Epigenetic Regulation of Bone Homeostasis in Osteoporosis: Mechanisms, Evidence Gaps, and Translational Prospects.

Osteoporosis arises from an imbalance among osteoblast-mediated bone formation, osteoclast-mediated bone resorption, and osteocyte-directed mechanosensory control, but the molecular events that connect aging, hormonal change, inflammation, and mechanical unloading to bone loss remain incompletely resolved. Epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs (ncRNAs), and RNA modifications, provide one route through which environmental and cellular signals reshape bone-cell function. This review summarizes current evidence linking epigenetic regulation to osteoblasts, osteoclasts, and osteocytes; distinguishes human, animal, and in vitro evidence; and evaluates the translational maturity of proposed biomarkers and therapies. DNA methylation and histone modifications have strong mechanistic support in bone-cell differentiation models, whereas ncRNA and N6-methyladenosine (m6A) pathways are expanding rapidly but remain largely preclinical. Blood-based methylation or RNA signatures and epigenetic therapies are promising but should be considered exploratory until validated in prospective cohorts, fracture-related endpoints, and bone-cell-specific intervention studies.