Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project

Abstract

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts.

Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012).

Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures.

Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

Figures

Fig. 1

Radiographic appearance of an atypical femoral fracture in a sixty-three-year-old woman who had been on bisphosphonate therapy for seven years prior to developing left thigh pain. The left panel is an initial anteroposterior radiograph of the left femur showing focal cortical thickening along the lateral proximal femoral diaphysis that represents an incomplete fracture (arrow). The central panel is an anteroposterior radiograph of the femur taken two days later showing a displaced fracture centered at the prior site of cortical thickening even though the patient had been placed on protected weight-bearing and did not sustain a trauma during the intervening time. The right panel is an anteroposterior radiograph of the right femur of the same patient, made after she had begun experiencing milder right thigh pain, demonstrating subtle cortical thickening along the lateral proximal aspect of the right femur that also represents a developing insufficiency fracture (arrow).

Fig. 2

Results of the literature search strategy. RCT = randomized controlled trial.

Fig. 3

Case reports in the literature and reports in the FAERS database of bisphosphonate-associated atypical femoral fractures from January 1996 to September 2011.