Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets

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. © 2019 American Society for Bone and Mineral Research.

Trial registration: ClinicalTrials.gov NCT02233322.

© 2019 American Society for Bone and Mineral Research.

Figures

Figure 1.

FGF23 during oral iron supplementation. Intact FGF23 (A) and percent change from baseline in intact FGF23 (B), along with C-terminal FGF23 (C) and percent change from baseline in C-terminal FGF23 concentrations (D). Each line represents an individual subject. Zero represents the baseline visit. The red dotted line represents the upper limit of normal for intact FGF23 (A) and C-terminal FGF23 (C), or a 20% decrease from baseline (B and D). The subject in green was on treatment with calcitriol and phosphate for 3 years prior to enrollment and stopped at Month 3. The subject in yellow started calcitriol at the baseline visit and stopped at Month 4. The subject in blue started calcitriol at Month 2 and stopped Month 9.

Figure 2.

Serum iron (A), ferritin (B), phosphorus (C) and alkaline phosphatase (D) during oral iron supplementation. Each line represents an individual subject. Zero represents the baseline visit. The red dotted line represents the lower limit of normal for serum iron (A), ferritin (B), and phosphorus (C), and the upper limit of normal for alkaline phosphatase (D). The subject in green was on treatment with calcitriol and phosphate for 3 years prior to enrollment and stopped at Month 3. The subject in yellow started calcitriol at the baseline visit and stopped at Month 4. The subject in blue started calcitriol at Month 2 and stopped Month 9.