Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland) Calcium plus vitamin D supplementation and the risk of colorectal cancer. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/Mineral Supplements and Chronic Disease Prevention The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. Interaction between current vitamin D supplementation and menopausal hormone therapy use on breast cancer risk: evidence from the E3N cohort. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Dietary supplement use and mortality in a cohort of Swedish men. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Vitamin and Mineral Supplements: What Clinicians Need to Know. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Postmenopausal breast cancer risk and interactions between body mass index, menopausal hormone therapy use, and vitamin D supplementation: Evidence from the E3N cohort. Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial The modulation of prostate cancer risk with alpha-tocopherol: a pilot randomized, controlled clinical trial. Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Supplemental and Dietary Vitamin E Intakes and Risk of Prostate Cancer in a Large Prospective Study Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. Antioxidant status and risk of cancer in the SU.VI.MAX study: is the effect of supplementation dependent on baseline levels? Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. A Randomized Controlled Trial for Chemoprevention of Gastric Cancer in High‐risk Japanese Population; Study Design, Feasibility and Protocol Modification Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial Calcium plus vitamin D3 supplementation facilitated Fat loss in overweight and obese college students with very-low calcium consumption: a randomized controlled trial Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements A Combination of Micronutrients Is Beneficial in Reducing the Incidence of Prostate Cancer and Increasing Survival in the Lady Transgenic Model 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. Vitamin D and Calcium Intakes from Food or Supplements and Mammographic Breast Density Changes in vitamin and mineral supplement use after breast cancer diagnosis in the Pathways Study: a prospective cohort study Vitamin E status during dietary fish oil supplementation in rheumatoid arthritis. Serum Antioxidant Nutrients, Vitamin A, and Mortality in U.S. Adults Long-term use of supplemental vitamins and minerals does not reduce the risk of urothelial cell carcinoma of the bladder in the VITamins And Lifestyle study. Vitamin C and E Supplementation Does Not Reduce the Risk of Superimposed PE in Pregnancy The impact of long-term vitamin supplementation on cognitive functioning Evaluation of vitamin E and selenium supplementation for the prevention of bladder cancer in SWOG coordinated SELECT. Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial The effects of vitamin C supplementation on incident and progressive knee osteoarthritis: a longitudinal study. [Preliminary report on the results of nutrition prevention trials of cancer and other common diseases among residents in Linxian, China]. Calcium intake in health maintenance – a systematic review Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. Lung Cancer Chemoprevention: A Randomized, Double-Blind Trial in Linxian, China Serum Vitamin D and Risk of Breast Cancer within Five Years Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women. Vitamin E and the risk of prostate cancer: Updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. The effect of various vitamin D supplementation regimens in breast cancer patients Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study--design, methods, and participant characteristics. SUpplementation en VItamines et Minéraux AntioXydants. Vitamin D status in irritable bowel syndrome and the impact of supplementation on symptoms: what do we know and what do we need to know? Possible immunologic involvement of antioxidants in cancer prevention. The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer. Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Brief Communication: The Prevalence of High Intake of Vitamin E from the Use of Supplements among U.S. Adults "The SU.VI.MAX Study": a primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers. SUpplementation on VItamines et Minéraux AntioXydants. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial Effect of Five-Year Supplementation of Vitamin C on Serum Vitamin C Concentration and Consumption of Vegetables and Fruits in Middle-Aged Japanese: A Randomized Controlled Trial Baseline characteristics of participants in the Women's Health Study. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women’s Health Study Folic Acid-Based Intervention in Non-ST Elevation Acute Coronary Syndromes Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms--the Beyond Ageing Project: a randomized controlled trial. Effects of selenomethionine supplementation on selenium status and thyroid hormone concentrations in healthy adults. Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE)
Summary of the Recommendations The U.S. Preventive Services Task Force ( USPSTF ) concludes that the evidence is insufficient to recommend for or against the use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . This is a grade I recommendation . ( See Appendix Table 1 for a description of the USPSTF classification of recommendations . ) The USPSTF found poor evidence to determine whether supplementation with these vitamins reduces the risk for cardiovascular disease or cancer . ( See Appendix Table 2 for a description of the USPSTF classification of levels of evidence . ) The available evidence from r and omized trials is either inadequate or conflicting , and the influence of confounding variables on observed outcomes in observational studies can not be determined . As a result , the USPSTF could not determine the balance of benefits and harms of routine use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . The USPSTF recommends against the use of beta-carotene supplements , either alone or in combination , for the prevention of cancer or cardiovascular disease . This is a grade D recommendation . The USPSTF found good evidence that -carotene supplementation provides no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older adults . In two trials restricted to heavy smokers , -carotene supplementation was associated with higher incidence of lung cancer and higher all-cause mortality . The USPSTF concludes that -carotene supplements are unlikely to provide important benefits and might cause harm in some groups . Clinical Considerations The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies , including pregnant and lactating women , children , elderly persons , and people with chronic illnesses .  Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins . Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate . With the exception of vitamins for which there is compelling evidence of net harm ( for example , beta-carotene supplementation in smokers ) , there is little reason to discourage people from taking vitamin supplements . Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet . All patients should receive information about the benefits of a diet high in fruits and vegetables , as well as information on other foods and nutrients that should be emphasized or avoided in their diet ( see the 2002 USPSTF recommendations on counseling to promote a healthy diet [ 1 ] ) . Patients who choose to take vitamins  should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes of the Institute of Medicine . Some vitamins , such as A and D , may be harmful in higher doses ; therefore , doses greatly exceeding the Recommended Dietary Allowance or Adequate Intake should be taken with care while considering whether potential harms outweigh potential benefits . Vitamins and minerals sold in the United States are classified as dietary supplements , and there is a degree of quality control over content if they have a U.S. Pharmacopeia seal ( 2 ) . Nevertheless , imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds . The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses . There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods . The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects . In 1996 , the USPSTF recommended folic acid for all women who are planning , or capable of , pregnancy ( see the 1996 USPSTF chapter on screening for neural tube defects [ 3 ] ) . Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications ( for example , folic acid supplementation for patients taking methotrexate ) . Scientific Evidence The USPSTF review s ( 4 - 6 ) focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on primary prevention of cancer and cardiovascular disease . These review s were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases ( 7 - 9 ) . The review s focused on prospect i ve trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease . The value of vitamins naturally occurring in food , the use of vitamin supplements for the prevention of other conditions ( for example , neural tube defects ) , and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these review s. Vitamin A No prospect i ve trials have examined the effect of vitamin A supplements alone on the risk for cancer . Observational studies provide no evidence that such supplements prevent cancer in men . In women , observational studies have reported a statistically significant inverse association between use of vitamin A supplements and risk for colon and breast cancer ( 10 , 11 ) . Despite efforts to adjust for confounding variables , the observational , nonr and om design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements .  No evidence from prospect i ve trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease . One good- quality cohort study found no effect of vitamin A supplementation in reducing cardiovascular disease mortality ( 12 ) . Vitamin C No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported . Observational studies have generally shown no statistically significant associations between use of vitamin C supplements and risk for cancer of the breast , prostate , colon , or lung ( 12 - 14 ) . The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results ( 12 , 15 , 16 ) . Vitamin E Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease . A r and omized , controlled trial ( RCT ) involving Finnish male smokers found that vitamin E supplementation is not protective against lung cancer but may have a beneficial impact on prostate cancer ( 14 ) . Because prostate cancer was not a primary end point of the trial and the trial had other limitations , further evidence is needed to confirm this finding . Observational studies have shown no statistically significant association between use of vitamin E supplements and risk for prostate , lung , or breast cancer ( 5 ) . One study suggested that vitamin E protects against colon cancer , but the influence of confounding variables can not be fully excluded ( 17 ) . Among primary prevention trials , two good- quality trials ( 14 , 18 ) and one fair- quality trial ( 19 ) found no statistically significant benefit of vitamin E supplementation in preventing cardiovascular disease ( 20 ) . Only one of seven trials of vitamin E supplementation for secondary prevention demonstrated a statistically significant reduction in cardiac events ( 4 ) . Some prospect i ve cohort studies have suggested a significant benefit , but the results are mixed and the influence of confounding variables can not be excluded ( 4 ) . -Carotene A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung , prostate , colon , breast , or nonmelanoma skin cancer ( 14 , 21 - 25 ) . -Carotene supplements were associated with an increased risk for lung cancer among smokers , especially heavy smokers , in two RCTs ( 14 , 25 ) . Results from four RCTs demonstrated no reduced risk for cardiovascular events or death after beta-carotene supplementation ( 14 , 21 , 22 , 26 - 28 ) . Antioxidant Vitamin Combinations Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results . A recent RCT reported no statistically significant effect of daily supplementation with a combination of antioxidants : vitamin E , vitamin C , and beta-carotene ( 29 ) . Some studies have suggested an adverse effect of antioxidant combinations on cancer , but the results may have been confounded by the inclusion of beta-carotene ( 5 ) . Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease ( 13 , 30 , 31 ) , but other studies , including well- design ed RCTs , have shown no benefit ( 29 , 32 , 33 ) . One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements  ( 34 ) . Multiple Vitamin Combinations The incremental benefit of taking supplemental doses of folic acid and B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements ( 35 ) . In these analyses , folic acid supplementation was associated with significantly decreased risk for colon cancer , but the protective effect requires confirmation in prospect i ve trials . There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease . Among cohort studies , one good- quality study reported a statistically significant reduction in coronary events ( 36 ) , two good- quality studies reported no statistically significant effect on mortality ( 16 , 37 ) , and one BACKGROUND The General Population Nutrition Intervention Trial was a r and omized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991 , in which 29,584 adult participants in Linxian , China , were given daily vitamin and mineral supplements . Treatment with " factor D , " a combination of 50 microg selenium , 30 mg vitamin E , and 15 mg beta-carotene , led to decreased mortality from all causes , cancer overall , and gastric cancer . Here , we present 10-year follow-up after the end of active intervention . METHODS Participants were assessed by periodic data collection , monthly visits by village health workers , and quarterly review of the Linxian Cancer Registry . Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models . RESULTS Through May 31 , 2001 , 276 participants were lost to follow-up ; 9727 died , including 3242 from cancer ( 1515 from esophageal cancer and 1199 from gastric cancer ) . Participants who received factor D had lower overall mortality ( HR = 0.95 , 95 % CI = 0.91 to 0.99 ; P = .009 ; reduction in cumulative mortality from 33.62 % to 32.19 % ) and gastric cancer mortality ( HR = 0.89 , 95 % CI = 0.79 to 1.00 ; P = .043 ; reduction in cumulative gastric cancer mortality from 4.28 % to 3.84 % ) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years . Esophageal cancer deaths between those who did and did not receive factor D were not different overall ; however , decreased 17 % among participants younger than 55 ( HR = 0.83 , 95 % CI = 0.71 to 0.98 ; P = .025 ) but increased 14 % among those aged 55 years or older ( HR = 1.14 , 95 % CI = 1.00 to 1.30 ; P = .047 ) [ corrected ] . Vitamin A and zinc supplementation was associated with increased total and stroke mortality ; vitamin C and molybdenum supplementation , with decreased stroke mortality . CONCLUSION The beneficial effects of selenium , vitamin E , and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants . Late effects of other supplementation regimens were also observed BACKGROUND Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and beta-carotene might be associated with reduced risk of colorectal cancer . METHODS We tested the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol , Beta-Carotene Cancer Prevention ( ATBC ) Study , a double-blind , placebo-controlled trial among 29,133 50 - 69-year-old male cigarette smokers . Participants were r and omly assigned to receive alpha-tocopherol ( 50 mg ) , beta-carotene ( 20 mg ) , both agents , or a placebo daily for 5 - 8 years . Incident colorectal cancers ( n = 135 ) were identified through the nationwide cancer registry , and 99 % were histologically confirmed . Intervention effects were evaluated using survival analysis and proportional hazards models . RESULTS Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm compared to the no alpha-tocopherol arm , but this finding was not statistically significant ( relative risk ( RR ) = 0.78 , 95 % confidence interval ( CI ) 0.55 - 1.09 ; log-rank test p = 0.15 ) . Beta-carotene had no effect on colorectal cancer incidence ( RR = 1.05 , 95 % CI 0.75 - 1.47 ; log-rank test p = 0.78 ) . There was no interaction between the two substances . CONCLUSION Our study found no evidence of a beneficial or harmful effect for beta-carotene in colorectal cancer in older male smokers , but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect . The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk BACKGROUND Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials . However , r and omized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking . METHODS We conducted a r and omized , double-blind , placebo-controlled trial involving 36,282 postmenopausal women from 40 Women 's Health Initiative centers : 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [ corrected ] twice daily ( 1000 mg of elemental calcium and 400 IU of vitamin D3 ) and 18,106 received a matching placebo for an average of 7.0 years . The incidence of pathologically confirmed colorectal cancer was the design ated secondary outcome . Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study . RESULTS The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo ( 168 and 154 cases ; hazard ratio , 1.08 ; 95 percent confidence interval , 0.86 to 1.34 ; P=0.51 ) , and the tumor characteristics were similar in the two groups . The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups . There were no significant treatment interactions with baseline characteristics . CONCLUSIONS Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer  among postmenopausal women . The long latency associated with the development of colorectal cancer , along with the seven-year duration of the trial , may have contributed to this null finding . Ongoing follow-up will assess the longer-term effect of this intervention . ( Clinical Trials.gov number , NCT00000611 . ) National Institutes of Health ( NIH ) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1 ) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality ( AHRQ ) , 2 ) presentations by investigators working in areas relevant to the conference questions during a 2-day public session , 3 ) questions and statements from conference attendees during open discussion periods that are part of the public session , and 4 ) closed deliberations by the panel during the remainder of the second day and the morning of the third . This statement is an independent report of the panel and is not a policy statement of the NIH or the federal government . The statement reflects the panel 's assessment of medical knowledge available at the time the statement was written . Thus , it provides a snapshot in time of the state of knowledge on the conference topic . When reading the statement , keep in mind that new knowledge is inevitably accumulating through medical research . At least half of American adults take a dietary supplement , the majority of which are multivitamin/multimineral ( MVM ) supplements . As more and more Americans seek strategies for maintaining good health and preventing disease , and as the marketplace offers an increasing number of products to fulfill that desire , it is important that consumers have the best possible information to make their choices . Assessing the available scientific evidence on the benefits of MVM supplement use for chronic disease prevention , identifying the gaps in the evidence , and recommending an appropriate research agenda to meet the shortfalls are subjects considered in this report . The word vitamine was coined in 1912 , as an abbreviated term meant to capture the notion of important factors in the diet , or vital amines . This was preceded more than 150 years earlier by British navy physician James Lind 's discoveryin the first recorded controlled trialthat citrus juice , a good source of what was found 2 centuries later to be vitamin C , could prevent scurvy in sailors . In 1913 , the first vitamin was isolated : thiamin , the deficiency of which caused beriberi . Thirteen vitamins and 15 essential minerals have now been identified as important to human nutrition . Large-scale fortification of diets began in the United States with the addition of iodine to table salt in 1924 to prevent goiter , followed by the addition of vitamin D to milk in 1933 to prevent rickets and the addition of thiamin , riboflavin , niacin , and iron to flour in 1941 . Multivitamin/multimineral products providing more than vitamins A and D became available in pharmacies and grocery stores in the mid-1930s . In the early 1940s , the first MVM tablet was introduced . Although clinical deficiency of vitamins or minerals , other than iron , is now uncommon in the United States , growth in supplement use has accelerated rapidly with marketing spurred by cl aims some based on scientific studies that chronic conditions could be prevented or treated by supplement use . Annual sales of supplements to Americans are now reported at about $ 23 billion , a substantial share of which is spent on vitamins and minerals . Because of such widespread use of MVM , increasing public and medical confusion over apparently contradictory results from studies , and reports of possible adverse effects from overuse in certain circumstances , the Office of Dietary Supplements and the Office of Medical Applications of Research of the NIH convened a State-of-the-Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention , held on 1517 May 2006 , in Bethesda , Maryl and . The goal of the conference was to assess the evidence available on MVM use and outcomes for chronic disease prevention in the generally healthy population of adults and to make recommendations for future research . The conference focused on vitamins and minerals and did not deal with botanicals , hormones , or other supplements . It also did not address the treatment of vitamin or mineral deficiencies . Except for considerations of safety , the conference also did not review issues of primary relevance to pregnant women or children . Specifically , the conference explored the following key questions : 1 ) What are the current patterns and prevalence of the public 's use of MVM supplements ? 2 ) What is known about the dietary nutrient intake of MVM users versus nonusers ? 3 ) What is the efficacy of single vitamin/mineral supplement use in chronic disease prevention ? 4 ) What is the efficacy of MVM  in chronic disease prevention in the general population of adults ? 5 ) What is known about the safety of MVM  for the generally healthy population ? and 6 ) What are the major knowledge gaps and research opportunities regarding MVM use ? During the first 2 days of the conference , experts presented information on each of the key questions . After weighing the scientific evidence , including the data presented by the speakers and a formal evidence report commissioned through AHRQ , an independent panel prepared and presented a draft of this state-of-the-science statement addressing the conference questions . The evidence report prepared for the conference is available at www.ahrq.gov/clinic/tp/multivittp.htm . For the purpose of this statement , the term MVM refers to any supplement containing 3 or more vitamins and minerals but no herbs , hormones , or drugs , with each component at a dose less than the tolerable upper level determined by the Food and Nutrition Boardthe maximum daily intake likely to pose no risk for adverse health effects . Our review also included studies of the relationship of single-nutrient supplements and 2-nutrient supplements to certain disease outcomes . The term primary prevention refers to preventing the development of disease in a person who does not have the disease in question . The chronic conditions assessed include cancer ; age-related sensory loss ; and cardiovascular , endocrine , neurologic , musculoskeletal , gastroenterologic , renal , and pulmonary diseases . A word is warranted about the nature of the evidence base considered by the panel . The range of vitamins and minerals of possible interest was so broad that the conference planning committee chose to focus the evidence report on nutrients for which the potential for impact had been most strongly suggested and on conditions for which supplements were thought to have the most potential influence . The planning committee also limited the scope of the evidence report to consideration of r and omized , controlled trials ( RCTs ) , which are generally considered the gold st and ard for evidence -based decision making . These are studies in which participants are allocated by chance alone to receive or not to receive 1 of 2 or more clinical interventions . For example , while folate supplementation was initially shown to decrease the risk for neural tube defects in animal studies , outcome data in nonhuman models were not considered sufficient evidence on which to base policy recommendations . At the next level of evidence , observational studies in humans suggested efficacy of folate supplementation to prevent such defects . However , these were criticized because they were not r and omized and were potentially subject to bias . Not until these findings were confirmed by RCTs in humans was public policy implemented , including fortification of cereal grains with folate . An observational study is one in which the exposure or treatment of interest is not assigned to the participant by the investigator . Such studies suggested that -carotene intake might protect against the development of some types of cancer . However , RCTs of -carotene supplementation not only showed no benefit , they also found an increased risk for lung cancer in persons who smoked cigarettes or who were exposed to asbestos . These examples illustrate both the risk of relying only on observational studies and the advantage of RCTs in identifying both benefits and risks of MVM supplementation . Limiting the focus of our statement to RCTs has some inherent limitations , given the potential of other types of studies to provide important insights . Observational studies , for example , are particularly useful for generating hypotheses , defining adverse effects , and documenting long-term treatment consequences . They are often essential precursors to the well-conducted RCTs important for policy formation . Our principal recommendations focus on the compelling research activities that must be supported to better inform the decisions that millions of Americans are making each day to use or not to use MVM supplements to prevent chronic disease . At the same time , mindful of the constraints of the available evidence base , we have also taken care not to make premature recommendations about whether generally healthy Americans should or should not take MVM supplements . Because of the need for more reliable information on MVMs , we have made strong recommendations for research and for increased U.S. Food and Drug Administration ( FDA ) oversight of the MVM industry . 1 . What Are the Current Patterns and Prevalence of the Public 's Use of MVM Supplements ? More than half of American adults take dietary supplements in the belief that they will make them feel better , give them greater energy , improve their health , and prevent and treat disease . The use of supplements has been steadily increasing , and growth appears likely to continue . Currently , users spend more than $ 23 billion per year on supplements , and among this supplement-using population , MVM is the major category of supplements , used by about one third of Americans . Uncertainty remains in estimating prevalence of use because of problems defining these products ; increasing complexity in the formulation of supplements , including more non-MVM components and specialized formulas ; and varying frequency of use . It appears that use is higher BACKGROUND Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables , as well as high serum levels of vitamin E ( alpha-tocopherol ) and beta carotene , are associated with a reduced risk of lung cancer .  METHODS We performed a r and omized , double-blind , placebo-controlled primary -prevention trial to determine whether daily supplementation with alpha-tocopherol , beta carotene , or both would reduce the incidence of lung cancer and other cancers .  A total of 29,133 male smokers 50 to 69 years of age from southwestern Finl and were r and omly assigned to one of four regimens : alpha-tocopherol ( 50 mg per day ) alone , beta carotene ( 20 mg per day ) alone , both alpha-tocopherol and beta carotene , or placebo . Follow-up continued for five to eight years . RESULTS Among the 876 new cases of lung cancer diagnosed during the trial , no reduction in incidence was observed among the men who received alpha-tocopherol ( change in incidence as compared with those who did not , -2 percent ; 95 percent confidence interval , -14 to 12 percent ) . Unexpectedly , we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not ( change in incidence , 18 percent ; 95 percent confidence interval , 3 to 36 percent ) . We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer . Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not . Beta carotene had little or no effect on the incidence of cancer other than lung cancer . Alpha-tocopherol had no apparent effect on total mortality , although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not . Total mortality was 8 percent higher ( 95 percent confidence interval , 1 to 16 percent ) among the participants who received beta carotene than among those who did not , primarily because there were more deaths from lung cancer and ischemic heart disease . CONCLUSIONS We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene . In fact , this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects BACKGROUND Experimental studies suggest protective effects of vitamin D on breast carcinogenesis , particularly on estrogen receptor-positive tumors . Epidemiologic data are less conclusive . OBJECTIVE Our objective was to investigate the association between postmenopausal breast cancer risk and current or past vitamin D supplementation overall and according to the use of menopausal hormone therapy ( MHT ) . DESIGN Between 1995 and 2008 , 2482 invasive breast cancer cases were diagnosed among 57,403 postmenopausal women from the E3N prospect i ve cohort during 581,085 person-years .  Vitamin D supplementation was assessed from biennially self-administered question naires sent in 1995 , 2000 , 2002 , and 2005 and from medico-administrative data on drug reimbursements since 2004 . Multivariable HRs for primary invasive breast cancer and 95 % CIs were estimated by using Cox models . RESULTS A decreased postmenopausal breast cancer risk was associated with current ( HR : 0.82 ; 95 % CI : 0.69 , 0.97 ) but not past ( HR : 1.10 ; 95 % CI : 0.92 , 1.31 ) vitamin D supplementation ( P-homogeneity = 0.02 ) . The association with current vitamin D supplementation  differed according to MHT use : ever users ( HR : 0.74 ; 95 % CI : 0.60 , 0.90 ) and never users ( HR : 1.13 ; 95 % CI : 0.89 , 1.56 ) ; P-homogeneity = 0.02 . CONCLUSIONS In this observational study , current vitamin D supplementation , mostly taken daily and combined with calcium , was associated with a decreased postmenopausal breast cancer risk in MHT users . These findings should be confirmed before considering vitamin D supplementation to partly balance the MHT-associated increased breast cancer risk BACKGROUND Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants .  Although a vitamin E-vitamin K interaction was proposed to underlie this effect , it has not been systematic ally investigated in adults with normal baseline coagulation status . OBJECTIVE The objective was to study the effect of 12 wk of supplementation with 1000 IU RRR-alpha-tocopherol/d on biochemical measures of vitamin K status in men and women not taking oral anticoagulants . DESIGN  Vitamin K status , which was assessed with the use of plasma phylloquinone concentrations , the degree of under-gamma-carboxylation of prothrombin ( proteins induced by vitamin K absence-factor II , PIVKA-II ) , and the percentage of undercarboxylated osteocalcin ( ucOC ) , was determined in 38 men and women with rheumatoid arthritis ( study A ) and in 32 healthy men ( study B ) participating in 2 independent , 12-wk r and omized clinical trials of vitamin E supplementation ( 1000 IU/d ) . RESULTS Mean ( + /- SD ) PIVKA-II increased from 1.7 + /- 1.7 to 11.9 + /- 16.1 ng/mL ( P < 0.001 ) in study A and from 1.8 + /- 0.6 to 5.3 + /- 3.9 ng/mL ( P < 0.001 ) in study B in response to 12 wk of vitamin E supplementation . An increase in PIVKA-II is indicative of poor vitamin K status . In contrast , the other measures of vitamin K status ( ie , plasma phylloquinone concentration and percentage of ucOC ) did not change significantly in response to the supplementation . CONCLUSIONS High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy . The clinical significance of these changes warrants further investigation , but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined The use of dietary supplements has increased substantially in most industrialized countries . The aim of this study was to prospect ively examine the association between use of dietary supplements and  all-cause mortality , cancer mortality and CVD mortality in men . We used the population -based prospect i ve cohort of 38 994 men from central Sweden , 45 - 79 years of age , with no cancer or CVD at baseline and who completed a self-administered FFQ including questions on dietary supplement use and life-style factors in 1997 . During average 7.7 years of follow-up , 3403 deaths were ascertained ; among them , 771 due to cancer and 930 due to CVD ( during 5.9 years of follow-up ) . In multivariate adjusted models including all men there was no association observed between use of any dietary supplement or of multivitamins , vitamin C , vitamin E or fish oil specifically and all-cause mortality , cancer or CVD mortality . Among current smokers , regular use of any supplement was associated with statistically significant increased risk of cancer mortality : relative risk ( RR ) 1.46 ( 95 % CI 1.06 , 1.99 ) . Among men reporting an inadequate diet at baseline ( assessed by Recommended Food Score ) , there was a statistically significant inverse association between use of any dietary supplement and CVD mortality ( RR 0.72 ; 95 % CI 0.57 , 0.91 ) , no associations were observed among men with adequate diets . In conclusion , we can not exclude that the use of dietary supplements is harmful for smokers . On the other h and , among men with an insufficient diet , the use of supplements might be beneficial in reducing CVD mortality BACKGROUND A number of vitamins and minerals have been shown to influence carcinogenesis in experimental animals . In humans , epidemiologic evidence suggests that intake of fruits and vegetables may reduce risk of esophageal and other cancers . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian , China , have persistently low intake of multiple nutrients and exhibit one of the world 's highest rates of esophageal/gastric cardia cancer , with an exceptionally high risk of esophageal dysplasia . PURPOSE To determine whether supplementation with multiple vitamins and minerals may reduce esophageal/gastric cardia cancer among persons with esophageal dysplasia , we conducted a 6-year prospect i ve intervention trial in Linxian . METHODS Mortality and cancer incidence were ascertained from May 1985 through May 1991 for 3318 persons with cytologic evidence of esophageal dysplasia who were r and omly assigned to receive , throughout that period , daily supplementation with 14 vitamins and 12 minerals or placebo . Doses were typically two to three times U.S. Recommended Daily Allowances . Compliance was assessed by counting unused pills monthly for all trial participants and by assaying nutrient levels in blood collected from sample s of individuals r and omly selected without replacement every 3 months throughout the trial . Cancers were identified through routine surveillance and by special cytology and endoscopy screenings after 2 1/2 years and 6 years . RESULTS A total of 324 deaths occurred during the 6-year intervention period ; 167 occurred in the control ( placebo ) group and 157 occurred in the  supplement  group . Cancer was the leading cause of death ( 54 % of all deaths ) ; 18 % were due to cerebrovascular diseases and 29 % to other causes . Cumulative esophageal/gastric cardia death rates were 8 % lower ( relative risk [ RR ] = 0.92 ; 95 % confidence interval [ CI ] = 0.67 - 1.28 ) among individuals receiving supplements rather than placebo , a nonsignificant ( P > .10 ) difference . Risk of total mortality was 7 % lower ( RR = 0.93 ; 95 % CI = 0.75 - 1.16 ; P > .10 ) , total cancer 4 % lower ( RR = 0.96 ; 95 % CI = 0.71 - 1.29 ; P > .10 ) , cerebrovascular disease 38 % lower ( RR = 0.62 ; 95 % CI = 0.37 - 1.06 ; P = .08 ) , and other diseases 12 % higher ( RR = 1.12 ; 95 % CI = 0.74 - 1.69 ; P > .10 ) among the treated group . Cumulative cancer incidence rates were nearly the same in the two groups . CONCLUSIONS No substantial short-term beneficial effect on incidence or mortality for this type of cancer occurred following daily supplementation with multiple vitamins and minerals among adults with precancerous lesions of the esophagus . IMPLICATION S Although no statistically significant short-term benefits were observed , longer follow-up should be more informative about the effectiveness of this 6-year supplementation on cancer and other diseases among individuals with esophageal dysplasia Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease ( CVD ) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention . The VITamin D and Omega-A 3 TriaL ( VITAL ) is an ongoing nationwide , r and omized , double-blind , placebo-controlled clinical trial design ed to fill this knowledge gap . The study population consists of 25,874 U.S. adults without cancer or CVD at baseline , who were selected only on age ( men aged ≥50 and women aged ≥55 ) , with an oversampling of African Americans ( n=5,107 ) . In a 2 × 2 factorial design , participants were r and omized to one of four supplement groups : [ 1 ] active vitamin D3 ( cholecalciferol ; 2000 IU/d ) and active marine omega-3 fatty acids ( Omacor ® fish oil , eicosapentaenoic acid [ EPA ] and docosahexaenoic acid [ DHA ] , 1g/d ) ; [ 2 ] active vitamin D and omega-3 placebo ; [ 3 ] vitamin D placebo and active marine omega-3 fatty acids ; or [ 4 ] vitamin D placebo and omega-3 placebo . The mean length of the r and omized treatment period will be 5 years . The r and omization was successful , as evidence d by similar distributions of baseline demographic , health , and behavioral characteristics across treatment groups . The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed . VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD Dietary supplementation is approximately a $ 30 billion industry in the United States , with more than 90 000 products on the market . In recent national surveys , 52 % of US adults reported use of at least 1 supplement product , and 10%reporteduseofatleast4suchproducts.1 Vitamins and minerals are among the most popular supplements and are taken by 48 % and 39 % of adults , respectively , typically to maintain health and prevent disease . Despite this enthusiasm , most r and omized clinical trials of vitamin and mineral supplements have not demonstrated clear benefits for primary or secondary prevention of chronic diseases not related to nutritional deficiency . Indeed , some trials suggest that micronutrient supplementation in amounts that exceed the recommended dietary allowance (RDA)—eg , high doses of beta carotene , folic acid , vitamin E , or selenium — may have harmful effects , including increased mortality , cancer , and hemorrhagic stroke.2 In this Viewpoint , we provide information to help clinicians address frequently asked questions about micronutrient supplements from patients , as well as promote appropriate use and curb inappropriate use of such supplements among generally healthy individuals . Importantly , clinicians should counsel their patients that such supplementation is not a substitute for a healthful and balanced diet and , in most cases , provides little if any benefit beyond that conferred by such a diet . Clinicians should also highlight the many advantages of obtaining vitamins and minerals from food instead of from supplements . Micronutrients in food are typically better absorbed by the body and are associated with fewer potential adverse effects.2,3 A healthful diet provides an array of nutritionally important substances in biologically optimal ratios as opposed to isolated compounds in highly concentrated form . Indeed , research shows that positive health outcomes are more strongly related to dietary patterns and specific food types than to individual micronutrient or nutrient intakes.3 Although routine micronutrient supplementation is not recommended for the general population , targeted supplementation may be warranted in high-risk groups for whom nutritional requirements may not be met through diet alone , including people at certain life stages and those with specific risk factors ( discussed in the next 3 sections and in the Box ) RATIONALE Lung cancer is the leading cause of cancer-related mortality in the United States . Although supplements are used by half the population , limited information is available about their specific effect on lung cancer risk . OBJECTIVES To explore the association of supplemental multivitamins , vitamin C , vitamin E , and folate with incident lung cancer . METHODS Prospect i ve cohort of 77,721 men and women aged 50 - 76 years from Washington State in the VITAL ( VITamins And Lifestyle ) study . Cases were identified through the Seattle-Puget Sound SEER ( Surveillance , Epidemiology , and End Results ) cancer registry . MEASUREMENTS AND MAIN RESULTS Hazard ratios ( HRs ) for incident lung cancer according to 10-year average daily use of supplemental multivitamins , vitamin C , vitamin E , and folate . A total of 521 cases of lung cancer were identified . Adjusting for smoking , age , and sex , there was no inverse association with any supplement . Supplemental vitamin E was associated with a small increased risk of lung cancer ( HR , 1.05 for every 100-mg/d increase in dose ; 95 % confidence interval [ CI ] , 1.00 - 1.09 ; P = 0.033 ) . This risk of supplemental vitamin E was largely confined to current smokers ( HR , 1.11 for every 100-mg/d increase ; 95 % CI , 1.03 - 1.19 ; P < 0.01 ) and was greatest for non-small cell lung cancer ( HR , 1.07 for every 100-mg/d increase ; 95 % CI , 1.02 - 1.12 ; P = 0.004 ) . CONCLUSIONS Supplemental multivitamins , vitamin C , vitamin E , and folate were not associated with a decreased risk of lung cancer .  Supplemental vitamin E was associated with a small increased risk . Patients should be counseled against using these supplements to prevent lung cancer BACKGROUND To advance knowledge about the cancer-chemopreventive potential of individual nutrients , we investigated the effects of B vitamin and /or ω-3 fatty acid supplements on cancer outcomes among survivors of cardiovascular disease . METHODS This was an ancillary study of the Supplementation With Folate , Vitamins B(6 ) and B(12 ) and /or Omega-3 Fatty Acids ( SU.FOL.OM3 ) secondary prevention trial ( 2003 - 2009 ) . In all , 2501 individuals aged 45 to 80 years were r and omized in a 2 × 2 factorial design to one of the following 4 daily supplementation groups : ( 1 ) 5-methyltetrahydrofolate ( 0.56 mg ) , pyridoxine hydrochloride ( vitamin B(6 ) ; 3 mg ) and cyanocobalamin ( vitamin B(12 ) ; 0.02 mg ) ; ( 2 ) eicosapentaenoic and docosahexaenoic acid ( 600 mg ) in a 2:1 ratio ; ( 3 ) B vitamins and ω-3 fatty acids ; or ( 4 ) placebo .  Overall and sex-specific hazard ratios ( HRs ) and 95 % CIs regarding the cancer outcomes were estimated with Cox proportional hazards models . RESULTS After 5 years of supplementation , incident cancer was vali date d in 7.0 % of the sample ( 145 events in men and 29 in women ) , and death from cancer occurred in 2.3 % of the sample . There was no association between cancer outcomes and supplementation with B vitamins ( HR , 1.15 [ 95 % CI , 0.85 - 1.55 ] ) and /or ω-3 fatty acids ( HR , 1.17 [ 95 % CI , 0.87 - 1.58 ] ) . There was a statistically significant interaction of treatment by sex , with no effect of treatment on cancer risk among men and increased cancer risk among women for ω-3 fatty acid supplementation ( HR , 3.02 [ 95 % CI , 1.33 - 6.89 ] ) . CONCLUSION We found no beneficial effects of supplementation with relatively low doses of B vitamins and /or ω-3 fatty acids on cancer outcomes in individuals with prior cardiovascular disease . Trial Registration is rct n.org Identifier : IS RCT N41926726 Introduction Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures . A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects . Purpose and Methods Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have review ed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases , providing recommendations and guidelines for future studies in this field . Results and conclusions Robust mechanistic evidence is available from in vitro studies and in vivo animal studies , usually employing cholecalciferol , calcidiol or calcitriol in pharmacologic rather than physiologic doses . Although many cross-sectional and prospect i ve association studies in humans have shown that low 25-hydroxyvitamin D levels ( i.e. , < 50 nmol/L ) are consistently associated with chronic diseases , further strengthened by a dose-response relationship , several meta-analyses of clinical trials have shown contradictory results . Overall , large r and omized controlled trials with sufficient doses of vitamin D are missing , and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels  > 50 nmol/L , did not simultaneously assess multiple outcomes , and did not report overall safety ( e.g. , falls ) . Thus , no recommendations can be made to date for the use of vitamin D supplementation in general , parental compounds , or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases . Moreover , attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health can not be recommended based on current evidence , since safety has yet to be confirmed . Finally , the promising findings from mechanistic studies , large cohort studies , and small clinical trials obtained for autoimmune diseases ( including type 1 diabetes , multiple sclerosis , and systemic lupus erythematosus ) , cardiovascular disorders , and overall reduction in mortality require further confirmation The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind , placebo-controlled , r and omized trial , in which 12,741 French adults ( 7,713 women aged 35 - 60 years and 5,028 men aged 45 - 60 years ) received a combination of ascorbic acid ( 120 mg ) , vitamin E ( 30 mg ) , beta-carotene ( 6 mg ) , selenium ( 100 microg ) and zinc ( 20 mg ) , or placebo daily for a median follow-up time of 7.5 years [ October 1994 to September 2002 ] . Antioxidant supplementation decreased total cancer incidence and total mortality in men . Postintervention follow-up assessment of total cancer incidence , ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [ September 1 , 2002 , to September 1 , 2007 ] . No late effect of antioxidant supplementation  was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women . Regarding duration of intervention effects in men , the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up . During the postsupplementation period , the relative risk ( RR ) for total cancer incidence ( n = 126 ) was 0.98 ( 95 % confidence interval [ CI ] , 0.75 - 1.27 ) among antioxidant recipients compared to nonrecipients . For total mortality ( n = 90 ) , the RR was 0.98 ( 95 % CI , 0.75 - 1.26 ) for men receiving antioxidants compared to nonrecipients . In conclusion , beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up The Alpha-Tocopherol Beta-Carotene ( ATBC ) Cancer Prevention Study was a placebo-controlled , r and omized intervention trial testing the hypothesis that beta-carotene and alpha-tocopherol ( vitamin E ) supplements prevent lung and other cancers . The study is predicated on a substantial body of evidence supporting a role in cancer prevention for these micronutrients . Based on the 2 x 2 factorial study design , 29,133 eligible male cigarette smokers aged 50 - 69 y were r and omly assigned to receive beta-carotene ( 20 mg ) , alpha-tocopherol ( 50 mg ) , beta-carotene and alpha-tocopherol , or placebo daily for 5 - 8 y. Capsule compliance was high ( median = 99 % ) . beta-Carotene treatment did not result in a decrease in cancer at any of the major sites but rather in an increase at several sites , most notably lung , prostate , and stomach ( number of cases 474 compared with 402 , 138 compared with 112 , and 70 compared with 56 , respectively ) . The vitamin E group had fewer incident cancers of the prostate and colorectum compared with the group not receiving vitamin E ( number of cases 99 compared with 151 and 68 compared with 81 , respectively ) , but more cancers of the stomach ( 70 compared with 56 ) . In contrast to these intervention-based findings for beta-carotene and vitamin E supplements , we observed lower lung cancer rates in men with higher amounts of both serum and dietary beta-carotene and vitamin E at baseline Experimental studies suggest protective effects of vitamin D on breast carcinogenesis , but epidemiological evidence is not conclusive . Body mass index ( BMI ) has been shown to modulate the effect of supplementation on the vitamin D status , but its potential influence on the relationship with breast cancer risk has been little studied . We investigated a potential interaction between BMI and vitamin D supplementation  on breast cancer risk while considering an already reported interaction between vitamin D supplementation and menopausal hormone therapy ( MHT ) use . Vitamin D supplementation was prospect ively investigated in 57,403 postmenopausal women from the French E3N cohort including 2,482 incident breast cancer cases diagnosed between 1995 and 2008 .  Multivariable hazard ratios ( HR ) for primary invasive breast cancer and 95 % confidence intervals ( CI ) were estimated using Cox models . Among MHT ever users , vitamin D supplementation was associated with decreased breast cancer risk , similarly across BMI strata ( Phomogeneity = 0.83 ) . Among MHT never users , ever vitamin D supplementation was associated with increased postmenopausal breast cancer risk in women with baseline BMI < 25 kg/m(2 ) ( HR = 1.51 , 95 % CI : 1.13 , 2.02 ) , but not in women with higher BMI ( 0.98 , 95 % CI : 0.62 , 1.56 ) , Phomogeneity = 0.12 . In conclusion , our findings suggest that vitamin D supplementation may reduce the excess breast cancer risk in MHT users , but draw attention on a potential risk in postmenopausal women not exposed to high exogenous or endogenous hormones , i.e. non-overweight MHT-non users , especially in the present context of increasing vitamin D supplement use and decreasing MHT use Objective Vitamin E and selenium are promising nutrients for the prevention of prostate cancer , and both are currently being tested in a large r and omized trial for prostate cancer . However , results are not expected for at least 6 years . We aim ed to investigate the association of vitamin E and selenium supplementation with prostate cancer in the VITamins And Lifestyle ( VITAL ) study , a cohort study specifically design ed to examine supplement use and future cancer risk . Methods In a prospect i ve design , 35,242 men recruited between 2000 and 2002 from western Washington State completed a question naire , including detailed questions about vitamin E and selenium supplement intake during the past 10 years from br and -specific multivitamins and single supplements . Using linkage to the western Washington SEER cancer registry , we documented 830 new cases of prostate cancer from baseline through December 2004 . Results A 10-year average intake of supplemental vitamin E was not associated with a reduced prostate cancer risk overall [ hazard ratio ( HR ) 0.86 , 95 % confidence interval ( CI ) 0.65–1.1 for ≥400 IU/day vs. non-use , p for trend 0.36 ] ; however , risk for advanced prostate cancer ( regionally invasive or distant metastatic , n = 123 ) decreased significantly with greater intake of supplemental vitamin E ( HR 0.43 , 95 % CI 0.19–1.0 for 10-year average intake ≥400 IU/day vs. non-use , p for trend 0.03 ) . There was no association  between selenium supplementation and prostate cancer risk ( HR 0.90 , 95 % CI 0.62–1.3 for 10-year average intake > 50 μg/day vs. non-use , p for trend 0.97 ) . Conclusions In this prospect i ve cohort , long-term supplemental intake of vitamin E and selenium were not associated with prostate cancer risk overall ; however , risk of clinical ly relevant advanced disease was reduced with greater long-term vitamin E supplementation BACKGROUND Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers , including cancers of the esophagus and stomach . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian County , China , have one of the world 's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients . PURPOSE We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian . METHODS Individuals of ages 40 - 69 were recruited in 1985 from four Linxian communes . Mortality and cancer incidence  during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period . The subjects were r and omly assigned to intervention groups according to a one-half replicate of a 2(4 ) factorial experimental design . This design enabled testing for the effects of four combinations of nutrients : ( A ) retinol and zinc ; ( B ) riboflavin and niacin ; ( C ) vitamin C and molybdenum ; and ( D ) beta carotene , vitamin E , and selenium . Doses ranged from one to two times U.S. Recommended Daily Allowances . RESULTS A total of 2127 deaths occurred among trial participants during the intervention period .  Cancer was the leading cause of death , with 32 % of all deaths due to esophageal or stomach cancer , followed by cerebrovascular disease ( 25 % ) . Significantly ( P = .03 ) lower total mortality ( relative risk [ RR ] = 0.91 ; 95 % confidence interval [ CI ] = 0.84 - 0.99 ) occurred among those receiving supplementation with beta carotene , vitamin E , and selenium . The reduction was mainly due to lower cancer rates ( RR = 0.87 ; 95 % CI = 0.75 - 1.00 ) , especially stomach cancer ( RR = 0.79 ; 95 % CI = 0.64 - 0.99 ) , with the reduced risk beginning to arise about 1 - 2 years after the start of supplementation with these vitamins and minerals . No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc , riboflavin and niacin , or vitamin C and molybdenum . Patterns of cancer incidence , on the basis of 1298 cases , generally resembled those for cancer mortality . CONCLUSIONS The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults , particularly with the combination of beta carotene , vitamin E , and selenium , may effect a reduction in cancer risk in this population . IMPLICATION S The results on their own are not definitive , but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements BACKGROUND It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer . To date , however , the published results of r and omized , placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect . We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population . METHODS The Supplementation en Vitamines et Mineraux Antioxydants ( SU.VI.MAX ) study is a r and omized , double-blind , placebo-controlled primary prevention trial . A total of 13 017 French adults ( 7876 women aged 35 - 60 years and 5141 men aged 45 - 60 years ) were included . All participants took a single daily capsule of a combination of 120 mg of ascorbic acid , 30 mg of vitamin E , 6 mg of beta carotene , 100 mug of selenium , and 20 mg of zinc , or a placebo . Median follow-up time was 7.5 years . RESULTS No major differences were detected between the groups in total cancer incidence ( 267 [ 4.1 % ] for the study group vs 295 [ 4.5 % ] for the placebo group ) , ischemic cardiovascular disease incidence ( 134 [ 2.1 % ] vs 137[2.1 % ] ) , or all-cause mortality ( 76 [ 1.2 % ] vs 98 [ 1.5 % ] ) . However , a significant interaction between sex and group effects on cancer incidence was found ( P = .004 ) . Sex-stratified analysis showed a protective effect of antioxidants in men ( relative risk , 0.69 [ 95 % confidence interval [ CI ] , 0.53 - 0.91 ] ) but not in women ( relative risk , 1.04 [ 95 % CI , 0.85 - 1.29 ] ) . A similar trend was observed for all-cause mortality ( relative risk , 0.63 [ 95 % CI , 0.42 - 0.93 ] in men vs 1.03 [ 95 % CI , 0.64 - 1.63 ] in women ; P = .11 for interaction ) . CONCLUSIONS After 7.5 years , low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women . Supplementation may be effective in men only because of their lower baseline status of certain antioxidants , especially of beta carotene Background Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women , but the long-term benefits and potential harms are unknown . This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss , bone turnover , and fractures . Methods and Findings This single-center study was design ed as a 2-y r and omized , placebo-controlled , double-blind trial , extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures . A total of 440 postmenopausal women with osteopenia were r and omized to either 5 mg of vitamin K1 or placebo daily . Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points , bone turnover markers , height , fractures , adverse effects , and health-related quality of life . This study has a power of 90 % to detect 3 % differences in BMD between the two groups . The women in this study were vitamin D replete , with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline . Over 2 y , BMD decreased by −1.28 % and −1.22 % ( p = 0.84 ) ( difference of −0.06 % ; 95 % confidence interval [ CI ] −0.67 % to 0.54 % ) at the lumbar spine and −0.69 % and −0.88 % ( p = 0.51 ) ( difference of 0.19 % ; 95 % CI −0.37 % to 0.75 % ) at the total hip in the vitamin K and placebo groups , respectively . There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period . Daily vitamin K1 supplementation  increased serum vitamin K1 levels by 10-fold , and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels ( bone formation marker ) . However , C-telopeptide levels ( bone resorption marker ) were not significantly different between the two groups . Fewer women in the vitamin K group had clinical fractures ( nine versus 20 , p = 0.04 ) and fewer had cancers ( three versus 12 , p = 0.02 ) . Vitamin K supplements  were well-tolerated over the 4-y period . There were no significant differences in adverse effects or health-related quality of life between the two groups . The study was not powered to examine fractures or cancers , and their numbers were small . Conclusions Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD , but may protect against fractures and cancers in postmenopausal women with osteopenia . More studies are needed to further examine the effect of vitamin K on fractures and cancers . Trial registration : Clinical Trials.gov ( # NCT00150969 ) and Current Controlled Trials ( # IS RCT N61708241 PURPOSE Studies suggest that vitamin E may decrease the risk of  prostate cancer .  The Prevention Research Veteran Affairs E-vitamin Nutrition Trial is a r and omized , double-blind , placebo controlled study design ed to assess the effects of vitamin E supplementation on biomarkers associated with prostate cancer risk in peripheral blood and prostate tissue . MATERIAL S AND METHODS A total of 44 patients with increased prostate specific antigen ( PSA ) and /or abnormal digital rectal examination on initial evaluation were r and omized to receive 400 IU vitamin E ( 22 ) vs placebo ( 22 ) . Serum vitamin E , PSA , dehydroepi and rosterone , testosterone and insulin-like growth factor-1 ( IGF-1 ) were measured in the 2 groups at baseline and then at 3-month intervals . Results are reported in 28 patients  ( placebo in 14 and vitamin E in 14 ) who completed the treatment as specified by the protocol . RESULTS Serum Vitamin E was significantly higher in patients on  vitamin E supplementation . alpha-Tocopherol supplementation did not affect the levels of PSA , serum and rogens ( testosterone and dehydroepi and rosterone ) or ( IGF-1 ) . CONCLUSIONS Serum alpha-tocopherol is increased by oral supplementation of vitamin E. We found that alpha-tocopherol supplementation has no effect on serum and rogens , IGF-1 or PSA . The lack of an effect of vitamin supplementation on PSA avoids any bias in the diagnosis of prostate cancer in  vitamin E treated patients . Our results suggest that a decrease in prostate cancer risk with alpha-tocopherol is likely to occur through a mechanism that is nonhormonal and independent of IGF-1 BACKGROUND Some evidence suggests that vitamin D may reduce  breast cancer risk . Despite the biological interaction between vitamin D and calcium , few studies have evaluated their joint effects on breast cancer risk . OBJECTIVE The objective was to evaluate the associations and potential interaction between vitamin D and calcium ( from food and supplements ) and breast cancer risk in a population -based case-control study . DESIGN Breast cancer cases aged 25 - 74 y ( diagnosed 2002 - 2003 ) were identified through the Ontario Cancer Registry . Controls were identified by using r and om digit dialing ; 3101 cases and 3471 controls completed epidemiologic and food-frequency question naires . Adjusted odds ratios ( ORs ) and 95 % CIs were estimated by using multivariate logistic regression . RESULTS Vitamin D and calcium intakes from food only and total combined intakes ( food and supplements ) were not associated with breast cancer risk , although the mean intake of vitamin D was low . Vitamin D supplement intake > 10 microg/d ( 400 IU/d ) compared with no intake was associated with a reduced risk of breast cancer ( adjusted OR : 0.76 ; 95 % CI : 0.59 , 0.98 ) . No categories of calcium supplement intake were significantly associated with reduced breast cancer risk , but a significant inverse trend was observed ( P = 0.04 ) . There were no significant interactions involving vitamin D , calcium , or menopausal status . CONCLUSIONS No associations were found between overall vitamin D or calcium intake and breast cancer risk .  Vitamin D from supplements was independently associated with reduced breast cancer risk . Further research is needed to investigate the effects of higher doses of vitamin D and calcium supplements Supplemental vitamin E ( α-tocopherol ) has been linked to lower prostate cancer incidence in one r and omized trial and several , although not all , observational studies . The evidence regarding dietary intake of individual vitamin E isoforms and prostate cancer is limited and inconclusive , however . We prospect ively examined the relations of supplemental vitamin E and dietary intakes of α- , β- , γ- , and δ- tocopherols to prostate cancer risk among 295,344 men , ages 50 to 71 years and cancer-free at enrollment in 1995 to 1996 , in the NIH-AARP Diet and Health Study . At baseline , participants completed a question naire that captured information on diet , supplement use , and other factors . Proportional hazards models were used to estimate relative risks ( RR ) and 95 % confidence intervals ( 95 % CI ) of prostate cancer . During 5 years of follow-up , 10,241 incident prostate cancers were identified . Supplemental vitamin E intake was not related to prostate cancer risk ( for > 0 - 99 , 100 - 199 , 200 - 399 , 400 - 799 , and ≥800 IU/d versus never use : RR , 0.97 , 0.89 , 1.03 , 0.99 , and 0.97 ( 95 % CI , 0.87 - 1.07 ) respectively ; Ptrend = 0.90 ) . However , dietary γ-tocopherol , the most commonly consumed form of vitamin E in the United States , was significantly inversely related to the risk of advanced prostate cancer ( for highest versus lowest quintile : RR , 0.68 ; 95 % CI , 0.56 - 0.84 ; Ptrend = 0.001 ) . These results suggest that supplemental vitamin E does not protect against prostate cancer , but that increased consumption of γ-tocopherol from foods is associated with a reduced risk of clinical ly relevant disease . The potential benefit of γ-tocopherol for prostate cancer prevention deserves further attention . ( Cancer Epidemiol Biomarkers Prev 2007;16(6):1128–35 CONTEXT Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer , and vitamins E and C are among the most common individual supplements . A large-scale r and omized trial suggested that vitamin E may reduce risk of prostate cancer ; however , few trials have been powered to address this relationship . No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer . OBJECTIVE To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men . DESIGN , SETTING , AND PARTICIPANTS The Physicians ' Health Study II is a r and omized , double-blind , placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31 , 2007 . A total of 14,641 male physicians in the United States initially aged 50 years or older , including 1307 men with a history of prior cancer at r and omization , were enrolled . INTERVENTION Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily . MAIN OUTCOME MEASURES Prostate and total cancer . RESULTS During a mean follow-up of 8.0 years , there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers . Compared with placebo , vitamin E had no effect on the incidence of prostate cancer ( active and placebo vitamin E groups , 9.1 and 9.5 events per 1000 person-years ; hazard ratio [ HR ] , 0.97 ; 95 % confidence interval [ CI ] , 0.85 - 1.09 ; P = .58 ) or total cancer ( active and placebo vitamin E groups , 17.8 and 17.3 cases per 1000 person-years ; HR , 1.04 ; 95 % CI , 0.95 - 1.13 ; P = .41 ) . There was also no significant effect of vitamin C on total cancer ( active and placebo vitamin C groups , 17.6 and 17.5 events per 1000 person-years ; HR , 1.01 ; 95 % CI , 0.92 - 1.10 ; P = .86 ) or prostate cancer ( active and placebo vitamin C groups , 9.4 and 9.2 cases per 1000 person-years ; HR , 1.02 ; 95 % CI , 0.90 - 1.15 ; P = .80 ) . Neither vitamin E nor vitamin C had a significant effect on colorectal , lung , or other site-specific cancers . Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results . Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk . CONCLUSIONS In this large , long-term trial of male physicians , neither vitamin E nor C supplementation reduced the risk of prostate or total cancer . These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00270647 The SUpplementation en VItamines et Mineraux AntioXydants ( SU.VI.MAX ) study , a r and omised double-blind , primary -prevention trial showed that after 7.5 years , low-dose antioxidant supplementation lowered the total cancer incidence in men , but not in women . To explain this difference in the impact of antioxidant supplementation in men and women , we hypothesised that the effect of supplementation is dependent on initial antioxidant status ; 12 741 French adults ( 7713 females aged 35 - -60 years ; 5028 males aged 45 - -60 years ) received daily antioxidant supplementation ( 120 mg vitamin C , 30 mg vitamin E , 6 mg beta-carotene , 100 microg Se , 20 mg Zn daily ) or a matching placebo . Cut-off limits for baseline serum concentrations of the different antioxidant vitamins and minerals were defined as follows for both men and women : 0.3 micromol/l for beta-carotene , 11.4 micromol/l for vitamin C , 15 micromol/l for vitamin E , 0.75 micromol/l for Se and 10.7 micromol/l for Zn . The percentage of men with serum concentrations under cut-off limits was higher for vitamins C and E and beta-carotene in those who developed a cancer than in those who did not . The risk of cancer was higher in men with baseline concentrations of serum vitamin C or vitamin E under cut-off limits , but not in women . The effect of supplementation  was greater in men with baseline serum concentrations of vitamin C , vitamin E and beta-carotene below the cut-off limits compared with those above it . This effect was maintained only for vitamin E after adjustment for age , tobacco , and alcohol consumption and BMI . No effect of  supplementation  could be seen in women . Baseline antioxidant status is related to the risk of cancer in men but not in women and therefore does not entirely explain the differences observed in the effect of antioxidant supplementation  on cancer risk between sexes in the SU.VI.MAX study BACKGROUND Frequent use of personal , non protocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D ( CaD ) on cardiovascular risk in the Women 's Health Initiative ( WHI ) . OBJECTIVE We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study ( WHI CaD ) by using the WHI limited-access clinical trials data set . DESIGN The WHI CaD was a 7-y , r and omized , placebo-controlled trial of CaD ( 1 g Ca/400 IU vitamin D daily ) in 36,282 community-dwelling , postmenopausal women . The incidence of total cancer ( excluding nonmelanoma skin cancers ) , breast and colorectal cancers , hip and total fracture , and mortality was assessed by using Cox proportional hazards models . RESULTS In the WHI CaD , interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total , breast , and colorectal cancers but not for fracture or mortality .  In 15,646 women ( 43 % ) who were not taking personal calcium or vitamin D supplements at r and omization , CaD significantly decreased the risk of total , breast , and invasive breast cancers by 14 - 20 % and nonsignificantly reduced the risk of colorectal cancer by 17 % . In women taking personal calcium or vitamin D supplements , CaD did not alter cancer risk ( HR : 1.06 - 1.26 ) . CONCLUSIONS For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at r and omization , CaD decreased the risk of total , breast , and colorectal cancers and did not change the risk of fractures or total mortality . The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements . The WHI CaD trial is registered at clinical trials.gov as NCT00000611 BACKGROUND R and omized trials have yielded mixed results on the effects of treatment for Helicobacter pylori and little information on the effects of vitamins or garlic supplements on precancerous gastric lesions . We conducted a r and omized trial to test the effects of one-time H. pylori treatment and long-term vitamin or garlic supplements in reducing the prevalence of  advanced precancerous gastric lesions . METHODS Most of the adults aged 35 - 64 years in 13 r and omly selected villages in Linqu County , Sh and ong Province , China , were identified and given baseline endoscopies in 1994 . In 1995 , 3365 eligible subjects were r and omly assigned in a factorial design to three interventions or placebos : amoxicillin and omeprazole for 2 weeks in 1995 ( H. pylori treatment ) ; vitamin C , vitamin E , and selenium for 7.3 years ( vitamin supplement ) ; and aged garlic extract and steam-distilled garlic oil for 7.3 years ( garlic supplement ) . Subjects underwent endoscopies with biopsies in 1999 and 2003 , and the prevalence of precancerous gastric lesions was determined by histopathologic examination of seven st and ard biopsy sites . The 3365 eligible r and omized subjects represented 93.5 % of those with baseline endoscopy and included all baseline histologic categories except gastric cancer . Only 0.18 % had normal gastric mucosa . Logistic regression was used to estimate the intervention effects on the odds of advanced precancerous gastric lesions , and t-tests were used to assess effects on histologic severity . All statistical tests were two-sided . RESULTS H. pylori treatment result ed in statistically significant decreases in the combined prevalence of severe chronic atrophic gastritis , intestinal metaplasia , dysplasia , or gastric cancer in 1999 ( odds ratio [ OR ] = 0.77 ; 95 % confidence interval [ CI ] = 0.62 to 0.95 ) and in 2003 ( OR = 0.60 ; 95 % CI = 0.47 to 0.75 ) , and had favorable effects on the average histopathologic severity and on progression and regression of precancerous gastric lesions in 2003 . H. pylori treatment did not reduce the combined prevalence of dysplasia or gastric cancer . However , fewer subjects receiving H. pylori treatment ( 19/1130 ; 1.7 % ) than receiving placebo ( 27/1128 ; 2.4 % ) developed gastric cancer ( adjusted P = .14 ) . No statistically significant favorable effects were seen for garlic or vitamin supplements . CONCLUSION H. pylori treatment reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence , but further data are needed to prove the latter point . Long-term vitamin or garlic supplementation had no beneficial effects on the prevalence of precancerous gastric lesions or on gastric cancer incidence Osteoporosis is a major public health issue leading to significant morbidity , loss of independence and excess loss of life . It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis ( 1 , 2 ) . This is associated with almost 1.5 million fractures annually , including 300,000 hip fractures ( 2 , 3 ) . A review of the evidence by Cumming in 1990 ( 4 ) and subsequently published r and omized clinical trials have shown that calcium and /or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women ( 5–9 ) . However , there are a limited number of calcium and /or vitamin D trials ( 10–13 ) and observational studies [ review of evidence by Cumming and Nevitt ( 14 ) and Kanis ( 15 ) ] , to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures . It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence ( 16–21 ) . To address these major health concerns of postmenopausal women , the Calcium-Vitamin D ( CaD ) trial of the Women ’s Health Initiative ( WHI ) was design ed to test the primary hypothesis that women who are r and omized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily , a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo . The objective of this paper is A clinical trial of vitamin E and beta-carotene supplementation for lung cancer prevention among male smokers in Finl and recently reported an unexpected , strong protective effect of vitamin E against prostate cancer incidence and mortality . Our objective was to prospect ively examine supplemental vitamin E intake and prostate cancer risk in a distinct U.S. population . In 1986 , we identified 47,780 U.S. male health professionals , free from diagnosed cancer , who completed a dietary and lifestyle question naire ; supplemental vitamin E and prostate cancer incidence were up date d biennially through 1996 . We estimated relative risks ( RRs ) from multivariate pooled logistic regression models . There were 1896 total ( non-stage A1 ) , 522 extraprostatic , and 232 metastatic or fatal incident prostate cancer cases diagnosed between 1986 - 1996 . Men consuming at least 100 IU of supplemental vitamin E daily had multivariate RRs of 1.07 ( 95 % confidence interval [ CI ] , 0.95 - 1.20 ) for total and 1.14 ( 95 % CI , 0.82 - 1.59 ) for metastatic or fatal prostate cancer compared with those consuming none . Current use , dosage , and total duration of use of specific vitamin E supplements or multivitamins were not associated with risk . However , among current smokers and recent quitters , those who consumed at least 100 IU of supplemental vitamin E per day had a RR of 0.44 ( 95 % CI , 0.18 - 1.07 ) for metastatic or fatal prostate cancer compared with nonusers . Thus , supplemental vitamin E was not associated with prostate cancer risk generally , but a suggestive inverse association between supplemental vitamin E and risk of metastatic or fatal prostate cancer among current smokers and recent quitters was consistent with the Finnish trial among smokers and warrants further investigation We have initiated a population ‐based , double‐blind , r and omized controlled trial to examine the effects of supplementation of beta‐carotene and vitamin C on the incidence of  gastric cancer . The subjects were participants in an annual health screening program conducted by four municipalities in Akita prefecture , one of the regions with the highest mortality from gastric cancer in Japan . We measured their serum levels of pepsinogens ( PGs ) I and II , and asked persons diagnosed with chronic atrophic gastritis ( defined as PGI < 70 ng/ml and PGI/PGII ratio < 3.0 ) to take diet supplements containing 0 or 15 mg/day beta‐carotene and 50 or 500 mg/day vitamin C for 5 years . During the first year of recruitment conducted in one village from June through September , 1995 , 52 % ( 635/1214 ) of screening participants had chronic atrophic gastritis and 73 % ( 439/602 ) of eligible persons responded . However , in response to a National Cancer Institute press report released on January 18 , 1996 , indicating that two beta‐carotene trials had shown no benefit and potential harm from the supplement , we discontinued the beta‐carotene and continued with the trial using only vitamin C.  Of 397 participants remaining at this point , 77 % ( 305 ) consented to stay in the study . The results indicate that a r and omized controlled trial for cancer prevention is feasible in the Japanese asymptomatic population BACKGROUND Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures . Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk . OBJECTIVE This study [ B-vitamins for the PRevention Of Osteoporotic Fractures ( B-PROOF ) ] aim ed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals . DESIGN This was a double-blind , r and omized , placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations ( 12 - 50 μmol/L ) . Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3 . The primary endpoint was time to first osteoporotic fracture . Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per- protocol principles . RESULTS Osteoporotic fractures occurred in 61 persons ( 4.2 % ) in the intervention group and 75 persons ( 5.1 % ) in the placebo group . Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses ( HR : 0.84 ; 95 % CI : 0.58 , 1.21 ) or per- protocol analyses ( HR : 0.81 ; 95 % CI : 0.54 , 1.21 ) . For persons aged > 80 y , in per- protocol analyses , osteoporotic fracture risk was lower in the intervention group than in the placebo group ( HR : 0.27 ; 95 % CI : 0.10 , 0.74 ) . The total number of adverse events ( including mortality ) did not differ between groups . However , 63 and 42 participants in the intervention and placebo groups , respectively , reported incident cancer ( HR : 1.56 ; 95 % CI : 1.04 , 2.31 ) . CONCLUSIONS These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population . Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged > 80 y. However , treatment was also associated with increased incidence of cancer , although the study was not design ed for assessing cancer outcomes . Therefore , vitamin B-12 plus folic acid supplementation can not be recommended at present for fracture prevention in elderly people . The B-PROOF study was registered with the Netherl and s Trial Register ( trialregister.nl ) as NTR1333 and at clinical trials.gov as NCT00696414 In Linxian China , the esophageal/gastric cardia cancer mortality rates are among the highest in the world . There is suspicion that the population 's chronic deficiencies of multiple micronutrients are etiologically involved . We conducted two r and omized , placebo-controlled nutrition intervention trials to test the effects of vitamin and mineral supplements in lowering the rates of esophageal/gastric cancer . In the first trial , the dysplasia trial , 3318 adults with a cytological diagnosis of esophageal dysplasia received daily supplementation with 26 vitamins and minerals in doses typically 2 - 3 times the United States Recommended Daily Allowances , or placebos , for 6 years . The second trial , the general population trial , involved 29,584 adults and used a one-half replicate of a 2(4 ) factorial experimental design which tested the effects of four combinations of nutrients : A , retinol and zinc ; B , riboflavin and niacin ; C , vitamin C and molybdenum ; and D , beta-carotene , vitamin E , and selenium . Doses for these daily supplements ranged from 1 to 2 times the United States Recommended Daily Allowances , and the different vitamin/mineral combinations or placebos were taken for a period of 5.25 years . As part of the general population trial , and end-of-intervention endoscopy survey was carried out in a small ( 1.3 % ) sample of subjects to see if supplementation affected the prevalence of dysplasia and early cancer . Herein we review the methods of these trials and the results of the endoscopic survey . Fifteen esophageal and 16 gastric cancers were identified in endoscopic biopsies from the 391 subjects evaluated from two villages , and nearly all were asymptomatic . No significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen with any of the four supplement groups . However , the prevalence of gastric cancer among participants receiving retinol and zinc was 62 % lower than those not receiving those supplements ( P = 0.09 ) , while participants receiving beta-carotene , vitamin E , and selenium had a 42 % reduction in esophageal cancer prevalence ( 0.34 ) . We have reported separately that cancer mortality over the entire 5.25-year period was significantly reduced among those receiving beta-carotene , vitamin E , and selenium . The findings from the overall trial and the endoscopic sample offer a hopeful sign and should encourage additional studies with these agents in larger numbers of subjects Both these papers were published in The Lancet , both are thought to be method ologically sound , and both are widely cited , yet their conclusions are contradictory . In this example , in the r and omised trial vitamin C was part of a multivitamin supplement , whereas in the observa- tional study plasma concentrations of vitamin C were assessed . However , it is difficult to see why a combination of vitamin C with other vitamins should reduce its protective effects , if they were real . Furthermore , in the case of other antioxidant vitamins , notably vitamin E , results of single-factor trials and observational studies show a similar discordance to those seen in our figure for vitamin C. 2 - 4 Why did observational studies and r and omised controlled trials come up with different answers ? Several reasons have been proposed for the disparity between the results of observational epidemiological studies and trials . First , antioxidants might be useful only for primary prevention of cardiovascular disease , and not protective once atherosclerosis is established . 6 However , trials 4,7 found that antioxidants did not reduce cardio- vascular disease risk in participants who had no evidence of this disorder at r and omisation . Second , in many of the trials the choice of antioxidant regimen has been criticised . Background Observational studies have frequently reported an association between cognitive function and nutrition in later life but r and omised trials of B vitamins and antioxidant supplements have mostly found no beneficial effect . We examined the effect of daily supplementation with 11 vitamins and 5 minerals on cognitive function in older adults to assess the possibility that this could help to prevent cognitive decline . Methods The study was carried out as part of a r and omised double blind placebo controlled trial of micronutrient supplementation based in six primary care health centres in North East Scotl and . 910 men and women aged 65 years and over living in the community were recruited and r and omised : 456 to active treatment and 454 to placebo . The active treatment consisted of a single tablet containing eleven vitamins and five minerals in amounts ranging from 50–210 % of the UK Reference Nutrient Intake or matching placebo tablet taken daily for 12 months . Digit span forward and verbal fluency tests , which assess immediate memory and executive functioning respectively , were conducted at the start and end of the intervention period . Risk of micronutrient deficiency at baseline was assessed by a simple risk question naire . Results For digit span forward there was no evidence of an effect of supplements in all participants or in sub-groups defined by age or risk of deficiency . For verbal fluency there was no evidence of a beneficial effect in the whole study population but there was weak evidence for a beneficial effect of supplementation in the two pre-specified subgroups : in those aged 75 years and over ( n 290 ; mean difference between supplemented and placebo groups 2.8 ( 95 % CI -0.6 , 6.2 ) units ) and in those at increased risk of micronutrient deficiency assessed by the risk question naire ( n 260 ; mean difference between supplemented and placebo groups 2.5 ( 95 % CI -1.0 , 6.1 ) units ) . Conclusion The results provide no evidence for a beneficial effect of daily multivitamin and multimineral supplements on these domains of cognitive function in community-living people over 65 years . However , the possibility of beneficial effects in older people and those at greater risk of nutritional deficiency deserves further attention Background Recent evidence suggests that higher calcium and /or vitamin D intake may be associated with lower body weight and better metabolic health . Due to contradictory findings from intervention trials , we investigated the effect of calcium plus vitamin D3 ( calcium+D ) supplementation on anthropometric and metabolic profiles during energy restriction in healthy , overweight and obese adults with very-low calcium consumption . Methods Fifty-three subjects were r and omly assigned in an open-label , r and omized controlled trial to receive either an energy-restricted diet ( −500 kcal/d ) supplemented with 600 mg elemental calcium and 125 IU vitamin D3 or energy restriction alone for 12 weeks . Repeated measurements of variance were performed to evaluate the differences between groups for changes in body weight , BMI , body composition , waist circumference , and blood pressures , as well as in plasma TG , TC , HDL , LDL , glucose and insulin concentrations . Results Eighty-one percent of participants completed the trial ( 85 % from the calcium + D group ; 78 % from the control group ) . A significantly greater decrease in fat mass loss was observed in the calcium + D group ( −2.8±1.3 vs.-1.8±1.3 kg ; P=0.02 ) than in the control group , although there was no significant difference in body weight change ( P>0.05 ) between groups . The calcium + D group also exhibited greater decrease in visceral fat mass and visceral fat area ( P<0.05 for both ) . No significant difference was detected for changes in metabolic variables ( P>0.05 ) . Conclusion Calcium plus vitamin D3 supplementation for 12 weeks augmented body fat and visceral fat loss in very-low calcium consumers during energy restriction . Trial registration Clinical Trials.gov ( NCT01447433 , http:// clinical trials.gov/ ) Importance Previous r and omized clinical trials have reported inconsistent results on the effect of vitamin D supplementation on cancer incidence . Objective To examine whether high-dose vitamin D supplementation received monthly , without calcium , is associated with a reduction in  cancer incidence and cancer mortality in the general population . Design , Setting , and Participants This is a post hoc analysis of data from the Vitamin D Assessment ( ViDA ) study , a r and omized , double-blind , placebo-controlled trial that recruited participants from family practice s and community groups in Auckl and , New Zeal and , from April 5 , 2011 , through November 6 , 2012 , with follow-up completed December 31 , 2015 . Participants were adult community residents aged 50 to 84 years . Of 47 905 adults invited from family practice s and 163 from community groups , 5110 participants were r and omized to receive vitamin D3 ( n = 2558 ) or placebo ( n = 2552 ) . Two participants withdrew consent , and all others ( n = 5108 ) were included in the primary analysis . Data analysis was by intention to treat . Interventions Oral vitamin D3 , in an initial bolus dose of 200 000 IU and followed by monthly doses of 100 000 IU , or placebo for a median of 3.3 years ( range , 2.5 - 4.2 years ) . Main Outcomes and Measures Post hoc primary outcome was the number of all primary invasive and in situ malignant neoplasms ( excluding nonmelanoma skin cancers ) diagnosed from r and omization until the study medication was discontinued on July 31 , 2015 . Results Of the 5108 participants included in the analysis , the mean ( SD ) age was 65.9 ( 8.3 ) years , 58.1 % were male , and 4253 ( 83.3 % ) were of European or another race/ethnicity , with the remainder being Polynesian or South Asian .  Mean ( SD ) baseline deseasonalized 25-hydroxyvitamin D concentration was 26.5 ( 9.0 ) ng/mL. In a r and om sample of 438 participants , the mean follow-up 25-hydroxyvitamin D concentration consistently was greater than 20 ng/mL higher in the vitamin D group than in the placebo group . The primary outcome of cancer comprised 328 total cases of cancer ( 259 invasive and 69 in situ malignant neoplasms ) and occurred in 165 of 2558 participants ( 6.5 % ) in the vitamin D group and 163 of 2550 ( 6.4 % ) in the placebo group , yielding an adjusted hazard ratio of 1.01 ( 95 % CI , 0.81 - 1.25 ; P = .95 ) . Conclusions and Relevance High-dose vitamin D supplementation prescribed monthly for up to 4 years without calcium may not prevent cancer . This study suggests that daily or weekly dosing for a longer period may require further study . Trial Registration anzctr.org.au Identifier : CONTEXT Public health authorities around the world recommend widely variable supplementation strategies for adults , whereas several professional organizations , including The Endocrine Society , recommend higher supplementation . METHODS We analyzed published r and omized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health . CONCLUSIONS The extraskeletal effects of vitamin D are plausible as based on pre clinical data and observational studies . However , apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly , causality remains yet unproven in r and omized controlled trials ( RCTs ) . The greatest risk for cancer , infections , cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D ( 25OHD ) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis , estimated from serum 1,25-dihydroxyvitamin D and PTH , calcium absorption , or bone mass , can be normalized by 25OHD levels above 20 ng/mL. Moreover , vitamin D supplementation ( 800 IU/d ) in combination with calcium can reduce fracture incidence by about 20 % . Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women . Based on calculations of the metabolic clearance of 25OHD , a daily intake of 500 - 700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore , the recommendations for a daily intake of 1500 - 2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects , as suggested by The Endocrine Society Task Force , are premature . Fortunately , ongoing RCTs will help to guide us to solve this important public health question Background Low serum 25-hydroxyvitamin D [ 25(OH)D ] levels have been associated with higher risk of many diseases that affect mortality , including cardiovascular disease ( CVD ) and cancer . The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A , due to interactions of vitamin A at the level of the vitamin D nuclear receptor . In this prospect i ve cohort study , we investigated whether the association of 25(OH)D with all-cause , cancer , and CVD mortality  was modified by circulating vitamin A or preformed vitamin A intake from supplements . Methods We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey ( NHANES III ) , 1988–1994 . Mortality data for all-cause ( n = 3890 ) , cancer ( n = 844 ) , and CVD mortality ( n = 1715 ) were assessed through December 2006 .  Serum 25(OH)D was measured using a radioimmunoassay kit , vitamin A biomarkers were measured by HPLC , and information on supplement use was obtained by self-report . Multivariable hazard ratios ( HRs ) and corresponding 95 % confidence intervals ( CI ) were estimated by proportional hazards regression . Results Serum 25(OH)D was significantly inversely associated with all-cause mortality ( HR 0.93 , 95 % CI 0.89 , 0.97 , per 10 ng/mL increase ) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes , but not with cancer mortality . The observed inverse associations remained statistically significant only among participants with serum retinyl esters < 7.0 μg/dL. High intake ( > 5000 IU/day ) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality . The observed interactions were not statistically significant . Conclusions 25(OH)D was inversely associated with overall mortality , CVD mortality , and mortality due to non-cancer/non-CVD causes , but not with cancer mortality . A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration We have previously shown that administration of a combination of micronutrients ( selenium , vitamin E , and lycopene ) inhibits prostate cancer ( PCa ) development in the Lady transgenic model . In the present study , we examine timing of initiation of micronutrients , and the effect of micronutrient combinations , on PCa development in Lady transgenic model . Transgenic males were r and omized to either a control diet ; control diet supplemented with human equivalent doses of vitamin E , selenium , and lycopene ( E+S+L ) ; or control diet supplemented with vitamin E and selenium ( E+S ) . In separate experiments , the combination of E+S+L was initiated at varying time points ( 4 , 8 , 20 , and 36 weeks of age ) . A combination of E+S+L result ed in a significant reduction in PCa and liver metastasis when intervention was commenced within 8 weeks of age ( P < 0.0001 ) . Immunohistochemical analysis revealed a strong correlation between disease-free state with up-regulation of the prognostic marker p27Kip1 ( P < 0.0001 ) and decreased expression of proliferating cell nuclear antigen and significantly increased apoptotic index ( P < 0.0001 ) . On the contrary , a combination of E+S was not effectual in preventing PCa , with a high proportion ( 84.6 % ) of animals developing PCa and a small proportion ( 11.5 % ) developing high- grade PIN . Early commencement of micronutrients ( E+S+L ) is beneficial in reducing PCa . Lycopene is an essential component of the combination and effective ( when used with E+S ) for PCa prevention . These observations provide support for their chemopreventive effect and some clues about their mechanism of action . These key findings will be complementary to the outcome from the Selenium and Vitamin E Chemoprevention Trial CONTEXT We wanted to investigate vitamin D in low-risk prostate cancer . OBJECTIVES The objective of the study was to determine whether vitamin D(3 ) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen ( PSA ) or in the rate of progression . DESIGN In this open-label clinical trial ( Investigational New Drug 77,839 ) , subjects were followed up until repeat biopsy . SETTING All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center , both in Charleston , SC . PATIENTS AND OTHER PARTICIPANTS All subjects had a diagnosis of low-risk prostate cancer . Fifty-two subjects were enrolled in the study , 48 completed 1 yr of supplementation , and 44 could be analyzed for both safety and efficacy objectives . INTERVENTION The intervention included vitamin D(3 ) soft gels ( 4000 IU ) . MAIN OUTCOME MEASURES Adverse events were monitored throughout the study . PSA serum levels were measured at entry and every 2 months for 1 yr . Biopsy procedures were performed before enrollment ( for eligibility ) and after 1 yr of supplementation . RESULTS No adverse events associated with vitamin D(3 ) supplementation were observed . No significant changes in PSA levels were observed . However , 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 .  CONCLUSION Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3 ) supplementation at 4000 IU/d Background : A better underst and ing of factors that affect breast density , one of the strongest breast cancer risk indicators , may provide important clues about breast cancer etiology and prevention . This study evaluates the association of vitamin D and calcium , from food and /or supplements , to breast density in premenopausal and postmenopausal women separately . Methods : A total of 777 premenopausal and 783 post-menopausal women recruited at two radiology clinics in Quebec City , Canada , in 2001 to 2002 , completed a food frequency question naire to assess vitamin D and calcium .  Breast density from screening mammograms was assessed using a computer-assisted method . Associations between vitamin D or calcium and breast density were evaluated using linear regression models . Adjusted means in breast density were assessed according to the combined daily intakes of the two nutrients using generalized linear models . Results : In premenopausal women , total intakes of vitamin D and calcium were inversely related to breast density ( β = −1.4 ; P = 0.004 for vitamin D ; β = −0.8 ; P = 0.0004 for calcium ) . In multivariate linear regression , simultaneous increments in daily total intakes of 400 IU vitamin D and 1,000 mg calcium were associated with an 8.5 % ( 95 % confidence interval , 1.8 - 15.1 ) lower mean breast density . The negative association between  dietary vitamin D intake and breast density tended to be stronger at higher levels of calcium intake and vice versa . Among postmenopausal women , intakes of vitamin D and calcium were not associated with breast density . Conclusion : These findings show that higher intakes of vitamin D and calcium from food and supplements are related to lower levels of breast density among premenopausal women . They suggest that increasing intakes of vitamin D and calcium may represent a safe and inexpensive strategy for breast cancer prevention Background Vitamin and mineral supplement use after a breast cancer diagnosis is common and controversial . Dosages used and the timing of initiation and /or discontinuation of supplements have not been clearly described . Methods We prospect ively examined changes in use of 17 vitamin/mineral supplements in the first six months following breast cancer diagnosis among 2,596 members ( 28 % non-white ) of Kaiser Permanente Northern California . We used multivariable logistic regression to examine demographic , clinical , and lifestyle predictors of initiation and discontinuation . Results Most women used vitamin/mineral supplements before ( 84 % ) and after ( 82 % ) diagnosis , with average doses far in excess of Institute of Medicine reference intakes . Over half ( 60.2 % ) reported initiating a vitamin/mineral following diagnosis , 46.3 % discontinuing a vitamin/mineral , 65.6 % using a vitamin/mineral continuously , and only 7.2 % not using any vitamin/mineral supplement before or after diagnosis . The most commonly initiated supplements were calcium ( 38.2 % ) , vitamin D ( 32.01 % ) , vitamin B6 ( 12.3 % ) and magnesium ( 11.31 % ) ; the most commonly discontinued supplements were multivitamins ( 17.14 % ) , vitamin C ( 15.97 % ) and vitamin E ( 45.62 % ) . Higher education , higher intake of fruits/vegetables , and receipt of chemotherapy were associated with initiation ( p-values < 0.05 ) . Younger age and breast-conserving surgery were associated with discontinuation ( p-values < 0.05 ) . Conclusions In this large cohort of ethnically diverse breast cancer patients , high numbers of women used vitamin/mineral supplements in the 6 months following breast cancer diagnosis , often at high doses and in combination with other supplements . The immediate period after diagnosis is a critical time for clinicians to counsel women on supplement use The primary objective of this study was to determine whether it is the fish oil itself or the alpha-tocopherol that is added to the fish oil preparations ( to prevent peroxidation ) that is responsible for the beneficial effects of dietary supplementation with fish oil in patients with rheumatoid arthritis ( RA ) . One group of RA patients took fish oil supplements and another group took alpha-tocopherol-enriched coconut oil supplements ( placebo controls ) , both for 3 months . Clinical and laboratory indices of RA activity in relation to cellular and plasma vitamin E levels were assessed at the beginning and the end of the trial . The results of the study provide evidence that the beneficial effects of fish oil supplementation can not be ascribed to the antioxidizing properties of the alpha-tocopherol per se Background : Observational studies have suggested that antioxidant nutrients may reduce cancer and overall mortality risks . However , most r and omized trials have failed to show survival benefits . Examining nonlinear associations between antioxidant levels and health outcomes may help to explain these discrepant findings . Methods : We evaluated all-cause , cancer , and cardiovascular mortality risks associated with quintiles ( Q1–Q5 ) of serum antioxidant ( vitamins C and E , β-carotene , and selenium ) and vitamin A levels , in 16,008 adult participants of The Third National Health and Nutrition Examination Survey ( NHANES III ; 1988–1994 ) . Results : Over a median follow-up period of 14.2 years , there were 4,225 deaths , including 891 from cancer and 1,891 from cardiovascular disease . We observed a dose – response decrease in cancer and overall mortality risks with higher vitamin C levels . In contrast , for vitamin A , risk of cancer death decreased from Q1–Q2 , with no further decline in risk at higher levels . For vitamin E , having levels in Q4 was associated with the lowest cancer mortality risk . Both vitamin A and E had U-shaped associations with all-cause mortality . Cancer mortality risks decreased from Q1–Q2 for β-carotene and from Q1–Q4 for selenium . However , for β-carotene and selenium , overall mortality risks decreased from Q1–Q2 but then did not change significantly with higher levels . Conclusions : Antioxidant supplement use should be studied in the context of overall mortality and other competing mortality risks . Impact : These data suggest the need for novel intervention studies where doses of these agents are individualized based on their serum levels , and possibly , markers of oxidative stress and systemic inflammatory response . Cancer Epidemiol Biomarkers Prev ; 22(12 ) ; 2202–11 . © 2013 AACR PURPOSE Urothelial carcinoma has the highest lifetime treatment cost of any cancer , making it an ideal target for preventative therapies . Previous work has suggested that certain vitamin and mineral supplements may reduce the risk of urothelial  carcinoma . We used the prospect i ve VITamins And Lifestyle cohort to examine the association of all commonly taken vitamin and mineral supplements as well as 6 common anti-inflammatory supplements with incident urothelial carcinoma in a United States population . MATERIAL S AND METHODS A total of 77,050 eligible VITAL participants completed a detailed question naire at baseline on supplement use and cancer risk factors . After 6 years of followup 330 incident urothelial carcinoma cases in the cohort were identified via linkage to the Seattle-Puget Sound SEER cancer registry . We analyzed use of supplemental vitamins ( multivitamins , beta-carotene , retinol , folic acid , and vitamins B1 , B3 , B6 , B12 , C , D and E ) , minerals ( calcium , iron , magnesium , zinc and selenium ) and anti-inflammatory supplements ( glucosamine , chondroitin , saw palmetto , ginkgo biloba , fish oil and garlic ) . For each supplement the hazard ratios ( risk ratios ) for urothelial carcinoma comparing each category of users to nonusers , and 95 % CIs , were determined using Cox proportional hazards regression , adjusted for potential confounders . RESULTS None of the vitamin , mineral or anti-inflammatory supplements was significantly associated with urothelial carcinoma risk in age adjusted or multivariate models . CONCLUSIONS The results of this study do not support the use of commonly taken vitamin or mineral supplements or 6 common anti-inflammatory supplements for the chemoprevention of urothelial carcinoma Background . Oxidative stress could play a role in the development of preeclampsia . There is some evidence to suggest that vitamin C and E supplements can reduce the risk of the disorder . We hypothesized its beneficial role in a group of pregnant women with essential hypertension . Methods . In this r and omized controlled trial , we enrolled 50 pregnant women with essential hypertension . We assigned the women 1000 mg vitamin C and 400 IU natural vitamin E ( RRR α tocopherol ; n = 25 ) , daily from the second trimester of pregnancy until delivery or no supplementation ( n = 25 ) . Our primary endpoint was development of superimposed preeclampsia , and main secondary endpoints were aggravation of hypertension , need for admission , need to increase antihypertensive drugs , and small size for gestational age ( < fifth customized birthweight centile ) . Results . We analyzed 50 women who completed the study .  The incidence of superimposed preeclampsia was similar in vitamin and control groups ( 8 % [ n = 2 ] vs 12 % [ n = 3 ] , p = 1.000 ) . Vitamin C and E supplementation also did not prevent aggravation of hypertension in group of women who took it ( 12 % [ n = 3 ] vs 32 % [ n = 8 ] , p = 0.172 ) . Small size for gestational age babies did not differ between groups ( 4 % [ n = 2 ] vs 6 % [ n = 3 ] , p = 1.000 ) . Conclusion . Vitamin C and E supplementation does not prevent development of superimposed preeclampsia in women with essential hypertension . Our results did not show any significant benefit of vitamin supplementation . There was some trend in lessening of hypertensive complications of pregnancy . Our results failed to find any correlation between development of superimposed preeclampsia and oxidative stress The possibility that the taking of vitamin supplements may influence cognitive functioning was explored . One hundred and twenty-seven young healthy adults took either ten times the recommended daily dose of nine vitamins , or a placebo , under a double-blind procedure , for a year . After 12 months better performance on two measures of attention was found in females who had taken the vitamin supplement , even though the blood status of nine vitamins reached a plateau after 3 months . The use of regression equations demonstrated the association between improved thiamin status and improved performance on a range of measures of cognitive functioning in females rather than males . Although it was not possible to establish the reason for a beneficial response in females rather than males , the evidence that females respond differently to dietary factors was discussed PURPOSE Epidemiological and biological evidence suggests a preventive effect of selenium and vitamin E on  bladder cancer .  We assessed the effect of selenium and /or vitamin E on bladder cancer development . MATERIAL S AND METHODS This was a secondary analysis of the r and omized , placebo controlled SELECT ( Selenium and Vitamin E Cancer Prevention Trial ) , which included 34,887 men r and omly assigned to 4 groups ( selenium , vitamin E , selenium plus vitamin E and placebo ) in double-blind fashion between August 22 , 2001 and June 24 , 2004 . The primary end point was bladder cancer incidence , as determined by routine clinical management . RESULTS During a median followup of 7.1 years ( IQR 6.4 - 8.0 ) 224 bladder cancer cases were recorded . Patients with bladder cancer were older , and more likely to be white and have a smoking history than those without bladder cancer . Most cancers were urothelial and nonmuscle invasive . There was no significant difference in the bladder cancer incidence between the 53 men in the placebo group and the 56 in the  vitamin E group ( HR 1.05 , IQR 0.64 - 1.73 , p=0.79 ) , the 60 in the selenium group ( HR 1.13 , 0.70 - 1.84 , p=0.52 ) or the 55 in the vitamin E plus selenium group ( HR 1.05 , 0.63 - 1.70 , p=0.86 ) . CONCLUSIONS This secondary analysis showed no preventive effect of selenium or vitamin E alone or combined on bladder cancer in this population of men . Further studies are needed to assess the effect in women , and at different doses and formulations R and omized trials have shown , unexpectedly , that supplementation with selenium or vitamin E is associated with a reduction of prostate cancer risk . We assess whether a supplementation with low doses of antioxidant vitamins and minerals could reduce the occurrence of prostate cancer and influence biochemical markers . The SU.VI.MAX trial comprised 5,141 men r and omized to take either a  placebo or a supplementation with nutritional doses of vitamin C , vitamin E , β‐carotene , selenium and zinc daily for 8 years . Biochemical markers of prostate cancer risk such as prostate‐specific antigen ( PSA ) and insulin‐like growth factors ( IGFs ) were measured on plasma sample s collected at enrollment and at the end of follow‐up from 3,616 men . Cox regression models were used to estimate the hazard ratio and related 95 % confidence interval of prostate cancer associated with the supplementation and to examine whether the effect differed among predetermined susceptible subgroups . During the follow‐up , 103 cases of prostate cancer were diagnosed . Overall , there was a moderate nonsignificant reduction in prostate cancer rate associated with the supplementation ( hazard ratio = 0.88 ; 95 % CI = 0.60–1.29 ) . However , the effect differed significantly between men with normal baseline PSA ( < 3 μg/L ) and those with elevated PSA ( p = 0.009 ) . Among men with normal PSA , there was a marked statistically significant reduction in the rate of prostate cancer for men receiving the supplements ( hazard ratio = 0.52 ; 95 % CI = 0.29–0.92 ) . In men with elevated PSA at baseline , the supplementation was associated with an increased incidence of prostate cancer of borderline statistical significance ( hazard ratio = 1.54 ; 95 % CI = 0.87–2.72 ) . The supplementation had no effect on PSA or IGF levels . Our findings support the hypothesis that chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals . © 2005 Wiley‐Liss , OBJECTIVE To evaluate the association between vitamin C supplementation and the incidence and progression of radiographic knee osteoarthritis ( OA ) .  DESIGN Prospect i ve cohort study . SETTING Clearwater Osteoarthritis Study ( COS ) : ( 1988 to the present ) a longitudinal study . SUBJECTS Male and female COS participants aged 40 years and above ( n 1023 ) . The study exposure was the participants ' self-reported history of vitamin C supplementation .  The participants underwent biennial , sequential knee radiographs , which were assessed using the Kellgren-Lawrence ordinal scale to determine evidence of the study 2 outcomes : incident radiographic knee OA ( RKOA ) and progression of RKOA . RESULTS Individuals without baseline knee OA who self-reported vitamin C supplement usage were 11 % less likely to develop knee OA than were those individuals who self-reported no vitamin C supplement usage ( risk ratio (RR)=0.89 , 95 % CI 0.85 , 0.93 ) . Among those participants with RKOA at baseline , vitamin C supplement usage did not demonstrate an association with RKOA progression ( RR=0.94 , 95 % CI 0.79 , 1.22 ) . CONCLUSIONS In the present prospect i ve cohort study , we found no evidence to support a protective role of vitamin C in the progression of knee OA . However , after controlling for confounding variables , these data suggest that vitamin C supplementation may indeed be beneficial in preventing incident knee OA . Given the massive public health burden of OA , the use of a simple , widely available and inexpensive supplement to potentially reduce the impact of this disease merits further consideration To examine whether vitamin/mineral supplementation may lower mortality and incidence from human cancer  and mortality from other diseases as well as to provide the scientific basis and feasible approach for human cancer prevention and control , between 1982 - 1991 scientists from China and USA conducted two r and omized , double-blind , and placebo-controlled nutrition intervention trials in Linxian , China , where the esophageal/gastric cardia cancer mortality rates are among the highest in the world and there is suspicion that the population 's chronic deficiencies of multiple nutrients are etiologically involved . In the first trial , the Dysplasia Trial , 3,318 individuals with a cytologic diagnosis of esophageal dysplasia received daily 26 vitamin/mineral supplements or placebos for 6 years ; The second trial , the General Population Trial , involved 29,584 individuals and used an one-half replicate of a 2(4 ) fractional factorial design which r and omized to 8 groups for testing the effects of daily supplementation of 4 different vitamin/mineral combinations and placebo for a period of 5 1/4 years . Compliance assessed by monthly pill counts and quarterly monitoring of biochemical assays indicated that the participant compliance was excellent . As endpoints of the trials , incident cancers and deaths were identified through all medical facilities in local areas , supplemented by special endoscopy and cytology examinations , and confirmed by 3-level review groups . A total of 323  deaths occurred during 6 year period among participants in the dysplasia trial , and 2,127 deaths from the general population trial during 5 1/4 years . Besides , an eye examination , which included detailed lens evaluations , was included in the extensive re-examination protocol to ascertain whether use of the supplements had affected the risk of developing age-related cataracts among participants in the two trials . Results from Dysplasia Trial indicated that after 6 years of daily supplementation with multiple vitamins and minerals , total mortality among those in the active treatment group was slightly ( 9 % ) lower than in the placebo group ; and deaths of esophageal cancer also declined by 17 % , as well as a sizeable reduction in cerebrovascular disease mortality ( near 40 % ) was seen , though none was statistically significant . However , intervention had decreased prevalence of eye nuclear cataract ( 43 % ) ( P < 0.01 ) . The findings from the General Population Trial provide support for the hypothesis that intake of specific micronutrients may inhibit cancer development . Significant reduction of total mortality ( 9 % ) , cancer mortality ( 13 % ) , gastric cancer mortality ( 20 % ) , and mortality of the other cancers ( 19 % ) occurred among those receiving beta-carotene/vitamin E/selenium supplementation ( P < 0.05 ) . Patterns of cancer incidence , based on 1307 cases , generally resembled those for cancer mortality . ( ABSTRACT TRUNCATED AT 400 WORDS Background Calcium ( Ca ) is an essential nutrient for the human body . Despite lively research , there is uncertainty about Ca requirements in terms of desirable health outcomes including an upper intake level above which the potential for harm increases . Objectives The aim was to conduct a review to up date requirements and desirable or harmful health effects of Ca on the current scientific evidence . Methods We search ed Medline and Swemed from January 2000 to December 2011 and included all systematic review s that reported Ca supplementation or usual Ca intake on health outcomes . Meta-analyses , r and omized clinical trials and cohort studies were included in the second search between May 2009 and March 2011 and an additional search covering studies till the end of 2011 . This review concentrated on studies reporting independent effects of Ca , although a few recent trials report sole effects of Ca on health outcomes , most trials use Ca in combination with vitamin D vs. placebo . Results In total , we review ed 38 studies addressing the effects of Ca on bone , pregnancy-related outcomes , cancers , cardiovascular outcomes , obesity , and mortality .  There was a lot of heterogeneity in the study protocol s , which made it difficult to draw any strong conclusions . According to the literature , high Ca intake seems to have a small positive effect on bone mineral content ( BMC ) or bone mineral density ( BMD ) in children and postmenopausal women . We did not find any consistent evidence on the effects of Ca on bone health in premenopausal women or men . Also , the evidence that Ca supplementation reduces fracture incidence is scarce and inconsistent . Maternal diet may influence the peak bone mass of offspring but more studies are required . There was no overall effect of Ca intake on cancers . Ca was associated with a decreased risk of breast cancer and a slightly increased risk of prostate cancer in two of the three studies . No associations were found with other cancers . We found no consistent association between cardiovascular outcomes and  Ca  intake except for blood pressure . A small decrease of 2–4 mmHg in systolic blood pressure was found in pregnant and in hypertensive subjects with Ca supplementation . Review ed studies did not show consistent evidence relating Ca intake to either mortality or obesity . Conclusion Based on this evidence , there is no need to change the Nordic recommendations for Ca intake . However , due to heterogeneity in the studies it is difficult to interpret the results and provide single summary statement BACKGROUND Vitamin A supplementation is being used successfully to treat some forms of cancer and the degenerative eye disease retinitis pigmentosa . The daily biological need for vitamin A is estimated to be 800 retinol equivalents (RE)/d ( 2667 IU/d ) for adult women and 1000 RE/d ( 3300 IU/d ) for adult men ; doses > or = 7500 RE ( > or = 25000 IU)/d are considered potentially toxic over the long term . OBJECTIVE We assessed the safety in adults of long-term vitamin A supplementation with doses above the daily biological need but < 7500 RE ( < 25000 IU)/d . DESIGN Adults aged 18 - 54 y with retinitis pigmentosa but in generally good health ( n = 146 ) were supplemented with 4500 RE ( 15000 IU ) vitamin A/d for < or = 12 y ( group A ) and compared with a similar group ( n = 149 ) that received 23 RE ( 75 IU)/d ( trace group ) . Mean total consumption of vitamin A  in group A was 5583 RE ( 18609 IU)/d ( range : 4911 - 7296 RE/d , or 16369 - 24318 IU/d ) and that in the trace group was 1053 RE ( 3511 IU)/d ( range : 401 - 3192 RE/d , or 1338 - 10638 IU/d ) . RESULTS Patients in group A showed an 8 % increase in mean serum retinol concentration at 5 y and an 18 % increase at 12 y ( P < 0.001 ) ; no retinol value exceeded the upper normal limit ( 3.49 micromol/L , or 100 microg/dL ) . Mean serum retinyl esters were elevated approximately 1.7-fold at 5 y and remained relatively stable thereafter . No clinical symptoms or signs of liver toxicity attributable to vitamin A excess were detected . CONCLUSIONS Prolonged daily consumption of < 7500 RE ( < 25000 IU ) vitamin A/d can be considered safe in this age group OBJECTIVE To study the association between dietary and serum antioxidant vitamins and carotenoids and risk for  colorectal cancer in male smokers . DESIGN A prospect i ve cohort study within a r and omised , double-blind , placebo-controlled trial testing supplementation with alpha-tocopherol ( 50 mg/day ) , beta-carotene ( 20 mg/day ) or both in preventing cancer . SUBJECTS AND METHODS Participants of the Alpha-Tocopherol , Beta-Carotene Cancer Prevention Study with complete dietary data and serum sample s available from baseline . These included 26,951 middle-aged male smokers among whom 184 colorectal cancer cases were diagnosed during 8 y of follow-up .  Relative risks were calculated with Cox proportional hazards models adjusting for trial supplementation , age , body mass index , serum cholesterol , cigarettes smoked per day and physical activity . RESULTS There was no significant association between dietary vitamin C or E , alpha-or gamma-tocopherol , retinol , alpha- or beta-carotene , lycopene or lutein+zeaxanthin and risk for colorectal cancer . Serum alpha-tocopherol , beta-carotene or retinol was also not associated with the risk , neither did the season when baseline blood was drawn modify the relationship between serum beta-carotene and colorectal cancer risk . CONCLUSIONS Our data support the results from previous studies in which no association between dietary antioxidant vitamins and carotenoids and risk for colorectal cancer has been observed . Likewise , no association between baseline serum antioxidant concentrations and colorectal cancer risk was evident . SPONSORSHIP The Alpha-Tocopherol , Beta-Carotene Cancer Prevention Study was supported by a contract with the US National Cancer Institute ( N01-CN-45165 ) BACKGROUND Epidemiologic studies have suggested that vitamin E and beta-carotene may each influence the development of prostate cancer . In the Alpha-Tocopherol , Beta-Carotene Cancer Prevention Study , a controlled trial , we studied the effect of alpha-tocopherol ( a form of vitamin E ) and beta-carotene supplementation , separately or together , on prostate cancer in male smokers . METHODS A total of 29133 male smokers aged 50 - 69 years from southwestern Finl and were r and omly assigned to receive alpha-tocopherol ( 50 mg ) , beta-carotene ( 20 mg ) , both agents , or placebo daily for 5 - 8 years ( median , 6.1 years ) . The supplementation effects were estimated by a proportional hazards model , and two-sided P values were calculated . RESULTS We found 246 new cases of and 62 deaths from prostate cancer during the follow-up period . A 32 % decrease ( 95 % confidence interval [ CI ] = -47 % to -12 % ) in the incidence of prostate cancer was observed among the subjects receiving alpha-tocopherol ( n = 14564 ) compared with those not receiving it ( n = 14569 ) . The reduction was evident in clinical prostate cancer but not in latent cancer . Mortality from prostate cancer was 41 % lower ( 95 % CI = -65 % to -1 % ) among men receiving  alpha-tocopherol .  Among subjects receiving beta-carotene ( n = 14560 ) , prostate cancer incidence was 23 % higher ( 95 % CI = -4%-59 % ) and mortality was 15 % higher ( 95 % CI = -30%-89 % ) compared with those not receiving it ( n = 14573 ) . Neither agent had any effect on the time interval between diagnosis and death . CONCLUSIONS Long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers . Other controlled trials are required to confirm the findings We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of  lung cancer mortality among 29,584 healthy adults from Linxian , China . In accord with a partial factorial design , the participants were r and omly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years . The combinations tested in this trial were as follows : factor A , retinol and zinc ; factor B , riboflavin and niacin ; factor C , ascorbic acid and molybdenum ; factor D , β-carotene , α-tocopherol , and selenium . Lung cancer deaths ( n = 147 ) identified during the trial period ( 1986 - 1991 ) and 10 years after the trial ended ( 1991 - 2001 ) were the study outcome . No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study , using log-rank tests ( all P values are > 0.20 ) or Cox proportional hazards models adjusted for age , sex , commune , and other treatments . No significant interactions were seen for age , sex , or smoking status . Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian , China . ( Cancer Epidemiol Biomarkers Prev 2006;15(8):1562–4 Background : Vitamin D is an environmental and dietary agent with known anticarcinogenic effects , but protection against breast cancer has not been established . Objective : We evaluated the association between baseline serum 25-hydroxyvitamin D [ 25(OH)D ] levels , supplemental vitamin D use , and breast cancer incidence over the subsequent 5 y of follow-up . Methods : From 2003–2009 , the Sister Study enrolled 50,884 U.S. women 35–74 y old who had a sister with breast cancer but had never had breast cancer themselves . Using liquid chromatography – mass spectrometry , we measured 25(OH)D in serum sample s from 1,611 women who later developed breast cancer and from 1,843 r and omly selected cohort participants . We estimated hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for the risk of developing breast cancer using Cox proportional hazards models . Results : We found that 25(OH)D levels > 38.0 ng/mL were associated with a 21 % lower breast cancer hazard ( highest versus lowest quartile : adjusted HR=0.79 ; CI : 0.63 , 0.98 ) . Analysis of the first 5 y of follow-up for all 50,884 Sister Study participants showed that self-reported vitamin D supplementation ≥4 times/wk was associated with an 11 % lower hazard [ HR=0.89 ( CI : 0.81 , 0.99 ) ] . These associations were particularly strong among postmenopausal women [ HR=0.72 ( CI : 0.57 , 0.93 ) and HR=0.83 ( CI : 0.74 , 0.93 ) , respectively ] . Conclusions : In this cohort of women with elevated risk , high serum 25(OH)D levels  and regular vitamin D supplement use were associated with lower rates of incident , postmenopausal breast cancer over 5 y of follow-up . These results may help to establish clinical benchmarks for 25(OH)D levels ; in addition , they support the hypothesis that vitamin D supplementation is useful in breast cancer prevention . The authors evaluated associations between intakes of folate and vitamin B(6 ) and  colorectal cancer risk among women enrolled in a r and omized trial on aspirin and vitamin E in disease prevention . At baseline ( 1992 - 1995 ) , 37,916 US women aged > or=45 years who were free of cancer and cardiovascular disease provided dietary information . During an average of 10.1 years of follow-up ( through February 20 , 2004 ) , 220 colorectal adenocarcinoma cases were documented . Total folate and vitamin B(6 ) intakes were not significantly associated with the risk of colorectal cancer . However ,  dietary intakes of folate and vitamin B(6 ) were significantly inversely associated with colorectal cancer risk among women who were not taking supplements containing folate and vitamin B(6 ) .  Multivariable relative risks among women in the highest quintiles of intake versus the lowest were 1.16 ( 95 % confidence interval ( CI ) : 0.76 , 1.79 ) for total folate , 1.14 ( 95 % CI : 0.77 , 1.69 ) for total vitamin B(6 ) , 0.46 ( 95 % CI : 0.26 , 0.81 ) for dietary folate , and 0.69 ( 95 % CI : 0.41 , 1.15 ) for dietary vitamin B(6  )  . The use of multivitamin supplements was not related to colorectal cancer risk . These findings suggest that higher dietary intakes of folate and vitamin B(6 ) may reduce  the risk of colorectal cancer in women . An alternative explanation is that other factors related to dietary intakes of folate and vitamin B(6 ) account for the inverse associations 7 Background : The initial report of the Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a non-statistically significant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer . METHODS SELECT r and omized 35,533 men from 427 study sites in the United States , Canada and Puerto Rico in a double-blind manner between August 22 , 2001 and June 24 , 2004 . Eligible men were 50 years or older ( African Americans ) or 55 years or older ( all others ) with a PSA < 4.0 ng/mL and a digital rectal examination not suspicious for prostate cancer . Included in the analysis are 34,887 men r and omly assigned to one of four treatment groups : selenium ( n=8752 ) , vitamin E ( n=8737 ) , both agents ( n=8702 ) , or placebo ( n=8696 ) . Data reflect the final data collected by the study sites on their participants through July 5 , 2011 . RESULTS This report includes 54,464 additional person-years of follow-up since the primary report . Hazard ratios ( 99 % confidence intervals [ CI ] ) and numbers of prostate cancers were 1.17 ( 99 % CI 1.004 - 1.36 , p=.008 , n=620 ) for vitamin E , 1.09 ( 99 % CI 0.93 - 1.27 , p=.18 , n=575 ) for selenium , 1.05 ( 99%CI 0.89 - 1.22 , p=.46 , n=555 ) for selenium + vitamin E vs. 1.00 ( n=529 ) for placebo . The absolute increase in risk compared with placebo for vitamin E , selenium and the combination were 1.6 , 0.9 and 0.4 cases of prostate cancer per 1,000 person-years . CONCLUSIONS Dietary supplementation with Vitamin E significantly increases the risk of prostate cancer among healthy men BACKGROUND Observational studies suggested that a diet high in fruits and vegetables , both of which are rich with antioxidants , may prevent cancer development . However , findings from r and omized trials of the association between antioxidant use and cancer risk have been mostly negative . METHODS From 8171 women who were r and omly assigned in the Women 's Antioxidant Cardiovascular Study , a double-blind , placebo-controlled 2 x 2 x 2 factorial trial of vitamin C ( 500 mg of ascorbic acid daily ) , natural- source vitamin E ( 600 IU of alpha-tocopherol every other day ) , and beta carotene ( 50 mg every other day ) , 7627 women who were free of cancer before r and om assignment were selected for this study . Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index . Cox proportional hazards regression models were used to assess hazard ratios ( represented as relative risks [ RRs ] ) of common cancers associated with use of antioxidants , either individually or in combination . Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk . All statistical tests were two-sided . RESULTS During an average 9.4 years of treatment , 624 women developed incident invasive cancer and 176 women died from cancer . There were no statistically significant effects of use of any antioxidant on total cancer incidence . Compared with the placebo group , the RRs were 1.11 ( 95 % confidence interval [ CI ] = 0.95 to 1.30 ) in the vitamin C group , 0.93 ( 95 % CI = 0.79 to 1.09 ) in the vitamin E group , and 1.00 ( 95 % CI = 0.85 to 1.17 ) in the beta carotene group . Similarly , no effects of these antioxidants were observed on cancer mortality . Compared with the placebo group , the RRs were 1.28 ( 95 % CI = 0.95 to 1.73 ) in the vitamin C group , 0.87 ( 95 % CI = 0.65 to 1.17 ) in the vitamin E group , and 0.84 ( 95 % CI = 0.62 to 1.13 ) in the beta carotene group . Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death . CONCLUSIONS Supplementation with vitamin C , vitamin E , or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality BACKGROUND The Selenium and Vitamin E Cancer Prevention Trial found no effect of selenium supplementation on prostate cancer ( PCa ) risk but a 17 % increased risk from vitamin E supplementation . This case-cohort study investigates effects of selenium and vitamin E supplementation conditional upon baseline selenium status . METHODS There were 1739 total and 489 high- grade ( Gleason 7 - 10 ) PCa cases and 3117 men in the r and omly selected cohort . Proportional hazards models estimated hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for effects of supplementation within quintiles of baseline toenail selenium . Cox proportional hazards models were used to estimate hazard ratios , and all statistical tests are two-sided . RESULTS Toenail selenium , in the absence of supplementation , was not associated with PCa risk . Selenium supplementation ( combined selenium only and selenium + vitamin E arms ) had no effect among men with low selenium status ( < 60th percentile of toenail selenium ) but increased the risk of high- grade PCa among men with higher selenium status by 91 % ( P = .007 ) . Vitamin E supplementation ( alone ) had no effect among men with high selenium status ( ≥40th percentile of toenail selenium ) but increased the risks of total , low- grade , and high- grade PCa among men with lower selenium status ( 63 % , P = .02 ; 46 % , P = .09 ; 111 % , P = .008 , respectively ) . CONCLUSIONS Selenium supplementation did not benefit men with low selenium status but increased the risk of high- grade PCa  among men with high selenium status . Vitamin E increased the risk of PCa among men with low selenium status . Men should avoid selenium or vitamin E supplementation at doses that exceed recommended dietary intakes Vitamin D deficiency in the patients treated for breast cancer is associated with numerous adverse effects ( bone loss , arthralgia , and falls ) . The first aim of this study was to assess vitamin D status , determined by 25-OH vitamin D levels , among women diagnosed with breast cancer according to demographic/ clinical variables and bone mineral density ( BMD ) . The second aim of this study was to evaluate the effect of daily low-dose and weekly high-dose vitamin D supplementation on 25-OH vitamin D levels . This retrospective study included 224 women diagnosed with stage 0–III breast cancer who received treatment at the James P. Wilmot Cancer Center at the University of Rochester Medical Center . Total 25-OH vitamin D levels ( D2 + D3 ) were determined at baseline for all participants . Vitamin D deficiency was defined as a 25-OH vitamin D level < 20 ng/ml , insufficiency as 20–31 ng/ml , and sufficiency as ≥32 ng/ml . BMD was assessed during the period between 3 months before and 6 months following the baseline vitamin D assessment . Based on the participants ’ baseline levels , they received either no supplementation , low-dose supplementation ( 1,000 IU/day ) , or high-dose supplementation ( ≥50,000 IU/week ) , and 25-OH vitamin D was reassessed in the following 8–16 weeks . Approximately 66.5 % had deficient/insufficient vitamin D levels at baseline . Deficiency/insufficiency was more common among non-Caucasians , women with later-stage disease , and those who had previously received radiation therapy ( P < 0.05 ) . Breast cancer patients with deficient/insufficient 25-OH vitamin D levels had significantly lower lumbar BMD ( P = 0.03 ) . Compared to the no-supplementation group , weekly high-dose supplementation significantly increased 25-OH vitamin D levels , while daily low-dose supplementation did not significantly increase levels . Vitamin D deficiency and insufficiency were common among women with breast cancer and associated with reduced BMD in the spine . Clinicians should carefully consider vitamin D supplementation regimens when treating vitamin D deficiency/insufficiency in breast cancer patients BACKGROUND Vitamin B-12 deficiency is associated with cognitive impairment in older people . However , evidence from r and omized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive . OBJECTIVE The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged > /=70 y with mild vitamin B-12 deficiency . DESIGN In a double-blind , placebo-controlled trial , 195 subjects were r and omly assigned to receive 1000 microg vitamin B-12 , 1000 microg vitamin B-12 + 400 microg folic acid , or placebo for 24 wk . Vitamin B-12 status was assessed on the basis of methylmalonic acid , total homocysteine ( tHcy ) , and holotranscobalamin ( holoTC ) concentrations before and after 12 and 24 wk of treatment . Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention , construction , sensomotor speed , memory , and executive function . RESULTS Vitamin B-12 status did not change significantly after treatment in the placebo group ; however , oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency .  Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36 % . Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone ( P = 0.0036 ) . Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains . CONCLUSION Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function CONTEXT Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons , who self-select for high intakes of vitamin E through diet or supplements , have decreased risks of cardiovascular disease and cancer . R and omized trials do not generally support benefits of vitamin E , but there are few trials of long duration among initially healthy persons . OBJECTIVE To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women . DESIGN , SETTING , AND PARTICIPANTS In the Women 's Health Study conducted between 1992 and 2004 , 39 876 apparently healthy US women aged at least 45 years were r and omly assigned to receive vitamin E or placebo and aspirin or placebo , using a 2 x 2 factorial design , and were followed up for an average of 10.1 years . INTERVENTION Administration of 600 IU of natural- source vitamin E on alternate days . MAIN OUTCOME MEASURES Primary outcomes were a composite end point of first major cardiovascular event ( nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death ) and total invasive cancer . RESULTS During follow-up , there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group , a nonsignificant 7 % risk reduction ( relative risk [ RR ] , 0.93 ; 95 % confidence interval [ CI ] , 0.82 - 1.05 ; P = .26 ) . There were no significant effects on the incidences of myocardial infa rct ion ( RR , 1.01 ; 95 % CI , 0.82 - 1.23 ; P = .96 ) or stroke ( RR , 0.98 ; 95 % CI , 0.82 - 1.17 ; P = .82 ) , as well as ischemic or hemorrhagic stroke . For cardiovascular death , there was a significant 24 % reduction ( RR , 0.76 ; 95 % CI , 0.59 - 0.98 ; P = .03 ) . There was no significant effect on the incidences of total cancer ( 1437 cases in the vitamin E group and 1428 in the placebo group ; RR , 1.01 ; 95 % CI , 0.94 - 1.08 ; P = .87 ) or breast ( RR , 1.00 ; 95 % CI , 0.90 - 1.12 ; P = .95 ) , lung ( RR , 1.09 ; 95 % CI , 0.83 - 1.44 ; P = .52 ) , or colon cancers ( RR , 1.00 ; 95 % CI , 0.77 - 1.31 ; P = .99 ) . Cancer deaths also did not differ significantly between groups . There was no significant effect of vitamin E on total mortality ( 636 in the vitamin E group and 615 in the placebo group ; RR , 1.04 ; 95 % CI , 0.93 - 1.16 ; P = .53 ) . CONCLUSIONS The data from this large trial indicated that 600 IU of natural- source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer , did not affect total mortality , and decreased cardiovascular mortality in healthy women . These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women CONTEXT Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events . Clinical trials have generally failed to confirm benefits , possibly due to their relatively short duration . OBJECTIVE To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer , cancer death , and major cardiovascular events .  DESIGN , SETTING , AND PATIENTS A r and omized , double-blind , placebo-controlled international trial ( the initial Heart Outcomes Prevention Evaluation [ HOPE ] trial conducted between December 21 , 1993 , and April 15 , 1999 ) of patients at least 55 years old with vascular disease or diabetes mellitus was extended ( HOPE-The Ongoing Outcomes [ HOPE-TOO ] ) between April 16 , 1999 , and May 26 , 2003 . Of the initial 267 HOPE centers that had enrolled 9541 patients , 174 centers participated in the HOPE-TOO trial . Of 7030 patients enrolled at these centers , 916 were deceased at the beginning of the extension , 1382 refused participation , 3994 continued to take the study intervention , and 738 agreed to passive follow-up . Median duration of follow-up was 7.0 years . INTERVENTION Daily dose of natural source vitamin E ( 400 IU ) or matching placebo . MAIN OUTCOME MEASURES Primary outcomes included cancer incidence , cancer deaths , and major cardiovascular events ( myocardial infa rct ion , stroke , and cardiovascular death ) . Secondary outcomes included heart failure , unstable angina , and revascularizations . RESULTS Among all HOPE patients , there were no significant differences in the primary analysis : for cancer incidence , there were 552 patients ( 11.6 % ) in the vitamin E group vs 586 ( 12.3 % ) in the placebo group ( relative risk [ RR ] , 0.94 ; 95 % confidence interval [ CI ] , 0.84 - 1.06 ; P = .30 ) ; for cancer deaths , 156 ( 3.3 % ) vs 178 ( 3.7 % ) , respectively ( RR , 0.88 ; 95 % CI , 0.71 - 1.09 ; P = .24 ) ; and for major cardiovascular events , 1022 ( 21.5 % ) vs 985 ( 20.6 % ) , respectively ( RR , 1.04 ; 95 % CI , 0.96 - 1.14 ; P = .34 ) . Patients in the vitamin E group had a higher risk of heart failure ( RR , 1.13 ; 95 % CI , 1.01 - 1.26 ; P = .03 ) and hospitalization for heart failure ( RR , 1.21 ; 95 % CI , 1.00 - 1.47 ; P = .045 ) . Similarly , among patients enrolled at the centers participating in the HOPE-TOO trial , there were no differences in cancer incidence , cancer deaths , and major cardiovascular events , but higher rates of heart failure and hospitalizations for heart failure . CONCLUSION In patients with vascular disease or diabetes mellitus , long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure BACKGROUND Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases ( CVD ) , the data from cohort studies and clinical trials are inconclusive . METHODS This prospect i ve cohort study was conducted among 83 639 male physicians residing in the United States who had no history of CVD or cancer . At baseline , data on use of vitamin E , ascorbic acid ( vitamin C ) , and multivitamin supplements were provided by a self-administered question naire . Mortality from CVD and coronary heart disease ( CHD ) was assessed by death certificate review . RESULTS Use of supplements was reported by 29 % of the participants . During a mean follow-up of 5.5 years , 1037 CVD deaths occurred , including 608 CHD deaths . After adjustment for several cardiovascular risk factors , supplement use was not significantly associated with total CVD or CHD mortality . For vitamin E use , the relative risks ( RRs ) were 0.92 ( 95 % confidence interval [ CI ] , 0.70 - 1.21 ) for total CVD mortality and 0.88 ( 95 % CI , 0.61 - 1.27 ) for CHD mortality ; for use of vitamin C , the RRs were 0.88 ( 95 % CI , 0.70 - 1.12 ) for total CVD mortality and 0.86 ( 95 % CI , 0.63 - 1.18 ) for CHD mortality ; and for use of multivitamin supplements , the RRs were 1.07 ( 95 % CI , 0.91 - 1.25 ) for total CVD mortality and 1.02 ( 95 % CI , 0.83 - 1.25 ) for CHD mortality . CONCLUSIONS In this large cohort of apparently healthy US male physicians , self-selected supplementation with vitamin E , vitamin C , or multivitamins was not associated with a significant decrease in total CVD or CHD mortality . Data from ongoing large r and omized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk BACKGROUND People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel . Antioxidant vitamins , which are present in vegetables and fruits , have been associated with a diminished risk of cancers at various anatomical sites . We conducted a r and omized , controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma , a precursor of invasive cancer . METHODS We r and omly assigned 864 patients , using a two-by-two factorial design , to four treatment groups , which received placebo ; beta carotene ( 25 mg daily ) ; vitamin C ( 1 g daily ) and vitamin E ( 400 mg daily ) ; or the beta carotene plus vitamins C and E. In order to identify new adenomas , we performed complete colonoscopic examinations in the patients one year and four years after they entered the study . The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations . RESULTS Patients adhered well to the prescribed regimen , and 751 completed the four-year clinical trial . There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas ; the relative risk for beta carotene was 1.01 ( 95 percent confidence interval , 0.85 to 1.20 ) ; for vitamins C and E , it was 1.08 ( 95 percent confidence interval , 0.91 to 1.29 ) . Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location . CONCLUSIONS The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer . Although our data do not prove definitively that these antioxidants have no anticancer effect , other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits BACKGROUND Exercise practitioners often take vitamin C supplements because intense muscular contractile activity can result in oxidative stress , as indicated by altered muscle and blood glutathione concentrations and increases in protein , DNA , and lipid peroxidation . There is , however , considerable debate regarding the beneficial health effects of vitamin C supplementation . OBJECTIVE This study was design ed to study the effect of vitamin C on training efficiency in rats and in humans . DESIGN The human study was double-blind and r and omized . Fourteen men ( 27 - 36 y old ) were trained for 8 wk . Five of the men were supplemented daily with an oral dose of 1 g vitamin C. In the animal study , 24 male Wistar rats were exercised under 2 different protocol s for 3 and 6 wk . Twelve of the rats were treated with a daily dose of vitamin C ( 0.24 mg/cm2 body surface area ) . RESULTS The administration of vitamin C significantly ( P=0.014 ) hampered endurance capacity . The adverse effects of vitamin C may result from its capacity to reduce the exercise-induced expression of key transcription factors involved in mitochondrial biogenesis . These factors are peroxisome proliferator-activated receptor co-activator 1 , nuclear respiratory factor 1 , and mitochondrial transcription factor A. Vitamin C also prevented the exercise-induced expression of cytochrome C ( a marker of mitochondrial content ) and of the antioxidant enzymes superoxide dismutase and glutathione peroxidase . CONCLUSION Vitamin C supplementation decreases training efficiency because it prevents some cellular adaptations to exercise The SUpplementation en VItamines et Minéraux AntioXydants ( SU.VI.MAX ) Study is a r and omized , double-blind , placebo-controlled , primary -prevention trial design ed to test the efficacy of daily supplementation with antioxidant vitamins ( vitamin C , 120 mg ; vitamin E , 30 mg ; and beta-carotene , 6 mg ) and minerals ( selenium , 100 microg ; and zinc , 20 mg ) at nutrition-level doses ( one to three times the daily recommended dietary allowances ) in reducing several major health problems in industrialized countries , especially the main causes of premature death , cancers and cardiovascular diseases . The present report describes the design , implementation , and baseline characteristics of participants in this 8-year cohort study , which started in 1994 in France ; 12,735 eligible subjects ( women aged 35 - 60 , and men aged 45 - 60 ) were included in 1994 and will be followed for 8 years . Participants undergo a yearly visit consisting , every other year , of either biological sampling or clinical examination . They also regularly provide information on health events and dietary intake by filling out computerized question naires using the Minitel Telematic Network . Data on baseline characteristics of the participants suggest that the present sample is close to the national population in terms of geographic density , socioeconomic status , and the distribution of various major risk factors for the diseases under study . The choice of the study population should allow the results of this trial to apply to adult population s of both sexes in France and other industrialized countries Background Low vitamin D status is associated with risk of colorectal cancer and has been implicated in inflammatory bowel disease . Irritable bowel syndrome ( IBS ) is a chronic , relapsing , functional bowel disorder . A nascent literature suggests a role for vitamin D in IBS , but this has not been collated or critiqued . To date , seven studies have been published : four observational studies and three r and omised controlled trials ( RCTs ) . All observational studies reported that a substantial proportion of the IBS population was vitamin D deficient . Two intervention studies reported improvement in IBS symptom severity scores and quality of life ( QoL ) with vitamin D supplementation . There are limited data around the role of vitamin D in IBS . Conclusions The available evidence suggests that low vitamin D status is common among the IBS population and merits assessment and rectification for general health reasons alone . An inverse correlation between serum vitamin D and IBS symptom severity is suggested and vitamin D interventions may benefit symptoms . However , the available RCTs do not provide strong , generalisable evidence ; larger and adequately powered interventions are needed to establish a case for therapeutic application of vitamin D in IBS The people of Linxian County , China have one of the world 's highest rates of esophageal cancer . Two intervention trials were conducted to determine whether supplementation with specific vitamins and minerals could lower mortality from or incidence of cancer in this population and whether supplementation with multiple vitamins and minerals would reduce esophageal and gastric cardia cancer in persons with esophageal dysplasia . About 30,000 general population ( GP ) subjects in the GP trial were r and omly assigned to one of eight intervention groups according to a one-half replicate of a 2(4 ) factorial experimental design and were supplemented for 5.25 y with four combinations of micronutrients at doses from one to two times the US recommended dietary allowance ( RDA ) . About 3000 subjects in whom dysplasia was diagnosed in the dysplasia trial were r and omly assigned to groups receiving daily supplementation with 14 vitamins and 12 minerals at two to three times the US RDA or placebo for 6 y. Results of the dysplasia trial indicate that in individuals with esophageal dysplasia , micronutrient supplementation had little effect on T lymphocyte responses . In contrast , male participants in the GP trial who were supplemented with beta-carotene , vitamin E , and selenium showed significantly ( P < 0.05 ) higher mitogenic responsiveness of T lymphocytes in vitro than those not receiving these micronutrients BACKGROUND Vitamin D , specifically serum 25(OH)D has been associated with mortality , cancer and multiple other health endpoints in observational studies , but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population -wide supplementation . We have therefore launched the D-Health Trial , a r and omized trial of vitamin D supplementation for prevention of mortality and cancer . Here we report the methods and describe the trial cohort . METHODS The D-Health Trial is a r and omized placebo-controlled trial , with planned intervention for 5years and a further 5years of passive follow-up through linkage with health and death registers . Participants aged 65 - 84years were recruited from the general population of Australia . The intervention is monthly oral doses of 60,000IU of cholecalciferol or matching placebo . The primary outcome is all-cause mortality . Secondary outcomes are total cancer incidence and colorectal cancer incidence . RESULTS We recruited 21,315 participants to the trial between February 2014 and May 2015 . The participants in the two arms of the trial were well-balanced at baseline . Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health , to be current smokers or to have diabetes than the Australian population . However , the proportion overweight or with health conditions such as arthritis and angina was similar . CONCLUSIONS Observational data can not be considered sufficient to support interventions delivered at a population level . Large-scale r and omized trials such as the D-Health Trial are needed to inform public health policy and practice Although multivitamin/mineral supplements are commonly used in the United States , the efficacy of these supplements in preventing chronic disease or premature death is unclear . To assess the relation of multivitamin use with mortality and cancer , the authors prospect ively examined these associations among 182,099 participants enrolled in the Multiethnic Cohort Study between 1993 and 1996 in Hawaii and California . During an average 11 years of follow-up , 28,851 deaths were identified . In Cox proportional hazards models controlling for tobacco use and other potential confounders , no associations were found between multivitamin use and mortality from all causes ( for users vs. nonusers : hazard ratio = 1.07 , 95 % confidence interval : 0.96 , 1.19 for men ; hazard ratio = 0.96 , 95 % confidence interval : 0.85 , 1.09 for women ) , cardiovascular diseases , or cancer . The findings did not vary across subgroups by ethnicity , age , body mass index , preexisting illness , single vitamin/mineral supplement use , hormone replacement therapy use , and smoking status . There also was no evidence indicating that multivitamin use was associated with risk of cancer , overall or at major sites , such as lung , colorectum , prostate , and breast . In conclusion , there was no clear decrease or increase in mortality from all causes , cardiovascular disease , or cancer and in morbidity from overall or major cancers among multivitamin supplement users BACKGROUND Oxidized low-density lipoprotein is involved in the pathogenesis of atherosclerosis . In epidemiological studies antioxidants have been inversely related with coronary heart disease . Findings from controlled trials are inconclusive . METHODS We studied the primary preventive effect of vitamin E ( alpha tocopherol ) and beta carotene supplementation on major coronary events in the Alpha-Tocopherol , Beta-Carotene Cancer Prevention Study , a controlled trial undertaken primarily to examine the effects of these agents on cancer . A total of 27 271 Finnish male smokers aged 50 to 69 years with no history of myocardial infa rct ion were r and omly assigned to receive vitamin E ( 50 mg ) , beta carotene ( 20 mg ) , both agents , or placebo daily for 5 to 8 years ( median , 6.1 years ) . The end point was the first major coronary event , either nonfatal myocardial infa rct ion ( surviving at least 28 days ; n = 1204 ) or fatal coronary heart disease ( n = 907 ) . RESULTS The incidence of primary major coronary events decreased 4 % ( 95 % confidence interval , -12 % to 4 % ) among recipients of vitamin E and increased 1 % ( 95 % confidence interval , -7 % to 10 % ) among recipients of beta carotene compared with the respective nonrecipients . Neither agent affected the incidence of nonfatal myocardial infa rct ion . Supplementation with vitamin E decreased the incidence of fatal coronary heart disease by 8 % ( 95 % confidence interval , -19 % to 5 % ) , but beta carotene had no effect on this end point . CONCLUSIONS Supplementation with a small dose of vitamin E has only marginal effect on the incidence of fatal coronary heart disease in male smokers with no history of myocardial infa rct ion , but no influence on nonfatal myocardial infa rct ion . Supplementation with beta carotene has no primary preventive effect on major coronary events Context Vitamin E supplements ( 400 IU or more daily ) have no clear clinical benefits and may be harmful . Contribution Self-reported data from 4609 adults who participated in the 19992000 National Health and Nutrition Examination Survey showed that about 11 % consumed at least 400 IU of vitamin E daily . Use was highest among older white adults who also consumed other antioxidant supplements .  Caution s We do not know the form of vitamin E that adults consumed , but -tocopherol is the form most commonly found in supplements . Implication s Many adults may be taking vitamin E supplements that have no proven clinical benefits and might be harmful . The Editors In a recent meta- analysis of r and omized clinical trials , Miller and colleagues reported that the intake of vitamin E of at least 400 IU per day from supplements was associated with a small increase in mortality from all causes ( 1 ) . The recent findings of the Women 's Health Study , in which participants consumed 600 IU of vitamin E every other day , were consistent with the results from this meta- analysis ( 2 , 3 ) . Furthermore , the Heart Outcomes Prevention Evaluation research ers linked the use of 400 IU of vitamin E per day to an increased risk for congestive heart failure ( 4 ) . Vitamin E intake of 400 IU per day or greater can practicably be achieved only through supplementation . Among adults older than 20 years of age who participated in the U.S. Department of Agriculture 's 19941996 Continuing Surveys of Food Intake by Individuals , the median intake of vitamin E was 5.6 mg of -tocopherol equivalents per day ( 6.7 IU ) for men and 4.0 ( 4.8 IU ) for women ( 5 ) . Supplemental use of vitamins and minerals has increased in the United States , and supplemental use of vitamin E increased rapidly between 1987 and 2000 ( 6 , 7 ) . The extent to which supplements containing high doses of vitamin E are used in the United States remains incompletely documented , however . Therefore , our objectives were to estimate the percentage of U.S. adults who use supplements leading to intake of vitamin E of 400 IU or greater per day and to examine the social and demographic variations in these estimates . Methods We used data from the National Health and Nutrition Examination Survey ( NHANES ) conducted from 1999 to 2000 ( 8) . This survey included a representative sample of the civilian , noninstitutionalized U.S. population selected through stratified , multistage sampling . Trained interviewers , using a computer-assisted personal interview system , interviewed participants at home . Subsequently , participants completed additional question naires ( including a single 24-hour dietary recall ) ; underwent basic neurosensory , anthropometric , fitness , and oral health evaluations ; and provided a blood sample at the mobile examination center . The response rate was 81.9 % for those interviewed and 76.3 % for those examined . An Institutional Review Board at the Centers for Disease Control and Prevention approved the survey . Participants provided informed consent . Participants who responded affirmatively to the question Have you used or taken any vitamins , minerals , or other dietary supplements in the past month ? were asked to provide additional details about the dose , frequency , and duration of use . The interviewer also asked to see the containers of the supplements to record information about the name and manufacturer of the supplements . If participants could not produce the containers , interviewers asked them to recall this information . We estimated the dietary intake of vitamin E from a single 24-hour recall . Laboratory personnel measured serum concentrations of - and -tocopherol using a Waters Alliance high-performance liquid chromatography system ( Waters Corp. , Milford , Massachusetts ) . A detailed description of laboratory quality control procedures used in the survey can be accessed at the Centers for Disease Control and Prevention Web site ( 9 ) . Among participants age 20 years or older , we estimated the percentage ( 95 % CI ) who 1 ) did not use supplements or used supplements that did not contain vitamin E , 2 ) consumed less than 400 IU per day from the use of supplements , and 3 ) used supplements providing at least 400 IU per day . We examined the variation in the intake of vitamin E , 400 IU or greater per day , by the following characteristics of participants : age ; sex ; race or ethnicity ; educational status ; presence of chronic conditions ( coronary heart disease , angina pectoris , stroke , and diabetes ) ; smoking behavior ; strata of blood pressure ; serum total cholesterol concentration ; and body mass index . We present results only for the 3 major racial or ethnic groups ( white , African-American , and Mexican-American ) because the sample sizes for the other groups were small . Other results are based on all available data . For 2- sample tests of proportions , we used a t-test . For characteristics with 3 levels , we tested the differences in the intake of vitamin E  from supplements with a test for linear trend . We used SUDAAN statistical analysis software ( Research Triangle Institute , Research Triangle Park , North Carolina ) to account for the complex sampling design of the survey and to produce proper estimates of the st and ard errors ( 10 ) . Results Figure 1 shows the numbers of participants who were included in the analyses . The participants who did not have a serum determination of -tocopherol were an average of 2.2 years older ( P= 0.017 ) than the other participants , but the percentages who were male , were white , and who had at least a high school education did not significantly differ . Figure 1 . Sample -size flow for 19992000 National Health and Nutrition Examination Survey . Overall , 11.3 % ( CI , 9.7 % to 13.1 % ) of adults used supplements that led to a daily intake of 400 IU or greater , and 25.7 % ( CI , 24.0 % to 27.5 % ) consumed less than 400 IU per day from such supplements . As illustrated in the Table , such intake increased with increasing age ( P < 0.001 for linear trend ) , was about equal for men and women ( P > 0.2 ) , and was more common among white persons than African-American ( P < 0.001 ) or Mexican-American persons ( P < 0.001 ) . Participants who had a history of coronary heart disease , angina pectoris , stroke , or diabetes were more likely to use high doses of vitamin E  than participants without these conditions ( P < 0.001 for all age-adjusted differences ) . Table . Unadjusted Percentages of Adults Aged 20 Years or Older Who Consume  400 IU of Vitamin E per Day from the Use of Vitamin , Mineral , or Dietary Supplements ( 19992000 National Health and Nutrition Examination Survey ) The distribution of concentrations of serum -tocopherol for 3875 participants reflected the intake of vitamin E ( Figure 2 ) . For participants who did not use supplements or did not use supplements containing vitamin E , the median serum concentration of -tocopherol was 22.85 mol/L ( n= 2506 ) ; in comparison , participants using supplements had median concentrations of 30.22 mol/L ( intake of < 400 IU per day ; n= 953 ) and 49.03 mol/L ( intake of 400 IU per day ; n= 409 ) . The ratios of concentrations of -tocopherol to total cholesterol for the 3 groups were , respectively , 4.47 mol/mmol ( n= 2494 ) , 5.85 mol/mmol ( n= 947 ) , and 9.04 mol/mmol ( n= 408 ) . Serum -tocopherol concentrations were 6.01 mol/L ( no supplementation ; n= 2172 ) , 4.40 mol/L ( < 400 IU per day ; n= 827 ) , and 2.08 mol/L ( 400 IU per day ; n= 377 ) ; the respective ratios of concentrations of - to -tocopherol were 3.61 mol/mol ( n= 2161 ) , 6.81 mol/mol ( n= 824 ) , and 24.22 mol/mol ( n= 358 ) . Figure 2 . Concentrations of serum -tocopherol ( top ) and -tocopherol ( bottom ) among U.S. adults age 20 years or older by intake of vitamin E from the  use of vitamin , mineral , or dietary supplements ( 19992000 National Health and Nutrition Examination Survey ) . To examine the Pearson correlation coefficients between log-transformed concentrations of the 2 tocopherols , we used a smaller set of participants ( n= 1474 ) who attended the mobile examination center in the morning , had fasted at least 8 hours , and had concentrations of triglycerides measured using a reference method that was performed only among morning attendees . After adjustment for age and concentrations of total cholesterol and triglycerides , the Pearson correlation coefficient was 0.62 . The adjusted correlations were 0.48 for participants who consumed at least 400 IU of vitamin E per day from supplements , 0.56 for participants who consumed less than 400 IU per day from such supplements , and 0.30 for participants who did not use supplements or did not consume vitamin E from supplements . Participants who used supplements containing vitamin E commonly used other antioxidants , such as vitamin C or -carotene . The percentages of participants who used  supplements containing vitamin C  were 84.9 % ( CI , 80.8 % to 89.1 % ) among participants who consumed 400 IU per day of vitamin E from supplements , 97.9 % ( CI , 96.7 % to 99.2 % ) among participants who consumed less than 400 IU per day from such supplements , and 6.4 % ( CI , 5.1 % to 7.8 % ) among participants who did not use supplements or did not consume vitamin E from supplements . For -carotene , these percentages were 50.4 % ( CI , 42.8 % to 58.1 % ) , 66.0 % ( CI , 61.8 % to 70.2 % ) , and less than 1.0 % , respectively . For the self-reported use of cholesterol-lowering medications , these percentages were 19.7 % ( CI , 14.8 % to 24.6 % ) , 7.1 % ( CI , 5.2 % to 9.0 % ) , and 6.3 % ( CI , 4.9 % to 7.8 % ) . Among 4239 participants who attended the mobile examination center  and completed the 24-hour dietary recall , the median intake of vitamin E  from diet was 7.40 mg of -tocopherol equivalents per day ( 8.8 IU ) and ranged from 0.03 to 153.26 mg of -tocopherol equivalents per day ( 0.04 to 182.7 IU ) . Among participants who consumed at least 400 IU per day from supplements , 1 participant 's total intake of vitamin E  from diet and supplements exceeded 400 IU per day . Discussion In this representative sample of U.S. adults , about 11.3 % used supplements leading to an intake of vitamin E 400 IU per The " SUpplementation en VItamines et Minéraux AntioXydants " ( SU.VI.MAX ) Study is a r and omized double-blind , placebo-controlled , primary -prevention trial which started in 1994 in France . This epidemiologic study is design ed to test the efficacy of a daily supplementation with antioxidant vitamins ( vitamin C , 120 mg , vitamin E , 30 mg , and beta-carotene , 6 mg ) and minerals ( selenium , 100 microg , and zinc , 20 mg ) at nutritional doses , in reducing the main causes of premature death ( cancers and cardiovascular diseases ) ; 12,735 eligible subjects ( women aged 35 to 60 years , and men aged 45 to 60 years ) were included in 1994 and and will be followed up for 8 years . Participants undergo a yearly visit consisting , every other year , of either biological sampling or clinical examination . They also regularly provide information on health events and dietary intake by filling out computerized question naires using the Minitel Telematic Network . After 2 years of supplementation , biochemical indicators of vitamin and trace element status reach reasonable level without reaching concentrations as high as those observed in intervention studies , which tested relatively high doses of antioxidants , and ended up with higher risk of pathology Importance Evidence suggests that low vitamin D status may increase the risk of cancer . Objective To determine if dietary supplementation with vitamin D3 and calcium reduces the risk of  cancer among older women . Design , Setting , and Participants A 4-year , double-blind , placebo-controlled , population -based r and omized clinical trial in 31 rural counties ( June 24 , 2009 , to August 26 , 2015—the final date of follow-up ) . A total of 2303 healthy postmenopausal women 55 years or older were r and omized , 1156 to the treatment group and 1147 to the placebo group . Duration of treatment was 4 years . Interventions The treatment group ( vitamin D3 + calcium group ) received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium ; the placebo group received identical placebos . Main Outcomes and Measures The primary outcome was the incidence of all-type cancer ( excluding nonmelanoma skin cancers ) , which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling . Results Among 2303 r and omized women ( mean age , 65.2 years [ SD , 7.0 ] ; mean baseline serum 25-hydroxyvitamin D level , 32.8 ng/mL [ SD , 10.5 ] ) , 2064 ( 90 % ) completed the study . At year 1 , serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group . A new diagnosis of cancer was confirmed in 109 participants , 45 ( 3.89 % ) in the vitamin D3 + calcium group and 64 ( 5.58 % ) in the placebo group ( difference , 1.69 % [ 95 % CI , −0.06 % to 3.46 % ] ; P = .06 ) . Kaplan-Meier incidence over 4 years was 0.042 ( 95 % CI , 0.032 to 0.056 ) in the vitamin D3 + calcium group and 0.060 ( 95 % CI , 0.048 to 0.076 ) in the placebo group ; P = .06 . In unadjusted Cox proportional hazards regression , the hazard ratio was 0.70 ( 95 % CI , 0.47 to 1.02 ) . Adverse events potentially related to the study included renal calculi ( 16 participants in the vitamin D3 + calcium group and 10 in the placebo group ) , and elevated serum calcium levels ( 6 in the vitamin D3 + calcium group and 2 in the placebo group ) . Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL , supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years . Further research is necessary to assess the possible role of vitamin D in cancer prevention . Trial Registration clinical trials.gov Identifier : Objective : This study was aim ed at evaluating the effect of long-term vitamin C supplementation on serum and dietary vitamin C and identifying the factors associated with change in serum concentration . Methods : A total of 439 subjects with atrophic gastritis initially participated in a r and omized clinical trial using vitamin C and β-carotene to prevent gastric cancer . We originally r and omized the participants into four treatment groups using a 2 × 2 factorial design , whereby 0 or 15 mg/day β-carotene and 50 or 500 mg/day vitamin C were administered in a double-blind manner . The β-carotene component was terminated early after a mean treatment duration of four months . Before and upon early termination of β-carotene supplementation , 134 subjects dropped out this trial , while 120 and 124 subjects took the vitamin C supplement at either 50 mg or 500 mg daily for five years . Results : Changes in serum vitamin C were significantly higher in the high-dose group ( 38.5 % increase , 95 % CI = 27.0–49.9 ) than in the low-dose group ( 13.0 % increase , 5.1–20.9 ) or in the dropout group ( 3.3 % increase , −2.1–8.6 ) after five-year supplementation . The serum vitamin C at baseline was negatively associated with changes in serum vitamin C ( p < 0.0001 ) , while high-dose ( p < 0.0001 ) and low-dose ( p < 0.05 ) supplementation and female gender ( p < 0.001 ) were positively associated . Dietary intake of vitamin C in the supplementation group was almost identical before and after five-year supplementation of vitamin C ( 2.31 mg/day decrease , 95 % CI = −15.3–10.7 ) , while a 17.7 mg/day decrease ( 95 % CI = −44.2–8.86 ) was observed in the drop-out group . Conclusion : Five-year vitamin C supplementation induces a remarkable increase in serum vitamin C concentration , and our intervention program appears to have no effect on dietary vitamin C intake The Women 's Health Study ( WHS ) is a r and omized , double-blind , placebo-controlled trial design ed to evaluate the balance of benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in women . A total of 39,876 female health professionals , age 45 years or older and without a history of cardiovascular disease or cancer ( other than nonmelanoma skin cancer ) , were r and omized in a 2x2 factorial design to one of four treatment groups : active aspirin and vitamin E placebo , aspirin placebo and active vitamin E , both active agents , or both placebos . The process of r and omization was successful , as evidence d by the equal distribution of a large number of baseline demographic , lifestyle , and health history characteristics among the four treatment groups . Similar distribution of known potential confounders , as well as the large sample size , provides reassuring evidence that unmeasured or unknown potential confounders are also equally distributed . As expected in a clinical trial , the women in the study are healthier in some respects than the general population , but they have very comparable rates of obesity , hypertension , and elevated cholesterol . With adequate duration of treatment and follow-up , this trial will provide important and relevant information on the balance of benefits and risks of aspirin and vitamin E supplementation in the primary prevention of cardiovascular disease and cancer in women Data from laboratory studies , observational research , and /or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease ( CVD ) , but primary prevention trials with adequate dosing in general population s ( i.e. , unselected for disease risk ) are lacking . The ongoing VITamin D and OmegA-3 TriaL ( VITAL ) is a large r and omized , double-blind , placebo-controlled , 2 x 2 factorial trial of vitamin D ( in the form of vitamin D(3 ) [ cholecalciferol ] , 2000 IU/day ) and marine omega-3 fatty acid ( Omacor fish oil , eicosapentaenoic acid [EPA]+docosahexaenoic acid [ DHA ] , 1g/day ) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55 . The mean treatment period will be 5 years . Baseline blood sample s will be collected in at least 16,000 participants , with follow-up blood collection in about 6000 participants . Yearly follow-up question naires will assess treatment compliance ( plasma biomarker measures will also assess compliance in a r and om sample of participants ) , use of non- study drugs or supplements , occurrence of endpoints , and cancer and vascular risk factors . Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment , and deaths will be ascertained through national registries and other sources . Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance ; hypertension ; cognitive decline ; depression ; osteoporosis and fracture ; physical disability and falls ; asthma and other respiratory diseases ; infections ; and rheumatoid arthritis , systemic lupus erythematosus , thyroid diseases , and other autoimmune disorders Vitamin D , a prosteroid hormone with anti-proliferative and pro-differentiation activity , is thought to act as a cancer chemopreventive agent . This study evaluated the association between vitamin D intake and  breast cancer risk among women in a large prospect i ve cohort study . A total of 34,321 postmenopausal women who had completed a question naire that included diet and supplement use were followed for breast cancer incidence from 1986 to 2004 .  Adjusted relative risks ( RR ) for breast cancer were calculated for dietary , supplemental , and total vitamin D intake among all women . The adjusted RR of breast cancer for women consuming > 800 IU/day versus < 400 IU/day total vitamin D was 0.89 ( 95 % CI : 0.77–1.03 ) . RRs were stronger among women with negative than positive ER or PR status . The association of high vitamin D intake with breast cancer was strongest in the first 5 years after baseline dietary assessment ( RR = 0.66 ; 95 % CI : 0.46–0.94 compared with lowest-intake group ) , and diminished over time . Changes in  vitamin D intake over time might have contributed to the diminished association observed in later years . Vitamin D intake of > 800 IU/day appears to be associated with a small decrease in risk of breast cancer among postmenopausal women . Studies evaluating all sources of vitamin D , especially sun exposure , are needed to fully underst and the association between vitamin D and breast cancer risk Homocysteinemia is a risk factor for cardiovascular diseases . Folic acid combined with vitamins B6 and B12 is effective in lowering homocysteine levels . This r and omized placebo-controlled study was design ed to determine the effect of a folic acid-based supplement on secondary prevention of clinical events in non-ST-segment elevation acute coronary syndromes . The study comprised 240 patients with either unstable angina or non-ST-elevation myocardial infa rct ion in the previous 2 weeks who were r and omized to a folate group ( n = 116 ) or a placebo group ( n = 124 ) . The folate group received 1 mg folic acid , 400 μg vitamin B12 , and 10 mg vitamin B6 daily . Clinical outcomes within 6 months were assessed . The composite endpoint of death , nonfatal acute coronary syndrome , and serious re-hospitalization was significantly higher in the folate group ; serious re-hospitalization alone was significantly higher in this group . Advanced age and diabetes increased susceptibility to the composite outcome . Folic acid-based supplementation is not beneficial and may even be harmful in the secondary prevention of cardiovascular events in patients with unstable angina and non-ST-elevation myocardial infa rct ion . Further studies on the safety of such supplements are suggested . Controlled Clinical Trials Registry no. IS RCT N30249553 BACKGROUND Evidence remains unclear as to whether folic acid ( FA ) and vitamin B-12 supplementation is effective in reducing depressive symptoms . OBJECTIVES The objective was to determine whether oral FA + vitamin B-12 supplementation prevented cognitive decline in a cohort of community-dwelling older adults with elevated psychological distress . DESIGN A r and omized controlled trial ( RCT ) with a completely crossed 2 × 2 × 2 factorial design comprising daily oral 400 μg FA + 100 μg vitamin B-12 supplementation ( compared with placebo ) , physical activity promotion , and depression literacy with comparator control interventions for reducing depressive symptoms was conducted in 900 adults aged 60 - 74 y with elevated psychological distress ( Kessler Distress 10-Scale ; scores > 15 ) . The 2-y intervention was delivered in 10 modules via mail with concurrent telephone tracking calls . Main outcome measures examined change in cognitive functioning at 12 and 24 mo by using the Telephone Interview for Cognitive Status-Modified ( TICS-M ) and the Brief Test of Adult Cognition by Telephone ( processing speed ) ; the Informant Question naire on Cognitive Decline in the Elderly was administered at 24 mo . RESULTS FA + vitamin B-12  improved the TICS-M total ( P = 0.032 ; effect size d = 0.17 ) , TICS-M immediate ( P = 0.046 ; d = 0.15 ) , and TICS-M delayed recall ( P = 0.013 ; effect size d = 0.18 ) scores at 24 mo in comparison with placebo . No significant changes were evident in orientation , attention , semantic memory , processing speed , or informant reports . CONCLUSION Long-term supplementation of daily oral 400 μg FA + 100 μg vitamin B-12 promotes improvement in cognitive functioning after 24 mo , particularly in immediate and delayed memory performance . This trial was registered at clinical trials.gov as NCT00214682 BACKGROUND Selenium , a potential cancer prevention agent currently being tested against prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) , plays an integral role in thyroid metabolism . The effects of long-term selenium supplementation on thyroid hormone concentrations are unknown . OBJECTIVE The objective was to investigate the effects of long-term selenium supplementation on thyroid hormone concentrations . DESIGN Twenty-eight healthy adults took 200 microg selenomethionine/d for 28 mo . The thyroid hormones triiodothyronine ( T3 ) , thyroxine ( T4 ) , and thyrotropin ( TSH ) were measured in plasma for 4 mo before supplementation and quarterly during supplementation . The assay methods were changed mid study ; the results of the 2 methods were not comparable . Therefore , one analysis was conducted based on the results of the first method , and a second analysis was based on all of the data , adjusted for the change . Serial data collection permitted a test for trends rather than simply a difference between initial and final values . RESULTS By 9 mo , mean ( + /-SEM ) plasma selenium concentrations had increased from 1.78 + /- 0.07 micromol/L at baseline to 2.85 + /- 0.11 micromol/L for men and from 1.64 + /- 0.04 to 3.32 + /- 0.1.2 micromol/L for women . T3 concentrations in men increased 5 % per year ( P = 0.01 ) . T4 and TSH concentrations were unchanged . CONCLUSIONS Selenium supplementation produced no clinical ly significant changes in thyroid hormone concentrations . A small but statistically significant increase in T3 concentrations was noted in men , with no corresponding decreases in TSH . A subset of SELECT subjects might be monitored periodically for changes during long-term selenium supplementation Summary The Women 's Health Initiative ( WHI ) double-blind , placebo-controlled clinical trial r and omly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo , with average intervention period of 7.0 years . The trial was design ed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture , and secondarily , total fracture and colorectal cancer . Introduction This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data , with emphasis on fractures , cardiovascular disease , cancer , and total mortality . Methods WHI calcium and vitamin D r and omized clinical trial ( CT ) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation , and these data were contrasted and combined with corresponding data from the WHI prospect i ve observational study ( OS ) . Results Among women not taking personal calcium or vitamin D supplements at baseline , the hazard ratio [ HR ] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 ( 95 % confidence interval ( CI ) , 0.38–1.00 ) . In combined analyses of CT and OS data , the corresponding HR was 0.65 ( 95 % CI , 0.44–0.98 ) . Supplementation effects were not apparent on the risks of myocardial infa rct ion , coronary heart disease , total heart disease , stroke , overall cardiovascular disease , colorectal cancer , or total mortality , while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive . Conclusion Though based primarily on a subset analysis , long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women . Other health benefits and risks of supplementation at doses considered , including an elevation in urinary tract stone formation , appear to be modest and approximately balanced Importance Oxidative stress is an established dementia pathway , but it is unknown if the use of antioxidant supplements can prevent dementia . Objective To determine if antioxidant supplements ( vitamin E or selenium ) used alone or in combination can prevent  dementia in asymptomatic older men . Design , Setting , and Participants The Prevention of Alzheimer ’s Disease by Vitamin E and Selenium ( PREADViSE ) trial began as a double-blind r and omized clinical trial in May 2002 , which transformed into a cohort study from September 2009 to May 2015 . The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) , a r and omized clinical trial of the same antioxidant supplements for preventing prostate cancer , which closed in 2009 owing to findings from a futility analysis . The PREADViSE trial recruited 7540 men , of whom 3786 continued into the cohort study . Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites , and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms . Interventions Participants were r and omized to vitamin E , selenium , vitamin E and selenium , or placebo . While taking study supplements , enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen . During the cohort study , men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen . In both phases , men were encouraged to visit their physician if the screen results indicated possible cognitive impairment . Main Outcomes and Measures Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information , including a functional assessment screen . Results The mean ( SD ) baseline age of the 7540 participants was 67.5 ( 5.3 ) years , with 3936 ( 52.2 % ) reporting a college education or better , 754 ( 10.0 % ) reporting black race , and 505 ( 6.7 % ) reporting Hispanic ethnicity . Dementia incidence ( 325 of 7338 men [ 4.4 % ] ) was not different among the 4 study arms . A Cox model , which adjusted incidence for participant demographic information and baseline self-reported comorbidities , yielded hazard ratios of 0.88 ( 95 % CI , 0.64 - 1.20 ) for vitamin E , 0.83 ( 0.60 - 1.13 ) for selenium , and 1.00 ( 0.75 - 1.35 ) for the combination compared with placebo . Conclusions and Relevance Neither supplement prevented dementia . To our knowledge , this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men
There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women .
Vitamin D₃ supplementation  decreased cancer mortality  and vitamin D supplementation  decreased all-cause mortality , but these estimates are at risk of type I errors due to the fact that too few participants were examined , and to risks of attrition bias originating from substantial dropout of participants .
Combined vitamin D₃ and calcium supplements  increased nephrolithiasis , whereas it remains unclear from the included trials whether vitamin D₃ , calcium , or both were responsible for this effect .
BACKGROUND The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory .
OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults .