Vitamin D supplementation - an update

Should healthy people supplement vitamin D?
As the organizer of the "Singapore Longevity and Health Meetup" I feel almost obliged to write about supplements. When people get interested in longevity and join such a meetup, it is because they want to be healthier now and not in a faraway future. In contrast, we, as scientists, deal with that future which is years or decades away. Of course many of us scientists also started as traditional pill-popping life extensionists because we had this passion for life and for health. Eventually, however, we came to realize that lifespan extension will require significant medical breakthroughs and that is why we end up focusing on basic research rather than supplements, diets or exercise.

It bears repeating. The best way to make radical and significant lifespan extension happen within our lifetimes is to donate to research or convince politicians, philanthropists, etc. to invest money in aging research and reform patent and FDA regulations so that aging can be targeted as if it were a disease. This has to be the foundation.

Meanwhile, while we wait for scientists to come up with some real anti-aging interventions, there is nothing wrong with optimizing one's health to reap the small life extension benefits that this brings. Between acarbose, metformin and rapamycin we are getting closer to having approved drugs that can moderately slow down the rate of aging. They work decently in mouse models, but as a human, taking any of these still constitutes a high risk/high reward game, and those inclined to do so, should consult with their doctor. Supplements and dietary interventions, in contrast, have a place, as lower risk, lower reward interventions.

When I think of supplements and aging, I try to rationalize these within some sensible framework like e.g. Bruce Ames triage theory. It stands to reason that the average intake of micronutrients is only sufficient to optimize reproduction and not long-term health. The only problem with this theory is that the average intake of micro- and macronturients could be either too low or too high for optimal health (for example, it might be too high for [animal] protein, total calories, iron and simple carbohydrates). It is always easy to make an evolutionary argument but we cannot infer the direction of effects from this argument. In order to find out we need to actually test micronutrient supplements for their clinical benefits.

Summary and TL;DR - what happened when we tested vitamin D in large trials?
Although vitamin D was considered an up-and-coming superstar micronutrient just 5 to 10 years ago, many controlled trials later, it did not live up to the hype. Nevertheless, controlled trials do suggest a small, borderline significant reduction in cancer and/or all-cause mortality. Given the promising data from other study types, the well-established safety of vitamin D, the prevalence of population-wide insufficiency and the cheap cost of supplemental vitamin D, there is only one rational answer to that question. Yes, we should supplement around 2000IU/d (or get tested) in order to reach blood levels of around 30ng/ml.

Vitamin D and health - the basics
Vitamin D is usually measured as 25-hydroxyvitamin D (25(OH)D) in blood, which is a relatively stable, semi-inactive precursor to the active "hormone" 1,25-dihydroxyvitamin D (1,25(OH)2D; calcitriol). It is produced from 7-dehydrocholesterol in skin through a couple of intermediate steps. Since sun exposure can quickly produce large amounts of vitamin D equivalent to 10000 IU of supplemental vitamin D or more, many people have mistakenly argued that large levels of supplementation have to be safe and beneficial. This, however, does not necessarily follow. It only tells us that large levels of supplementation have no acute side-effects in the healthy. Since evolution does not optimize for long-term health, this is all we can conclude. What we really need is a scientific answer to that question.

As has been known since the early 20th century, vitamin D is necessary for bone health and severe deficiency is a cause of rickets and other bone disorders. It was only quite recently that extra-skeletal effects of vitamin D have received attention, although studies hinted at such effects long ago.

Off the top of my head, I still remember what exactly put vitamin D on my radar. It was this meta-analysis of randomized trials by Autier and Gandini (2007) showing a 7% reduction in mortality (10). That 7% figure, I still remember it. It was a remarkable finding because, as aging researchers, we obsess over mortality rather than single disease outcomes. Measuring mortality in studies is a way to respect Taeuber's paradox, albeit an imperfect one. For example, it does not matter whether an intervention prevents cancer, if it increases risk from other diseases or the survivors end up dying from cardiovascular disease instead. Conrad Taeuber was one of the first demographers who noticed that all age-related diseases increase at the same time, thus any treatment which only mitigates one cause would be highly inefficient (Keyfitz et al. 1977).

Recent studies and meta-analyses
(this started out as a reddit post for r/longevity commenting on a recently published study but it quickly got too long.)

Let's not get too excited about this study (i.e. the DO-HEALTH trial). While this is definitely a promising signal, the study was quite small by the standards of prevention trials, tested multiple outcomes and only looked at cancer as a secondary endpoint (2). The authors found that vitamin D, exercise and omega 3 acids each led to 30% fewer invasive cancers in healthy older adults and the effects were cumulative so you can combine these treatments to increase the benefits.

Why is this not good enough? This kind of analysis is commonly known as a post hoc fishing expedition. As we all know, if you are not careful the ocean can swallow you and your scientific hypotheses at any time. How do we prevent this from happening?

So first of all, the original DO-HEALTH study failed for every single pre-specified endpoint (1). Vitamin D, omega-3 fatty acids or exercise did not help older adults (n=2157 participants) to be healthier, as far as we can tell based on the statistics.

The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years...These findings do not support the use of vitamin D... for these clinical outcomes among relatively healthy older adults.

What the authors published after the main results were reported is a "pre-defined exploratory analysis" of the original study. The authors make a convincing case that they have got a good hypothesis because earlier studies showed benefits of vitamin D supplementation on cancer.

The VITAL study with over 25000 participants found a significant 17% reduction in metastatic or fatal cancers in those randomized to vitamin D although there were "no significant differences for [overall] cancer incidence" (4). There was also a suggestive reduction in cancer mortality (HR = 0.83; 95% CI, 0.67-1.02]; P = .08).

Figure. invasive and fatal cancer combined after vitamin D treatment (2000 IU/day)

The effects of vitamin D may be so small that even VITAL did not have the power to pick them up. If we do not want to sail blindly on the vast ocean of speculative ideas we need to systematically review and quantify all vitamin D trials. Luckily, someone's done that work for us. A meta-analysis of RCTs by Keum et al. including VITAL (Manson et al. 2018) showed that "vitamin D supplementation significantly reduced total cancer mortality [by 13%] but did not reduce total cancer incidence" (5).

Crucially, "there was a statistically significant 7% reduction in total mortality in our meta-analysis where cancer death (n = 1591) accounted for 33% of total death (n = 4872)" which brings us back 15 years to the meta-analysis by Autier and Gandini. Maybe it was not so wrong back then? The cancer effect is real, at least in the sense that it is reproducible. A meta-analysis by Guo, Huang, Fan et al. 2022 finds exactly the same thing.

Vitamin D and mortality - do we have a consensus?
Now that we have established a potential beneficial effect on cancer mortality, what is the net impact on all-cause mortality? Keum et al. already suggested a benefit, but that is not the only line of evidence we have to consider. Given the vast amount of available data, different experts have performed dozens if not hundreds of meta-analyses, sometimes arriving at different conclusions. I particularly like the approach taken by Liu, Meng, Tian 2021, which is to consider prospective epidemiology, RCTs and mendelian randomization (MR) studies together. 

Both RCTs and MR argue against an effect on cancer incidence. MR data is inconsistent with the RCT data on cancer mortality, however, a quick look at the paper suggests that this is only based on the UK biobank study. While this is a great cohort to do MR, I think we can do better. More and larger analyses with improved genetic tools would be useful. Also, I have no clue whether vitamin D is suitable for MR. I trust the experts, but it seems a bit concerning that many of the MR studies were only based on two genes that regulate vitamin D levels.

The all-cause mortality data looks the most promising because it is consistent between RCTs, epidemiology and mendelian randomization (MR). However, here also several caveats apply. The MR data is based on a 2014 study using 3 cohorts, while a sample size of 100k is okay, we can do better. Pooled MR studies of iron biomarkers and longevity, including UK Biobank and other cohorts, have gone up to sample sizes of 1 million and such updated MR studies are slowly coming in (8). Furthermore, not all meta-analyses of RCTs show reduced all-cause mortality (see eg ref 6) after vitamin D treatment. Therefore I am worried that their reading of the literature is a bit too optimistic, and evidently not everyone agrees with such a rosy interpretation of the data (3).

Conclusion and my own thoughts - should we take vitamin D?
First of all, many people have low vitamin D levels, leaving them at risk of adverse health outcomes. Although exact cut-offs remain controversial, we do know that moderate deficiency of <20ng/ml (50nmole/L) is prevalent even in tropical countries like Singapore - with a whopping 40% of the population falling into this category. These levels are associated with increased mortality in epidemiologic studies. It is relatively uncontroversial to suggest that people should fix their low vitamin D levels even though we do not know the optimal level. However, in the absence of RCT data we can look at prospective epidemiology and Mendelian randomization studies (8) both suggesting an optimal level around 20-30ng/ml (50-80nmole/L), which is close, albeit a bit lower, than the numbers I recall from meta-analyses published almost 10 years ago.

Second of all, the controlled trials performed to date are consistent with a small benefit or no benefit (which is equivalent to no risk) and this has to be taken into consideration. However, it turns out that doctors are notoriously bad at evaluating risk-benefit ratios (3) and what we need here to make sense of the data is a gambler's mindset instead. Would you pay 4 cents or less per day for a non-zero chance of 5 to 10% reduced cancer and all-cause mortality with no potential downside? You would have to be a fool not take vitamin D, or to refuse a vitamin D blood test, if you ask me.

A 5 to 10% reduction in all-cause mortality or cancer mortality, while it would save trillions of dollars, would be very difficult to detect even in studies that have over 20k participants like VITAL. 

Nevertheless, although the data has shown some promise it remains hard to rule out no effect. Inconsistencies between studies are also worrying, how can we trust the data from the DO-HEALTH trial showing reduced cancer incidence when VITAL and meta-analyses only suggest benefits for cancer mortality?

There are some studies we can do relatively quickly to clarify the situation, but barring another large primary prevention trial the data will always remain speculative. Some things that would help are patient-level meta-analyses, better Mendelian randomization (MR) with larger cohorts and better genetic tools (7), longer-term follow-up of trial participants with better case ascertainment, and more consistent meta-analytic insight on the mortality data in vitamin D trials.

It will be also interesting to see stratification by vitamin D baseline levels and BMI. These seem to be the factors most often associated with differential outcomes. Indeed, one reason why the DO-HEALTH trial looked better than VITAL for cancer, might have been the lower vitamin D levels of the participants. Finally, another issue that has plagued n3 trials over the last decades, and was a problem in VITAL as well, is the enrollment of very healthy participants (9), which pushes down the effect sizes and reduces statistical power. It may well be that healthy people derive less benefit from these interventions, which is consistent with diminishing returns.

References and comments

this is very much a quick and dirty write-up. I have not read many of the cited papers in much detail, but the conclusions are generally straightforward, to me, after having followed the field for a decade on and off.

1. Bischoff-Ferrari, Heike A., et al. "Effect of vitamin D supplementation, omega-3 fatty acid supplementation, or a strength-training exercise program on clinical outcomes in older adults: the DO-HEALTH randomized clinical trial." Jama 324.18 (2020): 1855-1868.,major%20comorbidities%20aged%2070%20years

2. Bischoff-Ferrari, Heike A., et al. "Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial." Frontiers in Aging (2022): 33.

3. Bouillon, Roger, et al. "The health effects of vitamin D supplementation: Evidence from human studies." Nature Reviews Endocrinology (2021): 1-15.

4. Chandler, Paulette D., et al. "Effect of vitamin D3 supplements on development of advanced cancer: a secondary analysis of the VITAL randomized clinical trial." JAMA network open 3.11 (2020): e2025850-e2025850.

5. Keum, N., et al. "Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials." Annals of Oncology 30.5 (2019): 733-743.

6. Barbarawi, Mahmoud, et al. "Vitamin D supplementation and cardiovascular disease risks in more than 83 000 individuals in 21 randomized clinical trials: a meta-analysis." JAMA cardiology 4.8 (2019): 765-776.
6b. Zhang, Y., et al. "Association of vitamin D or calcium supplementation with cardiovascular outcomes and mortality: a meta-analysis with trial sequential analysis." The journal of nutrition, health & aging 25.2 (2021): 263-270.

Zhang, Yu, et al. "Association between vitamin D supplementation and mortality: systematic review and meta-analysis." Bmj 366 (2019).

Liu, Di, et al. "Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies." Advances in Nutrition (2021).

7.  "Depending on their number, these SNPs can explain from 2% to 10% of the variance in 25OHD levels."
"The identification of over 150 25OHD-associated genetic variants in 2020, which explain a considerable portion of the variance in 25OHD levels (~10.5%)43, has enabled a deeper understanding of the genetic determinants contributing to variation in circulating 25OHD levels. These newly identified SNPs will probably enable improved instrumentation of vitamin D in Mendelian randomization studies." from ref 3

8. Sofianopoulou, Eleni, et al. "Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses." The Lancet Diabetes & Endocrinology 9.12 (2021): 837-846.
Comment: Okay technically the authors provide strong evidence for a 40nmole/L cut-off below which vitamin D deficiency is particularly harmful, but, as far as I can tell, 80nmole/L seems closer to the optimum. The mortality data from MR is somewhat confusing with a RR of 0.99 across the whole sample, but when stratified the RR never reaches higher than 0.98 (Fig 2). Same story with finer stratification, only 2 out of 12 data points show a RR above 1.

9. "In the 2017–2020 megatrials (that is, VITAL, ViDA and D2d), overall mortality was much lower than shown in the previous meta-analyses... and did not show an effect of vitamin D supplementation on overall mortality" from ref 3

10. Arch Intern Med. 2007 Sep 10;167(16):1730-7.
Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
Autier P, Gandini S.
Comment: My understanding is that many earlier meta-analyses before the existence of isolated vitamin D megatrials were pooling data also from calcium+vitamin D arms. It is somewhat reassuring that meta-analyses including and excluding calcium trials tend to arrive at similar conclusions regarding cancer and all-cause mortality. Unfortunately, there is no one right way to pool studies. Negative meta-analyses often include studies with large bolus vitamin D and ergocalciferol, although there is reasonable evidence that these work worse than daily supplemental vitamin D.