The Circadian–Melatonin Axis in Bone Remodeling: Receptor-Dependent Signaling, Receptor-Independent Actions, and Translational Constraints

Bone remodeling is rhythmically regulated, yet the contribution of the circadian–melatonin axis to osteoporosis remains incompletely defined, in part because mechanistic findings obtained at high experimental concentrations are frequently extrapolated to physiological signaling. This narrative review examines that inference. PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched from inception to July 2026 for English-language studies of melatonin, circadian clock genes, and bone; molecular, preclinical, epidemiological, and clinical evidence was appraised with attention to receptor dependence, exposure concentration, and study architecture. In osteoblast-lineage cells, melatonin promotes osteogenic differentiation through MT2-linked Wnt/β-catenin and MEK1/2–MEK5 signaling, post-translational stabilization of SP7, and modulation of the OPG/RANKL axis. By contrast, direct antiosteoclastic and antioxidant effects are usually reported at micromolar concentrations, four to six orders of magnitude above nocturnal plasma levels, and are increasingly attributable to receptor-independent chemistry converging on the ROS–KEAP1–NRF2 node shared with structurally unrelated antioxidant compounds. This exposure mismatch suggests that conventional oral doses engage receptor-mediated osteoblast pathways rather than reproduce high-dose antiresorptive effects; sustained exposure at or above 1 µM is not attainable by conventional oral administration, and the chronic safety of the doses that would be required has not been characterized. In humans, bone resorption has an intrinsic circadian rhythm, and night-shift work is associated with adverse skeletal outcomes, although causality remains unresolved. The five available randomized trials are small and heterogeneous; none was powered for fracture prevention, and none compared administration times for a skeletal endpoint. Melatonin therefore cannot currently be recommended for the treatment of osteoporosis. Human bone and marrow pharmacokinetics, receptor-specific in vivo dose–response experiments, and adequately powered monotherapy trials in established primary osteoporosis are the studies that would change this assessment.