ABSTRACT:
FGF23-mediated hypophosphatemic rickets comprises inherited and acquired disorders in which excessive fibroblast growth factor 23 (FGF23) activity causes renal phosphate wasting and defective skeletal mineralization. X-linked hypophosphatemia (XLH), most commonly associated with pathogenic PHEX variants, is the best characterized inherited form; autosomal dominant and recessive hypophosphatemic rickets and tumor-induced osteomalacia (TIO) are additional important entities. This narrative review summarizes phosphate homeostasis, FGF23 biology, disease mechanisms, diagnosis, conventional treatment and targeted FGF23 inhibition. Evidence from clinical trials and contemporary guidance shows that conventional phosphate and active vitamin D therapy can improve mineralization but does not directly correct excess FGF23 and may be limited by treatment burden, hyperparathyroidism and nephrocalcinosis . Burosumab, a fully human monoclonal antibody against FGF23, directly targets the disease pathway and has demonstrated improvements in serum phosphate, radiographic rickets, bone mineralization, growth and selected patient-important outcomes, particularly in XLH. Evidence also supports benefit in selected patients with TIO when definitive tumor treatment is not feasible. Important challenges include delayed diagnosis, FGF23 assay variability, genetic testing access, treatment cost and uncertainty regarding some long-term outcomes. Mechanism-based therapy has transformed the management of FGF23-mediated disease and provides a foundation for precision therapeutic strategies.