Osteoporosis from the perspective of the gut-bone axis: gut microbiota, metabolites, and multi-system synergistic regulation.

PURPOSE: Evidence increasingly implicates the gut microbiota in skeletal homeostasis, but the mechanisms and clinical relevance of the gut-bone axis remain unclear. This narrative review aimed to synthesize evidence linking the gut microbiota and its metabolites to osteoporosis, delineate key regulatory pathways, and assess the potential of microbiota-targeted interventions.

METHODS

PubMed, Web of Science, and the Cochrane Library were searched through December 2025 for English-language original studies, clinical trials, and representative reviews addressing osteoporosis, the gut microbiota, microbial metabolites, probiotics, prebiotics, and fecal microbiota transplantation. After title, abstract, and full-text assessment, 125 references were included, prioritizing publications from 2020 to 2025 while retaining seminal earlier studies.

RESULTS

Preclinical and human evidence supports an association between gut microbial dysbiosis and altered bone homeostasis, particularly in postmenopausal osteoporosis. However, human evidence remains predominantly cross-sectional, taxonomic findings vary across cohorts, and data in men are scarce. Short-chain fatty acids, secondary bile acids, tryptophan-derived metabolites, and bacterial extracellular vesicles may regulate bone remodeling directly and through immune modulation, endocrine signaling, intestinal barrier integrity, and nutrient absorption. Findings for probiotics and prebiotics are strain-, substrate-, and population-dependent: some clinical studies report improvements in bone mineral density or turnover markers, whereas others show no significant benefit. Evidence for fecal microbiota transplantation remains preclinical.

CONCLUSION

The gut-bone axis provides a plausible framework for understanding osteoporosis and may offer adjunctive therapeutic targets. Clinical translation requires adequately powered longitudinal studies and randomized trials incorporating etiological and sex-based stratification, functional multi-omics, and clinically meaningful skeletal outcomes.