Vitamin D Supplementation in Multiple Sclerosis: Systematic Review Finds No Consistent Relapse Benefit

Vitamin D supplementation did not consistently reduce relapse rates among adults with multiple sclerosis (MS), although several studies reported reductions in inflammatory lesion activity on MRI, according to a systematic review published in Brain and Behavior.¹

Low serum vitamin D levels have been linked to a higher risk of developing MS and to a more severe disease course, and mechanistic research suggests vitamin D may suppress inflammatory pathways involved in the disease. However, clinical trial results have been mixed, and the authors noted that no prior systematic review had focused specifically on relapse rate and MRI activity.

Vitamin D and MS Systematic Review Design

The researchers searched PubMed, Cochrane, EBSCO, and Web of Science for English-language studies published from 2005 onward. Of 304 records identified, 11 primary studies were included: 8 randomized controlled trials (RCTs), 1 post hoc analysis of 2 phase 3 fingolimod trials, and 2 prospective observational cohorts. Doses ranged from 1 µg/day of alfacalcidol to 40,000 IU/day of cholecalciferol, and follow-up ranged from 6 to 48 months. Several trials tested vitamin D as an add-on to existing disease-modifying therapy. Because of heterogeneity in design and reporting, findings were synthesized narratively rather than through meta-analysis.

Vitamin D and MS Relapse Rates

Most RCTs reporting relapse data found no statistically significant difference in annualized relapse rate (ARR). In the SOLAR trial (n = 229), the largest primary RCT included, the observed ARR was 0.28 with vitamin D vs 0.41 with placebo, but the modeled incidence rate ratio (IRR) was not significant (0.80; 95% CI, 0.51-1.26; P = .34). In the VIDAMS (n = 172), 5000 IU/day did not reduce relapse risk compared with 600 IU/day among patients also receiving glatiramer acetate (HR, 1.17; 95% CI, 0.67-2.05; P = .57). The only trial reporting a relapse benefit used alfacalcidol, an active vitamin D analogue, with 8 relapses among 80 treated patients vs 25 among 78 receiving placebo (OR, ~0.20; 95% CI, 0.09-0.53; P < .001). This finding was not replicated.

Vitamin D and MRI Lesion Activity in MS

MRI outcomes were more variable. SOLAR reported fewer combined unique active lesions with vitamin D (IRR, 0.68; 95% CI, 0.52-0.89; P = .0045), and a trial of vitamin D added to interferon β-1b found fewer gadolinium-enhancing lesions (0.1 vs 0.6; P = .004). The fingolimod post hoc analysis and 1 observational cohort, both non-randomized, also reported favorable T2 lesion findings.

Other studies found no significant differences. VIDAMS showed no difference in new or enlarging T2 lesions (rate ratio, 1.47; 95% CI, 0.88-2.46; P = .14), and the CHOLINE trial found none in new or enlarging T2 lesions or gadolinium-enhancing lesions. The authors noted that suppression of MRI lesions and a reduction in relapses are distinct outcomes and that the evidence showed they did not consistently move in the same direction.

High-Dose Vitamin D in Clinically Isolated Syndrome

The review excluded studies of patients with clinically isolated syndrome (CIS). In the D-Lay MS trial, which enrolled 316 untreated patients with CIS typical of MS, oral cholecalciferol 100,000 IU every 2 weeks given as monotherapy reduced disease activity, a composite of relapse or new MRI activity (new or gadolinium-enhancing lesions), over 24 months compared with placebo (60.3% vs 74.1%; HR, 0.66; 95% CI, 0.50-0.87; P = .004). Relapse occurred in 17.9% of the vitamin D group vs 21.8% of the placebo group (HR 0.69; 95% CI, 0.42-1.16; P = .16), a difference that was not statistically significant, while all 3 secondary MRI outcomes favored vitamin D.²

Limitations and Future Research on Vitamin D in MS

All 3 non-randomized studies were judged to have a serious risk of bias. Among the RCTs, 1 was rated low risk, 4 had some concerns, and 3 were rated high risk. No formal GRADE assessment was performed, the review was not prospectively registered, and baseline serum 25-hydroxyvitamin D levels were inconsistently reported across trials. The authors concluded that current data do not support vitamin D as a disease-modifying therapy beyond correction of deficiency, and they called for larger multicenter RCTs powered for relapse as a primary end point, with standardized dosing, reporting of baseline serum levels, and follow-up of at least 2 to 3 years.¹

References

1. Hall K, Renteria J, Fernandez E, Abrahams J, Bhakta S. Vitamin D supplementation and its effect on relapse frequency and MRI activity in adults with multiple sclerosis: a systematic review. Brain Behav. 2026;16:e71692. doi:810.1002/brb3.71692
2. Thouvenot E, Laplaud D, Lebrun-Frenay C, et al; D-Lay MS Investigators. High-dose vitamin D in clinically isolated syndrome typical of multiple sclerosis: the D-Lay MS randomized clinical trial. JAMA. 2025;333(16):1413-1422. doi:10.1001/jama.2025.1604