Is vitamin D supplementation justified?


Vitamin D supplementation is routinely recommended for patients with multiple sclerosis. However, numerous studies have reported that there is no benefit on clinical or MRI outcomes associated with high-dose vitamin D.

The latest study is VIDAMS (Vitamin D to Ameliorate MS), reported at this year’s ACTRIMS Forum (Cassard et al. ACTRIMS Forum 2023; P079). Subjects were randomized to glatiramer acetate and either low-dose (600 IU/day) or high-dose (5000 IU/day) vitamin D. There were no differences between the two groups with respect to the rate of change in brain volume (grey-matter and white-matter volumes) or T2 lesion volume. There was also no difference between groups in the rate of developing new T2 or Gd+ lesions.

Enthusiasm for vitamin D supplementation peaked in 2018 when three meta-analyses were published. A Cochrane review identified 12 studies (n=933). At one year, vitamin D supplementation had no effect on annualized relapse rate (ARR), EDSS score or Gd+ lesion counts (Jagannath et al. Cochrane Database Syst Rev 2018;9(9):CD008422). There was no consistent effect on immune outcomes (e.g. T cell proliferation, cytokine levels).

A second analysis found no impact of vitamin D on ARR or EDSS scores (Zheng et al. Mult Scler Relat Disord 2018;23:56-61). A third meta-analysis of 12 studies (n=950) found no association between vitamin D supplementation and any outcome measure (McLaughlin et al. J Neurol 2018;265:2893-2905). However, the authors noted a non-significant trend to improvements in EDSS score and Gd+ lesions.

Two high-dose studies followed. The phase II SOLAR study randomized patients receiving interferon-beta-1a 44 mcg to high-dose supplementation (14,000 IU/day) or placebo (Hupperts et al. Neurology 2019;93:e1906-e1916). There was no benefit of add-on vitamin D with respect to the primary outcome (NEDA-3), but exploratory outcomes (combined unique active lesions, T2 lesion volume) suggested some effect. Similarly, in the CHOLINE trial, high-dose vitamin D (100,000 IU every other week) as an add-on to beta-interferon-1a had no effect on ARR (Camu et al. Neurol Neuroimmunol Neuroinflamm 2019;6:e597). However, there were improvements on secondary outcomes (T1 lesion volume, EDSS progression).

A conclusion from these failed trials was that vitamin D supplements were needed to maintain 25(OH)D levels >100 nmol/L (Smolders et al. CNS Drugs 2019;33:1187-1199), an opinion later supported by an expert panel (Boltjes et al. Expert Rev Neurother 2021;21:715-725). Smolders and colleagues subsequently reported that vitamin D supplementation had no impact on neurofilament-light chain (NfL) levels in MS patients in a subgroup analysis from SOLAR (Smolders et al. Acta Neurol Scand 2020;141:77-80). The median NfL level at 48 weeks was 25.4 pg/mL with vitamin D versus 25.3 pg/mL with placebo.

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