Vitamin D Deficiency

What Is The Real Vitamin D Story?

Author: Dr. Stephen Chaney

If you are like most people, you probably don’t know what to believe about vitamin D deficiency. Some experts tout vitamin D as a miracle nutrient that will help you lead a longer, healthier life. They leave you with the impression that everyone should be supplementing with vitamin D.

Other experts tell you that the supposed benefits of vitamin D are all hype. They tell you not to waste your money on vitamin D supplements.

When you pull back the curtain and look at the clinical studies behind the headlines, a pattern begins to emerge.

Most of the studies that support a role for vitamin D in preventing heart disease, preventing cancer and extending life have been population studies. They have compared populations with low vitamin D intake with populations with adequate vitamin D intake. While population studies are good for suggesting associations, they have their limitations:

Population studies are good at suggesting associations, but they do not prove cause and effect.

With population studies it is also very difficult to eliminate what scientists call “confounding variables”. Let me give you an example. Suppose someone had low 25-hydroxyvitamin D levels in their blood because they sat around all day watching TV and never got out in the sun. If they got sick you wouldn’t really know whether it was due to low 25-hydroxyvitamin D levels or due to inactivity. In this case, inactivity would be a confounding variable.

On the other hand, most of the studies that fail to find any benefit of vitamin D are double blind, placebo-controlled intervention studies in which one group was given supplemental vitamin D and the other group was given a placebo. While these studies are considered the most reliable clinical studies, they have their limitations as well.

In the case of vitamin D many of these studies were done with a cross section of the population in which most of the participants already had adequate blood levels of 25-hydroxyvitamin D at the start of the study. Those studies are incapable of telling us whether correcting a vitamin D deficiency would have been beneficial.

Even when the intervention studies focus on participants with low vitamin D status at the start of the trial they have another significant limitation. They are all short term studies. Typically, the best of these studies last no more than a couple of years. Longer term studies are far too expensive. In contrast, diseases such as heart disease and cancer take decades to develop. A one or two year intervention with vitamin D simply may not be sufficient to correct the damage caused by decades of vitamin D deficiency

This is the current dilemma that is creating all of the confusion in the vitamin D story. For the most part, population studies and intervention studies are coming to very different conclusions. And both kinds of studies have inherent limitations that are difficult to overcome.

Fortunately, a new kind of clinical study has been developed in recent years that overcomes the limitations of both population studies and intervention studies.

A New Kind of Clinical Study

The new approach is something called mendelian randomization. I apologize for the scientific jargon, but let me explain. In this case you are separating your population based on genetic variation rather than on the basis of biochemical or behavioral differences.

For example, in the clinical study I will describe in a minute the population was separated into groups based on genetic variations in the DHCR7 and CYP2R1 genes. The first gene is involved in the biosynthesis of cholesterol, which is a precursor of vitamin D, and the second gene converts vitamin D to 25-hydroxyvitamin D. Both genes affect blood levels of 25-hydroxyvitamin D.

This kind of study has several unique strengths:

Genetic variations are unaffected by confounding variables such as sun exposure, obesity, smoking, inactivity, and poor diet. If the study population is large enough, those confounding variables will be equally distributed among groups that are selected solely on the basis of genetic variations.

These studies are long term by definition. If someone has a genetic variant that lowers their 25-hydroxyvitamin D level, it will do so for their entire lifetime. They can increase their vitamin D status by sun exposure, for example, but their blood levels of 25 hydroxyvitamin D will always be less than someone with equal sun exposure who does not have that genetic variant.

Because these studies reflect lifelong exposure to 25-hydroxyvitamin D they are ideally suited for measuring the effect of vitamin D status on mortality and diseases that take decades to develop.

Do Vitamin D Genes Affect Mortality?

This study (S. Afzal et al, The British Medical Journal, 2014;p 349:g6330 doi: 10.1136/bmj.g6330) combined the data from three clinical studies conducted in Copenhagen between 1976 and 2013. The age of the participants ranged from 20 to 100 years and the follow-up was 6-19 years. 95,766 participants in these studies were genotyped for variants in the DHCR7 and CYP2R1 genes which were known to affect 25-hydroxyvitamin D levels. 35,334 of those participants also had blood 25-hydroxyvitamin D levels determined. By the end of the study 10,349 of the participants had died.

The individual genetic variants included in this study caused a relatively small (1.9 nmol/L) decrease in blood levels of 25-hydroxyvitamin D. However, because this was a very large study and the participants with those genetic variants were exposed to lower 25-hydroxyvitamin D levels for their entire lifespan, the decreased 25-vitamin D levels were associated with significant increases in all cause mortality and cancer mortality, but not with increased cardiovascular mortality.

When they extrapolated to a genetically caused 20 nmol/L decrease in 25-hydroxyvitamin D, the decrease in 25-hdroxyvitamin D was associated with a 30% increase in all cause mortality and a 30% increase in cancer mortality.

What Kind Of Studies Are Needed Next?

The authors noted that this is the first study of its kind, so it obviously needs to be confirmed by other large mendelian randomization studies that test the link between vitamin D status and mortality.

Ideally, it should also be verified by double blind, placebo controlled intervention studies, but that may not be possible. If one really wanted to verify this study, the intervention study should start with a population group with 25-hydroxyvitamin D levels at least 20 nmol/L below what is considered adequate and provide them with enough supplemental vitamin D to increase their 25-hydroxyvitamin D to the adequate range. That is difficult, but doable.

However, the intervention study would also need to be long enough (decades perhaps) to prevent cancer from developing. That kind of study will probably never be done.

The Bottom Line

The relationship between vitamin D status and mortality has been investigated with a new type of clinical study based on what is called mendelian randomization. Population groups were segregated based on genetic variations in two genes that affect blood 25-hydroxyvitamin D levels (a measure of vitamin D status).

This study concluded that a genetically determined decrease of 20 nmol/L in blood 25-hydroxyvitamin D was associated with a 30% increase in all cause mortality and a 30% increase in cancer mortality, but had no significant effect on cardiovascular mortality.

This kind of study is particularly strong because it measures the affect of lifelong exposure to 25-hydroxyvitamin D. This is important when assessing the effect of vitamin D status on mortality and diseases such as cancer that take decades to develop. In contrast, the double blind, placebo controlled intervention studies that are consider the “Gold Standard” for clinical studies may be too short term to adequately assess the effect of vitamin D status on cancer or all cause mortality.

This study supports the benefit of maintaining optimal vitamin D status, but it is the first clinical study of its kind and needs to be confirmed by other studies.

In the meantime, there is no harm to in maintaining your blood levels of 25-hydroxyvitamin D in the optimal range through diet, sun exposure and supplementation. This study suggests it just may help you live a longer, healthier life.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.