Epigenetic regulatory networks in the pathogenesis and treatment of osteoporosis subtypes.

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density and heightened bone fragility, encompassing primary (senile and postmenopausal) and secondary (glucocorticoid-induced and diabetic) subtypes. Maintaining skeletal health relies on the dynamic balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Among the multitude of factors orchestrating this bone remodeling process, epigenetics, which regulates gene expression via reversible chemical modifications without altering the primary DNA sequence, plays an essential role in maintaining bone homeostasis. While previous research has identified numerous epigenetic factors in bone metabolism, a comprehensive synthesis of their specific contributions to different osteoporosis subtypes and the corresponding therapeutic strategies remains lacking. This review outlines the major epigenetic mechanisms involved in bone metabolism, including DNA methylation, histone modifications, RNA modifications, and non-coding RNAs. Subsequently, we comprehensively elucidate how the dysregulation of these epigenetic landscapes drives the pathogenesis of distinct osteoporosis subtypes, emphasizing their roles in disrupting the osteoblast-osteoclast axis. Furthermore, we review emerging epigenetic-based therapeutics across distinct osteoporosis subtypes, ranging from systemic pharmacological inhibitors, such as DNA methyltransferase and histone demethylase inhibitors, to advanced delivery platforms targeting the skeletal microenvironment, such as engineered extracellular vesicles and functionalized nanocarriers. By integrating molecular mechanistic insights with these diverse therapeutic strategies, this review establishes a comprehensive framework for understanding the epigenetic heterogeneity in the pathogenesis and therapeutics of osteoporosis. Ultimately, it provides essential directions for future investigations, offering innovative epigenetic strategies to tackle various osteoporosis subtypes.