FGF23, Hypophosphatemia, and Emerging Treatments

Abstract

FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co-receptor Klotho, it modulates phosphate reabsorption and both 1α-hydroxylation and 24-hydroxylation in the renal proximal tubules. The most common FGF23-mediated hypophosphatemia is X-linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23-mediated forms of hypophosphatemia are characterized by phosphaturia and low or low-normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23-mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor-induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23-mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Keywords: BUROSUMAB; FGF23; KLOTHO; XLH; X‐LINKED HYPOPHOSPHATEMIA.

Figure 1

A now 14‐year‐old female with XLH (PHEX:c.[151C>T];[=] p.[Gln51*]) diagnosed at 7 months of age. (A) Radiograph of left hand and wrist at diagnosis with rachitic changes of distal radius and ulna and lacey appearance of bone. (B) Radiograph of right knee at 18 months old while treated with phosphate and calcitriol. There is fraying and splaying at the metaphyses and early cupping noted at the distal femur as well as the proximal tibia and fibula. (C) At 14 years old, she was managed with phosphate and calcitriol. She had short stature, normal ALP, and mild elevation in PTH. Symptoms included persistent ankle pain and waddling gait. There was also lateral bowing of both femora and tibias with widening of the proximal tibial growth plate. (D) Left hand radiograph at age 14 years showing widening of the proximal radius and ulna growth plates with evidence of rachitic changes.