Magnesium, vitamin D status and mortality:
results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III
BMC Medicine 2013, 11:187 http://www.biomedcentral.eom/1741-7015/11/187
Xinqing Deng1, Yiqing Song2, JoAnn E Manson2,3, Lisa B Signorello3, Shumin M Zhang2, Martha J Shrubsole1, Reid M Ness4, Douglas L Seidner4 and Qi Dai1,5
Background: Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level.
Methods: We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI).
Results: High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively.
Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency.
Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency.
Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median.
Conclusions: Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status.
The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium.
Future studies, including cohort studies and clinical trials, are necessary to confirm the findings.
Selected demographic characteristics and potential confounding factors by the three categories of serum 25 (OH)D status are shown in Table 1. Compared to the Estimate Average Requirements (EAR, intake levels for vitamin D (400 IU/day) and magnesium (330 mg/day) recommended by the US Food and Nutrition Board of the Institute of Medicine), the vitamin D normal group generally met the recommended intake levels for both vitamin D and magnesium whereas the average intake levels of these nutrients were significantly lower in the vitamin D-insufficient group and much lower among the vitamin D-deficient group.
After adjusting for confounding factors, the ORs (95% CI) for vitamin D deficiency and insufficiency were 0.10 (0.06 to 0.17) and 0.37 (0.27 to 0.51) comparing the highest quartile intake of total vitamin D versus the lowest (Ptrend <0.001) (Table 2). The corresponding Ors (95% CI) were 0.34 (0.21 to 0.56) and 0.62 (0.46 to 0.82) for total magnesium intake (Ptrend <0.001), respectively. In addition, we found that both dietary and supplemental intakes of vitamin D and magnesium were significantly inversely associated with risks of vitamin D deficiency and insufficiency.
In stratified analyses by intake of vitamin D and other factors related to vitamin D status (Table 3), we found intake of magnesium significantly interacted with intake of vitamin D in relation to both vitamin D deficiency (Pinteraction, <0.001) and insufficiency (Pinteraction, <0.001).
The inverse association between magnesium intake and risk of vitamin D deficiency only appeared significant among those older than 50 years or with serum PTH level being in the highest or lowest tertile category. Meanwhile, the inverse associations between magnesium intake and risk of vitamin D insufficiency were statistically significant only among people at high risk of vitamin D insufficiency, such as those whose samples were collected during winter (at southern latitude), those with vitamin D intake below the median, women, non-Hispanic Blacks, obese individuals or those with the PTH levels in the highest tertile.
As reported previously, high levels of serum 25(OH)D were associated with a reduced risk of mortality due to all-cause CVD [4,29,36], and colorectal cancer . We found that the inverse associations for higher serum 25 (OH)D with risks of total mortality and mortality due to CVD were only statistically significant among those with magnesium intake above the median (Table 4). Although the test for interaction was not statistically significant for total mortality, it was statistically significant for mortality due to CVD (Pinteraction, 0.03). Sample size was small for mortality due to colorectal cancer. None of the associations, including the main association, were statistically significant. However, the association pattern in stratified analysis (Pinteraction, 0.15) was very similar to that for total mortality and mortality due to CVD.
Consistent with our hypothesis, we observed that high intake of total, dietary or supplemental magnesium was independently and significantly associated with reduced risks of both vitamin D deficiency and insufficiency. Furthermore, intake of magnesium significantly interacted with intakes of vitamin D in relation to both vitamin D deficiency and insufficiency. In the NHANES III cohort, a population-based prospective study, we found the inverse associations of serum 25(OH)D with mortality, particularly mortality due to CVD and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median. In addition, we found the inverse association between magnesium intake and risk of vitamin D deficiency primarily occurred in those who had the highest or the lowest tertile of PTH level; while the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. To the best of our knowledge, this is the first study to examine the interaction between vitamin D and magnesium in association to mortality; and this is the first study to suggest a potential independent contribution of total magnesium intake and its interaction with vitamin D intake to vitamin D status in the general population.
Under normal physiologic conditions, 25(OH)D is derived primarily from endogenous synthesis via exposure of skin to sunlight because few natural foods contain vitamin D except by fortification or supplementation (see Figure 1). Vitamin D3 or D2 is transferred to the liver via vitamin D binding protein (VDBP) and converted to 25(OH)D by 25-hydroxylase and subsequently carried to the kidney by VDBP and converted to 1,25(OH)2D by 1a-hydroxylase enzyme. Both 25(OH)D and 1,25(OH)2D can be converted by 24-hydroxylase to the 24,25(OH)2D or 1,24,25(OH)3D, respectively .
Therefore, 25(OH)D levels are primarily determined by VDBP, 25-hydroxylase, 1a-hydroxylase and 24-hydroxylase activity, a fact that has recently been substantiated by a genome-wide association study . Based on previous in vitro studies, magnesium status regulates both 1a-hydroxylase and 24-hydroxylase activity [22,24].
Previous studies indicated both VDBP  and 25-hydroxylase [25,39] might also be magnesium dependent. Therefore, magnesium would be expected to play an important role in 25(OH)D metabolism.
A previous clinical study found that parenteral magnesium treatment without vitamin D replacement in 23 magnesium-deficient patients led to a 12% rise in 25 (OH)D and 30% increase in 1,25(OH)2D, but both changes were not statistically significant . In a subsequent study of five magnesium-deficient patients, intramuscular treatment with magnesium alone also did not significantly increase 25(OH)D, but magnesium infusion together with pharmacological dose of 25(OH)D substantially increased both 25(OH)D and 1,25(OH)2D among patients with magnesium deficiency. One interpretation is that magnesium treatment does not affect 25(OH)D status [23,27]. However, we postulate that several factors may have contributed to the insignificant increase in 25(OH)D status. First, the subjects participating in these studies had low concentrations of 25(OH)D and 1,25(OH)2D as well as pre-vitaminD3 and vitamin D3 as a result of limited sunlight exposure, underlying disease and/or lack of oral supplementation. Therefore, concentrations of 25(OH)D and 1,25(OH)2D did not substantially increase during short-term magnesium repletion because pre-vitamin D3 was not available in sufficient amounts. Second, there was a modest increase in the conversion of 25(OH)D to 1,25(OH)2D and, thus, a reduction in 25(OH) D level was expected due to this conversion . Finally, the sample size in these two studies was very small particularly if the direct effect of magnesium treatment on vitamin D status is only moderate.
We found that high magnesium intake was also associated with a reduced risk of vitamin D deficiency or insufficiency. We believe that this observation is the result of the interaction between various metabolic pathways that regulate 25(OH)D levels. Previous studies have shown that endogenously synthesized vitamin D3 is transferred almost completely by VDBP to liver and this . . . . .
PDF is attached at the bottom of this page
- Overview Magnesium and vitamin D
- Hypothesis: Magnesium accounts for some of the variation in vitamin D response – Oct 2013
which is an editorial of the paper on this page
- Magnesium and Vitamin D very synergistic – Aug 2013
- Vitamin D level can be high, but little benefit: due to kidney, genes, low Magnesium etc.
- Vitamin D increases mineral availability which protect against toxic elements - July 2015
- Magnesium – I used to believe that food had enough, now I supplement with 400 mg daily – Dr. Lundberg May 2015
- Magnesium and Vitamin D - similar, different and synergistic