- Vitamin D Supplements Don’t Reduce Cancer Incidence – National Cancer Institute
- Isolating the Effects of Vitamin D
- Higher Vitamin D Levels Did Not Lead to Greater Benefit
- Future Paths for Vitamin D Research
- Influence of vitamin D on cancer risk and treatment: Why the variability?
- Vitamin D and Cancer Prevention – National Cancer Institute
- Does Vitamin D Have a Role in Cancer Prevention?
Vitamin D Supplements Don’t Reduce Cancer Incidence – National Cancer Institute
December 13, 2018, by NCI Staff
Findings from a large clinical trial show that taking vitamin D supplements does not lower cancer risk.
In the largest-ever randomized clinical trial testing vitamin D for cancer prevention, the supplement did not reduce the risk of developing cancer.
A large body of epidemiology research had suggested that people with higher blood levels of vitamin D have a lower risk of cancer, said Barry Kramer, M.D., director of NCI’s Division of Cancer Prevention.
However, such studies can only highlight associations, not prove cause and effect, he added. “This is why it’s important to question intuitions and observational epidemiology studies, and fund large-scale trials,” Dr. Kramer continued; they can conclusively show whether a treatment—in this case, a dietary supplement—truly can help to prevent cancer.
Results from the trial, called the Vitamin D and Omega-3 Trial (VITAL), were published November 10 in the New England Journal of Medicine (NEJM).
Isolating the Effects of Vitamin D
The body produces vitamin D when the skin is exposed to sunlight. The vitamin is also found naturally in some foods, such as fatty fish and mushrooms, and is often added to others, including milk and some cereals.
For people with known vitamin D deficiencies, supplementation is recommended to maintain bone health and prevent fractures.
“The main goal of VITAL was to see if there’s benefit to getting above the recommended dietary allowance, more than what is considered necessary for bone health,” explained JoAnn Manson, M.D.
, of Brigham and Women’s Hospital and Harvard Medical School, who led the study.
Observational studies have suggested that people who take vitamin D supplements may have a lower risk of many diseases. But “people who take vitamins may be very different in important ways from people who don’t take vitamins,” explained Dr. Kramer.
They often have a higher income and are less ly to smoke, less ly to be overweight, and more ly to have health insurance, he added—all of which are strongly linked with a lower risk of a variety of chronic health conditions, including heart disease and many cancers.
Large randomized clinical trials with thousands of participants can avoid these biases by randomly assigning study participants to receive or not receive the treatment.
VITAL was designed so that it could study the effects of both vitamin D and omega-3 supplements.
The trial’s primary endpoints—the key outcomes it measured—were the supplements’ impact on the risk of developing cancer and heart disease.
It also had several secondary endpoints, including the risk of dying from cancer. VITAL was funded primarily by NCI and the National Heart, Lung, and Blood Institute.
Almost 26,000 participants with no history of invasive cancer or cardiovascular disease enrolled in the trial. Men had to be age 50 or older, and women age 55 or older, to enroll in the study. About half of the participants were women, and the participants were racially diverse, with about 20% being African American.
“The number of participants and the substantial proportion of black participants make this cohort a nationally representative sample,” wrote John Keaney, M.D., and Clifford Rosen, M.D., of the University of Massachusetts Medical School and the Maine Medical Center Research Institute, in an accompanying editorial.
Participants were randomly assigned to one of four groups: daily vitamin D plus a placebo, omega-3 supplements plus a placebo, both vitamin D and omega-3 supplements, or two placebos. The researchers followed the participants for a median of 5.3 years.
About 17,000 participants provided blood samples at the start of the trial, 1,600 provided a second sample a year into the study, another 5,000 provided follow-up blood samples at later time points. The researchers used these samples to measure blood levels of vitamin D and omega-3s in the different groups.
Higher Vitamin D Levels Did Not Lead to Greater Benefit
Participants taking vitamin D saw their blood levels of the vitamin rise by 40% on average during the trial.
However, despite this rise, the incidence of invasive cancer was about the same between the groups: 793 participants in the vitamin D group (6.1%) received a cancer diagnosis during the trial, compared with 824 in the placebo group (6.3%).
The incidence of cardiovascular events (such as heart attacks) was also similar between the vitamin D and placebo groups.
Over the follow-up period, there were 341 deaths from cancer: 154 among participants who took vitamin D (1.1%) and 187 among those who took the placebo (1.4%). Although this difference was not statistically significant, the difference in cancer deaths between the groups started to widen over time, the researchers reported.
The researchers plan to follow the participants for another 2 to 5 years, to see if a statistically significant difference in cancer deaths emerges.
Laboratory studies have suggested that high blood levels of vitamin D may decrease the aggressiveness of cancer cells and the lihood of metastasis, explained Dr. Manson. If so, longer follow-up will be needed to assess its effects on the risk of death from cancer, she added.
Other studies have suggested that regular use of vitamin D supplements may reduce the risk of dying from cancer, she said.
Supplementation with omega-3 fatty acids also did not significantly reduce the risk of cancer incidence or cancer death. Those results were presented in a separate paper, also published in NEJM.
No increased risk of side effects—including high blood calcium levels for vitamin D, bleeding with omega-3s, or gastrointestinal upset for either supplement—were found among people taking the supplements at these doses, compared to rates in the placebo groups.
Future Paths for Vitamin D Research
The VITAL trial “was well designed,” said Dr. Kramer. “And when it’s important to get the answer right— that is, when you’re potentially making recommendations to hundreds of thousands, or even millions, you want to make sure that your recommendations are very strong evidence,” he added.
Other research into vitamin D and cancer prevention is ongoing, such as studying whether some types of cancer may be more sensitive than others to the effects of supplementation.
For example, an NCI-sponsored clinical trial is currently looking at whether supplementation with vitamin D, calcium, or both can prevent the development of new colorectal adenomas in people who have already had one or more such precancerous growths removed. VITAL will also examine effects of the supplements on the risk of new colorectal adenomas.
Dr. Manson and her colleagues plan to follow the participants for at least 2 more years and hope to secure grant funding to follow them for a longer period, she said. They would also to study the potential influence of genetics on the effects of vitamin D supplementation.
“This is something we really want to look at—whether there are gene variants related to vitamin D metabolism, the vitamin D receptor, binding proteins, or even completely separate mechanisms, that could have influenced the effects of supplementation and could help identify those most ly to benefit,” Dr. Manson said.
The VITAL results don’t give reason for people taking vitamin D as recommended by their doctors to stop, she continued.
“If you have a clinical indication for taking vitamin D, such as a bone health problem or malabsorption condition, or use of other medications that interfere with the bioavailability of vitamin D—then of course you should keep taking it,” she concluded.
Influence of vitamin D on cancer risk and treatment: Why the variability?
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Vitamin D and Cancer Prevention – National Cancer Institute
Vitamin D is the name given to a group of fat-soluble prohormones (substances that usually have little hormonal activity by themselves but that the body can turn into hormones).
Vitamin D helps the body use calcium and phosphorus to make strong bones and teeth. Skin exposed to sunshine can make vitamin D, and vitamin D can also be obtained from certain foods.
Vitamin D deficiency can cause a weakening of the bones that is called rickets in children and osteomalacia in adults.
Two major forms of vitamin D that are important to humans are vitamin D2, or ergocalciferol, and vitamin D3, or cholecalciferol. Vitamin D2 is made naturally by plants, and vitamin D3 is made naturally by the body when skin is exposed to ultraviolet radiation in sunlight.
Both forms are converted to 25-hydroxyvitamin D in the liver. 25-Hydroxyvitamin D then travels through the blood to the kidneys, where it is further modified to 1,25-dihydroxyvitamin D, or calcitriol, the active form of vitamin D in the body.
The most accurate method of evaluating a person’s vitamin D status is to measure the level of 25-hydroxyvitamin D in the blood.
Most people get at least some of the vitamin D they need through sunlight exposure. Dietary sources include a few foods that naturally contain vitamin D, such as fatty fish, fish liver oil, and eggs. However, most dietary vitamin D comes from foods fortified with vitamin D, such as milk, juices, and breakfast cereals. Vitamin D can also be obtained through dietary supplements.
The Institute of Medicine (IOM) of the National Academies has developed the following recommended daily intakes of vitamin D, assuming minimal sun exposure (1,2):
- For those between 1 and 70 years of age, including women who are pregnant or lactating, the recommended dietary allowance (RDA) is 15 micrograms (μg) per day. Because 1 μg is equal to 40 International Units (IU), this RDA can also be expressed as 600 IU per day.
- For those 71 years or older, the RDA is 20 μg per day (800 IU per day).
- For infants, the IOM could not determine an RDA due to a lack of data. However, the IOM set an Adequate Intake level of 10 μg per day (400 IU per day), which should provide sufficient vitamin D.
Although the average dietary intakes of vitamin D in the United States are below guideline levels, data from the National Health and Nutrition Examination Survey revealed that more than 80 percent of Americans had adequate vitamin D levels in their blood (2).
Even though most people are unly to have high vitamin D intakes, it is important to remember that excessive intake of any nutrient, including vitamin D, can cause toxic effects.
Too much vitamin D can be harmful because it increases calcium levels, which can lead to calcinosis (the deposit of calcium salts in soft tissues, such as the kidneys, heart, or lungs) and hypercalcemia (high blood levels of calcium).
The safe upper intake level of vitamin D for adults and children older than 8 years of age is 100 μg per day (4000 IU per day). Toxicity from too much vitamin D is more ly to occur from high intakes of dietary supplements than from high intakes of foods that contain vitamin D.
Excessive sun exposure does not cause vitamin D toxicity. However, the IOM states that people should not try to increase vitamin D production by increasing their exposure to sunlight because this will also increase their risk of skin cancer (2).
Early epidemiologic research showed that incidence and death rates for certain cancers were lower among individuals living in southern latitudes, where levels of sunlight exposure are relatively high, than among those living at northern latitudes.
Because exposure to ultraviolet light from sunlight leads to the production of vitamin D, researchers hypothesized that variation in vitamin D levels might account for this association.
However, additional research stronger study designs is required to determine whether higher vitamin D levels are related to lower cancer incidence or death rates.
Experimental evidence has also suggested a possible association between vitamin D and cancer risk.
In studies of cancer cells and of tumors in mice, vitamin D has been found to have several activities that might slow or prevent the development of cancer, including promoting cellular differentiation, decreasing cancer cell growth, stimulating cell death (apoptosis), and reducing tumor blood vessel formation (angiogenesis) (3-6).
A number of epidemiologic studies have investigated whether people with higher vitamin D intakes or higher blood levels of vitamin D have lower risks of specific cancers. The results of these studies have been inconsistent, possibly because of the challenges in carrying out such studies.
For example, dietary studies do not account for vitamin D made in the skin from sunlight exposure, and the level of vitamin D measured in the blood at a single point in time (as in most studies) may not reflect a person’s true vitamin D status. Also, it is possible that people with higher vitamin D intakes or blood levels are more ly to have other healthy behaviors.
It may be one of these other behaviors, rather than vitamin D intake, that influences cancer risk.
Several randomized trials of vitamin D intake have been carried out, but these were designed to assess bone health or other non-cancer outcomes. Although some of these trials have yielded information on cancer incidence and mortality, the results need to be confirmed by additional research because the trials were not designed to study cancer specifically.
The cancers for which the most human data are available are colorectal, breast, prostate, and pancreatic cancer. Numerous epidemiologic studies have shown that higher intake or blood levels of vitamin D are associated with a reduced risk of colorectal cancer (7-10).
In contrast, the Women’s Health Initiative randomized trial found that healthy women who took vitamin D and calcium supplements for an average of 7 years did not have a reduced incidence of colorectal cancer (11).
Some scientists have pointed out that the relatively low level of vitamin D supplementation (10 μg, or 400 IU, once a day), the ability of participants to take additional vitamin D on their own, and the short duration of participant follow-up in this trial might explain why no reduction in colorectal cancer risk was found. Evidence on the association between vitamin D and the risks of all other malignancies studied is inconclusive.
Taken together, the available data are not comprehensive enough to establish whether taking vitamin D can prevent cancer (12).
To fully understand the effects of vitamin D on cancer and other health outcomes, new randomized trials need to be conducted (13). However, the appropriate dose of vitamin D to use in such trials is still not clear (14).
Other remaining questions include when to start taking vitamin D, and for how long, to potentially see a benefit.
To begin addressing these issues, researchers are conducting two phase I trials to determine what dose of vitamin D may be useful for chemoprevention of prostate, colorectal, and lung cancers (trial descriptions here and here).
In addition, larger randomized trials have been initiated to examine the potential role of vitamin D in the prevention of cancer.
The Vitamin D/Calcium Polyp Prevention Study, which has finished recruiting approximately 2,200 participants, is testing whether vitamin D supplements, given alone or with calcium, can prevent the development of colorectal adenomas (precancerous growths) in patients who previously had an adenoma removed.
The study’s estimated completion date is December 2017. The Vitamin D and Omega-3 Trial (VITAL) will examine whether vitamin D supplements can prevent the development of a variety of cancer types in healthy older men and women (15). The organizers of VITAL expect to recruit 20,000 participants and complete the trial by June 2016.
Researchers are also beginning to study vitamin D analogs–chemicals with structures similar to that of vitamin D–which may have the anticancer activity of vitamin D but not its ability to increase calcium levels (16).
Otten JJ, Hellwig JP, Meyers LD. Vitamin D. In: Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: National Academies Press, 2006.
Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011.
Thorne J, Campbell MJ. The vitamin D receptor in cancer. Proceedings of the Nutrition Society. 2008;67(2):115-127.
Moreno J, Krishnan AV, Feldman D. Molecular mechanisms mediating the antiproliferative effects of vitamin D in prostate cancer. Journal of Steroid Biochemistry and Molecular Biology 2005; 97(1–2):31–36.
Holt PR, Arber N, Halmos B, et al. Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D. Cancer Epidemiology, Biomarkers, and Prevention 2002; 11(1):113–119.
Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Reviews Cancer. 2007;7(9):684-700.
Ma Y, Zhang P, Wang F, et al. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. Journal of Clinical Oncology. 2011;29(28):3775-3782.
Gandini S, Boniol M, Haukka J, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. International Journal of Cancer. 2011;128(6):1414-1424.
Woolcott CG, Wilkens LR, Nomura AM, et al. Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: the multiethnic cohort study. Cancer Epidemiology, Biomarkers & Prevention. 2010;19(1):130-134.
Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. BMJ. 2010;340:b5500.
Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. New England Journal of Medicine 2006; 354(7):684–696.
Chung M, Lee J, Terasawa T, et al. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Annals of Internal Medicine. 2011;155(12):827-838.
IARC Working Group on Vitamin D. Vitamin D and cancer: A report of the IARC Working Group on Vitamin D. IARC Working Group Reports. Lyon, France: International Agency for Research on Cancer, 2008.
Yetley EA, Brulé D, Cheney MC, et al. Dietary Reference Intakes for vitamin D: Justification for a review of the 1997 values. American Journal of Clinical Nutrition 2009; 89(3):719–727.
Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemporary Clinical Trials. 2012;33(1):159-171.
Pereira F, Larriba MJ, Muñoz A. Vitamin D and colon cancer. Endocrine-Related Cancer. 2012;19(3):R51-71.
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Does Vitamin D Have a Role in Cancer Prevention?
Today we are discussing the role of vitamin D in cancer prevention with endocrinologist Michael F. Holick, PhD, MD.
Holick specializes in vitamin D and through his research has identified calcidiol, the major circulating form of vitamin D, and calcitriol, the active form of vitamin D.
He is a professor of medicine, physiology, and biophysics at the Boston University Medical Center where he is the director of the Heliotherapy, Light, and Skin Research Center.
—Interviewed by Anna Azvolinsky
Cancer Network: Why has there been a focus on vitamin D as a way to potentially prevent certain types of cancer? What are the potential preventive mechanisms?
Holick: Everyone knows vitamin D as the vitamin important for bone health and for preventing rickets in children, but we are now recognizing that the major source of vitamin D is coming from the sun, so by definition vitamin D is really a hormone.
Once you make vitamin D in your skin, or ingest it from your diet, it goes to your liver, is converted to 25-hydroxy- vitamin D known as calcidiol and then to the kidneys to the active form, 1,25-dihydroxy-vitamind D, also known as calcitriol.
It turns out that, yes, vitamin D is very important in helping you use the calcium in your diet by increasing intestinal calcium absorption, and to help mineralize the skeleton to have healthy bones in both children and adults.
But, we are now also recognizing that many cells in the body, separate from the kidneys, can activate vitamin D and there is mounting evidence that that function of vitamin D is to help regulate cellular growth.
There are several studies that have related higher blood levels of 25-hydroxy-vitamin D and reduced-risk of many deadly cancers including colon, breast, and prostate cancer to name a few.
Cancer Network: What do we know about how much vitamin D we require for optimal health including reducing the risk of cancers?
Holick: That’s a very good question and obviously, there continues to be a lot of debate about this question. From my perspective, we should really ask the question ‘what were our hunter, gatherer forefathers doing?’ They were always exposed to sunlight. What were their ly levels? How much vitamin D would you require to attain those levels?
One of the insights was done several years ago where a study was performed in Maasai herders that live in Kenya at the equator. Even though they have extremely dark skin, Mother Nature still has the ability to make some vitamin D in their skin.
Their blood levels were measured and it was determined that their 25-hydroxy-vitamin D levels were around 40–50 nanograms per milliliter. To get to that level, adults would need to take 3,000–5,000 units of vitamin D per day.
The recommendation from the Endocrine Society practice guidelines is at least 1,500–2,000 units per day and if you are obese, you need two to three times more. I personally take 5,000 units of vitamin D every day and my blood level is in the range of 60 nanograms per milliliter. All of my patients are on between 3,000–5,000 units of vitamin D per day and they are all doing very well.
Cancer Network: Let’s start with colon cancer. There have been numerous epidemiological studies on the possible benefit of vitamin D in preventing colon cancer. What do individual studies and meta-analyses tell us about vitamin D and colon cancer risk?
Holick: There continues to be association data saying that the higher your 25-hydroxy-vitamin D levels are, the lower your risk for colorectal cancer.
The earliest study was done by the Garland brothers back in the 1990s when they were relating latitude and colon cancer and then did a prospective study on vitamin D status and the risk of colon cancer.
They concluded two things. The first is that the higher latitude that you live, the higher your risk for colorectal cancer.
They also concluded that taking 1,000 units of vitamin D a day could potentially reduce your risk of colon cancer by as much as 50%.
Other studies have suggested that improving your vitamin D status would have the benefit of reducing colorectal cancer by about 25%–50%, depending on the study.
Cancer Network: Is there evidence from studies that vitamin D can mitigate the risk of other tumor types?
Holick: The one that is most significant concerns breast cancer. There was a very nice study was done from the Nurses’ Health Study that showed that nurses that had, on average, blood levels of 48 nanograms per milliliter, so around 50 nanograms per milliliter—that would require you to take about 3,000–5,000 units of vitamin D per day—reduced their risk of developing breast cancer by about 50%.
There was also a very nice study done by Dr. Knight in Canada.
She asked a question on the phone to women living in Canada who had breast cancer and asked the same number of women living in the same area who did not have breast cancer and concluded that women who had the most sun exposure as teenagers and young adults reduced the risk of developing breast cancer later in life by almost 70%. So, there is a reasonable amount of evidence to suggest that improvement in vitamin D status can help reduce the risk of breast cancer.
Cancer Network: Have there been randomized trials with vitamin D that focused on cancer prevention or slowing cancer progression?
Holick: There was a recent study that came out, known as the VITAL study. The authors concluded that 5 years on 2,000 IU’s of vitamin D per day that did not reduce the risk for developing colon cancer. But, they did find statistically significant 25% reduced risk of dying from colon cancer if patients took vitamin D.
When you look at that study carefully, most of the subjects were not vitamin D deficient. If they are vitamin D sufficient already, and getting some additional vitamin D, it is not clear that you would be able to see a significant benefit.
The senior author on the publication, Dr.
JoAnn Manson, even made the conclusion that it is also true that these types of cancers probably take more than a few years to develop, so introducing vitamin D for 5 years may not be a long enough time to see benefits.
That is all the more reason why I encourage my family and my patients that you should always be vigilant about your vitamin D status and take an adequate amount of vitamin D from birth until death.
Cancer Network: Are there currently ongoing human studies to better understand the potential role of vitamin D in cancer prevention?
Holick: There continue to be small studies that have concluded that there may or may not be any benefit. Again, you have to look at how these trials are designed and what their outcome measures are. I think it is still not clear that maintaining a blood level that we would consider to be in a healthy range for 25-hydroxy-vitamin D of 40–60 nanograms per milliliter as recommended by the Endocrine Society does have that additional health benefit of reducing risk of many deadly cancers.
From my perspective, all of the information that I have reviewed, I think overall, the data is suggestive that it does help reduce the risk of deadly cancers.
Cancer Network: Thank you so much for joining us today Dr. Holick.
Holick: My pleasure.