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

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2014 Jun 25

PMID 24960544

Citations 11

Authors

Hala Alshayeb

Arif Showkat

Barry M Wall

Geeta G Gyamlani

Valentin David

L Darryl Quarles

Affiliations

Soon will be listed here.

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.

Citing Articles

Vitamin D supplementation in primary hyperparathyroidism: effects on 1,25(OH) vitamin D and FGF23 levels.

Pallone S, Ohe M, Dos Santos L, Nacaguma I, Kunii I, da Silva R J Endocrinol Invest. 2024; 48(1):91-98.

PMID: 38922369 DOI: 10.1007/s40618-024-02422-2.

A rare combination of tumor-induced osteomalacia caused by sinonasal glomangiopericytoma and coexisting parathyroid adenoma: case report and literature review.

Brociek-Pilczynska A, Brodowska-Kania D, Szczygielski K, Lorent M, Zielinski G, Kowalewski P BMC Endocr Disord. 2022; 22(1):31.

PMID: 35090436 PMC: 8796561. DOI: 10.1186/s12902-022-00934-7.

Decrease in serum calcitriol (but not free 25-hydroxyvitamin D) concentration in hip fracture healing.

Vaculik J, Wenchich L, Bobelyak M, Pavelka K, Stepan J J Endocrinol Invest. 2021; 44(9):1847-1855.

PMID: 33492601 DOI: 10.1007/s40618-020-01489-x.

Oral vitamin D supplementation increases serum fibroblast growth factor 23 concentration in vitamin D-deficient patients: a systematic review and meta-analysis.

Charoenngam N, Rujirachun P, Holick M, Ungprasert P Osteoporos Int. 2019; 30(11):2183-2193.

PMID: 31372708 DOI: 10.1007/s00198-019-05102-7.

Effects of vitamin D supplementation on FGF23: a randomized-controlled trial.

Trummer C, Schwetz V, Pandis M, Grubler M, Verheyen N, Gaksch M Eur J Nutr. 2018; 58(2):697-703.

PMID: 29602956 PMC: 6437118. DOI: 10.1007/s00394-018-1672-7.

References

Bosworth C, Levin G, Robinson-Cohen C, Hoofnagle A, Ruzinski J, Young B . The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease. Kidney Int. 2012; 82(6):693-700. PMC: 3434313. DOI: 10.1038/ki.2012.193. View

Shapses S, Manson J . Vitamin D and prevention of cardiovascular disease and diabetes: why the evidence falls short. JAMA. 2011; 305(24):2565-6. PMC: 4014631. DOI: 10.1001/jama.2011.881. View

Malabanan A, Veronikis I, Holick M . Redefining vitamin D insufficiency. Lancet. 1998; 351(9105):805-6. DOI: 10.1016/s0140-6736(05)78933-9. View

Kandula P, Dobre M, Schold J, Schreiber Jr M, Mehrotra R, Navaneethan S . Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol. 2010; 6(1):50-62. PMC: 3022248. DOI: 10.2215/CJN.03940510. View

Marckmann P, Agerskov H, Thineshkumar S, Bladbjerg E, Sidelmann J, Jespersen J . Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. Nephrol Dial Transplant. 2012; 27(9):3523-31. DOI: 10.1093/ndt/gfs138. View

Khosla S . What do we tell our patients about calcium and vitamin D supplementation?. J Clin Endocrinol Metab. 2011; 96(1):69-71. DOI: 10.1210/jc.2010-2760. View

Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S . Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001; 98(11):6500-5. PMC: 33497. DOI: 10.1073/pnas.101545198. View

Gravesen E, Hofman-Bang J, Lewin E, Olgaard K . Ergocalciferol treatment and aspects of mineral homeostasis in patients with chronic kidney disease stage 4-5. Scand J Clin Lab Invest. 2013; 73(2):107-16. DOI: 10.3109/00365513.2012.744464. View

Parker B, Schurgers L, Brandenburg V, Christenson R, Vermeer C, Ketteler M . The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med. 2010; 152(10):640-8. PMC: 3079370. DOI: 10.7326/0003-4819-152-10-201005180-00004. View

10.

Dai B, David V, Alshayeb H, Showkat A, Gyamlani G, Horst R . Assessment of 24,25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites. Kidney Int. 2012; 82(10):1061-70. PMC: 3461248. DOI: 10.1038/ki.2012.222. View

11.

Heaney R, Holick M . Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res. 2011; 26(3):455-7. DOI: 10.1002/jbmr.328. View

12.

Biancuzzo R, Clarke N, Reitz R, Travison T, Holick M . Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013; 98(3):973-9. PMC: 3590486. DOI: 10.1210/jc.2012-2114. View

13.

Beckman M, Tadikonda P, Werner E, Prahl J, Yamada S, DeLuca H . Human 25-hydroxyvitamin D3-24-hydroxylase, a multicatalytic enzyme. Biochemistry. 1996; 35(25):8465-72. DOI: 10.1021/bi960658i. View

14.

Hoenderop J, Chon H, Gkika D, Bluyssen H, Holstege F, St-Arnaud R . Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice. Kidney Int. 2004; 65(2):531-9. DOI: 10.1111/j.1523-1755.2004.00402.x. View

15.

Alshayeb H, Wall B, Showkat A, Quarles L, Mangold T . Chronic kidney disease and diabetes mellitus predict resistance to vitamin D replacement therapy. Am J Med Sci. 2012; 345(4):314-320. PMC: 6350532. DOI: 10.1097/MAJ.0b013e31826af2d3. View

16.

Lips P . Vitamin D physiology. Prog Biophys Mol Biol. 2006; 92(1):4-8. DOI: 10.1016/j.pbiomolbio.2006.02.016. View

17.

Garcia-Lopes M, Pillar R, Kamimura M, Rocha L, Canziani M, Carvalho A . Cholecalciferol supplementation in chronic kidney disease: restoration of vitamin D status and impact on parathyroid hormone. Ann Nutr Metab. 2012; 61(1):74-82. DOI: 10.1159/000339618. View

18.

White K, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom T, Econs M . Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 2001; 60(6):2079-86. DOI: 10.1046/j.1523-1755.2001.00064.x. View

19.

Takeyama K, Kato S . The vitamin D3 1alpha-hydroxylase gene and its regulation by active vitamin D3. Biosci Biotechnol Biochem. 2011; 75(2):208-13. DOI: 10.1271/bbb.100684. View

20.

Shab-Bidar S, Bours S, Geusens P, van der Velde R, Janssen M, van den Bergh J . Suboptimal effect of different vitamin D3 supplementations and doses adapted to baseline serum 25(OH)D on achieved 25(OH)D levels in patients with a recent fracture: a prospective observational study. Eur J Endocrinol. 2013; 169(5):597-604. DOI: 10.1530/EJE-13-0068. View