Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance

Significance Since the first reports of atypical femoral fractures (AFFs), a clinical phenomenon in which patients experience catastrophic brittle fractures of the femoral shaft with minimal trauma, the risk associated with bisphosphonates, the most widely prescribed pharmaceuticals for osteoporosis, has become increasingly well-established. However, the underlying cause of AFFs and their causal relationship to bisphosphonates is unknown. Here we examine bone tissue from women with AFFs and show that long-term bisphosphonate treatment degrades the fracture-resistance toughening mechanisms that are inherent to healthy bone. Our work resolves the apparent paradox of AFFs as a side effect of the most common osteoporosis treatment by clarifying the differing effects of bisphosphonates on bone tissue structure and mechanical properties across multiple length scales.