Vitamin D: more is not better and may even be worse.
Article Type: Editorial
Subject: Alfacalcidol (Health aspects)
Calcifediol (Health aspects)
Vitamin D (Health aspects)
Cancer (Prevention)
Cancer (Methods)
Author: Gaby, Alan R.
Pub Date: 02/01/2012
Publication: Name: Townsend Letter Publisher: The Townsend Letter Group Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 The Townsend Letter Group ISSN: 1940-5464
Issue: Date: Feb-March, 2012 Source Issue: 343-344
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 282825239
Full Text: In recent years, many laboratories have increased the reference range for serum 25-hydroxyvitamin D (25[OH]D), and now a surprisingly large proportion of the population can be found to have vitamin D deficiency or insufficiency. In addition, some investigators and practitioners have argued that increasing serum 25(OH)D to an "optimal" level by taking relatively large doses of vitamin D could have multiple health benefits, including protection against cancer, autoimmune disease, osteoporosis, cardiovascular disease, and other chronic diseases.

The scientific evidence supporting an increase in the laboratory reference range for 25(OH)D, and the scientific evidence supporting the safety and efficacy of taking large doses of vitamin D (such as more than 2000 JU per day) to achieve an "optimal" 25(OH)D level are both quite weak. As I have pointed out previously, there are a number of problems with the idea that we should be measuring everyone's 25(OH)D level (usually at a cost of $125 per test) and supplementing with enough vitamin D to raise serum 25(OH)D to an arbitrary level. (1)

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How Reliable Is Lab Testing?

First, serum 25(OH)D appears to bean unreliable indicator of vitamin D status (except at the extremes of toxicity and severe deficiency). 25(OH)D is just one of more than 50 vitamin D metabolites in the body, and an individual's vitamin D nutritional status might be a function of complex interactions between various vitamin D metabolites. Different people may have different serum 25(OH)D "set points" for adequate and "optimal" vitamin D status. Moreover, 25(OH)D may be an unreliable indicator of vitamin D status in people with inflammatory diseases, because serum 25(OH) D levels decline in response to inflammation.

Was Increasing the Lab Reference Range Appropriate?

Second, the recent increase in the laboratory reference range for serum 25(OH)D may have been inappropriate. This increase was based on associations between serum 25(OH)D and biomarkers of vitamin D status such as serum parathyroid hormone levels and percent absorption of an oral calcium load. The validity of using these biomarkers to assess vitamin D status has been called into question.

Limitations of Observational Studies

Third, observational studies in which higher serum 25(OH)D levels were associated with better health outcomes are limited by numerous confounding factors, including age, body mass index, and chronic inflammation. In addition, there is reason to believe that 25(OH)D is a marker both of gonadal function (vitamin D is 25-hydroxylated by gonadal tissues) and of the capacity of the liver to detoxify xenobiotics (hepatic 25-hydroxylase enzymes are also involved in phase 1 detoxification pathways). Since gonadal steroids and detoxification capacity both influence a wide range of health conditions, the association between 25(OH)D and these health conditions may be spurious.

Vitamin D Supplementation and Sunlight Exposure Are Not the Same

Fourth, the safety and efficacy of vitamin D supplementation cannot be inferred from data regarding the safety and efficacy of sunlight exposure. Sunlight exposure results in numerous biochemical and physiological effects that do not occur with vitamin D supplementation. These include the production of photodegradation products of vitamin D that appear to modulate the action of vitamin D; the synthesis of corticotropin-releasing hormone (an immunomodulator) by the skin; and possible direct stimulation of the hypothalamic-pituitary axis through the retina.

Safety Concerns

Fifth, the safety of using high doses of vitamin D has not been adequately studied. In pigs fed an atherogenic diet, increasing the daily dose of vitamin D3 from 300 IU per day to 900 IU per day (human equivalent dose, based on body weight) increased the severity of atherosclerosis. At present, we cannot rule out the possibility that high-dose vitamin D is also atherogenic in humans. In addition, there is concern that taking too much vitamin D could increase the risk of kidney stones.

Controlled Trials Needed

The only way to determine whether large vitamin D doses are safe and more desirable than modest doses (such as 800-1200 IU per day) is to conduct randomized controlled trials that compare different doses. While very few such trials have been completed, the available evidence does not support the idea that more vitamin D is better. To the contrary, the evidence (although still preliminary) is consistent with the possibility that modest doses are in many situations preferable to higher doses.

New Evidence Supports a Cautious Approach

In a recently published study, 297 postmenopausal women (mean age, 63 years) with low bone mass were randomly assigned to receive, in double-blind fashion, 6500 IU per day (high dose) or 800 IU per day (standard dose) of vitamin D3 for 1 year. (2) The mean serum 25(OH)D level at baseline was 71 nmol/L, which indicates mild vitamin D insufficiency according to the new reference range, but normal vitamin D status according to the old reference range. Mean bone mineral density (BMD) of the total hip, femoral neck, lumbar spine, and total body increased in both groups; the mean increase in BMD was nonsignificantly greater in the standard-dose group than in the high-dose group for each of the 4 measured sites. Thus, there was a trend toward better outcomes with 800 IU per day than with 6500 IU per day.

A post hoc analysis of the Women's Health Initiative study also supports the possibility that lower vitamin D doses are preferable to higher doses. (3) In that study, 36,282 postmenopausal women (mean age, 63 years) were randomly assigned to receive supplemental vitamin D (400 IU per day) and calcium (1000 mg per day) or placebo for 7 years. Personal vitamin D supplements up to 600 IU per day (and later up to 1000 IU per day) and personal calcium supplements up to 1000 mg per day were permitted. In the group as a whole, assignment to vitamin D/calcium treatment had no effect on the incidence of colorectal or breast cancer. Among the 43% of women who were not taking personal vitamin D or calcium supplements, assignment to vitamin D/calcium treatment significantly decreased the incidence of breast cancer and total cancer by 14% to 20%, and nonsignificantly decreased the incidence of colorectal cancer by 17%. Among women who were taking personal vitamin D or calcium supplements at randomization, assignment to vitamin D/calcium treatment nonsignificantly increased total cancer, breast cancer, and colorectal cancer incidence by 6% to 26%. Interpretation of these results with respect to vitamin D is complicated by the fact that calcium was also given, and by the fact that post hoc analyses tend to be less reliable than primary analyses. However, the findings are consistent with the possibility that modest doses of vitamin D reduce the risk of developing cancer, but that slightly higher than modest doses provide no additional benefit and may even negate the benefit of lower doses or increase the risk of cancer.

Four hundred-thirty Japanese children (mean age, 10 years) were randomly assigned to receive, in double-blind fashion, 1200 IU per day of vitamin D or placebo for 4 months during the winter. Among children who were not taking vitamin D on their own, vitamin D treatment reduced the incidence of influenza by 64% compared with placebo. Among children who were taking vitamin D on their own (average amount, about 150 IU per day), randomization to receive an additional 1200 IU per day was associated with a nonsignificant 11% increase in the incidence of influenza compared with placebo. (4) These findings suggest that the children in this study had suboptimal vitamin D status; that correcting suboptimal vitamin D status helped prevent influenza; that taking 150 IU per day was sufficient to correct suboptimal vitamin D status; and that among children who were taking 150 IU per day, supplementing with an additional 1200 IU per day provided no further benefit and may have had a deleterious effect.

What to Make of It All

It is important to remember that vitamin D is not really a nutrient, but rather a hormone precursor synthesized in the skin after exposure to ultraviolet irradiation. Throughout most of human history, typical diets contained little or no vitamin D. In modern times, vitamin has been used successfully as partial replacement therapy for the complex endocrine disorder that results from sunlight deficiency. However, there is no precedent in human evolution for the use of large oral doses of vitamin D. While it is possible that future studies will demonstrate a role for high-dose vitamin D for specific medical conditions, it remains unclear whether routine use of high doses is necessary or safe.

Published research has demonstrated that 800 to 1200 IU per day of oral vitamin D is effective for preventing osteoporosis, falls, influenza, and colds, whereas 400 IU per day has generally been ineffective. It is not known whether taking more than 1200 IU per day would improve results for the average person. Because of the potential adverse effects of high doses, I tell most patients to get some sunshine, take 800 to 1200 IU per day, and find some better use for their money than measuring their 25(OH)D level. Monitoring 25(OH) D levels and taking higher doses of vitamin D (such as 2000 IU per day or more) may be worthwhile for selected patients, such as those with advanced age, malabsorption syndromes, or certain other health conditions, and people with dark skin or minimal sunlight exposure.

Notes

(1.) Gaby AR. Vitamin D. In Nutritional Medicine. Chapter 24. Concord, NH; 2011. www.doctorgaby.com.

(2.) Grimnes G et al. The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass - a randomized controlled 1-year trial. Osteoporos Int. Epub Sep 10 2011.

(3.) Bolland M) et al. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am I Clin Nutr. 2011;94:1144-1149.

(4.) Urashima M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am I Clin Nutr. 2010;91:1255-1260.
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