Oral iron replacement normalizes fibroblast growth factor 23 in iron‐deficient patients with autosomal dominant hypophosphatemic rickets

Imel, Erik A.; Liu, Ziyue; Coffman, Melissa; Acton, Dena; Mehta, Rakesh; Econs, Michael J.

Affiliations

¹Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

²Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

³Department of Biostatistics, Indiana University School of Public Health, Indianapolis, IN, USA

⁴Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

Abstract

Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations impairing cleavage of fibroblast growth factor 23 (FGF23). FGF23 gene expression increases during iron deficiency. In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. We conducted a prospective open label pilot clinical trial of oral iron replacement over 12 months in ADHR patients to test the hypothesis that oral iron administration would normalize FGF23 concentrations. Eligibility criteria included: FGF23 mutation; and either serum iron <50 μg/dL; or serum iron 50 to 100 μg/dL combined with hypophosphatemia and intact FGF23 >30 pg/mL at screening. Key exclusion criteria were kidney disease and pregnancy. Oral iron supplementation started at 65 mg daily and was titrated based on fasting serum iron concentration. The primary outcome was decrease in fasting intact FGF23 by ≥20% from baseline. Six adults (three male, three female) having the FGF23‐R176Q mutation were enrolled; five completed the 12‐month protocol. At baseline three of five subjects had severely symptomatic hypophosphatemia (phosphorus <2.5 mg/dL) and received calcitriol with or without phosphate concurrent with oral iron during the trial. The primary outcome was met by 4 of 5 (80%) subjects all by month 4, and 5 of 5 had normal intact FGF23 at month 12. Median (minimum, maximum) intact FGF23 concentration decreased from 172 (20, 192) pg/mL at baseline to 47 (17, 78) pg/mL at month 4 and 42 (19, 63) pg/mL at month 12. Median ferritin increased from 18.6 (7.7, 82.5) ng/mL at baseline to 78.0 (49.6, 261.0) ng/mL at month 12. During iron treatment, all three subjects with baseline hypophosphatemia normalized serum phosphorus, had markedly improved symptoms, and were able to discontinue calcitriol and phosphate. Oral iron repletion normalized FGF23 and phosphorus in symptomatic, iron‐deficient ADHR subjects. Thus, the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency.

Links

DOI: 10.1002/jbmr.3878

PubMed: 31652009

WoS: 000492485700001

History

Received: 2019-06-05

Revised: 2019-08-20

Accepted: 2019-09-28

Cited By (5)

Year	Entry
2021	Imel EA. Congenital conditions of hypophosphatemia in children. Calcif Tiss Int. January 2021;108(1):74-90.
2020	Högler W, Kapelari K. Oral iron for prevention and treatment of rickets and osteomalacia in autosomal dominant hypophosphatemia. J Bone Miner Res. February 2020;35(2):226-230.
2021	Roszko KL, Brown S, Pang Y, Huynh T, Zhuang Z, Pacak K, Collins MT. C‐terminal, but not intact, FGF23 and EPO are strongly correlatively elevated in patients with gain‐of‐function mutations in HIF2A: clinical evidence for EPO regulating FGF23. J Bone Miner Res. February 2021;36(2):315-321.
2021	Noonan ML, Ni P, Agoro R, Sacks SA, Swallow EA, Wheeler JA, Clinkenbeard EL, Capitano ML, Prideaux M, Atkins GJ, Thompson WR, Allen MR, Broxmeyer HE, White KE. The HIF-PHI BAY 85-3934 (Molidustat) improves anemia and is associated with reduced levels of circulating FGF23 in a CKD mouse model. J Bone Miner Res. June 2021;36(6):1117-1130.
2021	Liu C, Li X, Zhao Z, Chi Y, Cui L, Zhang Q, Ping F, Chai X, Jiang Y, Wang O, Li M, Xing X, Xia W. Iron deficiency plays essential roles in the trigger, treatment, and prognosis of autosomal dominant hypophosphatemic rickets. Osteoporos Int. April 2021;32(4):737-745.