Analysis Downplays Bisphosphonates' Risk

Abstract

The risk of subtrochanteric and diaphyseal femur fractures is not significantly increased in women taking bisphosphonates, even among those treated for up to 10 years, a secondary analysis of data from three large randomized bisphosphonate trials suggests. The findings follow several case reports that hinted at an increased risk of these atypical fractures in bisphosphonate users. However, the current study, which included a review of 283 hip or femur fractures in 14,195 women with 51,287 patient-years of follow-up showed that only 12 subtrochanteric or diaphyseal femur fractures occurred in 10 women, for a rate of 2.3 per 10,000 patient-years, Dennis M. Black, PhD, of the University of California, San Francisco and his colleagues wrote. The data analyzed in the current study were from the phase III Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N. Engl. J. Med. 2010 March 24[doi10.1056/NEJMoa1001086]). Even in the FLEX trial, which included up to 10 years of treatment with alendronate, the risk of femur fracture and atypical femur fracture was low, with no significantly increased risk of fracture among those who continued treatment for the full 10 years and those who discontinued treatment. “Although we can confidently conclude that absolute rates of such fractures are low, wide confidence intervals (resulting from the very low incidence of events) preclude definitive conclusions regarding the relative risk of treatment,” the investigators wrote. However, using data they analyzed, the investigators estimated that 3 years of bisphosphonate treatment in 1,000 women with osteoporosis would prevent about 100 fractures, including 71 vertebral fractures and 29 nonvertebral fractures—including 11 hip fractures. Balanced against the annual rate of 2.3 subtrochanteric and diaphyseal femur fractures seen in the three trials, “the hypothetical risk is quite small,” the researchers concluded. Additional research is needed to more fully address the matter of bisphosphonate use and the risk of subtrochanteric and diaphyseal fractures, Elizabeth Shane, MD, of Columbia University, New York wrote in an accompanying editorial. It is reasonable to consider drug holidays, particularly in those with substantially reduced levels of bone turnover markers, but again, the evidence of persistent antifracture efficacy after discontinuation must be balanced with data showing that 10 vs. 5 years of alendronate use is associated with significantly fewer new vertebral and nonvertebral fractures in those with bone mineral density T scores of −2.5 or lower, she wrote. This study was supported by Merck and Novartis. The investigators reported support from those and other pharmaceutical manufacturers, as well. Sharon Worcester is with the Southeast bureau of Elsevier Global Medical News. The data on bisphosphonates are good, and this is one area where we may be able to change outcomes (reducing fractures). There are obviously patients for whom these drugs are contraindicated for various reasons, including esophageal sensitivity, but it behooves us to consider their use in many more patients than are currently receiving them. The minuscule risks of complications such as jaw osteonecrosis and atypical fractures, in my opinion, are far outweighed by the drugs' benefits. —Karl Steinberg, MD, CMD Editor in Chief