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 25 years. Nowadays, patients with Paget's disease can live more normal lives.
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 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.
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.
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.
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.
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 side effect. 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.
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 utilized 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.
Pain directly attributable to Paget’s disease is generally relieved through anti-osteoclast treatment as described above. Some pain may be the result of bone deformity or arthritic or neurological complications. In this case, analgesics, non-steroidal anti-inflammatory drugs (NSAIDS) or COX-2 inhibitors may be helpful for the management of pagetic pain.
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.
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.
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.
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.