Long-Term Bisphosphonate Use Associated with Greater Risk of Atypical Fractures

A large cohort study of women found that use of oral bisphosphonates for >5 years increased the risk of subtrochanteric or femoral shaft fractures, although the absolute risk of these fractures is low [JAMA. 2011;305(8):783-789]. Whereas studies have shown that bisphosphonates have become a mainstay of treatment for reducing the risk of osteoporotic fractures, concerns have recently emerged that bisphosphonate-related suppression of bone remodeling may adversely influence bone strength. An increasing number of case reports describe women who develop fractures involving the subtrochanteric or shaft region of the femur in the setting of long-term bisphosphonate therapy, generally after minimal trauma. Fractures at these sites are often described as atypical because of their location and characteristic appearance on x-rays. The US Food and Drug Administration recently began monitoring instances of such cases. The American Society for Bone and Mineral Research also released a task force report about the issue. The growing number of reports on the issue and conflicting studies led researchers to examine the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures among postmenopausal women. Researchers from Li Ka Shing Knowledge Institute of St. Michael’s Hospital (Toronto, Canada) conducted a population-based, nested case-control study of Ontario women ≥68 years of age who started treatment with a bisphosphonate (alendronate, risedronate, or etidronate) between April 1, 2002, and March 31, 2008. Cases were identified as women hospitalized with a subtrochanteric or femoral shaft fracture between April 1, 2003, and March 31, 2009. Women in the cohort were matched with up to 5 controls with no such fracture. Study participants were followed until the first subtrochanteric or femoral shaft fracture, death, or the end of the study period. Over the study period, the researchers identified 205,466 women treated with bisphosphonate therapy, and within this group, 716 women (0.35%) had subtrochanteric (n=411) or femoral shaft fracture (n=305). These cases were matched to 3580 controls of the same age and time of cohort entry. In the primary analysis, the researchers found the use of bisphosphonates for 5 years or longer was associated with an increased risk of hospitalization for subtrochanteric or femoral shaft fracture, compared with transient use (<100 days in total) of bisphosphonates (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.25-6.02). In the secondary analysis, the authors examined the risk of typical osteoporotic fractures among 9723 women with fractures of the femoral neck or intertrochanteric region during bisphosphonate therapy. Extended bisphosphonate use (≥5 years) was associated with a lower risk of fracture, compared with transient use (OR, 0.76; 95% CI, 0.63-0.93). Women with intermediate bisphosphonate use (3-5 years) showed a similarly low risk, whereas a shorter duration of bisphosphonate use (100 days-3 years) was associated with a nonsignificant reduction in the risk of such fractures (OR, 0.93; CI, 0.81-1.07). The absolute risk was estimated from 52,595 women in the cohort with at least 5 years of bisphosphonate therapy. Among these women, 71 (0.13%) sustained a subtrochanteric or femoral shaft fracture during the following year and 117 (0.22%) within 2 years. The authors reported study limitations. This study was defined by fracture site and absence of trauma. The authors used administrative data and did not have access to lifestyle behaviors. They also relied on prescription data to determine duration of bisphosphonate exposure. Additionally, this study did not include women <68 years of age. Finally, during the study period (2002-2008) only a small proportion of the cohort received ≥5 years of bisphosphonate treatment. The study results should not deter clinicians and patients from using bisphosphonates in appropriate patients, concluded the authors. These findings also underscore the need for assessment of individual risk of fractures when bisphosphonate therapy is considered, particularly in patients at relatively low risk of fracture. The authors added that more research is needed to ascertain whether interruptions in therapy could reduce the risk of such atypical fractures over the long term.