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Personalized magnesium intervention to improve vitamin D metabolism: applying a systems approach for precision nutrition in large randomized trials of diverse populations.

Greater intakes of micronutrients and minerals such as vitamin D, calcium, and magnesium have long been associated with decreased incidence of many late-onset disorders in observational studies (1–5), although large randomized intervention trials that directly evaluate their clinical efficacies have generated inconsistent results (6–8). Nevertheless, some observations have been well recognized, including high prevalence of vitamin D and magnesium insufficiency in westernized populations (9, 10) and the large interpersonal variations of vitamin D and magnesium metabolisms in the general population (11). Studies have shown that magnesium plays a critically important role in the synthesis and metabolism of vitamin D, raising the possibility that magnesium should be included in any vitamin D regimen for optimal biological functioning (12). In this issue of the Journal, Dai et al. (13) report very interesting findings from a randomized trial showing that 12 wk of magnesium supplementation using a personalized dosing scheme adjusted to participants’ dietary intakes significantly changed vitamin D metabolism dependent upon vitamin D status at baseline. Specifically, concentrations of 25-hydroxycholecalciferol [25(OH)D3] were found to increase among those whose baseline concentrations of 25-hydroxyvitamin D [25(OH)D] were <30 ng/mL but decrease among those whose concentrations of 25(OH)D were in the range of 30–50 ng/mL. More interestingly, magnesium supplementation also appeared to selectively deactivate cytochrome P450 3A4 (CYP34A) to degrade vitamin D3 over D2 when plasma 25(OH)D was high. These data therefore provide for the first time some tantalizing evidence in support of the notion that adequate magnesium status could directly improve vitamin D deficiency and its related adverse events. Dai et al. (13) also noted that all trial participants at baseline had a Ca:Mg intake ratio >2.6, which was reduced to 2.3 after being given magnesium supplementation. However, whether a 3-way interaction of calcium–magnesium–vitamin D existed and how it might have influenced the effects of the magnesium dosing strategy on vitamin D metabolites were not explored, probably owing to statistical inefficacy. Moreover, other limitations also need to be kept in mind when interpreting these findings. First, dietary intakes were assessed via 24-h recall, and measurement error was likely to affect the estimates of the Ca:Mg intake ratios reported. It would have been informative if the status of calcium and magnesium had also been assessed using biomarkers in different tissues (urine, plasma, and red blood cells). Second, the exact number of participants in each stratum of baseline 25(OH)D concentrations (<12, 20, 30, 40, 50, >50 ng/mL) was not reported but is likely to be small. As acknowledged by the authors, there were only 2 participants with baseline 25(OH)D <12 ng/mL, making it powerless to determine any magnesium–vitamin D interaction among those with such low concentrations at baseline. Similarly, findings of 25(OH)D2 had wide 95% CIs among those whose baseline 25(OH)D was >50 ng/mL. Moreover, 2 other vitamin D metabolites— 25(OH)D3 and 24,25-dihydroxyvitamin D3—appeared to decrease after magnesium supplementation among those with baseline 25(OH)D at 50 ng/mL, whereas when baseline 25(OH)D concentrations were <30 mg/mL, 25(OH)D3 increased, but not for 24,25-dihydroxyvitamin D3. These observations raise the possibility that both false positives and false negatives were possible alternative explanations for their findings. In fact, of the 265 participants who met the inclusion criteria and were randomly assigned, 239 completed the study and only 180 (68% of enrolled participants) were included in the current analysis. To improve statistical efficiency, the authors opted for not carrying out an intent-to-treat analysis, abolishing the randomization design. As such, the effect size measure for magnesium–vitamin D interaction may have been biased, particularly for those with baseline 25(OH)D3 ≥30 ng/mL. Finally, trial participants had previously been diagnosed with colorectal adenomas or hyperplastic polyps (and 14 participants were polyp-free individuals with a high risk of colorectal cancer), thus they were clearly not representative of the general population