William B Grant corresponding author

" The health benefits of vitamin D extend beyond cancer to cardiovascular diseases, , bacterial , and viral infections,, autoimmune diseases,, dental caries and periodontal disease, and dementia.,104 "

Abstract

The International Agency for Research on Cancer (IARC) released a report, Vitamin D and Cancer, on November 25, 2008. The report focused on the current state of knowledge and level of evidence of a causal association between vitamin D status and cancer risk. Although presenting and evaluating evidence for the beneficial role of UVB and vitamin D in reducing the risk of cancer, it discounted or omitted important evidence in support of the efficacy of vitamin D. The report largely dismissed or ignored ecological studies on the grounds that confounding factors might have affected the findings. The report accepted a preventive role of vitamin D in colorectal cancer but not for breast cancer.

The only randomized controlled trial (RCT) on cancer incidence that used a sufficiently high dose of vitamin D (1,100 IU/day) and calcium (1,400–1,500 mg/day) found a 77% reduction in the risk of all-cancer incidence in postmenopausal women who received both, of which approximately 35% reduction in risk was attributed to vitamin D alone. Unfairly, the report dismissed these findings on the basis of a flawed critique.

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Does Less Sun mean More Disease

English as well as German, Spanish, Swedish, French,..
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William B Grant

Introduction

The International Agency for Research on Cancer (IARC) recently released a report, Vitamin D and Cancer.1 This report was ostensibly a comprehensive review of the evidence that vitamin D reduces the risk of cancer. The report lists 1,368 references, many of which supported a beneficial role of solar ultraviolet-B (UVB) and vitamin D in reducing the risk of many types of cancer. Despite listing these many studies with positive findings, the report's conclusions overemphasized the relatively few negative studies. Only the first and fifth conclusions are consistent with the data that were included in the studies that the report cited. Some of the conclusions seem to be incorrect or unfairly dismissive based on available evidence. The seven conclusions are as follows:

The epidemiological observational evidence supports a role of vitamin D in reducing the risk of colorectal cancer; however, this evidence is not considered causal, and the randomized controlled trials (RCTs) to date have not supported the observational evidence.
There is similar evidence for breast cancer, but that evidence is considered weaker.
The observational evidence does not support a beneficial role of vitamin D in reducing the risk of prostate cancer.
The evidence for other cancers was considered insufficient for evaluation.
Results from observational studies and RCTs suggest that vitamin D supplements may lower all-cause mortality.
There are no data available on the health hazards of long-term maintenance of high 25-hydroxyvitamin D [25(OH)D] serum levels over long periods. Also, past experiences with other compounds have shown adverse effects of chronic use of supplements or long-term maintenance of high serum levels.
Hypotheses on vitamin D status and colorectal cancer, cardiovascular diseases and all-cause mortality should be tested in appropriately designed RCTs.

These conclusions are much weaker with regard to vitamin D and calcium for cancer prevention than a more comprehensive review of the scientific evidence warrants. Existing evidence from observational studies actually is consistent with a meaningful role of vitamin D in prevention of several types of cancer. In the following, I comment on several flawed analyses in the IARC report.

Chapter 3. Sunlight and Skin Cancer: Recall of Essential Issues

Chapter 5. Toxicity of Vitamin D and Long-Term Health Effects

Chapter 8. Biological Effects of Vitamin D Relevant to Cancer

Chapter 11. Observational Studies on Dietary Intakes of Vitamin D and Cancer

Chapter 11 reviewed most of the studies in the literature. Surprisingly, the only study showing a strong inverse correlation with dietary vitamin D was for pancreatic cancer, a cohort study involving 112,000 participants. There was a significantly reduced risk for three of the five quintiles of vitamin D from diet. The problem with most such observational studies is that diet provides too little vitamin D to have a significant effect on cancer risk. National diets including fish and fortified milk provide about 250–300 IU/day of vitamin D, which is too little to have an effect. Reducing the risk of cancer incidence by at least 30% takes at least 1,100 IU/day to 1,500 IU/day.,–

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Chapter 12. Observational Studies on Serum 25-hydroxyvitqamin D, Cancer and All-Cause Mortality

Interestingly, the IARC report accepted the existence of a preventive role of vitamin D in colorectal cancer, yet it unfairly discounted similar evidence of approximately the same level of benefit in reducing the risk of breast cancer. This duality is inexplicable because the effect on breast cancer of being in the top half of the population distribution on 25(OH)D cancer mortality rates (0.28, p < 0.0x) was identical to that of being in the top tertile of the population distribution for colorectal cancer (0.28, p < 0.02).

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Chapter 13. Meta-Analyses of Observational Studies on Vitamin D Levels on Colorectal, Breast and Prostate Cancer and Colorectal Adenoma

Although the Working Group's meta-analyses for colorectal and breast cancer in chapter 13 are good, their not discussing the similar meta-analyses by Gorham et al. and Garland et al. is puzzling. The data for incidence rate in these studies were plotted versus serum 25(OH)D, which gives a graphical representation of the relationships. In Gorham et al. colorectal cancer incidence was reduced by 50% for a serum 25(OH)D level of 34 ng/mL. In Garland et al. the 50% reduction point for breast cancer was 52 ng/mL.

For ovarian cancer, Garland,81 using data from Tworoger et al. calculated a 48% reduction in incidence for a serum 25(OH)D level of 30 ng/mL.

Chapter 15. Vitamin D, Cancer Prognostic Factors and Cancer Survival

The IARC report's discussion of skin solar elastosis correctly concludes that solar elastosis is not a good marker of lifetime solar UVB irradiance and vitamin D production. However, one overlooked reason in this discussion is the role of smoking in elastosis. Smoking produces skin elastosis the same as does solar UV irradiance. As recently found, there is a strong inverse correlation between smoking and risk of melanoma. This effect, then, probably explains the finding of increased survival with melanoma for all measures of solar UV irradiance. Other studies such as that by Tuohimaa et al. and the study of cancer in Spain did not find that incidence or death from melanoma was correlated with reduced risk of internal cancers.

A study of women diagnosed with breast cancer in Toronto found that during a 12-year follow-up period, those with serum 25(OH)D levels greater than 30 ng/mL at time of diagnosis had a 17% all-cause mortality rate, whereas those with a level less than 20 ng/mL had a 34% mortality rate.89

Chapter 17. Vitamin D in Specific Populations or Conditions

Chapter 17 of the IARC report discussed cancer rates for African Americans, Hispanic Americans and Native Americans. For African Americans, the IARC report discussed and largely dismissed the study by Giovannucci et al. on the basis of the small number of cases (99) and lack of serum 25(OH)D measurements. For some reason, the report also did not discuss two ecological studies of cancer mortality rates for African Americans. Grant reported that solar UVB doses for July 1992,were inversely correlated with bladder, colon, lung and rectal cancer for males and breast, lung and pancreatic cancer for females. In a later study that also included indices for alcohol consumption, poverty, smoking and urban residence, UVB was inversely correlated with all less lung, colon, esophageal, gastric, lung and rectal cancer for males and all less lung, breast, gastric and rectal cancer for females with a p value of less than 0.05.

Chapter 18. Vitamin D: Prediction or Cause of Cancer and other Chronic Health Conditions

Chapter 18 suggests that it is not known whether poor health leads to low serum 25(OH)D levels or, conversely, whether low serum 25(OH)D levels lead to increased risk of cancer and other chronic diseases. From our reading of the journal literature, the second statement is the more generally correct one. The chapter also indicates that an RCT is the only way to determine which statement is correct. The IARC report did not look far for evidence that low vitamin D levels increased the risk of disease.

Dental health is an example of how low solar UVB leads to chronic disease. An ecological study in the 1930s found that adolescent white males living in the southwestern United States, with more than 3,000 hours of sunlight/year, had half as many dental caries as those living in the Northeast, with fewer than 2,200 hours of sunlight/year, with those living between having a number of dental caries proportional to annual sunlight level. The mechanism was unknown then but is now known to be the production of human cathelicidin (LL-37) by 1,25(OH)2D, which has strong antibacterial properties., More recently, periodontal disease was linked to low serum 25(OH)D., From these findings, as well as the series of studies this year reporting that low serum 25(OH)D is inversely correlated with vascular disease incidence and mortality rates,– and a recent analysis on the role of vitamin D in neuroprotection, comes evidence that low serum 25(OH)D is an important risk factor for dementia (vascular dementia and Alzheimer's disease).104

Chapter 19. Should Recommendations for Sun Protection and Vitamin D Intakes be Changed?

There is a statement on p. 296 that is inconsistent with the results of the Lappe et al. RCT: “Setting a lower limit of “adequate” serum 25-hydroxyvitamin D levels at 20 or 30 ng/mL is currently inappropriate since there are no results from randomised trials suggesting that maintenance of such “adequate” serum 25-hydroxyvitamin D level actually prevents any cancer and any other chronic condition.”

In the Lappe et al. study, the women taking 1,100 IU/day of vitamin D raised their serum 25(OH)D levels from 28 to 38 ng/mL and had a 35% reduction in all-cancer incidence between the ends of the first and fourth years of the study attributed to vitamin D supplementation.

Summary and Conclusion

The health benefits of vitamin D extend beyond cancer to cardiovascular diseases, 78,120 bacterial 95,96 and viral infections,37,38 autoimmune diseases,34,121 dental caries94 and periodontal disease97,98 and dementia.103,104

While this paper includes reference to several papers published after the Working Group reviewed the literature and six papers by the author of this paper that are in press, most of these recent works are reviews based on published literature and, thus, could have been anticipated by members of the Working Group.

Increasing serum 25(OH)D levels at the population level will do much to reduce the economic burden of disease. Although people with a few types of granulomatous diseases such as sarcoidosis should be careful about increasing serum 25(OH)D levels, and those with red hair and freckles should be careful in the sun, for nearly all people, the health benefits of careful solar UV irradiance and increased vitamin D supplementation greatly outweigh the adverse effects. Although I agree that positive results from well-designed RCTs will help convince the skeptics, the evidence to date is strong enough that vitamin D can be recommended to prevent and treat cancer. The sooner that health policies are changed based on present-day evidence, the better for disease prevention.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715207/

perjantai 3. huhtikuuta 2015

A critical review of Vitamin D and Cancer - A report of the IARC Working Group