Abstract
Studies have suggested that vitamin D supplementation may increase serum fibroblast growth factor 23 (FGF23) among vitamin D-deficient patients although the results were inconsistent across the studies. This systematic review and meta-analysis was conducted to summarize all available data. A systematic review was conducted using MEDLINE and EMBASE database from inception to February 2019 to identify studies that provided oral vitamin D3 supplement to vitamin D-deficient participants (25-hydroxyvitamin D < 20 ng/mL). Mean serum FGF23 concentration and standard deviation of participants at baseline and after vitamin D3 supplementation were extracted to calculate standard mean difference (SMD). Pooled SMD was calculated by combining SMDs of each study using random effects model. Nine studies were eligible for the meta-analyses. Seven studies measured serum intact FGF23, and two studies measured serum C-terminal FGF23. The meta-analyses found that serum intact FGF23 increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.36 (95%CI, 0.14, 0.57; p = 0.001; I2 of 36%). Serum C-terminal FGF23 also increased after vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.28 although without reaching statistical significance (95%CI, − 0.08, 0.65; p = 0.13; I2 of 0%). Funnel plot of the meta-analysis of serum intact FGF23 did not provide a suggestive evidence for publication bias. Vitamin D supplementation leads to a significant increase in serum intact FGF23 among vitamin D-deficient patients. An increase in serum C-terminal FGF23 was also observed although the number of included studies was too small to demonstrate statistical significance. The present systematic review and meta-analysis revealed that serum intact FGF23 concentration increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants. An increase in serum C-terminal FGF23 concentration was also observed although the number of included studies was too small to demonstrate statistical significance.
Similar content being viewed by others
References
Holick MF (2007) Vitamin D Deficiency. N Engl J Med 357(3):266–281. https://doi.org/10.1056/NEJMra070553
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911–1930. https://doi.org/10.1210/jc.2011-0385
Holick MF (2006) Resurrection of vitamin D deficiency and rickets. J Clin Invest 116(8):2062–2072. https://doi.org/10.1172/jci29449
Bonewald LF, Wacker MJ (2013) FGF23 production by osteocytes. Pediatr Nephrol 28(4):563–568. https://doi.org/10.1007/s00467-012-2309-3
Prié D, Friedlander G (2010) Reciprocal control of 1,25-Dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clin J Am Soc Nephrol 5(9):1717–1722. https://doi.org/10.2215/CJN.02680310
Erben RG (2018) Physiological actions of fibroblast growth factor-23. Front Endocrinol 9:267–267. https://doi.org/10.3389/fendo.2018.00267
Lanske B, Razzaque MS (2014) Molecular interactions of FGF23 and PTH in phosphate regulation. Kidney Int 86(6):1072–1074. https://doi.org/10.1038/ki.2014.316
Yu X, Sabbagh Y, Davis SI, Demay MB, White KE (2005) Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 36(6):971–977. https://doi.org/10.1016/j.bone.2005.03.002
Wahl P, Wolf M (2012) FGF23 in chronic kidney disease. Adv Exp Med Biol 728:107–125. https://doi.org/10.1007/978-1-4614-0887-1_8
Kinoshita Y, Fukumoto S (2018) X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases: prospect for new treatment. Endocr Rev 39(3):274–291. https://doi.org/10.1210/er.2017-00220
Alshayeb H, Showkat A, Wall BM, Gyamlani GG, David V, Quarles LD (2014) Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol. J Clin Endocrinol Metab 99(10):E1830–E1837. https://doi.org/10.1210/jc.2014-1308
Carvalho JTG, Schneider M, Cuppari L, Grabulosa CC, Aoike DT, Redublo BMQ, Batista MC, Cendoroglo M, Moyses RM, Dalboni MA (2017) Cholecalciferol decreases inflammation and improves vitamin D regulatory enzymes in lymphocytes in the uremic environment: a randomized controlled pilot trial. PLoS One 12(6). https://doi.org/10.1371/journal.pone.0179540
De Niet S, Coffiner M, Da Silva S, Jandrain B, Souberbielle JC, Cavalier E (2018) A randomized study to compare a monthly to a daily administration of vitamin D3 supplementation. Nutrients 10(6). https://doi.org/10.3390/nu10060659
Garcia-Lopes MG, Pillar R, Kamimura MA, Rocha LA, Canziani MEF, Carvalho AB, Cuppari L (2012) Cholecalciferol supplementation in chronic kidney disease: restoration of vitamin D status and impact on parathyroid hormone. Ann Nutr Metab 61(1):74–82. https://doi.org/10.1159/000339618
Kamelian T, Saki F, Jeddi M, Dabbaghmanesh MH, Omrani GHR (2018) Effect of cholecalciferol therapy on serum FGF23 in vitamin D deficient patients: a randomized clinical trial. J Endocrinol Investig 41(3):299–306. https://doi.org/10.1007/s40618-017-0739-2
Nygaard B, Frandsen NE, Brandi L, Rasmussen K, Oestergaard OV, Oedum L, Hoeck HC, Hansen D (2014) Effects of high doses of cholecalciferol in normal subjects: a randomized double-blinded, placebo- controlled trial. PLoS One 9(8):e102965. https://doi.org/10.1371/journal.pone.0102965
Turrini F, Scarlini S, Giovanardi P, Messora R, Roli L, Chester J, Mussi C, Bertolotti M, Trenti T, Bondi M (2017) Effects of cholecalciferol supplementation in patients with stable heart failure and low vitamin D levels (eCSPloiT-d): a double-blind, randomized, placebo-controlled pilot study. Minerva Cardioangiol 65(6):553–562. https://doi.org/10.23736/S0026-4725.17.04340-7
Mesinovic J, Mousa A, Wilson K, Scragg R, Plebanski M, de Courten M, Scott D, Naderpoor N, de Courten B (2019) Effect of 16-weeks vitamin D replacement on calcium-phosphate homeostasis in overweight and obese adults. J Steroid Biochem Mol Biol 186:169–175. https://doi.org/10.1016/j.jsbmb.2018.10.011
Trummer C, Schwetz V, Pandis M, Grübler MR, Verheyen N, Gaksch M, Zittermann A, März W, Aberer F, Steinkellner J, Friedl C, Brandenburg V, Voelkl J, Alesutan I, Obermayer-Pietsch B, Pieber TR, Tomaschitz A, Pilz S (2018) Effects of vitamin D supplementation on FGF23: a randomized-controlled trial. Eur J Nutr 58:1–7. https://doi.org/10.1007/s00394-018-1672-7
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. https://doi.org/10.1136/bmj.327.7414.557
Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17(5):1305–1315. https://doi.org/10.1681/ASN.2005111185
Ito M, Sakai Y, Furumoto M, Segawa H, Haito S, Yamanaka S, Nakamura R, Kuwahata M, Miyamoto K-i (2005) Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells. Am J Physiol Endocrinol Metab 288(6):E1101–E1109. https://doi.org/10.1152/ajpendo.00502.2004
Chesney RW, Zimmerman J, Hamstra A, DeLuca HF, Mazess RB (1981) Vitamin D metabolite concentrations in vitamin D deficiency: are calcitriol levels normal? JAMA Pediatr 135(11):1025–1028. https://doi.org/10.1001/archpedi.1981.02130350029010
Fukumoto S (2014) Phosphate metabolism and vitamin D. BoneKEy Rep 3:497–497. https://doi.org/10.1038/bonekey.2013.231
Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD (2008) Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab 93(3):677–681. https://doi.org/10.1210/jc.2007-2308
Turner C, Dalton N, Inaoui R, Fogelman I, Fraser WD, Hampson G (2013) Effect of a 300 000-IU loading dose of ergocalciferol (vitamin D2) on circulating 1,25(OH)2-vitamin D and fibroblast growth Factor-23 (FGF-23) in vitamin D insufficiency. J Clin Endocrinol Metab 98(2):550–556. https://doi.org/10.1210/jc.2012-2790
Burnett-Bowie S-AM, Leder BZ, Henao MP, Baldwin CM, Hayden DL, Finkelstein JS (2012) Randomized trial assessing the effects of ergocalciferol administration on circulating FGF23. Clin J Am Soc Nephrol 7(4):624–631. https://doi.org/10.2215/CJN.10030911
Ketteler M (2011) Phosphate metabolism in CKD stages 3-5: dietary and pharmacological control. Int J Nephrol 2011:970245–970245. https://doi.org/10.4061/2011/970245
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Nipith Charoenngam, Pongprueth Rujirachun, and Patompong Ungprasert declare that they have no conflict of interest. Michael F. Holick is a consultant for Quest Diagnostics Inc. and Ontometrics Inc., and on the speaker’s Bureau for Abbott Inc.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Charoenngam, N., Rujirachun, P., Holick, M. et al. Oral vitamin D3 supplementation increases serum fibroblast growth factor 23 concentration in vitamin D-deficient patients: a systematic review and meta-analysis. Osteoporos Int 30, 2183–2193 (2019). https://doi.org/10.1007/s00198-019-05102-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-019-05102-7