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Where Have You Gone Vitamin D?

by Dr. Len March 23, 2011

Oh, vitamin D, where have ye gone?  We miss ya!!


That might be the refrain of many who have labored so long to promote awareness of vitamin D as a possible cancer prevention agent for the past number of years. 


Not that the advocates have lost their faith-a recent article from Dr. Cedric Garland, who is an expert on vitamin D as a case in point-but a report from the Institute of Medicine (IOM) has thrown a bit of a damper on the unbridled enthusiasm that vitamin D was the answer to cancer prevention that many have been seeking for some time.


No, the IOM did not endorse vitamin D as a cancer prevention agent.  And based on what they could say from the literature, the panel did endorse the concept that vitamin D is important for bone health, while blood tests that reportedly showed substantial deficiencies throughout the United States were in fact not being appropriately interpreted.


Now, in a "Perspective" piece in this week's New England Journal of Medicine, three of the IOM panel members share their thoughts with the public as to why the panel did not reach the conclusion that vitamin D decreases cancer risk.  And, while they support that conclusion, they also don't lose sight of the possibility that there may just be some truth behind the claims-bit it hasn't been proven just yet.


First, the authors-all highly regarded-make the general observation that "the prevalence of vitamin D inadequacy in North America has been overestimated.  Most North Americans have serum 25-hydroxyvitamin D concentrations above 20 ng per milliliter, which is adequate for bone health in at least 97.5% of the population."


That statement is important, because bone health is the one area that the panelists agree the evidence is adequate that vitamin D does something valuable in our bodies.


But when it comes to cancer, the authors paint a less complete picture about the evidence surrounding the benefits of vitamin D as a cancer prevention agent.


According to the authors, the committee's review of the evidence surrounding vitamin D and cancer "revealed that the research is inconsistent and doesn't establish a cause-effect relationship."


One of the real sticking points is the absence of forward-looking, randomized trials where vitamin D was the sole variant and cancer incidence was the endpoint.  Too many of the trials look at different information that was collected in a variety of ways to assess the impact of vitamin D on cancer outcomes.  There are simply too many factors that could and did interfere with the interpretation of that data, and they cited circumstances where data analysis which appeared to show a benefit of vitamin D on a particular cancer in fact didn't pan out when the data was analyzed a different way, taking into account some of those "interfering factors" (which we call "confounders").


What are some of those factors?


As the authors note, some that are associated with a higher cancer risk include obesity (which harbors vitamin D in fatty tissue), the absence of outdoor activity (not being active is associated with all sorts of health problems, including cancer), dark skin pigment (reducing the amount of vitamin D made in the skin because of less production), diet, and whether or not a person takes vitamin D supplements.


So, just because something appears to be the case doesn't mean that it is the case.


If you went to the Eastern shore of Maryland and didn't know anything about life, and you saw a lot of sunburned people drinking beer and eating crabs at night, you might think that beer and crabs caused sunburn.  That is an example of "true-true-but-not-related."  The same thing may be happening in a lot of the research reported on the association of vitamin D and cancer.  That's why properly done clinical trials-which admittedly take a long time to do-are what we need to definitively answer the question up or down as to whether or not vitamin D decreases cancer risk, and for which cancers.


This is not a new problem by any stretch of the imagination. 


Very competent and committed scientists have drawn similar conclusions about different vitamins and minerals in the past, based on data seen in various clinical studies.  Selenium, beta-carotene and vitamins C and E are but a few examples that have been suggested as cancer preventive agents previously.


But when the appropriate trials were done, the associations did not hold up.  In fact, in one classic and frequently cited study, the beta-carotene actually had the opposite effect, by leading to the deaths of more smokers that occurred on the control arm of the trial, where they did not receive the vitamin in question.


It is important to note, however, that the authors of the current paper in the Journal do not close the door on the possible activity of vitamin D on preventing cancer:


"The theory that vitamin D can help prevent cancer is biologically plausible.  The vitamin D receptor is expressed in most tissues.   Studies in cell culture and experimental models suggest that calcitriol promotes cell differentiation, inhibits cancer-cell proliferation, and exhibits anti-inflammatory, proapoptotic (cancer cell death mechanisms0 and antiangiogenic (slows growth of tumor-related blood vessels) properties.  Such findings suggest, but don't prove, that vitamin D has a role in preventing the development of cancer or slowing its progression."


I wouldn't call that a "death knell" statement regarding the possible relationship between vitamin D and cancer prevention.  Just a bit of a hazard warning while moving on to a better scientific place where the ground is firmer and the sky a little less cloudy.


The authors go on to site data regarding some specific cancers and previous claims that vitamin D reduced the risk of getting those cancers.  They include breast cancer, colorectal and prostate cancers.  In each situation, they point out the conflicting and/or inconclusive evidence regarding the possible association.  They also comment that for less common cancers, the evidence is equally conflicting or not adequate to draw firm conclusions.  Of interest was their observation that in one study of pancreatic cancer, higher levels of vitamin D were actually associated with a significantly increased risk of getting that usually fatal illness.  Similar increased risk has also been reported for esophageal cancers.


Their final statement in their report was pretty blunt:


"Despite biologic plausibility and widespread enthusiasm, the IOM committee found that the evidence that vitamin D reduces cancer incidence and related mortality was inconsistent and inconclusive as to causality.   New trials assessing moderate-to-higher dose vitamin D supplementation for cancer prevention are in progress and should provide additional information within 5 to 6 years.  Although future research may demonstrate clear benefits of vitamin D related to cancer and other nonskeletal health outcomes, and possibly support higher intake requirements, the existing evidence falls short."


I guess that statement is pretty conclusive, isn't it? And if we have waited this long to find out what we don't know for certain, maybe waiting another couple of years to get better answers may not be a bad idea. 


Just don't get burned in the sunshine getting your vitamin D while you are waiting for the results of the research.  At least we know for certain that sunburn is not good for your health.




3/30/2011 4:19:39 PM #

David Collin

Yes, the evidence is not conclusive, but vitamin D is important in many aspects of health (http://bit.ly/hDZU4w ). I moved from California to Oregon a year ago. Now my wife has vitamin D deficiency and is taking a supplement. Vitamin D deficiency is rampant up here. As  for me, when the winter clouds move out I'm going to get myself plenty of sunshine. Reality is that we need a broad, integrated understanding of our health. I'm not so sure anymore that a single-disease focus is all that helpful.

David Collin

4/14/2011 7:16:23 PM #

Cedric F. Garland, Dr.P.H., F.A.C.E.

Dear Dr. Len, Thanks for citing our work.  Our research group continues a high degree of enthusiasm in favor of the ability of vitamin D and calcium to reduce the incidence of colon and breast cancer.  The IOM seems to have neglected an excellent randomized, placebo controlled, clinical trial (RCT) that identified a 60-77% reduction in the incidence of all invasive cancers combined  in postmenopausal women who were randomly assigned to vitamin D and calcium combined compared to placebo.   The effect of vitamin D alone was in the same direction but smaller than the effect of vitamin D plus calcium.  This superb RCT was intended to test whether vitamin D and calcium supplementation reduced incidence of fractures.  Instead the most important findings concerned their effect on reducing incidence of cancer.  This outstanding RCT confirmed on experimental grounds that vitamin D and calcium reduce the incidence of cancer in women  (the main cancers in the women were the usual suspects breast, colon and lung).   Of course vitamin D and calcium cannot prevent smoking-induced lung cancer, but this RCT adds to numerous lines of evidence from many types of studies in several countries reporting that it reduces the risk of breast and colon cancer.   Of course some studies have missed the association, mainly due to design flaws.  This is to be expected, as this is science, and scientific data are not always 100% in agreement, as not all studies are necessarily perfect.   We should act even if we only accept that vitamin D and calcium prevent colon cancer, since colorectal cancer is the second leading cause of cancer death in the US.  Preventing breast cancer (ductal adenocarcinoma) is likely to be a very pleasant bonus for women who take this action.  The RCT raised the serum 25-hydroxyvitamin D to about 40 ng/ml on the average in the treatment group compared to 30 ng/ml in the placebo group. The intervention consisted of 1,100 IU/day of vitamin D3 and 1450 mg/day of  elemental calcium, as calcium carbonate.  Our research indicates that men in the US should aim for a serum 25(OH)D concentration of 40-60 ng/m. Women should aim for this range as a minimum.  Women at hugh risk of breast cancer may want to consult with their physician, and if there is consensus, aim for a serum concentration of 60-80 ng/ml.  These serum concentrations are safe as they are well below the minimal threshold for toxicity of serum 25-hydroxyvitamin D, specifically, 200 ng/ml.  To benefit from the research that has been conducted during the pst 2 decades, and this new RCT, now rather than waiting another 5-6 years for another RCT, US men should take 4000 IU/day, on the average; women should take 8000 IU/day. These intakes are both below the Institute of Medicine No Observed Adverse Effect Level (NoAEL) in the new IOM monograph (Committee to Review Dietary Reference Intakes for Vitamin D and Calcium, Institute of Medicine, National Academy of Sciences, Report on Dietary Reference Intakes for Vitamin D and Calcium. Washington DC: National Academy Press,December 2010- available online).  Of course, the person's physician should be consulted.  Physicians may also order the serum 25(OH)D test to help with monitoring serum 25-hydroxyvitamin D.  The measurement should be made in February or MArch, when 25-hydroxyvitamin D is usually lowest in the blood.
This RCT that confirmed the association of vitamin D-deficiency with cancer can be found using PubMed or at any medical library. It is:  Lappe JM, Travers-Gustafson D, Davies KM, et al.  Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.  American Journal of Clinical Nutrition 2007;85:1586 –91.
Cedric F. Garland, Dr.P.H., F.A.C.E.

Cedric F. Garland, Dr.P.H., F.A.C.E.

About Dr. Len

Dr. Len

J. Leonard Lichtenfeld, MD, MACP - Dr. Lichtenfeld is Deputy Chief Medical Officer for the national office of the American Cancer Society.