In the setting of an on-going clinical trial in a population of patients with a history of colorectal adenoma, we are proposing to evaluate the effect of magnesium (Mg) supplementation on serum levels of vitamin D metabolites. Despite food fortification and dietary supplementation, vitamin D insufficiency/deficiency is still relativly common in the US. Many epidemiologic studies consistently found that low vitamin D status was associated with increased risks of non-skeletal chronic diseases including colorectal cancer (CRC). However, randomized clinical trials generated inconsistent results. One striking observation is that a large portion of the inter-person variation in serum 25- hydroxyvitamin D (25(OH)D) levels is unexplained. Further, there is a substantial inter-individual variation in serum 25(OH)D in response to the same dose of vitamin D supplementation. Mg plays a critical role in the synthesis and metabolism of vitamin D. The activities of 3 key enzymes determining 25(OH)D level may be Mg-dependent. Further, Mg deficiency has been implicated in "Mg-dependent vitamin-D-resistant rickets" and Mg supplementation substantially reversed resistance to vitamin D treatment. Very recently, we found intake of Mg significantly interacted with intake of vitamin D in relation to risks of vitamin D deficiency and insufficiency. Furthermore, we found the associations of serum 25(OH)D with mortality, including mortality due to CRC, may be modified by Mg intake, and the reduction in risk associated with high serum concentrations of 25(OH)D appeared primarily among those with Mg intake e median. Our novel finding of Mg-vitamin D interaction may explain some of the variability in 25(OH)D levels and may provide another possible interpretation to explain previous inconsistencies. Very recently, an animal study found the Mg-deficient diet significantly reduced the mRNA of the enzyme that primarily converts 25(OH)D to its active form, 1,25-dihydroxyvitamin D (1,25(OH)D), and significantly increased mRNA expression of the enzyme which mainly converts 25(OH)D to 24,25- dihydroxyvitamin D (24,25(OH)D). Further, a randomized clinical trial of vitamin D supplementation observed changes in vitamin D metabolite conversion with a significant increase in conversion of 25(OH)D to 24,25(OH)D. However, the ratio of serum 24,25(OH)D to serum 25(OH)D was only temporarily and slightly affected by vitamin D supplementation. Furthermore, the initial ratio predicted the efficacy of vitamin D treatment (i.e. rise in 25(OH)D). Based on these findings, we hypothesize that Mg supplementation reduces 24,25(OH)D and the ratio of 24,25(OH)D/ 25(OH)D (two markers of Mg deficiency), and, thus, improves resistance to vitamin D and reduces risk of CRC. To test hypothesis, we propose to measure serum levels of 24,25(OH)D, 25(OH)D, and 1,25 (OH)D in samples collected prior to and at the conclusion of a 12-week Mg intervention in 180 individuals (90 Mg-treatment and 90 placebo). This study will be the first to evaluate the effect of Mg supplementation on resistance to vitamin D and will lay the foundation for future prevention trials.
The proposed study will investigate the effect of magnesium treatment on change in vitamin D metabolite levels and ratio. This study is very critical to understand whether vitamin D metabolism and vitamin D resistance (i.e. insensitivity to vitamin D supplementation) can be improved by magnesium supplementation and to translate it into a preventive strategy for colorectal cancer and, possibly, other cancers. Thus, the proposed study has profound public health and clinical implications.