MOLECULAR AND METABOLIC INTERPLAY BETWEEN CIRCADIAN RHYTHMS AND BONE REMODELING IN MENOPAUSE

*Afthab K. Shajahan, Gifty N. Shah, Mariya Varghese, Roniya Babu, Dr. Lincy George

ABSTRACT

Postmenopausal osteoporosis arises from estrogen deficiency – driven imbalance between bone resorption and formation, but an underappreciated second layer of pathology involves disruption of the circadian clock. This review examines the bidirectional relationship between circadian biology and bone remodelling in the postmenopausal context, with a focus on the molecular mechanisms linking clock gene function to skeletal homeostasis. Bone turnover markers – including serum CTX and osteocalcin – exihibit reliable diurrinal rhythmicity governed by the endogenous circadian system. The clock gene BMAL1 plays a pivotal role, regulating antioxidant capacity via CLOCK/BMAL1 transcriptional complexes and suppressing the ROS/MAPK-p38 pro – survival pathway in osteoclast precursors. Melatonin, the primary hormonal output of the circadian system, activates this BMAL1 – mediated pathway, thereby promoting osteoclast precursor apoptosis and reducing bone resorption. Evidence from ovariec tomized mouse models and early randomized clinical trials supports melatonin supplementation as a potential skeletal – protective strategy. Furthermore, sleep disruption and circadian misalignment – both prevalent during the menopausal transition – compound estrogen deficiency through elevated sympathetic tone, pro – inflammatory cytokines, and diminished antioxidant buffering. Chronotherapy strategies , including timed administration of existing anti resorptive agents and melatonin supplementation, represent emerging clinical opportunities. This review synthesizes current molecular, preclinical, and clinical evidence and identifies key research gaps that must be addressed to fully integrate circadian medicine into the management of postmenopausal osteoporosis.

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