Health Benefits of Vitamin D : Prostate Cancer, Etc.

1. Health Benefits of Vitamin D: Prostate Cancer, Etc. A presentation to theProstate Awareness FoundationDecember 6, 2007 by William B. Grant, Ph.D. Sunlight, Nutrition, and Health Research CenterSan Francisco, California, 94109 USA www.sunarc.org

2. Golden Age • We are in the “Golden Age” of research on solar ultraviolet-B irradiance and vitamin D. • New findings are being reported weekly. • If vitamin D could be patented and sold for huge profits, you would see it advertised everywhere. • Instead, the establishment tries to suppress the information on vitamin D in order to maintain the high profit rates in our disease-treatment health system. • As John Cannell, MD, likes to say, Linus Pauling was on the right track, but off by one letter.

3. Disclosure I am pleased to acknowledge funding from these organizations: • UV Foundation (McLean, Virginia) www.uvfoundation.org • The Vitamin D Society (Canada) www.vitamindsociety.org • The European Sunlight Association www.europeansunlight.eu

4. Outline Definitions Cancer  Ecologic and cohort studies • Internal cancers after diagnosis of skin cancer • Prospective supplementation study Respiratory viral diseases / implications for other diseases • Autoimmune diseases • Viral infections, cancer risk Effect of vitamin D on mortality rates Vitamin D sources and cautions

5. Definitions • Vitamin D3 (cholecalciferol) is made in the skin from 7-dehydrocholesterol from ultraviolet-B (UVB) and a thermal process. • Solar UVB extends from 290-315 nm UVA extends from 315-400 nm • Vitamin D3 is converted in the liver to 25-hydroxyvitamin D3 (calcidiol), the circulating form. • Calcidiol is converted in the kidney and other organs to 1,25-dihydroxyvitamin D3 (calcitriol), the hormonal version.

6. Definitions, continued • Vitamin D receptors (VDRs) hold calcitriol where it can work its magic. • VDRs come in different alleles, with some more helpful than others. • The half life of vitamin D3 is about 4-6 weeks. • Vitamin D2 (ergocalciferol) is made from vegetable matter, and is about half as effective as vitamin D3; however, MDs can prescribe it but not vitamin D3.

7. Studies of UVB and Cancer Ecological Studies of UVB and Cancer Incidence and Mortality • Ecological studies treat populations defined geographically as the units, averaging all data at that level. • The Garland brothers made the first ecological study of cancer and solar UVB in 1980. • They saw that cancer rates were lowest in the sunniest part of the country and highest in the least sunny part. • They hypothesized that since vitamin D production is the most important physiological effect of solar radiation, vitamin D was likely the agent.

8. 300 300 350 350 300 350 300 350 400 400 450 500 500 450 Colon cancer mortality rates, males, 1970-94

9. UVB Doses (kJ/M2) for July 1992

10. breast prostate stomach kidney, urinary

11. Cancer Risk Modifying Factors • There are a number of factors that modify the risk of cancer. • They can often be included in studies by means of indices. • Examples include diet, smoking, alcohol consumption, ethnic heritage, and urban residence.

13. Cancer Incidence and Mortality Cancer incidence and mortality rates in the United States • Based on the incidence and mortality rate data in the United States, ecological studies have identified over 20 UVB/vitamin D-sensitive cancers. • The inverse correlation is stronger for mortality than incidence rate; • the likely reason is that there are many risk-modifying factors for cancer incidence and progression but few for metastasis.

14. Other Risk-Modifying Factors In our multi-factorial ecological study1 of cancer mortality rates in the United States, we found: • UVB: inverse for 15 types of cancer • Smoking: risk for 10 types of cancer • Alcohol: risk for 9 types of cancer • Hispanic heritage: risk for 3 types of cancer • Latitude: risk for 1 type (prostate) 1. Grant and Garland, Anticancer Research, 2006.

15. Diet and Cancer Risk Diet is a very important cancer risk factor. • For many types of cancer, animal products are associated with increase risk, perhaps though production of insulin-like growth factor. • For prostate cancer, animal products are an important risk factor, but milk and calcium are also associated with risk, while onions, garlic, and cooked tomatoes are associated with reduced risk. • Those eating high amounts of onions and garlic were found to have a 20-30% reduced risk for prostate cancer (and many other types of cancer).

16. Vitamin D and Cancer Risk Harvard cohort study on vitamin D and cancer • Edward Giovannucci developed a vitamin D index based on vitamin D from oral intake and UVB production, and controlled for other factors. • Significant inverse correlations with vitamin D were found for colon, esophageal, oral, pancreatic, and rectal cancer and leukemia. • Insignificant inverse correlations were found for bladder, gastric, lung, prostate, and renal cancer. • They estimated that male cancer deaths could be reduced by 29% for 1500 IU of vitamin D3/day.

17. UVB Irradiance Studies based on indices of UVB irradiance rather than vitamin D dose • Critics of ecological studies based on solar UVB doses related to geographic location of residence question whether UVB dose translates to UVB irradiance. • There is a simple way to determine lifetime UVB irradiance at the personal or population level: development of non-melanoma skin cancer (NMSC) after controlling for smoking.

18. Risk of Second Cancer Meta-analysis of risk of second cancer after diagnosis of NMSC When adjusted for smoking, diagnosis of NMSC is significantly inversely correlated with colon cancer risk (lung cancer risk ratio = 1.0) Colon Cancer Risk Ratio Lung Cancer Risk Ratio

19. Prostate cancer vs. NMSC In sunny countries, diagnosis of NMSC is associated with reduced risk of prostate cancer1 • Basal cell carcinoma: SIR = 0.63 (0.44-0.89) • Squamous cell carcinoma: SIR = 0.43 (0.23-0.73) • But not melanoma: SIR = 1.20 (1.10-1.30) • (SIR = standardized incidence rate with 95% confidence intervals) • BCC and SCC are linked to lifetime UVB irradiance; melanoma is linked to UVA and sunburning 1 Tuohimaa et al., 2007

20. Vitamin D Indices by Strength Vitamin D indices for cancer studies in order of strength of correlation • Solar UVB doses • Non-melanoma skin cancer incidence rates • Hybrid oral intake plus UVB irradiance • Personal sun exposure history • Oral intake • Pre-diagnostic serum calcidiol • Note that most studies of pre-diagnostic serum calcidiol have not found an inverse correlation with prostate cancer for lags of 5 to 15 years.

21. Number of UVB-Cancer Studies Number of Observational Studies on UVB and Cancer Risk Reduction • 10+ breast, colon, ovarian, pancreatic, prostate cancer, NHL • 7-9 esophageal, lung, rectal cancer • 5-6 renal, Hodgkin’s lymphoma • 3-4 bladder, gallbladder, gastric, uterine corpus cancer, multiple myeloma • 2 laryngeal, oral, thyroid cancer, leukemia • 1 biliary, cervical, pleural, small intestine, soft tissue, vulvar cancer 20 types of cancers with 2 or more studies

22. Vitamin D, Calcium and Cancer Risk Recent prospective study of vitamin D3 and calcium and cancer risk1 • Randomized, double-blind, placebo-controlled study of post-menopausal women in Nebraska • 1100 IU of vitamin D3 and, in some cases, 1400 mg of calcium per day, or a placebo. • The all-cancer incidence for women over the age of 55 years at time of enrollment was reduced by 77% between the ends of the first and fourth years of the study. (OR = 0.23, CI: 0.09, 0.60; P < 0.005) • The baseline serum calcidiol level for these women was 28 ng/mL (mean value in the U.S.). 1. Lappe JM et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007 Jun; 85(6): 1586-91.

23. Dose-Response Relations It is important to determine the dose-response relations between vitamin D and cancer risk: • To verify that the effect is causal; • To be able to make policy recommendations. This has been done for breast and colorectal cancer through meta-analyses of published studies of prediagnostic serum calcidiol. • 1500 IU/day for 50% reduction in colorectal cancer; • 3600 IU/day for 50% reduction in breast cancer.

24. Gorham et al., 2007

25. Seasonal Cancer Survival Cancer Survival with Respect to Season of Diagnosis • Studies in Norway, Boston, and England have found that those diagnosed with cancer in summer or fall have better survival over the next 1.5-5 years. • The most likely reason is higher levels of solar UVB and vitamin D.

26. Seasonal Survival in Norway Cancer Survival with Respect to Season of Diagnosis in Norway1(mortality rate differences in southeast Norway vs. midwest winter for 36 months) • Prostate cancer: 0.80 (0.75-0.85)* • Breast cancer: 0.75 (0.7-0.8)* • Colon cancer: 0.79 (0.7-0.84)* • Lung cancer: 0.93 (0.89-0.96)* • Hodgkin’s lymphoma: 0.80 (0.9-1.1) * indicates statistically significant 1. Porojnicu et al., 2007.

27. Vitamin D Supplements Those with cancer should consider vitamin D supplements. • The magnitude of the effect from just solar UVB suggests vitamin D3 supplements of several thousand IU per day should be considered for those with most types of cancer. • Those with Hodgkin’s and non-Hodgkin’s lymphoma should be a cautious due to possible adverse effects on calcium.

28. UVB-D-Cancer Causality? A. B. Hill laid down the criteria for establishing causality in a biological system. The most important ones are well satisfied: • Strength of association • Repeated in many diverse populations • Linear dose-response relation • Confounding factors accounted for • Mechanisms understood • Experimental verification • Cause precedes the effect

29. Precautionary Principle • As an alternative to the requirement for a randomized controlled trial, we propose that a set of well-conducted observational studies be used, along with the precautionary principle. • The precautionary principle looks at the risks and benefits of a policy, and if the preponderance of the evidence supports the policy, it is adopted. • The precautionary principle is more likely to be used in European countries than the U.S.

30. Respiratory Viral Diseases John Cannell, M.D., noticed that patients in his ward in Atascadero had much lower rates of influenza one winter than those in other wards. His patients were supplementing with 1000-2000 IU of vitamin D3. Cannell et al.1 hypothesized that epidemic influenza is seasonal in part due to seasonal variations of solar UVB and vitamin D. 1. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E.Epidemic influenza and vitamin D. Epidemiol Infect. 2006 Dec;134(6):1129-40.

31. Cold and Flu Prevention • Results of a prospective double blind vitamin D supplementation study involving 208 African-American post-menopausal women living in or near Mineola, NY. • The vertical scale refers to cases of common cold or flu. • Aloia JF, Li-Ng M. Epidemiol Infect. 2007.

32. Respiratory Syncytical Virus Yusuf et al. [2007] showed that solar UVB modulates the seasonal incidence of respiratory syncytical virus (bronchitis) in a latitudinally consistent manner. Other important factors associated with increased number of cases were temperature and relative humidity. • Low temperature impairs white blood cells from getting to the surface. • Low relative humidity makes exhaled viruses smaller.

33. Calcitriol and Cathelicidin Calcitriol Induces Production of Human Cathelicidin • The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D (calcitriol) can induce the production of cathelicidin, a component of the innate immune system. • Cathelicidin induction from vitamin D seems to explain the beneficial role of UVB and vitamin D for bacterial and viral infections that peak in winter.

34. Sepsis Sepsis (infectious blood disease related to bacterial and viral infections) has these epidemiological features in the United States: • Highest in the Northeast, lowest in the Southwest. • Highest in winter, lowest in fall. • Higher in black Americans than white Americans. • Rapid increase with advancing age. • Comorbid diseases are vitamin D sensitive. These features are explained by the epidemiological features of solar UVB and vitamin D [Grant, submitted].

35. Autoimmune Diseases Theoretical Extension to Autoimmune Diseases • There are a number of diseases for which viral infections are a risk factor. • The virus can embed itself in various tissues and live for many years with few symptoms. • As the body tries to fight the infection, it may generate an autoimmune response.

36. Multiple Sclerosis Theoretical extension to multiple sclerosis (MS) and possibly other autoimmune diseases • Risk of MS is linked to viral diseases such as infectious mononucleosis linked to Epstein-Barr virus. • UVB and vitamin D reduce the risk of MS. • The prevalence of MS increases with increasing latitude in Australia, Europe south of Nordic countries, and the United States.

37. Multiple Sclerosis Prevalence for US WWII KC Veteransat Time of Entry into the Armed Forces Versus Latitude MS Prevalence (relative units) Latitude (degrees North)

38. Hypothesis for MS The multiple sclerosis vitamin-D hypothesis: • UVB, through production of vitamin D, reduces the risk of MS primarily by fighting the viral infections that lead to MS, especially in youth, when such viral infections are more common. • The quadratic latitudinal gradient in disease outcome is linked to wintertime solar UVB, when infectious diseases are more common, as opposed to summertime UVB, which has an asymmetrical pattern in the US.

39. Viral Risk of Cancer Viral infections pose a known risk for a number of cancer types: • Well-known cancers cervical, esophageal, nasopharyngeal cancer, lymphoma • Less-well-known cancers bladder, gastric, prostate, testicular, and thyroid cancer

40. Viral Infections and Cancer Immunosuppression and cancer risk from viral infections: • For cervical, esophageal, and nasopharyngeal cancer, UV-induced immunosuppression seems to play an important role in cancer risk. • For many of these cancers, higher solar UV is associated with increased risk.

41. Vitamin D and Viruses Vitamin D-mediated reduction in cancer risk due to viral infections • The mortality rate map for prostate cancer is very similar to that for multiple sclerosis. • Prediagnostic serum calcidiol levels are generally not inversely correlated with prostate cancer incidence rates. • There are many indications that young men have more genital infections than older men. • Viruses can lead to cancer via inflammation.

42. Prostate cancer mortality rates

43. Viral Infections Leading to Cancer Ecological study supports a role for vitamin D in combating viral infections leading to cancer: • For the cancers less well known as linked to viral infections, they all show an increase in mortality rate with increasing latitude in the U.S. (an index for wintertime solar UVB/vitamin D). • This finding suggests that vitamin D is lowest in the season of highest viral infection rate. • The benefit likely occurs early in life. • Other common cancers, such as breast, colon, and ovarian cancer, have neither such a variation nor evidence in the literature for a viral link. Grant, Photochem. Photobiol., in press

44. Vitamin D and Mortality Low vitamin D status could be associated with higher mortality from life-threatening conditions: • cancer, cardiovascular disease, and diabetes mellitus • 60% to 70% of total mortality in high-income countries We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation on any health condition. • 18 independent randomized controlled trials • including 57,311 participants • A total of 4777 deaths from any cause occurred • Mean daily vitamin D dose was 528 IU • The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). Autier P. Gandini S. Arch Intern Med. 2007 Sep 10;167(16):1730-7.

45. Benefits of 2000 IU of D3 /day I have just completed an analysis of the estimated health benefit of 2000 IU of vitamin D3 per day in reducing the risk of eight diseases in Canada: cancer, infections, autoimmune diseases, hip fractures, and metabolic diseases. Conclusions: • Mortality rate would be 12% less (range: 6-18%) • People would live longer (1-2 years?) • Total economic burden would be 8% less (4-12%)

46. Canadian Recommendation 8 June 2007, Toronto: The Canadian Cancer Society is recommending a specific amount of Vitamin D supplementation for Canadians to consider taking. This first-time recommendation is based on the growing body of evidence about the link between Vitamin D and reducing risk for colorectal, breast and prostate cancers. • Adults living in Canada should consider taking Vitamin D supplementation of 1,000 IU a day during the fall and winter. • Adults at higher risk of having lower Vitamin D levels should consider taking vitamin D supplementation of 1,000 IU/day all year round.

47. Sources of Vitamin D3 Fortified food and fish in the United States provide about 250-300 IU of vitamin D3/day. However, milk and orange juice are not on my list of health foods, and cold water fatty fish are both a dwindling resource and contain mercury and other toxins.

48. Milk and Parkinson’s Disease I have just completed an ecologic study and review of risk factors for Parkinson’s disease (PD). • Peroxynitrite, formed from dietary components, is an important risk factor. • Uric acid blocks the formation of peroxynitrite. • Milk protein (casein) reduces the production of uric acid, and is the strongest dietary risk factor for PD. • Other anti-oxidants from fruits and vegetables also reduce risk.

49. UVB Production of vitamin D Ultraviolet-B irradiance • Young fair-skinned people can make 1000 IU of vitamin D3 in 30 minutes at noon in the Bay Area in summer with 10% of their body exposed. • Older people take up to 4-5 times longer. • It is impossible to produce too much vitamin D from UVB due to UV destruction of vitamin D and production of inert metabolites.

50. Production rates for vitamin D in San Francisco at noon for a pale young person with 10% of the body exposed.