The Food and Drug Administration's safety review of bisphosphonates has not found a clear association between treatment with a bisphosphonate and atrial fibrillation.
“Based on the data available at this time, health care professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication,” the FDA stated on its MedWatch Web site.
The review compared data on 19,687 patients treated with a bisphosphonate with 18,358 patients who received placebo, who were followed from 6 months up to 3 years. These data, from the manufacturers of alendronate, ibandronate, risedronate, and zoledronic acid, were provided at the FDA's request in October 2007, after concerns about a possible association between bisphosphonates and an increased risk for serious atrial fibrillation were raised in a study and letter published 5 months earlier in the New England Journal of Medicine (2007;356:1809–22; 2007;356:1895–6).
The review found that cases of atrial fibrillation were “rare,” with two or fewer cases reported in most of the studies. The absolute difference in rates of atrial fibrillation between each bisphosphonate and placebo arm ranged from 0 to 3 cases/1,000 people, according to the FDA.
In a large zoledronic acid study, however, the rate of serious atrial fibrillation cases was significantly higher among treated patients. But “across all studies, no clear association between overall bisphosphonate exposure and rate of serious or nonserious atrial fibrillation was observed,” the FDA statement said. In addition, increasing the dose or duration of treatment was not associated with an increased rate of atrial fibrillation. (The label for zoledronic acid, given intravenously once a year for osteoporosis, includes information about the increased risk for serious atrial fibrillation.)
The statement said that the FDA is aware of “discordant results” from the literature and epidemiologic studies of the incidence and clinical course of atrial fibrillation in patients taking bisphosphonates and is “exploring the feasibility of conducting additional epidemiologic studies to examine this issue.” The FDA also continues to monitor postmarketing reports of atrial fibrillation in people treated with bisphosphonates, which are approved for treating osteoporosis, Paget disease, and some cancer-related indications.
In the 2007 studies, 1.3% of the women on Reclast and 1.5% of those on Fosamax developed serious atrial fibrillation (life threatening or resulting in hospitalization), compared with 0.5% and 1.0%, respectively, of those on placebo. When combined, rates of serious and nonserious cases of atrial fibrillation were not significantly different in the treatment and placebo groups. The patients were women aged 65–89 years with osteoporosis.
The bisphosphonates approved by the FDA are alendronate (Fosamax, Fosamax plus D), etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel, Actonel with calcium), tiludronate (Skelid), and zoledronic acid (Reclast, Zometa).
The FDA statement is available at www.fda.gov/medwatch/safety/2008/safety08.htm#bisphosphonates2www.fda.gov/MedWatch/report.htm