Vitamin D supplementation in multiple sclerosis: an expert opinion based on the review of current evidence

Figures & data

Table 1. Randomized clinical trials of vitamin D supplementation in MS patients with clinical outcome measures

Study	Year	Patients^a	Follow up (weeks)	Choice of supplement and dose	Primary outcomes *	Secondary outcomes*
Burton et al. [33]	2010	49/47	52	D3 40,000 IU vs 4000 IU/day	Mean change in serum calcium	Change in ARR Proportion with relapses
Stein et al. [34]	2011	23/20	26	D2 6,000 IU vs 1,000 IU/day	Number of new Gd+^b T1 lesions Change total volume T2 lesions	Change in EDSS**, number of relapses
Mosayebi et al. [45]	2011	62/59	26	D3 300.000 IU/month vs placebo	Not defined	Change in EDSS Level of serum 25(OH)D, IFN-γ, IL-10, TGF-β^c
Soilu-Hänninen et al. [35]	2012	66/62	52	D3 20,000 IU/week vs placebo	T2 burden of disease on MRI	ARR, changes in EDSS, times 25-foot walk test, timed 10 foot tandem walk test
Shaygannejad et al. [36]	2012	50/50	52	calcitriol 50 mcg/day vs placebo	EDSS progression	change in ARR Relapse free patients
Kampman et al. [37]	2012	71/68	96	D3 20,000 IU/week vs placebo	Bone density	Relapse free patients Change in ARR, EDSS, MSFC components^d, grip strength, FSS^e
Golan et al. [38]	2013	45/30	52	D3 4,370 IU vs 800 IU/day	Serum levels vitamin D, calcium and PTH	EDSS, relapses, quality of life
Achiron et al. [39]	2015	158/143	26	alfacalcidol 1 mcg/day vs placebo	Fatigue impact scale score	quality of life, EDSS progression, relapses, relapse free patients
Sotirchos et al. [40]	2016	40/35	26	D3 10,400 IU vs 800 IU/day	Adverse effects	CD4 T cells, relapses
Hupperts et al. (SOLAR) [41]	2019	229/183	48	D3 14,000 IU/day vs placebo	NEDA-3^b, Proportion of relapse free patients, change total volume T2 lesions	ARR, time to first relapse, confirmed EDSS progression
Camu et al. (CHOLINE) [42]	2019	129/90	96	D3 100,000 IU every other week vs placebo	Change in ARR	Time to first relapse, EDSS progression, change in cognitive abilities, change in quality of life
Dörr et al. (EVIDIMS) [43]	2020	53/38	78	D3 20,400 IU vs 400 IU every other day	Number of new T2-w lesions	Relapse, EDSS, MSFC^d

^arandomized/completed

^bNEDA-3: no relapses, EDSS progression, or combined unique active (CUA) lesions (new gadolinium-enhancing or new/enlarging T2 lesions. Primary outcome was changed during the trial

^cIFN-γ: Interferon-gamma, IL-10: interleukin-10, TGF-β: transforming growth factor-beta

^dMSFC: multiple sclerosis functional composite, composed of timed 25-foot walk test, Nine hole peg test and Paced Auditory Serial Addition Test

^eFSS: Fatigue severity scale

* outcomes that reached statistically significant difference in bold

** After adjusting for entry EDSS, EDSS change was higher in the high dose group (p = 0,05)

Table 2. Randomized clinical trials of vitamin D supplementation in MS patients with radiological outcome measures

Study	Year	Patients^a	Follow up (weeks)	Dose	Primary outcome*	Secondary outcomes*
Stein et al. [34]	2011	23/20	26	D2 6,000 IU vs 1,000 IU/day	Number of new Gd+^b T1 lesions Change total volume T2 lesions
Mosayebi et al. [45]	2011	62/59	26	D3 300.000 IU/month vs placebo	Not defined	Number of Gd+ T1 lesions
Soilu-Hänninen et al. [35]	2012	66/62	52	D3 20,000 IU/week vs placebo	T2 burden of disease	Number of Gd+ T1 lesions T1 Gd+ lesion volume New/enlarging T2 lesions Number of patients with T1 Gd+ or new/enlarging T2 lesions
Hupperts et al. (SOLAR) [41]	2019	229/183	48	D3 14,000 IU/day vs placebo	NEDA-3 Proportion of relapse free patients, change total volume T2 lesions	CUA lesions^c New T1 hypointense lesions Percent brain volume change
Camu et al. (CHOLINE) [42]	2019	129/90	96	D3 100,000 IU every other week vs placebo	Change in ARR	T1 lesions rate ratio Total volume T1w(eighted) lesions new or enlarged T1- and T2-w lesions T2-w lesion load Number of T1-w Gd+ lesions total brain volume brain gray and white matter volume
Dörr et al. (EVIDIMS) [43]	2020	53/38	78	D3 20,400 IU vs 400 IU every other day	Number of new T2-w lesions	Change total volume T2 lesions Number of new Gd+ T1 lesions Thalamic volume Brain parenchymal fraction

* outcomes that reached statistical significant difference in bold

^arandomized/completed

^bGd+: gadolinium-enhancing

^cCombined Unique Active lesions, defined as new gadolinium enhancing or new/enlarging T2 lesions

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