Paget disease of bone: Diagnosis and drug therapy

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Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.52 When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.53 Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.54 The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.55 The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.56 It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.57 In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.58

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).59

In the observational extension study of zoledronic acid described above,58 three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.62 The risk of esophageal cancer is not confirmed at this time.63 Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.66

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),67 the United Kingdom (2004),68 Japan (2006),69 and Canada (2007).70 Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management71 are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.34,72

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