Modeling the Clockwork of Bone: A Narrative Review of Experimental Approaches to Circadian Rhythm in Bone Metabolism.

Circadian rhythms are fundamental regulators of skeletal homeostasis, coordinating osteoblast and osteoclast activity through tightly controlled temporal programs. Disruption of these rhythms, whether through environmental misalignment or genetic perturbation of core clock components, alters bone formation, enhances resorption, and contributes to skeletal fragility. This review synthesizes current knowledge on circadian regulation of bone biology across in vivo, ex vivo, and in vitro model systems, highlighting how each platform reveals distinct aspects of rhythmic gene expression, cellular function, and tissue-level remodeling. We critically evaluate the strengths and limitations of these models, outline key controversies such as the interpretation of global clock-gene knockouts, and discuss the emerging relevance of human-derived systems including iPSC-based models, organoids, and microphysiological "bone-on-chip" platforms. Integrative approaches that combine multiple model systems provide the most reliable framework for understanding circadian control of bone and for identifying targets for chronotherapeutic intervention. Advancing human-relevant models and refining temporal experimental design will be essential for translating circadian biology into clinical strategies for metabolic bone diseases.