The gut-bone axis in osteoporosis: Microbiota-associated immune-metabolic remodeling of the bone marrow...

Osteoporosis is a common systemic skeletal disease in the aging population, and its pathogenesis involves multiple mechanisms such as estrogen deficiency, aging, reduced mechanical load, chronic low-grade inflammation, and imbalance of the calcium‑phosphorus-vitamin D-PTH/FGF23 axis. In recent years, the gut-bone axis has increasingly been recognized as a complementary regulatory network for understanding the systemic heterogeneity of osteoporosis, rather than a single dominant pathway independent of classical mechanisms. Existing studies suggest that intestinal barrier status, microbiota imbalance, and their related inflammatory/metabolic signals may affect the bone marrow immune-metabolic state and bone remodeling balance through a continuous mechanism chain of "gut output-bone marrow microenvironment translation-bone remodeling imbalance." Accordingly, the main significance of the gut-bone axis lies in supplementing the explanation from a cross-organ perspective of how classical osteoporosis mechanisms such as inflammation, aging, and abnormal mineral metabolism collectively converge on bone marrow microenvironment imbalance and bone loss. This article reviews how intestinal barrier dysfunction, microbiota imbalance, and their related metabolic pathways affect the bone marrow microenvironment and alter osteoblast-osteoclast coupling, focusing on three levels: gut signal output, bone marrow immune-metabolic translation, and dysregulation at the bone remodeling execution level. Currently, relatively consistent supporting evidence mainly comes from animal and preclinical mechanism studies; population studies more often suggest a correlation between the gut-bone axis and osteoporosis, while genetic/MR inference and clinical intervention evidence remain limited. Therefore, the gut-bone axis is more suitable as an analysis framework for integrating immune, metabolic, and bone marrow microenvironment changes in osteoporosis, and its translational potential is currently limited to providing insights for mechanism and stratification research levels, rather than serving as a mature intervention pathway.