Aging-Driven Inter-Organ Crosstalk in Postmenopausal Osteoporosis: From Immunometabolic Drift to Multisystem Frailty.

Postmenopausal osteoporosis (PMOP) is increasingly recognized as an aging-associated, multisystem vulnerability state in which estrogen withdrawal amplifies immune and metabolic drift across bone marrow, muscle, adipose tissue, the gut, vasculature, and neural circuits. We synthesize evidence that key control nodes including RANKL-RANK-OPG imbalance, Th17/Treg disequilibrium, loss of regulatory B cell IL-10 restraint, inflammatory myeloid polarization, and expansion of bone marrow adipose tissue encode persistent osteoclastogenic tone and impaired formation. We map how microbiota-derived metabolites and barrier dysfunction tune osteoimmunity, and how exercise-responsive myokines and metabolites can counteract drift. Extracellular vesicles emerge as bidirectional couriers that propagate senescence and inflammation or support repair, but clinical translation requires ISEV-aligned methodological rigor and robust manufacturing, biodistribution, and safety frameworks. Building on these inter-organ axes, we propose a phenotype-aware "network reset" roadmap that integrates antifracture therapy with functional restoration, falls prevention, cardiometabolic risk control, and inflammatory monitoring, prioritizing composite endpoints and real-world implementation infrastructure. This systems framing shifts PMOP management from bone-only correction toward coordinated restoration of whole-body resilience.