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Current impediments to acceptance of the ultraviolet-B-vitamin D-cancer hypothesis. Grant WB, Boucher BJ. Anticancer Res. 2009 Sep;29(9):3597-604. PMID: 19667154 The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 1980. There have been numerous ecological, observational and other studies of the hypothesis. There are about 14 types of cancer for which it seems to apply: bladder, breast, colon, endometrial, esophageal, gallbladder, gastric, ovarian, pancreatic, rectal, renal and vulvar cancer and both Hodgkin's and non-Hodgkin's lymphoma. Nonetheless, the hypothesis has not yet been accepted by public health agencies. Some of the reasons for this include a distrust of ecological studies, some mistrust of observational studies, and the existence of just one positive randomized controlled trial, an analysis of a vitamin D and calcium supplementation study involving post-menopausal women in Nebraska. Paradigm shifts such as this generally take time, in part due to opposition from those content with the status quo. In this paper, results of ecological studies in the United States using summertime solar UVB as the index of vitamin D production, which is highly asymmetrical with respect to latitude, and indices for other cancer risk-modifying factors (air pollution, alcohol consumption, dietary iron and zinc, ethnic background, socioeconomic status, smoking and urban/rural residence) are discussed in terms of supporting the hypothesis. These studies were not considered while other ecological studies were examined in recent critiques of the hypothesis. While additional randomized controlled trials would, of course, be helpful, the current evidence seems to satisfy the criteria for causality as outlined by A. Bradford Hill.

"June 29, 2009 | Shelley Wood Boston, MA - A massive, National Institutes of Health-sponsored study looking at whether vitamin-D and/or omega-3 fatty-acid supplementation can reduce the risk of developing heart disease, stroke, or cancer will get under way in January 2010, according to a website for the study. Drs JoAnn Manson and Julie Buring (Harvard Medical School/ Brigham and Women's Hospital, Boston, MA) will head up the Vitamin D and Omega-3 Trial (VITAL). The study is aiming to enroll 20 000 men and women, one-quarter of whom will be black. According to a Brigham and Women's Hospital press release, the study is intentionally aiming to illuminate a potential racial and ethnic disparity hypothesized to be linked to vitamin D [1]. "African Americans have a higher risk of vitamin-D deficiency as well as a greater frequency of diabetes, hypertension, and certain types of cancer," a press release notes. For VITAL, women need to be over age 65 to enter the study; men need to be over age 60. Study participants will be randomized to one of four groups: daily vitamin D (2000 IU) and fish oil (1 g); daily vitamin D and fish-oil placebo; daily vitamin-D placebo and fish oil; or daily vitamin-D placebo and fish-oil placebo. The trial will run for five years and is expected to cost US $20 million."

Vitamin D and type 2 diabetes: are we ready for a prevention trial? Scragg R. Diabetes. 2008 Oct;57(10):2565-6. PMID: 18820212 doi: 10.2337/db08-0879 Despite evidence from the current article (3) and the Finnish study (17), doubts still remain about whether low vitamin status is a cause of type 2 diabetes. Further cohort studies are required, assessing baseline vitamin D status using blood 25(OH)D to be sure that the Ely and Finnish studies are not false-positive results. Glucose clamp studies are also required because we are still not sure of the mechanism influenced by vitamin D-whether it is insulin resistance, secretion, or both. But most importantly, given that nearly three decades have passed since the first studies linking vitamin D with insulin metabolism (6,7), well-designed clinical trials of the effect of vitamin D supplementation on glycemia status and diabetes risk are urgently required to settle this question. And they need to prevent past mistakes. In particular, the vitamin D dose given in such trials needs to be high enough-above 2,000 IU per day (19)-to raise blood 25(OH)D levels above 80 nmol/l because diabetes risk is lowest at this level (9,20). If well-designed trials are carried out and confirm a protective effect from vitamin D, it could be used by the general population as a simple and cheap solution to help prevent the diabetes epidemic.

Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. Hollis BW, Wagner CL, Drezner MK, Binkley NC. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):631-4. Epub 2007 Jan 10. PMID: 17218096 In the present study, we sought to investigate what circulating 25(OH)D levels would result in populations exhibiting no substrate limitations to the vitamin D-25-hydroxylase. To perform this, we chose two distinct populations. The first were individuals from a year-found sunny environment who spent a good deal of time outdoors. The second were a group of lactating women receiving a substantial daily oral dose of vitamin D3. Surprisingly, a study such as this previously had not been undertaken. There are several reasons for this. First, finding a group of sun-exposed individuals is not an easy task; in fact, we had to go to Hawaii to find them. Secondly, very few studies have been performed where subjects actually received adequate vitamin D3 supplementation to make them replete. Finally, it is very difficult and costly to measure circulating vitamin D3 and relate it to circulating 25(OH)D. The results of our study are far-reaching. This study also demonstrates that individuals can be vitamin D deficient with significant sun exposure if the skin area exposed is limited as was suggested several years ago (19). Finally, whether one receives their vitamin D3 orally or through UV exposure, the vitamin D-25-hydroxylase appears to handle it in an equivalent fashion with respect to maintaining circulating 25(OH)D levels. Thus, we believe that the relationship between circulating vitamin D and 25(OH)D may define adequate nutritional vitamin D status.

Vitamin D and breast cancer. Bertone-Johnson ER. Ann Epidemiol. 2009 Jul;19(7):462-7. Epub 2009 Feb 20. Review. PMID: 19230714 Though the relationship between vitamin D and breast cancer remains unclear, a growing body of evidence suggests that vitamin D may modestly reduce risk. A large number of in vitro studies indicate that vitamin D can inhibit cell proliferation and promote apoptosis and cell differentiation in breast tumor tissue. Results from analytic studies of sunlight exposure and dietary intake have been inconsistent but together generally support a modestly protective role of vitamin D, at least in some population subgroups. Studies using blood vitamin D metabolites to assess vitamin D status may be less prone to misclassification than those of diet and sunlight exposure. Overall, the two prospective and four case-control studies of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D tend to support a protective effect in older women. The relationship between common vitamin D receptor polymorphisms and risk remains unclear. Many questions about this relationship clearly remain, including the utility of assessing vitamin D through diet and sunlight exposure, the relationship between plasma metabolites, and the potential modifying effects of age, menopausal status and tumor characteristics. Given that vitamin D status is modifiable, additional prospective studies are necessary to determine if vitamin D may have important potential for breast cancer prevention.

Serum vitamin D concentration and prostate cancer risk: a nested case-control study. Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, Horst RL, Hollis BW, Huang WY, Shikany JM, Hayes RB; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Project Team. J Natl Cancer Inst. 2008 Jun 4;100(11):796-804. Epub 2008 May 27. PMID: 18505967 doi:10.1093/jnci/djn152 CONCLUSION: The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease. In summary, results from this large prospective study of men who underwent standardized prostate cancer screening in the context of a screening trial do not support the hypothesis that higher serum vitamin D status is associated with decreased risk of prostate cancer. The study showed no association of vitamin D level with nonaggressive disease; however, it raises the possibility that higher vitamin D level may be associated with increased risks for aggressive disease, although a clear monotonic dose-response relationship was lacking. Along with recent reports of adverse associations for higher vitamin D status and risk of pancreatic (32) and esophageal (33,34) cancer, caution should be taken in recommending high doses of vitamin D or sunlight exposure to the general public for prostate cancer prevention. Future analyses are warranted to confirm these results and to further clarify the effects of vitamin D on aggressive prostate cancer.

"For what reason I don't know, but this January 2009 editorial by William Faloon of the Life Extension Foundation is making the rounds. Perhaps it just came available on the web. It's a good read, particularly in light of the billions and trillions of dollars the thieves & thugs in DC are about to flush down the crapper on your behalf. Some notable excerpts. A large number of new vitamin D studies have appeared in the scientific literature since I wrote my plea to the federal government. These studies don't just confirm what we knew 16 months ago-they show that optimizing vitamin D intake will save even more lives than what we projected. For instance, a study published in June 2008 showed that men with low vitamin D levels suffer 2.42 times more heart attacks. Now look what this means in actual body counts. Each year, about 157,000 Americans die from coronary artery disease-related heart attacks. Based on this most recent study, if every American optimized their vitamin D status, the number of deaths prevented from this kind of heart attack would be 92,500. To put the number of lives saved in context, tens of millions of dollars are being spent to advertise that Lipitor® reduces heart attacks by 37%. This is certainly a decent number, but not when compared with how many lives could be saved by vitamin D. According to the latest study, men with the higher vitamin D levels had a 142% reduction in heart attacks."

Statins and vitamin D. Aloia JF, Li-Ng M, Pollack S. Am J Cardiol. 2007 Oct 15;100(8):1329. Epub 2007 Jul 5. No abstract available. PMID: 17920383 A total of 208 women were randomized to receive vitamin D3 (n=104) or placebo (n=104). 51 women were on statins. At baseline, the subjects on statins had a significantly higher 25-OHD level than the subjects who were not on statins (51.2 ± 20.1 nmol/L versus 43.2 ± 18.0 nmol/L respectively, p=0.008). This was also true when averaging 25-OHD levels across the 3-year study period and looking at active and placebo patients separately. 185 subjects had follow-up 25-OHD levels drawn every 6 months during the study. Higher levels were seen in the statin use subgroup whether they were on placebo or active vitamin D (Figure 1Figure 1). There was no interaction seen between vitamin D use and statin use, i.e. the impacts are additive (p=0.5502). This significant difference is comparable to the increase in 25-OHD levels seen in Pérez-Castrillón's study (41 ± 19 versus 47 ± 19 nmol/L, p=0.003) [1]. Although Pérez-Castrillón et al found a statistically significant relation between total cholesterol and 25-OHD (r=0.277, p=0.002), we did not find a significant relation between total cholesterol and 25-OHD in our study population.

An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Grant WB. Cancer. 2002 Jan 1;94(1):272-81. PMID: 11815987 CONCLUSIONS It is hypothesized that animal products are associated with risk for breast carcinoma because they are associated with greater amounts of insulin-like growth factor-1and lifetime doses of estrogen. Vegetable products contain several risk reduction components including antioxidants and phytoestrogens. The association with latitude is very likely because of solar UV-B radiation and vitamin D. Alcohol modulates estrogen's effects on breasts. Fish intake is associated with risk reduction through vitamin D and n-3 oils. These results are consistent with those of many case-control and cohort studies but should be assessed in well designed cohort studies.

Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Hyppönen E, Power C. Am J Clin Nutr. 2007 Mar;85(3):860-8. PMID: 17344510 Conclusion: Prevalence of hypovitaminosis D in the general population was alarmingly high during the winter and spring, which warrants action at a population level rather than at a risk group level. Data from the 1958 birth cohort suggest that, at different cutoffs for hypovitaminosis D, a substantial public health problem exists in British whites. Obese participants and those living in Scotland were at the highest risk of hypovitaminosis D. However, the prevalence in the general population was very high during the winter and spring, which suggests that, to improve the situation, action is required at a population level rather than at a risk-group level. In the United States, calls have gone out for an increase in vitamin D fortification of foods (11), and the data from the current study suggest that such action is also warranted in the United Kingdom. Vitamin D is currently available without prescription as a dietary supplement only as part of cod liver oil or multivitamin products; hence, a need clearly exists to consider increased availability of over-the-counter supplements. Hypovitaminosis D has been implicated in the development of serious conditions, including diabetes, various types of cancer, and cardiovascular diseases, in addition to its essential role in maintaining bone health (1, 2). The high rates of hypovitaminosis D reported in this study suggest that immediate action is needed to improve the vitamin D status of the British population.

25-Hydroxyvitamin D and functional outcomes in adolescents. Lamberg-Allardt CJ, Viljakainen HT. Am J Clin Nutr. 2008 Aug;88(2):534S-536S. Review. PMID: 18689396 CONCLUSIONS Cross-sectional studies have shown a relation among serum 25(OH)D concentration, serum PTH concentration, and BMD in adolescents. Long-term randomized controlled intervention studies have shown that vitamin D3 supplementation has a positive effect on BMD in adolescence; some of these studies found an effect with doses as small as 5 µg (200 IU) to 10 µg (400 IU) per day, or without supplemental calcium.

Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Diabetes. 2008 Oct;57(10):2619-25. Epub 2008 Jun 30. PMID: 18591391 doi: 10.2337/db08-0593 CONCLUSIONS: This prospective study reports inverse associations between baseline serum 25(OH)D and future glycemia and insulin resistance. These associations are potentially important in understanding the etiology of abnormal glucose metabolism and warrant investigation in larger, specifically designed prospective studies and randomized controlled trials of supplementation.

A multicountry ecologic study of risk and risk reduction factors for prostate cancer mortality. Grant WB. Eur Urol. 2004 Mar;45(3):271-9. PMID: 15036670 CONCLUSIONS: These results are consistent with insulin-like growth factor-I (IGF-I), being an important risk factor for prostate cancer, with alcohol and calcium being less important risk factors, and with allium family vegetables, and, to a lesser extent, vitamin D being important risk reduction factors. These results should provide guidance for additional studies on dietary and environmental links to prostate cancer.

Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Grant WB, Mohr SB. Ann Epidemiol. 2009 Jul;19(7):446-54. Epub 2009 Mar 9. PMID: 19269856 CONCLUSION: These findings provide strong evidence that vitamin D status plays an important role in controlling the outcome of cancer. Support for the UVB-vitamin D-cancer theory is now scientifically strong enough to warrant use of vitamin D in cancer prevention, and as a component of treatment. More research studies would help to explore whether there are benefits beyond the substantial effects that have been observed.

Sunlight, vitamin D and the prevention of cancer: a systematic review of epidemiological studies. Rhee HV, Coebergh JW, Vries ED. Eur J Cancer Prev. 2009 Aug 26. [Epub ahead of print] PMID: 19730382 We, therefore, conclude that there is accumulating evidence for sunlight as a protective factor for several types of cancer. The same conclusion can be made concerning high vitamin D levels and the risk of colorectal cancer. This evidence, however, is not conclusive, because the number of (good quality) studies is still limited and publication biases cannot be excluded. The discrepancies between the epidemiological evidence for a possible preventive effect of sunlight and vitamin D and the question of how to apply the findings on the beneficial effects of sunlight to (public) health recommendations are discussed.

Assessment of dietary vitamin D requirements during pregnancy and lactation. Hollis BW, Wagner CL. Am J Clin Nutr. 2004 May;79(5):717-26. Review. PMID: 15113709 We found that high-dose maternal vitamin D supplementation not only improves the nutritional vitamin D status of breastfeeding infants but also elevates the maternal concentrations into the mid-normal range. Thus, a dual benefit is achieved from high-dose maternal supplementation. It is noteworthy that in the Finnish study, the authors added a disclaimer, "A sufficient supply of vitamin D to the breastfed infant is achieved only by increasing the maternal supplementation up to 2000 IU/d. Such a dose is far higher than the RDA [DRI] for lactating mothers [and therefore] its safety over prolonged periods is not known and should be examined by further study." This point of concern was valid when this study was conducted in 1986 (92); however, on the basis of the current findings of Vieth et al (2) and of Heaney et al (3)-which showed that vitamin D intakes <= 10 000 IU/d (250 µg) are safe for prolonged periods (up to 5 mo)-we believe that it is time to reexamine the understated DRI of vitamin D for lactating mothers. This work is now being conducted in our clinics and laboratory.

Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Grant WB, Mohr SB. Ann Epidemiol. 2009 Jul;19(7):446-54. Epub 2009 Mar 9. Review. PMID: 19269856 CONCLUSION: These findings provide strong evidence that vitamin D status plays an important role in controlling the outcome of cancer. Support for the UVB-vitamin D-cancer theory is now scientifically strong enough to warrant use of vitamin D in cancer prevention, and as a component of treatment. More research studies would help to explore whether there are benefits beyond the substantial effects that have been observed.

Serum 25(OH)-vitamin D concentration and risk of esophageal squamous dysplasia. Abnet CC, Chen W, Dawsey SM, Wei WQ, Roth MJ, Liu B, Lu N, Taylor PR, Qiao YL. Cancer Epidemiol Biomarkers Prev. 2007 Sep;16(9):1889-93. PMID: 17855710 doi: 10.1158/1055-9965.EPI-07-0461 Background: Squamous dysplasia is the precursor lesion for esophageal squamous cell carcinoma, and nutritional factors play an important role in the etiology of this cancer. Previous studies using a variety of measures for vitamin D exposure have reached different conclusions about the association between vitamin D and the risk of developing esophageal cancer. Conclusions: Higher serum 25(OH)D concentrations were associated with significantly increased risk of squamous dysplasia. No obvious source of measured or unmeasured confounding explains this finding. In conclusion, we found that a higher serum 25(OH)D concentration was associated with an increased risk of esophageal squamous dysplasia, the precursor lesion for ESCC. This finding concurs with our previous prospective study which found that higher vitamin D status was associated with increased risk of incident ESCC in this same population. These unexpected findings suggest that further studies of the association of vitamin D and digestive tract cancers are needed before the effect of vitamin D in different populations can be elucidated.

Meta-analysis of longitudinal studies: Serum vitamin D and prostate cancer risk. Yin L, Raum E, Haug U, Arndt V, Brenner H. Cancer Epidemiol. 2009 Dec;33(6):435-45. Epub 2009 Nov 25. PMID: 19939760 doi:10.1016/j.canep.2009.10.014 CONCLUSIONS: According to available evidence from longitudinal studies, serum 25(OH)D is not associated with PC incidence.

A seasonal variation of calcitropic hormones, bone turnover and bone mineral density in early and mid-puberty girls - a cross-sectional study. Viljakainen HT, Palssa A, Kärkkäinen M, Jakobsen J, Cashman KD, Mølgaard C, Lamberg-Allardt C. Br J Nutr. 2006 Jul;96(1):124-30. PMID: 16870000 Seasonal variation in S-25-OHD and bone remodelling markers accompanied by negative correlation between S-25-OHD and S-iPTH was seen in this cross-sectional study of adolescent girls. In addition, the seasonal rhythm contributed 7.0-7.6 % difference in the BMD of lumbar vertebrae and left femur in early puberty girls. This variation should be avoided since it could hamper peak bone mass attainment.