Bone Marrow Immunometabolic Remodeling in Osteoporosis: From Systemic Risk Factors to Precision Intervention.

Osteoporosis has traditionally been viewed as a bone remodeling disorder characterized by excessive bone resorption and inadequate bone formation. However, this paradigm does not fully explain its systemic heterogeneity, persistent progression, or variable therapeutic responses. This review reconceptualizes osteoporosis as a systemic remodeling disorder driven by immunometabolic dysregulation within the bone marrow microenvironment. Upstream risk factors, including estrogen deficiency, inflammaging, gut microbiota dysbiosis, lipid dysmetabolism, and chronic low-grade inflammation, do not act solely on terminal osteoblasts or osteoclasts; instead, they are hierarchically translated within the marrow niche. These perturbations reshape hematopoietic lineage commitment, redirect Bone Marrow Mesenchymal Stem Cells(BMSC) osteogenic-adipogenic fate, promote pathological marrow adipose tissue expansion, and establish a pro-inflammatory, osteoclastogenic milieu through T helper 17 (Th17)/regulatory T (Treg) imbalance, monocyte/macrophage remodeling, inflammasome activation, and osteoclast metabolic reprogramming. Consequently, the marrow niche shifts from an osteogenesis-supportive state toward a self-reinforcing pathological ecosystem marked by enhanced resorption, impaired formation, and marrow adiposity. We further discuss emerging strategies involving microecological remodeling, immune phenotype correction, metabolic checkpoint modulation, BMSC fate regulation, and biomaterial-based niche repair. Importantly, the current evidence base is derived predominantly from postmenopausal osteoporosis and ovariectomized animal models, whereas validation across other osteoporosis subtypes and in prospective human studies remains limited. Accordingly, the broader applicability of this immunometabolic framework should be regarded as an emerging hypothesis requiring further clinical validation. Nevertheless, it may provide a conceptual basis for understanding osteoporosis heterogeneity and developing subtype-stratified precision interventions beyond conventional anti-resorptive and anabolic therapies.