Vitamin D—A Sleeping Giant?

Vitamin D Might
Prolong Your Life

It reduces risk for all-cause mortality and helps
prevent cancer; experts suggest taking much more of it
By Will Block

he headlines are not all bad. OJ may meet justice at long last, the San Diego Zoo has a cute little giant panda cub, Google keeps on getting better and making more money, wine and chocolate (in moderation) are good for you, and wolves have made a comeback in Yellowstone National Park. But here are a few headlines you may have missed:

  • Vitamin D Supplements May Lengthen Life1

  • Vitamin D Supplementation May Reduce Mortality Rate2

  • More Vitamin D Could Mean Fewer Cancers3

  • Low Vitamin D Linked to Greater Rectal Cancer Risk4

Stories such as these and others have prompted some medical researchers to suggest that vitamin D, the “sunshine vitamin,” is a sleeping giant in the supplements arena, one whose multiple health benefits have gone unappreciated for too long. Most of the focus on vitamin D has been on its “traditional” role in regulating calcium and phosphorus metabolism, which underlies its critical importance for bone and tooth health. The scientific evidence for that is solid.

Vitamin D Is Essential for Overall Health & Well-Being

Less definitive, but still impressive, is evidence demonstrating the importance of vitamin D in “nontraditional” roles, as well as the adverse consequences of vitamin D deficiency in increasing the risk for many common diseases. Notable among the latter are cancer, cardiovascular disease, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis; there are also indications that a vitamin D deficiency may be associated with type 2 diabetes.* Much of the evidence for these claims is summarized and discussed in a paper by a leading authority on the subject, Dr. Michael Holick of Boston University, who stated,5

Vitamin D can no longer be thought of as a nutrient necessary for the prevention of rickets among children. Vitamin D should be considered essential for overall health and well-being . . . The photosynthesis of vitamin D has been occurring in living organisms for over 500 million years, and it is not surprising that vitamin D has evolved into such an important and necessary hormone, which acts as an indicator of overall health and well-being.

*For two recent articles on nontraditional benefits of vitamin D, see “Vitamin D May Improve Mood and Cognition in the Elderly” (February 2007) and “Vitamin D and Calcium Combat Cancer” (August 2007).

Illumination through Meta-Analysis

Many studies have been published on the beneficial effects of supplemental vitamin D in reducing the risk for various diseases. Each yielded a ray of light on the specific questions at hand. But any given ray may be insufficient to illuminate the broader questions to which we want answers—questions such as, “Will it prolong life?” To combine the individual rays so as to illuminate better the issue of vitamin D’s comprehensive health benefits—its benefits on overall health and well-being, as Dr. Holick put it—requires a meta-analysis of the studies.

Meta-analysis is the process of using statistical methods to combine the results of different studies on a given subject in order to reach conclusions of greater probable validity than could be obtained from the results of any one study.* It’s a complex endeavor, requiring not just expert knowledge and judgment in the subject matter but also great analytical skills and expertise in the mathematical methods employed. The results are likely to be something you can “take to the bank.”

*The prefix meta- has different meanings, depending on the subject matter in question. In medicine and biology, it denotes the concepts of after, subsequent to, behind, or hindmost. Thus a meta-analysis is an analysis subsequent to previously published research, and your metacarpal and metatarsal bones are behind your carpal and tarsal bones (as you look outward toward your hands and feet), respectively.

A Focus on Mortality

A pair of researchers—Dr. Philippe Autier from the International Agency for Research on Cancer in Lyon, France, and Dr. Sara Gandini from the European Institute of Oncology in Milan, Italy—recently published their meta-analysis of 18 previously published, randomized, controlled trials of the use of supplemental vitamin D—as either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol)—for any health condition.6 Collectively, the studies involved 57,311 individuals from 11 countries, more than enough to gladden the heart of any statistician. Most were frail elderly people who were at high risk for falls and bone fractures.

The focus of the meta-analysis was on “all-cause mortality,” i.e., the risk of dying from any cause. Mortality data had been reported in all the studies, but mortality itself had not been a focus of analysis in any of them. Instead, the primary focus in almost all the studies was on bone mineral density and bone fractures, a major concern in people with vitamin D deficiency.

The amounts of vitamin D used in the studies ranged from 300 to 2000 IU (international units) per day, but most of the doses were in the range 400 to 833 IU/day. When the different sizes of the trials were taken into account, the average dose turned out to be 528 IU/day. The duration of the studies ranged from 6 months to 7 years, and the average was 5.7 years.

Vitamin D Reduced All-Cause Mortality by 7%

During the periods of all 18 trials, a total of 4777 deaths occurred. Meta-analysis of the data gave the remarkable result that the risk of death from all causes was reduced by 7% in those who took supplemental vitamin D vs. those who did not. In an interview with HealthDay News, Dr. Autier said,1

The intake of usual doses of vitamin D seems to decrease mortality from any cause of death. . . . This is the first study that shows that taking one vitamin has an impact on mortality. If you want to increase your vitamin D intake by taking supplements, it looks like a great idea.

No relationship was found between the amount of vitamin D taken and the reduction in mortality risk, and the large variations in the size of the trials and in the subjects’ compliance with the daily vitamin regimen precluded any conclusion regarding an optimal dose for this purpose. Also precluded, however, was the possibility of any appreciable risk of adverse effects associated with the use of vitamin D at the levels in question.

Two Intriguing Side Issues

Somewhat unexpectedly, the 7% risk reduction was unaffected by whether or not supplemental calcium was taken in addition to vitamin D. That does not mean, however, that calcium supplementation isn’t useful, especially in combination with vitamin D. See, e.g., the August 2007 Life Enhancement article cited above, which discusses the benefits of vitamin D and calcium in combating cancer. The study in question was described as “a breakthrough of great medical and public health importance” by Dr. Cedric Garland of UC San Diego (whom we will meet again below).

As an aside, Drs. Autier and Gandini mentioned the demonstrated ability of statin drugs, which are widely prescribed for reducing cholesterol levels, to decrease all-cause mortality. They suggested that this effect might be due in part to increases in vitamin D levels that the statins would induce, or to the statins’ acting as vitamin D analogs on cellular vitamin D receptors. (A receptor that was designed by evolution to respond to a particular compound, such as vitamin D, can sometimes be stimulated by another compound whose effects on the cell mimic those of the “designated” compound.)

Vitamin D’s Benefits Were Probably Underestimated

In an editorial comment on the meta-analysis, Dr. Edward Giovannucci, a distinguished authority on nutrition from the Harvard School of Public Health, explained why, for various technical reasons that were beyond the authors’ control, the meta-analysis probably underestimated the benefits of vitamin D in reducing mortality.7 He also pointed out the importance of viewing most vitamin D supplementation not as adding more to an existing acceptable level but as making up for a probable deficiency. He stated (references omitted),7

The Achilles’ heel of the intricate vitamin D system is that the precursor molecule, cholecalciferol, is entirely dependent on sun exposure or dietary intake. As a species, we do not get as much sun exposure as we used to, and dietary sources of vitamin D are minimal. . . . Efforts to avoid excessive sun exposure . . . remain important, but the extreme avoidance of sun exposure may have inadvertently contributed to widespread vitamin D deficiencies. . . .

In recent years, an increasing number of researchers from various fields have been arriving at the conclusion that the levels of vitamin D in many people are inadequate for optimal health. The results from this meta-analysis provide additional evidence from randomized trials of the dire consequences from vitamin D deficiency. . . .

Given the high probability of benefit for at least some of the many conditions that have been associated with vitamin D deficiency, and the low likelihood of harm, it seems prudent that physicians measure 25-hydroxyvitamin D levels in their patients. . . .

. . . based on the total body of evidence of health conditions associated with vitamin D deficiency, abetted with the results from this meta-analysis, a more proactive attitude to identify, prevent, and treat vitamin D deficiency should be part of standard medical care.

Note that cholecalciferol (vitamin D3) is referred to above as a precursor molecule. That’s because it’s converted in the liver to 25-hydroxyvitamin D, the compound whose blood levels provide the best measure of a person’s actual vitamin D activity.

Vitamin D Up, Cancer Risk Down

Although Drs. Autier and Gandini were not able to recommend an optimal daily amount of supplemental vitamin D for mortality reduction, other researchers have recently made bold recommendations regarding this vitamin. Accompanying the August 2007 article mentioned above is a sidebar entitled “How Much Vitamin D and Calcium Do We Need?” For vitamin D, the answer given there was that “ideal daily doses of vitamin D exceed current recommendations by an order of magnitude,” i.e., roughly ten times the government’s recommended daily intake of 400 IU. The quote was taken from a paper published in 2006 by a number of leading authorities on the subject, including Drs. Holick, Giovannucci, and Garland.8

Vitamin D Protects Against Rectal Cancer

Not to get overly graphic, but we don’t usually make much of a distinction between the colon and the rectum when it comes to cancer (or anything else). That’s why the term colorectal cancer is so common—the two entities are lumped together, so to speak. But sometimes the distinction turns out to be important after all, as was the case in a recently published study of the relationship between vitamin D deficiency and colorectal cancer.1

The Japanese researchers gathered data on the 25-hydroxyvitamin D blood levels in 38,373 men and women, aged 40–69, and correlated them with the incidence of colorectal cancer over a follow-up period of 11.5 years. After correcting for potentially confounding factors, they found no statistically significant correlation. This contrasts with the results of some other (but not all other) studies, which have shown that vitamin D deficiency correlates with an increased risk of colorectal cancer.

Looking at colon cancer specifically, the researchers again found no correlation. When they looked a little farther down, however, they found a correlation between vitamin D deficiency and rectal cancer in the men and women in the lowest quartile (lowest 25%) of 25-hydroxyvitamin D levels. When these individuals were compared with all those in the top three quartiles combined, it turned out that the men had a 4.6-fold greater risk, and the women had a 2.7-fold greater risk (large factors!), of rectal cancer.

But why the rectum and not the colon? The researchers speculated that it might be due to differences between these two entities in the expression of the vitamin D receptors on their cell surfaces. They also pointed out that certain genetically determined variants of the vitamin D receptor are protective against colorectal cancer and that the Japanese have a low prevalence of these variants compared with other ethnic groups. This might make the Japanese more susceptible to rectal cancer than people of other ethnicities.


  1. Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S, for the Japan Public Health Center-Based Prospective Study Group. Plasma vitamin D and risk of colorectal cancer: the Japan Public Health Center-Based Prospective Study. Brit J Cancer 2007;97:446-51.

Now Dr. Garland and another team of colleagues have published a new study proposing more specific daily intakes (in the same general range), based on their analysis of the dose-response relationship between vitamin D and the reduction of risk for two cancers: breast and colon (or colorectal—they used the terms interchangeably).9 In both cases, there is a well-documented inverse relationship: the higher one’s vitamin D levels, the lower one’s risk for cancer (such a relationship holds for ovarian cancer as well).

Experts Recommend at Least 2000 IU/Day

The authors pointed out that the existence of a clear dose-response relationship is one of the key criteria for determining whether an association between a preventive agent and an effect is causal rather than coincidental. In this case, the dose-response relationships led the authors to state (references omitted),9

The lower limit for any benefit of vitamin D would correspond to 1000 IU/day of vitamin D3 for the first meaningful increment of colorectal cancer prevention and 2000 IU/day for the first meaningful increment of breast cancer prevention. . . .

In North America, a projected 50% reduction in colon cancer incidence would require universal intake of 2000 IU/day of vitamin D3, while a similar reduction in breast cancer incidence would require 3500 IU/day. The intake expected to prevent half of breast cancer incidence would be above the 2000-IU/day upper limit established by the National Academy of Sciences. These gradients for cancer risk suggest that the upper limit should be revised upward, since there is considerable benefit, and no established adverse effect of vitamin D3 intake below 10,000 IU/day. In the meantime, 2000 IU/day of vitamin D3 for all individuals aged 12 years and older would be far safer than the present median adult intake in the US of approximately 230 IU/day. . . . Use of ergocalciferol (vitamin D2), which is popular in Europe and is used in some major US brands of multivitamins, should be discontinued immediately in favor of vitamin D3.

To amplify on that, it’s worth quoting Dr. Giovannucci again, who said, “Individuals can make up to 20,000 IU/day of vitamin D from sun exposure, and no case of sun-induced vitamin D toxic effects have [sic] ever been documented.”7 He too, by the way, recommends that only vitamin D3 be used as a supplement, because vitamin D2 is not as effective.

Vitamin D Could Prevent Hundreds of Thousands of Cancers Annually

© Gnani
Dr. Garland et al. went on to state that, to prevent cancer, it may be advisable for all adults to maintain a circulating 25-hydroxyvitamin D level of at least 55 nanograms per milliliter (a nanogram is one-billionth of a gram) throughout life.9 This should be attainable, according to their analysis, with a daily intake of several thousand IU of vitamin D3, especially by people in northern latitudes (above about 40º) during winter months, when sun exposure is minimal.

If this blood level of 25-hydroxyvitamin D were the universal standard, they said, it would prevent at least 60,000 cases of colorectal cancer and 85,000 cases of breast cancer annually in North America. They estimated the total annual prevention figures worldwide to be 250,000 cases and 350,000 cases of colorectal and breast cancer, respectively.

The Giant Awakens

Let sleeping dogs lie, goes the old adage, but what about sleeping giants? Let’s poke this one in the ribs, shall we? It might be fun to see what ensues. No need to worry, though, for this is a benevolent giant who would certainly not harm us. Quite the contrary! The benefits of vitamin D described above are stunning, and they lend credence to the claim that this vitamin—in much larger amounts than had traditionally been thought necessary—is indeed essential for our overall health and well-being.


  1. Anon. Vitamin D supplements may lengthen life. They could fight cancer, heart disease, researchers say. HealthDay News, Sept. 10, 2007.
  2. Anon. Vitamin D supplementation may reduce mortality rate. Reuters Health, Sept. 11, 2007.
  3. Anon. More vitamin D could mean fewer cancers: study. Reuters Health, Sept. 4, 2007.
  4. Anon. Low vitamin D linked to greater rectal cancer risk. Reuters Health, Aug. 22, 2007.
  5. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80(6):1678S-88S.
  7. Giovannucci E. Can vitamin D reduce total mortality? Arch Intern Med 2007;167(16):1709-10.
  8. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134(6):1129-40.
  9. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. What is the dose-response relationship between vitamin D and cancer risk? Nutr Rev 2007;65(8):S91-5.


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