March 12 2017
Jacob Schor, ND, FABNO
We may have gotten ahead of ourselves with vitamin D, gotten too excited about all the possibilities and all the promises. It may be time to slow down and even back track a bit.
For the last decade vitamin D has been the biggest, most exciting newest and best thing in nutritional medicine. It seems like almost every patient is taking vitamin D and doing so in doses once thought massive.
Since the mid 1990s, thousands of studies have linked low serum vitamin D to a list of maladies including heart, cancer, infection, autoimmune, obesity, osteoporosis, depression and so on. While early studies focused on UV radiation exposure and its inverse association with disease, along the way we made the jump and started talking about vitamin D as if it were the only active agent in sunlight.
Go to PubMed.gov and run a search for “vitamin D and futility”. The results are surprising.
Avenell’s 2014 Cochrane review combined data from 54 clinical trials in which vitamin D was given in the hope of reducing bone fractures. This is perhaps the most common and well-accepted use we have for vitamin D. Vitamin D taken alone is unlikely to prevent hip or other fractures (n=91,791). Actually, people given vitamin D in clinical trials trend toward greater risk of hip and other fractures. Combined with calcium Vitamin D did slightly reduce risk of hip fracture, but only by about 5% (n=49,976). Risk of dying was not affected by taking vitamin D or vitamin D plus calcium (n= 71,032).
Vitamin D supplementation was however associated with double the risk for mild hypercalcemia (n=17,124) and gastrointestinal symptoms (n=47,761). [i]
A meta-analysis by Bolland published in April 2014 examined vitamin D supplementation on skeletal, vascular and cancer outcomes. Using vitamin D to change any of these conditions was termed ‘futile’.[ii] “Futile” is not what we expected.
A second meta-analysis by Bolland et al was published in July 2014 looked only at vitamin D given to prevent falls. Data from 20 randomized controlled trials (n=29,535) again reported that supplementation proved futile. [iii] Recent reports actually suggest high doses of D increase risk of falls in the elderly. In fact a warning was published in November 2016 that vitamin D “bolus dosing or daily doses should not exceed 3,000 IU and serum levels of 25-hydroxyvitamin D should not exceed 40-45 ng/ml in elderly individuals.”[iv]
A Cochrane review by Bjelakovic et al published in June 2014 analyzed only data from clinical trials on cancer prevention in adults: data from 18 randomized clinical trials (n=50,623), done in high-income countries, mostly older women (47-97 years old) supplemented with vitamin D for a mean of 6 years. In the end, 7.6% of the women receiving vitamin D developed cancer versus 7.7% of the women in the control group not receiving D. Again using vitamin D proved futile. [v]
Taking vitamin D is not having the massive impact on disease we were hoping for. Just a few years ago we were thinking vitamin D would decrease risk of cancer and other diseases by half or more. [vi] [vii] [viii] These promises now seem futile.
It’s time to rethink what we know and move on from this vitamin D as a panacea paradigm.
What happened to nature cure? That whole Vis medicatrix naturae, the healing power of nature thing? How did we convert our appreciation of the healing action of sunlight into a hormone deficiency?
Actually it is not hard to understand where we made the wrong turn. We were trained in the paradigm of deficiency disease. For 400-years, intractable diseases have responded to and been cured by specific and necessary dietary components. Thomas Sydenham first began treating anemia with iron in the 1600s. James Lind explained scurvy as a lack of vitamin C in 1754; Christiaan Eljkman linked beriberi to poor diet in 1907 leading to the eventual discovery of thiamine; pellagra was first described in 1735, though that niacin as a cure wasn’t identified until 1937. Pernicious anemia, described and then named after Addison in 1855, was cured by eating liver in the 1920s and then by vitamin B-12, isolated from liver, in 1948. It was easy to believe that vitamin D was going to be the next big cure-all.
Sunlight has a range of actions on the human body, only some of which we understand. Besides triggering vitamin D production it also triggers production of p53 [ix] the enzyme that regulates apoptosis (cell suicide) and destroys cancer cells, or at least is supposed to.
Increasing p53 activity is the primary goal of both conventional and naturopathic oncologists. This may be why sun exposure is associated with decreased cancer risk.
Sunlight also triggers nitric oxide production (NO) production, which in turn causes vasodilation, lowering blood pressure. NO may be why sunlight lowers risk of heart disease and strokes.
Perhaps it’s not the D but the sun that is protective. As high blood pressure is the leading cause of death in the world, even small improvements in blood pressure might have widespread consequences. This NO discovery explains a long time mystery, why blood pressures are higher during the winter. It also explains why blood pressures increase with latitude.
A December 2016 article in the journal Medical Hypotheses, suggests several other possible explanations for the benefits of sunlight including immunomodulation, melatonin, serotonin, and the effect on circadian clocks, are also involved in triggering the health benefits of sunlight. [x] A paper published in late January 2017 reported that sun exposure stimulates lymphocyte motility, it gets those white blood cells to chase down invading microbes in the body. [xi] Perhaps this is why sun exposure reduces rates of infection?
Sun avoidance clearly is a problem. Lindqvist reported on all cause mortality risk in people with a history of melanoma who purposefully avoided sun exposure. (n= 29,518). All-cause mortality was inversely related to sun exposure habits. The mortality rate amongst sun avoiders was about twice as high compared with the highest sun exposure group….” [xii] Clearly we need something in sunlight, it just might not be only the vitamin D.
Thus the benefits we expect to see from taking vitamin D may be the result of some other more complex and more dynamic actions caused by sun exposure. We should go back to thinking of vitamin D more as a measure of sun exposure, but not the direct effecter. It may be a combination of responses that sunlight triggers that certainly might include vitamin D action but may involve a combination of reactions. While our patients may love the ease of swallowing vitamin D, we need to remember that randomized clinical trials have not confirmed the promises. Rather meta-analyses of multiple trials suggest our efforts are proving futile. If you want a patient to get the benefits of sunlight, they may have to do it the old fashioned way.
Fleischer and Fleischer reported in March 2016 on solar radiation in the US comparing average daily sunlight with CDC cancer mortality statistics. They found what was suspected twenty years ago, “Invasive cancer risk is inversely related to ultraviolet light exposure.” Interestingly though, only “…11 of 22 leading cancers significantly decreased with increased solar radiation.” Solar radiation did change mortality only, “ … for 7 of 22 leading cancers, including cancers of the uterus, leukemias, lung, ovary, and urinary bladder, increased solar radiation predicted decreased mortality.” But for some cancers the opposite effect was observed: “… increasing solar radiation, increased incidence and cancer mortality … for liver cancer and increased incidence but not mortality was observed for cervical cancer.” [xiii] This is proving to be more complex than we once thought. Perhaps more complicated than our patients want to hear about.
Taking vitamin D is not as safe as we once thought and it is time to let our patients know this. For men with prostate cancer there seems to be a sweet spot for vitamin D levels. Lower or higher levels are associated with greater total cancer risk. Risk was reduced among men with what the authors describe as moderate concentrations, 18 to 28 ng/ml. Few of us would be content to see levels this low and would typically encourage supplementation. [xiv] At lower or higher levels mortality increased.
A similar U-shaped curve is seen with heart disease. Earlier studies associated low vitamin D levels with increased mortality following heart attacks. Aleksova evaluated vitamin D levels on long-term mortality in patients who had experienced an acute myocardial infarction. During an almost five year follow up (n=477), 20% of the patients died. The researchers report a U-shaped relationship between vitamin D levels and long-term mortality. Patients, whose vitamin D levels were below 10 ng/ml or greater than 30 ng/ml, had higher risks of dying than those with levels between 10 and 30 ng/ml. D levels on either extreme, low or high, were associated with triple the risk of dying. [xv]
More information that doesn’t fit the common wisdom was published in Sept 2016; in a Dutch group of older men and women (n=257), there was a synergistic association between serum vitamin D and vitamin K levels with the risk of hypertension. During a 6.1 year follow-up, 52% of the cohort (n = 133) developed hypertension. Those with higher vitamin D levels (≥20 ng/ml) were 72% more likely to have hypertension than those with lower levels. Those with lower vitamin K levels were less prone to hypertension in combination with higher D levels. [xvi]
Recall how we once thought vitamin D was totally safe. As naturopathic physicians we pride ourselves for being on the cutting edge of nutritional medicine, of being early adopters of new discoveries, the explorer scouts who range ahead of mainstream medicine. That’s well and good, but sometimes it is our responsibility to turn back and warn our followers, “Sorry, we made a mistake, we need to back up and rethink where we are headed.”
[i] Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014 Apr 14;(4):CD000227. d
[ii] 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.
[iii] Bolland MJ, Grey A, Gamble GD, Reid IR. Vitamin D supplementation and falls: a trial sequential meta-analysis.Lancet Diabetes Endocrinol. 2014 Jul;2(7):573-80.
[iv] Gallagher JC. Vitamin D and falls – the dosage conundrum. Nat Rev Endocrinol. 2016 Nov;12(11):680-684.
[v] Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, Gluud C. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev. 2014 Jun 23;(6):CD007469.
[vi] Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002 Mar 15;94(6):1867-75.
[vii] Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, Giovannucci EL. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2004 Sep;13(9):1502-8.
[viii] Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol, Oct 2005;97(1-2):179-94.
[ix] Cui R, Widlund HR, Feige E. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell, March 9, 2007;128(5):853-64.
[x] van der Rhee HJ, de Vries E, Coebergh JW. Regular sun exposure benefits health.
Med Hypotheses. 2016 Dec;97:34-37.
[xi] Phan TX, Jaruga B, Pingle SC, Bandyopadhyay BC, Ahern GP. Intrinsic Photosensitivity Enhances Motility of T Lymphocytes. Sci Rep. 2016 Dec 20;6:39479.
[xii] Lindqvist PG, Epstein E, Landin-Olsson M, Ingvar C, Nielsen K, Stenbeck M, Olsson H. Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Melanoma in Southern Sweden cohort. J Intern Med. 2014 Jul;276(1):77-86.
[xiii] Fleischer AB Jr, Fleischer SE. Solar radiation and the incidence and mortality of leading invasive cancers in the United States. Dermatoendocrinol. 2016 Mar 28;8(1):e1162366.
[xiv] Kristal AR, Till C, Song X, Tangen CM, Goodman PJ, Neuhauser ML, Schenk JM, et al. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E CancerPrevention Trial. Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1494-504.
[xv] Aleksova A, Beltrami AP, Belfiore R, Barbati G, Di Nucci M, Scapol S, De Paris V, et al. U-shaped relationship between vitamin D levels and long-term outcome in large cohort of survivors of acute myocardial infarction. Int J Cardiol. 2016 Nov 15;223:962-966.
[xvi] Van Ballegooijen A, Van Schoor N, Brouwer I, Visser M, Beulens J. OS 06-09 THE SYNERGISTIC ASSOCIATION BETWEEN VITAMIN D AND VITAMIN K WITH INCIDENT HYPERTENSION. J Hypertens. 2016 Sep;34 Suppl 1 – ISH 2016 Abstract Book:e64.