Abstract
Purpose
In patients with Primary Hyperparathyroidism (PHPT) vitamin D deficiency has been associated with more severe presentations. Our aim was to investigate the effects of Vitamin D supplementation on mineral homeostasis and related hormones in individuals with and without PHPT.
Methods
Individuals with and without PHPT (CTRL) received 14,000 IU/week of oral vitamin D3 for 12 weeks. At baseline and endpoint, blood samples were collected to measure 1,25(OH)2vitamin D (1,25(OH)2D), intact Fibroblast Growth Factor 23 (FGF23), 25OHD, Parathormone, and other biochemical markers. The 1,25(OH)2D measurement was performed using liquid chromatography and mass spectrometry (LC–MS/MS).
Results
70 PHPT patients and 75 CTRL were included, and 55 PHPT and 64 CTRL completed the 12-week protocol. After the intervention, there were significant increases in the FGF23 levels (PHPT: 47.9 ± 27.1 to 76.3 ± 33.3; CTRL: 40.5 ± 13.9 to 59.8 ± 19.8 pg/mL, p < 0.001), and significant decreases in 1,25(OH)2D levels (PHPT: 94.8 ± 34.6 to 68.9 ± 25.3; CTRL: 68.7 ± 23.5 to 56.4 ± 20.7 pg/mL, p < 0.001). The reduction of 1,25(OH)2D was inversely associated with the increase of FGF23 in both the PHPT (r = −0.302, p = 0.028) and CTRL (r = −0.278, p = 0.027). No changes in plasmatic or uninary calcium concentrations were observed in both groups.
Conclusion
The weekly administration of 14,000 IU of Vitamin D3 was safe and efficient to increase in 25OHD levels in both groups. However, a paradoxical decrease in 1,25(OH)2D levels measured by LC–MS/MS was associated with a significant increase in FGF23 levels in both groups. This phenomenon might represent a defense against hypercalcemia after vitamin D supplementation and paves the way for new studies in this regard.
Data availability
Data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Özbey N et al (2006) Correlations between vitamin D status and biochemical/clinical and pathological parameters in primary hyperparathyroidism. World J Surg 30:321–326
Untch BR et al (2007) Impact of 25-hydroxyvitamin D deficiency on perioperative parathyroid hormone kinetics and results in patients with primary hyperparathyroidism. Surgery 142:1022–1026
Priya G et al (2008) Clinical and laboratory profile of primary hyperparathyroidism in India. Postgrad Med J 84:34–39
Lang BHH, Lo CY (2010) Vitamin D3 deficiency is associated with late-onset hypocalcemia after minimally invasive parathyroidectomy in a vitamin D borderline area. World J Surg 34:1350–1355
Rolighed L et al (2014) Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial. J Clin Endocrinol Metab 99:1072–1080
Bilezikian JP et al (2022) Management of Primary Hyperparathyroidism. J Bone Miner Res 37:2391–2403
Kabadi UM (2020) Low 25-Hydroxyvitamin D in primary hyperparathyroidism: enhanced conversion into 1,25-hydroxyvitamin D may not be ‘true’ deficiency. JBMR plus 4:e10415
Song A et al (2021) Safety and efficacy of common vitamin D supplementation in primary hyperparathyroidism and coexistent vitamin D deficiency and insufficiency: a systematic review and meta-analysis. J Endocrinol Invest 44:1667–1677
Holick MF et al (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930
Shimada T et al (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435
Walton RJ, Bijvoet OLM (1975) Nomogram for derivation of renal threshold phosphate concentration. Lancet (London, England) 2:309–310
Goltzman D, Mannstadt M, Marcocci C (2018) Physiology of the calcium-parathyroid hormone-vitamin D axis. Front Horm Res 50:1–13
Singh RJ, Kumar R (2003) Fibroblast growth factor 23 concentrations in humoral hypercalcemia of malignancy and hyperparathyroidism. Mayo Clin Proc 78:826–829
Yamashita H et al (2004) Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. Eur J Endocrinol 151:55–60
Tebben PJ, Singh RJ, Clarke BL, Kumar R (2004) Fibroblast growth factor 23, parathyroid hormone, and 1alpha,25-dihydroxyvitamin D in surgically treated primary hyperparathyroidism. Mayo Clin Proc 79:1508–1513
Witteveen JE, Van Lierop AH, Papapoulos SE, Hamdy NAT (2012) Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism? Eur J Endocrinol 166:55–60
Kobayashi K et al (2006) Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. Eur J Endocrinol 154:93–99
Nagata Y et al (2019) Attenuated dentin matrix protein 1 enhances fibroblast growth factor 23 in calvaria in a primary hyperparathyroidism model. Endocrinology 160:1348–1358
Nagata Y et al (2022) Parathyroid hormone regulates circulating levels of sclerostin and FGF23 in a primary hyperparathyroidism model. J Endocr Soc 6:1–10
Alshayeb H et al (2014) Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol. J Clin Endocrinol Metab 99:E1830–E1837
Nygaard B et al (2014) Effects of high doses of cholecalciferol in normal subjects: a randomized double-blinded, placebo-controlled trial. PLoS One 9:e102965
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 Invest 41:299–306
Charoenngam N, Rujirachun P, Holick MF, Ungprasert P (2019) 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
Zittermann A, Berthold HK, Pilz S (2021) The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr 75:980–987
Ratsma DMA, Muller M, Koedam M, Zillikens MC, van der Eerden BCJ (2023) In vitro regulation of fibroblast growth factor 23 by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D synthesized by osteocyte-like MC3T3-E1 cells. Eur J Endocrinol 189:448–459
De Niet S et al (2018) A randomized study to compare a monthly to a daily administration of vitamin D3 supplementation. Nutrients 10:659
Zittermann A, Ernst JB, Birschmann I, Dittrich M (2015) Effect of vitamin D or activated vitamin D on circulating 1,25-dihydroxyvitamin D concentrations: a systematic review and metaanalysis of randomized controlled trials. Clin Chem 61:1484–1494
Trummer C et al (2017) Effects of vitamin D supplementation on IGF-1 and calcitriol: a randomized-controlled trial. Nutrients 9:623
Okai GG et al (2022) LC-MS/MS reduces interference by high levels of 25(OH)D and its metabolites on measured 1,25(OH)2D. Steroids 187:109095
Martineau AR et al (2019) Differential effects of oral boluses of vitamin D2 vs vitamin D3 on vitamin D metabolism: a randomized controlled trial. J Clin Endocrinol Metab 104:5831–5839
Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF (2013) 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 98:973–979
Bislev LS et al (2018) The effect of vitamin D3 supplementation on markers of cardiovascular health in hyperparathyroid, vitamin D insufficient women: a randomized placebo-controlled trial. Endocrine 62:182–194
Stubbs JR, Zhang S, Friedman PA, Nolin TD (2014) Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD. Clin J Am Soc Nephrol 9:1965–1973
Castellano E et al (2017) Nephrolithiasis in primary hyperparathyroidism: a comparison between silent and symptomatic patients. Endocr Pract 23:157–162
Isidro ML, Ruano B (2009) Biochemical effects of calcifediol supplementation in mild, asymptomatic, hyperparathyroidism with concomitant vitamin D deficiency. Endocrine 36:305–310
Corbetta S et al (2005) Risk factors associated to kidney stones in primary hyperparathyroidism. J Endocrinol Invest 28:122–128
Minisola S, Gianotti L, Bhadada S, Silverberg SJ (2018) Classical complications of primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 32:791–803
Shah VN, Shah CS, Bhadada SK, Sudhakar Rao D (2014) Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature. Clin Endocrinol (Oxf) 80:797–803
Acknowledgements
We thank the Laboratories of Grupo Fleury, São Paulo, Brazil, for performing the FGF23 and the 1,25(OH)2 vitamin D measurements. We thank the Coordenaçao para o Aperfeiçoamento de Pessoal de Nivel Superior (CAPES) for supporting the Post-graduation Program of Endocrinology at the Universidade Federal de São Paulo (UNIFESP).
Funding
This research was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Mantecorp-Farmasa Inc kindly provided the vitamin D3 (Addera D3) used in this study. SGP received doctor scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq, and the Comissao de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES) supports the Post-Graduation Program of UNIFESP.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Research involving human participants and/or animals
The study was approved by the Ethics and Research Committee of the Federal University of São Paulo (registration number 89044117.9.0000.5505).
Informed consent
All participants signed an Informed Consent Form.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pallone, S.G., Ohe, M.N., dos Santos, L.M. et al. Vitamin D supplementation in primary hyperparathyroidism: effects on 1,25(OH)2 vitamin D and FGF23 levels. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-024-02422-2
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s40618-024-02422-2