Osteoporosis (OP) is a common metabolic bone disorder characterized by decreased bone mass and deterioration of bone microarchitecture that result in increased bone fragility and fracture risk, especially in postmenopausal women and older adults. The gut microbiota-immune-endocrine axis has recently emerged as an important regulator of bone homeostasis, but its mechanistic role in OP pathogenesis remains incompletely understood. This review synthesizes current evidence on how gut dysbiosis, immune dysregulation, and endocrine changes interact to promote bone loss. Clinical and preclinical studies indicate that gut dysbiosis in OP is characterized by reduced microbial diversity and an increased Firmicutes/Bacteroidetes ratio, leading to altered levels of key microbial metabolites-such as decreased short-chain fatty acids (SCFAs) that normally promote bone formation, and increased lipopolysaccharide (LPS) that drives inflammation. Immune changes include chronic low-grade inflammation with elevated pro-inflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] and an imbalanced T-cell profile skewed toward osteoclastogenic T helper 17 (Th17) over anti-osteoclastogenic regulatory T (Treg) cells, which together favor bone resorption. Endocrine factors further modulate this gut-bone crosstalk: estrogen deficiency (in postmenopausal OP) promotes gut dysbiosis and Th17 expansion; excess glucocorticoids compromise the gut barrier and induce dysbiosis; gut-derived incretin hormones [e.g., glucagon-like peptide-1 (GLP-1) and peptide YY (PYY)] are influenced by microbial metabolites like butyrate; and parathyroid hormone (PTH) effects on bone are both regulated by and dependent on the gut microbiota. Overall, OP can be viewed as a multi-system disorder involving an interplay among the gut microbiome, the immune system, and the endocrine system. This integrated perspective on the "gut-bone axis" suggests that interventions targeting the gut microbiota (probiotics, prebiotics, etc.) could complement traditional therapies for OP. Enhancing skeletal health may require a multidisciplinary approach that considers gut microbial status, immune function, and hormonal milieu in tandem.
