Bisphosphonate use and atypical femoral fractures: getting down to brass tacks.

No doubt about it—times are rough for clinicians and their patients trying to make rational decisions about when and how to use (or stop) effective therapies for osteoporosis. On the one hand, we have increasingly clear evidence that bisphosphonates given to older women and men with osteoporosis [defined as an existing vertebral fracture or a bone mineral density (BMD) T-score less than 2.5] prevent future hip, vertebral, and non-spine fractures (1–3). Conversely, with help from the Internet, highprofile newspaper articles, and even the Food & Drug Administration (4), we seem to be reminded on a daily basis that bisphosphonates may cause serious harm, such as osteonecrosis of the jaw, atrial fibrillation, esophageal cancer, and spontaneous femur fractures. It is no wonder that patients are worried and openly share their angst about osteoporosis treatment with their doctors, while clinicians are equally worried about causing more harm than good. The numerous reports of the “unusual femur fractures” in particular have been disquieting; clinicians are not happy to hear that they may be responsible for causing the problem they thought they were treating to prevent. The worry that excessive bisphosphonate dosing or prolonged use might cause microdamage accumulation from oversuppression of bone remodeling and increase rather than decrease skeletal fragility is not new (5). Such concerns were voiced a decade ago (6) but seemed unlikely after the above-mentioned large fracture endpoint studies showed beneficial effects on fracture risk with few complications. The catch? Placebo-controlled fracture endpoint trials have been at most 3–5 yr in duration, so inferences about any effects of treatment beyond 5 yr, both beneficial and harmful, are lacking solid evidence. Numerous case reports of unusual fractures of the femur among bisphosphonate-treated women have appeared over the last 5 yr (7–9). These “atypical” fractures were subtrochanteric (below the lesser trochanter) or diaphyseal (above thedistalmetaphysis), occurredwith little trauma, and were characterized by transverse or nearly transverse “chalk-like” fracture lines as opposed to the more typical spiral or comminuted femoral shaft fractures. Subsequent reports highlighted the presence of prodromal thigh pain, bilateral involvement, the presence of other diseases such as rheumatoid arthritis and diabetes, and the concomitant use of other medications such as corticosteroids or proton pump inhibitors. Some reports, but certainly not all, suggest marked suppression of bone turnover as assessed by bone turnover markers and iliac crest histomorphometry (7). Even if causally related, these atypical fractures must be quite rare among women receiving bisphosphonate therapy for 3to 5-yr duration because the rates of all types of subtrochanteric and diaphyseal fractures were low and similar between placebo and bisphosphonate-treated women in a reanalysis of three large clinical trials (FIT, FLEX, and HORIZON) (10). Although the study is reassuring, an important limitation is that few women received more than 5 yr of bisphosphonate treatment, information on atypical features was not specifically collected, and for the most part only radiographic reports were reviewed. Large observational studies have also examined the relationship between bisphosphonate use and subtrochanteric or diaphyseal fractures (11). In this issue of JCEM, Abrahamsen et al. (12) extend their previous work using