Deoxycholic Acid (DCA) a Secondary Bile Acid, Mitigates Ovariectomy-Induced Bone Loss and promotes Bone Healing: A Novel Candidate for Orthopaedic Applications
Introduction Postmenopausal osteoporosis (PMO) is a metabolic disorder, characterized by accelerated bone loss, gut microbiota (GM) dysbiosis and altered microbial metabolites. Deoxycholic acid (DCA) is a secondary bile acid with an FDA-approved drug status for submental fat treatment in adults; however its effect on bone health remains underexplored. Materials and Methods This study investigated the effects of DCA on bone health using both preclinical animal model of PMO and clinical samples from PMO women. DCA (20 mg/kg) was administered to ovariectomised (OVX) mice for 45 days, and its effects on bone microarchitecture and serum cytokines were analysed. Osteoclastogenesis and osteoblastogenesis were evaluated using murine and human samples. Untargeted and targeted metabolomics analyses were performed using an ultra-high-performance liquid chromatographic system coupled with high-resolution Orbitrap mass spectrometry (HRMS). Secondary analysis of 16S rRNA sequencing data was performed using R programming. Results GM analysis and plasma metabolomics revealed an alteration in bacterial taxa associated with secondary BA synthesis and reduced circulating DCA levels. DCA administration improved impaired trabecular and cortical bone microarchitecture in the OVX mice by inhibiting osteoclastogenesis and enhancing osteoblastogenesis. Moreover, DCA altered circulating osteoclastogenic (IL-6, Il-9, IL-17A, IFN-{gamma}, RANKL) and osteoblastogenic (OPG, TGF-{beta}, IL-10) factors. Mechanically, DCA suppressed osteoclast differentiation and the expression of genes associated with osteoclast formation (NFATC1, NFKB, TRAF6, TREM2, SYNB), fusion (CSF1R, DC-STAMP, CD47), and resorption (CTSK, ATP6VOD1, ATP6VOD2, CAR2, SPP1) in human peripheral blood mononuclear cells (PBMCs), while promoting osteogenic differentiation and matrix mineralization in bone marrow-derived mesenchymal stem cells (BMSCs) from PMO women. Additionally, DCA enhanced the nascent calcium deposition at the fracture site and improved bone healing via inhibiting osteoclastogenesis. Conclusion Overall, reduced DCA availability was associated with PMO, while DCA treatment mitigated OVX-induced bone loss and improved bone healing. This study highlights the therapeutic potential of DCA for maintaining both bone homeostasis in PMO and fracture healing with immense orthopaedic applications.