Chronobiology of fracture repair: local molecular clocks, rhythm protection, and time-anchored translation.

Fracture repair is a prototypic regenerative process in adult tissues and proceeds through a temporally organised sequence of haematoma formation and inflammation, cartilaginous callus formation, hard callus mineralisation, and callus remodelling. Conventional fracture research has primarily attributed variation in healing outcomes to mechanical stability, vascular supply, inflammation, metabolic bone status, drug exposure, nutrition, and rehabilitation loading. Time, by contrast, has often been treated as a background variable. Emerging evidence from circadian biology and molecular-clock research indicates that bone turnover markers, endocrine signals, immune responses, vascular function, sleep-wake organisation, and the activities of osteoblasts, osteoclasts, chondrocytes, macrophages, and endothelial cells are subject to rhythmic regulation. In particular, Per2::Luc oscillation at the mouse femur fracture site and its responsiveness to parathyroid hormone (PTH) provide direct preclinical evidence that a local molecular clock can operate within the fracture repair niche. Fracture chronobiology, however, remains at an early translational stage. Current evidence is derived largely from animal models, cell studies, human bone-marker physiology, sleep and circadian-disruption experiments, and perioperative literature. Direct time-resolved clinical data in human fracture repair remain sparse. Accordingly, the available evidence does not justify recommending a specific clock time for surgery, drug administration, blood sampling, loading, or rehabilitation to improve fracture healing. We argue that the immediate translational value of fracture chronobiology lies not in premature clinical chronotherapy but in moving fracture research and perioperative care from a time-agnostic to a time-anchored framework. The perioperative period should be regarded as a rhythm-vulnerable window in which avoidable disruption from trauma, pain, anaesthesia, nocturnal light, sleep fragmentation, and medication exposure may be reduced. At the same time, fracture studies should systematically record the timing of injury, admission, anaesthesia, surgery, drug administration, biological sampling, sleep, light exposure, activity, rehabilitation, and imaging follow-up. A time-anchored research framework can clarify whether rhythmic variables influence callus formation, mineralisation, remodelling, nonunion, and functional recovery, thereby providing a measurable foundation for future fracture chronobiology trials.