Parzhin Khazdoozi
1 
, Abnoos Mokhtariardekani
2 , Mansooreh Kashefi
3 , Somayeh Ghamkhari
4, Hojjat Eghbali Jelodar
5 , Hanie Fooladi
6 , Asaad Abass Fadhel Khalif
7* 1 School of Nursing, Gerash University of Medical Sciences, Gerash, Iran.
2 Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Science & Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran.
3 Department of Nursing, Se.C., Islamic Azad University, Semnan, Iran.
4 Department of Medical Biotechnology, Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran.
5 Department of Surgery and Orthopedic, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
6 Department of Nursing, Faculty of Nursing and Midwifery, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
7 Department of Pharmacology and Toxicology, Al-Mustansiriyah University, College of Pharmacy, Baghdad, Iraq.
Abstract
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.