FDA Report Advises Caution Over Long-Term Bisphosphonate Use

Studies suggest minimal improvements after 5 years of bisphosphonate use, and long-term use has been associated with serious, although rare, side effects.

Long-term bisphosphonate use may not help prevent fractures or improve bone density in certain patients with osteoporosis, according to 2 reports published online on May 31, 2012, in the New England Journal of Medicine.

Based on concerns about serious side effects, FDA researchers reviewed several studies that looked at the effects of extended bisphosphonate use. The researchers focused on 3 separate studies analyzing alendronate (Fosamax), zoledronic acid, and risedronate (Actonel), respectively. These studies were extensions of initial trials, and treatment ranged from 6 to 10 years. Study participants were postmenopausal women with baseline fractures, low bone mineral density, or both.

According to the FDA report, the 3 studies showed increases in bone density through 5 years of treatment with bisphosphonates. Beyond 5 years of treatment, bone mineral density was maintained in the neck and increased in the lumbar spine for participants who remained on the drugs. Participants who were switched to placebo experienced a slight decrease in bone mineral density in the femoral neck during their first few years off the drug, after which the decrease stabilized. However, participants taking placebo also saw bone mineral density in the lumbar spine increase.

The FDA researchers’ analysis of vertebral fractures after extended bisphosphonate therapy was inconclusive, since several of the trials showed reductions in the rate of certain vertebral fractures but others did not. In the alendronate study, rates of vertebral and nonvertebral fractures were similar regardless of whether study participants received the medication or placebo. A time-to-fracture analysis showed consistent fracture rates as well.

Pooled data from all 3 FDA treatment studies showed fracture rates of 9.3% to 10.6% for participants who remained on bisphosphonates. Meanwhile, participants who were switched to placebo saw fracture rates of 8.0% to 8.8%. In addition, serious side effects in the studies, although rare, included atypical leg fractures, osteonecrosis of the jaw, and esophageal cancer. All bisphosphonates approved for osteoporosis treatment have been effective in preventing fractures in trials lasting 3 to 4 years, the FDA researchers noted.

The FDA researchers note that the data from the studies do not allow the agency to identify patient subgroups that might benefit from extended treatment, due to limitations on statistical power, sample size, selection bias, and timing issues.

An accompanying report analyzing the study data, whose lead author was Dennis Black, PhD, of the University of California, San Francisco, found that the risk of vertebral fracture among both sets of study participants correlated to bone mineral density at the trial’s start. Participants with femoral neck T scores below -2.5 and participants with preexisting vertebral fractures and femoral neck T scores between -2.5 and -2.0 were most likely to benefit from continued treatment, Dr. Black and his colleagues note. Those with femoral neck T scores above -2.0 after the initial treatment period, however, were unlikely to benefit from continued treatment, although the authors note that further data on monitoring after discontinuing medication is needed.

The agency researchers and the authors of the accompanying report both recommended exercising caution when switching between bisphosphonates and other antiresorptive medicines, and also recommend further research into the benefits and risks of long-term bisphosphonate therapy.