Decades After WHI: Calcium, Vitamin D Linked to Different CVD, Cancer Outcomes

Women who take calcium and vitamin D supplements for many years may, in the long run, see a lower risk of dying from cancer, according to two decades’ worth of data from the Women’s Health Initiative (WHI). But over that same horizon, there was a small but significant increase in the risk of dying from cardiovascular disease.

The results were published online this week in the Annals of Internal Medicine.

Cynthia A. Thomson, PhD, RD (University of Arizona, Tucson), lead author of the paper, told TCTMD that it’s important to keep the findings in perspective. “We just have to remember this is a post hoc analysis of a clinical trial,” she pointed out, adding that when the trial was first designed in the early 1990s, even the concept of “coronary artery calcification was kind of in its infancy.”

The new results join a long line of data drawing a link between calcium supplements and atherosclerosis, with some evidence hinting that the mechanism relates to increased calcification of coronary arteries. Though it appears overall that calcium supplements are relatively safe, they’re also unlikely to provide the cardiovascular benefits that many people expect when paying for a presumed health boost from pills and powders. Evidence on behalf of vitamin D supplements is also lacking.

We have had the scientific integrity to be able to look at a really well-characterized group of women for 30 years. Cynthia A. Thomson

For the WHI, investigators randomized 36,282 postmenopausal women with no history of breast or colorectal cancer to receive either placebo or 1,000 mg of calcium carbonate (400 mg of elemental calcium) plus 400 IU of vitamin D₃ taken in half doses twice daily over an average period of 7 years.

Both the main trial data and a later report looking at what happened 5 years after the intervention stopped showed “largely null” results, Thomson et al note, though there were some signs of survival differences.

This analysis, with a median cumulative follow-up of 22.3 years, showed a 6% increase in CVD mortality but a 7% decrease in cancer mortality. There was no link between supplement use and all-cause mortality.

WHI: Median Cumulative Follow-up of 22.3 Years

The researchers then stratified the women by whether they’d taken calcium/vitamin D₃supplements prior to study entry. Those that reported supplement use had higher CVD mortality when randomized to the calcium/vitamin D₃ versus placebo arm (HR 1.09; 95% CI 1.02-1.16). This difference in risk between study arms wasn’t seen in women who hadn’t been taking supplements before the trial, which Thomson said perhaps reflects how long it takes for CVD to develop.

Take the Long View

As to why their study uncovered a potential signal while its predecessors did not, “it may be that you have to have a lot of women, and you've got to [take supplements] for a long time, and the effect is small,” Thomson said. “It’s enough [that] we should pay attention, but it's very small in the scheme of risk factors.”

Thomson pointed out that the risk-benefit tradeoff varies by individual.

Clinicians treating patients known to have coronary artery calcium, for example, might “assess their calcium supplementation and make sure it's not excessive,” she suggested. Someone with a family history of colorectal cancer, on the other hand, might decide calcium and vitamin D are worth taking, even if there’s a slight rise in CV risk as a result. For a person with multiple, competing risk factors, what makes the most sense, she said, is to err on the side of caution—if they do take supplements, they should only take amounts that don’t exceed recommended levels.

“I think this is where we're going in medicine. We're going to personalize it more and more based on what your risk profile is, and . . . be able to guide people based on their genetics and their lifestyle and their environment that they grew up in,” Thomson said. “But we're just not quite there yet.”

Beyond the clinical implications, though, these data are a reminder that it’s worth taking a long look at health, Thomson stressed. “It's now 30 years since we enrolled the first woman in these trials.”

Most research is now funded in 5-year cycles, but “you’re never going to find this kind of risk in 5 years, because you just don't have enough of a dose for a long enough period for the physiology to play out,” she said, adding that trialists and funders need to be open at the outset to designing studies that can capture how disease evolves over decades.

And unlike the Nurses’ Health Study and other observational studies, with the randomized design of the WHI, “we had the benefit of knowing more specifically what their actual exposure was, particularly during that trial period, . . . and have adjudicated outcomes. So I think for me, the blessing is that we have had the scientific integrity to be able to look at a really well-characterized group of women for 30 years,” Thomson noted.

Although the original WHI concluded in 2005, ongoing extension studies have continued to measure things like function, vision, hearing, and other health metrics. “We're learning so much about what it means to be a healthy 80 to 100-plus year old,” she said. “What is it that keeps people vital as they get older?”