The Health Benefits of Vitamin D

A presentation for

East Tennessee State University

September 18, 2012

by William B. Grant, Ph.D.

Sunlight, Nutrition, and Health Research Center San Francisco, California www.sunarc.org

Disclosure

I am pleased to acknowledge funding from these organizations:

Bio-Tech-Pharmacal (Fayetteville, AR) Sunlight Research Forum (Veldhoven, Netherlands) The UV Foundation (McLean, VA) The Vitamin D Council (San Luis Obispo, CA) The Vitamin D Society (Canada)

Outline

Vitamin D physiologyEpidemiological studies and randomized

controlled trialsVitamin D and cancerSelected vitamin D-sensitive diseases from a list

of 100 such diseases Infectious diseases, cardiovascular diseases

Mortality ratesU-shaped serum 25(OH)D-health outcomesVitamin D sources and recommendations

Annual Number of Vitamin D Publications Listed at Pubmed.gov

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Vitamin D Physiology

Vitamin D3 (cholecalciferol) is made by the action of ultraviolet-B (UVB) radiation on 7-dehydrocholesterol in the skin, followed by 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 [25(OH)D], the circulating form.

25(OH)D is converted in the kidneys to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D, for circulation in the blood.

It is also converted in other organs as needed, such as to fight cancer.

Vitamin D continued

Vitamin D receptors (VDRs) are activated by 1,25(OH)2D and affect expression of over 200 genes, upregulating about two-thirds, downregulating one-third.

VDRs come in different alleles, with different effects. The half life of 25(OH)D3 is about 4-6 weeks. Vitamin D is stored in adipose tissue; 25(OH)D is stored

in muscles, and along with 1,25(OH)2D, circulates in the blood.

Vitamin D2 (ergocalciferol) is made in mushrooms or from yeast, and is much less effective than vitamin D3.

Types of Epidemiological Studies

There are four basic types of epidemiological studies used to identify and quantify links between risk-modifying factors and disease: Nested case-control from cohort studies – a defined

population followed for years after blood draw; Case-control – blood drawn at time of diagnosis; Cross-sectional – survey of a large population; Ecological – populations are defined geographically

or temporally (seasons or longitudinal); both disease outcome and risk-modifying factors are averaged by region or time.

Strengths and Weaknesses

Nested case control – weakness: single serum 25(OH)D concentration at time of enrollment.

Case-control – strength: 25(OH)D concentration at time of diagnosis; weakness – disease state may influence 25(OH)D concentration.

Cross-sectional – weakness: health conditions may affect 25(OH)D concentration.

Ecological – strengths: solar UVB is primary vitamin D source, large numbers of cases, many data sets, can account for confounding factors, works well for cancer, multiple sclerosis. Weaknesses: other factors also affect seasonality or trends.

All-cause Mortality Rate Hazard Ratio vs. Follow-up Period

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Grant, Dermato-Grant, Dermato-Endocrinology 2012Endocrinology 20124(2)4(2)

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95% CI95% CI

Regression Regression fitfit

Randomized Controlled Trials (RCTs)

RCTs are essential for pharmaceutical drugs to demonstrate efficacy and uncover risks.

Many vitamin D RCTs used doses that were too low (400 IU/day) to produce any effects.

There have been a number of successful vitamin D RCTs, including those for hip-fractures, all-cause mortality rate, cancer incidence, and type A influenza.

Hill’s Criteria for Causality in a Biological System

A. Bradford Hill [1965] laid down criteria for causality in a biological system . The main criteria are: Strength of association Consistency (repeated in different populations) Biological gradient Plausibility (mechanisms) Experiment (e.g., randomized controlled trial) Analogy (Account for confounding factors)

Ecological Studies of UVB, Vitamin D, Cancer

The first epidemiological study hypothesizing that solar UVB, through production of vitamin D, reduced the risk of cancer was published in 1980.

The brothers Cedric Garland and Frank Garland, beginning graduate students at Johns Hopkins School of Public Health in 1974, looked at the map of colon cancer mortality rates in the U.S. and saw a link to solar radiation.

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Colon cancer mortality rates, Colon cancer mortality rates, males, 1970-94; males, 1970-94; Index of annual solar radiationIndex of annual solar radiation

Higher UVB in the westHigher UVB in the westis due to higher surface is due to higher surface elevation and thinner elevation and thinner stratospheric ozone layerstratospheric ozone layer

19 Vitamin D-Sensitive Cancers (from several ecological and observational studies)

Vitamin D-sensitive cancers with moderate-to-strong support after accounting for other factors:Gastrointestinal: colon, esophageal,

gallbladder, gastric, pancreatic, rectalUrinary: bladder, kidney; Male: prostateFemale: breast, cervical, endometrial,

ovarian, vulvarBlood: Hodgkin’s and non-Hodgkin’s

lymphoma, leukemiaMiscellaneous: melanoma

Why Ecological Studies of Cancer Are Powerful

Solar UVB is the primary source of vitamin D.The risk for cancer can occur anytime in life including

youth. Studies found reduced risk for breast and prostate cancer for UVB in youth.

Cancers generally take 15-40 years to progress from initiation to detection or death.

Vitamin D has effects at all stages of cancer, initiation, progression, and metastasis.

Thus, integrated serum 25(OH)D levels over long periods of time are important in reducing the risk of cancer incidence and death.

Observational Studies of Breast and Colorectal Cancer vs. Serum 25(OH)D

Observational studies provide useful data for determining the serum 25(OH)D concentration-cancer incidence rate relation for breast and colorectal cancer.

Stronger inverse correlations between 25(OH)D concentrations and cancer incidence are found for case-control studies or cohort studies with short follow-up times.

Breast Cancer Incidence vs. Follow-up Period

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Only studies with Only studies with follow-up periods follow-up periods less than three yearsless than three yearsfound statistically found statistically significant inverse significant inverse correlationscorrelations

Meta-Analysis of Breast Cancer Risk with Respect to Diagnostic Serum 25(OH)D

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Based on five Based on five case-controlcase-controlstudies from Germany, studies from Germany, Mexico, UK, and USAMexico, UK, and USA

Cancer Survival with Respect to Serum 25(OH)D Level

Vitamin D reduces the risk of dying from cancer by reducing angiogenesis around tumors and reducing metastasis.

Higher survival rates have been reported for higher serum 25(OH)D concentrations at time of diagnosis for breast, colorectal, lung, ovarian, prostate cancer, melanoma and non-Hodgkin’s lymphoma.

Hazard ratios for all cause mortality among 304 colorectal cancer patients by prediagnostic mean plasma 25-hydroxyvitamin D concentration by quartiles, multiple-adjusted, Nurses Health and Health Professionals Study CohortsSource: Ng K, Meyerhardt JA, Wu K, Feskanich D, Hollis BW, Giovannucci EL, Fuchs CS. Circulating 25-hydroxyvitamin D levels and survival in patients with colorectal cancer J Clin Oncol 2008; 26: 2984-91.

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Colon Cancer Survival

Can Vitamin D Explain Cancer Disparities?

There are 13 types of cancer for which African-Americans have lower survival rates than white-Americans after consideration of socioeconomic status, stage at diagnosis, and treatment.

African-Americans have lower serum 25(OH)D concentrations than white-Americans (16 ng/ml vs 25 ng/ml).

This difference likely accounts for a 20% difference in survival rates.

Grant and Peiris, Dermato-Endocrinology, 2012

Treatment of Prostate Cancer

All subjects had a diagnosis of low-risk prostate cancer. Vitamin D(3) supplementation at 4000 IU/d for 1 yr. 24 of 44 subjects (55%) showed a decrease in the

number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score.

Marshall DE, et al. Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J Clin Endocrinol Metab. 2012 Jul;97(7):2315-24.

Mechanisms for Cancer Risk Reduction

Effects on cellular differentiation and proliferation

Maintains epithelial cell integrity and tight junctions between cells

Increased calcium absorptionAnti-angiogenesisAnti-metastasis

1-25-dihydroxyvitamin D

1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer.

Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions.

1-25-dihydroxyvitamin D - 2

Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg).

Dietary vitamin D(3) inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week).

Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested.

1-25-dihydroxyvitamin D - 3

Both calcitriol and dietary vitamin D(3) were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D(3) supplementation in cancer prevention and therapy.

Swami S, Krishnan AV, Wang JY, Jensen K, Horst R, Albertelli MA, Feldman D. Endocrinology. 2012 Jun;153(6):2576-87.

Hill’s Criteria Applied to Cancer

Strength of association - yes Consistency (repeated in different populations) – yes –

ecological studies in Australia, China, France, Japan, Spain, United States; case-control studies for breast cancer in four countries

Biological gradient – yes Plausibility (mechanisms) - yes Experiment (e.g., randomized controlled trial) – yes (two) Analogy – yes, similar geographical findings for dental

caries (shown later) (Account for confounding factors) - yes

Infectious Diseases – Induction of Cathelicidin and Defensins

1,25-dihydroxyvitamin D induces production of human cathelicidin, LL-37, a polypetide with modest antimicrobial and potent antiendotoxin activities, and defensins.

There is strong evidence that LL-37 can fight bacterial infections: dental caries, pneumonia, septicemia, TB.

There is also evidence that LL-37 can fight some viral infections: Epstein-Barr virus, influenza, rhinovirus. However, the effect of vitamin D may be mediated through modification of the cytokine production by the innate immune system.

Infectious Diseases – Vitamin D and Cytokines

Another important role of vitamin D is the regulation of cytokines and related proteins.

Cytokines are proteins that deliver signals to other cells.

Many cytokines are pro-inflammatory such as interleukin-4 (IL-4) and IL-6.

Vitamin D shifts the cytokine balance away from inflammatory ones.

Thus, vitamin D reduces inflammation during infection.

Epidemic Influenza

Edgar Hope-Simpson pointed out that influenza outbreaks were inversely correlated with solar UV.

John Cannell, M.D., et al. hypothesized that epidemic influenza is seasonal in part due to seasonal variations of solar UVB and vitamin D.

However, cold temperatures and low relative humidity in winter also affect the seasonality.

Hope-Simpson RE. The role of season in the epidemiology of influenza. J Hyg (Lond). 1981 Feb;86(1):35-47.

Cannell JJ, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006 Dec;134(6):1129-40.

RCT with Vitamin D for Type A Influenza

“Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D(3) group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D(3) compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006).”

Urashima et al., Am J Clin Nutr. 2010 May;91(5):1255-60.

Hospital-Acquired Infections (HAIs)

There are many types of HAIs: Bacteremia, bacterial sepsis, Clostridium difficile,

pneumonia, surgical site infections, catheter-associated urinary tract infections, and virulent organisms such as MRSA.

Many people arrive in hospitals due to diseases related to low serum 25(OH)D concentrations.

Increasing serum 25(OH)D concentrations would reduce risk of HAIs.

Dima A. Youssef, Tamra Ranasinghe, William B. Grant and Alan N. Peiris, Dermato-Endocrinology 2012;4(2):167-175

Dental Caries

Dental caries are caused by oral bacteria.Vitamin D, through induction of cathelicidin,

reduces concentration of oral bacteria.This was first shown in a study of vitamin D2

supplementation in 1928 by May Mellanby.Several recent studies identified cathelicidin as

a way to reduce dental caries. Grant WB. A review of the role of solar ultraviolet-B

irradiance and vitamin D in reducing risk of dental caries. Dermatoendocrinol. 2011;3(3):193-198.

Dental Rank vs. Solar UVB Dose in July

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Cardiovascular Disease

Several recent observational studies found that those with lower serum 25(OH)D had higher risk of cardiovascular disease (coronary heart disease and/or stroke) incidence or mortality rate.

The mechanisms appear to include reducing risk of metabolic disease through effects on insulin sensitivity, blood pressure, and arterial calcification, as well as reducing risk of infectious diseases and inflammation.

Meta-analysis of CVD Incidence Rate vs. 25(OH)D Concentration

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Data from Data from Dobnig, 2008; Dobnig, 2008; Giovannucci, 2008; Giovannucci, 2008; Ginde, 2009; Ginde, 2009; Kilkkinen, 2009Kilkkinen, 2009

Seasonality of CVD

Risk of cardiovascular disease is about 20-25% higher in winter than in summer.

Inflammation is an important risk factor.Infection, such as by influenza virus, increases

inflammation through increasing production of proinflammatory cytokines.

A study in China found cytokines associated with influenza significantly increased among those with acute myocardial infarction. Inflamm Res. 2012 Jun;61(6):591-8

Periodontal Disease (PD)

PD is characterized by tooth attachment loss and bacteria.

PD is associated with systemic diseases such as cardiovascular disease and diabetes.

PD is also associated with adverse pregnancy outcomes such as gestational diabetes, pre-eclampsia, premature delivery, and low birth weight.

Treatment of PD sometimes reduces adverse pregnancy outcomes, sometimes does not.

Periodontal Disease Ramifications

Vitamin D reduces risk of PD by killing bacteria through cathelicidin, reducing inflammation, and reducing concentrations of Matrix metalloproteinases (MMPs).

Thus, periodontal disease can serve as an indication of vitamin D deficiency.

Pregnant women with PD should be advised to take 4000 IU/d vitamin D3 and achieve a serum 25(OH)D concentration of 40 ng/ml.

Hollis BW, et al. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011 Oct;26(10):2341-57.

Erectile Dysfunction

“Erectile dysfunction (ED) is a multifactorial disease, and its causes can be neurogenic, psychogenic, hormonal and vascular. ED is often an important indicator of cardiovascular disease (CVD) and a powerful early marker for asymptomatic CVD.”

“We show here that risk factors associated with a higher CVD risk also associate with a higher ED risk. Such factors include diabetes mellitus, hypertension, arterial calcification and Inflammation in the vascular endothelium.” Sorenson and Grant, Dermato-Endocrinology 2012;4(2)

Diabetes and Erectile Dysfunction

A total of 3,791 CV events were reported in 3 cohort studies and 9 cross-sectional studies (covering 22,586 subjects). Across the cohort studies, the overall odds ratio (OR) of diabetic men with ED versus those without ED was 1.74 (95% confidence interval [CI]: 1.34-2.27; P<0.001) for CV events and 1.72 (95% CI: 1.5-1.98; P<0.001) for coronary heart disease (CHD).

Diabetes and Erectile Dysfunction

In the cross-sectional studies, the OR of diabetic men with ED versus those without ED was 3.39 (95% CI: 2.58-4.44; P<0.001) for CV events (N = 9), 3.43 (95% CI: 2.46-4.77; P<0.001) for CHD (N = 7), and 2.63 (95% CI: 1.41-4.91; P = 0.002) for peripheral vascular disease (N = 5).

Yamada T, et al. PLoS One. 2012;7(9):e43673.

Mortality Rate and Vitamin D

Overall, 12 original studies were included in the review and meta-analysis comprising 32,142 mainly elderly study participants with measured 25(OH)D of whom 6921 died during follow-up. An inverse association between 25(OH)D levels and all-cause mortality was found in all but two studies that was statistically significant in several of the individual studies. In meta-analysis, 25(OH)D levels were significantly inversely associated with all-cause mortality with a pooled HR of 0.92 (95% confidence interval: 0.89-0.95) for a 20 nmol/l increase in 25(OH)D levels.

Schöttker B, Ball D, Gellert C, Brenner H. Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort

studies. Ageing Res Rev. 2012 Feb 16.

U-shaped 25(OH)D Concentration-Health Outcome Relations

There have been a number of reports that U-shaped relations between serum 25(OH)D and health outcomes.

Some of these findings do not show statistically-significant relations.

Some are in disagreement with many other studies of the same outcome.

Some may be due to including people who were recently told by their physician to take vitamin D supplements

Serum 25(OH)D and Frailty

Two studies were reported on frailty status of elderly Americans approximately four years after serum 25(OH)D concentration measurement.

For men, frailty index increased as serum 25(OH)D decreased (Ensrud, 2011).

For women, there was a U-shaped relation (Ensrud, 2010)

My interpretation is that the women were more likely to be told to take vitamin D, but that doing so did not erase adverse effects of previous vitamin D deficiency.

AcneAcute lower respiratory infectionAlzheimer’s diseaseAmyotrophic lateral sclerosisAnaphylaxisAnemiaAnkylosing spondylitisAnxietyAsthmaAthersclerosisAutismBacterial vaginosisBiliary cirrhosis, primary (PBC)Birth defectsBones – fracturesBones - osteopenia

Bones – osteoporosisBones – Paget’s disease? Bones – ricketsBrain injury, traumaticBronchitisCancer – 20 types (Bladder, breast, cervical, colorectal, endometrial, esophageal, gallbladder, gastric, Hodgkin’s lymphoma, leukemia, lung, melanoma, multiple myeloma, non-Hodgkin’s lymphoma, ovarian, pancreatic, prostate, renal, vulvar)Cardiovascular diseaseCeliac diseaseCeliac diseaseCerebrovascular diseaseCerebrovascular diseaseChronic kidney diseaseChronic kidney diseaseChronic liver diseaseChronic liver disease

Chronic, non-specific Chronic, non-specific muscle painmuscle painCognitive impairmentCognitive impairmentCommon coldCommon coldEpstein-Barr virusEpstein-Barr virusCongestive heart failureCongestive heart failureChronic obstructive Chronic obstructive pulmonary diseasepulmonary diseaseCoronary heart diseaseCoronary heart diseaseCraniotabiesCraniotabiesCystic fibrosisCystic fibrosisDental cariesDental cariesDepressionDepressionDiabetes, type 1Diabetes, type 1Diabetes, type 2, Diabetes, type 2, EpilepsyEpilepsy

List of Vitamin D-Sensitive Diseases A-EList of Vitamin D-Sensitive Diseases A-E

Fertility, regular mensesFertility, regular mensesFibromyalgiaFibromyalgiaHashimoto's thyroiditis Hashimoto's thyroiditis (HT)(HT)HeadacheHeadacheHearing lossHearing lossHepatitisHepatitisHIV/AIDSHIV/AIDSHypercalcemiaHypercalcemiaHyperparathyroidismHyperparathyroidismHypertensionHypertensionInflammatory bowel Inflammatory bowel disease disease Influenza, type AInfluenza, type AInsulin resistanceInsulin resistanceIschemic cardiac Ischemic cardiac arrhythmiasarrhythmiasKidney stonesKidney stones

LupusLupusMacular degenerationMacular degenerationMeningitisMeningitisMetabolic diseaseMetabolic diseaseMononucleosisMononucleosisMultiple sclerosisMultiple sclerosisMuscle strengthMuscle strengthOsteoarthritisOsteoarthritisPancreatisPancreatisParkinson’s diseaseParkinson’s diseasePelvic floor statusPelvic floor statusPeriodontal diseasePeriodontal diseasePeripheral artery diseasePeripheral artery diseasePneumoniaPneumoniaPolycystic ovary Polycystic ovary syndromesyndromePost herpetic neuralgia Post herpetic neuralgia PreeclampsiaPreeclampsia

Premature birth and lowPremature birth and lowbirth weightbirth weightPsoriatic arthritisPsoriatic arthritisRenal failureRenal failureRenal osteodystrophyRenal osteodystrophyRheumatoid arthritisRheumatoid arthritisRespiratory syncytial virus Respiratory syncytial virus SchizophreniaSchizophreniaSepsis/septicemiaSepsis/septicemiaSickle cell diseaseSickle cell diseaseSystemic sclerosisSystemic sclerosisTonsillitis Tonsillitis Tuberculosis Tuberculosis ThrombosisThrombosisUterine leiomyomas Uterine leiomyomas (fibroids)(fibroids)Vascular dementiaVascular dementiaVitiligo vulgaris108Vitiligo vulgaris108

List of Vitamin D-Sensitive Diseases F-VList of Vitamin D-Sensitive Diseases F-V

Sources of Vitamin D

Solar UVB, especially near solar noon, with as much skin exposed as possible, not so long as to turn pink or red. Gradual increase in UV in spring/summer leads to tanning and development of a SPF value of 2-4. Solar UVB is the source of 90% of vitamin D for most Americans.

Supplements, 1000-4000 IU/day recommended. Diet, provides 250-300 IU/day in the U.S., Canada

Increase in Serum 25(OH)D from Vitamin D Supplementation

Garland et al.,Garland et al.,Anticancer Anticancer Research,Research,20112011

Testing Serum 25(OH)D is Suggested

Garland et al., Anticancer Research, 2011Garland et al., Anticancer Research, 2011

Conclusion

There is enough evidence now to conclude that serum 25(OH)D concentrations of at least 40 ng/ml, can significantly reduce the burden of breast and many other types of cancer, other chronic and infectious diseases, adverse pregnancy outcomes, and increase healthy and total life expectancy.

Solar UVB irradiance or vitamin D supplements can be used to reach these concentrations.

It could take 1000-5000 IU/day vitamin D3Testing serum 25(OH)D recommended.