Deoxycholic acid ameliorates postmenopausal osteoporosis by rebalancing BMSC differentiation and suppressing NF-κB...

Postmenopausal osteoporosis (PMOP) represents a significant global health issue associated with aging, primarily driven by estrogen deficiency. Although the gut-bone axis has garnered increasing attention, the specific bioactive metabolites and molecular mechanisms linking gut dysbiosis to bone loss remain to be fully elucidated. In this study, we investigated the gut-bile acid-bone axis by integrating clinical data with mechanistic studies in an ovariectomized mouse model. Clinically, serum total bile acid levels were positively correlated with bone mineral density in PMOP patients. In ovariectomized mice, estrogen withdrawal induced alterations in the abundance of gut microbiota involved in secondary bile acid biosynthesis, including Clostridium, Bifidobacterium, and Bacteroides, resulting in decreased serum deoxycholic acid (DCA) levels. Notably, Mendelian randomization analysis provided genetic evidence supporting a causal relationship between serum DCA levels and lumbar spine bone mineral density. Therapeutically, DCA supplementation effectively mitigated trabecular bone loss and improved microarchitectural integrity, while simultaneously regulating white adipose metabolism and hepatic bile acid synthesis. Mechanistically, DCA restores the balance of bone remodeling by promoting osteoblastogenesis over adipogenesis in bone marrow mesenchymal stem cells and inhibiting osteoclastogenesis through the suppression of the IκB-α/NF-κB/NFATC1 signaling pathway in bone marrow-derived macrophages. Collectively, these findings position DCA as a promising therapeutic agent for regulating bone homeostasis, thereby validating the gut-bile acid-bone axis as a viable target for PMOP treatment.