New insights into the pathogenesis of osteoporosis and the translational approach to personalized therapy.

Abstract

Osteoporosis is increasingly recognized as a heterogeneous syndrome rather than a single disease, driven by diverse pathophysiological mechanisms. Subtypes-including postmenopausal estrogen deficiency, age-related bone loss, anorexia nervosa, and GLP-1 receptor agonist-associated weight loss-exhibit distinct bone turnover, fracture patterns, and therapeutic responses. Recent studies have established bone marrow adipose tissue (BMAT) as a critical regulator of the marrow microenvironment in postmenopausal and age-related bone loss. Weight loss of various origins-anorexia, GLP-1 agonists, caloric restriction, and intermittent fasting-impairs bone through reduced mechanical loading, hormonal alterations, IGF-1 resistance, adipokine dysregulation, and mesenchymal stem cell lineage shifts. Parathyroid hormone (PTH) shows bidirectional effects, with continuous exposure promoting resorption and intermittent stimulation enhancing formation, providing a rationale for subtype-guided therapy. Exercise exerts skeletal benefits via mechanical loading, myokines, autophagy, non-coding RNAs, and epigenetics, with effects varying by type and combination. This review synthesizes these mechanistic advances, differentiates the skeletal consequences of weight loss by etiology, and discusses the clinical application of PTH analogs, sclerostin antibodies, and tailored exercise prescriptions in personalized osteoporosis care.