Femur Fracture Outcomes Associated with Bisphosphonate Use

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DESCRIPTION (provided by applicant): Osteoporosis is a highly prevalent disorder in older postmenopausal women, with 1 in 2 women of white race expected to experience an osteoporotic fracture in her lifetime - a risk that is substantially reduced with osteoporosis therapy. In clinical practice, the oral bisphosphonate drugs are considered one of the primary therapies for osteoporosis, based on strong randomized clinical trial evidence showing a significant reduction in the risk of hip, vertebral and non-vertebral clinical fractures during the first 3-5 years of therapy. However, data are limited regarding fracture outcomes beyond this initial treatment period, and recent reports of atypical femur fracture in women receiving long-term bisphosphonate therapy have raised concerns regarding the optimal duration of treatment. The atypical femur fractures present as a transverse fracture in the femoral diaphysis extending medially from an area of localized periosteal reaction in the lateral femoral cortex. These unusual fractures are thought to develop secondary to chronic suppression of normal bone remodeling and impaired micro-crack repair, with pathologic extension of unimpeded crack progression in an area of high mechanical stress. Preliminary findings point to an increased risk of atypical femur fracture in patients receiving bisphosphonate therapy. Furthermore, while the risk of atypical fracture appears to be much lower than the risk for typical osteoporotic hip fractures, the risk of atypical fracture is increased with longer bisphosphonate treatment duration and may be much higher for women of Asian race. This study will utilize two population cohorts to address two Specific Aims: Aim 1 will examine the association of early discontinuation of bisphosphonate therapy and subsequent risk of atypical femur fracture among women who initiate bisphosphonate therapy. Aim 2 will examine the association of long-term continuation of bisphosphonate therapy and risk of atypical femur fracture among women who have been treated for at least three years. This collaborative investigation, to be conducted within Kaiser Permanente Northern and Southern California, will assemble one of the largest populations of women receiving bisphosphonate therapy for which treatment exposures and femur fracture outcomes can be systematically identified. With an anticipated large subpopulation of Asian women comprising up to 15-20% of women with bisphosphonate exposure, this study will fill an important knowledge gap in the management of postmenopausal women with osteoporosis and potential racial/ethnic disparities in treatment outcome.