Biomechanical mechanisms of atypical femoral fracture

Antiresorptives such as bisphosphonates (BP) and denosumab are commonly used osteoporosis treatments that are effective in preventing osteoporotic fractures by suppressing bone turnover. Although these treatments reduce fracture risk, their long-term use has been associated with atypical femoral fracture (AFF), a rare potential side effect. Despite its rare occurrence, AFF has had a disproportionately significant adverse impact on society due to its severe outcomes such as loss of function and delayed healing. These severe outcomes have led to the decrease in the use and prescription of osteoporosis treatment drugs due to patient anxiety and clinician reluctance. This creates the risk for increasing osteoporotic fracture rates in the population. The existing information on the pathogenesis of AFF primarily relies on retrospective observational studies. However, these studies do not explain the underlying mechanisms that contribute to AFF, and therefore the mechanistic origins of AFF are still poorly understood. The purpose of this review is to outline the current state of knowledge of the mechanical mechanisms of AFF. The review focuses on three major potential mechanical mechanisms of AFF based on the current literature which are (1) macroscale femoral geometry which influences the stress/strain distribution in the femur under loading; (2) bone matrix composition, potentially altered by long-term remodeling suppression by BPs, which directly influences the material properties of bone and its mechanical behavior; and (3) microstructure, potentially altered by long-term remodeling suppression by BPs, which impacts fracture resistance through interaction with crack propagation. In addition, this review presents the critical knowledge gaps in understanding AFF and also discusses approaches to closing the knowledge gap in understanding the underlying mechanisms of AFF.