By bedeviling confounding in a new epidemiological study …

Vitamin D Lowers the Risk of Dying
… may be said with more assurance

By Will Block


Too many redheads can skew the result of a vitamin D study if not confounded.

A dequate amounts of vitamin D can increase your healthspan and even your lifespan, by extending it beyond when you might “normally” have developed a disease or died. That’s a widely held conclusion by many scientists and physicians who are aware of many of the overwhelming number of clinical trials reported in the National Library of Medicine (over 4,100!) — a great many of which show positive results for vitamin D. That’s important, because more life extension is sure to come in the near future, and to come faster, improving and extending health even more so. You may want to be there! Yet there has been a lot of confusion generated by recent epimemiological studies that have been published on vitamin D. This is because of something called confounding.

Confound It!

Alternate explanations of why something may be true or false are based on what are called confounding factors. They’re the bane of researchers studying almost any aspect of health or disease, because they make it difficult to isolate one factor of interest and link it unequivocally to some particular health outcome, such as living longer.

In statistics, a confounding factor is an extraneous variable in a model that correlates (directly or indirectly) with both the independent variable and the dependent variable (see Fig. 1). As an example, the color of hair (normally an extraneous variable) may result in greater vitamin D production if one’s hair color is red, because the genetics of red hair is associated with the ability to produce vitamin D from sunlight more readily.

In the recent vitamin D epimemiological (the branch of medicine dealing with the incidence and prevalence of disease in populations) studies — designed to determine the relationship between vitamin D levels and mortality — the independent variable is a binary variable for adequate and inadequate levels of vitamin D, and the dependent variable would be the risk of dying.

The Failure to Confound

If such a study oversamples Irish or Scotch (who have much more red hair) without confounding, then the results will be skewed away from a more reliable conclusion. In technical terms, the perceived relationship between the independent variable and dependent variable would have been misestimated due to the failure to account for a confounding factor. This is termed a spurious relationship, and the presence of misestimation for this reason is termed an “omitted-variable bias.”


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Observational Studies Are those without Treatment

In epidemiology, observational studies draw inferences about the possible effect of a treatment on subjects. However, in these studies, individuals are observed but not treated; i.e., subjects are outside the control of investigators. This is a crucial distinction that needs to be made in order to understand what we are finding out about the supplemental use of vitamin D3. Observational studies are indicating that low concentrations of vitamin D are associated with increased all-cause, cardiovascular, and cancer mortality. Two such studies have recently shown this.

In the first of these recent observational studies,1 published just last April (2014), researchers concluded that the circulating levels of vitamin D levels inversely correspond with risks of death due to cardiovascular disease, cancer, and other causes. This is significant. Supplementation with vitamin D3 appreciably reduces overall mortality among older adults.


Circulating levels of vitamin D levels
inversely correspond with risks of
death due to cardiovascular disease,
cancer, and other causes.


In the second, published two months later in June2 — despite the strong differences of levels of vitamin D levels among country, sex, and season — the association between these levels and all-cause and cause-specific mortality was remarkably consistent.

However, observational studies have their limitations. Correlation does not constitute causality.

Experimental Studies Often Fail to Support Observational Ones

In experimental studies, by contrast, randomized controlled trials have not repetitively found reduced mortality after vitamin D supplementation.3 Whether low vitamin D concentrations are a cause of increased mortality or simply a consequence of poor health is thus unclear in the findings of many of these studies.

This is an important question, because millions of people the world over are regularly taking vitamin D supplements, with the goal of preventing diseases and even extending life.

But there are limitations to experimental studies, too, especially if they are not properly confounded — and many are not. Remember that these limitations apply to observational studies, too.

An Observational Study with Genetic Confounding

With the aim of clarifying whether low serum vitamin D itself increases the risk of death, a new observational study used a technique to reduce confounding.4 In the study, Danish researchers used data from government health records of 95,766 subjects. Noting that genetic variants have been reliably associated with circulating concentrations of vitamin D, the Danes set out to test the theory that genetically low vitamin D levels are associated with increased mortality. To avoid confounding, they used a technique called Mendelian randomization. This method measures variation in genes of known function to examine the causal effect of a modifiable exposure on disease in non-experimental studies. It is a method for obtaining unbiased estimates of the effects of a presumed causal variable without conducting a traditional randomized trial.


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All subjects were tested for a genetic variant that reduces their vitamin D levels, and 35,334 also had their vitamin D serum levels measured. There were 10,349 deaths over the course of the study, which took place from 1981 to 2013. Genetic studies are largely free of confounding, as the random assortment of genes that occurs during gamete (fertilization) formation secures an equal distribution of confounding factors among different genotypes. Thus, these studies can be used for assessing whether genetically affected risk factors are related to clinical outcomes.

By studying two large populations, one of which had the genetic variant for low vitamin D and the other of which did not, the researchers were able to virtually eliminate the impact of confounding factors like other diseases, habits and behaviors that might be contributing to poor health. These traits would be evenly distributed in the populations studied, leaving only the genetic difference between them.

Persuasive Evidence

In their conclusions, the scientists found that having the genes associated with lifelong low vitamin D increases the risk of cancer death by more than 40 percent, and the risk of death from any cause by more than 30 percent. They found no effect on cardiovascular disease-related death. Thus, when compared with other vitamin D observational studies, the Danish study provides persuasive evidence. And thus, this observational study had increased reliability over the others. Of course, this did not prevent the researchers from calling for experimental studies to make the finding airtight (and probably to keep their colleagues and themselves permanently employed!). But until then, no supplementation.

Optimal Health

According to much of the experimental research, vitamin D is a micronutrient that is needed for optimal health. As vitamin D3 (cholecalciferol) it can be either synthesized in the human skin upon exposure to the UV light of the sun, or obtained from the diet. In winter, or especially in the northern climates, it is useful to obtain it from supplementation.


Despite the strong differences of
levels of vitamin D levels among
country, sex, and season — the
association between these levels and
all-cause and cause-specific mortality
was remarkably consistent.


Surprisingly, among the elderly, southern climates do not necessarily produce enough vitamins D, because as we get older, we avoid the sun as our skin gets thinner and becomes more susceptible to overexposure and damage. For this and other reasons, the elderly rarely obtain sufficient sun exposure to make adequate levels of vitamin D, so supplements are necessary to achieve healthy vitamin D levels.

Severe vitamin D deficiency can lead to a multitude of avoidable illnesses, including bone diseases like osteoporosis, a number of autoimmune diseases, many different cancers, and some cardiovascular diseases like hypertension.

Not Available Via Foods

Vitamin D is found naturally in only very few foods. These include some fatty fish, fish liver oils, and eggs from hens that have been fed vitamin D, and some fortified foods in countries with respective regulations.

Based on geographic location or food availability, adequate vitamin D intake is not sufficient on a global scale. The International Osteoporosis Foundation (IOF) has collected the vitamin D plasma levels in the populations of different countries using published data, and developed a global vitamin D map.5 This map shows the parts of the world where vitamin D does not reach adequate levels: 6.7% of the papers report vitamin D plasma levels below 25 nmol  /  L, which indicates vitamin D deficiency, 37.3% are below 50 nmol  /  L, and only 11.9% found 25-hydroxyvitamin D plasma levels above 75 nmol  /  L target as suggested by vitamin D experts. None of these levels are optimal (see subsections below: “Identifying the Right Dose”). The IOF’s latest figures show that globally about 88% of the population does not have an optimal vitamin D status.6

The Foundation’s map adds further fuel to the fire of the debate regarding vitamin D insufficiency, which is a major issue in the undeveloped world because of malnutrition. And, without enough nutrient-containing foods consumed, inadequacy of vitamin D is often rampant. Thus the nutrition community is highly interested in the molecular mechanism that underlies the vitamin D insufficiency-caused effects. In recent years, important methods have been developed for nutritional approaches summarized in emerging scientific fields of nutrigenomics, nutrigenetics, or nutriepigenetics. “It is believed that with the help of these novel concepts, further understanding can be generated to develop future sustainable nutrition solutions to safeguard nutrition security.” Should the same be true of the developed world, where these ideas are frequently taken less seriously?


Table 1. Diagnostic Cut-Offs of Serum Levels of 25[OH]D
25[OH] Level
(ng  /  mL)
25 OH]D Level
(nmol  /  L)
Laboratory
Diagnosis
Recommended
Amount

< 20 ng  /  ml
< 50 nmol  /  L
Deficiency
 
1000 IU  /  day
< 30 ng  /  ml
< 75 nmol  /  L
Insufficiency (mild)
2000, 5000, or even
10,000 IU / day
>30 ng  /  ml *
>75 nmol  /  L
Protective Effect
 
 
Range: 36 – 40 ng  /  ml
Range: 90 – 100 nmol / L
Optimal
 
 

* John Cannell, MD, is the president of The Vitamin D Council, a non-profit group that advocates higher vitamin D intake. According to Dr. Cannell, adults need to take 5,000 IU a day of vitamin D to put the vast majority of them (97.5%) above the 50 ng / mL level. And furthermore, Dr. Cannell argues that optimal doses for adults are between 4,600 and 10,000 IU, with persuasive evidence that 10,000 IU a day of supplemental vitamin D is not toxic.8-14

Since our analysis uncovered 85% of blood test results are far below 50 ng / mL, it appears that virtually all members should supplement with 5,000 to 8,000 IU of vitamin D3 each day — especially in winter months!

Fears of vitamin D toxicity have caused health-conscious people to limit their vitamin D3 intake to only a few thousand IU (international units) a day. This amount is clearly inadequate to optimally protect against disease, based on recently published studies.

Identifying the Right Dose

In the last few years, significant numbers of researchers have recommended that vitamin D deficiency be redefined. The result is that many laboratories have changed their reference range for serum levels of vitamin D to comply with new recommendations.7

Historically, the lower limit of normal for serum levels has been 10 – 15 ng  /  ml (25 – 37.5 nmol  /  L). But now, many laboratories are defining vitamin D deficiency as a serum < 20 ng  /  ml (< 50 nmol  /  L), and mild vitamin D deficiency as a level < 30 ng  /  ml (< 75 nmol  /  L). Some have suggested increasing serum levels to an “optimal” level could improve a wide range of health outcomes, including fewer falls and fractures, better bone and dental health, and possible protection against cancer and autoimmune disease.

One review article found that a protective effect began at a 30 ng  /  ml (75 nmol  /  L), and that the best outcomes were seen in people with levels of 36 – 40 ng  /  ml (90 – 100 nmol  /  L).

According to Alan Gaby, MD: If one accepts these new laboratory criteria, then inadequate vitamin D status emerges as a major epidemic, being present in 40 – 50% of participants in many studies.” The amount of supplemental vitamin D needed to achieve “adequate” or “optimal” status is well above 800 IU  /  day of vitamin D.

Furthermore writes Dr. Gaby (see Table 1):

  • “[I]t has been estimated that only 50% of people who take 1,000 IU  /  day of vitamin D will attain a serum 25(OH)D level of 30 ng  /  ml (75 nmol  /  L)

  • “The estimated dosage needed to achieve a level of 30 – 32 ng  /  ml (75 – 80 nmol  /  L) in nearly all healthy adults has ranged from 1,644 IU  /  day to more than 3,440 IU  /  day in different studies.

  • “Even larger doses would be needed to achieve an “optimal” level of 36 – 40 ng  /  ml (90 – 100 nmol  /  L).

  • “Based on these findings, some practitioners are recommending long-term supplementation with 2,000, 5,000, or even 10,000 IU  /  day of vitamin D for many of their patients.”

Resveratrol Potentiates Vitamin D

Derived from vitamin D, the 1,25-dihydroxyvitamin D3 (1,25D) hormone, which circulates in the blood, binds to and activates the vitamin D receptor (VDR) in target tissues. These tissues include the kidney, the colon’s small intestine, bone, and muscle.

In a new study, researchers tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (VDRE) and a mammalian transcriptional system technology.

They found that VDR-mediated transcription was activated by resveratrol, which had a cooperative effect on transactivation when observed with resveratrol plus 1,25D. Cells treated with both resveratrol and 1,25D displayed synergistic stimulation, thereby increasing vitamin D’s effects in our cells.

This allows populations at risk to be determined, and resveratrol could potentially be utilized as a preventive nutritional supplement to boost VDR activity in patients with genetical dispositions that attenuate vitamin D action.

Because the cancer preventive properties of resveratrol also lessen the impact of UV radiation and oxidative damage, additional clinical application of combined vitamin D and resveratrol may be translated to other types of malignancy such as skin and breast cancer.

The interplay between resveratrol and vitamin D could be exploited to enhance treatment or facilitate preventive measures for bone mineral diseases.

Reference

  1. Dampf-Stone A1, Batie S, Sabir M, Jacobs ET, Lee JH, Whitfield GK, Haussler MR, Jurutka PW. Resveratrol Potentiates Vitamin D and Nuclear Receptor Signaling. J Cell Biochem. 2014 Dec 23. doi: 10.1002/jcb.25070. [Epub ahead of print]

References

  1. Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
  2. Schottker B, Jorde R, Peasey A, Thorand B, Jansen EH, Groot L, et al. Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ. 2014;348:g3656.
  3. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 2014;1:CD007470.
  4. Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Genetically low vitamin D concentrations and increased mortality: mendelian randomization analysis in three large cohorts. BMJ. 2014 Nov 18;349:g6330. doi:10.1136 / bmj.g6330.
  5. Bendik I, Friedel A, Roos FF, Weber P, Eggersdorfer M. Vitamin D: a critical and essential micronutrient for human health. Front Physiol. 2014 Jul 11;5:248. doi: 10.3389 / fphys.2014.00248.
  6. Péter S, Eggersdorfer M, van Asselt D, Buskens E, Detzel P, Freijer K, Koletzko B, Kraemer K, Kuipers F, Neufeld L, Obeid R, Wieser S, Zittermann A, Weber P. Selected Nutrients and Their Implications for Health and Disease across the Lifespan: A Roadmap. Nutrients. 2014 Dec 22;6(12):6076 – 94.
  7. Gaby AR. Vitamin D: Irrational Exuberance? Integrative Practitioner. http://www.integrativepractitioner.com/article.aspx?id=17867 Accessed: December 28, 2014.
  8. Vieth R. Vitamin D toxicity, policy, and science. J Bone Miner Res. 2007 Dec;22 Suppl 2:V64 – 8.
  9. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005 Feb;135(2):317 – 22.
  10. Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr. 2001 Feb;73(2):288 – 94.
  11. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6 – 18.
  12. Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266 – 81.
  13. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003 Jan;77(1):204 – 10. Erratum in: Am J Clin Nutr. 2003 Nov;78(5):1047.
  14. Norman AW, Bouillon R, Whiting SJ, Vieth R, Lips P. 13th Workshop consensus for vitamin D nutritional guidelines. J Steroid Biochem Mol Biol. 2007 Mar;103(3 – 5):204 – 5.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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