Phlorizin attenuates chronic kidney disease induced bone loss by mitigating sclerostin mediated inhibition of Wnt/β-catenin signaling and ameliorating metabolic alterations.

CKD-MBD is a metabolic disorder characterized by disrupted mineral metabolism, leading to vascular calcification, renal osteodystrophy, and high fracture risk. Sclerostin, an osteocyte-derived Wnt inhibitor, is a key regulator of both bone loss and vascular calcification. This study explored the role of phlorizin (SGLT1 and SGLT2 inhibitor) on bone loss and metabolic profile in CKD-MBD. Calvarial osteoblasts were treated with phlorizin and evaluated for ALP activity, viability, mineralization, and gene/protein expression. Molecular docking and simulation studies were performed to check phlorizin-sclerostin interactions. This was further validated by LRP-SOST interaction and TOP-FLASH luciferase reporter assays. For in vivo studies, CKD-MBD was induced in adult female SD rats via 5/6th nephrectomy. Bone samples were analysed by micro-CT, histomorphometry, and metabolite profiling, while renal function markers were measured using serum ELISA and biochemistry analyser. Phlorizin promotes primary osteoblastic cell ALP activity, mineralization, and osteogenic marker expression. It disrupts the sclerostin-LRP6 complex, promoting β-catenin nuclear localization and activating Wnt/β-catenin signaling. Phlorizin also reduced sclerostin secretion in osteocytes and reversed its inhibitory effects on primary osteoblastic cells, confirming a sclerostin-dependent mechanism. In vivo, phlorizin improved fracture healing and attenuated bone loss in 5/6th nephrectomised rats. It also improved renal function, corrected mineral imbalance, restored bone mass, and mitigated metabolic dysfunction. Phlorizin supported adaptive metabolism and sex hormone pathways, highlighting its potential as an osteo- and reno-protective agent in CKD-MBD. In conclusion, Phlorizin attenuates bone loss by disrupting the sclerostin-LRP interaction, activating Wnt/β-catenin signaling, and ameliorating metabolic alterations in CKD-MBD.