Postmenopausal Osteoporosis: From Molecular Pathways to Therapeutic Targets-A Mechanism-to-Practice Framework...

The next frontier in postmenopausal osteoporosis management lies not in novel pharmacological agents, but in the systematic integration of mechanism-guided drug selection, fall prevention, and long-term adherence strategies into a unified patient-centered care model. This review is intended for clinicians and clinical researchers involved in the diagnosis, treatment, and long-term management of postmenopausal osteoporosis. We provide a mechanism-to-practice framework that explicitly maps each therapeutic class to the specific molecular pathway it targets: bisphosphonates inhibit osteoclast function downstream of RANKL activation; denosumab blocks RANKL directly at the cytokine level; romosozumab inhibits sclerostin to restore Wnt-mediated bone formation. This mechanistic foundation supports a risk-stratified treatment paradigm in which antiresorptives address accelerated remodeling in moderate-risk patients, while patients at very high fracture risk-characterized by severe bone deficit or recent fragility fractures-benefit from an anabolic-first approach followed by consolidation. Beyond drug selection, we examine the persistent treatment gap in which fewer than 20% of post-fracture patients receive therapy, arguing that fall prevention-responsible for >90% of hip fractures-and medication adherence deserve equal priority in clinical practice. We further analyze key controversies, including T-score- versus FRAX-based intervention thresholds, limitations of the trabecular bone score, cost-effectiveness constraints on anabolic-first sequencing, and evidence gaps in post-denosumab transition strategies. By synthesizing mechanistic insights, guideline recommendations, and critical appraisal of current limitations, this review offers not only an overview of existing knowledge but a coherent decision-support model aimed at improving fracture prevention through comprehensive, individualized care.