Fucoidan from giant kelp alleviates postmenopausal osteoporosis by regulating the betaine-OPG/RANKL/RANK signaling axis.

Postmenopausal osteoporosis (PMOP), characterized by excessive bone resorption and impaired bone remodeling, remains a significant global health challenge. This study investigated the protective effects of fucoidan from giant kelp (GKP) against PMOP and its underlying mechanisms in ovariectomized mice. GKP supplementation attenuated bone loss by preserving trabecular microarchitecture, normalizing systemic mineral homeostasis, and suppressing osteoclastogenesis, as evidenced by the downregulation of osteoclast-related genes. 16S rRNA gene sequencing revealed that GKP reshaped the gut microbiota by decreasing the Bacteroidota/Firmicutes ratio and enriching beneficial taxa, which promoted short-chain fatty acid production. Targeted metabolomics revealed that GKP induced profound systemic metabolic reprogramming, particularly amino acid metabolism, and identified betaine as a key systemic metabolite effector upregulated following GKP treatment. In vitro assays demonstrated that betaine suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and mitigated inflammation. In vivo validation demonstrated that betaine intervention recapitulated the osteoprotective phenotype observed in GKP-treated mice, which was associated with regulation of the osteoprotegerin/RANKL/RANK signaling axis. These results indicate that GKP exerts anti-osteoporotic effects in association with changes in gut microbiota and systemic metabolism, while betaine-mediated regulation of the OPG/RANKL/RANK signaling may contribute to its osteoprotective activity.