The vitamin D-ilemma

Part 6: Optimising vitamin D activation

Fine-tuning calcitriol

As I’ve stressed in previous instalments of this miniseries (which has, thanks to the breadth and complexity of the vitamin D research literature, burgeoned into a maxiseries), the only biologically active member of the triad of compounds collectively known as ‘vitamin D’ is the secosteroid hormone calcitriol, or 1,25-dihydroxyvitamin D.

Supplementing with vitamin D in either the D2 form (ergocalciferol) or D3 form (cholecalciferol) does raise serum levels of 25-hydroxyvitamin D (the major circulating metabolite, and the form that is measured when you have a ‘vitamin D blood test’), because the enzyme¹ that carries out this conversion is poorly regulated. But supplementation does not raise serum calcitriol levels. Calcitriol synthesis and breakdown are very tightly regulated, and for good reason: as you might remember from Part 2, calcitriol raises serum calcium levels by, among other things, triggering the breakdown of bone. Uncontrolled production of calcitriol would not only weaken your bones but also trigger kidney stone formation, muscle cramping and abnormal heart rhythm.

You might also remember from Part 2 that calcitriol functions both as an endocrine agent – that is, a hormone that is released by one organ (the kidneys, in this case) and then travels through the bloodstream to affect the function of other organs – and as an intracrine and paracrine agent – that is, a signalling molecule that acts on the same cell that produced it, and/or on neighbouring cells.

Calcitriol production within the kidney is ‘switched on’ by parathyroid hormone and ‘switched off’ by rising serum calcium, phosphate and fibroblast growth factor 23 (FGF23) levels.

Outside the kidney, the cells that have the capacity to synthesise calcitriol – including those located in the inner lining of blood vessels (endothelium), breast, prostate, parathyroid glands, muscles, placenta, brain, skin, and colon, along with certain immune system cells – do so when prompted by a change in their local environment. For example, when toll-like receptors (TLRs) in the membranes of monocytes (a type of immune system cell) and the cells lining our mucous membranes sense the presence of pathogens, they induce the 1α-hydroxylase enzyme that synthesises calcitriol from 25-hydroxyvitamin D, and the gene which directs the production of the vitamin D receptor (VDR).

This hormone will self-destruct in five seconds…

The final step in regulation of calcitriol levels is that calcitriol itself induces the expression of a gene which codes for the enzyme that initiates its own breakdown and removal process, CYP24A1. Moreover, CYP24A1 also metabolises the precursor to calcitriol, 25-hydroxyvitamin D, into an inactive form, in effect limiting the amount of calcitriol that can be produced.

I hope it will be clear to you by now, that your body is highly invested in making sure that you never end up with too much calcitriol. It might also be becoming apparent that if you’re manifesting any of the signs and symptoms of low vitamin D activity described in Part 2, shovelling in more vitamin D in the form of cholecalciferol supplements may not solve your problems, because of the self-destruct mechanism and bottlenecking of calcitriol production described in the previous paragraph.

Magnesium – the master controller of vitamin D activity

The mineral magnesium is a cofactor² for the enzymes that catalyse the activation of cholecalciferol and ergocalciferol into 25-hydroxyvitamin D, and 25-hydroxyvitamin D into calcitriol. It’s also a cofactor for the enzymes that inactivate both 25-hydroxyvitamin D and calcitriol:

So without adequate magnesium, the entire vitamin D roadshow grinds to a screaming halt. In fact, there’s even a condition dubbed ‘magnesium-dependent vitamin-D-resistant rickets‘, in which patients manifest “all the clinical and biochemical features of the advanced stage of vitamin-D deficiency, despite adequate intake of the vitamin.” While even massive doses of vitamin D, either orally or intramuscularly, failed to deliver any improvement, a reasonably modest daily oral dose of magnesium chloride brought about rapid resolution:

But just how common is inadequate dietary intake of magnesium? Very bloody common. As of 2011-2012 (which was the last time the Australian government conducted a nationwide survey to assess the population’s nutrient intake; after that, they decided to lavish our taxpayer dollars on their Big pHarma friends instead), one in three people aged two years and over had an inadequate intake of magnesium. The age groups 14-18 and 71+ had the highest prevalence of inadequate intake. 61 per cent of 14-18 year old males, and 72 per cent of females, consumed less than the Estimated Average Requirement (EAR) of magnesium. Among those aged over 71, 64 per cent of males and 49 per cent of females fell short of the EAR.

And if you think that sounds bad, wait – it’s even worse. At least for women, the Australian EAR for magnesium – 255-265 mg per day – falls well short of the European Union’s Adequate Intake of 300 mg/day. (The Australian EAR for men – 330-350 mg per day – is on par with the EU’s AI of 350 mg/day). If we were to apply the EU’s more rigorous standards for adequate magnesium intake to the Australian population, no doubt more than half of us would be failing to make the grade. But even the EU’s recommendations are puny when you consider that the diet consumed by our paleolithic ancestors is estimated to have supplied roughly 600 mg of magnesium per day.

It’s the same sorry story in the US, where 79 per cent of adults fail to meet the Recommended Dietary Allowance of magnesium. (Notably, Americans consumed roughly 500 mg of magnesium per day in the early 1900s, but average intake is only 250 mg today.) And same story in France, Germany, Taiwan, Japan… large proportions of the populations of pretty much every wealthy nation fail to meet even the low bar for magnesium intake set by government nutrition advisory bodies.

Studies assessing magnesium status through blood tests and muscle biopsies have confirmed that this low magnesium intake translates to functional magnesium deficiency, which increases the risk of coronary artery disease, hypertension (high blood pressure), cardiac arrhythmias, stroke, type 2 diabetes, osteoporosis and dementia, among a litany of other chronic illnesses.

Why is our magnesium intake so abysmally low? Because the Western diet is based on highly processed foods and land animal products, which are poor sources of magnesium. As you’ll see from skimming any random list of magnesium-rich foods, leafy green vegetables, nuts, seeds, legumes and whole grains are the major dietary sources of this essential mineral, with some forms of seafood also delivering decent amounts. Conversely, dairy products, eggs, meat and poultry are very poor sources of magnesium. The refining of grains leads to precipitous declines in their magnesium content; white flour has only one-sixth as much magnesium as wholemeal/wholewheat flour, while brown rice has four times the magnesium content of white rice.

Furthermore, increased dietary intake of calcium (with which processed foods are frequently ‘fortified’), phosphorus (which is added to soft drinks/sodas, and is also now more abundant in plants due to unbalanced crop fertilisation) and – drum roll please – vitamin D – all increase magnesium loss from the body, and hence our dietary requirement for magnesium. As far back as 1965, it was known that acute magnesium deficiency could be induced in rats by injecting large doses of vitamin D (ergocalciferol, or vitamin D2, in this case).

With all this in mind, let’s take a look at a randomised trial which examined the effect of magnesium supplementation on vitamin D metabolism.

In an ancillary study nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), 180 participants were randomised to receive either magnesium supplementation, in a dose which was individually customised to reduce the calcium-to-magnesium intake ratio to approximately 2.3 (a ratio shown in previous studies to be associated with decreased risk of gastroesophageal reflux and cancer, colorectal cancer, and mortality).

The researchers’ aim was to assess the impact of magnesium supplementation on participants’ levels of 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D2 (the two ‘flavours’ of calcitriol made from 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 respectively), and 24,25-dihydroxyvitamin D3, the breakdown product of 25-hydroxyvitamin D3.

What they found was absolutely fascinating:

In participants whose 25-hydroxyvitamin D levels were above 75 nmol/L (30 ng/mL), magnesium supplementation reduced both 25-hydroxyvitamin D3 and its breakdown product, 24,25-dihydroxyvitamin D3. This throttling of 25-hydroxyvitamin D3 was particularly marked in participants whose 25-hydroxyvitamin D level was 125 nmol/L (50 ng/mL). As the authors noted,

“When baseline 25(OH)D concentrations are >30 ng/mL, CYP3A4 activity starts to elevate and the activity is further enhanced by magnesium supplementation, which leads to a significant reduction in concentrations of 24,25(OH)₂D₃.”

Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial

In other words, once your level of 25-hydroxyvitamin D level rises above 75 nmol/L, your body starts taking active measures to lower it, providing it has access to sufficient magnesium to do so.

Magnesium supplementation also significantly changed plasma 25-hydroxyvitamin D3 concentration depending on the patient’s baseline plasma 25-hydroxyvitamin D concentration; among participants with a lower baseline 25-hydroxyvitamin D, those who received magnesium supplementation had an increase in 25-hydroxyvitamin D3.

But when baseline 25-hydroxyvitamin D was high, magnesium supplementation appeared to shift CYP3A4 to selectively degrade vitamin D3 over vitamin D2, resulting in higher plasma concentrations of 25-hydroxyvitamin D2, which is associated with less toxicity than D3.

Between this effect and the accelerated metabolism and breakdown of 25-hydroxyvitamin D3 when its plasma level is (too?) high, the authors concluded that

“Our findings provide the first evidence that adequate magnesium status could potentially prevent vitamin D–related adverse events.”

Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial

The following graphs show the relationship between baseline levels of 25-hydroxyvitamin D3 and D2, and 24,25-dihydroxyvitamin D3, the breakdown product of 25-hydroxyvitamin D3, and levels after taking either magnesium supplements or placebo. Note how magnesium supplementation shifts the balance between the D2 and D3 metabolites, and lowers the concentration of 25-hydroxyvitamin D3 in those with high baseline levels:

No interaction between baseline 25-hydroxyvitamin D level, magnesium supplementation and calcitriol levels was found in this study, but it’s important to point out that none of the participants was assessed as being magnesium deficient, merely at risk of deficiency because of their unfavourable calcium:magnesium intake ratio. What this study makes clear, however, is that magnesium orchestrates the metabolism of all the compounds in the vitamin D family in a highly complex fashion, so as to optimise the pool of 25-hydroxyvitamin D2 and D3 that is available for calcitriol production.

Fine-tuning the vitamin D receptor

Magnesium’s role doesn’t stop at regulation of vitamin D metabolism. It also upregulates the synthesis of the vitamin D receptor (VDR) in cells that respond to calcitriol.

Another essential mineral, zinc, is a structural component of the VDR and is considered to be an essential cofactor for vitamin D activity. Like 25-hydroxyvitamin D, zinc is a negative acute phase reactant; that is, its plasma concentration drops during both acute and chronic inflammation. And like magnesium, inadequate dietary intake of zinc is common, especially in the elderly.

You might remember from Part 3 that there are over 900 variants of the VDR gene (called ‘polymorphisms’) that have been identified thus far. VDR gene variance affects vitamin D metabolism, such that serum 25-hydroxyvitamin D levels may vary substantially between individuals, even at the same intake dose of vitamin D.

Genetic polymorphisms are essentially ‘misspellings’ of the DNA sequence that codes for a particular protein. The misspelling results in substitution of one amino acid in the protein for a different one, and this substitution causes the protein to have a slightly different shape, which in turn alters its function. Many such polymorphisms result in proteins that are relatively inefficient, such that there is an increased need for nutrients that serve as its cofactors.

Certain VDR polymorphisms are associated with increased propensity to autoimmune diseases, type 2 diabetes, cardiovascular disease and cancer. It’s food for thought that all of these conditions have also been linked to a diet low in essential minerals including zinc and magnesium (e.g. see this study, and this one, and this one, and this one). Is the association between low 25-hydroxyvitamin D levels and chronic disease, at least in part due to consumption of a diet lacking in key nutrients involved in vitamin D metabolism? It seems likely. There is preliminary evidence, for example, that inadequate magnesium intake could be more harmful to bone metabolism in people with certain VDR gene polymorphisms.

The lesson I draw from this is that everyone should be switching to a diet rich in vitamin D cofactors, since a) you’re unlikely to know which vitamin D-related polymorphisms you have and b) there is insufficient evidence at this stage, to formulate precision diets based on genetic polymorphisms. In practice, this means a diet comprised mostly of unprocessed plant foods, with judicious intake of zinc-rich animal products (such as oysters) if you so choose.

And finally, if you’re obtaining adequate UVB exposure as described in Part 5, you’ve adopted a micronutrient-dense diet, and yet your 25-hydroxyvitamin D level remains stubbornly low (let’s say, below the apparent ‘sweet spot’ of 75 nmol/L [30 ng/mL]), and especially if you have an autoimmune disease, you might want to consider testing for chronic intracellular infection – for example by Epstein-Barr virus, Cytomegalovirus, Borrelia burgdorferi or Aspergillus fumigatus. As you may remember from Part 4, certain intracellular pathogens can downregulate the VDR in order to shield themselves from the innate immune response. Taking vitamin D supplements in such circumstances is inadvisable, as it results in further immunosuppression which potentiates the infection.

Summing up

At the end of this lengthy exploration of the family of compounds collectively known as ‘vitamin D’, it’s appropriate to remind ourselves of how its story began: Somewhere back in the dim, dark mists of time, through means that we do not understand, primitive organisms developed the capacity to utilise ultraviolet-B radiation from the sun. This capacity proved so useful for genetic fitness that it persisted, with its biological applications multiplying as the organisms themselves became more and more complex.

One of those life forms – human beings – evolved in a sun-drenched location, eating nutrient-dense plant and animal foods that allowed it to make optimal use of the ‘sunshine hormone’. As humans dispersed from their African homeland into higher latitudes, they developed genetic polymorphisms that allowed them to thrive despite reduced sun exposure. But up until an evolutionary eyeblink ago, most humans spent much of their times outdoors, and ate a diet of minimally processed foods. The Industrial Revolution herded rural populations into burgeoning towns and cities which had strictly limited access to fresh foods, and it drove the majority of the population indoors, to live and work under artificial lighting. It also brought steam-powered mills which stripped micronutrients from staple grains, and made former luxury items such as sugar, cheap and ubiquitous.

Now, in the 21st century, we have what we are told is an ‘epidemic of vitamin D deficiency’ which we should address by taking vitamin D supplements. As H.L. Mencken acerbically observed,

“For every complex problem there is an answer that is clear, simple, and wrong.”

That’s not to say that vitamin D supplements are inherently toxic, or that no one benefits from taking them. But complex problems demand sophisticated thinking, and almost invariably, a suite of solutions that are tailored to the nuances of the problem’s many manifestations. Anyone who promotes the use of vitamin D supplements as a one-size-fits-all solution to the widespread problem of (apparent) vitamin D deficiency should be viewed with scepticism. Just as ‘low magnesium intake’ is a reductionist description of the real problem, which is inadequate intake of minimally-processed plant foods, ‘vitamin D deficiency’ is a reductionist diagnosis which obscures the real problem, which is living out of alignment with our environment of evolutionary adaptedness. And you can’t solve that problem with a vitamin D pill.

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1. Enzymes are proteins that act as biological catalysts – that is, they speed up biochemical reactions in living organisms. ↩︎
2. A cofactor is a molecule (such as a vitamin or mineral) that, when added to an inactive enzyme, ‘switches on‘ that enzyme into its active form. ↩︎