Say No to Vitamin D Testing and Supplementation

This is one of those problems in medicine that just does not go away. Each time you think the issue is settled, researchers who believe in the magical powers of vitamin D continue to come up with studies trying to show its usefulness in everything from reduced mortality to reduced risk of all kinds of diseases.  The amount of energy and money that vitamin D research sucks away from other important research questions is far out of proportion to any perceived benefits that may exist.

I have earlier written about the hype and hoopla around vitamin D and why supplementation is of no use and could perhaps even be harmful, unless you are nutritionally deprived, malnourished or have clinical symptoms and signs related to vitamin D deficiency. The earlier presumptions that vitamin D supplementation in normal individuals could increase healthspan and lifespan were mainly from observational studies…these presumptions have not panned out in recent randomized controlled trials including Vital and D-Health. The USPSTF also does not recommend routine supplementation or measurement of vitamin D levels, which unfortunately is being done more and more these days as part of annual health check-ups and in most people who don’t feel well for any reason whatsoever.

A recent study by the EPIC group [1] used Mendelian randomization on a large cohort of almost 500,000 plus people to show a causal relationship between vitamin D levels below 16 ng/ml (40 mmol / ml) and mortality. This potentially makes sense, because below 20 ng / ml is considered insufficiency and below 12 ng / ml,  deficient and a vitamin D level less than 16 ng / ml could perhaps be associated with increased all-cause mortality.

Except…Mendelian randomization is a new technique that uses genetic variants of a particular biomarker, in this case vitamin D, to define separate population subgroups that may or may not be susceptible to the effects of vitamin D deficiency - this is a complex methodology, understood by very few people (at least four geneticists I reached out to in India confessed they had no clue). It also makes a bunch of assumptions related to the genetic methods and the statistics used. The claim by researchers using Mendelian randomization is that it eliminates confounders and improves causal relationships between problems and outcomes. Unfortunately, the technique itself comes with its own problems.

In this particular case, there were two rebuttal letters [2] published recently in the same journal that challenged these assumptions and the statistical inferences…arguments which the authors accepted. Their final conclusion is that they cannot find a relationship between low vitamin D levels and increased mortality [2]. Unfortunately, unless someone also reads this retraction of the conclusion by the authors (the article itself does not need retraction, because the study is not ethically flawed), the original conclusion will continue to remain in the minds of the people who have read it, either in the journal or in the lay press.

There are two other articles [3,4] that have used the same UK biobank data to arrive at similar conclusions suggesting that low vitamin D levels are associated with either increased mortality [3] or increased cardiovascular risk [4]. Both these studies use similar flawed assumptions and statistical analyses and their conclusions also need to be corrected.

It gets even more interesting.

In July, LeBoff MS and colleagues [5] published a randomized controlled trial that showed that the use of vitamin D supplementation in the general population did not reduce the risk of fractures as compared to placebo, a finding that is also in line with the USPSTF recommendations. An accompanying editorial [6] has this to say, “Adding those findings to previous reports from VITAL and other trials showing the lack of an effect for preventing numerous conditions suggests that providers should stop screening for 25-hydroxyvitamin D levels or recommending vitamin D supplements, and people should stop taking vitamin D supplements to prevent major diseases or extend life.”

More tellingly, a recent study from Mongolia by Ganmaa D and colleagues [7] in children with low vitamin D levels found that while vitamin D supplementation increased vitamin D levels, there was no effect on growth, body composition or pubertal development. The authors however gave no explanation for this result.

What does this mean for you and I?

As I said in the earlier article on the iatrogenesis of vitamins…,

1. Say no to the measurement of vitamin D levels unless you have a disease or disorder that predisposes to vitamin D deficiency and even then, measuring the level is usually irrelevant.

2. Say no to supplementation, unless you are elderly and indoors all the time, debilitated or have major illness such as cancers or malabsorption or other illnesses that can lead to nutritional deficiencies.

Footnotes

1. Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration. Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses. Lancet Diabetes Endocrinol. 2021 Dec;9(12):837-846. 2. Burgess S et al. Mendelian randomisation and vitamin D: the importance of model assumptions - Authors' reply. Lancet Diabetes Endocrinol. 2023 Jan;11(1):15-16.

3. Sutherland JP, Zhou A, Hyppönen E. Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study. Ann Intern Med. 2022 Nov;175(11):1552-1559.

4. Zhou A, Selvanayagam JB, Hyppönen E. Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. Eur Heart J. 2022 May 7;43(18):1731-1739.

5. LeBoff MS et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. N Engl J Med. 2022 Jul 28;387(4):299-309.

6. Cummings SR, Rosen C. VITAL Findings - A Decisive Verdict on Vitamin D Supplementation. N Engl J Med. 2022 Jul 28;387(4):368-370.

7. Ganmaa D et al. Influence of Vitamin D Supplementation on Growth, Body Composition, and Pubertal Development Among School-aged Children in an Area With a High Prevalence of Vitamin D Deficiency: A Randomized Clinical Trial. JAMA Pediatr. 2022 Nov 28:e224581.