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Vitamin D Supplementation in the Age of Lost Innocence

Eliseo Guallar, MD, DrPH; Edgar R. Miller III, MD, PhD; Jose M. Ordovas, PhD; and Saverio Stranges, MD, PhD
[+] Article, Author, and Disclosure Information

From Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; National Center for Cardiovascular Research, Madrid 28029, Spain; Friedman School of Nutrition Science and Policy at Tufts University, Boston, MA 02111; and Health Sciences Research Institute, University of Warwick Medical School, Coventry CV4 7AL, United Kingdom.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0183.

Requests for Single Reprints: Eliseo Guallar, MD, DrPH, Welch Center for Prevention, Epidemiology, and Clinical Research, 2024 East Monument Street, Room 2-639, Baltimore, MD 21205; e-mail, eguallar@jhsph.edu.

Current Author Addresses: Drs. Guallar and Miller: Welch Center for Prevention, Epidemiology, and Clinical Research, 2024 East Monument Street, Baltimore, MD 21205.

Dr. Ordovas: Tufts University, 711 Washington Street, Boston, MA 02111.

Dr. Stranges: Health Sciences Research Institute, Gibbet Hill Campus, Medical School Building, Room A105, Coventry CV4 7AL, United Kingdom.

Ann Intern Med. 2010;152(5):327-329. doi:10.7326/0003-4819-152-5-201003020-00013
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Recently, we have witnessed an explosion of scientific and media attention to the health effects of vitamin D status and vitamin D supplementation (1). Vitamin D3 (cholecalciferol), the most powerful form of vitamin D, is synthesized in the skin from 7-dehydrocholesterol by action of sunlight (ultraviolet B radiation) (2). Vitamin D is biologically inert and must be converted to the active hormone 1,25-dihydroxy vitamin D [1,25(OH)2D] (calcitriol). Vitamin D's pivotal role in regulating calcium homeostasis and bone metabolism has been long recognized (24); however, mounting evidence suggests that vitamin D may also influence various nonskeletal medical conditions, including cardiovascular disease, hypertension, diabetes, cancer, autoimmune disorders, and overall mortality (58). Indeed, claims that large segments of the population have inadequate vitamin D concentrations have prompted calls to increase vitamin D intake through supplementation or fortification (910).


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Considering Vitamin D supplementation in elderly people and hypothetical added bennifit in Chronic Kidney Disease Patients
Posted on March 29, 2010
Dr.Hriday Ranjan Das
IPGMER & SSKM Hospital
Conflict of Interest: None Declared

In developing countries of the third world due to increased life expectancy the number of elderly population is rapidly increasing.If they are offered Vitamin D3 prophylactically ,they will be benefitted from the standpoint of osteoporosis ,fracture,cardiovascular and cerebrovascular morbidity and mortality.Even in developing countries which receive plenty of sunlight ,the upwaradly mobile people are exposed less to it as they mostly remain indoors or offices or in cars.So they develope a relative deficiency of Vitamin D3. It is well known that Chronic Kidney Disease patients have increased cardiovascular and cerebovascular morbidity and mortality.Vitamin D3 is often given to those CKD patients whose Calcim level is below normal to prevent renal osteodystrophy. So can we speculate that Vitamin D3 will reduce cardiovascular and cerebrovascular morbidity and mortlitiy in this subset of patients? .

Vitamin D supplementation is warranted
Posted on April 2, 2010
William B. Grant
Sunlight, Nutrition, and Health Research Center (SUNARC)
Conflict of Interest: None Declared

Sir: The recent editorial on vitamin D supplementation (1) is unduly pessimistic regarding the benefits. One reference forming the basis for the editorial, Ref. 15 in (1), investigated cardiometabolic outcomes as a function of serum 25-hydroxyvitamin D [25(OH)D]. It reported a significant inverse correlation between serum 25(OH)D and cardiovascular disease, in agreement with another recent paper (2), which also found significant inverse correlations for metabolic syndrome and diabetes mellitus.

The other Ref. 16 in (1), reported statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95% CI, 0.77 to 1.05]) with vitamin D supplementation at moderate to high doses (approximately 1000 IU/d). The main problems with vitamin D randomized controlled trials (RCTs) include that solar ultraviolet-B irradiance contributes to serum 25(OH)D levels, that many in RCTs have additional oral intake (3), and that serum 25(OH)D level response to oral dosing varies with genetic factors, body mass index, and other dietary factors. In addition, many earlier RCTs used too little vitamin D to have a significant effect.

Some important RCTs were not included in (1). The recent one showing significant benefits for influenza A and asthma (3) was published after the editorial, but seems representative of well-conducted trials. The only RCT with over 1000 IU/d of vitamin D for cancer found a 40% reduced risk of cancer incidence between the ends of the first and fourth years (4).

It is undeniable that oral vitamin D raises serum 25(OH)D levels. Meta-analyses of observational studies are considered just slightly lower evidence than RCTs. Based on serum 25(OH)D level-disease outcome relations for cancer, cardiovascular disease, influenza, falls, and septicemia from meta-analyses of observational studies and RCTs, it was estimated that if all Americans raised their serum 25(OH)D levels to 45 ng/mL, 400,000 premature deaths/y could be avoided, thereby reducing the mortality rate by 15% and extending life expectancy by about two years. The adverse effects of higher oral vitamin D are minimal, primarily affecting those with specific preexisting conditions.

Comparing vitamin D to B-carotene and vitamin E is disingenuous as of the three, only vitamin D is based on robust observational studies and associated with manifest genetic differences with respect to natural availability, skin pigmentation.


1. Guallar E, Miller ER 3rd, Ordovas JM, Stranges S. Vitamin D supplementation in the age of lost innocence. Ann Intern Med. 2010;152:327 -9. PMID: 20194240

2. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65:225-36. PMID: 20031348

3. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010 Mar 10. [Epub ahead of print] PMID: 20219962

4. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91. PMID: 17556697

5. Grant WB. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermato- Endocrinology, 2009;1:207-14.

Conflict of Interest:

I receive funding from the UV Foundation (McLean, VA), the Sunlight Research Forum (Veldhoven), Bio-Tech-Pharmacal (Fayetteville, AR), and the Vitamin D Council (San Luis Obispo, CA), and have received funding from the Vitamin D Society (Canada).

Vitamin D Supplementation in the Age of Lost Innocence
Posted on April 2, 2010
Robert P. Heaney
Creighton University
Conflict of Interest: None Declared

Editor: It is exceedingly disappointing to find, in the world's leading journal of internal medicine, two poorly conceived systematic reviews of vitamin D effects on the cardiovascular system (1, 2), accompanied by a largely supportive editorial (3), all three of which exhibit a limited awareness of current vitamin D physiology. For example, the review by Wang et al. (1) identifies a group of six prospective studies, only one of which used actual vitamin D (cholecalciferol). The others all used various 1- hydroxylated derivatives. Nor did the editorial, citing those six, pick up this critical distinction. Presumably the authors of the studies included were operating on the premise that, since calcitriol [1,25(OH)2D] is the ultimate, active form of the vitamin, it made sense to use that compound in their studies. That use, in hindsight, is understandable, even if now recognized to be inappropriate. The authors of the systematic reviews, however, should have been aware of current biology and therefore excluded them. The fact that the authors of the papers concerned used the term "vitamin D as a key word, or explicitly in their titles, simply highlights why individuals doing systematic reviews need to have up-to-date content knowledge of the subject they are reviewing.

A very large body of literature, published over the past 10 years, makes clear that the non-calcium effects of vitamin D are autocrine (4), not endocrine, and that the 1- hydroxylated form of the vitamin is synthesized intracellularly by the target tissues concerned and is not derived from circulating calcitriol (5). Available evidence indicates that the concentration of calcitriol required to produce these non-calcium effects is higher than can safely be achieved through the mediation of serum calcitriol (5). Rather, serum 25(OH)D, present in thousand-fold greater concentration than calcitriol, provides the substrate for cells to manufacture as much calcitriol as they need, confined to the tissues concerned. But that works only so long as serum 25(OH)D levels are themselves adequate. Hence the critical importance of sufficient cholecalciferol input. One review hedges its conclusions with the qualifier "the dosages used which, as it turns out, were small. Both the editorial and Wang et al. speak of doses of 700-1000 IU/d as high. True, 700-800 IU is above the 1997 AI for vitamin D, but more than 95% of what is currently known about vitamin D has been published since those 1997 recommendations. It is now clear that outdoor summer workers commonly have serum 25(OH)D values between 120 and 200 nmol/L and that this may well be the primitive human level, as judged by values found in agricultural workers in the tropics (6). Both controlled dosing studies and extensive experience in recent years have established that serum 25(OH)D rises by about 0.6-1.0 nmol/L/ (or 1.5-2.5 nmol/L/100 IU/d) (7). Thus serum levels of 80 nmol/L require continuous inputs from all sources on the order of 4000 IU/d, and 100 nmol/L, 5000 IU/d, etc. Such doses are not only not high but physiological, as they occur in normal individuals under conditions approximating those experienced by our ancestors. Finally, the editorial raises a note of caution by way of comparison with trials of e.g, -carotene. While moving subjects from normal to high vitamin A levels may well produce harm, that is quite different from moving subjects from low to physiological levels of vitamin D. In brief, the systematic reviews were largely non-informative and the cautionary note struck by the editorial has essentially no basis in the evidence.


1. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152:315-323.

2. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et al. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 2010;152:307-314.

3. Guallar E, Miller ER III, Ordovas JM, Stranges S. Vitamin D supplementation in the age of lost innocence. Ann Intern Med 2010;152:327- 329.

4. Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med 2008;29:361-368.

5. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik S, et al. Toll- like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311:1770-1773.

6. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D levels, and safety. Am J Clin Nutr 1999;69:842-856.

7. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25 -hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210.

Conflict of Interest:

None declared

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