Circadian regulation of osteoclast lysosomal-resorption machinery: implications for osteoporosis therapy

Osteoporosis (OP) is a systemic degenerative skeletal disorder characterized by reduced bone mass and compromised biomechanical properties, with its pathogenesis closely associated with excessive osteoclast activation and dysregulated bone resorption. Emerging evidence has revealed that the osteoclast lysosomal-resorption apparatus (LRA) serves not only as the principal effector system responsible for bone matrix degradation but also as a critical hub governing the circadian regulation of bone resorption. Disruption of circadian rhythms can impair LRA homeostasis and function, thereby promoting osteoclast hyperactivity and accelerating pathological bone loss. In this review, we systematically summarize the mechanistic roles of the LRA in osteoclastic bone resorption and comprehensively discuss the multilayered regulatory network through which the circadian clock modulates LRA activity. Particular emphasis is placed on the pathological significance of circadian clock-LRA interactions in distinct forms of osteoporosis. Furthermore, we highlight emerging therapeutic strategies targeting circadian regulation and lysosomal homeostasis restoration as potential approaches for osteoporosis intervention. Elucidating the mechanistic basis of the circadian clock-LRA axis will not only advance our understanding of osteoporosis pathogenesis and progression but also provide a theoretical framework for chronopharmacology and rhythm-based therapeutic interventions. These insights may ultimately facilitate the development of more precise and personalized strategies for osteoporosis prevention, treatment, and long-term management.