Incidence of Atypical Femoral Fractures and Bisphosphonate Use

Patients with osteoporosis benefit from treatment with bisphosphonates; the medications used to increase bone density and reduce the risk of vertebral and proximal femur fractures. However, according to researchers, the drugs have a biological half-life >10 years, which may induce long-lasting inhibition of bone remodeling, which in turn could affect the healing of “physiologic microcracks.” These microcracks would then cause clinically apparent stress fractures in areas with high mechanical stress loads, including the outer cortex of the femoral shaft.

Clinical literature has begun to report the existence of a new type of subtrochanteric and femoral shaft stress fractures that are occurring in patients who are being treated with bisphosphonates. The fractures are defined as atypical fractures; the radiographic features include a transverse fracture line that originates at an abnormal thickening of the lateral cortex of the femoral shaft.

According to researchers, there is conflicting evidence regarding the association between treatment with bisphosphonates and atypical fractures. Current studies suggest that there is such an association, but it is not clear what the extent of the risk is. Researchers recently conducted a case-control study of patients who sustained subtrochanteric or femoral shaft fractures over a 12-year period. Study results were reported online in Archives of Internal Medicine [doi:10.100/archinternmed.2012.1796].

The study cohort included 477 patients ≥50 years of age who were admitted to a single university hospital with a fracture of the subtrochanteric or femoral shaft areas between January 1, 1999, and December 31, 2010. The fractures were diagnosed using International Classification of Diseases, 10th Revision codes. The researchers also identified a random sample of 200 healthy individuals without femoral fractures.

Using admission radiographs and medical and treatment records, the researchers identified 39 patients with atypical fractures and 438 with classic fractures. Multivariate logistic regression was used to assess the association of bisphosphonate use and atypical femoral fracture. The incidence rates of each type of fracture over time were also calculated.

Of the patients with atypical fractures, 82.1% (n=32) had been treated with bisphosphonates. Of the patients with classic fractures, 6.4% (n=28) had received bisphosphonate therapy (odds ratio [OR], 66.9; 95% confidence interval [CI], 27.1-65.1). Of those in the group without fractures, 11.5% (n=23) used bisphosphonates (OR, 35.2; 95% CI, 13.9-88.8).

Following adjustment for potential risk factors (vitamin D, corticosteroids, proton pump inhibitor, sex, and age), use of bisphosphonates (any vs none) was associated with an OR of 69.1 (95% CI, 22.98-209.5) for an atypical fracture compared with the classic fracture group. When patients with classic fractures were compared with those without fractures, the OR was 0.5 (95% CI, 0.3-0.9; P=.03) for bisphosphonate use, yielding a 47% reduction in risk of classic fracture.

Once categorized by duration of treatment, compared with no use of bisphosphonates, the ORs for atypical fractures with bisphosphonates were 35.1 (95% CI, 10.0-123.6) for <2 years, 46.9 (95% CI, 14.2-154.4) for 2 to 5 years, 117.1 (95% CI, 34.2-401.7) for 5 to 9 years, and 175.7 (95% CI, 30.0-1027.6) for >9 years.

The incidence rates, averaged over the 12-year study period, were 357 cases per million person-years for classic fractures and 32 cases per million person-years for atypical fractures. The researchers noted that between 1999 and 2010, the overall incidence rate of atypical fractures increased; the incidence rate of classic fractures remained stable during that time period.

In conclusion, the researchers summarized their results: “Atypical femoral fractures were associated with bisphosphonate use; longer duration of treatment resulted in augmented risk. The incidence of atypical fractures increased over a 12-year period, but the absolute number of such fractures was very small.”