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Indications for Bisphosphonate Treatment


Paget Disease: When to Treat and When Not to Treat

  • Authors: Frederick R. Singer, MD
  • CME Released: 8/4/2009
  • Valid for credit through: 8/4/2010
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Target Audience and Goal Statement

This activity is intended for primary care physicians, orthopaedists, endocrinologists, rheumatologists, and other physicians who care for patients with Paget's disease.

The goal of this activity is to diagnose and treat Paget's disease effectively.

Upon completion of this activity, participants will be able to:

  • Identify elements of the clinical presentation of Paget's disease
  • Describe complications of Paget's disease
  • Specify the most potent bisphosphonate in the treatment of Paget's disease
  • Classify who should receive immediate treatment for Paget's disease


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  • Frederick R. Singer, MD

    Director, Endocrine/Bone Disease Program, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California; Clinical Professor of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California


    Disclosure: Frederick R. Singer, MD, has disclosed that he has acted as a consultant for Amgen Inc. Dr. Singer has also disclosed that he has acted as a consultant to, been involved in speaker's bureaus for (honoraria), and has received grant/research support (including for clinical trials) from Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Procter & Gamble.

CME Author(s)

  • Charles P. Vega, MD, FAAFP

    Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine


    Disclosure: Charles P. Vega, MD, FAAFP, has disclosed no relevant financial relationships.


  • Jenny Buckland

    Editor, Nature Reviews Rheumatology


    Disclosure: Jenny Buckland has disclosed no relevant financial relationships.

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Paget Disease: When to Treat and When Not to Treat: Therapy: Past and Present


Therapy: Past and Present

Pharmacologic Agents

Between the publication of Paget’s initial paper in 1877[1] and the availability of calcitonin, the first effective antiresorptive drug in the 1970s, a wide variety of therapies were tried in patients with Paget disease.[25] Arsenic, magnesium carbonate, aluminum acetate, anabolic steroids, folic acid, phenylbutazone, acetylsalicylic acid, glucocorticoids, adrenocorticotropic hormone, sodium fluoride, sodium phosphate and glucagon were administered to small numbers of patients without clear benefit. Subsequently, intravenous mithramycin[26] and subcutaneous gallium nitrate[27] were shown to be effective in reducing disease activity, but their potential toxicity prevented their acceptance as standard therapy.

Calcitonin. The first effective therapy which became widely used was salmon calcitonin,[28] a peptide hormone that rapidly inhibits osteoclast activity. Subcutaneous injections of 50-100 units given daily or three times a week reduced levels of biochemical markers of bone turnover by up to 50% over a period of 3-6 months. Bone resorption markers began to decrease immediately and bone formation markers began to decrease secon darily after about 2 weeks. Patients with bone pain noted relief within a week. With longterm therapy (>1 year), osteolytic lesions often resolved on radiologic examination (Figure 2). Although improvements in hearing deficits were not seen, progression of hearing loss seemed diminished.[29] Adverse effects included facial flushing and nausea, and, although allergic reactions were rare, 50% or more of the patients developed circulating anti bodies to the foreign protein.[30] About 20% of patients had a rise in biochemical para meters of disease activity after an initial reduction in these biochemical markers of bonecell activity. These patients had the highest titers of antibodies against salmon calcitonin. When such patients were later treated with sub cutaneous human calcitonin, they again were responsive to the inhibi tory effects of the hormone.[31] Currently, however, human calcitonin is no longer available for treatment.

Figure 2.


Effects of salmon calcitonin on osteolytic lesions in a patient with Paget disease. a Osteolytic lesions in the skull before treatment and b nearly complete resolution after 13 months of treatment with salmon calcitonin.

Bisphosphonates. Several years after the introduction of salmon calcitonin, disodium etidronate—the first of a family of drugs termed bisphosphonates—was approved for the treatment of Paget disease.[32] These drugs are analogs of inorganic pyrophosphate, a factor thought to be needed for the process of bone mineralization. The central core of these drugs consists of a P-C-P moiety, which, unlike the central P-O-P core of pyrophosphate, is resistant to metabolic degradation. This allows oral use of the drugs, although several have been evaluated for intravenous use. Bisphosphonates have the unique attribute of localiz ing to hydroxyapatite in bone;[33] the portion of drug not taken up by the skeleton is excreted unchanged by the kidneys. Like calcitonin, these agents inhibit osteoclast activity, but through entirely different mechanisms of action. The earlier bisphosphonates (etidronate and clodronate) inhibit osteoclast activity by generating nonhydrolyzable analogs of adenosine triphosphate.[34] The later generations of bisphosphonates, with one or more amino groups, inhibit farnesyl pyrophosphate synthase, an important enzyme in the mevalonate pathway.[34] Over time bisphosphonates of greater potency and with a higher binding affinity for hydroxyapatite have been developed; this has led to considerable improvement in the medical management of Paget disease.

Etidronate, given at an oral dose of 400 mg daily for 6 months, was widely used and reduced biochemical markers of bone turnover in patients with Paget disease by ~50%.[32] Despite an initial increase in bone pain in some patients, bone pain when present before treatment was usually relieved by this agent. Unlike calcitonin, resolution of osteolytic lesions was seldom observed with etidronate, even when osteoclast activity was clearly reduced. In some cases osteolytic lesions actually progressed, but introduction of calcitonin therapy or morepotent bisphosphonate therapy[35] often reversed the abnormality. Other disadvantages of etidronate treatment were that some patients developed osteomalacia,[36] and prolonged intermittent use of etidronate therapy was much less effective in suppressing bone turnover in patients with severe disease.[37]

The approval of pamidronate in the mid 1990s brought about a considerable improvement in the treatment of Paget disease.[38] Intravenous infusion of pamidronate was generally more effective in suppressing bone turnover than any of the preceding drugs used to treat the disease. One problem with the use of this agent was that consen sus on a treatment regimen was never established: regimens included 30 mg intravenously over 4 h on three consecutive days, or single 60 mg or 90 mg infusions over 2-4 h, repeated as clinically indicated. In patients with mild Paget disease (serum alkaline phosphatase activity twice normal levels), a 60 mg infusion produced normaliza tion for at least 1 year;[39] however, in patients with markedly elevated serum alkaline phosphatase activity, multiple infusions totaling up to 2.5 g did not lower the alkaline phosphatase to within the normal range.[40] Some degree of resistance to chronic therapy has been reported in patients treated for more than 3 years with intermittent infusions.[41] Pamidronate was generally well tolerated, but a considerable number of patients developed an acutephase reaction producing a flulike syndrome, mainly after the first infusion and usually lasting for several days.

Within several years of the introduction of pamidronate therapy, two other potent oral bisphosphonates became available. The first, alendronate, was administered as a 40 mg dose 30 min before breakfast with water only.[42] Patients were instructed not to lie down after ingesting the drug when it became appreciated that esophageal erosions or even perforation might occur if the pill did not pass promptly into the stomach.[43] Therapy was continued daily for 6 months and produced excellent suppression of bone turnover and relief of bone pain. Recurrent therapy given after the serum alkaline phosphatase activity increased from its nadir seemed to be as effective as the initial therapy. The second potent oral agent, risedronate, also proved to be a highly effective therapy with an apparent advantage over alendronate in that a 30 mg daily dose for only 2 months produced a similar suppression of disease activity as 6 months of alendronate.[44] The suppression of bone turnover by risedronate persisted for about 1 year.

Although several other bisphosphonates have been developed for clinical use (including tiludronate, olpadronate, neridronate), the most impressive data reported thus far has emerged from studies of zoledronate. This seems to be the most potent of the bisphosphonate family, as well as the agent with the highest affinity for hydroxyapatite.[32] This agent was originally approved for the treatment of cancer patients with hypercalcemia or bone metastases, or both. In a randomized, doubleblind clinical trial of treatment of Paget disease, a single 15 min infusion of 5 mg zoledronate was compared with standard oral risedronate treatment of 30 mg daily for 2 months.[45] At 90 days, serum alkaline phosphatase activity was in the normal range in 88% of patients treated with zoledronate and in 58% of patients treated with risedronate. At 6 months posttrial, only 1 of 113 patients did not have a sustained reduction in serum alkaline phosphatase activity after zoledronate therapy compared with 21 of 82 patients who received risedronate. Further followup of the study patients at 2 years posttreatment revealed that nearly every patient who received a single zoledronate infusion remained at the same level of suppressed disease activity.[46] Further anecdotal observations suggest that a single infusion can produce disease suppression for at least 3 years.[47] Fever, beginning about 8 h after an infusion, occurs in a minority of patients, similarly to patients given pamidronate.

Experience of treating patients with Paget disease with bisphosphonates over the past 30 years has proven the very low risk-benefit ratio of these drugs. Allergic reactions are quite rare. Uveitis or scleritis, or both, have been reported, most often after pamidronate therapy.[48] Impairment of renal function is unusual, except when pamidronate or zoledronate are infused too rapidly;[49] however, infusions are not recommended in patients with renal failure. Osteonecrosis of the jaw is extremely rare in patients with Paget disease.[50]


Surgery for complications of marked cranial overgrowth,[51] spinal abnormalities,[11] arthropathy adjacent to pagetic regions,[52-55] lower extremity deformities,[56,57] or femoral fracture fixation[58] might be needed in a small percentage of patients with Paget disease. It is appropriate to institute drug therapy to reduce disease activity 2-3 months before elective surgery; this reduces blood flow in the affected skeletal region[59] and should minimize perioperative and postoperative hemorrhage without impairing bone healing.