ReviewBisphosphonates in Paget's disease
Introduction
Paget's disease has an importance in the history of the bisphosphonates which far exceeds its world-wide prevalence. As the best example of a high turnover bone disease, it is ideally suited to exploratory studies of new inhibitors of bone resorption. Almost all of the major bisphosphonates have first been studied in Paget's disease, and as a result many of the fundamental principles that underpin our use of this powerful class of drugs in a wide range of metabolic bone diseases have first been revealed (but not always recognized except in hind-sight) by clinical studies in this condition.
Paget's disease is a skeletal condition characterized by foci of increased bone turnover which result from a loss of the usually tight control of bone cell activity. Osteoclasts typically predominate early in the course of a pagetic focus, resulting in osteolysis (with the attendant risks of deformity and fracture), and this usually gives way to osteoblast predominance as the lesion matures (Fig. 1). Osteoblast over-activity leads to the formation of structurally disorganized bone and to bone expansion, sometimes resulting in bone pain, premature arthritis, and nerve compression. The disease progresses along a long bone at a rate of about 1 cm per year [1], so most patients have had active disease for one or more decades before presentation. Unaffected areas of the skeleton are completely normal. Paget's disease results in pain, skeletal deformity, premature arthritis (as a result of this deformity), deafness, and fracture, as well as rare neurological complications. One or other of these complications was seen in 62% of 889 patients in a chart review from the United Kingdom [2]. These are expensive problems to treat and are associated with a substantial reduction in patients' quality of life [3].
Disease distribution and activity can be demonstrated with scintigraphy using radio-labeled bisphosphonates, since these compounds are taken up by bone in proportion to local bone turnover. This makes these drugs particularly suitable for the therapy of Paget's disease, since they are selectively delivered to affected tissues. While other anti-osteoclastic agents, such as calcitonin, have been used in the past, the capacity of the bisphosphonates to normalize bone turnover is much greater and their effects are substantially more durable, so that these drugs now monopolize treatment of this condition. This has arisen as a result of programs to develop increasingly potent bisphosphonates, and of trials demonstrating their efficacy in Paget's disease, which will now be reviewed.
Section snippets
First generation bisphosphonates
Seen from our current clinical perspective, where we have access to highly potent amino-bisphosphonates, it is easy to forget just what a substantial advance in treatment was offered by the early drugs such as etidronate, clodronate and tiludronate. They initiated the long intellectual journey from relief of symptoms, through percentage reductions in bone turnover to the achievement of long-term disease control. It is ironic that the recent PRISM trial [4] suggests that this journey may have
Amino-bisphosphonates
The therapeutics of Paget's disease took a great leap forwards with the publication of a clinical study by Bijvoet's group in 1979 [19]. Eighteen patients with Paget's disease were treated orally with pamidronate. In most cases bone resorption became normal within a week of treatment, whereas the return to normal bone formation took 3–6 months. In bone biopsies taken during treatment, the numbers of osteoclasts and osteoblasts decreased towards normal and excess osteoid disappeared. The
Determinants of response
A probably irreconcilable divide among those who treat Paget's disease is the issue of what is the best assessment of response. Relief of patients' symptoms is what we all want to achieve and yet we know that this is attended by a 33% placebo response [7]. The emphasis on quantitative measurements of bone turnover has an obvious attraction, not least because it can identify the optimal type of therapeutic strategy, though its relationship to symptoms is not well established.
Although the
Indications for treatment
There are a number of approaches to the use of the therapies described previously. This diversity is attributable, in part, to deficiencies in the available evidence base, and also to an evolution in therapeutic approaches as a result of recent clinical trials. In the past, some doctors used bisphosphonates with a view to normalizing bone turnover in all patients. With earlier agents, this was expensive, involved significant side-effects, and was often unsuccessful. In response to this
Conclusions
Up to the present time, Paget's has caused substantial morbidity in the elderly population. However, it is now possible to achieve sustained normalization of biochemical markers with the potent bisphosphonates, which can also normalize histology and heal radiological lesions. Therefore, use of these agents early in the disease course has the potential to prevent the development of significant complications from this condition.
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