Long-Term Bisphosphonates May Be OK for Select Patients

Emma Hitt, PhD

May 14, 2012

May 14, 2012 — An analysis of long-term bisphosphonate use, evaluating a composite endpoint of both vertebral and nonvertebral fractures in postmenopausal women, showed minimal benefit of continued bisphosphonate treatment beyond 5 years, although some patients at high risk might consider taking these agents longer.

Marcea Whitaker, MD, from the US Food and Drug Administration's (FDA's) Division of Reproductive and Urologic Products, Office of New Drugs, and colleagues, in response to postmarketing reports of rare but serious bisphosphonate-related adverse effects (eg, atypical femur fractures, osteonecrosis of the jaw, and esophageal cancer), conducted a systematic review of long-term bisphosphonate efficacy.

Dr. Whitaker and colleagues described their findings in a perspective article published online May 9 in the New England Journal of Medicine.

The FDA focused their review on 3 long-term extension trials that evaluated bisphosphonate treatment for from 6 to 10 years: the Fosamax Fracture Intervention Trial Long-Term Extension (FLEX), the Reclast Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZONPFT) extension, and the Actonel Vertebral Efficacy with Risedronate Therapy–Multinational Trial (VERT-MN) extension.

All women in the studies had were postmenopausal and had baseline fractures, low bone mineral density T scores (−1.5 or less), or both.

The FDA considered rate of fracture, rather than bone mineral density, to be a more meaningful endpoint for long-term efficacy. Although the findings for the 3 trials showed a similar benefit in patients treated for 5 years, the FLEX trial, which included 10 years of bisphosphonate exposure, became the focus of the FDA efficacy review.

According to the FDA analysis of the FLEX trial, the rates of vertebral and nonvertebral osteoporotic fractures were similar whether participants continued to receive alendronate for up to 10 years (a rate of 17.7%) or were switched to placebo for the extension period (16.9%). However, a post hoc analysis of FLEX indicated that the subgroup of patients without vertebral fractures at baseline but with a femoral-neck T score of less than −2.5 did show a benefit in terms of a reduced number of nonvertebral fractures.

In contrast, pooled data from all 3 trials of patients treated with bisphosphonates for more than 6 years failed to show a benefit in terms of a reduced number of fractures.

"These data raise the question of whether continued bisphosphonate therapy imparts additional fracture-prevention benefit, relative to cessation of therapy after 5 years," the authors write.

According to the researchers, however, "patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, whereas patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy."

An accompanying perspective article by Dennis M. Black, PhD, from the Departments of Epidemiology and Biostatistics at the University of California, San Francisco, and colleagues also discussed risk levels at which bisphosphonates might be continued past 5 years, based on the FDA analysis.

Dr. Black and colleagues suggest that patients with "low bone mineral density at the femoral neck (T score below −2.5) after 3 to 5 years of treatment are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of bisphosphonates. Patients with an existing vertebral fracture who have a somewhat higher (although not higher than −2.0) T score for bone mineral density may also benefit from continued therapy." However, "[p]atients with a femoral neck T score above −2.0 have a low risk of vertebral fracture and are unlikely to benefit from continued treatment," they suggest.

Dr. Black and colleagues also point out that not all drugs in this class are alike, "so recommendations for discontinuation of bisphosphonates need to be drug-specific."

Bisphosphonates that are approved for treatment of osteoporosis are currently labeled with an Important Limitation of Use statement: "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."

New Engl J Med. Published online May 9, 2012. Whitaker article, Black article

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