Controversy continues to rage regarding vitamin D supplementation. But new research is finding that the long-held assumption that synthetic vitamin D supplementation is therapeutic may have been misplaced.
And new research also adds doubt to whether even synthetic vitamin D3 is as therapeutic as envisioned. What’s the real story?
Vitamin D deficiency linked to many disease conditions
Research linking vitamin D deficiency to disease has all but brought the medical industry and health media to a standing ovation. Vitamin D has been heralded as the world’s most important vitamin.
And truly, vitamin D deficiency has now been linked to dozens of medical conditions in the research, including insomnia, hypertension, arthritis, asthma, autism, low-back pain, Parkinson’s disease, multiple sclerosis, heart and cardiovascular disease, chronic fatigue, tuberculosis, Crohn’s disease, neuropathy, osteoporosis, diabetes, heart disease, cancer, liver disease, mental disorders, different cancers and other conditions.
The assumption has been that since deficiency is linked to these diseases, removing the deficiency with supplementation should vastly reduce these conditions. Right? Not so fast.
A big review sheds doubts on vitamin D’s therapeutic value
A large review of research published in the British Medical Association journal Lancet — analyzed 290 clinical studies that examined vitamin D deficiency, and 172 clinical studies for disease outcomes. The research comes from the International Prevention Research Institute from Lyons, France.
Indeed, the study found significant (“moderate to strong”) associations between vitamin D and:
“cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality.”
However, the research did not find associations between higher vitamin D levels in the blood and cancer outside of colorectal cancer.
Okay, so maybe vitamin D deficiency is associated with all the conditions mentioned above, but enough to be important. Heart disease? Multiple sclerosis? Mortality? Cognitive function? Yes, vitamin D is critical.
But the blockbuster of the study was that even though deficiency was linked to all those conditions, supplementation did not have a therapeutic effect on any disease.
The researchers analyzed 34 “intervention” studies — studies that tested vitamin D supplementation using some form of randomization — amongst those with many of the conditions listed above.
The researchers stated that:
“Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer.”
The supplementation studies utilized vitamin D at levels greater than 50 micrograms per day — equivalent to 2000 IU of vitamin D. But the researchers added that those studies using less than 2000 IU didn’t fare any better:
“In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 Î¼g per day or more did not show better results.”
Vitamin D supplementation and bone density
Another blow to the notion that vitamin D supplementation is the magic cure for so many conditions — is research negating the assumption that vitamin D supplementation will decrease bone density.
University of Auckland researchers — funded by Health Research Council of New Zealand – found that vitamin D supplementation has little benefit to bone density of elderly persons. The study is published in January 2014’s issue of the British Medical Journal Lancet.
This effect of vitamin D — that it increases bone density due to its synergistic relationship with calcium — has been one of the bedrocks upon which the need for vitamin D supplementation has been laid.
Using the Cochrane Database and Cochran’s Q meta-analysis calculations, the New Zealand researchers reviewed 23 clinical studies that measured the effects of vitamin D supplementation on bone density. Out of these, only one study showed benefit for more than one site. And among all the studies, the meta-analysis showed no effects at any site with the exception of a small effect at the femoral neck region.
This result dealt a significant blow to the general recommendation that elderly persons should supplement with vitamin D to help prevent osteoporosis.
The researchers concluded:
“Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate.”
Note they suggest “without risk factors for vitamin D deficiency” here. They are suggesting that supplementation for vitamin D deficiency is still recommended.
But is this correct?
Is vitamin D a chicken-and-egg problem?
In trying to explain these odd results, the French researchers concluded that low levels of vitamin D were the result of ill health and inflammatory processes. Their conclusion is that aging and ill health causes vitamin D deficiency instead of the other way around:
“The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders.”
But the fact that some studies have shown that vitamin D supplementation can help reduce mortality and a few other conditions caused the researchers to back away from the hard line:
“In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.”
And it wasn’t as if the supplementation in these studies didn’t increase blood levels of 25-hydroxyvitamin D (25(OH)D) — the generic calciferol measurement that doesn’t differentiate between the types of vitamin D (as we’ll discuss below).
Certainly their conclusion certainly has its merits. However, before we throw the baby out with the bath water on vitamin D, there are a few other issues to consider.
Is it possible that the forms of vitamin D being supplemented in most of these trials is the issue?
A study by researchers from France’s International Prevention Research Institute conducted a meta-analysis of studies that compared blood-levels of 25-hydroxyvitamin D that resulted from the supplementation of either vitamin D2 or vitamin D3, among those over the age of 50. They found 76 clinical studies between 1984 and 2011 that measured these.
They found that vitamin D2 (ergocalciferol) and supplementation of vitamin D3 (cholecalciferol) did increase blood-levels of 25-hydroxyvitamin D (25(OH)D), but the D2 supplementation increased 25(OH)D levels significantly less.
Another study, this from the UK’s University of Surrey, also found that D2 increased blood levels of 25(OH)D significantly less than did D3. They concluded:
“This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3) could potentially become the preferred choice for supplementation.”
But blood levels of 25(OH)D aren’t the only issues to consider. And certainly it isn’t the bigger issue, as most of the studies in the Lancet’s French review above did show significantly higher blood levels of 25(OH)D among those receiving the vitamin D supplementation — regardless of whether the supplement was D2 or D3.
But then the physiology runs deeper, as it relates to vitamin D receptors and the fact that the steps that eventually convert calciferol to calcitriol favor the physiologically-produced calciferol — sulfated-25(OH)D3 – through a process called hydroxylation.
“Data suggested that these proposed differences between the 2 calciferols are due to their differing affinities for the vitamin D receptor (VDR), which appears to be linked to an additional step of 24-hydroxylation that inactivates calcitriol. In addition, it is thought that vitamin D3 is potentially the preferred substrate for hepatic 25-hydroxylase, which in combination with the possible difference in the 24-hydroxylation rate, only reinforces the importance of determining whether these metabolic anomalies impact on health.”
The last statement is critical, as both supplemented versions of vitamin D – vitamin D2 (ergocalciferol) and supplementation of vitamin D3 (cholecalciferol) — are both analogs of the real vitamin D3 used by the body — 25-Hydroxyvitamin D3-3-beta-sulphate, also referred to as 25(OH)D3-sulfate. This is converted from 7-dehydrocholesterol and the sun’s UVB rays.
The liver converts cholecalciferol from the blood to calcifediol. Calcifediol is then converted to calcitriol in the kidneys. Calcitriol is the biologically active form of vitamin D. If this is inactivated during D2 conversion (from the extra hydroxylation step) as the researchers note, then this is like taking two steps forward and three steps backward.
When doctors and researchers measure vitamin D levels in the blood, they don’t measure calcitriol levels. They measure the assumed precursors — 25(OH)D in all its various forms, which include 25(OH)D2 (ergocalciferol) and 25(OH)D3 (cholecalciferol).
Furthermore, the ergocalciferol (D2) molecule is significantly different than cholecalciferol in that it has an additional methyl group on its 24th carbon. This is why it has to undergo that extra hydroxylation step in order to render calciferol.
But more importantly, as mentioned above, calcitriol becomes inactivated in this extra hydroxylation step. This means the process actually renders less available calcitriol – which the body utilizes, as it binds to cell receptors.
The critical issue is the binding of vitamin D in cells – Here is how the French researchers put it:
“First, vitamin D receptors have been found in various organs, and activation of these receptors by 1Î±,25 dihydroxyvitamin D3 (calcitriol), the physiologically active form of vitamin D, induces cell differentiation and inhibits proliferation, invasiveness, angiogenesis, and metastatic potential.”
But as noted, the the conversion from ergocalciferol removes calcitriol. This is why D2 has also been shown to render far less sustainable vitamin D activity.
“This differentiation between ergocalciferol and cholecalciferol is due to the fact that once 1,24,25(OH)3D2 has been formed, ergocalciferol has been deactivated and, therefore, is irretrievable. In contrast, cholecalciferol [now 1,24,25(OH)3D3] retains its capacity to bind to the VDR [vitamin D receptors] and still requires an additional side-chain oxidation to become deactivated. Thus, this additional step gives a vast advantage and potential for cholecalciferol to remain biologically active and, thus, maintain vitamin D status, which only strengthen the hypothesis that cholecalciferol is the preferred substrate compared with ergocalciferol.”
The statement “to remain biologically active” is precisely at issue when it comes to the research showing the poor therapeutic results of vitamin D supplementation (typically D2).
And even after vitamin D2 is converted to 25(OH)D in the blood, it is not sustainable. It does not readily convert to calcitriol. This was confirmed in a study by researchers from Nebraska’s Creighton University. The researchers gave 50,000 IU per week of either D2 or D3 to 33 healthy adults for four months. They tested the subjects’ 25-hydroxyvitamin D [25(OH)D] as well as their change in calciferol levels within subcutaneous fat cells — a measure of the body’s retention and utilization of the vitamin D.
Yes, D3 was better retained in the blood, but D2 was also retained as 25(OH)D2. The researchers found that the 25(OH)D blood levels of those taking the D3 were nearly double those who took the D2 — 45 ng/ml versus 24 ng/ml.
Even more revealing was that calciferol levels within subcutaneous fat cells increased by 104 micrograms per kilogram among those taking D3, yet only increased by a measly .033 micrograms per kilogram (33 nanograms per kilogram) among those taking the D2. This means that the amount of vitamin D that reached the cells with D2 supplementation was 0.0031% – or 0.000031 — less than D3.
The researchers calculated that D3 supplementation is 87% “more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2.”
This was emphasized in a similar study:
“When the evidence from the studies that focused on vitamin D metabolism at the cellular level is compared with the evidence from clinical trials, it is clear that, overall, there was consistency in the results that shows cholecalciferol appears to have advantageous biological qualities that allows it to sustain its systemic influence for far longer and at far greater concentrations than does ergocalciferol.”
But as far as sustained bioactivity — its final storage within fat cells, the researchers concluded that neither supplementation program resulted in significant accumulation among fat cells:
“For neither was there evidence of sequestration in fat, as had been postulated for doses in this range.”
This last point brings up the question of whether D2 supplementation — and possibly even supplemented D3 – is even therapeutic (see below).
The research showing little benefit to vitamin D supplementation utilized studies that primarily utilized vitamin D2 — though some used D3.
Furthermore, the characterization that vitamin D deficiency is linked to osteoporosis, cardiovascular disease, cancers and many other conditions has been determined by linking vitamin D deficiency with these conditions. This means that the question that has yet to be proven is whether vitamin D supplementation with synthetic forms — especially D2 and possibly even D3 — will reverse the type of vitamin D deficiencies linked among these conditions.
Because most of us — even the elderly — get some sun exposure, it is likely that vitamin D2 supplementation will actually reduce the more biologically active form of vitamin D — D3 — in the blood. And by doing that, actually reduce vitamin D function in the body.
Vitamin D2 reduces blood levels of the more therapeutic D3
In fact, a recent study confirms the physiology stated above, and brings this question to the forefront: Vitamin D2 supplementation actually lowers levels of the physiologically-active form of calciferol.
For six weeks, the UC researchers gave 38 adult volunteers either mushrooms not treated with UV exposure (containing 34 IU of D per 100 grams), UV-treated mushrooms (containing from 352 to 684 IU per 100 grams), or a supplement containing 1000 IU of D2 along with untreated mushrooms. The researchers tested the blood levels of vitamin D2 and D3 (25(OH)D2 and 25(OH)D3) before and after the testing to determine whether the mushrooms and/or supplement was increasing the vitamin D status of the subjects.
Surprisingly, the researchers found that while their blood vitamin D2 (25(OH)D2) levels went up, their 25(OH)D3 levels went down about the same, leaving their net vitamin D levels about the same and not increased as one would assume.
The disturbing thing about this study comes when we blend the understanding from the other research that blood levels of 25(OH)D2 do not convert well to vitamin D-receptor synergistic calcitriol very well. This has led to the conclusion from the study above:
While ergocalciferol may push 25(OH)D2 levels up, 25(OH)D3 produced from cholecalciferol suffers, leaving little net gain.
The researchers confirmed this in their discussion:
“Thus, ergocalciferol intake from mushrooms is beneï¬cial for participants at risk of deï¬ciency but may not improve status cholecalciferol participants with considerable sun exposure and resulting cutaneous synthesis of cholecalciferol.”
“Cutaneous synthesis of cholecalciferol” means the sulfated form of cholecalciferol.
Yes, we can now conclude that vitamin D2 is not so therapeutic and can even reduce our levels of the more therapeutic 25(OH)D3 levels. But this issue of sulfated cholecalciferol is critical to the topic of whether vitamin D supplementation is therapeutic.
Synthetic forms of vitamin D3 are typically unsulfated forms of vitamin D, while the vitamin D produced by the sun is 25-Hydroxyvitamin D3 3 beta-sulphate. This is a water-soluble form of 25(OH)D3 — sometimes referred to as vitamin D3-sulfate.
Yes, the form of vitamin D3 from supplements is not conjugated with sulfate. Does this make a difference?
Quite possibly. In fact, the research that discerned the difference between the sulfated and unsulfated forms tested 60 patients for serum levels of both. The research concluded that:
“The study also shows that unconjugated 25-hydroxyvitamin D3 is not readily sulphated by man in vivo.”
This certainly indicates that supplemented vitamin D3 may well not act the same within the body as does the body’s own sulfated form of vitamin D3 produced from sunlight.
Yes, it is the sunlight-produced form of vitamin D3 – sulfated-D3 – that is the most biologically active form of vitamin D. And because it is so biologically active, nature’s form of vitamin D produced through UVB sunlight exposure is stored within the body. So we don’t even need it every day.
Remember the one bright star of the Lancet study above was that mortality was slightly reduced by vitamin D supplementation. And this study result is mirrored by a 2007 review of 18 studies. However, the improvement in mortality was slight — between 4% and 6% among the studies.
But the problem with even this small result is that the studies these results came from were primarily of very elderly persons living in elderly-care facilities. This is problematic because they were undoubtedly deficient in vitamin D. And curiously, lower levels of vitamin supplementation — below 800 IU per day — did not change the risk of mortality. This brings into question dose-dependency, and the entire association.
The other problem with this result is that most of the patients given vitamin D in these studies were also given calcium supplements – because the two were taken together to help prevent osteoporosis. While a couple of different reviews found no difference between the effects of vitamin D with or without calcium, the calcium serves as a confounder – according to the researchers — especially when combined with the fact that the vitamin D dose did not make any difference.
The bottom line is that while unsulfated-vitamin D3 supplementation might indeed provide some help to those severely deficient in blood vitamin D levels, it remains to uncertain whether vitamin D supplementation by those who get even a marginal amount of sunlight exposure — is therapeutic.
The understanding of whether supplemented unsulfated-D3 is therapeutic may not be factually determined until at least researchers begin measuring and differentiating between the different types of 25(OH)D within the bloodstream. Measuring calcitriol would be even better. Until this is done, the issue of whether even vitamin D3 supplementation is effective will remain unresolved.
Otherwise we are simply connecting dots in the dark rather than establishing sheer relationships between supplementation and disease prevention.
This was underscored by two medical professors from the Wisconsin School of Medicine, who stated in their review of research:
“Efforts to standardize vitamin D measurement and improve understanding of the physiologic consequences of other vitamin D metabolites such as 3-epi and 24,25(OH)2D (and potentially other vitamin D compounds) are needed. Currently, measurement of circulating 25(OH)D is accepted as the approach to define an individual’s vitamin D status. However, existing 25(OH)D assays may include other vitamin D metabolites such as the 3-epimer of 25(OH)D and 24,25(OH)2D. It seems unlikely that the controversy will soon be resolved.”
What is known for certain is that the form of vitamin D our own bodies make when exposed to UVB sunlight is therapeutic, and our bodies need it.
Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: A systematic review. Lancet Diab Endo. 2014; 2(1):76-89 doi:10.1016/S2213-8587(13)70165-7
Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014 Jan 11;383(9912):146-55. doi: 10.1016/S0140-6736(13)61647-5.
Autier P, Gandini S, Mullie P. A systematic review: influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol Metab. 2012 Aug;97(8):2606-13. doi: 10.1210/jc.2012-1238.
Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat T, Pischon T, Jansen EH, Slimani N, Byrnes G, Rinaldi S, TjÃ¸nneland A, Olsen A, Overvad K, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Kaaks R, Linseisen J, Boeing H, Bergmann MM, Trichopoulou A, Misirli G, Trichopoulos D, Berrino F, Vineis P, Panico S, Palli D, Tumino R, Ros MM, van Gils CH, Peeters PH, Brustad M, Lund E, Tormo MJ, Ardanaz E, RodrÃguez L, SÃ¡nchez MJ, Dorronsoro M, Gonzalez CA, Hallmans G, Palmqvist R, Roddam A, Key TJ, Khaw KT, Autier P, Hainaut P, Riboli E. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ. 2010 Jan 21;340:b5500. doi: 10.1136/bmj.b5500.
Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011 Mar;96(3):E447-52. doi: 10.1210/jc.2010-2230.
Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, HyppÃ¶nen E, Berry J, Vieth R, Lanham-New S. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012 Jun;95(6):1357-64. doi: 10.3945/ajcn.111.031070.
Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 Sep 10;167(16):1730-7.
Axelson M. 25-Hydroxyvitamin D3 3-sulphate is a major circulating form of vitamin D in man. FEBS Lett. 1985 Oct 28;191(2):171-5.
Binkley N, Wiebe D. Clinical controversies in vitamin D: 25(OH)D measurement, target concentration, and supplementation. J Clin Densitom. 2013 Oct-Dec;16(4):402-8. doi: 10.1016/j.jocd.2013.08.006.