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Nature knows best: A response to the Dror study

We have had a lot of emails about a recent study by Dror et al (1). They found a nonlinear risk of 25(OH)D levels, with levels above 36 ng/ml conferring a small but significant risk but levels below 20 ng/ml conferring a major risk. The authors measured 25(OH)D levels in more than 400,000 subjects and then followed them to see who had died or had heart attacks. After up to 54 months of observation, more than 3,900 subjects had died or had heart attacks. Compared to those with 25(OH)D levels between 20-36 ng/ml, the adjusted hazard ratios for heart attacks among those with levels of

Most vitamin D experts believe the elevated risk in those with levels above 36 ng/ml in Dror et al were due to the fact that sick people tend to take or get vitamin D prescribed to them more often than well people do, thus skewing the curve. That is, more very sick people are taking or given vitamin D and that vitamin D comes too late to prevent them from dying.

Doctor John A. Eisman of New South Wales University in Australia wrote that Dror et al reported the attributable risk for mortality and acute coronary syndrome events is 32% for 25-OH D values below 20 ng/ml but only  0.55% for 25-OH D values above 36 ng/ml (2). Thus, if one were to take these risks at face value, it seems that the ratio of benefit to risk of indiscriminant vitamin D supplementation in an unscreened population would exceed 50:1.

Dr. Eisman also pointed out there was no evidence of a dose–response relationship at the higher levels of 25-OH D with virtually the same apparent adjusted risk for levels of 36–40 ng/ml, 40–44 ng/ml, and > 44 ng/ml. If higher blood levels of vitamin D were dangerous, then the higher the level the greater the danger but Dror et al did not find that. However, fewer than 1% of the subject had 25(OH)D levels greater than 36 ng/ml so further analysis of that group was problematic.

However I believe that nature knows best. I found Dror et al unconvincing because they claim they know more than nature and natural 25(OH)D levels are dangerous. I think this highly unlikely. By natural I mean those levels obtained by free-living hunter-gatherers in equatorial Africa, which average about 46 ng/ml. (3) I also do not know of a mechanism by which 25(OH)D levels above 36 ng/ml could be dangerous. Vitamin D toxicity may start with levels somewhere above 150 ng/ml but certainly not at 36 ng/ml. (4)

I theorize that Dror et al’s findings were due to confounding with vitamin A. In a Cochrane Review meta-analysis of randomized controlled trials, they found people who take vitamin A have a 16% increased rate of dying (5). Examining dietary intakes in the Nurses’ Health Study, Oh et al found that women in the highest quintile of vitamin D intake also took the most vitamin A, about 10,000 IU/d of retinol, much higher than what anybody recommends (6).

Cheng and Neuhouser have recently shown that a very significant nutrient-nutrient interaction occurs between vitamin A and vitamin D (7). They found that elevated retinyl ester levels were common among those with high 25(OH)D levels and those retinyl ester levels confounded 25(OH)D’s favorable effect on lung cancer. Excess vitamin A intake and subclinical vitamin A toxicity is a real problem (8). Mice fed excess vitamin A develop heart disease (9). Vitamin A also increases CRP (10).

So we know that excess vitamin A causes death, that people who have the highest vitamin D intakes also have highest vitamin A intakes and that a significant nutrient-nutrient interaction occurs between vitamin A and vitamin D. If Dror et al had measured serum retinyl esters in his population, current evidence predicts he would have found elevated retinyl esters in those with the highest 25(OH)D levels, thus confounding their study.

Are levels above 40 ng/ml a good idea? In a recent study of gene expression, the person in the study who had an initial 25(OH)D level of 30 ng/ml, and who obtained 25(OH)D of above 40 ng/ml after supplementation, had differential expression of 33 genes, suggesting there is a significant benefit  of 40 ng/ml (11). It has been shown that bisphosphonates work best when the 25 hydroxy vitamin D level are greater than 40 ng/ml (12).

Bone mineral density progressively increases as the serum level of 25 hydroxy vitamin D increases to 40 ng/ml or more (13). There are additional benefits in maintaining 25(OH)D levels even higher than 40 ng/ml, for example autoimmune disease, cancer and diabetes (14). Pregnant women supplemented with 4,000 and 6,400 IU/day had fewer complications of pregnancy than did women on 400 IU/day and many of those women had levels above 36 ng/ml (15).

However, as a zoologist, I go back to the common sense idea that nature knows best. Mean natural 25(OH)D levels are around 46 ng/ml. In fact, a follow up study showed that pregnant hunter-gatherers in Tanzania had mean levels of 60 ng/ml and one pregnant hunter-gatherer was above 100 ng/ml (16). Until a randomized controlled trial shows high dose supplementation is dangerous, I will maintain natural vitamin D levels.

  1. Dror Y et al.  Vitamin D levels for preventing acute coronary syndrome and mortality: evidence of a nonlinear association. J Clin Endocrinol Metab. 2013 May;98(5):2160-7.
  2. Eisman JA. When is a u-curve actually a j-curve? Is it really too much of a good thing? J Clin Endocrinol Metab. 2013 May;98(5):1863-4.
  3. Luxwolda MF et al. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012 Nov 14;108(9):1557-61.
  4. Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
  5. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007176.
  6. Oh K, Willett WC, Wu K, Fuchs CS, Giovannucci EL Calcium and vitamin D intakes in relation to risk of distal colorectal adenoma in women. Am J Epidemiol. 2007 May 15;165(10):1178-86.
  7. Cheng TY, Neuhouser ML. Serum 25-hydroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient-nutrient interaction. Cancer Causes Control. 2012 Sep;23(9):1557-65.
  8. Cannell JJ et al.  Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann Otol Rhinol Laryngol. 2008 Nov;117(11):864-70. Review.
  9. Huk DJ, Hammond HL, Kegechika H, Lincoln J. Increased dietary intake of vitamin A promotes aortic valve calcification in vivo. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):285-93.
  10. Farhangi MA et al.  Vitamin A supplementation, serum lipids, liver enzymes and C-reactive protein concentrations in obese women of reproductive age. Ann Clin Biochem. 2013 Jan;50(Pt 1):25-30.
  11. Hossein-Nezhad A, Spira A, Holick MF.  Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial. PLoS One. 2013;8(3):e58725.
  12.  Carmel AS, Shieh A, Bang H, Bockman RS.The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33 ng/ml.Osteoporos Int. 2012 Oct;23(10):2479-87.
  13. Hollis, B, et al. Circulating 25-Hydroxyvitamin D levels Indicative of Vitamin D Sufficiency J Nutr. (2005); 235, 317-322.
  14. Garland C et al, Vitamin D Supplement Doses and Serum 25-Hydroxyvitamin D in the Range Associated with Cancer Prevention, Anticancer Research (2011), 31; 607-612.
  15. Hollis BW, Wagner CL. Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int. 2013 Feb;92(2):128-39.
  16. Luxwolda MF, Kuipers RS, Kema IP, van der Veer E, Dijck-Brouwer DA, Muskiet FA. Vitamin D status indicators in indigenous populations in East Africa. Eur J Nutr. 2013 Apr;52(3):1115-25.

About John Cannell, MD

Dr. John Cannell is founder of the Vitamin D Council. He has written many peer-reviewed papers on vitamin D and speaks frequently across the United States on the subject. Dr. Cannell holds an M.D. and has served the medical field as a general practitioner, emergency physician, and psychiatrist.
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9 Responses to Nature knows best: A response to the Dror study

  1. Rita and Misty says:

    Thank you. :)

  2. Again, this appears to be a D3 vs. D2 issue! If sick(er) patients are prescribed vitamin D you can be sure it is D2, the patented chemical that does not work very well, as real vitamin D(3) does, in animals.

  3. jmeshon says:

    It’s amazing the glee taken in headlines like “Too much vitamin D can be harmful”. Of course, if you read the article it says that too low vitamin D DOUBLES YOUR RISK OF PREMATURE DEATH. But the anomaly of a small increase in death among the small sample with higher vitamin D levels, as explained by Dr. Cannell, is what they chose to go with. Makes you wonder what their agenda is. It certainly does not seem to be the public’s health.

  4. Jim says:

    Difficult to analyze an abstract.

    This is an observational study. It is NOT an RCT.

    These are folks >45 y/o. I call this the Lazarus Syndrome. Folks have poor health for 45 years, then you expect one thing to magically fix everything?

    I view reporting relative risk without showing absolute risk to be unethical. I know… harsh.


    As Vieth pointed out, it is not only the D levels, it is the consistency of them that is important (sort of like only changing your oil in your car in the summer). Can’t tell from the abstract when or how often the D serum draws were.

    In any case, the hazard risk ratios are not equal, and you can’t lump them together.

  5. Rita and Misty says:

    @jmeshon…I agree with you. It’s very sad how the media insists on portraying vitamin d so negatively. Sometimes, it does make me wonder if this negativism is propelled by big pharma, etc….

    However, what disturbs me even more is how easily the general public appears to be swayed.

    Few people will take the time to read past that first headline. But, many will repeat that headline over and over (and over) again. Propagating inaccurate information.

    (Yikes. Sigh.)

    I’m always grateful to belong to this vitamin d community. I am a firm believer that there is strength in numbers…bring your friends here and perhaps we can start our own positive vitamin d campaign…

    It’s a team effort, for sure.

  6. Mark Richards says:

    Is “Nature knows best” taught in medical school? Is it a core principle in medicine today?

    That we have allowed technology to surpass science (for profit) is sufficient evidence to suggest “nature knows best” has been abandoned in its entirety: what we cannot measure and control is worthless.

    Technological tribes find distinction in heralding what they are not. “We’re science-based, unlike those Naturopaths”, claim the physicians, who have also unwittingly divorced themselves from their original rooting. Things happen when you chop off the last thread of sustenance. One of the first is a withering.

    We can’t measure and control everything. Admission of this fact, and of our limited power, might be a good first step towards restoration of medicine.

    Sunlight, nutrition, proper rest, exercise..

    Sometimes the simplest things contain the greatest wisdom, but only if our arrogance will listen.

  7. Rita and Misty says:

    @Mark Richards….

    I agree with you completely. We can’t measure and control everything. (believe me–I have tried!)

    Additionally, the drugs of modern medicine are not without their side effects.

    And, sometimes the modern cure is worse than the illness.

    We must remember that the goal of life is to be healthy, happy and productive (at least for me); and, not to cheat the grim reaper (this cannot be done successfully IMO).

    “Sunlight, nutrition, proper rest, exercise..”

    These are words of wisdom, for sure. (we share a philosophy :) )

    You speak of arrogance, and I assume you are referring to physicians/modern medicine?

    I challenge you to include the patient in this mix.

    Patients demand a pill…or some easy solution…some quick fix…for the illnesses which plaque them (up to and including death).

    Few patients will be content to hear from their physicians: “Sunlight, nutrition, proper rest, exercise..”

    I am one of the FEW patients who would LOVE to hear my physician utter these words..where may I find one of these physicians???? (certainly there are none on the Island of Disbelief)

    I’ve said it before, and I will say it again:

    Every problem does have a solution; and every solution does have its own unique set of problems.

    Be well.

    Rita (and Misty)

  8. Rita and Misty says:

    Correction to above comment: “Patients demand a pill…or some easy solution…some quick fix…for the illnesses which PLAGUE them (up to and including death).”

    (yes…I know I am anal…it is one of my more endearing qualities-I hope) :)

  9. I have seen the Dror study quoted (without an explanation) by an endocrinologist at a medical conference who received funding from osteoporosis companies.