Activation of FGF-23 Mediated Vitamin D Degradative Pathways by Cholecalciferol

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)(2)D can guide cholecalciferol replacement. Design: Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH) D levels < 20 eta g/mL and eGFR > 60 mL/min/1.73m(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)(2)D, 24,25(OH)(2)D, 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 eta g/mL, P = .001; 12.2 +/- 9 eta g/mL, P = .0001) and 24,25(OH) 2D(1.14 +/- 0.89 eta g/mL, P = .0024; 1.0 +/- 0.72 +/- eta g/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 eta g/mL, P = .01). Increments in serum 25(OH) D positively correlated with serum FGF-23 and 24,25(OH)(2)D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH) D by (16.6 +/- 6.6 +/- eta g/mL P <= .05) without changing 24,25(OH)(2)D, 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 eta g/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)(2)D after cholecalciferol administration.