Vitamin D insufficiency is widely believed to be a potential risk factor development of multiple sclerosis (MS). Observational studies have indicated that higher serum levels of 25-hydroxyvitamin D (25(OH)D) are linked to a reduced risk of developing MS and decreased clinical activity in established MS. This includes a lower risk of relapse and a decrease in disease activity observed on brain Magnetic Resonance Imaging (MRI) (Sintzel et al., 2018). However, recent studies suggest that vitamin D supplements may not effectively reduce MS disease activity (Cassard et al., 2023; Feige et al., 2020; Hanaei et al., 2021; Zheng et al., 2018).

The impact of vitamin D supplementation on reducing MS disease activity is inconsistent (Martínez-Lapiscina et al., 2020; McLaughlin et al., 2018) and may be influenced by factors such as the dosage of supplementation, trial duration, and the levels of improvement in serum 25(OH)D3. In a clinical trial, MS patients exhibited a lesser increase in serum 25(OH)D3 levels compared to healthy counterparts when administered equivalent doses of oral cholecalciferol supplementation (50,000 IU/day vitamin D3 for 90 days), which is the predominant form of vitamin D used in such studies (Bhargava et al., 2016).

When considering exogenous supplementations, cholecalciferol emerges as the preferred form of vitamin D, with calcifediol (25(OH)D3) serving as its major primary metabolite. Calcifediol is produced through the hydroxylation of cholecalciferol at its 25th position. While cholecalciferol is the predominant form used for supplementation, calcifediol is deemed beneficial for individuals with low responsiveness to vitamin D supplementation. Clinical trials have illustrated that oral calcifediol is more effective in elevating circulating levels of 25-(OH)D3 compared to oral cholecalciferol (Biancuzzo et al., 2013; Cashman et al., 2012; R. Cesareo, R. et al., 2019; Holick et al., 2011). This pilot randomized trial represents the first attempt, to the best of our knowledge, to consider the impact of oral calcifediol versus an equivalent dose of cholecalciferol on clinical outcomes in MS patients.