Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol

Abstract

Context: The optimal circulating concentration of 25(OH) vitamin D is controversial.

Objective: The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement.

Design: Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ηg/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14).

Setting: The study was conducted at the Veterans Affairs clinics.

Main outcome measure: Serum FGF-23, PTH, 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, calcium, and phosphorous concentrations, and urinary excretion of calcium and phosphorus at baseline and after 8 weeks of treatment.

Results: Cholecalciferol treatment increased concentrations of serum 25(OH)D by (19.3 ± 8 ηg/mL, P = .001; 12.2 ± 9 ηg/mL, P = .0001) and 24,25(OH)2D (1.14 ± 0.89 ηg/mL, P = .0024; 1.0 ± 0.72 ηg/mL P = .0002), and reduced serum PTH (-11 ± 21 pg/mL, P = .0292; -42 ± 68 pg/mL, P = .0494) in normal and CKD subjects, respectively. Cholecalciferol increased serum FGF-23 levels only in normal subjects (44 ± 57 ηg/mL, P = .01). Increments in serum 25(OH)D positively correlated with serum FGF-23 and 24,25(OH)2D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH)D by (16.6 ± 6.6 ηg/mL P ≤ .05) without changing 24,25(OH)2D, FGF-23 or PTH levels.

Conclusion: Modest elevations of serum 25(OH)D levels after cholecalciferol treatment are sufficient to induce compensatory degradative pathways in patients with sufficient renal reserves, suggesting that optimal circulating 25(OH)D levels are approximately 20 ηg/mL. In addition, catabolism of 25(OH)D may also contribute to the low circulating vitamin D levels in CKD, since elevations of FGF-23 in CKD are associated with increased 24,25(OH)2D after cholecalciferol administration.

Trial registration: ClinicalTrials.gov NCT01528176.

Figure 1.

Effects of cholecalciferol treatment on serum parameters. Respective correlation between serum 25(OH)D and FGF-23, PTH, 1,25(OH)₂D, and 24,25(OH)₂D in subjects without (A, B, C, D) and with (E, F, G, H) CKD. Serum 25(OH)D was positively correlated with FGF-23 in subjects with normal renal function (A), but not in those with CKD (E). Serum 25(OH)D was significantly negatively correlated with PTH (B) and positively correlated with 1,25(OH)₂D (C) in subjects with normal renal function, but not in subjects with CKD (F and G). 25(OH)D was positively correlated with 24,25(OH)₂D in both subjects with normal renal function (D) and with CKD (H). Values represent serum concentrations obtained before and after treatment with cholecalciferol in subjects with normal renal function (n = 25) and CKD (n = 27), except for 24,25(OH)₂D values, which were available only in the matched CKD (n = 14) and normal renal function (n = 14) cohort.