Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis

Abstract

Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral fractures (AFF). Recent published studies examining this potential association are conflicting regarding the existence and strength of this association. We conducted a systematic review and meta-analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random-effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta-analysis: five case-control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF, with adjusted RR of 1.70 (95% confidence interval [CI], 1.22-2.37). Subgroup analysis of studies using the American Society for Bone and Mineral Research criteria to define AFF suggests a higher risk of AFF, with bisphosphonate use with RR of 11.78 (95% CI, 0.39-359.69) as compared to studies using mainly diagnosis codes (RR, 1.62; 95% CI, 1.18-2.22), although there is a wide confidence interval and severe heterogeneity (I(2) = 96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI, 1.29-2.04). This meta-analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long-term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.

Keywords: ATYPICAL FEMUR FRACTURE; BISPHOSPHONATES; FEMORAL SHAFT FRACTURE; OSTEOPOROSIS; SUBTROCHANTERIC FRACTURE.

Figure 1

Selection of the studies included in the meta-analysis.

Figure 2

Random effects analysis of the studies for the association between bisphosphonate use and subtrochanteric, femoral shaft, and atypical femur fracture (AFF), stratified by study design. Point (square) and overall (diamond) estimates are given as risk ratios with 95% confidence interval (CI) (horizontal bar).

Figure 3

Random effects analysis of the studies for the association between bisphosphonate use and subtrochanteric, femoral shaft, and atypical femur fracture (AFF), stratified by outcome definition (x-ray confirmation of fractures and/or confirmation of fractures meeting ASBMR criteria for AFF). Point (square) and overall (diamond) estimates are given as risk ratios with 95% confidence interval (CI) (horizontal bar). ^aAlthough most cases met the ASBMR-criteria, Feldstein et al did include a small number of cases which did not have the classic “transverse” or “short oblique” fracture angle required for ASBMR definition of AFF.

Figure 4

Random effects analysis of the studies for the association between long-term bisphosphonate use (5 years or greater) and subtrochanteric and femoral shaft fractures. Point (square) and overall (diamond) estimates are given as risk ratios with 95% confidence interval (CI) (horizontal bar).