Fibroblast growth factor 23 at the crossroads of mineral metabolism and bone disease

Fibroblast growth factor 23 (FGF23) is an endocrine regulator of phosphate homeostasis produced by bone. This review aims to examine the role of FGF23 in bone biology, with a focus on its contributions to skeletal abnormalities in hereditary hypophosphatemia and chronic kidney disease (CKD).

In hereditary hypophosphatemic disorders, FGF23 excess leads to renal phosphate wasting and impaired bone mineralization. Therapies targeting FGF23 demonstrated clear clinical benefits in restoring phosphate levels and improving skeletal defects. Recent evidence indicates that FGF23 may also exert direct effects on osteoblast differentiation independent of phosphate levels. In CKD, preclinical studies suggest that reducing FGF23 improves bone outcomes, but the contribution of FGF23 to altered osteoblast differentiation and bone loss in CKD remains to be tested directly.

FGF23 contributes to bone disease both indirectly by regulating phosphate homeostasis and directly by inhibiting osteoblast differentiation. Targeting FGF23 represents a promising therapeutic approach, but in CKD, strategies blocking FGF23 must be carefully balanced against the risk of further disrupting phosphate balance. A better understanding of the mechanisms underlying the direct effects of FGF23 on bone is essential for the development of safe and effective treatments.