Vitamin D Supplementation Is A Double-Edged Sword
/A new randomized trial shows it can reduce the risk of cancer, while increasing the risk of heart disease.
Imagine, if you will, the great Cathedral of Our Lady of Correlation is Not Causation. You walk through the majestic oak doors depicting the link between ice cream sales and shark attacks, past the rose window depicting the cardiovascular benefits of red wine, and down the aisles frescoed in dramatic images showing how Facebook usage is associated with less life satisfaction. And then, you reach the altar. The holy of holies. Where, emblazoned in shimmering pyrite, you see the patron saint of this church. Vitamin D.
Yes, if you’ve watched this space you know I have little truck with the wildly popular supplement. In all of clinical research, I believe there is no molecule with stronger data for correlation and weaker data for causation.
Low serum vitamin D levels have been linked to higher risks of heart disease, cancer, falls, COVID, dementia, C. Diff, and others. And yet when we actually do randomized trials of Vitamin D supplementation – the thing that can prove that the low level was causally linked to the outcome of interest – we get negative results.
Trials aren’t perfect of course – and we’ll talk in a moment about a big one that had some issues. But we are at a point where we need to either be Vitamin D apologists – saying forget what those lying RCTs tell you and buy this supplement – (an $800 million a year industry by the way) – or conclude that Vitamin D levels are a convenient marker of various lifestyle factors that do associate with better outcomes – a marker of exercise, of getting outside, of eating a varied diet.
Or perhaps… just perhaps… Vitamin D supplements do actually have an effect. It’s just that the beneficial effects are matched by the harmful. Stay tuned.
The Women’s Health Initiative remains among the largest randomized trials of Vitamin D and Calcium supplementation ever conducted – and a major contributor to the negative outcomes of Vitamin D trials.
But if you dig into the inclusion and exclusion criteria for this trial, you’ll find that individuals were allowed to continue taking vitamins and supplements while they were in the trial, regardless of their randomization status. In fact, the majority took supplements at baseline, and more took supplements over time.
Source: Tomson et al. ANnals of Internal Medicine. 2024
That means, of course, that people in the placebo group – who were getting sugar pills instead of Vitamin D and Calcium, may have been taking Vitamin D and Calcium on the side. That would certainly bias the results of the trial towards the null, which is what the primary analyses showed. To whit – the original analysis of the Women’s Health Initiative trial showed no effect of randomization to Vitamin D supplementation on improving cancer or cardiovascular outcomes.
But the Women’s Health Initiative trial started 30 years ago. Today, with the benefit of decades of follow-up, we can re-investigate – and perhaps re-litigate – those findings courtesy of this study appearing in the Annals of Internal Medicine.
Dr. Cynthia Thompson of the Mel and Enid Zuckerman College of Public Health at the University of Arizona and colleagues led this updated analysis focused on two findings that had been hinted at, but not statistically confirmed, in other Vitamin D studies: a potential for the supplement to reduce the risk of cancer, and a potential for it to increase the risk of heart disease.
Now, the randomized trial itself only lasted seven years. What we are seeing in this analysis of 36,282 women is outcomes that happened at any time from randomization to the end of 2023 – around 20 years after the randomization to supplementation stopped. But, the researchers would argue, that’s probably OK. Cancer and heart disease take time to develop – we see lung cancer long after people stop smoking after all – so a history of consistent Vitamin D supplementation may indeed be protective… or harmful.
OK you want some findings. Here’s the top line results. Those randomized to Vitamin D and Calcium supplementation had a 7% reduction in the rate of death from cancer, driven primarily by a reduction in colorectal cancer. This was statistically significant. Also statistically significant? Those randomized to supplementation had a 6% increase in the rate of death from cardiovascular disease. Put those findings together and what do you get? Stone cold nothing in terms of overall-mortality.
Source: Tomson et al. ANnals of Internal Medicine. 2024
OK, you say, but what about all that supplementation that was happening outside of the context of the trial, biasing our results towards the null?
The researchers finally clue us in.
First of all, I’ll tell you that, yes – people who were supplementing outside of the trial had higher baseline Vitamin D levels – a median of 54.5 versus 32.8 nmol/L. This may be because they were supplementing with Vitamin D, but it could also be because people who take supplements tend to do other healthy things – another correlation to add to the great cathedral.
In order to get a better view of the real effects of randomization, the authors restrict the analysis to just those who did NOT use outside supplements. If Vitamin D supplements help – these are the people they should help. This group had about a 11% reduction in the incidence of cancer – statistically significant – and a 7% reduction in cancer mortality that did not meet the bar for statistical significance.
Source: Tomson et al. ANnals of Internal Medicine. 2024
There was no increase in cardiovascular disease among this group. But this small effect on cancer was nowhere near enough to significantly reduce the rate of all-cause mortality.
Among those using supplements, Vitamin D supplementation didn’t really move the needle on any outcome.
I know what you’re thinking – how many of these women were Vitamin D deficient when we got started? These results may simply be telling us that people who have normal Vitamin D levels are fine to go without further additions.
Nearly ¾ of women who were not taking supplements entered the trial with Vitamin D levels below the 50nmol/L cutoff the authors suggest would qualify for deficiency. Around half of those who used supplements were deficient. And yet frustratingly, I could not find data on the effect of randomization to supplementation stratified by baseline Vitamin D level. I even reached out to Dr. Thomson to ask about this. She said:
“We did not stratify on baseline values because the numbers are too small statistically to test this”.
Sorry.
In the meantime, I can tell you that for your average woman, Vitamin D supplementation likely has no effect on mortality. It might modestly reduce the risk of certain cancers, while increasing the risk of heart disease (through coronary calcification probably). So, there might be some room for personalization here. Perhaps women with a strong family history of cancer or other risk factors would do better with supplements, and those with a high risk of heart disease would do worse. Seems like a strategy that could be tested in a clinical trial. But maybe we ask the participants to give up their extra-curricular supplement use before they enter it.
A version of this commentary first appeared on Medscape.com.