Two recent papers have been published recently that seem to support that vitamin D does something to prevent or treat COVID-19. Except for a tiny little problem – both of the studies terribly weak and are unconvincing except to those who just want supplements to do something to end this pandemic. Don’t get your hopes too high.
Of course, the COVID-19 pandemic has caused interest in vitamin D to skyrocket, because there has been a belief that vitamin D improves the immune system against the disease. The sales of vitamin D supplements have increased substantially since pre-pandemic times.
But is there any evidence supporting its use to prevent COVID-19 or improve outcomes for serious cases? Yes, there is evidence, but it’s far from convincing. There are better ways to prevent a COVID-19 infection, and vitamin D is not one of them.
Boosting the immune system
The basis of the vitamin D belief system is that somehow in some unknown way it “boosts the immune system.” I remember watching Quora soon after the start of the pandemic and there were hundreds of questions asking how to boost the immune system.
I tried to remind everyone that “boosting” the immune system against COVID-19 is one of those bogus beliefs pushed by the pseudoscience world – the immune system is a highly complex interconnected apparatus within our physiology that connects unique cells, biochemicals, and organs. If you think you can prevent COVID-19 by guzzling a kale-blueberry smoothie filled with vitamin D to make your immune system impervious to the disease, then you probably should quit reading nonsense from internet grifters and go take some real immunology courses in a real college.
Just to remind everyone, the only way we humans are going to be able to “boost our immunity” against COVID-19 is by getting vaccinated against COVID-19. They have demonstrated that they prevent the disease (at least in the short-term) in large double-blinded, randomized clinical trials.
By the way, when we talk about vitamin D and COVID-19 next, the evidence is not large, not double-blinded, and not randomized, clinical trials. This is something that I always seem to find when people make wild claims about supplements.
What is vitamin D?
Vitamin D is a group of fat-soluble secosteroids (it’s a scientific name for steroids with a “broken” ring). The most important chemicals in this group are vitamin D3 (known as cholecalciferol) and D2 (known as ergocalciferol).
Very few foods contain either of the important types of vitamin D. However, there are some foods that can be good sources for the vitamin:
- Fatty fish, like tuna, mackerel, and salmon
- Foods fortified with vitamin D, like some dairy products, orange juice, soy milk, and cereals
- Beef liver
- Egg yolks
Many people with broad diets that include a lot of fish, eggs, and other foods can get sufficient vitamin D without supplementation. As I’ve repeated often, short of chronic malnutrition, we get plenty of vitamin D.
Moreover, vitamin D is produced by a process called dermal synthesis. That is, sunlight, specifically UV-B radiation, causes the synthesis of vitamin D in the skin. Technically, vitamin D isn’t a vitamin, because we can manufacture it, it is really a hormone. For this article, we’ll just call it a vitamin, even though scientifically it is not.
Although we can manufacture sufficient vitamin D by sunbathing every day, the body has a feedback loop that shuts down production to prevent toxicity. Yes, excess vitamin D is quite dangerous leading to many conditions such as over absorption of calcium to hypertension to fatigue. But it also can lead to some dangerous chronic conditions that we’ll discuss later.
Although humans can manufacture vitamin D by sitting in bright sun, there’s one major problem – the risk of skin cancer. As I’ve written before, there are very few ways to actually prevent cancer, but staying out of the sun is one of them.
Finally, vitamin D we consume or produce in sunlight is not biologically active. It is generally activated by enzymatic conversion (in a process called hydroxylation) in the kidneys and liver so that the body can use it.
What does vitamin D do or don’t do?
Based on real scientific evidence, vitamin D has a very narrow, but important, set of effects.
First, it is responsible for enhancing intestinal absorption of calcium, iron, magnesium, phosphate, and zinc, important minerals for the continued health of any human being. Many of these minerals (and vitamin D itself) is necessary for good bone health.
Second, since vitamin D is important to calcium homeostasis and metabolism, a deficiency of the vitamin results in rickets, or the adult form of the disease, osteomalacia. Rickets, because it happens in immature bones, leads to frequent fractures and skeletal deformities. Osteomalacia, because it occurs in adults with fully formed bones, usually only results in numerous fractures.
At this point, that’s it. Robust evidence only supports those two physiological effects.
However, here are few claims made by the supplement-pushing crowd:
- Vitamin D prevents breast cancer – no evidence.
- Vitamin D prevents breast cancer – no evidence again.
- Vitamin D reduces blood pressure – no again.
- Vitamin D reduces the risk of death – no evidence.
- Vitamin D improves cardiometabolic outcomes – systematic review says no. (Note – systematic- and meta-reviews are considered the pinnacle of the hierarchy of biomedical research).
- Vitamin D reduces the risk of colorectal cancers – no evidence.
- Vitamin D improves skeletal, vascular or cancer outcomes – meta-analysis says no.
- Vitamin D improves mortality outcomes for elderly patients – a massive meta-review says there is weak evidence, but that’s clouded by various reporting biases that make the data almost worthless.
- Vitamin D improves cardiovascular disease outcomes – a large systematic review says no.
Despite this utter lack of evidence, vitamin D has continued to be the panacea for all that ails humans. For those of us who only care about large, high-quality, peer-reviewed studies, vitamin D is overrated, unless you need to prevent rickets.
Vitamin D supplements don’t hurt, right?
Right now, we know that vitamin D does two things – helps the absorption of minerals and prevents calcium homeostasis which causes bone damage. Most people in developed countries get sufficient vitamin D from sunlight or foods.
And even if a person doesn’t, there are blood tests that can confirm a vitamin D deficiency, and an appropriate supplementation level should be prescribed. In other words, if an issue is discovered through a real diagnosis, then a healthcare plan can be implemented to prevent any consequences of low vitamin D.
Now some people try to claim that recommended vitamin D levels are too low according to beliefs rather than science. But people keep pushing this trope, yet real science just doesn’t support it.
In 2011, the National Academy of Medicine, one of the most prestigious science-based medicine institutions in the world, concluded a serum 25(OH)D (a metabolite of vitamin D that is a proxy for overall levels of vitamin D) level of 20 ng/mL (50 nmol/L) is needed for bone and overall health. The Institute found serum 25(OH)D concentrations above 30 ng/mL (75 nmol/L) are “not consistently associated with increased benefit”. Serum 25(OH)D levels above 50 ng/mL (125 nmol/L) may be cause for concern.
But let’s say you refuse to accept my evidence that vitamin D is more or less useless, except for those very few who have low levels. You just believe in the charlatans who are pushing megadoses of vitamin D, even if you have not been diagnosed with a chronic deficiency. I would almost say, no harm, no foul.
Except for a small little issue. There is a lot of evidence that vitamin D supplementation not only has no benefit (except again in two physiological situations) but it might actually cause harm. Here are just some of the risk of vitamin D supplements:
- A study of 409 elderly people in Finland showed that vitamin D supplements failed to offer benefits compared to placebo or exercise – and, in fact, the study suggested that fracture rates were slightly higher in the study population.
- Another study in Australia established that patients that had “optimal blood levels” of vitamin D had increased rates of fractures and falls compared to those on low doses or who failed to reach those blood levels.
- Excess maternal vitamin D during pregnancy may lead to hypercalcemia (excess blood calcium) which can increase fetal sensitivity to the effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.
- Excess vitamin D may include symptoms such as mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression.
And I barely touched the surface of the body of research that establishes the potential dangers of excess vitamin D. And unless you have had blood tests to determine the level of vitamin D in your blood, even a small supplement may push you over into the toxic range.
Vitamin D and COVID-19 – paper number 1
The first paper by Entrenas Castillo et al., published in the Journal of Steroid Biochemistry and Molecular Biology, examined the effect of calcifediol treatment compared to the “best available therapy” for COVID-19 in a randomized clinical study of 1000 patients.
However, they really showed nothing at all, let me recount the ways:
- Despite planning to include 1000 patients, the published study only included. 50 treated and 26 untreated controls. That is a tiny study that actually tells us nothing. Why? Because pivotal studies would require a huge number of patients (even 1000 is insufficient) to find a statistical difference. For example, if the improved outcome is only 1%, you can’t see that without a large population.
- The study was not double-blinded. It’s not even worth discussing this article further, but the pro-supplement crowd needs to understand this point.
- These 19 subjects apparently were used to show that the group receiving vitamin D had a lower risk of serious disease. However, we don’t have any information that would confirm this like – actual 25(OH)D levels, oxygen saturation, and other diagnostics that would tell us how interpret this tiny bit of data.
- Lior Pachter analyzed some of the data (in the chart) and wrote:
The fact that admission to the ICU could be decided in part based on the presence of co-morbidities, and that there was a significant imbalance in one of the comorbidities, immediately renders the study results meaningless. There are several other problems with it that potentially confound the results: the study did not examine the Vitamin D levels of the treated patients, nor was the untreated group administered a placebo.
Most importantly, the study numbers were tiny, with only 76 patients examined. Small studies are notoriously problematic and are known to produce large effect sizes . Furthermore, sloppiness in the study does not lead to confidence in the results. The authors state that the “rigorous protocol” for determining patient admission to the ICU is available as Supplementary Material, but there is no Supplementary Material distributed with the paper. There is also an embarrassing typo: Fisher’s exact test is referred to twice as “Fischer’s test”. To err once in describing this classical statistical test may be regarded as a misfortune; to do it twice looks like carelessness.
There is nothing here that provides us with any type of evidence that vitamin D can do anything for COVID-19. I’m not even sure why this article was published in the Journal of Steroid Biochemistry and Molecular Biology, except maybe they generally publish basic science articles and not much in clinical studies. Or something like that.
Vitamin D and COVID-19 – paper number 2
In a preprint by X. Nogués et al., the authors claimed that “In patients hospitalized with COVID-19, calcifediol treatment at the time of hospitalization significantly reduced ICU admission and mortality.”
This sounds promising, but once again, there is much to criticize. Let me list the ways:
- I know that in the world of COVID-19 research, preprints are the fastest, though not the best, way to get information out into the scientific community. But it’s important to point out that preprints are not peer-reviewed, and we have no clue whether this paper will be published by anyone. This does not make it worthless, but it is not considered real evidence that can be cited by anyone attempting to use vitamin D as a frontline treatment for COVID-19.
- Neil O’Leary wrote a series of Tweets (the new peer-review system) where he actually analyzed the data in a way that made sense with this type of study:
- Dr. O’Leary concludes by Tweeting this:
- But there’s more. Most importantly, this is not a “randomized” study. Randomization is a method to reduce bias in clinical trials by placing patients in either the treatment or non-treatment arms without any other considerations. What if the treatment group got the least problematic patients? And the non-treatment group got the most severe cases?
- Another Twitter peer-review concluded this:
- I could go on and on with Twitter peer-review describing that this is not a controlled, randomized trial. At that point, it is almost impossible to accept that this study has any usefulness at all. People complain about peer review all the time, but a competent peer review would have kicked this article back to the authors with a serious reprimand.
A couple of caveats
Individuals with low blood levels of vitamin D who present to the hospital with COVID-19 need to have vitamin D supplements. It isn’t to treat COVID-19 directly (it’s not going to boost your immune system), it’s to reduce certain comorbidities that can make COVID-19 outcomes much worse.
Also, infections like COVID-19 can reduce vitamin D levels in many people. But we have no data whether the drop in vitamin D levels have any effect on outcomes.
But don’t worry, science does move on. There are 78 studies listed in the clinical trial database that are examining any links between vitamin D supplementation and COVID-19. Maybe in a couple of years we will know whether it is useful or not.
On the other hand, if you have been diagnosed with a vitamin D deficiency and you take a proper dose of the vitamin, it won’t hurt. But megadoses will not help and will cause harm.
Stay tuned. Maybe there will be a well-designed, large, randomized, double-blind, clinical trial that might give us some evidence as to whether it works or not. Oh, there is one.
- Barbarawi M, Kheiri B, Zayed Y, Barbarawi O, Dhillon H, Swaid B, Yelangi A, Sundus S, Bachuwa G, Alkotob ML, Manson JE. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. JAMA Cardiol. 2019 Jun 19;. doi: 10.1001/jamacardio.2019.1870. [Epub ahead of print] PubMed PMID: 31215980; PubMed Central PMCID: PMC6584896.
- Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover DC, Bostick RM, Ivanova A, Cole BF, Ahnen DJ, Beck GJ, Bresalier RS, Burke CA, Church TR, Cruz-Correa M, Figueiredo JC, Goodman M, Kim AS, Robertson DJ, Rothstein R, Shaukat A, Seabrook ME, Summers RW. A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. N Engl J Med. 2015 Oct 15;373(16):1519-30. doi: 10.1056/NEJMoa1500409. PubMed PMID: 26465985; PubMed Central PMCID: PMC4643064.
- Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;1:CD007470. doi: 10.1002/14651858.CD007470.pub3. Review. PubMed PMID: 24414552.
- Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014 Apr;2(4):307-20. doi: 10.1016/S2213-8587(13)70212-2. Epub 2014 Jan 24. Review. PubMed PMID: 24703049.
- Braganza SF, Ozuah PO. Fad therapies. Pediatr Rev. 2005 Oct;26(10):371-6. Review. PubMed PMID: 16199591.
- Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA. 2019 Aug 27;322(8):736-745. doi: 10.1001/jama.2019.11889. PubMed PMID: 31454046; PubMed Central PMCID: PMC6714464.
- Cummings SR, Kiel DP, Black DM. Vitamin D Supplementation and Increased Risk of Falling – A Cautionary Tale of Vitamin Supplements Retold. JAMA Internal Med. 2016 Jan. 4. doi: 10.1001/jamainternmed.2015.7568.
- Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, Quesada Gomez JM. “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study“. J Steroid Biochem Mol Biol. 2020 Oct;203:105751. doi: 10.1016/j.jsbmb.2020.105751. Epub 2020 Aug 29. PMID: 32871238; PMCID: PMC7456194.
- Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Washington (DC): National Academies Press (US); 2011. PMID: 21796828.
- Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010 Mar 2;152(5):307-14. doi: 10.7326/0003-4819-152-5-201003020-00009. Review. PubMed PMID: 20194237; PubMed Central PMCID: PMC3211092.
- Quyyumi AA, Al Mheid I. The Demise of Vitamin D for Cardiovascular Prevention. JAMA Cardiol. 2019 Jun 19;. doi: 10.1001/jamacardio.2019.1906. [Epub ahead of print] PubMed PMID: 31215963.
- Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010 May 12;303(18):1815-22. doi: 10.1001/jama.2010.594. Erratum in: JAMA. 2010 Jun 16;303(23):2357. PubMed PMID: 20460620.
- Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56. Review. PubMed PMID: 10232622.
- Vogiatzi MG, Jacobson-Dickman E, DeBoer MD; Drugs, and Therapeutics Committee of The Pediatric Endocrine Society. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014 Apr;99(4):1132-41. doi: 10.1210/jc.2013-3655. Epub 2014 Jan 23. Review. PubMed PMID: 24456284.