Vitamins and Faith

I'd mentioned in an earlier post that a relative was prescribed fairly high dose vitamin D by her primary care physician despite a blood test showing that her vitamin D level was in the normal range. Her PCP may not be much of an outlier. Among the residents I work with, I've been encountering a lot of desire to prescribe vitamin D to pretty much everyone.

Why the willingness to administer vitamins? Would these same doctors feel that a drug with similar levels of evidence for safety and efficacy should be administered to tens of millions of generally healthy people?

Somehow patients and providers alike seem willing to treat vitamins as articles of faith -- as substances that must be good for humans based on their very name and nature. Yet the actual track record of vitamins, and particularly the fat-soluble vitamins, should not lead us to be so sanguine.

Based on their antioxidant properties, vitamin A/beta carotene and vitamin E were believed to be good for health before any reasonable studies had been performed. Doctors recommended beta carotene and vitamin E at moderate or high doses, and health-conscious patients took even higher doses. Then the results of randomized trials started to come in:

 Two large randomized trials of vitamin A/beta carotene found increased rates of lung cancer in smokers, pretty much putting an end to the notion of using beta carotene to prevent cancer. Then, a meta-analysis of trials of vitamin E found an apparent increase in mortality in patients treated with higher doses of vitamin E, and suddenly vitamin E no longer appeared so benign.

With this as a backdrop, we might expect physicians, at least, to show some skepticism before recommending other vitamins, and particularly other fat-soluble vitamins.

Yet, in their defense, vitamin D has been studied in randomized trials (mainly for prevention of fractures/osteoporosis), and these trials have reported other outcomes including cancer rates and mortality.

Although much larger trials have found no effects of vitamin D on cancer rates, one trial that I've heard people cite did indeed find a reduction in cancer rates in patients supplemented with calcium and vitamin D. The RR was 0.23 -- in other words, the supplementation appeared to reduce cancers by 77%. Since virtually nothing in medicine has an effect that large, and such an effect would be hard to have missed in other trials of calcium and vitamin D, this result seems implausible at best.

With regard to mortality, a meta-analysis of randomized trials found that vitamin D supplementation appeared to decrease mortality by 7%. A concern, though, is that the result was just barely statistically significant, and there could be reporting bias with regard to mortality: trials that found larger differences in mortality (or any other safety endpoint -- these were, after all, not trials designed to look at mortality) would be more likely to report on mortality than trials that found nothing interesting when they looked at their safety data. Given the risk that the results could be due to chance, even a small amount of reporting bias would be worrisome.

So, I've now objected to one trial of vitamin D for having too large an effect to be believable, and a meta-analysis for having too small an effect to convincingly rule out chance plus bias. Am I being fair and true to the evidence?

If we were talking about a therapy for a morbid illness where we were compelled to treat, I'd likely accept the evidence from the meta-analysis as being sufficiently hopeful to make vitamin D worth a try. After all if treatment is required, even if vitamin D eventually turned out to be harmful, we would know that we had needed to do something for the ill patient and so we made our best guess.

But that is not the case here. Instead, we are talking about administering a therapy to enormous numbers of healthy people with the hope of preventing disease, and where causing even small increases in harmful outcomes would have no justification. And remember the history of vitamin E and beta carotene. If that is not sufficient to make you concerned, read what happened to cancer rates and mortality in two trials of folate/B12 supplementation in Norway, published just last week in JAMA.

In such a situation we should wait for (and demand) more convincing evidence before we act. It may turn out that vitamin D really does prevent cancer, decrease mortality, and protect people from everything from influenza to the common cold. But I would rather be late jumping on this bandwagon than jump early and find that I hadn't learned a thing from past mistakes.

Comments

[Dan Hackam]

I agree with you David. I don't even measure vitamin D levels in my patients. There is a big planned trial, planned by Harvard, of vitamin D and omega-3 fatty acids in primary prevention, but the results will not be available for at least 5 years.

At least the mortality numbers seem to be in the right direction, but we've seen off-target effects for so many of the vitamins now - vitamin C and hemorrhagic stroke, folic acid and cancer, vitamin A and cancer, etc. It makes you shiver. I tell all my patients that the vitamin cocktail they are consuming is really a drug cocktail, and we try to pare it back from there.

[James Gaulte]

Welcome to medical blogging.How we gather and use evidence and put it all together are things I have pondered about for quite a while and still manage to confuse myself with some regularity but I keep plugging away.

[Abby]

What kinds of levels are we talking about? I do take some vitamin D for bone health with my calcium and magnesium supplement. I'm also almost never in the sun. That's not a mega dose or anything.

I'm also curious as to whether there are any studies on vitamin D and seasonal affective disorder. No evidence yet, but I think it could be interesting.

[Bob Biggard]

I am amazed how naive educated physicians can be about supplements. In case most of you don't know, vitamins cannot function without mineral cofactors. Minerals, vitamins, amino acids & fatty acids & physiological & biological functions are dependent on each other. Balance, is that such a hard concept to understand? I see studies which use single vitamins, or combinations of a few or others that use synthetic forms of vitamins, some with the inorganic forms of minerals, both of these types of studies prove absolutely nothing if it isn't what the body needs. Take for instance calcium. Calcium supplementation alone will do absolutely nothing for something like osteoporosis. All minerals that make up bone & bone matrix & their cofactors are need for the body to rebuild bone density. Another is chromium supplementation for diabetes. There are 23 other cofactors essential for chromium to work. So when the author questions supplementation via studies he is correct since those studies are inadequate because of the focus on the targeted vitamins. There are other factors which are clearly not considered. Perhaps there should be more focus on the macro effect of a balanced supplementation program rather than piece mealing a few of the nutrients without the necessary cofactors.

[Robert]

I've always been weary of megadoses of vitamins, especially vitamin B supplements that give 40,000% of the recommended daily value. I know they're water soluble, but that's still a bit much to swallow.

[JE]

Many questions have been raised over the Norway folic acid study:
http://www.orthomolecular.org/resources/omns/v05n08.shtml

Then there was this new folic acid study, which has gotten virtually no media attention:
MATERNAL FOLIC ACID MAY SLASH HEART PROBLEMS IN CHILDREN:
http://www.nutraingredients.com/Research/Maternal-folic-acid-may-slash-heart-problems-in-children

[sanjiva86]

Dan Hackam: "At least the mortality numbers seem to be in the right direction, but we've seen off-target effects for so many of the vitamins now - vitamin C and hemorrhagic stroke"

Don't you mean vitamin *E* and hemorrhagic stroke?

[Kevan Gelling]

"we are talking about administering a therapy to enormous numbers of healthy people with the hope of preventing disease"

Ironically, this exactly what is happening with skin cancer sun avoidance advice - SPF 15, seek shade, avoid tanning etc.

A therapy of hormone depletion for enormous numbers of healthy people with the hope of preventing skin cancer, based solely on correlation and without trials to determine efficacy and side-effects.

[Kevan Gelling]

I understand the point that you are making (although the innuendo - failed supplement - is a bit under-hand), however there is now a mountain of evidence that vitamin D (or rather pre-hormone D) is lot more than just a maybe.

Epidemiological, longitudinal and prospective studies (1) provide strong correlation and in vivo/vitro experiments show plausibility. There's even an analysis using Hill's criteria for causality (2).

The glaring omission in the evidence trail is the lack of large scale, large dosage, serum measured RCTs. NIH's upcoming 5 year VITAL trial should settle a few things.

Your caution about fat-soluble vitamins is probably warranted though. An analysis of NHANES II data (3) found low levels of 25(OH)D "was associated with a 26% increased rate of all-cause mortality" with an optimal 25(OH)D level between 30 and 49 ng/mL. However, levels above 50ng/ml increased mortality.

-------
1. Giovannucci, E. et al. Prospective study of predictors of vitamin d status and cancer incidence and mortality in men. J. Natl. Cancer Inst. 98, 451-459 (2006). URL http://dx.doi.org/10.1093/jnci/djj101.
2. Grant, W. B. How strong is the evidence that solar ultraviolet b and vitamin d reduce the risk of cancer? an examination using hill's criteria for causality. Dermato-Endocrinology 1, 17-24 (2009). URL http://dx.doi.org/10.4161/derm.1.1.7388.
3. Melamed, M. L., Michos, E. D., Post, W. & Astor, B. 25-hydroxyvitamin d levels and the risk of mortality in the general population. Archives of internal medicine 168, 1629-1637 (2008) (http://view.ncbi.nlm.nih.gov/pubmed/18695076)

[vaal]

Thanks for the report... I'm probably going to do like you mention in your conclusion and wait a bit for more studies before "jumping the bandwagon." Too many studies keep poping up about how x helps you do x. I like to wait that other studies re-comfirm those discoveries...

[Vladimir]

Some people just don't care about evidence, they still want to do what they "Feel" is right. They still want to experience the vitamins, or drugs, or other natural remedies on their own.