The prevention of fragility fractures in bone—pathologic fractures resulting from daily activity and mostly occurring in the elderly population—has been a long-term clinical quest. Recent research indicating that falls in the elderly might be the conse- quence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. Is day-to-day cyclic loading, instead of a single-load event such as a fall, the main cause of progressively growing fractures? Are fragility fractures predominantly affected by bone quality rather than bone mass, which is the clinical indicator of fracture risk? Do osteocytes actively participate in the bone repair process? In this Perspective, we discuss the central role of cyclic fatigue in bone fragility fracture.