Altered Light‐Dark Cycles Promote Osteoclast Activity and Decrease Bone Density in Mice: The Modulatory Role of Melatonin and Sirt3‐SOD2 Signaling

The circadian rhythm system plays an essential role in maintaining skeletal homeostasis, yet the precise impact of circadian rhythm abnormalities on bone mineral density (BMD) remains poorly understood. In this study, we systematically investigated the effects of rhythm disruption on bone metabolism by establishing murine models exposed to winter‐simulated extended darkness (8‐h light:16‐h dark) and severe non‐24‐h light‐dark cycles (8L:8D, 6L:6D, and 4L:4D). Our structural and histological analyses revealed that abnormal circadian rhythms profoundly uncouple bone remodeling, leading to a precipitous decline in trabecular bone mass. Crucially, we demonstrated that enhanced osteoclast activity due to the extended period of darkness in winter increases the risk of fractures, and this skeletal deterioration is further exacerbated under increasingly fragmented non‐24‐h rhythms. Mechanistically, circadian misalignment induced a severe downregulation of the Sirt3‐SOD2 signaling pathway in bone tissue, which released physiological constraints on RANKL expression and subsequently drove rampant osteoclastogenesis. Pharmacological intervention with the endogenous circadian synchronizer melatonin partially mitigated this rhythm‐disrupted bone loss by restoring Sirt3 expression and predominantly enhancing osteoblast anabolism; however, its capacity to directly suppress rhythm‐induced osteoclast hyperactivation was limited. Furthermore, co‐treatment with the Sirt3 inhibitor 3‐TYP abolished the osteoprotective effects of melatonin by concurrently impairing osteoblast function. Collectively, these findings identify circadian rhythm disruption as a critical intrinsic driver of BMD decline. This chronobiological perspective elucidates that photoperiod‐induced circadian disruptions may act as a risk factor for diminished bone density by driving osteoclastogenesis, warranting further translational research in humans.