IV Bisphosphonate Approved to Treat Paget's Disease of Bone


A 5-mg intravenous formulation of zoledronic acid has been approved by the Food and Drug Administration for treating Paget's disease of bone, based on 6-month studies that found that a single infusion resulted in superior and more sustained responses than did 60 days of daily treatment with an oral bisphosphonate.

The package insert says that treatment is indicated “to induce remission” in patients with elevations in serum alkaline phosphatase (ALP) that are at least two times the upper limit of the age-specific normal reference range, or in patients who are symptomatic or are at risk for complications from the disease. Remission is defined as normalization of serum ALP.

The 5-mg formulation of the potent bisphosphonate, marketed as Reclast by Novartis Pharmaceuticals Corp., is administered as a single intravenous infusion over 15 minutes. Reclast, which is under review at the FDA for approval as a treatment for postmenopausal osteoporosis, is approved for Paget's disease in more than 50 countries, according to Novartis.

In the two 6-month identical studies, published in 2005, of 347 men and women with moderate to severe radiographically confirmed Paget's disease—all of whom had serum ALP levels as stated in the indication—the patients received either a single infusion of Reclast at the start of the study or daily doses of 30 mg of risedronate (Actonel) for 60 days. At 6 months, 96% of those who received Reclast had had a therapeutic response (defined as normalization of the ALP level or a reduction of at least three-fourths of ALP excess), compared with 74% of those on risedronate.

Levels dropped significantly more rapidly among those on Reclast, and ALP levels normalized in nearly 90% of those on Reclast, versus 58% of those on risedronate, also highly significant. The higher response rates associated with Reclast were independent of age, sex, baseline ALP, and the presence or absence of previous therapies for Paget's.

Pain scores improved in both groups, and there were trends toward improved quality of life at 3 and 6 months, as measured with a patient questionnaire, among those on Reclast, with more mixed results among those on risedronate. During a mean 190-day extension of the study in patients who had had a therapeutic response, the therapeutic response was lost in nearly 26% of those on risedronate vs. 0.9% of those on Reclast.

Those who received the infusion had twice as many adverse events in the first 3 days of treatment, primarily influenzalike symptoms that were mild to moderate; most resolved after 4 days. The rates of GI and renal or urinary disorders were similar; one patient in each group had moderate increases in serum creatinine levels, and eight patients on Reclast and one patient on risedronate developed hypocalcemia (N. Engl. J. Med. 2005;353:898–908).

“There is quite a long biochemical and clinical remission when this drug is used,” said Dr. Kenneth W. Lyles, professor of medicine at Duke University, Durham, N.C., who was one of the studies' authors. He disclosed that he has received research support from and serves as a consultant to Novartis.

Reclast is contraindicated in hypocalcemia and during pregnancy and lactation, and is not recommended for patients with severe renal impairment, according to the label.

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