Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study

Abstract

Summary: Recent evidence has linked long-term bisphosphonate use with insufficiency fractures of the femur in postmenopausal women. In this case-control study, we have identified a significant association between a unique fracture of the femoral shaft, a transverse fracture in an area of thickened cortices, and long-term bisphosphonate use. Further studies are warranted.

Introduction: Although clinical trials confirm the anti-fracture efficacy of bisphosphonates over 3-5 years, the long-term effects of bisphosphonate use on bone metabolism are unknown. Femoral insufficiency fractures in patients on prolonged treatment have been reported.

Methods: We performed a retrospective case-control study of postmenopausal women who presented with low-energy femoral fractures from 2000 to 2007. Forty-one subtrochanteric and femoral shaft fracture cases were identified and matched by age, race, and body mass index to one intertrochanteric and femoral neck fracture each.

Results: Bisphosphonate use was observed in 15 of the 41 subtrochanteric/shaft cases, compared to nine of the 82 intertrochanteric/femoral neck controls (Mantel-Haenszel odds ratio (OR), 4.44 [95% confidence interval (CI) 1.77-11.35]; P = 0.002). A common X-ray pattern was identified in ten of the 15 subtrochanteric/shaft cases on a bisphosphonate. This X-ray pattern was highly associated with bisphosphonate use (OR, 15.33 [95% CI 3.06-76.90]; P < 0.001). Duration of bisphosphonate use was longer in subtrochanteric/shaft cases compared to both hip fracture controls groups (P = 0.001).

Conclusions: We found a significantly greater proportion of patients with subtrochanteric/shaft fractures to be on long-term bisphosphonates than intertrochanteric/femoral neck fractures. Bisphosphonate use was highly associated with a unique X-ray pattern. Further studies are warranted.

Fig. 1

Representative radiographs of subtrochanteric/shaft cases on a bisphosphonate with evidence of the simple with thick cortices pattern with comparison radiographs of subtrochanteric/shaft fracture cases not on a bisphosphonate. a, b Representative radiographs of ten of the 41 subtrochanteric/shaft cases that were associated with bisphosphonate use. Prominent cortical thickening near the fracture site and beaking of the cortex on one side can be seen. a An 83-year-old women with a 9-year history of alendronate use. b A 61-year-old woman with a 9-year history of alendronate use. c, d Representative radiographs of subtrochanteric/shaft fractures in women not on bisphosphonate. Fractures are more complex in nature, cortical thickening is minimal, and there is no identifiable beaking at the fracture site. These fractures are not consistent with our definition of the characteristic X-ray pattern associated with prolonged bisphosphonate use. c An 83-year-old woman with no history of bisphosphonate use. d A 60-year-old woman with no history of bisphosphonate use cortices pattern. The calculated OR for simple with thick cortices pattern and its association with bisphosphonate use was 15.33 ([95% CI 3.06–76.90]; P<0.001). Representative radiographs of the subtrochanteric/shaft cases with and without the pattern associated with bisphosphonate use can be seen in Fig. 1.

Fig. 2

Correlation of duration of bisphosphonate use with normalized cortical thickness. Cortical thickness normalized to diameter for all subtrochanteric/shaft cases, and those intertrochanteric/femoral neck on bisphosphonate treatment was correlated to duration of bisphosphonate use. While blinded to all patient information, including bisphosphonate history, normalized cortical thickness was measured distal to the fracture site in each case. Duration represents length of time on bisphosphonate up to the date of fracture. The mean normalized cortical thickness of all subtrochanteric/shaft cases not on a bisphosphonate was 0.19±0.048, represented as a triangle data point with error bars depicting ±SD. Spearman’s rank coefficient, ρ, for correlation of subtrochanteric/shaft cases cortical thickness/ diameter with duration of bisphosphonate use was 0.7, yielding P<.001. ST/S+Bis subtrochanteric/shaft cases on a bisphosphonate, IT/FN+Bis intertrochanteric/femoral neck controls on a bisphosphonate, ST/S–Bis Average mean value for subtrochanteric/shaft not on a bisphosphonate

Fig. 3

Distribution of all fractures associated with bisphosphonate use. All fractures associated with bisphosphonate use were grouped by the type of femoral fracture and displayed according to duration of bisphosphonate use. Black bars represent subtrochanteric/shaft (ST/S) fractures, gray bars represent intertrochanteric (IT) fractures, and white bars represent femoral neck (FN) fractures. Kruskal–Wallis one-way variance analysis of the duration of bisphosphonate use in patients in all three groups yielded P=0.001. Time on a bisphosphonate differed for subtrochanteric/shaft fractures as compared to both intertrochanteric (P=0.01) and femoral neck fractures (P=0.001). There was no significant difference between time on a bisphosphonate between intertrochanteric and femoral neck fractures (P=0.3). Single asterisk One patient in this group was taking risedronate. Double asterisks This patient was taking etidronate for 5 years and then took alendronate for 2 years