Molecular pathways shaping bone function following SGLT2 inhibitor therapy; a narrative insight from metabolic and endocrine crosstalk

A sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy promotes renal glucosuria, which triggers phosphaturia and initiates a cascade of metabolic and hormonal disturbances. The resulting hypophosphatemia stimulates secondary hyperparathyroidism, which in turn elevates fibroblast growth factor 23 (FGF23), further suppressing serum phosphate, calcitriol, and calcium levels. Concurrently, the osmotic diuresis and caloric loss induce a negative energy balance, shifting metabolism toward ketogenesis. Elevated β-hydroxybutyrate not only serves as an alternative fuel but also directly stimulates osteoclast activity while inhibiting osteoblast function. Compounding this, therapy-associated hypoinsulinemia diminishes anabolic signaling through insulin and insulin-like growth factor-1 (IGF-1), both critical for bone formation. At the heart of this skeletal disruption lies osteocyte dysfunction. Hypophosphatemia and altered hormonal milieu—particularly increased PTH and FGF23 upregulate sclerostin, a potent inhibitor of the Wnt/β-catenin pathway, thereby suppressing bone formation. Furthermore, alterations in adipokines following weight loss further modulate bone metabolism. Critically, these pathways interact synergistically: PTH enhances bone resorption and sclerostin production; FGF23 suppresses calcitriol, worsening hypocalcemia; and ketones amplify RANKL-driven osteoclastogenesis. Additionally, mechanical unloading from rapid weight loss independently increases sclerostin expression. The net effect is a profound uncoupling of bone remodeling, accelerated resorption driven by PTH, RANKL, ketones, and inflammatory cytokines, coupled with suppressed formation due to sclerostin, hypoinsulinemia, and direct ketone effects. Clinically, this manifests as rapid trabecular bone loss, deteriorated microarchitecture, and a markedly elevated fracture risk, particularly during the initial months of treatment. Therefore, SGLT2 inhibitors confer significant cardio-renal benefits; however, they may impose substantial skeletal trade-offs that warrant careful monitoring.