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Long-term bisphosphonate risk-benefit.

Three to five years of bisphosphonate treatment increases bone density by slowing bone resorption and reduces the rate of osteoporotic fractures, but the value of longer treatment is being questioned at the US Food and Drug Administration. The agency recently conducted a systematic review of long-term bisphosphonate efficacy based on three extension trials. Marcea Whitaker, MD, and colleagues summarized the results in a New England Journal of Medicine article (May 31, 2013). The review focused primarily on the Fosamax Fracture Intervention Trial Long-Term Extension (FLEX).

All participants in FLEX had received Fosamax during a previous five-year study that compared Fosamax with placebo. During the extension trial, the FLEX participants either continued to use Fosamax or were given a placebo for an additional 5 years.

Although the initial study showed significantly less osteoporotic fracture incidence in the treatment group (10.6%) compared with the placebo group (21.0%), the extension trial did not: continuous Fosamax treatment had a fracture incidence of 17.7% compared with 16.9% for those who were switched to placebo. Pooled data from all three extension trials in the FDA review showed that "... patients who received continuous bisphosphonate treatment for 6 or more years result in fracture rates ranging from 9.3 to 10.6%, whereas the rate for patients switched to placebo is 8.0 to 8.8%," according to Whitaker et al. "These data raise the question of whether continued bisphosphonate therapy imparts additional fracture-prevention benefit, relative to cessation of therapy after 5 years."

Efficacy is only half of the risk-benefit equation. Bisphosphonates have multiple adverse effects. For years, the FDA has been aware of serious but rare adverse events such as atypical femur fractures, osteonecrosis of the jaw, atrial fibrillation, and esophageal cancer. Gastric disorders (i.e., dyspepsia, abdominal pain, nausea, and gastritis) and musculoskeletal pain are more common side effects, according to a 2012 literature review conducted by Pooneh Salari and Mohammed Abdollahi. People's Pharmacy has received multiple reports of muscle aches and spasms, deep bone pain, and back and joint pain from readers who attribute their symptoms to bisphosphonate use. These problems, along with tingling in extremities, fatigue, flulike feelings, headache, dizziness, skin irritation, and eye damage, are recognized by bisphosphonate manufacturers as possible adverse effects.

At this point, practitioners have no clear guidelines for weighing benefit vs. risk. It does appear, however, that the benefits decrease and the risks increase with long-term bisphosphonate treatment. As bisphosphonate labeling states, "'The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.'"

Reclast side effects incapacitate patient [Web page]. The People's Pharmacy. April 15, 2013. Accessed November 14, 2013.

Salari P, Abdollahi M. Long term bisphosphonate use in osteoporotic patients; a step forward, two steps back. / Pharm Pharmaceut Sci. 2012; 15(2):305-317. Available at Accessed November 14, 2013.

Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis--where do we go from here? N Engl J Med. May 31,2012;366(22):2048-2051.

briefed by Jule Klotter
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Title Annotation:Shorts
Author:Klotter, Jule
Publication:Townsend Letter
Article Type:Clinical report
Geographic Code:1USA
Date:Feb 1, 2014
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