Gut microbiota and metabolic products regulate bone homeostasis and immune checkpoints in osteoporosisGut Health May Play a Key Role in Bone Health

Osteoporosis (OP) remains a major global health burden, yet current pharmacological interventions are constrained by adverse effects, limited efficacy, and a bone-centric therapeutic paradigm that overlooks upstream pathogenic drivers. Emerging evidence positions the gut microbiota (GM) as a critical rheostat of bone homeostasis, operating through a gut–immune–bone axis that integrates microbial metabolism, intestinal barrier integrity, and systemic immune regulation. This review systematically examines the immunopathological mechanisms of OP, with particular emphasis on the GM-derived metabolites—short-chain fatty acids, secondary bile acids, tryptophan derivatives, lipopolysaccharide, and trimethylamine N-oxide—that orchestrate osteoclastogenic versus osteoprotective outcomes via key immune checkpoints including the Th17/Treg, macrophage phenotypic polarization, and regulatory B cell axes. We further delineate the subtype-specific heterogeneity of this axis across postmenopausal, senile, glucocorticoid-induced, and diabetic osteoporosis, highlighting distinct microbial and immune signatures that mandate stratified therapeutic approaches. Importantly, we evaluate the translational potential of GM-targeted interventions—probiotics, prebiotics, fecal microbiota transplantation, and dietary modulation—as adjunctive or standalone strategies, and discuss their synergistic interplay with conventional anti-osteoporotic agents. By reframing OP as a systems-level disorder of the gut–immune–bone circuitry, this review establishes a mechanistic groundwork for precision medicine, identifies novel druggable targets, and charts a course toward safer, more durable, and disease-modifying anti-osteoporotic therapies.