Abstract
The multiple effects of vitamin D on skeletal and extra-skeletal tissues increased the attention of scientists and public to the possible relationship between hypovitaminosis D and a variety of acute and chronic diseases. However, several points are still largely debated. In particular, the definition of optimal vitamin D status [as assessed by the circulating levels of 25-hydroxyvitamin D (25(OH)D)] remains controversial, and experts still disagree about several related outcomes: how to estimate the prevalence of vitamin D deficiency, when to start treatment, how to reach optimal 25(OH)D levels, which type of vitamin is preferable for supplementation, which dosing strategy is the better option. In this context, a matter of major debate is represented by the measurement of circulating level of 25(OH)D, whose determination is affected by the lack of standardization and by several technical problems. It has been recently hypothesized that free and bio-available, rather than total 25(OH)D, mostly determine its biological action. However, further evaluation of directly measured free 25(OH)D levels is needed, in order to establish its role in research and clinical practice. Finally, it is not yet defined if a threshold of optimal vitamin D status for reducing the risk of extra-skeletal diseases exists. Actually, it is plausible that the desired 25(OH)D level may vary widely, depending on the health outcome in question. However, this topic is uncertain, partly due to the lack of randomized controlled trials assessing the effect of vitamin D supplementation on extra-skeletal end-points.
Similar content being viewed by others
References
Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber G, Maixent JM (2013) Vitamin D metabolism, functions and needs: from science to health claims. Eur J Nutr 52:429–441
Sattar N, Welsh P, Panarelli M, Forouhi NG (2012) Increasing requests for vitamin D measurement: costly, confusing, and without credibility. Lancet 379:95–96
Bolland MJ, Grey A, Gamble GD, Reid IR (2014) The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. doi: 10.1016/S2213-8587(13)70212-2
Bouillon R, Van Schoor NM, Gielen E, Boonen S, Mathieu C, Vanderschueren D, Lips P (2013) Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. J Clin Endocrinol Metab 98:E1283–E1304
Heaney RP (2013) What is Vitamin D insufficiency? and does it matter? Calcif Tissue Int 92:177–183
Romagnoli E, Pepe J, Piemonte S, Cipriani C, Minisola S (2013) Management of endocrine disease: value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation. Eur J Endocrinol 169:R59–R69
Binkley N, Wiebe D (2013) Clinical controversies in vitamin D: 25(OH)D measurement, target concentration, and supplementation. J Clin Densitom 16:402–408
Farrell CJL, Martin S, McWhinney B, Straub I, Williams P, Herrmann M (2012) State-of-the-art vitamin D assays: a comparison of automated immunoassays with liquid chromatography-tandem mass spectrometry methods. Clin Chem 58:531–542
Phinney KW, Bedner M, Tai SS et al (2012) Development and certification of a standard reference material for vitamin D metabolites in human serum. Anal Chem 17:956–962
Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M (2013) Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2013.09.012
Didriksen A, Grimnes G, Hutchinson MS, Kjærgaard M, Svartberg J, Joakimsen RM, Jorde R (2013) The serum 25-hydroxyvitamin D response to vitamin D supplementation is related to genetic factors, BMI, and baseline levels. Eur J Endocrinol 169:559–567
Johnsen MS, Grimnes G, Figenschau Y, Torjesen PA, Almås B, Jorde R (2014) Serum free and bio-available 25-hydroxyvitamin D correlate better with bone density than serum total 25-hydroxyvitamin D. Scand J Clin Lab Invest (Epub ahead of print)
Glendenning P, Chew GT, Inderjeeth CA, Taranto M, Fraser WD (2013) Calculated free and bioavailable vitamin D metabolite concentrations in vitamin D-deficient hip fracture patients after supplementation with cholecalciferol and ergocalciferol. Bone 56:271–275
Schwartz JB, Lai J, Lizaola B, Kane L, Markova S, Weyland P, Terrault NA, Stotland N, Bikle D (2014) A comparison of direct and calculated free 25(OH)D levels in clinical populations. J Clin Endocrinol Metab (Epub ahead of print)
Adami S, Romagnoli E, Carnevale V, Scillitani A, Giusti A, Rossini M, Gatti D, Nuti R, Minisola S (2011) Guidelines on prevention and treatment of vitamin D deficiency. Reumatismo 63:129–147
American Geriatrics Society workgroup on vitamin D supplementation for older adults (2014) Recommendations abstracted from the American Geriatrics Society consensus statement on vitamin D for prevention of falls and their consequences. J Am Geriatr Soc 62:147–152
Rizzoli R, Boonen S, Brandi ML, Bruyère O, Cooper C, Kanis JA, Kaufman JM, Ringe JD, Weryha G, Reginster JY (2013) Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin 29:305–313
Ross AC, Taylor CL, Yaktine AL, Del Valle HB (2011) Institute of Medicine: dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington, DC
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 96:1911–1930
Need AG, O’Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE (2008) Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Min Res 23:1859–1863
Heaney RP, Dowell MS, Hale CA, Bendich A (2003) Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 22:142–146
Carnevale V, Nieddu L, Romagnoli E et al (2010) Regulation of PTH secretion by 25-hydroxyvitamin D and ionized calcium depends on vitamin D status: a study in a large cohort of healthy subjects. Bone 47:626–630
Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716
Bischoff-Ferrari HA, Willett WC, Orav EJ et al (2012) A pooled analysis of vitamin D dose requirements for fracture prevention. New Engl J Med 367:40–49
Moyer VA on behalf of the US Preventive Services Task Force (2013) Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 158:691–696
Reid IR, Bolland MJ, Grey A (2014) Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 383:146–155
Murad MH, Elamin KB, Abu Elnour NO et al (2011) The effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 96:2997–3006
Priemel M, von Domarus C, Klatte TO et al (2010) Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 25:305–312
Ahn J, Yu K, Stolzenberg-Solomon R et al (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19:2739–2745
Drincic A, Fuller E, Heaney RP, Armas LA (2013) 25-hydroxyvitamin D response to graded vitamin D3 supplementation among obese adults. J Clin Endocrinol Metab 98:4845–4851
Zittermann A, Ernst JB, Gummert JF, Börgermann J (2014) Vitamin D supplementation, body weight and human serum 25-hydroxyvitamin D response: a systematic review. Eur J Nutr 53:367–374
Shab-Bidar S, Bours SP, Geusens PP, van der Velde RY, Janssen MJ, van den Bergh JP (2013) 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 169:597–604
Heaney RP (2012) Vitamin D—baseline status and effective dose. New Engl J Med 367:77–78
Autier P, Gandini S, Mullie P (2012) A systematic review: influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol Metab 97:2606–2613
Romagnoli E, Mascia ML, Cipriani C, Fassino V, Mazzei F, D’Erasmo E, Carnevale V, Scillitani A, Minisola S (2008) Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (D3) in the elderly. J Clin Endocrinol Metab 93:3015–3020
Cipriani C, Romagnoli E, Scillitani A et al (2010) Effect of a single oral dose of 600,000 IU of cholecalciferol on serum calciotropic hormones in young subjects with vitamin D deficiency: a prospective intervention study. J Clin Endocrinol Metab 95:4771–4777
Sanders KM, Nicholson GC, Ebeling PR (2013) Is high dose vitamin D harmful? Calcif Tissue Int 92:191–206
Minisola S, Colangelo L, Cilli M, Cipriani C, Pepe J, Romagnoli E (2013) Intermittent high doses of vitamin D: a need for further studies? Calcif Tissue Int 92:487–488
Sinha A, Cheetham TD, Pearce SHS (2013) Prevention and treatment of vitamin D deficiency. Calcif Tissue Int 92:207–215
Heaney RP (2013) Health is better at serum 25(OH)D above 30 ng/mL. J Steroid Biochem Mol Biol 136:224–228
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM (2012) Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab 97:1153–1158
Gallagher JC, Sai A, Templin T 2nd, Smith L (2012) Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med 156:425–437
Brouwer-Brolsma EM, Bischoff-Ferrari HA, Bouillon R et al (2013) Vitamin D: do we get enough? a discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe. Osteoporos Int 24:1567–1577
Autier P, Boniol M, Pizot C, Mullie P (2014) Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2:76–89
Tripkovic L, Lambert H, Hart K et al (2012) Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr 95:1357–1364
Russo S, Carlucci L, Cipriani C et al (2011) Metabolic changes following 500 μg monthly administration of calcidiol: a study in normal females. Calcif Tissue Int 89:252–257
Jetter A, Egli A, Dawson-Hughes B, Staehelin HB, Stoecklin E, Goessl R, Henschkowski J, Bischoff-Ferrari HA (2014) Pharmacokinetics of oral vitamin D(3) and calcifediol. Bone 59:14–19
Zittermann A, Prokop S, Gummert JF, Borgermann J (2013) Safety issues of vitamin D supplementation. Anticancer Agents Med Chem 13:4–10
Rathi MS, Gonzalez S, Wright D, Ellis NR, Peacey SR (2014) Management of hypovitaminosis D in patients with primary hyperparathyroidism. J Endocrinol Invest (Epub ahead of print)
Battista C, Viti R, Minisola S, Chiodini I, Frusciante V, Scillitani A, Carnevale V (2013) Over-supplementation of vitamin D in two patients with primary hyperparathyroidism. Hormones (Athens) 12:598–601
Vieth R (2007) Vitamin D toxicity, policy, and science. J Bone Min Res 22(S2):V64–V68
Conflict of interest
All the authors declare that they do not have conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Romagnoli, E., Carnevale, V., Biondi, P. et al. Vitamin D supplementation: when and how?. J Endocrinol Invest 37, 603–607 (2014). https://doi.org/10.1007/s40618-014-0071-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-014-0071-z