Tuesday, December 18, 2018

Magnesium Could be in Charge of Your Vitamin D Levels: Supplements Lower High and Increases Low 25OHD Levels

D3 and Mg Supplements not mandatory w/ sun + balanced diet
If you subscribed to the @SuppVersity Facebook Page, you will have read the news, already: "Magnesium status and supplementation influence vitamin D status and metabolism" (Dai 2018) - that is both the title and the main results of a recent study from the Vanderbilt University that is important enough to make it from the short format on Facebook to a detailed SuppVersity article of its own - the article at hand ;-)

The 25OHD-balancing effects Dai et al. observed in their 180 participants (aged 40–85 y) could after all do much more than point towards a reason why everyone and his mama seems to be D-ficient - it could force us to redefine what "optimal" 25OHD levels are - significantly below those many Internet "health experts" recommend.
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The study is a National Cancer Institute independently funded ancillary study, nested within the "Personalized Prevention of Colorectal Cancer Trial" (PPCCT), which enrolled 250 participants at risk of developing colorectal cancer. The PPCCT is a double-blind 2 × 2 factorial randomized controlled trial conducted in the Vanderbilt University Medical Center.

Customized supplementation with magnesium glycinate brought the subjects' total magnesium into the range of the RDA (men 400-420 mg/d, women 310-320 mg/d)

What makes the study stick out is that doses for both magnesium and placebo were customized based on baseline dietary intakes - in other words: The less magnesium in the diet, the more was supplemented. Furthermore, the scientists tested not just 25OHD (which is what your doctor will test if you ask for a "vitamin D test") but also changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] - all by liquid chromatography–mass spectrometry.

Based on the somewhat disappointing observation that vitamin D was not related to cardiovascular disease in the recent VITAL trial (Kubiak 2018) - even in subjects with baseline vitamin D insufficiency(!) - the researchers whose current main objective is to elucidate the role that magnesium may play with cancer as part of the previously mentioned "Personalized Prevention of Colorectal Cancer Trial" speculated that "magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration" (Dai 2018).

In previous experiments, the scientists had already observed that people's ability to synthesize "vitamin D" depended on their magnesium status.

About both, the US's vitamin D and magnesium status, co-author Martha Shrubsole, Ph.D., research professor of Medicine, points out in the corresponding press release:
Magnesium is at the center of vitamin D metabolism - as part of CYP, cytochrome P450 enzymes (dark gray indicates deactivating enzymes, and light gray indicates activating enzymes | Dai 2018)
"Vitamin D insufficiency is something that has been recognized as a potential health problem on a fairly large scale in the U.S. A lot of people have received recommendations from their health care providers to take vitamin D supplements to increase their levels based upon their blood tests. 
In addition to vitamin D, however, magnesium deficiency is an under-recognized issue. Up to 80 percent of people do not consume enough magnesium in a day to meet the recommended dietary allowance (RDA) based on those national estimates" (from Vanderbilt press release). 
[Worth mentioning:] "Shrubsole stressed that the magnesium levels in the trial were in line with RDA guidelines, and she recommended dietary changes as the best method for increasing intake. Foods with high levels of magnesium include dark leafy greens, beans, whole grains, dark chocolate, fatty fish such as salmon, nuts and avocados." (ibid.). 
Incidentally, the hypothesis that these two deficiency nutrients may interact is not even new. You can go back as far as 50 years and will find (rodent) studies showing how vitamin D affects not just calcium but also magnesium levels (Harrison 1964). Hitherto, though, this interaction has often been ascribed to the ability of vitamin D to increase Mg absorption irrespective of one's vitamin D status.
Having high(er) 25OHD levels was found to be associated with 11-13% reduced all-cause mortality hazards in a 2013 study using data from NHANES 2001-06 - for those of the subjects that consumed high(er) amounts of magnesium the hazard reduction compared to D-ficient levels of <20ng/ml was 23%-30% and the overall HRs up to 20% lower (Deng 2013).
The opposite, i.e. putative effect of magnesium on vitamin D, on the other hand, has been largely ignored - despite the fact that more recent studies, such as Deng et al. 2013, in which the authors analyzed NHANES data from 2001 to 2006 seem to suggest that there's a two-way interaction of magnesium and vitamin D in relation to risk of both vitamin D deficiency and insufficiency - with literally life-threatening/saving implications (Deng 2013).
Which Mg is best? Plasma an bone (primary axis) as well as red blood cell (RBC; 2ndary axis(!)) content after 14 days of supplementation with identical amounts of magnesium in different organic and inorganic forms (Coudray. 2005 | learn more) - unfortunately, the study was conducted in rodents and used only gluconate, not glycinate as it was used in the PPCT trial.
Now, we shouldn't forget that, in Deng's study, we're talking about correlations/associations of which Zittermann in a 2013 writes that it "provides important findings concerning potential metabolic interactions between magnesium and vitamin D and its clinical relevance.
In 10 lab-workers, the mean serum 25(OH)D varied widely [from 17.1 (4.6) to 35.6 (5.2) ng/ml; P < 0.005] between laboratories (error bars represent SEM). B, Similarly, marked within-individual variation was observed in 25(OH)D measurement in different laboratories. This means: Whether an individual has hypovitaminosis D (threshold = dashed line) depends on which laboratory was used. 
I've heard the vitamin D test is inaccurate - Is that accurate or #fakeNews? Accurate. As Holick points out in a 2009 paper, "the first assays for 25(OH)D used the competitive protein binding format with the vitamin D binding protein (DBP) as the binder" - advantage: recognizes 25(OH)D2 equally as well as 25(OH)D3; disadvantage: the assay will also measure all sorts of D-metabolites including 24,25-dihydroxyvitamin D [24,25(OH)2D], 25,26-dihydroxyvitamin D and the 25,26-dihydroxyvitamin D -26, 23-lactone, which reduces the accuracy by ~10-15%.

The same issue(s) exist(s) for the radioimmunoassay (RIA | Diasorin@) which "typically overestimated 25(OH)D levels by approximately 10-20%" (ibid). Moreover, IDS has recently developed an RIA "which has a 100% specificity for 25(OH)D3 and only 75% specificity for 25(OH)D2 (ibid) and could thus be a more accurate alternative (still, if you're D-ficient or not often depends on which lab you're using (see Figure on the right | from Binkley 2004)

So how do you get the absolute accurate levels? You don't... well, actually you don't have to. Scientists, on the other hand, should use liquid chromatography tandem mass spectroscopy (LC-MS) to measure 25(OH)D in human serum, directly. This assay quantitatively measures both 25(OH)D2 and 25(OH)D3.
However, results should be considered preliminary since biochemical data on individual magnesium status were lacking, [and] confounding cannot be excluded" (Zittermann 2013). That's in contrast to the more recent observations by Dai et al. whose data come from a tightly controlled clinical trial - a trial that clearly suggests this link could be mechanistic.

The relationship between 25OHD and magnesium is complex and probably U-shaped

Mechanistic, but not simplistic, to be more precise: In the latest study by Dai et al. the relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different depending on the baseline concentrations of 25(OH)D, and significant interactions persisted after Bonferroni corrections (meaning including statistical correction of multiple comparisons which increase the likelihood of false positives). More specifically, the subjects from the "Personalized Prevention of Colorectal Cancer Trial" whose data the Vanderbilt scientists analyzed revealed that ...
  • The main result of the study: The provision of adequate (RDA) amounts of magnesium seems to help balance the 25OHD levels of the subjects in the PPCCT trial at ~30ng/ml.
    magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, ...
  • but decreased the levels of 25(OH)D3 when the baseline 25(OH)D was higher (from ∼30 to 50 ng/mL | insufficient data to reliable statements about even higher concentrations);
  • moreover, at higher baseline 25OHD concentrations, other 25OHD metabolites, i.e. 25-hydroxyvitamin D2 [25(OH)D2], and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were likewise affected by magnesium supplements, how and at which levels this affects the hitherto often ignored ratio of these D-metabolites and hence our health will have to be elucidated in future studies, though (see figure below).
Overall, the provision of (sufficient =RDA) magnesium seems, as the authors from Vanderbilt University rightly point out, to allow our bodies to keep our 25OHD levels within the middle range of a previously established and repeatedly confirmed U-shaped curve that illustrates the general or specific cardiovascular disease risk as a function of serum 25OHD levels (Ross 2011Abraham 2011).
Somewhat surprising for the "more is more" proponents, high 25OHD3 and 24,25(OH)2D3 decreased with magnesium supplementation; the often derided 25(OH)D2, on the other hand, increased (Dai 2018).
In the discussion of the results, Dai et al. (2018) write that "magnesium supplementation may not only accelerate the metabolism and degradation of 25(OH)D3 but also shift CYP3A4 to selectively degrade vitamin D3 over vitamin D2 when plasma 25(OH)D is high" - it doesn't take a scientists to realize that the findings of the study at hand thus "provide the first evidence that adequate magnesium status could potentially prevent vitamin D–related adverse events" (Dai 2018).

The existence of such a "comfort zone" is also in line with some recently published paper in the Journal of Steroid Biochemistry and Molecular Biology in which Mohammed S. Razzaque highlights that "Vitamin D status is more likely to be a consequence rather than a cause of a disease" (Razzaque 2018). That magnesium may help keeping your levels within this "comfort zone" may hence be either the results of direct interactions or simply the consequence of the well-proven cardiovascular and metabolic benefits of getting enough of the precious mineral in your diet.
More Than a Diet Myth? Dark Chocolate/Cacao Won't Get You Jacked, but it May Help Maintain a Slim Waist Over Time | read the whole SuppVersity Classic
Another reason to eat more chocolate... just kiddin', although Dai et al. rightly point out that, in spite full-blown deficiency intakes in  79% of US adults (NHANES), sufficient amounts of magnesium can be easily consumed with our diet if the latter contains copious amounts of foods with high levels of magnesium include dark leafy greens, beans, whole grains, fatty fish such as salmon, nuts, avocados and dark chocolate!

In this context, it seems appropriate to remind you that the overall result of the study at hand underlines the futility of the Western concept "more helps more", which doesn't seem to hold for vitamin D. In fact, it may well fail you when it comes to magnesium supplementation, too... and I am not just talking about magnesium (and other nutrient) losses due to the laxative effects of the Internet's favorite macromineral, here (noteworthy in this context: 1st study on transdermal magnesium + Mg-bioavailability).

From a mechanistic perspective, the interaction could be a result of the previously illustrated role of magnesium in vitamin D metabolizing enzymes: 1α-hydroxylase (i.e., CYP27B1) and 24-hydroxylase (i.e., CYP24A1), which synthesize and metabolize 25(OH)D and 1,25(OH)2D, respectively. In that, the study at hand is the first large(r)-scale study to (a) be done in people w/out severe Mg-deficiency and to (2) show that normalizing magnesium will not simply increase 25OHD, but seems to modulate it towards ~30-40ng/ml. This warrants mentioning that similar interactions do/could exist with calcium & phosphorus (Harrison 1958Gray 1977), as well as potassium (Bikle 1978; Rafferty 2008) and salt (Breslau 1982). And guess what: One of them, i.e. calcium or rather a Ca:Mg ratio of ≥2.6, which has previously been found in >76% of the US general adult population, is also characteristic of the subjects in the study at hand - whether high Ca:Mg diets actually 'cause the vitamin D deficiency epidemic will yet have to be elucidated in future studies | Comment!
References:
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