Bob Frost
Vitamin D research money has dried up, say scientists. The US and British governments have turned away from funding large trials of the substance. The loss of funding is “a tragedy,” says Bruce W. Hollis, PhD, professor of pediatrics at the Medical University of South Carolina, who believes D has substantial untapped potential for generating health.1
The funding shift has developed over the last decade. It accelerated in 2019 in the wake of a massive study known as “VITAL” sponsored by the National Institutes of Health. VITAL (short for “Vitamin D and Omega-3 Trial”)2 has profoundly shaped the vitamin D landscape, scientists say—limiting research money, persuading doctors’ organizations to steer members away from the vitamin, and sparking mainstream media articles expressing doubt about D’s value.
An example of the latter is a piece in Scientific American in its issue of January 2024, titled “How Much Vitamin D Do You Need to Stay Healthy?”3 The 4,000-word article by Christie Aschwanden is built around a review of VITAL. The subtitle sums up its main thrust: “Most People Naturally Have Good Vitamin D Levels. Overhyped Claims That the Compound Helps to Fight Diseases From Cancer to Depression Aren’t Borne Out by Recent Research.” Excerpts:
For a while vitamin D was looking like a bona fide health elixir….Thousands of studies had linked low levels of vitamin D to an assortment of medical conditions….The problem is that this evidence came mostly from observational studies, a type of analysis that can’t show cause and effect and that might produce misleading results.
In 2009 (endocrinologist/epidemiologist JoAnn Manson M.D.) and her team (at Harvard Medical School) embarked on the world’s largest and most far-reaching randomized vitamin D trial, called VITAL. The study followed nearly 26,000 generally healthy adults, randomized to receive either 2,000 international units (IU) of vitamin D or a placebo, for an average of 5.3 years….The results came as a shock….[Vitamin D did not] make a dent in rates of cancer or heart disease….did not prevent falls, improve cognitive function, reduce atrial fibrillation, change body composition, reduce migraine frequency, improve stroke outcomes (etc.).
The notion that our lives would be better if we all just raised our vitamin D levels began to look like a fantasy….National (U.S.) population sampling showed that most people were already getting enough of the vitamin….Most people probably don’t need supplements.
There’s another side to the vitamin D debate, examined here, based on feedback from several scientists, all of whom have studied the substance for many years: Bruce W. Hollis; William B. Grant, PhD, founder of the non-profit Sunlight, Nutrition, and Health Research Center in San Francisco; Martin Hewison, PhD, a molecular biologist at the University of Birmingham; Reinhold Vieth, PhD, a nutritional researcher at the University of Toronto; and Scott T. Weiss, MD, MS of Harvard Medical School. None of these researchers were contacted by Scientific American for comment.
The Future of Major Trials
Big trials like VITAL typically cost millions of dollars. In the wake of VITAL, it is “essentially impossible,” says Hollis,1 to get funding for D studies in the United States. VITAL was the “nail in the coffin” for such work, he continues, along with a 2011 Institute of Medicine study.4 Even small research grants, Hollis continues, “are affected by this prevailing notion that ‘Vitamin D is mostly worthless.’”1
In the United Kingdom, the funding situation is similar, says Hewison: “It is almost impossible to get funding here for fundamental vitamin D research. The thinking of potential funders is, ‘Why should we spend more millions of dollars on this work given that we have already spent so much?’”5
Hewison adds, “In the past, there have been cyclical gyrations in D funding. The current downward trend feels to me like something more serious and discouraging than a short-term cyclical downturn.”
Hewison says young people are “very wary” of joining the vitamin D research community because they can’t get early-career financial backing. As a result, senior scientists are running out of people to mentor. A great deal of experience is in danger of vanishing, Hewison believes, because a number of D researchers are in the latter stages of their career, including Grant, Hollis, and Weiss, along with Bruce Ames, PhD, and Michael F. Holick, MD, PhD.
Procedures of VITAL Questioned
As noted, VITAL was a randomized controlled trial (RCT). It followed procedures used in RCTs of new drugs. According to some researchers, protocols used in drug studies should not be used in trials of nutrients such as vitamin D. Instead, says this argument, nutrient studies should adhere to a model proposed in 2014 by Robert P. Heaney, MD, in “Guidelines for Optimizing Design and Analysis of Clinical Studies of Nutrient Effects.”1 Heaney writes:
Evidence-based medicine guidelines, developed specifically for drugs, have been applied to nutrients without apparent attention to the important differences between them. The rules set forth (in this paper) are explicitly specific to nutrients and are, to the author’s knowledge, the first attempt to do this.
Heaney’s proposed rules: Use the basal (base) nutrient status of potential trial participants as “inclusion criterion” for entry into a study; basal nutrient status should be low for entry; the change in nutrient intake must be large enough to change nutrient status; the hypothesis to be tested must be that a change in nutrient status (not just a change in diet) produces the sought-for effect; and co-nutrient status must be optimized in order to ensure that the test nutrient is the only nutrition-related factor in the response.
Hollis says that vitamin D research has been “ruined” by using RCTs designed for drugs: “RCTs were never intended to be used for nutrient trials. RCTs are horribly confounded by the presence of circulating vitamin D in people, prior to the study, resulting, almost always, in null results.” He elaborates: “Suppose a new statin drug is being developed to decrease cholesterol. Do you think the pharmaceutical company, conducting a trial, would recruit subjects who were already using an old statin drug, who have already-suppressed cholesterol levels? Certainly not. If they did, and conducted the study, their new drug would provide null results because the previous drug had done its job.”1
According to Hollis, “all vitamin D RCTs require re-analysis” taking into account the entry level of vitamin D in subjects. “I have challenged the VITAL authors to baseline correct and re-analyze their data,” he says, “but they have refused. They have the capacity to re-analyze. But they will not do so, as it would change the narrative they have established, which is, supplemental vitamin D is worthless.”1
Grant points out two problems with trial guidelines adhering to drug protocols: (1) they assume the control group does not receive any of the material being tested and (2) they assume a linear dose-response relationship.7 In 2017, Grant elaborated on Heaney’s idea in the co-authored article “Why Vitamin D Clinical Trials Should Be Based on 25-Hydroxyvitamin D Concentrations”8:
Many randomized controlled trials (RCTs) aiming to confirm (observational outcome studies) have failed….The most likely reason for that failure is inappropriate design, conduct, analysis, and interpretation of RCTs. Most RCTs used principles designed to test pharmaceutical drugs….Neither vitamin D dose-responses or health outcome-serum 25(OH)D concentration relationships are linear—larger changes being induced with low rather than high baseline 25(OH)D values.
Reinhold Vieth examines trial procedures in his chapter in the textbook Feldman and Pike’s Vitamin D9:
In the context of the role of any nutrient or dietary supplement in the primary prevention of disease, the expectation for the sort of evidence demanded in very high: You need multiple clinical trials that involve a healthy cohort, randomized to a supplementary intake of the nutrient in question….(But) very few nutrients suit the short-term contexts that can be conducted realistically for clinical trials….What complicates nutritional, primary-prevention-of-disease research is the reality that development of new disease events may take more than the 5-year maximum time frame that is within the realm of what granting agencies are capable of supporting.
Vieth summarizes: “Cynics win when the demand is for causal ‘Level 1 Evidence’ from randomized clinical trials that does not and cannot exist for any nutrient.”10
Vieth notes that healthy volunteer participants in VITAL trial had average baseline serum 25(OH)D levels of 29.3 ng/ml, which is high, at the 80th percentile value of the American population. Those background serum levels “revealed a healthy volunteer bias for the VITAL study.”9
William Grant explains:
Scientific studies seek to eliminate or reduce bias. A ‘healthy volunteer bias’ is a significant bias. Dose-response relationships from observational studies show that risks reduce rapidly as 25(OH)D levels increase from near zero to 20 ng/ml, then more slowly thereafter. Since the benefits of better vitamin D status increase rapidly from very low to 15 or 20 ng/mL, better trial results would be obtained by including only those with low 25(OH)D, even if it were a much smaller study.11
Heaney’s proposed guidelines are endorsed by increasing numbers of scientists in the vitamin D field1 but are not considered by many scientists.
Too Low?
VITAL’s administration of daily dosages of 2,000 IU of D was too low to prevent adverse outcomes, say Grant and others.
Two thousand IU is a “very small dose,” Grant says,12 noting it’s possible for a person to make 10,000 IU, internally, in a couple of hours in the summer sun with a fair amount of skin exposed. In his opinion, 4,000 IU would have been more appropriate for VITAL. He says, “If using 2,000 amount was a deliberate effort to undermine the effect of vitamin D, to show that vitamin D does not work, this is bad science. If not deliberate, it’s a major error.”
Weiss comments:
VITAL used too low a dose of vitamin D in the treatment arm, and contaminated the control arm, minimizing the differences between the two groups.
The bone effects of vitamin D are controlled by serum levels of 25(OH)D and by serum parathyroid hormone (PTH).
The nonendocrine effects of vitamin D that influence cancer, heart disease, dementia risk, etc., are controlled by the level of 25(OH)D influencing immune system cells in the tissues via autocrine and paracrine effects. The relevant metric of risk for these diseases is the tissue level, not the serum level, of 25(OH)D.
All immune cells have the capacity to convert 25(OH)D to 1,25(OH)D, the active form, in the tissues. For the conditions studied in VITAL, the serum level is simply a proxy for the tissue level, which is unmeasurable.13
Grant notes that all participants in the VITAL study, including people given placebos, were permitted to take 600 or 800 IU daily of D. This, he says, had the potential of skewing results because it might reduce the incidence of disease in the study’s placebo arm.14
Hewison: “Many or most big randomized controlled trial are flawed in some way. It’s very difficult to organize such trials. We’re learning more all the time about how to conduct this work. In the meantime, unfortunately, the results of such trials are taken by some observers as ‘the final word’ and ‘the decisive verdict.’”5
Diabetes Risk
“In terms of D’s positive impacts,” says Hewison, “some successes have been found in follow-up studies to VITAL. This fact does not come across strongly in the Scientific American article.”5
For example, Scientific American says that extra vitamin D also didn’t lower diabetes risk, citing a trial published in 201915 where endocrinologist Anastassios G. Pittas, MD, of Tufts University randomized more than 2,400 people at risk for diabetes to take either 4,000 IU of vitamin D or a placebo daily. After two and a half years, says the magazine, “a similar number of people in each group went on to develop the disease.”3
In 2020, the Pittas data was re-analyzed in the article “Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study.”16 Conclusion: “Daily vitamin D supplementation to maintain a serum 25(OH)D level ≥100 nmol/L is a promising approach to reducing the risk of diabetes in adults with prediabetes.” (The serum level cited in the quotation is equivalent to 40 ng/mL. For explication of blood level figures, see below, “How Much D to Take?”) The Scientific American piece doesn’t mention the re-analysis.
Inaccuracy
Scientific American: “Your liver and fat cells store vitamin D for future use (says Anastassios Pittas). That means you don’t necessarily need a big dose every day.”3
Hewison: “Although liver and fat tissue are indeed reservoirs for vitamin D, there is no evidence these reservoirs provide a meaningful source of D for future use.”5
Decisive Verdict?
VITAL, notes Aschwanden, was called a “decisive verdict” on vitamin D supplementation in an editorial in the New England Journal of Medicine by Steven R. Cummings M.D. and Clifford Rosen, MD17—i.e., in their view, the study gives a categorical thumbs-down on D supplementation. The phraseology calls into question their objectivity, says Grant, and that of the New England journal: “The word ‘decisive’ suggests study of vitamin D supplementation can, and should, end here. Might science best be served by an unstoppable quest for new knowledge?”7 Writer Aschwanden touches on that question in Scientific American, saying there is “plenty more to understand” about D, and there’s value in interpreting scientific results “with humility.”3
How Much D to Take?
Scientific American notes that JoAnn Manson of VITALdoesn’t recommend D intakes higher than 2,000 IU daily “because some studies have found that excess vitamin D can increase the risk of dangerous falls….”3
Vieth responds: “Warnings about higher intakes of vitamin D are often disingenuous….(They are) fixated on the same publication, ‘Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women: A Randomized Controlled Trial’ by K.M. Sanders et al. (2010)18….a clinical trial….in which vitamin D was given as an annual bolus dose. It should not come as a surprise to anyone, if there is harm associated with the once-yearly administration of any nutrient.”9
Grant takes 5,000 IU of vitamin D3 per day in capsule form. Hewison: 4,000 IU daily of D3 in capsules. Hollis: 10,000 IU of D3 every day in capsules. Weiss: 4,000 IU daily of D3 as gummy vitamins.19
The key number, says Hollis, is not how much D one takes in a given day but the circulating blood level of D. The way to know this level is to have it measured with an inexpensive blood test. “Once you reach the circulating blood level that you desire,” says Hollis, “you will stay there, and not exceed it, if you maintain the daily dosage that got you there. My circulating blood level is 82 nanograms per milliliter (ng/mL). A circulating blood level in the 80s or 90s is safe and appropriate. Those levels can be attained naturally from sun exposure; such levels are physiologic and healthy.”1
Many experts recommend a blood level in the range of 20 to 40 ng/mL.20 The National Institutes of Health recommends a daily D intake of 400 to 800 IU, which, says Hollis, has roots in decades-old recommendations by Dr. Gilbert B. Forbes and are “not based on careful science.”1
Hollis, Grant, and others speculate about levels of D maintained over millennia by our ancestors, people who were outside much of the time. There’s a possibility, say researchers, our forebears routinely had blood levels in the 80s and 90s.19
Magnesium makes metabolic conversion of vitamin D more efficient, notes Hollis, who takes 400 to 500 milligrams daily of the mineral.1
Clinical Decision-Making
Clinical decisions are being made about vitamin D based on VITAL, says Hollis.1 Governing bodies of physicians, such as the American College of Obstetricians and Gynecologists, make D recommendations to their members “relying on science that uses an archaic way of gathering data,” Hollis says.
Hollis has a special interest in D’s potential positive impact on pregnancy, which is “not debatable at this point,” he says. He cites a study known as VDAART led by Weiss: “Based on the VDAART results,21 prevention of almost all childhood asthma could happen if doctors dosed mothers early in their pregnancy, or preconception, with 4,000 to 6,000 IU of D per day.”1
Observational Studies
Sharon M. Friedman is a professor emerita in the Dept. of Journalism & Communication at Lehigh University who has devoted her career to studying science communication. She comments:
What is presented in Scientific American is a bit of a one-sided approach, to not mention in some detail the observational studies and their data. These could have been balanced against the experimental data (double-blind, etc.), trying to explain the different approaches and not dismissing either one. There are advantages to both the observational and the experimental approaches. They both provide valuable data.22
An additional opinion on the value of observational surveys is offered by Catherine Shanahan, MD, a board-certified family physician in Denver, co-author of Deep Nutrition, where she writes, “Observational surveys…are indeed a valuable research tool.”23
‘Big Pharma’
Grant is author of the article “Vitamin D Acceptance Delayed by Big Pharma Following the Disinformation Playbook” (2018).24 It’s published at Orthomolecular.org, a nonprofit educational website based on principles put forward by Linus Pauling. Grant believes pharmaceutical companies are deliberately and aggressively attempting to subvert D because of its threat to their income and profits.
Hollis: “Vitamin D is competing with pharmaceuticals. This is a factor in why D is so widely disparaged.”1
Observations
The physician who writes at Substack.com under the nom de plume “A Midwestern Doctor” (2023) offers this thought: “Innovative ideas which challenge longstanding orthodoxies and commercial interests are always attacked by the medical profession.”25
History provides evidence for the idea that doctors resist new ideas. Decades were required for mainstream medical acceptance of scurvy amelioration by citrus fruit after its efficacy was proven by field work; of rickets treatment by sunlight and cod liver oil; of the antiseptic ideas of Ignaz Semmelweiss; etc. “Healthcare is famously resistant to change,” writes Benjamin Schwartz, MD, MBA. “We are traditionalistic, cautious, conservative, and slow to evolve.”26
Seven Recent Vitamin D Papers of Interest
1. “Vitamin D and Marine Omega 3 Fatty Acid Supplementation and Incident Autoimmune Disease: VITAL Randomized Controlled Trial” by J. Hahn et al. (2022).27 This study found important benefits for rheumatoid arthritis in the latter half of the VITAL trial: “Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%.”
2. “Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial” by P.D. Chandler et al. (2020).28 “Supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort.”
3. “25-Hydroxyvitamin D and Total Cancer Incidence and Mortality: A Meta-Analysis of Prospective Cohort Studies” by J. Han et al. (2019).29 “This meta-analysis provides evidence that a higher 25-hydroxyvitamin D concentration is associated with a lower cancer incidence and cancer mortality.”
4. “The Metabolic Role of Vitamin D in Children’s Neurodevelopment: A Network Study” by M. De Marzio et al. (2023).30 “Vitamin D has been increasingly implicated in autism spectrum disorder (ASD) pathogenesis….Our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders.”
5. “Prenatal Vitamin D Supplementation to Prevent Childhood Asthma: 15-Year Results From the Vitamin D Antenatal Asthma Reduction Trial (VDAART)” by S. T. Weiss et al. (2023).31 “These results demonstrate a statistically significant reduction in asthma among offspring aged 3 and 6 years when comparing vitamin D supplementation (4,400 IU/day) to the standard prenatal multivitamin with vitamin D (400 IU/day).”
6. “Effectiveness of Prenatal Vitamin D Deficiency Screening and Treatment Program: A Stratified Randomized Field Trial” by M. Rostami et al. (2018).32 This paper reports benefits in measuring and supplementing D in pregnant women: “A prenatal vitamin D screening and treatment program is an effective approach in detecting deficient women, improving 25(OH)D levels, and decreasing pregnancy adverse outcomes.”
The New England Journal of Medicine (NEJM) declined this paper. It was published in the Journal of Clinical Endocrinology and Metabolism (JCEM). In 2018, NEJM published a piece by D.E. Roth et al. finding no benefit in vitamin D supplementation in terms of fetal and infant growth (“Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth”).33 “The study by Roth et al.,” Hollis writes, “….highlights how NOT to reproduce past positive studies—i.e., supplementing far too little vitamin D far too late in gestation to influence the conditions that are being monitored, such as maternal safety and fetal growth monitoring.”34
The Rostami paper was regarded as so significant by JCEM that the journal issued a commentary to highlight the research, “A Call to Action: Pregnant Women In-Deed Require Vitamin D Supplementation for Better Health Outcomes” by Michael F. Holick M.D., Ph.D.35: “The results from this study are monumental….If a pharmaceutical company had developed a drug to reduce (pregnancy risks) by even 10% they would have a multibillion dollar business.”
7. “VITAL Study: An Incomplete Picture?” by M. Infante et al. (2019).36
A Final Thought
Hollis: “A lot could be done with a proper large trial of vitamin D. Our only hope, and it’s a slim one, is if some billionaire, let’s say some tech tycoon, were to say, ‘Here is twenty million dollars, go to work.’ If we could get in front of someone like that and make a proposal, we could make it happen.”1
References
1. Conversation with author, 1/9/24.
2. https://www.nejm.org/doi/full/10.1056/nejmoa1809944
3. https://www.scientificamerican.com/article/how-much-Vitamin-d-do-you-need-to-stay-healthy/ (The title in the print edition is “The Rise and Fall of Vitamin D.”)
5. Conversation with author, 1/8/23.
6. https://pubmed.ncbi.nlm.nih.gov/24330136/
7. Email to author, 2/10/2024.
8. https://pubmed.ncbi.nlm.nih.gov/28842142/
9. Feldman and Pike’s Vitamin D edited by Martin Hewison et al. (2024 fifth edition).
10. Email to author, 1/5/2024.
11. Email to author, 12/24/2023.
12. Email to author, 12/30/2023.
13. Email to author, 1/15/24.
14. Email to author, 12/28/2023.
15. https://www.nejm.org/doi/full/10.1056/NEJMoa1900906
16. https://pubmed.ncbi.nlm.nih.gov/33020052/
17. https://www.skyline725.com/wp-content/uploads/2022/07/Vitamin-D.pdf
18. https://pubmed.ncbi.nlm.nih.gov/20460620/
19. Emails and conversations, 12/23 and 1/24.
21. https://pubmed.ncbi.nlm.nih.gov/37852328/
22. Email to author, 2/3/2024.
23. Deep Nutrition by Catherine Shanahan With Luke Shanahan (2016 second edition).
24. http://orthomolecular.org/resources/omns/v14n22.shtml
25. https://www.midwesterndoctor.com/p/how-the-heart-controls-exactly-where
27. https://pubmed.ncbi.nlm.nih.gov/35082139/
28. https://pubmed.ncbi.nlm.nih.gov/33206192/
29. https://pubmed.ncbi.nlm.nih.gov/31561503/
30. https://www.biorxiv.org/content/10.1101/2023.06.23.546277v1.full.pdf
31. https://pubmed.ncbi.nlm.nih.gov/37852328/
32. https://pubmed.ncbi.nlm.nih.gov/29788364/
33. https://www.nejm.org/doi/full/10.1056/nejmoa1800927
34. https://www.mdpi.com/2072-6643/14/4/899
35. https://academic.oup.com/jcem/article/104/1/13/5098355
36. https://www.europeanreview.org/wp/wp-content/uploads/3142-3147.pdf
Further Resources
https://vitamindforall.org/letter.html
https://www.youtube.com/watch?v=P92PF_4BqNw&t=2612s
Published March 23, 2024
About the Author
Bob Frost is a journalist based in San Francisco and a contributing writer for Townsend Letter. He has published in many venues including West, the former Sunday magazine of the San Jose Mercury News, newspaper of record for Silicon Valley, where he covered health and wellness for a number of years. His email is BobFrostMail@aol.com.