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) Serum 25-Hydroxyvitamin D and the Incidence of Acute Viral Respiratory Tract Infections in Healthy Adults Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer. 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 and multiple sclerosis hospital admissions in Scotland. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale Large-scale trials of vitamin C. High‐Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long‐Term Care Residents: A Randomized Clinical Trial [Preliminary report on the results of nutrition prevention trials of cancer and other common diseases among residents in Linxian, China]. Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. Evidence for the vitamin D hypothesis: The NHANES III extended mortality follow-up. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Effect of vitamin A supplementation on morbidity of low-birth-weight neonates. Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. Impact of massive dose of vitamin A given to preschool children with acute diarrhoea on subsequent respiratory and diarrhoeal morbidity Probiotics and vitamin C for the prevention of respiratory tract infections in children attending preschool: a randomised controlled pilot study Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design What is needed to keep persons with multiple sclerosis vitamin D-sufficient throughout the year? Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence Association between plasma 25-hydroxyvitamin D levels and fracture risk: the EPIC-Oxford study. Vitamin supplements, socioeconomic status, and morbidity events as predictors of wasting in HIV-infected women from Tanzania. 158 Efficacy of Immnunotherapy with an Oral Bacterial Lysate and Vitamin C in the Primary Prevention of Acute Respiratory Tract Infections in Children Therapeutic Effect of Vitamin D3 in Multiple Sclerosis Patients
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 Background Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections . This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections . Methodology / Findings In this prospect i ve cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009–2010 in 198 healthy adults , blinded to the nature of the substance being measured . The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations . The incidence of infection in participants with different concentrations of vitamin D was determined . One hundred ninety-five ( 98.5 % ) of the enrolled participants completed the study . Light skin pigmentation , lean body mass , and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant ( p<0.0001 ) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill . Conclusions / Significance Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby , at least during the fall and winter in temperate zones . The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections , including influenza , in the general population and in sub population s with lower 25-hydroxyvitamin D concentrations , such as pregnant women , dark skinned individuals , and the obese CONTEXT Epidemiological and experimental evidence suggests that high levels of vitamin D , a potent immunomodulator , may decrease the risk of  multiple sclerosis .  There are no prospect i ve studies addressing this hypothesis . OBJECTIVE To examine whether levels of 25-hydroxyvitamin D  are associated with risk of multiple sclerosis . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nested case-control study among more than 7 million US military personnel who have serum sample s stored in the Department of Defense Serum Repository . Multiple sclerosis cases were identified through Army and Navy physical disability data bases for 1992 through 2004 , and diagnoses were confirmed by medical record review . Each case ( n = 257 ) was matched to 2 controls by age , sex , race/ethnicity , and date s of blood collection . Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum sample s collected before the date of initial multiple sclerosis symptoms . MAIN OUTCOME MEASURES Odds ratios of multiple sclerosis associated with continuous or categorical levels ( quantiles or a priori-defined categories ) of serum 25-hydroxyvitamin D within each racial/ethnic group . RESULTS Among whites ( 148 cases , 296 controls ) , the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D ( odds ratio [ OR ] for a 50-nmol/L increase in 25-hydroxyvitamin D , 0.59 ; 95 % confidence interval , 0.36 - 0.97 ) . In categorical analyses using the lowest quintile ( < 63.3 nmol/L ) as the reference , the ORs for each subsequent quintile were 0.57 , 0.57 , 0.74 , and 0.38 ( P = .02 for trend across quintiles ) . Only the OR for the highest quintile , corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L , was significantly different from 1.00 ( OR , 0.38 ; 95 % confidence interval , 0.19 - 0.75 ; P = .006 ) . The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years . Among blacks and Hispanics ( 109 cases , 218 controls ) , who had lower 25-hydroxyvitamin D levels than whites , no significant associations between vitamin D and multiple sclerosis risk were found . CONCLUSION The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis Background Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults . Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D , mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse . We here present the protocol of an interventional clinical phase II study to test the hypothesis , that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects . Methods / Design The EVIDIMS trial is a German multi-center , stratified , r and omized , controlled and double-blind clinical phase II pilot study . Eighty patients with the diagnosis of definite multiple sclerosis or clinical ly isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be r and omized to additionally receive either high-dose ( average daily dose 10.200 IU ) or low-dose ( average daily dose 200 IU ) cholecalciferol for a total period of 18 months . The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla . Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration , clinical parameters for disease activity , as well as cognition , fatigue , depression , and quality of life . Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters . Discussion In light of the discrepancy between existing epidemiological and pre clinical data on the one h and and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients . The study design presented here fulfills the criteria of a high- quality clinical phase II trial in MS.Trial Registration Clinical Trials.gov Identifier : BACKGROUND Epidemiological evidence supports a relationship between vitamin D and mental well-being , although evidence from large-scale placebo-controlled intervention trials is lacking . AIMS To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women ; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms ; and if there is an association between serum 25-hydroxyvitamin D levels and mental health . METHOD A double-blind , r and omised , placebo-controlled trial of women aged 70 or older ( the Vital D Study : IS RCT N83409867 and ACTR12605000658617 ) . Participants were r and omly assigned to receive 500 000 IU vitamin D(3 ) ( cholecalciferol ) orally or placebo every autumn/winter for 3 - 5 consecutive years . The tools utilised at various time points were the General Health Question naire , the 12-item Short Form Health Survey , the Patient Global Impression-Improvement scale and the WHO Well-Being Index . Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants . RESULTS In this non- clinical population , no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health . Serum 25-hydroxyvitamin D levels in the vitamin D group were 41 % higher than the placebo group 12 months following their annual dose . Despite this difference , scores from the question naires did not differ . Furthermore , there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups . CONCLUSIONS The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3 ) is a practical intervention to prevent depressive symptoms in older community-dwelling women 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 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 It is now acknowledged that seasonality is a main feature of the complex neurological disorder multiple sclerosis ( MS ) . Having a spring birthday and being exposed to low levels of sunshine significantly increase the risk of MS later in life.1,2 Although global environment is dominated by seasonality , the observation that vitamin D status is inversely associated with risk of MS later in life and that vitamin D regulates the expression of a large number of MS associated genes , strongly indicate that ultra-violet ( UV ) light exposure and consequent effects on vitamin D production are involved in MS etiology.3,4 Intriguingly this essential hormone appears to also play an important role in influencing MS disease course . Studies have shown an inverse association between 25-hydroxyvitamin D ( 25-OH-D ) levels and clinical MS severity and relapse rate.5 Furthermore , in a recent prospect i ve investigation of a large cohort of MS patients , vitamin D status inversely correlated with relapses over the subsequent 6 months.6 Similar Objective : Low vitamin D status has been associated with multiple sclerosis ( MS ) prevalence and risk , but the therapeutic potential of vitamin D in established MS has not been explored . Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical , immunologic , and clinical outcomes in patients with MS prospect ively . Methods : An open-label r and omized prospect i ve controlled 52-week trial matched patients with MS for demographic and disease characteristics , with r and omization to treatment or control groups . Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [ 25(OH)D ] rapidly and assess tolerability , followed by 10,000 IU/day ( 12 weeks ) , and further downtitrated to 0 IU/day . Calcium ( 1,200 mg/day ) was given throughout the trial . Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups . Secondary endpoints included 25(OH)D and other biochemical measures , immunologic biomarkers , relapse events , and Exp and ed Disability Status Scale ( EDSS ) score . Results : Forty-nine patients ( 25 treatment , 24 control ) were enrolled [ mean age 40.5 years , EDSS 1.34 , and 25(OH)D 78 nmol/L ] . All calcium-related measures within and between groups were normal . Despite a mean peak 25(OH)D of 413nmol/L , no significant adverse events occurred . Although there may have been confounding variables in clinical outcomes , treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls . Conclusions : High-dose vitamin D ( ∼10,000 IU/day ) in multiple sclerosis is safe , with evidence of immunomodulatory effects . Classification of evidence : This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation . The trial , however , lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures ( relapses and Exp and ed Disability Status Scale scores ) , providing only Class level IV evidence for these outcomes 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 Among the many cl aims made about the value of large doses of vitamin C , those relating to the prevention and treatment of " colds " have aroused most interest , and the first question to be answered is whether there is any real evidence that such an effect exists , or whether the cl aims are based entirely on wishful thinking . If there is no good evidence of an effect , then there is little point in pursuing the matter . If , on the other h and , the evidence suggests that there is some sort of effect , a host of secondary questions present themselves : ( 1 ) Is the effect specific for the common-cold group of viruses , or is it a more general anti-infective ( or even antistress ) effect ? ( 2 ) Is it a reflection of an increased metabolic need in certain individuals or at certain times , or is it a pharmacological action unrelated to the normal metabolic function of ascorbic acid ? ( 3 ) Is the beneficial effect related to a regular daily intake ( " prophylactic " ) or to extra intake during the course of an illness ( " therapeutic " ) or to a com bination of both ? ( 4 ) Are large doses really necessary , or could equally good results be ob tained with a more moderate supplementation of normal dietary intake ? ( 5 ) If large doses are necessary , does the risk of side effects outweigh the possible benefits ? From a practical point of view it is this last question that most urgently needs to be answered . Further , since it seems reasonable to suppose that side effects are more likely to appear with higher doses and with prolonged intake , the first point to establish is whether there is any value to the regular " prophylactic " use of large doses of vitamin C , and whether in fact the size of the daily dose is as important as has been cl aim ed . In passing , it may be noted that although we have seen no symptomatic evidence of toxicity result ing from doses of up to 2000 mg daily over three or four months in healthy persons , this does not mean that this dose level is necessarily safe for longer periods , particularly in individuals with preexisting disease , or that the occasional individual might not show some unusual and undesirable reaction . Furthermore , while perhaps not a side effect in the ordinary sense of the word , the depression in blood ascorbate levels that occurs on sudden withdrawal of a chronic high intake should be recognized as a potentially harmful reaction . For example , an individual admitted to the hospital with an acute medical or surgical condition might be at a physiological disadvantage if this period of unusual stress coincided with an acute  hypoascorbemia  due to sudden withdrawal of a regular high intake . What then , is the evidence regarding the prophylactic use of large doses of vitamin C ? There is , of course , a great deal of anecdotal evidence , but this is of dubious value because of the well-recognized interaction between mental OBJECTIVES To determine the efficacy and safety of high-dose vitamin D supplementation for prevention of acute respiratory infection ( ARI ) in older long-term care residents . DESIGN R and omized controlled trial investigating high-dose vs st and ard-dose vitamin D from 2010 to 2014 . SETTING Colorado long-term care facilities . PARTICIPANTS Long-term care residents aged 60 and older ( n = 107 ) . INTERVENTION The high-dose group received monthly supplement of vitamin D3 100,000 IU , the st and ard-dose group received a monthly placebo ( for participants taking 400 - 1,000 IU/d as part of usual care ) or a monthly supplement of 12,000 IU of vitamin D3 ( for participants taking < 400 IU/d as part of usual care ) . MEASUREMENTS The primary outcome was incidence of ARI during the 12-month intervention . Secondary outcomes were falls and fractures , 25-hydroxyvitamin D levels , hypercalcemia , and kidney stones . RESULTS Participants ( 55 high dose , 52 st and ard dose ) were r and omized and included in the final analysis . The high-dose group had 0.67 ARIs per person-year and the st and ard-dose group had 1.11 ( incidence rate ratio ( IRR ) = 0.60 , 95 % confidence interval ( CI ) = 0.38 - 0.94 , P = .02 ) . Falls were more common in the high-dose group ( 1.47 per person-year vs 0.63 in st and ard-dose group ; IRR = 2.33 , 95 % CI = 1.49 - 3.63 , P < .001 ) . Fractures were uncommon and similar in both groups ( high dose 0.10 vs st and ard dose 0.19 per person-year ; P = .31 ) . Mean trough 25-hydroxyvitamin D levels during the trial were 32 . ng/mL in the high-dose group and 25.1 ng/mL in the st and ard-dose group . There was no hypercalcemia or kidney stones in either group . CONCLUSION Monthly high-dose vitamin D3 supplementation reduced the incidence of ARI in older long-term care residents but was associated with a higher rate of falls without an increase in fractures 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 Abstract Background : In observational studies vitamin D deficiency is associated with increased risk of infections , whereas the effect of vitamin D supplementation in r and omized controlled trials is non-conclusive . Methods : Five hundred and eleven subjects with prediabetes were r and omized to vitamin D3 ( 20,000 IU per week ) versus placebo for five years . Every sixth month , a question naire on respiratory tract infections ( RTI ) ( common cold , bronchitis , influenza ) and urinary tract infection ( UTI ) was filled in . Results : Mean baseline serum 25-hydroxyvitamin D ( 25(OH)D ) level was 60 nmol/L. Two hundred and fifty-six subjects received vitamin D and 255 placebo . One hundred and sixteen subjects in the vitamin D and 111 in the placebo  group completed the five-year study . Eighteen subjects in the vitamin D group and 34 subjects in the placebo group reported UTI during the study ( p < 0.02 ) , whereas no significant differences were seen for RTI . The effect on UTI was most pronounced in males . The effect of vitamin D on UTI was unrelated to baseline serum 25(OH)D level . Conclusion : Supplementation with vitamin D might prevent UTI , but confirmatory studies are needed 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 AND AIMS Emerging evidence suggests that low levels of vitamin D may be an important risk factor for multiple chronic diseases and mortality , but the evidence is mixed . Vitamin D levels are associated with sun exposure , diet , and metabolic status . One potential explanation for the lack of consistent findings amongst various studies is that low vitamin levels may be associated with poor diets or other risk factors that we were not adequately controlled for in different analyses . METHODS Prospect i ve analysis of adults over the age of 35 in NHANES III data ( 1988 - 1994 ) with 20 year mortality follow-up . Sequential Cox proportional hazard models quartiles of 25OH vitamin D adjusted for age , season , geography , sociodemographic ( SD ) , CVD risk factors ( CVD ) and nutritional factors ( NF ) were performed . RESULTS Gender , race , diabetes , anti-hypertensive meds , income , taking  vitamin D supplements , physical activity , alcohol consumption , region , body mass index , blood pressure , creatinine , albumin , CRP , thyroxine , iron , RBC folate , vitamin A , E , alpha-carotene , and lycopene were all associated with different quartiles of vitamin D and as well as CHD and all-cause mortality and thus are important potential confounders of this relationship . Adjusting for the confounding factors , higher levels of vitamin D demonstrate an inverse relationship with all-cause mortality , but only the top quartile of vitamin D shows an inverse relationship with CHD mortality . CONCLUSIONS The highest quartile compared to the lowest quartile of 25OH vitamin D levels is inversely associated with CHD and all-cause mortality adjusting for multiple confounders . Whether supplementation of individuals with low vitamin D will result in similar benefits will require a r and omized clinical trial Vitamin D has been shown to be an important immune system regulator . Vitamin D insufficiency during winter may cause increased susceptibility to upper respiratory tract infections ( URIs ) . To determine whether vitamin D supplementation during the winter season prevents or decreases URI symptoms , 162 adults were r and omized to receive 50 microg vitamin D3 ( 2000 IU ) daily or matching placebo for 12 weeks . A bi-weekly question naire was used to record the incidence and severity of URI symptoms . There was no difference in the incidence of URIs between the vitamin D and placebo groups ( 48 URIs vs. 50 URIs , respectively , P=0.57 ) . There was no difference in the duration or severity of URI symptoms between the vitamin D and placebo groups [ 5.4+/-4.8 days vs. 5.3+/-3.1 days , respectively , P=0.86 ( 95 % CI for the difference in duration -1.8 to 2.1 ) ] . The mean 25-hydroxyvitamin D level at baseline was similar in both groups ( 64.3+/-25.4 nmol/l in the vitamin D group ; 63.0+/-25.8 nmol/l in the placebo group ; n.s . ) . After 12 weeks , 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group , whereas there was no change in vitamin D levels in the placebo group . There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter . Further studies are needed to determine the role of vitamin D in infection BACKGROUND Recent studies suggest a role for vitamin D in innate immunity , including the prevention of respiratory tract infections ( RTIs ) . We hypothesize that serum 25-hydroxyvitamin D ( 25[OH]D ) levels are inversely associated with self-reported recent upper RTI ( URTI ) . METHODS We performed a secondary analysis of the Third National Health and Nutrition Examination Survey , a probability survey of the US population conducted between 1988 and 1994 . We examined the association between 25(OH)D level  and  recent URTI in 18 883 participants 12 years and older . The analysis adjusted for demographics and clinical factors ( season , body mass index , smoking history , asthma , and chronic obstructive pulmonary disease ) . RESULTS The median serum 25(OH)D level was 29 ng/mL ( to convert to nanomoles per liter , multiply by 2.496 ) ( interquartile range , 21 - 37 ng/mL ) , and 19 % ( 95 % confidence interval [ CI ] , 18%-20 % ) of participants reported a recent URTI . Recent URTI was reported by 24 % of participants with 25(OH)D levels less than 10 ng/mL , by 20 % with levels of 10 to less than 30 ng/mL , and by 17 % with levels of 30 ng/mL or more ( P < .001 ) . Even after adjusting for demographic and clinical characteristics , lower 25(OH)D levels were independently associated with recent URTI ( compared with 25[OH]D levels of > or = 30 ng/mL : odds ratio [ OR ] , 1.36 ; 95 % CI , 1.01 - 1.84 for < 10 ng/mL and 1.24 ; 1.07 - 1.43 for 10 to < 30 ng/mL ) . The association between 25(OH)D level and URTI seemed to be stronger in individuals with asthma and chronic obstructive pulmonary disease ( OR , 5.67 and 2.26 , respectively ) . CONCLUSIONS Serum 25(OH)D levels are inversely associated with recent URTI . This association may be stronger in those with respiratory tract diseases . R and omized controlled trials are warranted to explore the effects of vitamin D supplementation on RTI BACKGROUND Low-birth-weight ( LBW ) infants ( < 2,500 g ) are at increased risk of respiratory infection in the first few months of life and have low liver stores of vitamin A. As retinol is essential for respiratory epithelial cell differentiation , deficiency could result in pathological changes in the respiratory epithelium , with respiratory problems . OBJECTIVE A r and omised , double-blind , placebo-controlled trial to investigate the effect of vitamin A supplementation on the incidence and severity of respiratory infections in LBW infants during their first year of life . METHOD One hundred and thirty LBW infants ( gestational age < 36 weeks and birth weight 950 - 1,700 g ) were enrolled in the study . The infants were r and omly allocated to a vitamin A or placebo group . Infants in the vitamin A group received 25,000 IU of vitamin A ( retinyl palmitate , Arovit drops , Roche , Basle , Switzerl and ) on study days 1 , 4 and 8 . Study day 1 was between 36 and 60 hours after delivery . Infants in the placebo group received a placebo ( formulated by Roche ) with a similar appearance and packed in the same dropper bottles as the vitamin A drops . RESULTS Vitamin A supplementation markedly improved serum retinol levels . After the last vitamin A dose , the vitamin A group had higher mean serum retinol concentrations than the placebo group ( 45.77 + /- 17.07 micrograms/dl v. 12.88 + /- 6.48 micrograms/dl , P = 0.0001 ) . There was no evidence of improvement in neonatal or post-neonatal respiratory problems associated with vitamin A supplementation . Vitamin A and placebo groups did not differ in the occurrence or duration of respiratory distress or the need for head-box oxygen . There were also no significant differences in the cumulative probability of developing lower or upper respiratory tract infection through the first year of life . There was a slight suggestion of an increase in the risk of hospitalisation with pneumonia associated with vitamin A supplementation . The cumulative probability of being hospitalised with pneumonia by 6 months of age was 24.6 % ( 7 hospitalisations ) in the vitamin A group compared with 7.4 % ( 2 hospitalisations ) in the placebo group ( log rank test P = 0.04 ) . After adjusting for risk factors this difference was no longer significant . CONCLUSION Vitamin A supplementation in LBW neonates may not reduce incidence or severity of respiratory infections . These results do not negate the importance of improving vitamin A status in children as an important public health measure to reduce morbidity and mortality from other childhood infections Importance Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections . However , whether winter supplementation of vitamin D reduces the risk among children is unknown . Objective To determine whether high-dose vs st and ard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children . Design , Setting , and Participants A r and omized clinical trial was conducted during the winter months between September 13 , 2011 , and June 30 , 2015 , among children aged 1 through 5 years enrolled in TARGet Kids ! , a multisite primary care practice –based research network in Toronto , Ontario , Canada . Interventions Three hundred forty-nine participants were r and omized to receive 2000 IU/d of vitamin D oral supplementation ( high-dose group ) vs 354 participants who were r and omized to receive 400 IU/d ( st and ard-dose group ) for a minimum of 4 months between September and May. Main Outcome Measures The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months . Secondary outcomes included the number of influenza infections , noninfluenza infections , parent-reported upper respiratory tract illnesses , time to first upper respiratory tract infection , and serum 25-hydroxyvitamin D levels at study termination . Results Among 703 participants who were r and omized ( mean age , 2.7 years , 57.7 % boys ) , 699 ( 99.4 % ) completed the trial . The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 ( 95 % CI , 0.91 - 1.19 ) for the high-dose group and 1.03 ( 95 % CI , 0.90 - 1.16 ) for the st and ard-dose group , for a between-group difference of 0.02 ( 95 % CI , −0.17 to 0.21 ) per child . There was no statistically significant difference in number of laboratory-confirmed infections between groups ( incidence rate ratio [ RR ] , 0.97 ; 95 % CI , 0.80 - 1.16 ) . There was also no significant difference in the median time to the first laboratory-confirmed infection : 3.95 months ( 95 % CI , 3.02 - 5.95 months ) for the high-dose group vs 3.29 months ( 95 % CI , 2.66 - 4.14 months ) for the st and ard-dose group , or number of parent-reported upper respiratory tract illnesses between groups ( 625 for high-dose vs 600 for st and ard-dose groups , incidence RR , 1.01 ; 95 % CI , 0.88 - 1.16 ) . At study termination , serum 25-hydroxyvitamin D levels were 48.7 ng/mL ( 95 % CI , 46.9 - 50.5 ng/mL ) in the high-dose group and 36.8 ng/mL ( 95 % CI , 35.4 - 38.2 ng/mL ) in the st and ard-dose group . Conclusions and Relevance Among healthy children aged 1 to 5 years , daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections . These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections . Trial Registration clinical trials.gov Identifier : BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) often have vitamin D deficiency , which is associated with increased susceptibility to upper respiratory infection-a major precipitant of exacerbation . Multicentre trials of vitamin D supplementation for prevention of exacerbation and upper respiratory infection in patients with COPD are lacking . We therefore investigated whether vitamin D3 ( colecalciferol ) supplementation would reduce the incidence of moderate or severe COPD exacerbations and upper respiratory infections . METHODS We did a r and omised , double-blind , placebo-controlled trial of vitamin D3 supplementation in adults with COPD in 60 general practice s and four Acute National Health Service Trust clinics in London , UK . Patients were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 or placebo over 1 year in a 1:1 ratio using computer-generated permuted block r and omisation . Participants and study staff were masked to treatment assignment . Co primary outcomes were time to first moderate or severe exacerbation and first upper respiratory infection . Analysis was by intention to treat . A prespecified subgroup analysis was done to assess whether effects of the intervention on the co primary outcomes were modified by baseline vitamin D status . This trial is registered with Clinical Trials.gov , number NCT00977873 . FINDINGS 240 patients were r and omly allocated to the vitamin D3 group ( n=122 ) and placebo group ( n=118 ) . Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation ( adjusted hazard ratio 0·86 , 95 % CI 0·60 - 1·24 , p=0·42 ) or time to first upper respiratory infection ( 0·95 , 0·69 - 1·31 , p=0·75 ) . Prespecified subgroup analysis showed that vitamin D3 was protective against moderate or severe exacerbation in participants with baseline serum 25-hydroxyvitamin D concentrations of less than 50 nmol/L ( 0·57 , 0·35 - 0·92 , p=0·021 ) , but not in those with baseline 25-hydroxyvitamin D levels of at least 50 nmol/L ( 1·45 , 0·81 - 2·62 , p=0·21 ; p=0·021 for interaction between allocation and baseline serum 25-hydroxyvitamin D status ) . Baseline vitamin D status did not modify the effect of the intervention on risk of upper respiratory infection ( pinteraction=0·41 ) . INTERPRETATION Vitamin D3 supplementation protected against moderate or severe exacerbation , but not upper respiratory infection , in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L. Our findings suggest that correction of vitamin D deficiency in patients with COPD reduces the risk of moderate or severe exacerbation . FUNDING UK National Institute for Health Research BACKGROUND Asthma exacerbations , most often caused by respiratory tract infections , are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs . Vitamin D status might play a role in preventing asthma exacerbations . OBJECTIVES We sought to assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations . METHODS We measured  25-hydroxyvitamin D levels in sera collected from 1024 children with mild-to-moderate persistent asthma at the time of enrollment in a multicenter clinical trial of children r and omized to receive budesonide , nedocromil , or placebo ( as-needed beta-agonists ) : the Childhood Asthma Management Program . Using multivariable modeling , we examined the relationship between baseline vitamin D levels and the odds of any hospitalization or emergency department visit over the 4 years of the trial . RESULTS Thirty-five percent of all subjects were  vitamin D insufficient , as defined by a level of 30 ng/mL or less 25-hydroxyvitamin D. Mean vitamin D levels were lowest in African American subjects and highest in white subjects . After adjusting for age , sex , body mass index , income , and treatment group , insufficient vitamin D status was associated with a higher odds of any hospitalization or emergency department visit ( odds ratio , 1.5 ; 95 % CI , 1.1 - 1.9 ; P = .01 ) . CONCLUSION Vitamin D insufficiency is common in this population of North American children with mild-to-moderate persistent asthma and is associated with higher odds of severe exacerbation over a 4-year period Abstract Objective : To assess the impact of vitamin A supplementation on  morbidity from acute respiratory tract infections and diarrhoea .  Design : Double blind r and omised placebo controlled field trial . Setting : An urban slum area in New Delhi , India . Subjects—900 children aged 12 - 60 months attending a local health facility for acute diarrhoea of less than seven days ' duration r and omly allocated to receive vitamin A 200000 IU or placebo . Main outcome measures : Incidence and prevalence of acute lower respiratory tract infections and diarrhoea during the 90 days after termination of the enrolment diarrhoeal episode measured by twice weekly household surveillance . Results : The incidence ( relative risk 1.07 ; 95 % confidence interval 0.92 to 1.26 ) and average number of days spent with acute lower respiratory tract infections were similar in the vitamin A supplementation and placebo groups . Among children aged 23 months or less there was a significant reduction in the incidence of measles ( relative risk 0.06 ; 95 % confidence interval 0.01 to 0.48 ) . The incidence of diarrhoea was also similar ( relative risk 0.95 ; 0.86 to 1.05 ) in the two groups . There was a 36 % reduction in the mean daily prevalence of diarrhoea associated with fever in the vitamin A supplemented children older than 23 months . Conclusions : Results were consistent with a lack of impact on acute lower respiratory tract related mortality after vitamin A supplementation noted in other trials and a possible reduction in the severity of diarrhoea Background : This pilot study investigates the efficacy of a probiotic consortium ( Lab4 ) in combination with vitamin C on the prevention of respiratory tract infections in children attending preschool facilities . Subjects/ methods : In a double-blind , r and omised , placebo-controlled pilot study with children aged 3–6 years , 57 received 1.25 × 1010 colony-forming units of Lactobacillus acidophilus CUL21 ( NCIMB 30156 ) , Lactobacillus acidophilus CUL60 ( NCIMB 30157 ) , Bifidobacterium bifidum CUL20 ( NCIMB 30153 ) and Bifidobacterium animalis subsp . lactis CUL34 ( NCIMB 30172 ) plus 50 mg vitamin C or a placebo daily for 6 months . Results : Significant reductions in the incidence rate of upper respiratory tract infection ( URTI ; 33 % , P=0.002 ) , the number of days with URTI symptoms ( mean difference : −21.0 , 95 % confidence interval (CI):−35.9 , −6.0 , P=0.006 ) and the incidence rate of absence from preschool ( 30 % , P=0.007 ) were observed in the active group compared with the placebo . The number of days of use of antibiotics , painkillers , cough medicine or nasal sprays was lower in the active group and reached significance for use of cough medicine ( mean difference : −6.6 , 95 % CI : −12.9 , −0.3 , P=0.040 ) . No significant differences were observed in the incidence rate ratio or duration of lower respiratory tract infection or in the levels of plasma cytokines , salivary immunoglobulin A or urinary metabolites . Conclusions : Supplementation with a probiotic/vitamin C combination may be beneficial in the prevention and management of URTIs Background Low serum levels of 25-hydroxyvitamin D3 are associated with an increased risk of respiratory tract infections ( RTIs ) . Clinical trials with vitamin D3 against various infections have been carried out but data are so far not conclusive . Thus , there is a need for additional r and omised controlled trials of effects of vitamin D3 on infections . Objective To investigate if supplementation with vitamin D3 could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs . Design A double-blind r and omised controlled trial . Setting Karolinska University Hospital , Huddinge . Participants 140 patients with antibody deficiency ( selective IgA subclass deficiency , IgG subclass deficiency , common variable immune disorder ) and patients with increased susceptibility to RTIs ( > 4 bacterial RTIs/year ) but without immunological diagnosis . Intervention Vitamin D3 ( 4000 IU ) or placebo was given daily for 1 year . Primary and secondary outcome measures The primary endpoint was an infectious score based on five parameters : symptoms from respiratory tract , ears and sinuses , malaise and antibiotic consumption . Secondary endpoints were serum levels of 25-hydroxyvitamin D3 , microbiological findings and levels of antimicrobial peptides ( LL-37 , HNP1–3 ) in nasal fluid . Results The overall infectious score was significantly reduced for patients allocated to the vitamin D group ( 202 points ) compared with the placebo group ( 249 points ; adjusted relative score 0.771 , 95 % CI 0.604 to 0.985 , p=0.04 ) . Limitations A single study centre , small sample size and a selected group of patients . The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level . Conclusions Supplementation with vitamin D3 may reduce disease burden in patients with frequent RTIs BACKGROUND Although the risk of clinical attacks of multiple sclerosis seems to be significantly increased with viral upper respiratory tract infections ( URTI ) , serological evidence for the reported association remains controversial . In addition , although MRI is six to 10 times more sensitive than clinical exacerbations in indexing disease activity , any possible association between URTI and MRI activity has yet to be investigated . OBJECTIVES To examine the relation between URTI and disease activity , in multiple sclerosis patients participating in a placebo controlled trial of interferon β-1a  , as indexed both by clinical exacerbation rate and by the number and volume of gadolinium - diethylenetriaminepenta acetic acid ( Gd-DTPA ) enhancing lesions on MRI  . “ At risk ” periods were defined around symptomatic URTI , with or without serological confirmation . RESULTS The relative risk of clinical relapse for serologically unconfirmed symptomatic URTI was 2.1 ( p=0.004 ) . Raised antiviral antibody titres conferred a relative risk of multiple sclerosis exacerbations that was 3.4 times higher than the “ not at risk ” periods ( annual attack rates of 5.7 v 1.6 , respectively , p=0.006 ) . There was no definite relation between the number or the volume of active lesions on MRI and either symptomatic or serologically defined at risk periods . CONCLUSIONS These results confirm the previously reported association between viral infections and multiple sclerosis exacerbations and indicate that the relative risk may be even higher when viral infection is serologically confirmed . However , the results , perhaps because of the confounding effects of interferon β-1a , do not provide convincing evidence of increased blood-brain barrier breakdown or inflammation during periods of virally induced immune stimulation Prostate cancer is the commonest non-skin malignancy in the United States and has a substantial mortality rate despite the use of PSA-based screening . Furthermore , therapy for prostate cancer by surgery , radiotherapy or hormonal manipulation carries a significant risk of treatment-related morbidity . Recent analysis of secondary endpoints of several large-scale r and omized prospect i ve clinical trials for other malignancies has suggested that selenium or vitamin E may result in a decreased incidence and mortality from prostate cancer . In vitro and pre clinical studies of these antioxidants support this hypothesis . This review outlines the rationale and design of SELECT , the Selenium and Vitamin E Cancer Prevention Trial , design ed to test the hypothesis that selenium or vitamin E alone or in combination can reduce the clinical incidence of prostate cancer in a population -based cohort of men at risk . SELECT is a phase III , r and omized , double-blinded , prospect i ve , 2 × 2 factorial clinical trial which will r and omize 32,400 healthy men with normal DRE and serum PSA to one of four study arms : selenium alone , vitamin E alone , selenium+vitamin E , or placebo . Study agents will be taken orally for a minimum of 7 and maximum of 12 y with assessment s of general health , incident prostate cancer and toxicity performed at 12 month intervals . Under the assumptions described , the detectable risk reduction is 25 % for an effective single agent relative to placebo , with an additional 25 % reduction for the combination relative to an effective single agent . The estimated power for the comparison of a single agent vs placebo is 96 % and the power for the comparison of an effective single agent vs combination is 89 % . Secondary endpoints will include prostate cancer-free survival , all-cause mortality , and the incidence and mortality of other cancers and diseases potentially impacted by the chronic use of  selenium and vitamin E.  Other trial objectives will include periodic quality of life assessment s , assessment of serum micronutrient levels and prostate cancer risk , and studies of the evaluation of biological and genetic markers with the risk of prostate cancer Vitamin D sufficiency has been associated with lower risk of multiple sclerosis and may also have a favorable effect on the course of the disease . The aim of this work was to identify predictors of serum 25-hydroxy vitamin D ( 25[OH]D ) levels in persons with multiple sclerosis ( MS ) and to assess the effect of high-dose vitamin D3 supplementation on vitamin D status . A 96-week r and omized controlled trial was performed to assess the effect of supplementation with 20,000 IU of vitamin D3 weekly on bone mineral density in 68 patients . We collected  data on vitamin D intake and UV-exposure  and repeatedly measured serum 25(OH)D levels . Half of the participants had sufficient winter vitamin D levels at baseline ( ≥50 nmol/l ) . Vitamin D status was predicted by sun exposure during the last 3 months and by ingested vitamin D from diet and supplements . In the placebo group , the proportion of the participants with sufficient levels increased from 55 % in winter to 92 % during the summer . In the intervention group , all participants had winter 25(OH)D levels above 50 nmol/l at the end of the study . MS patients who have no sun exposure and low dietary vitamin D intake during the winter months should be recommended to take vitamin D supplements to achieve serum 25(OH)D levels of at least 50 nmol/l Background Osteoporosis is a major health problem , and the economic burden is expected to rise due to an increase in life expectancy throughout the world . Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk . As vitamin B12 and folate intake and status play a large role in homocysteine metabolism , it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration . Methods / Design The B-PROOF ( B-Vitamins for the PRevention Of Osteoporotic Fractures ) study is a r and omized double-blind placebo-controlled trial . The intervention comprises a period of two years , and includes 2919 subjects , aged 65 years and older , independently living or institutionalized , with an elevated homocysteine concentration ( ≥ 12 μmol/L ) . One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet . In both tablets 15 μg ( 600 IU ) vitamin D is included . The primary outcome of the study is osteoporotic fractures . Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers , physical performance and physical activity including falls , nutritional intake and status , cognitive function , depression , genetics and quality of life . This large multi-center project is carried out by a consortium from the Erasmus MC ( Rotterdam , the Netherl and s ) , VUmc ( Amsterdam , the Netherl and s ) and Wageningen University , ( Wageningen , the Netherl and s ) , the latter acting as coordinator . Discussion To our best knowledge , the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population . We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013 . The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures . Trial Registration The B-PROOF study is registered with the Netherl and s Trial ( NTR NTR1333 ) and with Clinical Trials.gov ( NCT00696514 ) The importance of vitamin D for bone health is well established , but few data exist on the relation between plasma levels of 25-hydroxyvitamin D and risk of fracture . The authors examined this association within the EPIC-Oxford ( European Prospect i ve Investigation into Cancer and Nutrition-Oxford cohort ) study of men and women in the United Kingdom ( 1993 - 1999 ) . Five years after recruitment , participants completed a follow-up question naire where fracture incidence was self-reported . Plasma 25-hydroxyvitamin D concentration was measured in 730 incident fracture cases and 1,445 matched controls . There was a clear association between plasma 25-hydroxyvitamin D concentration and month of blood draw , the highest values being during the summer months . Among women , there were significant relations between 25-hydroxyvitamin D levels and age , body mass index , marital status , use of hormone therapy , physical activity , diet group , dietary intake of vitamin D , and alcohol . Similar relations were seen among men , although often they were nonsignificant because of smaller numbers . There was no evidence of an association between plasma 25-hydroxyvitamin D and fracture risk for men or women ; the relative risks associated with a doubling of plasma 25-hydroxyvitamin D were 1.15 ( 95 % confidence interval : 0.82 , 1.61 ) and 0.95 ( 95 % confidence interval : 0.80 , 1.13 ) , respectively . These results were not affected by adjustment for potential confounders and were consistent across a number of subgroups BACKGROUND Wasting is a strong independent predictor of mortality in HIV-infected persons .  Vitamin supplements delay the disease progression , but their effect on wasting is not known . Data are lacking on the risk factors for wasting in African HIV-infected persons . OBJECTIVES The objectives were to examine the effect of vitamin supplements on wasting in HIV-infected women and to assess the effects of sociodemographic characteristics , morbidity events , and immunologic progression on the risk of wasting . DESIGN HIV-infected women ( n = 1078 ) from Tanzania were r and omly assigned to receive 1 of 4 daily oral regimens : multivitamins ( B complex , C , and E ) , vitamin A plus beta-carotene , multivitamins that included vitamin A plus beta-carotene , or placebo . The endpoints of the study included first episodes of a midupper arm circumference < 22 cm or a body mass index ( BMI ; in kg/m2 ) < 18 and the incidence of weight loss episodes during a median 5.3 y of follow-up . RESULTS Multivitamins alone significantly reduced the risk of a first episode of a midupper arm circumference < 22 cm ( relative risk : 0.66 ; 95 % CI : 0.47 , 0.94 ; P = 0.02 ) . In multivariate-adjusted Cox models , the woman 's age , education level , and height were inversely related to the incidence of wasting . Episodes of diarrhea , nausea or vomiting , lower respiratory tract infections , oral ulcers , thrush , severe anemia , and low CD4 + cell counts were each significantly related to an increased risk of wasting . CONCLUSIONS Vitamins C and E and the vitamin B complex have a protective effect on wasting in HIV-infected women . Prevention of diarrhea , severe respiratory tract infections , and anemia are likely to decrease the burden of wasting Background Airway infections are of great importance worldwide and nearly half of the pediatric consultations in industrialized countries are caused by respiratory tract infections ( RTIs ) . Acute respiratory tract infections ( ARTIs ) are among the main causes of morbidity and mortality in children and recurrent infections of the respiratory tract are the most frequent cause of pharmacotherapy in pediatric practice . The aim of this study was to evaluate the efficacy and tolerability of immunotherapy with oral bacterial lysates + vitamin C in the prevention of ARTIs in children . Methods 109 children with ages between 4 and 16 years with frequent respiratory tract infections ( 2–5 infections the previous winter ) were evaluated . Participants were r and omly allocated in 2 groups : 52 patients ( mean age 6.8 ± 2.9 years ; 20 males 32 females ) received no preventive therapy ( NPT group ) and 57 ( mean age 9.0 ± 3.3 years ; males 36 females 21 ) received immunotherapy with oral bacterial lysates + vitamin C ( VC group ) at the recommended dosage . Patients were followed up for 6 months , including the administration period . Primary end points were the type and number of ARTIs . Secondary end points ( after the infection occured ) included : time to clinical cure , severity of infection , absenteeism from school due to an ARTI , number of antibiotic courses or other drugs prescribed , and duration of concomitant drug treatment . Results There were significant differences between groups in the cumulative number of acute infectious episodes : 170 in NPT group ( 141 upper ARTIs , 29 lower ARTI , and 26 otitis episodes ) vs 55 in VC group ( 50 upper ARTIs , 5 lower ARTI and 4 otitis episodes ) . Patients in the NPT group received 127 antibiotic courses compared to 28 in the VC group ( P < 0.0001 ) . Patients in the NPT group had 475 days of absenteeism from school compared to 100 days in the VC group ( P < 0.0001 ) . No adverse events related to the trial medications were reported . Conclusions Immunotherapy with oral bacterial lysates and vitamin C appears to be very effective in the prevention of infectious episodes in pediatric patients with frequent respiratory tract infections . Future studies are needed to further explore the role of oral bacteroial lysates in ARTIs prevention Multiple sclerosis ( MS ) is an inflammatory disease in which the myelin sheaths around the axons of the central nervous system are damaged . The damage leads to demyelination and scarring as well as a broad spectrum of signs and symptoms . The epidemiological data suggest a possible influence of vitamin D as an immunomodulatory agent on multiple sclerosis susceptibility as well as on clinical course of the disease . We investigated the effects of short-term vitamin D3 therapy on Iranian patients with MS . In a prospect i ve r and omized controlled trial study , 62 MS patients received 300,000 IU/month vitamin D3 or placebo as intramuscular injection for 6 months . Our results showed no significant difference between the treatment and the control groups in the exp and ed disability status scale scores and number of gadolinium-enhancing lesions during the 6-month treatment period . After 6 months , the levels of cell proliferation in the vitamin D treatment group were significantly lower than the control group . Also , the levels of transforming growth factor-beta and interleukin-10 in the vitamin D treatment group were significantly higher than the control group . This result suggests that vitamin D therapy may help prevent the development of MS and could be a useful addition to the therapy
The evidence shows that vitamin D supplementation provides some benefit in fracture prevention ( likely ∼10–15 % relative reduction ) , particularly at a dose ≥800 IU and with calcium ; a likely benefit in the rate of falls , though it is less clear whether the number of fallers changes ; and a possible small ( ∼5 % ) relative reduction in mortality .
Evidence does not support the use of vitamin D supplementation for the prevention of cancer , respiratory infections or rheumatoid arthritis .
Similarly , evidence does not support vitamin D supplementation for the treatment of multiple sclerosis and rheumatoid arthritis or for improving depression/mental well-being .
Regular testing of 25-hydroxyvitamin D is generally not required , and mega-doses ( ≥300,000 IU ) appear to increase harms .
Over the past decade , a large body of observational evidence has suggested an association between  lower vitamin D status ( 25-hydroxyvitamin D ) and multiple acute and chronic disorders , including cancer , multiple sclerosis , depression and respiratory tract infections .
This evidence has fostered the hypothesis that increasing vitamin D intake may treat and prevent such disorders .
Our objective was to perform a critical analysis of the highest-level evidence for ten common beliefs regarding vitamin D for the prevention of falls , fractures and respiratory tract infections , the reduction of cancer incidence/mortality and overall mortality , and the prevention or treatment of depression/mental well-being , rheumatoid arthritis and multiple sclerosis , as well as maximum dosing and regular testing .