Vitamin D and Cancer

Vitamin D and Cancer

Creighton study finds 30 percent reduction in cancer from vitamin D supplements

By Therese Vaughn

It’s said that statistics is the art of never having to say you’re wrong. When a much-awaited Creighton University study on vitamin D and cancer fell just a whisker short of statistical significance, principal investigator Joan Lappe, PhD, MS’85, said no problem, we are not wrong.

Lappe and her Creighton research colleagues — including Robert Recker, MD’63, director of Creighton’s Osteoporosis Research Center; Dianne Travers-Gustafson, PhD, BSN’79, MS’93; and Patrice Watson, PhD — made pioneer tracks with their work on vitamin D’s relationship to cancer risk, showing a 30 percent lower incidence. Professor Robert Heaney, BS’47, MD’51, who died last August, helped to inspire and plan the study. Co-investigators were professors Cedric Garland, PhD, and Edward Gorham, PhD, of the University of California San Diego, and professor Keith Baggarly, PhD, and Sharon McDonnell from MD Anderson.

The team met the gold standard of scientific rigor through the first randomized clinical trial of the effects of vitamin D supplementation on all types of cancer combined. Their findings were published in March by the prestigious Journal of the American Medical Association (JAMA).

Funded by the National Institutes of Health (NIH), the four-year study included 2,303 healthy, older women in rural Nebraska, in which half were randomized to daily doses of 2,000 International Units (IU) of vitamin D3 and 1,500 milligrams of calcium supplements and the rest were given placebos. Cancer struck at a 30 percent lower incidence in the supplemented group than in the control group.

While that 30 percent narrowly missed statistical significance in the study, the findings add to a critical mass of evidence that supports that vitamin D does offer important value in health promotion and disease prevention.

“It’s enough to keep me taking my vitamin D every day,” says Lappe, who is a professor of nursing and medicine and holder of the Criss/Beirne Endowed Chair in Nursing.

Lappe’s adventures in vitamin D research began more than 30 years ago with the relatively new study of osteoporosis. In 1984, she joined the Creighton faculty with a joint appointment in the College of Nursing and the School of Medicine. In 1988, Heaney invited her to join the team at the Osteoporosis Research Center half-time as a project manager. There, she fell in love with clinical research — that dynamic process of investigation, “doing the thinking, reading and coming up with the right research questions,” she says. The “right question” is where scientific scrupulousness comes together with awe at the hidden workings of creation.

One of Lappe’s first questions considered bone health in children. She and her national research partners helped to establish the normal bone density reference levels for children and to demonstrate the importance of physical activity and calcium in their bone development. The study continues to impact public health policy.

Later, Lappe worked on a project through a Department of Defense grant to look at the high risk for stress fractures among young military recruits. Finding that calcium and vitamin D supplements decreased fractures by 20 percent, the Navy implemented a new regimen for all female basic trainees. When the study appeared in the New York Times, President George W. Bush’s personal physician called Lappe to ask what supplements to suggest to the president’s wife.

Lappe’s research not only breaks ground, it ripples out seismically. Just like the work of her late mentor and research partner, Heaney, who was widely acknowledged as the world’s foremost expert on bone biology, calcium and vitamin D.

“He was a brilliant man and a rigorous scientist,” she says. “He understood the importance of vitamin D in every cell in our body and the role it plays in every step of cancer development and progression. He was convinced by the large body of evidence that it had an effect — not just on cancer — but on many diseases.”

In the early 2000s, Lappe was principal investigator on a study to determine whether vitamin D and calcium protected against osteoporosis fractures. She and her team conducted a secondary analysis of the nutrients’ effect on cancer. “At that time, researchers were beginning to find a link between living in a sunny climate and a lower incidence of cancer,” she explains. “We found that really intriguing.”

When the results of Lappe’s analysis indicated a 60 percent lower incidence of cancer with supplementation, their paper “went viral,” generating headlines around the globe.

“What was unique about our study was that it was the first randomized clinical trial of vitamin D and cancer,” she says. “However, in the scientific field, there is a tremendous emphasis on rigor. We needed a study in which cancer was a primary outcome. At that point, we submitted a proposal, which was very similar to the first study, to the NIH, and this was funded.”

While this second study showed a 30 percent reduction in cancer, there were several confounding factors involved, Lappe explains. For instance, the women in the trial showed a higher baseline level of vitamin D in their blood. This indicated that they were closer to being vitamin D replete and less likely to show any effect of vitamin D supplementation as compared to individuals with lower blood levels of vitamin D.

“Vitamin D is a threshold nutrient; once you have enough, taking more won’t do you any good,” Lappe adds.

But, not getting enough vitamin D poses a serious risk: blood levels of the nutrient, specifically 25-hydroxyvitamin D (25(OH)D), were significantly lower in women who developed cancer during the study than in those who remained healthy. The average 25(OH)D level in the women’s blood at the beginning of the study (33 nanograms/milliliter, ng/mL) was higher than the usual target levels that currently range from 20-30 ng/mL, according to various guidelines. This suggests that higher vitamin D levels than are currently recommended are needed for substantially decreasing risk of cancer.

“The findings were very exciting,” Lappe says. “They confirm what a number of vitamin D proponents have suspected for some time but that, until now, have not been substantiated through clinical trial.

“Decreasing cancer incidence by 30 percent is substantial, so the clinical effect is important, even though the analysis did not quite reach statistical significance. It was close, however. In fact, if there had been one more cancer case in the placebo group, the findings would have been statistically significant.”

Statistical significance is a tricky business. Basically, it is the mathematical probability that a difference between two or more factors exists. Practical significance, on the other hand, is when science meets its maker: What works for the greater good and causes the least harm?

Since the study of vitamin D’s effect on developing cancer failed to meet statistical significance, the findings from this study will not be used to set clinical guidelines for use of vitamin D.

“What we do know is that lack of statistical significance does not mean that it had no effect,” Lappe says. “We really believe that the 30 percent reduction is important, and it’s consistent with all the literature. There’s a huge body of evidence that points to the positive effects of vitamin D.”

While many people in the science community, health professions and households worldwide will recognize the strength of cumulative evidence in the case for vitamin D, the media seems to cast a whole lot of shade on the sun nutrient. Days after the landmark study’s publication in JAMA, several news outlets responded with gloomy headlines: “High doses of vitamin D fail to cut cancer risk, study finds” wrote Health U.S. News, “New study raises doubts” claimed CBS News and “Sorry, your vitamin D megadose is basically useless” heralded Wall Street Pit.

“When Creighton published the press release that vitamin D does have an effect, I knew it would cause controversy,” Lappe says. “But statistical significance and real effect are not mutually exclusive.

“One of the things that fascinates me is the political nature of vitamin D. There are scientists and community groups that are very passionate about it. Advocates such as Dr. Heaney have proposed that everyone should be taking supplements and raising their blood levels of vitamin D higher than current recommendations. Others caution that there is no evidence of a positive effect and that there may be unknown risks of too much vitamin D. I’ve been in conference rooms and lecture halls where there have been heated debates.”

Lappe says her mentor, though gracious in temperament and rigorous in science, never shied away from the fight. “Dr. Heaney was part of the political debate, right out there, with all the policymakers and stakeholders. He was even considered somewhat of a radical. He was so convinced by the science, and, as his career and life were coming to a close, he felt it was very important that the world accept the significance of vitamin D.”

Over the course of his career, Heaney led a valiant push for increasing vitamin D intake from the government’s Recommended Daily Allowance (RDA) of 600 IU for most people and 800 IU for people over 70 years of age. While Lappe suggests an intake of at least 2,000 IU of vitamin D daily, as well as getting your blood levels checked, Heaney recommended more than twice that amount.

Can one overdose on vitamin D? Lappe says vitamin D has been shown to be very safe except in people with tuberculosis, sarcoidosis or metastatic cancer. “It appears that there are no ill effects for daily doses below 10,000 IU, but I would not recommend doses nearly that high,” she cautions.

How about sunshine? Since humans make their own vitamin D3 when they are exposed to sunlight, can we catch too many rays?

Acknowledging the risks of photoaging and skin cancer from overexposure to sunlight, Lappe says, “Most dermatologists would probably say some sunlight is helpful. We don’t want to be giving children a bunch of supplements. It’s OK if they run and play outside, get a little color.”

In further research on vitamin D and cancer, a study involving 26,000 subjects is underway today at Harvard University. This large-scale trial will examine the role of vitamin D supplementation in preventing cancer and cardiovascular disease.   

“I knew when it started that this larger Harvard study would be the decisive trial,” Lappe says modestly, even though it is her work that first lit up the field.