Paget's disease of bone, the second most common skeletal remodeling disorder (after osteoporosis), is frequently diagnosed and managed by rheumatologists. New, effective therapies are available to treat Paget's disease, and most affected patients have the desired response to a single course of therapy. In this issue of Arthritis & Rheumatism, Joshua et al offer new insights into the rare but important phenomenon of resistance to the bisphosphonate pamidronate and provide new data on how to treat patients who have this problem (1).

Paget's disease of bone is a localized disorder of accelerated skeletal remodeling that can affect a single bone (monostotic) or multiple bones (polyostotic). The increased turnover rates in affected bones lead to enlargement, expansion of the cortices, and abnormal structure, which can cause deformities, fractures, and arthritis; rarely, malignant degeneration occurs. In patients with Paget's disease, spinal stenosis, deafness, and cranial nerve palsies can also develop, as well as vascular disease (2). Most affected patients are asymptomatic; when the diagnosis is made, only 10–30% of patients have symptoms referable to their disease.

Paget's disease has a distinctive geographic distribution indicating that there are both genetic and environmental influences related to its occurrence. It is common in the UK, North America, New Zealand, Australia, France, and Germany. In contrast, the disease is unusual in Scandinavia, southern Europe, Africa, and Asia. Paget's disease affects older persons, occurring in 1.5–3% of individuals older than age 60 years in the US and 1.5–2.5% of those over age 55 years in Great Britain. Recently, several different studies conducted in Great Britain, New Zealand, and Spain have confirmed that the prevalence and severity of Paget's disease have declined compared with rates observed 20 years previously (3–5). The best epidemiologic evidence shows that the prevalence of Paget's disease in 10 British medical centers in 1994 was 40% of that observed in the same centers in 1974 (6).

Although the studies described above provide evidence that some environmental factor is a cause of Paget's disease, its etiology is still unclear. For almost 30 years, a series of studies have suggested that a paramyxovirus (measles virus, respiratory syncytial virus, and canine distemper virus) may have a role in the etiology of the disease. In several laboratories, nucleocapsid-like structures, viral messenger RNA, and paramyxovirus transcripts in osteoclasts and their precursors were found (7, 8). To date, however, no virus has ever been cultured in osteoclasts or osteoclast precursors. In other laboratories, investigators using sensitive techniques could find no evidence of viral RNA in osteoclasts, and no evidence of prior viral infection (9). The question of whether paramyxovirus plays a role in the pathogenesis of Paget's disease is still unsettled, but a vigorous debate over the subject continues (10, 11).

The notion of a genetic etiology for Paget's disease is supported by data showing that 15–30% of patients have a positive family history of the disease. In Madrid, 40% of patients have an affected first-degree relative (12). There are 5 susceptibility loci for Paget's disease, on chromosomes 2, 5, 6, 10, and 18, which suggests that there is genetic heterogeneity in Paget's disease (13).

Although the etiology of Paget's disease is still unknown, and the genes causing the disorder have not been fully identified, significant progress has been made in therapies for this potentially crippling disorder. Salmon calcitonin was the first agent that was used to treat Paget's disease, with 3 weekly injections of 100 IU of the drug causing a 50% reduction in serum alkaline phosphatase (AP) levels. Patients can experience a plateau of their AP level, and in 20-40% of patients, continuing therapy results in an increase in bone remodeling activity manifested by a rise in AP levels (14). Although salmon calcitonin is a Food and Drug Administration–approved therapy for Paget's disease of bone, bisphosphonates have become the drugs of choice, due to their superior efficacy.

Bisphosphonates are compounds that are characterized by 2 phosphate groups attached to a carbon atom (P-C-P) and are analogs of the naturally occurring compounds, pyrophosphates (P-O-P). Bisphosphonates inhibit osteoclast activity in 1 of 2 ways. The amino bisphosphonates (alendronate, pamidronate, risedronate, and zoledronic acid) prevent prenylation of GTP-binding proteins through inhibition of farnesyl diphosphate synthetase. The non-amino bisphosphonates (clodronate, etidronate, and tiludronate) are incorporated into nonhydrolyzable analogs of ATP that accumulate within the osteoblasts, inhibiting their function.

One of the problems in treating Paget's disease is that patients become “resistant” to the effects of salmon calcitonin and bisphosphonates. Such resistance is manifested when the patient is receiving the antipagetic drug and has a reduced serum AP level, but the AP increases or does not return to the nadir achieved with initial treatment. Fortunately, this resistance is seen less frequently now than when salmon calcitonin and etidronate were the only therapeutic agents. With the advent of the more potent amino bisphosphonates as therapies for Paget's disease, normalization of bone remodeling rates (normal serum AP levels) occurs much more frequently after 1 or 2 courses of therapy. Still, patients who receive the amino bisphosphonate pamidronate may become resistant to that drug's ability to reduce bone turnover rates.

The biochemical mechanism of bisphosphonate resistance is unknown, but 2 potential explanations are proposed. First, with bisphosphonate therapy a group of osteoclasts are selected that become resistant to the apoptotic effect of the drug. Second, continued therapy with a bisphosphonate may induce a series of enzymes that confer resistance to a subset of osteoclasts or their precursor cells. Further studies of bisphosphonate resistance in Paget's disease will provide new insights into osteoclast biology and the mechanism(s) of action of bisphosphonates.

The importance of the current report by Joshua et al is the evidence that most patients with Paget's disease in whom pamidronate therapy is unsuccessful can be treated with a second, newer bisphosphonate (alendronate or tiludronate) and achieve normalization of their bone remodeling rates. The 2 patients in their study who did not respond to clodronate and repeated therapy with pamidronate should have been given risedronate to absolutely prove the point. Miller et al have demonstrated similar results in a double-blind study of etidronate and risedronate, in which patients who had received etidronate previously had a blunted response to etidronate, but not to risedronate (15).

Recommendations for treatment of Paget's disease of bone have been suggested by several groups, and a set of such recommendations is outlined in Table 1. When physicians treat a patient with Paget's disease of bone, they should choose one of the following new bisphosphonates: alendronate, pamidronate, risedronate, or tiludronate. Patients can be told that they have a 60–80% chance of having their AP level return to the normal range. If, after 2 months following discontinuation of the bisphosphonate, the serum AP level does not return to normal, administer a second course of the same bisphosphonate. Two months after stopping the second course of medication, repeat the AP determination. If the AP level remains elevated, administer a second bisphosphonate.

Table 1. Recommendations for treatment of Paget's disease of bone*
  • *

    Adapted, with permission, from the American Society for Bone and Mineral Research. Lyles KW, Siris ES, Singer FR, Meunier PH. A clinical approach to diagnosis and management of Paget's disease of bone. J Bone Miner Res 2001;16:1379–87.

1.To reduce symptoms caused by Paget's disease, such as bone pain referable to a pagetic site or fatigue fracture, pain from neurologic syndromes associated with pagetic changes.
2.In a patient having surgery on a pagetic site to minimize the increased blood flow in pagetic bone and to reduce blood loss through a reduction in hypervascularity.
3.In the management of hypercalcemia that may occur in the setting of prolonged immobilization of a patient with polyostotic disease and an elevated serum alkaline phosphatase level.
4.To decrease local progression and reduce the risk of future complications in asymptomatic patients whose sites of disease and degree of metabolic hyperactivity place them at risk of progression and complications.

Although randomized, controlled clinical trials in patients with Paget's disease of bone probably will never be performed to conclusively show that bisphosphonate therapy reduces the progression of deformity and disability, most patients with resistant disease can be treated with 2 different agents and have the biochemical indices of disease controlled. It is hoped that such regimens will also lessen the disability and functional impairments seen in some affected patients.


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