Atypical Femoral Fractures and Use of Bisphosphonates

Among patients with osteoporosis, the use of bisphosphonates reduces the overall risk of fracture with long-lasting beneficial effect. However, there have been reports of atypical fractures associated with the use of bisphosphonates. In published case reports that classified femoral fractures as stress fractures or nonstress fractures according to their radiographic appearance, among patients admitted to tertiary centers, such stress fractures (atypical femoral fractures) were more common in patients who had received bisphosphonates than in those who did not. Because a large proportion of patients receiving bisphosphonates who had atypical fractures also received other medications, including systemic glucocorticoids and proton pump inhibitors, it has been suggested that those 2 types of drugs are not only markers of coexisting conditions but may also contribute to the risk of the development of atypical femoral fractures.

Studies have shown conflicting results regarding the association between bisphosphonates and possible excess risk of atypical fractures in the femoral shaft. There was no association found between atypical fractures and bisphosphonate use based on registry identification of atypical femoral fractures or in randomized trials in which the classification of fractures was based on radiologic reports. Researchers recently conducted a review of radiographs of all femoral subtrochanteric and shaft fractures that occurred in 2008 in the entire population of Sweden. By linking these fracture cases to national registries, the researchers were able to conduct a nationwide cohort analysis and a population-based case-control study to examine the relationship between atypical femoral fractures and bisphosphonate use. They reported their findings in the New England Journal of Medicine [2011;364(18):1728-1737].

According to the National Swedish Patient Register, 12,777 women ≥55 years of age sustained a fracture of the femur in 2008. Of those, 1271 had afemoral subtrochanteric or shaft fracture (International Classification of Diseases, Ninth Revision diagnosis code S722 or S732 with externalcause code W [ie, excluding any type of transportation accident]). The researchers obtained digitized radiographs for 1234 patients; the radiographs were reviewed and classified according to the pattern of fractures. The classification revealed 59 women with atypical fractures (case patients). Following the classification of the fractures, the researchers obtained data on drug use and inpatient and outpatient care. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated via a national cohort analysis. In addition, the 59 case patients were compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. The age-adjusted relative risk of atypical fracture with any use of bisphosphonates was 47.3 cases (95% confidence interval [CI], 25.6-87.3) per 10,000 patient-years.

The difference in the risk of atypical fracture between users and nonusers of bisphosphonates was 5 cases (95% CI, 4-7) per 10,000 patientyears, corresponding to an average number needed to harm (number of bisphosphonate users needed for 1 case of fracture to occur) of 2000 per year of use. The risk was not associated with coexisting conditions or with concurrent use of other drugs with known effects on bone. Longer duration of use increased the risk; in addition, most bisphosphonate users with atypical fractures had a history of recent use. Following drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21-0.38). The researchers offered the following conclusions: “These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small.”