Is Vitamin D Cancer-Protective?

It’s the million-dollar question: Is vitamin D cancer-protective?

In preparing for presentations at several upcoming conferences, I’ve been scouring recent months’ flurry of scientific journal articles on this question. More than ever, research is looking beyond bones to vitamin D’s potential to reduce risk of cancer and perhaps improve outcome when cancer does occur. As strong as today’s research has become about a role for vitamin D, we are left with big questions as we puzzle over what to do about this apparent link.

If you read just one magazine or website article, you may think the answer is crystal clear. Not true. Researchers who are highly respected for their expertise in this area look at the data and for now, differ in the bottom-line message they offer.

Read on for my take-away based on my latest exploration of the research.

Vitamin D and Lower Cancer Rates: The Big Splash

We get vitamin D both from our diet and from what we produce in our skin in response to sunlight. The same amount of vitamin D consumption and sunlight exposure can result in different amounts of active vitamin D produced. Most research focuses on blood level of the inactive form of vitamin D — called 25(OH)D – as a marker of how much vitamin D is getting to cells, where it can then be activated and used.

The latest analyses pulling together results from multiple population studies show exciting potential:

• Higher compared to lower blood levels of vitamin D – in its 25(OH)D form – were linked to 14% fewer deaths from cancer in an analysis of 12 population studies that tested people’s blood levels and followed them for several years.
• Higher compared to lower blood levels of 25(OH)D were linked to 35% fewer deaths from all causes in analysis of 27 studies.
• The type of cancer most consistently tied to vitamin D levels, colorectal cancer risk, was 34% lower in people with highest 25(OH)D than in those with lowest levels, according to an analysis that pulled together eight prospective population studies.
• Breast cancer risk shows less consistent association with vitamin D levels, but an analysis of population studies showed a 48% lower risk of breast cancer in those with higher versus lower levels. Because the type of studies in this analysis are not as statistically strong as the prospective studies discussed above, conclusions based on the analysis are more tentative.
• Among breast cancer survivors, in analysis of five studies combined, women with highest levels of 25(OH)D had about half the rate of breast cancer death as women with the lowest blood levels.
• Lower risk for prostate and lung cancers and Non-Hodgkin’s lymphoma also link to adequate vitamin D levels in some studies. However, recent analyses of multiple studies have tended to show no clear association. The Vitamin D Pooling Project of Rarer Cancers, in looking at 25(OH)D levels before a cancer diagnosis generally is showing no overall association for these cancers, including esophageal and stomach cancers.

Links to cancer deaths can signal effects on risk of cancer and on prognosis among those who get it. These are observational studies, however, which means they do not show cause-and-effect.  Although researchers statistically adjust for known risk factors like age, smoking and lack of exercise, there can be things about the lifestyle of people whose diets or time in the sun lead to higher vitamin D levels that are also providing cancer protection.

Making sense of research involving cancer survivors is even trickier. If blood levels of vitamin D are measured after (or shortly before) the diagnosis of cancer, low levels linked with poor outcomes could mean tumors grow and spread faster without vitamin D’s influence thwarting these processes. But it could also reflect sicker patients having lower levels of vitamin D because they are going outside less, or reflect changes in vitamin D that result from, rather than cause, advanced cancer.

Why D and Cancer?

You may think of vitamin D mainly as a nutrient related to calcium metabolism and bone health. This could be part of D’s link to lower risk of colorectal cancer. However, laboratory cell and animal studies now suggest that vitamin D in its activated form could also directly help control cells’ growth and promote their development into stable forms less likely to develop into cancer, and also act further along in the cancer process, stimulating self-destruction of abnormal cells (apoptosis) and limiting cancer cells’ ability to spread. Additional protection against breast cancer in postmenopausal women could result from active vitamin D’s effects decreasing formation of estrogen and inhibiting estrogen receptors in breast cancer cells.

Vitamin D Levels: Plenty of Confusion

Blood concentrations of 25(OH)D are considered a good biomarker of vitamin D status, reflecting combined influence of foods, supplements, and exposure to sunlight.

Here are several key points to keep in mind when you hear about vitamin D research or try to make sense of what you will do about it:

• Blood levels of vitamin D are measured using two different units. To interpret blood levels, checking the units is essential. Research studies often express levels as nmol/L.  Doctors’ offices and hospitals tend to report vitamin D levels in ng/mL. To convert levels expressed as ng/mL to nmol/L, multiply by 2.5. (A level of 20 ng/mL is approximately 50 nmol/L.)
• Although evidence is mounting that having enough vitamin D could play a cancer-protective role, the question is how much is enough, and how much might be too much. Dietary recommendations have been based on blood levels of 25(OH)D linked with bone health. The Institute of Medicine (IOM) committee based the current RDA (Recommended Dietary Allowance) for vitamin D on reaching a target blood level of 20 ng/mL (equal to 50 nmol/L). The Endocrine Society, composed of researchers and physicians specializing in endocrinology (hormone-related disease), recommends a target of 30 ng/mL (or 75 nmol/L).
• How many Americans are lacking adequate vitamin D? Most Americans reportedly meet the 20 ng/mL blood level target of the IOM. When you hear that 69.5% of the population has insufficient levels of vitamin D, that is based on 30 ng/mL as the goal.

Is More Better? Or Just More?

Inactive 25(OH)D is converted to its active form, 1,25(OH)₂D, which is actually a hormone (also known as calcitriol). In the kidney, the body regulates its production carefully. However, inactive vitamin D can also be converted to its active form in various cells of the body, including cancer cells. Current research suggests that production outside the kidney is not regulated in the same way, and amounts produced are primarily driven by amounts of the inactive 25(OH)D available. The activated D produced in these tissues then acts locally to affect signals that regulate cell growth and development into cancer. This could mean that blood levels of 25(OH)D higher than needed for bone health might lead to levels of active vitamin D in cells throughout the body even more able to protect against cancer. But we don’t know that.

•  In analysis based on deaths from all causes (not just cancer), the clearest difference was between people with a blood level that is definitely deficient (less than 10 ng/mL) compared to those in the highest range (over 30 ng/mL).  Levels of inactive vitamin D in the range of 10 to 20 ng/mL also clearly were associated with higher mortality than those over 30. The answer to the key question – What about a 25(OH)D level between the IOM standard of 20 and the Endocrine Society standard of 30? – is much less clear. In analysis of 14 studies in the British Journal of Medicine, this mid-level range is associated with 7% greater mortality risk. Analysis as part of the American Institute for Cancer Research/World Cancer Research Fund Continuous Update Project found that colorectal cancer risk declined continuously as 25(OH)D level increased, up to about 40 ng/mL.
• People differ from one another in many ways. Differences in several genes that control metabolism of vitamin D and regulate the receptor through which it works likely mean that the same level of 25(OH)D will bring different results in different people. Some researchers caution that these genetic differences could make some people vulnerable to negative effects of high vitamin D with smaller amounts than others, and urge caution until we better understand these inter-individual differences.
• Body fat is sometimes referred to as a “Vitamin D sink”, because vitamin D is pulled out of circulation and stored there. That may make raising blood levels especially challenging in people with excess body fat – now about 69% of U.S. adults – and we don’t know whether to aim for the same blood level as a target.
• Could there be a blood level of 25(OH)D that is too high to be safe? Theodoratou and colleagues, in a recent analysis in the British Medical Journal, say that no analysis of observational population studies has identified increased risk with higher levels. Several vitamin D researchers have written commentaries suggesting they see no evidence of what is known as a “U-shaped curve” for vitamin D. However, we’ve seen several nutrients over the years that seemed sure to be an example of “more is better”, only to find that to be untrue.

Where Does that Leave Us?

Evidence does now seem reasonably strong that having enough of the inactive vitamin D available for the body to convert to its active form could play a role in supporting overall health, including lower  cancer risk and mortality. If you are likely to be lacking D, based on little exposure to sunlight to turn on skin production and also unlikely through your food choices to reach current RDA of 600 IU per day (or 800 IU if you’re over age 70), then it would be smart to discuss choosing a vitamin D supplement with your physician or registered dietitian. People who are at risk of kidney stones need to be cautious about high intake, as this can increase risk of their formation in some people.

• As you consider how much vitamin D you are currently getting, count foods high in vitamin D both naturally and through fortification, including cereals, bars, drinks and other choices not traditionally considered vitamin D sources; if you take a multi-vitamin, make sure to include that too.
• If you choose to aim for a total beyond the RDA (such as 1000 IU per day total from food and supplements), as some suggest may be needed if a 25(OH)D level of 30 ng/mL is targeted, the IOM Dietary Reference Intakes identify that as safe. But remember we don’t have controlled trials of long-term use that demonstrate any added cancer protection.
• Studies have gone back and forth over the years whether vitamin D₂ supplements are as effective as vitamin D₃. Vegetarians prefer the D₂ form, also known as ergocalciferol, which comes from plants. However, a recent Cochrane Database analysis of randomized controlled trials of vitamin D in older adults found 12% decrease in cancer mortality with use of D₃ supplements (regardless of whether dose was below or above 800 IU), yet no significant effect of D₂ supplements. More research is needed.

The Bottom Line: To reduce cancer risk and promote overall health, set your priorities on reaching and maintaining a healthy weight, creating eating habits that make nutrient-rich plant foods the centerpiece, and being physically active every day. As part of that overall plan, it makes sense to at least make sure your vitamin D is not at the low levels clearly linked with increased risk of colorectal cancer, and perhaps others. Beyond that, it’s reasonable, but not a sure thing at this time, to either meet the 600 (or 800) IU recommendation, or perhaps go a little higher, especially if you have a blood test indicating that your 25(OH)D level is not above the 20 or 30 ng/ML target you and your doctor agree is best for you.

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Resources

For more on Vitamin D sources and the background on recommended amounts, the Office of Dietary Supplements of the National Institutes fo Health offers a Quick Facts sheet with the essential information, as well as a detailed fact sheet for Health Professionals.

To get a more detailed picture of how much vitamin D your food choices do – and could – supply, you can check content of a variety of foods in the USDA National Nutrient Database vitamin D information.

References

Chowdhury R, Kunutsor S, Vitezova A et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014 Apr 1;348:g1903.

Lee JE, Li H, Chan AT, Hollis BW et al. Circulating levels of vitamin D and colon and rectal cancer: the Physicians’ Health Study and a meta-analysis of prospective studies. Cancer Prev Res (Phila). 2011 May;4(5):735-43.

Chen P, Li M, Gu X et al. Higher blood 25(OH)D level may reduce the breast cancer risk: evidence from a Chinese population based case-control study and meta-analysis of the observational studies. PLoS One. 2013;8(1):e49312.

Mohr SB, Gorham ED, Kim J, Hofflich H, Garland CF. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer. Anticancer Res. 2014 Mar;34(3):1163-6.

Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014 Apr 1;348:g2035.

Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014 May;14(5):342-57.

Touvier M, Chan DS, Lau R, et al. Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms and colorectal cancer risk. Cancer Epidemiol Biomakers Prev. 2011; 20: 1003-16.

Bjelakovic G, Gluud LL, Nikolova D et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470.

Ross AC, Manson JE, Abrams SA et al. The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. J Am Diet Assoc. 2011 Apr;111(4):524-7.