Vitamin D in multiple sclerosis: Implications for assessment and treatment

Expert Review of Neurotherapeutics

Volumn 12, Issue 9, 2012, Pages 1101-1112

  Holmoy, Trygve ^a,b   Kampman, Margitta T ^c,d   Smolders, Joost ^e,f  

^a AKERSHUS UNIVERSITY HOSPITAL   (Norway)

^b UNIVERSITY OF OSLO   (Norway)

^c UNIVERSITY HOSPITAL OF NORTH NORWAY   (Norway)

^d UNIVERSITY OF TROMSØ   (Norway)

^e NETHERLANDS INSTITUTE FOR NEUROSCIENCE   (Netherlands)

^f MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

assessment; etiology; immunology; multiple sclerosis; pathogenesis; treatment; vitamin D

Indexed keywords

25 HYDROXYVITAMIN D; COLECALCIFEROL; FISH OIL; VITAMIN D; VITAMIN D RECEPTOR;

CLINICAL ASSESSMENT; DIETARY INTAKE; DISEASE ASSOCIATION; DISEASE COURSE; FRAGILITY FRACTURE; HUMAN; MULTIPLE SCLEROSIS; OSTEOPOROSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT OUTCOME; ULTRAVIOLET B RADIATION; VITAMIN BLOOD LEVEL; VITAMIN SUPPLEMENTATION;

ANIMALS; EVIDENCE-BASED MEDICINE; HUMANS; MULTIPLE SCLEROSIS; NUTRITION ASSESSMENT; OSTEOPOROSIS; RISK FACTORS; SEVERITY OF ILLNESS INDEX; VITAMIN D; VITAMIN D DEFICIENCY;

EID: 84867313632     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.12.99     Document Type: Review

References (137)

1. Ramagopalan SV, Sadovnick AD. Epidemiology of multiple sclerosis. Neurol. Clin. 29(2), 207-217 (2011).
2. Swank RL, Lerstad O, Stroøm A, Backer J. Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N. Engl. J. Med. 246(19), 722-728 (1952).
3. Goldberg D. Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence. Int. J. Environ. Stud. 6, 19-27 (1974).
4. Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med. Hypotheses 21(2), 193-200 (1986).
5. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221(4616), 1181-1183 (1983).
6. Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 224(4656), 1438-1440 (1984).
7. van der Mei IA, Simpson S Jr, Knippenberg S, Winzenberg T, Taylor BV. Role of vitamin D in multiple sclerosis: implications for disease management. Neuroden Dis Manage. 1, 523-536 (2012).
8. van der Mei IA, Simpson S Jr, Stankovich J, Taylor BV. Individual and joint action of environmental factors and risk of MS. Neurol. Clin. 29(2), 233-255 (2011).
9. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 9(6), 599-612 (2010).
10. Berlanga-Taylor AJ, Disanto G, Ebers GC, Ramagopalan SV. Vitamin D-gene interactions in multiple sclerosis. J. Neurol. Sci. 311(1-2), 32-36 (2011).
11. Munger KL, Ascherio A. Prevention and treatment of MS: studying the effects of vitamin D. Mult. Scler. 17(12), 1405-1411 (2011).
12. Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 76(9), 1294-1296 (2005).
13. Stein MS, Liu Y, Gray OM et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 77(17), 1611-1618 (2011).
14. Kimball SM, Ursell MR, O'Connor P, Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am. J. Clin. Nutr. 86(3), 645-651 (2007).
15. Smolders J, Hupperts R, Barkhof F et al. Efficacy of vitamin D(3) as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon ?-1a: a Phase II, multicenter, double-blind, randomized, placebocontrolled trial. J. Neurol. Sci. 311(1-2), 44-49 (2011).
16. Dörr J, Ohlraun S, Skarabis H, Paul F. Efficacy of vitamin D supplementation in multiple sclerosis (EVIDIMS trial): study protocol for a randomized controlled trial. Trials 13, 15 (2012).
17. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am. J. Clin. Nutr. 69(5), 842-856 (1999).
18. Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J. Clin. Endocrinol. Metab. 96(3), E447-E452 (2011).
19. White P, Cooke N. The multifunctional properties and characteristics of vitamin D-binding protein. Trends Endocrinol. Metab. 11(8), 320-327 (2000).
20. Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am. J. Clin. Nutr. 87(6), 1738-1742 (2008).
21. Hollis BW. Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it. Calcif. Tissue Int. 58(1), 4-5 (1996).
22. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem. Sci. 29(12), 664-673 (2004).
23. Lips P. Vitamin D physiology. Prog. Biophys. Mol. Biol. 92(1), 4-8 (2006).
24. Jongen MJ, van der Vijgh WJ, Lips P, Netelenbos JC. Measurement of vitamin D metabolites in anephric subjects. Nephron 36(4), 230-234 (1984).
25. Zehnder D, Bland R, Williams MC et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alphahydroxylase. J. Clin. Endocrinol. Metab. 86(2), 888-894 (2001).
26. Haussler MR, Whitfield GK, Haussler CA et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J. Bone Miner. Res. 13(3), 325-349 (1998).
27. Loøken-Amsrud KI, Holmoøy T, Bakke SJ et al. Vitamin D and disease activity in multiple sclerosis before and during interferon-b treatment. Neurology 79(3), 267-273 (2012).
28. Gozdzik A, Barta JL, Weir A et al. Serum 25-hydroxyvitamin D concentrations fluctuate seasonally in young adults of diverse ancestry living in Toronto. J. Nutr. 140(12), 2213-2220 (2010).
29. Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr. Scand. Suppl. 35(147), 132-147 (1960).
30. Kurtzke JF. On the fine structure of the distribution of multiple sclerosis. Acta Neurol. Scand. 43(3), 257-282 (1967).
31. Koch-Henriksen N, Sorensen PS. Why does the north-south gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere? J. Neurol. Sci. 311(1-2), 58-63 (2011).
32. Simpson S Jr, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J. Neurol. Neurosurg. Psychiatr. 82(10), 1132-1141 (2011).
33. Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 123(Pt 5), 968-974 (2000).
34. Kampman MT, Wilsgaard T, Mellgren SI. Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J. Neurol. 254(4), 471-477 (2007).
35. van der Mei IA, Ponsonby AL, Dwyer T et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ 327(7410), 316 (2003).
36. Ramagopalan SV, Handel AE, Giovannoni G, Rutherford Siegel S, Ebers GC, Chaplin G. Relationship of UV exposure to prevalence of multiple sclerosis in England. Neurology 76(16), 1410-1414 (2011).
37. Orton SM, Wald L, Confavreux C et al. Association of UV radiation with multiple sclerosis prevalence and sex ratio in France. Neurology 76(5), 425-431 (2011).
38. Beretich BD, Beretich TM. Explaining multiple sclerosis prevalence by ultraviolet exposure: a geospatial analysis. Mult. Scler. 15(8), 891-898 (2009).
39. Becklund BR, Severson KS, Vang SV, DeLuca HF. UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production. Proc. Natl Acad. Sci. USA 107(14), 6418-6423 (2010).
40. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23), 2832-2838 (2006).
41. Munger KL, Zhang SM, O'Reilly E et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 62(1), 60-65 (2004).
42. Moen SM, Celius EG, Sandvik L, Nordsletten L, Eriksen EF, Holmoøy T. Low bone mass in newly diagnosed multiple sclerosis and clinically isolated syndrome. Neurology 77(2), 151-157 (2011).
43. Lucas RM, Ponsonby AL, Dear K et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology 76(6), 540-548 (2011).
44. Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC; Canadian Collaborative Study Group. Timing of birth and risk of multiple sclerosis: population based study. BMJ 330(7483), 120 (2005).
45. Staples J, Ponsonby AL, Lim L. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. BMJ 340, c1640 (2010).
46. Mirzaei F, Michels KB, Munger K et al. Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann. Neurol. 70(1), 30-40 (2011).
47. Huang J, Xie ZF. Polymorphisms in the vitamin D receptor gene and multiple sclerosis risk: a meta-analysis of case-control studies. J. Neurol. Sci. 313(1-2), 79-85 (2012).
48. Sundqvist E, Bäärnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I. Confirmation of association between multiple sclerosis and CYP27B1. Eur. J. Hum. Genet. 18(12), 1349-1352 (2010).
49. Sawcer S, Hellenthal G, Pirinen M et al.; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case-Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359), 214-219 (2011).
50. Torkildsen Oø, Knappskog PM, Nyland HI, Myhr KM. Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis. Arch. Neurol. 65(6), 809-811 (2008).
51. Ramagopalan SV, Dyment DA, Cader MZ et al. Rare variant the CYP27B1 gene are associated with multiple sclerosis. Ann. Neurol. 70(6), 881-886 (2008).
52. Handel AE, Ramagopalan SV. Vitamin D and multiple sclerosis: an interaction between genes and environment. Mult. Scler. 18(1), 2-4 (2012).
53. Ramagopalan SV, Maugeri NJ, Handunnetthi L et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 5(2), e1000369 (2009).
54. Agliardi C, Guerini FR, Saresella M et al. Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. Brain Behav. Immun. 25(7), 1460-1467 (2011).
55. Cox MB, Ban M, Bowden NA, Baker A, Scott RJ, Lechner-Scott J. Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis. Mult. Scler. 18(1), 16-22 (2012).
56. Bäärnhielm M, Hedström AK, Kockum I et al. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15. Eur. J. Neurol. 19(7), 955-962 (2012).
57. Hayes CE, Cantorna MT, DeLuca HF. Vitamin D and multiple sclerosis. Proc. Soc. Exp. Biol. Med. 216(1), 21-27 (1997).
58. Fernandes de Abreu DA, Eyles D, Féron F. Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 34(Suppl. 1), S265-S277 (2009).
59. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J. Neuroimmunol. 194(1-2), 7-17 (2008).
60. Smolders J, Damoiseaux J. Vitamin D as a T-cell modulator in multiple sclerosis. Vitam. Horm. 86, 401-428 (2011).
61. Gottfried E, Rehli M, Hahn J, Holler E, Andreesen R, Kreutz M. Monocyte-derived cells express CYP27A1 and convert vitamin D3 into its active metabolite. Biochem. Biophys. Res. Commun. 349(1), 209-213 (2006).
62. Sigmundsdottir H, Pan J, Debes GF et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8(3), 285-293 (2007).
63. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179(3), 1634-1647 (2007).
64. Correale J, Ysrraelit MC, Gaitán MI. Immunomodulatory effects of vitamin D in multiple sclerosis. Brain 132(Pt 5), 1146-1160 (2009).
65. Lysandropoulos AP, Jaquiéry E, Jilek S, Pantaleo G, Schluep M, Du Pasquier RA. Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects. J. Neuroimmunol. 233(1-2), 240-244 (2011).
66. Heine G, Niesner U, Chang HD et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur. J. Immunol. 38(8), 2210-2218 (2008).
67. van Halteren AG, van Etten E, de Jong EC, Bouillon R, Roep BO, Mathieu C. Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). Diabetes 51(7), 2119-2125 (2002).
68. Cantorna MT, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc. Natl Acad. Sci. USA 93(15), 7861-7864 (1996).
69. Spach KM, Hayes CE. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J. Immunol. 175(6), 4119-4126 (2005).
70. Mayne CG, Spanier JA, Relland LM, Williams CB, Hayes CE. 1,25-dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis. Eur. J. Immunol. 41(3), 822-832 (2011).
71. Peelen E, Damoiseaux J, Smolders J et al. Th17 expansion in MS patients is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. J. Neuroimmunol. 240-241, 97-103 (2011).
72. Smolders J, Menheere P, Thewissen M et al. Regulatory T cell function correlates with serum 25-hydroxyvitamin D, but not with 1,25-dihydroxyvitamin D, parathyroid hormone and calcium levels in patients with relapsing remitting multiple sclerosis. J. Steroid Biochem. Mol. Biol. 121(1-2), 243-246 (2010).
73. Smolders J, Thewissen M, Peelen E et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS ONE 4(8), e6635 (2009).
74. Royal W 3rd, Mia Y, Li H, Naunton K. Peripheral blood regulatory T cell measurements correlate with serum vitamin D levels in patients with multiple sclerosis. J. Neuroimmunol. 213(1-2), 135-141 (2009).
75. Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT. Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J. Neuroimmunol. 134(1-2), 128-132 (2003).
76. Burton JM, Kimball S, Vieth R et al. A Phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 74(23), 1852-1859 (2010).
77. Kimball S, Vieth R, Dosch HM et al. Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. J. Clin. Endocrinol. Metab. 96(9), 2826-2834 (2011).
78. Knippenberg S, Peelen E, Smolders J et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naïve/memory Breg ratio during a relapse but not in remission. J. Neuroimmunol. 239(1-2), 80-86 (2011).
79. Knippenberg S, Smolders J, Thewissen M et al. Effect of vitamin D(3) supplementation on peripheral B cell differentiation and isotype switching in patients with multiple sclerosis. Mult. Scler. 17(12), 1418-1423 (2011).
80. Goverman J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9(6), 393-407 (2009).
81. Lossius A, Vartdal F, Holmoy T. Vitamin D sensitive EBNA-1 specific T cells in the cerebrospinal fluid of patients with multiple sclerosis. J. Neuroimmunol. 240-241, 87-96 (2011).
82. Holmoøy T, Lossius A, Gundersen TE et al. Intrathecal levels of vitamin D and IgG in multiple sclerosis. Acta Neurol. Scand. 125(6), e28-e31 (2012).
83. Smolders J, Moen SM, Damoiseaux J, Huitinga I, Holmoy T. Vitamin D in the healthy and inflamed central nervous system: access and function. J. Neurol. Sci. 311(1-2), 37-43 (2011).
84. Wergeland S, Torkildsen Oø, Myhr KM, Aksnes L, Moørk SJ, Boø L. Dietary vitamin D3 supplements reduce demyelination in the cuprizone model. PLoS ONE 6(10), e26262 (2011).
85. Lefebvre DC, Montero-Menei CN, Bernard R, Couez D. Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line. J. Neurosci. Res. 71(4), 575-582 (2003).
86. Furman I, Baudet C, Brachet P. Differential expression of M-CSF, LIF, and TNF-alpha genes in normal and malignant rat glial cells: regulation by lipopolysaccharide and vitamin D. J. Neurosci. Res. 46(3), 360-366 (1996).
87. Naveilhan P, Neveu I, Wion D, Brachet P. 1,25-dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport 7(13), 2171-2175 (1996).
88. Brown J, Bianco JI, McGrath JJ, Eyles DW. 1,25-dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci. Lett. 343(2), 139-143 (2003).
89. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1?-hydroxylase in human brain. J. Chem. Neuroanat. 29(1), 21-30 (2005).
90. Soilu-Hänninen M, Airas L, Mononen I, Heikkilä A, Viljanen M, Hänninen A. 25-hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult. Scler. 11(3), 266-271 (2005).
91. Holmoøy T, Moen SM, Gundersen TA et al. 25-hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis. Mult. Scler. 15(11), 1280-1285 (2009).
92. Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna JP, Lilius EM, Mononen I. A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 79(2), 152-157 (2008).
93. Simpson S Jr, Taylor B, Blizzard L et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann. Neurol. 68(2), 193-203 (2010).
94. Mowry EM, Krupp LB, Milazzo M et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann. Neurol. 67(5), 618-624 (2010).
95. van der Mei IA, Ponsonby AL, Dwyer T et al. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J. Neurol. 254(5), 581-590 (2007).
96. Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult. Scler. 14(9), 1220-1224 (2008).
97. Weinstock-Guttman B, Zivadinov R, Qu J et al. Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients. J. Neurol. Neurosurg. Psychiatr. 82(2), 189-195 (2011).
98. McDowell TY, Amr S, Culpepper WJ et al. Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis. Neuroepidemiology 37(1), 52-57 (2011).
99. Woolmore JA, Stone M, Pye EM et al. Studies of associations between disability in multiple sclerosis, skin type, gender and ultraviolet radiation. Mult. Scler. 13(3), 369-375 (2007).
100. Auer DP, Schumann EM, Kümpfel T, Gössl C, Trenkwalder C. Seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann. Neurol. 47(2), 276-277 (2000).
101. Embry AF, Snowdon LR, Vieth R. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann. Neurol. 48(2), 271-272 (2000).
102. Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst. Rev. 12, CD008422 (2010).
103. Nordvik I, Myhr KM, Nyland H, Bjerve KS. Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol. Scand. 102(3), 143-149 (2000).
104. Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol. Invest. 40(6), 627-639 (2011).
105. Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects of adjunct low-dose vitamin D on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult. Scler. Int. 2012, 452541 (2012).
106. 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 b-1b in patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 83(5), 565-571 (2012).
107. Kampman MT, Steffensen LH, Mellgren SI, Joørgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult. Scler. 18(8), 1144-1151 (2012).
108. Kampman MT, Eriksen EF, Holmoøy T. Multiple sclerosis, a cause of secondary osteoporosis? What is the evidence and what are the clinical implications? Acta Neurol. Scand. Suppl. 191, 44-49 (2011).
109. Nieves J, Cosman F, Herbert J, Shen V, Lindsay R. High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology 44(9), 1687-1692 (1994).
110. Gibson JC, Summers GD. Bone health in multiple sclerosis. Osteoporos. Int. 22(12), 2935-2949 (2011).
111. Hearn AP, Silber E. Osteoporosis in multiple sclerosis. Mult. Scler. 16(9), 1031-1043 (2010).
112. Steffensen LH, Mellgren SI, Kampman MT. Predictors and prevalence of low bone mineral density in fully ambulatory persons with multiple sclerosis. J. Neurol. 257(3), 410-418 (2010).
113. Terzi T, Terzi M, Tander B, Cantürk F, Onar M. Changes in bone mineral density and bone metabolism markers in premenopausal women with multiple sclerosis and the relationship to clinical variables. J. Clin. Neurosci. 17(10), 1260-1264 (2010).
114. Bazelier MT, van Staa T, Uitdehaag BM et al. The risk of fracture in patients with multiple sclerosis: the UK general practice research database. J. Bone Miner. Res. 26(9), 2271-2279 (2011).
115. Bazelier MT, de Vries F, Bentzen J et al. Incidence of fractures in patients with multiple sclerosis: the Danish National Health Registers. Mult. Scler. 18(5), 622-627 (2011).
116. Bazelier MT, van Staa TP, Uitdehaag BM et al. Risk of fractures in patients with multiple sclerosis: a population-based cohort study. Neurology 78(24), 1967-1973 (2012).
117. Moen SM, Celius EG, Nordsletten L, Holmoøy T. Fractures and falls in patients with newly diagnosed clinically isolated syndrome and multiple sclerosis. Acta Neurol. Scand. Suppl. 191, 79-82 (2011).
118. Poole KE, Compston JE. Osteoporosis and its management. BMJ 333(7581), 1251-1256 (2006).
119. Writing Group for the ISCD Position Development Conference. Diagnosis of osteoporosis in men, premenopausal women, and children. J. Clin. Densitom. 7(1), 17-26 (2004).
120. Kanis JA, Burlet N, Cooper C et al. European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos. Int. 19(4), 399-428 (2008).
121. Shaygannejad V, Golabchi K, Haghighi S, Dehghan H, Moshayedi A. A comparative study of 25 (OH) vitamin D serum levels in patients with multiple sclerosis and control group in Isfahan, Iran. Int. J. Prev. Med. 1(3), 195-201 (2010).
122. Ozgocmen S, Bulut S, Ilhan N, Gulkesen A, Ardicoglu O, Ozkan Y. Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacity. J. Bone Miner. Metab. 23(4), 309-313 (2005).
123. Gelfand JM, Cree BA, McElroy J et al. Vitamin D in African Americans with multiple sclerosis. Neurology 76(21), 1824-1830 (2011).
124. de Paula FJ, Rosen CJ. Vitamin D safety and requirements. Arch. Biochem. Biophys. 523(1), 64-72 (2012).
125. Vieth R. Why the minimum desirable serum 25-hydroxyvitamin D level should be 75 nmol/l (30 ng/ml). Best Pract. Res. Clin. Endocrinol. Metab. 25(4), 681-691 (2011).
126. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos. Int. 16(7), 713-716 (2005).
127. Priemel M, von Domarus C, Klatte TO et al. 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(2), 305-312 (2010).
128. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am. J. Med. 116(9), 634-639 (2004).
129. Institute of Medicine of The ational Academies. Daily reference values for cacum and vitamin D. Concensus report. The National Academic Press, Washington DC, USA (2011).
130. Holmoy T, Lossius A, Gundersen T, et al. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res. 29(9), 3713-3720 (2009).
131. Hollis BW. Measuring 25-hydroxyvitamin D in a clinical environment: challenges and needs. Am. J. Clin. Nutr. 88(2), 507S-510S (2008).
132. Ish-Shalom S, Segal E, Salganik T, Raz B, Bromberg IL, Vieth R. Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients. J. Clin. Endocrinol. Metab. 93(9), 3430-3435 (2008).
133. Vieth R, Ladak Y, Walfish PG. Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. J. Clin. Endocrinol. Metab. 88(1), 185-191 (2003).
134. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am. J. Clin. Nutr. 77(1), 204-210 (2003).
135. Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr. J. 3, 8 (2004).
136. Steffensen LH, Joørgensen L, Straume B, Mellgren SI, Kampman MT. Can vitamin D supplementation prevent bone loss in persons with MS? A placebocontrolled trial. J. Neurol. 258(9), 1624-1631 (2011).
137. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am. J. Clin. Nutr. 85(3), 860-868 (2007).