of individuals who suffer from it also have an affected family relative.
Present treatments:
Therapy with medicines aims at suppressing bone breakdown. A major goal of Paget’s
treatment is to reduce levels of the enzyme serum alkaline phosphatase (SAP), an indicator of disease activity, to a normal level. Experts recommend initiating treatment
when the SAP level rises to 125 to 150 per cent of normal values. Follow-up SAP monitoring may range from every three months to annually. Patients should be followed
on a long-term basis because of the increased risk of malignant transformation in
cases with longstanding Paget’s disease. Currently, there are two major classes of
medications that inhibit bone resorption and are used in the treatment of Paget’s disease. These include bisphosphonates and calcitonin. Other medicines may be prescribed to treat bone pain at the same time.
Paget’s disease is a bone
disorder where bones
become weaker and
deformed. Research by the
pharmaceutical industry
has resulted in major
improvements in treatment over the last twenty
five years. Nowadays,
patients with Paget’s
disease can live more
normal lives.
Today, the bisphosphonates are the first-line treatment. Their way of action is
suppressing or reducing bone resorption by osteoclasts. They do this both directly, by hindering the recruitment and function of osteoclasts and perhaps indirectly, by stimulating osteoblasts to produce an inhibitor of osteoclast formation.
Bisphosphonates can be given either by intravenous injection or are taken orally. Oral calcium and vitamin D supplements are recommended for patients using
this therapy to lessen hypocalcaemia, a common but rarely symptomatic sideeffect. Meanwhile, researchers have recognised that secondary resistance to
individual bisphosphonates can occur. Therefore, a patient may need to use
more than one bisphosphonate in the long-term management of the disease.
Due to certain properties of each of these medications, it is vital that patients
take oral bisphosphonates in their prescribed manner to avoid poor absorption
of the medicines.
Skull
Spine
Pelvis
Calcitonin is a hormone produced by certain cells of the thyroid and parathyroid
glands that helps to regulate calcium metabolism by reducing the rate of bone
resorption. As well as reducing bone loss, calcitonin exerts a certain analgesic
effect. The calcitonin class includes intranasal and subcutaneous forms. Subcutaneous injection of calcitonin obtained from salmon was the first widely utilised
therapy for Paget’s disease. Today, human recombinant calcitonin is also available. The molecule has been shown to reduce raised levels of bone turnover by
50 per cent, decrease symptoms of bone pain, reduce warmth over affected
bones, and improve some neurological complications. Its use today is limited
mostly to patients who do not tolerate bisphosphonates. In the case of secondary resistance to salmon calcitonin, a switch to human calcitonin is possible.
Thigh bone
(femur)
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The bones commonly affected
by Paget’s disease
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Localised Paget’s disease requires no treatment if there are no symptoms and no
evidence of active disease. Orthopaedic surgery may be required to correct a
specific deformity in severe cases.
Shin bone
(tibia)
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Pain directly attributable to Paget’s disease is generally relieved through antiosteoclast treatment as described above. Some pain may be the result of bone
deformity or arthritic or neurological complications. In this case, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDS) or COX-2 inhibitors may be helpful
for the management of pagetic pain.
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What’s in the development pipeline?
The development of specific inhibitors of osteoclast-mediated resorption, particularly
the three generations of bisphosphonates, has brought about major changes to the
treatment of Paget’s disease in the past 25 years. Although the long-term effects of
disease suppression is unknown, the capacity to restore the bone remodelling process
to normal gives reason to believe that reduction in long term complications has now
become possible. This is one of the subjects of today’s clinical research.
Currently, third-generation bisphosphonate formulations for oral and/or
intravenous use are undergoing large-scale clinical trials to reduce the
dosage scheme and the frequency of administration. This will most probably
permit an interval of about three months between individual doses.
The longer-term future:
Research has identified novel inhibitors of osteoclast formation and activation that may give rise to new lead compounds. The new inhibitors stop the
differentiation of osteoclast precursor cells.
Over the years, there has been considerable controversy as to what causes
Paget’s disease. More recently, interest has focused on the possibility that
genetic factors may be more important. Scientists have identified genes that
may cause the disease with evidence of at least five others that remain to be
discovered. Of special interest are mechanisms by which one gene (called
SQSTM1) may cause Paget’s disease. The SQSTM1 gene is known to be a
component of a pathway involved in regulating bone resorption. Researchers
speculate that there are mutations of this gene in patients with the disease
which cause activation of this pathway and increase bone resorption.
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Investigators are also screening other regions of the genome thought to contain genes for Paget’s disease. All these approaches will allow better understanding as to how the condition occurs and so develop improved strategies
for prevention and treatment. They will allow developing genetic markers for the disease which could be used to predict who is at risk in families and the general community. These new avenues will provide a greater understanding of the pathways that
regulate bone cell activity and bone remodelling which could also be beneficial for
patients with other bone diseases such as arthritis and osteoporosis.
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Editing Board: Dr. Robert Geursen (Chief Editor), Peter Heer, Bill Kirkness, Philippe Loewenstein, Steve Mees,
Dr. Jean-Marie Muschart, Marie-Claire Pickaert (Coordinator).
Photocredits: ABPI, Allergan, AstraZeneca, EFPIA/Lander Loeckx, Damian Foundation, Galderma, Hilaire Pletinckx,
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