Vitamin D is not only an essential nutrient for bone homeostasis but has also been implicated in many other disorders including cardiovascular disease (CVD) and autoimmune diseases. Here we review the problem of vitamin D deficiency and guidelines to help achieve adequate levels in both the general population and in multiple sclerosis (MS) patients and its role in MS and impact on treatment. Although there is a lack of consensus on vitamin D deficiency and insufficiency, they have been defined as a serum level of 25(OH)D <50 nmol/L or 52.5–72.5 nmol/L, respectively. Deficiency is common in all age groups. Vitamin D is probably involved in the prevention of a number of disease states and 25(OH)D is thought to regulate at least 2,000 genes. Vitamin D toxicity is very rare, with none seen at doses up to 20,000 IU/day. However, the majority of primary care clinicians are not aware of the recommended dose for vitamin D supplementation and optimum serum level in terms of patients with MS. Several organisations have concluded that vitamin D screening cannot be recommended in the general population. Guidelines have been published on treatment and prevention of vitamin D deficiency, particularly for at-risk groups and during pregnancy. There is much evidence for the protective effects of vitamin D in MS. A higher level of sun exposure and intake of vitamin D as well as of serum 25 (OH)D, are associated with a lower risk of MS. It also has a beneficial effect on the clinical course of MS, such as lowering the risk of relapses. Growing evidence indicates that the effects of interferon-beta are additively enhanced by 25(OH)D in MS and this may be due to its modulating vitamin D metabolism.
Michael F Holick serves as a consultant for Bayer HealthCare Pharmaceuticals, Inc. Stuart Cook has received prior grant support from Bayer HealthCare Pharmaceuticals, Inc. and Biogen and has received prior honoraria from Bayer, Biogen and EMD Serono. Gustavo Suarez is an employee of Bayer HealthCare Pharmaceuticals. Mark Rametta is an employee of Bayer HealthCare Pharmaceuticals
Medical writing support, including preparation of the drafts under the guidance of the authors, was provided by Ray Ashton, Richmond Medical Communications. and funded by Bayer HealthCare Pharmaceuticals, Inc. All named authors meet the criteria of the International Committee of Medical Journal Editors for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
October 20, 2015 Accepted:
November 30, 2015
Michael F Holick, Boston University School of Medicine, 85 E. Newton St Fuller Building, Boston, US. E: email@example.com.
The publication of this article was supported by Bayer HealthCare Pharmaceuticals, Inc. The views and opinions expressed in the article are those of the authors
and not necessarily those of Bayer HealthCare Pharmaceuticals, Inc.
Vitamin D is an essential nutrient for bone homeostasis that has also been implicated in numerous other disorders, such as cardiovascular disease (CVD) and autoimmune diseases. Originally vitamin D deficiency was associated only with rickets and it was considered that the fortification of food resolved this disorder. However, it is now realised that rickets represents just one manifestation of vitamin D deficiency.1,2 The recommended Dietary Reference Intakes are solely based on the skeletal effects of vitamin D, with the recommended dietary allowance (RDA) ranging from 400 to 800 IU/day depending on age as recommended by the Institute of Medicine to maintain blood levels of 25-hydroxyvitamin D (25[OH]D) of at least 50 nmol/L (20 ng/mL). However to achieve non-skeletal benefits of vitamin D, a multitude of studies have suggested that maintenance of a level of 25[OH]D >30 ng/mL may be required. The majority of primary care clinicians are not aware of the recommended dose for vitamin D supplementation and the optimum level in terms of patients with multiple sclerosis (MS). This article reviews the role of vitamin D in MS and its impact on MS treatment. In addition, the extent and consequences of vitamin D deficiency and guidelines to help the general population and those with MS achieve sufficient levels will be considered.
Vitamin D Deficiency and its Consequences There is considerable debate on the blood level of 25[OH]D that constitutes deficiency in both the general population and with respect to certain disorders, such as MS. Conflicting recommendations have been published by different organisations. Experts disagree on the optimal 25(OH)D concentration and thus many definitions of deficiency and insufficiency have been proposed. In the general population, a serum level of at least 50 nmol/L 25(OH)D is generally considered to be required for maximum bone health and thus vitamin D deficiency has been defined as a 25(OH)D <50 nmol/L.3,4 The Endocrine Society also recognised that vitamin D had non-skeletal health benefits, and defined vitamin D insufficiency as a 25(OH)D level of 51–74 nmol/L.
1. Holick MF, Vitamin D deficiency, New Engl J Med, 2007;357:266–81.
2. Canadian Agency for Drugs & Technologies in Health. Vitamin D testing in the general population: A review of the clinical and cost-effectiveness and guidelines. 16 January 2015
3. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, Editors. Dietary reference intakes for calcium and vitamin D. Committee to review dietary reference intakes for vitamin D and calcium, Institute of Medicine . The National Academies Press, Washington, DC. ISBN 978-0-309-16394-1. 2011, released November 30 2010
4. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al., Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab, 2011;96:1911–30.
5. Hossein-Nezhad A, Holick MF, Vitamin D for Health: A global perspective, J Mayo Clin Proc, 2013;88:720–55.
6. Nowson CA, McGrath JJ, Ebeling PR, et al., Vitamin D and health in adults in Australia and New Zealand: a position statement, Med J Aust, 2012;196:686–7.
7. Chung M, Lee J, Terasawa T, et al., Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force, Ann Intern Med, 2011;155:827–38.
8. Saccone D, Asani F, Bornman L, Regulation of the vitamin D receptor gene by environment, genetics and epigenetics, Gene, 2015;561:171–80.
9. Fetahu IS, Hobaus J, Kallay E, Vitamin D and the epigenome, Front Physiol, 2014;5:1–12.
10. Hossein-Nezhad, Spira A, Holick MF, Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: A randomized double-blind clinical trial, PloS One, 2013;8:e58725.
11. Ekwaru JP, Zwicker, JD, Holick MF, Giovannucci E, The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers, PLoS One, 2014;9:e111265.
12. Holick MF, Vitamin D Is not as toxic as was once thought: A historical and an up-to-date perspective, Mayo Clin Proc, 2015;90:561–4.
13. Dudenkov DV, Yawn BP, Oberhelman SS, Fischer PR, et al., Changing incidence of serum 25-hydroxyvitamin D values above 50 ng/mL. A 10-year population-based study, Mayo Clin Proc, 2015;90:577–86.
14. Melamed ML, Michos ED, Post W, Astor B, 25-hydroxyl vitamin D levels and the risk of mortality in the general population, Arch Intern Med, 2008;168:1629–37.
15. Garland CF, Kim JJ, Mohr SB, et al., Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D, Am J Public Health, 2014;104:e43–50.
16. Kroll MH, Bi C, Garber CC, Kaufman HW, et al., Temporal relationship between vitamin D status and parathyroid hormone in the United States, PLoS ONE, 2015;10:e0118108.
17. LeFevre ML, on behalf of the U.S. Preventive Services Task Force, Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force Recommendation Statement, Ann Intern Med, 2015;162:133–40.
18. Manson JE, Bassuk SS, Vitamin D research and clinical practice. At a crossroad, JAMA, 2015;313:1311–2.
19. Moore CE, Murphy MM, Holick MF, Vitamin D intakes by children and adults in the United States differ among ethnic groups, J Nutr, 2005;135:2478–85.
20. Pietras SM, Obayan BK, Cai MH, Holick MF, Vitamin D2 treatment for vitamin D deficiency and insufficiency for up to 6 years, Arch Intern Med, 2009;169:1806–8.
21. Shirazi HA, Rasouli J, Ciric B, et al., 1,25-dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol, 2015;98:240–5.
22. Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D, PLoS Genet, 2009;5:c1000369.
23. Wacker M, Holick MF, Sunlight and vitamin D: A global perspective for health, Dermatoendocinol, 2013;5:51–108.
24. Correale J, Ysrraelit MC, Gaitán MI, Vitamin D-mediated immune regulation in multiple sclerosis, J Neurol Sci, 2011;311:23–31.
25. Lucas RM, Ponsonby AL, Dear K, Valery PC, Sun exposure and vitamin D are independent risk factors for CNS demyelination, Neurol, 2011;76:540–8.
26. Munger KL, Zhang SM, O’Reilly E, et al., Vitamin D intake and incidence of multiple sclerosis, Neurol, 2004;62:60–5.
27. Simpson S, Taylor B, Blizzard L, Ponsonby AL, et al., Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis, Ann Neurol, 2010;68:193–203.
28. Runia TF, Hop WC, de Rijke YB, et al., Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis, Neurol, 2012;76:261–6.
29. Mowry EM Waubant E, McCulloch CE, Okuda DT, et al., Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis, Ann Neurol, 2012;72:234–40.
30. Ascherio A, Munger KL, White R, Köchert K, et al., Vitamin D as an early predictor of multiple sclerosis activity and progression, JAMA Neurol, 2014;71:306–14.
31. Ascherio A, Munger KL, White R, et al., Presented at: the Annual Meeting of the American Academy of Neurology, Philadelpia, PA, USA; 26 April–3 May 2014.
32. Stewart N, Simpson S Jr, van der Mei I, et al., Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS, Neurol, 2012;79:254–60.
33. Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis, JNNP, 2012;83:565–71.
34. Loken-Amsrud KI, Holmøy T, Bakke SJ, et al., Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment, Neurol, 2012;79:267–73.
35. Rotstein D, Healy B, Malike MT, et al., Differential effects of vitamin D in GA- versus IFN-treated MS patients, Neurology, 2014;82(Suppl. S24.005):Abstract S24.005.
36. Kuhle J, Disanto G, Dobson R, et al., Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study, J Mult Scler, 2015;21:1013–24.
37. Munger KL, Köchert K, Simon KC, Kappos L, et al. Molecular mechanism underlying the impact of vitamin D on disease activity of MS, Ann Clin Transl Neurol, 2014;72:605–17.
38. Waschbisch A, Sanderson N, Krumbholz M, Vlad G, et al., Interferon beta and vitamin D synergize to induce immunoregulatory receptors on peripheral blood monocytes of multiple sclerosis patients, PLoS ONE, 2014;9:e115488.