Effect of Monthly Vitamin D Supplementation on Preventing Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease in Older Adults: Post Hoc Analysis of a Randomized Controlled Trial.

Randomized controlled trials have suggested that vitamin D supplementation can prevent asthma and chronic obstructive pulmonary disease (COPD) exacerbations. For COPD, the benefit appears to be limited to individuals with baseline 25-hydroxyvitamin D (25OHD) levels <25 nmol/L. We performed a post hoc analysis of data from a randomized, double-blinded, placebo-controlled trial to investigate the effect that monthly, high-dose vitamin D supplementation (versus placebo) had on older adults with asthma and/or COPD. Specifically, we investigated whether vitamin D supplementation prevented exacerbations of these conditions. Participants were randomly assigned either to an initial oral dose of 200,000 IU vitamin D3 followed by 100,000 IU monthly or to placebo, with an average follow-up period of 3.3 years. Among the 5110 participants, 775 had asthma or COPD at the beginning of the study, and were eligible for inclusion in this analysis. Exacerbations were defined by the prescription of a short-burst of oral corticosteroids. The mean age of the participants was 67 years old, and 56% were male. The mean baseline blood 25OHD level was 63 nmol/L; 2.3% were <25 nmol/L. Overall, we found that vitamin D supplementation did not affect the exacerbation risk (hazard ratio 1.08; 95%CI 0.84-1.39). Among those with baseline 25OHD <25 nmol/L, however, the hazard ratio was 0.11 (95%CI 0.02-0.51); p for interaction = 0.001. Although monthly vitamin D supplementation had no overall impact on risk of exacerbations of asthma or COPD, we found evidence of a probable benefit among those with severe vitamin D deficiency.

Plasma Sulfur Amino Acids and Risk of Cerebrovascular Diseases: A Nested Case-Control Study in the EPIC-Norfolk Cohort.

BACKGROUND AND PURPOSE: B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular diseases. METHODS: Nested within the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk cohort, we established a case-control study with 480 incident cases of cerebrovascular diseases and 480 controls matched by age, sex, and year of baseline examination (1993-1997). Using baseline plasma samples, we assayed sulfur-containing compounds including methionine, homocysteine, cystathionine, cysteine, glutathione, and taurine with liquid chromatography-tandem mass spectrometry. We examined the association of concentrations of each of the compounds and the ratio of methionine to homocysteine (representing activity of one-carbon metabolism) with risk of incident cerebrovascular diseases, adjusted for potential confounders. RESULTS: Plasma methionine and the methionine/homocysteine ratio were inversely associated with risk of cerebrovascular diseases, with odds ratios per 1 SD of 0.83 (95% CI, 0.72-0.96) and 0.82 (95% CI, 0.71-0.95), respectively. The association of methionine remained significant after adjustment for homocysteine. None of the other examined compounds was significantly associated with incident cerebrovascular diseases. CONCLUSIONS: These findings suggest that greater availability of methionine, an essential amino acid, may play a role in the prevention of cerebrovascular diseases and explain the previously recognized link between elevated homocysteine and stroke. Further research is needed to determine causation and the potential of circulating methionine as a target in cerebrovascular disease prevention.

Long-term effects of gestational diabetes on bone mineral density and fracture risk: Analysis of the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) population-based study.

OBJECTIVES: Gestational diabetes mellitus (GDM) is a common pregnancy complication. This study aims to investigate the association between a history of GDM and bone mineral density (BMD), fractures, and falls in later life. STUDY DESIGN: We used data from the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk) where BMD at calcaneum was measured at second health check (1997-2000) using broadband ultrasound attenuation (BUA) and velocity of sound (VOS) in 7,515 women. Fractures and falls were documented from hospital admissions data via linkage with ENCORE (East Norfolk Commission Record) and history of GDM from health questionnaires at baseline. We examined the relationship between GDM and BUA/VOS using linear regression. Cox regression was used to estimate hazard ratios (HRs) for incident fractures and falls, controlling for age, BMI, smoking status, physical activity, area deprivation, self-reported stroke, use of diuretics, calcium and vitamin D supplements, social class and education, statin and total blood cholesterol, prevalent diabetes, hormone therapy and menopausal status. RESULTS: History of GDM (n = 183) was not statistically significantly associated with BUA/VOS in fully adjusted linear regression models with unstandardised beta coefficients (standard error): -0.37 (1.40) and -5.41 (3.48). GDM was significantly (p < 0.05) associated with risk of hip and all fractures, fully adjusted HRs(95 %CI) 2.46(1.54-3.92) and 1.60(1.09-2.35), respectively. Median follow-up from first live birth to date of admission was 53 and 52 years, respectively. CONCLUSION: There was an association between history of GDM and risk of any fracture as well as hip fracture specifically. Further research is required to confirm this.

Calcium intake, calcium supplementation and cardiovascular disease and mortality in the British population: EPIC-norfolk prospective cohort study and meta-analysis.

The role of dietary calcium in cardiovascular disease prevention is unclear. We aimed to determine the association between calcium intake and incident cardiovascular disease and mortality. Data were extracted from the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Multivariable Cox regressions analysed associations between calcium intake (dietary and supplemental) and cardiovascular disease (myocardial infarction, stroke, heart failure, aortic stenosis, peripheral vascular disease) and mortality (cardiovascular and all-cause). The results of this study were pooled with those from published prospective cohort studies in a meta-analsyis, stratifying by average calcium intake using a 700 mg/day threshold. A total of 17,968 participants aged 40-79 years were followed up for a median of 20.36 years (20.32-20.38). Compared to the first quintile of calcium intake (< 770 mg/day), intakes between 771 and 926 mg/day (second quintile) and 1074-1254 mg/day (fourth quintile) were associated with reduced all-cause mortality (HR 0.91 (0.83-0.99) and 0.85 (0.77-0.93), respectively) and cardiovascular mortality [HR 0.95 (0.87-1.04) and 0.93 (0.83-1.04)]. Compared to the first quintile of calcium intake, second, third, fourth, but not fifth quintiles were associated with fewer incident strokes: respective HR 0.84 (0.72-0.97), 0.83 (0.71-0.97), 0.78 (0.66-0.92) and 0.95 (0.78-1.15). The meta-analysis results suggest that high levels of calcium intake were associated with decreased all-cause mortality, but not cardiovascular mortality, regardless of average calcium intake. Calcium supplementation was associated with cardiovascular and all-cause mortality amongst women, but not men. Moderate dietary calcium intake may protect against cardiovascular and all-cause mortality and incident stroke. Calcium supplementation may reduce mortality in women.

A prediction tool for vitamin D deficiency in New Zealand adults.

PURPOSE: This study aims to develop a model for predicting vitamin D deficiency in New Zealand adults using easily accessible clinical characteristics. METHODS: Data were derived from the Vitamin D Assessment (ViDA) study dataset. Included participants in the main analysis were aged 50-84 years and resided in Auckland, New Zealand. The dataset was split into a discovery dataset in which the prediction model was developed (n = 2036) and a validation dataset in which it was tested (n = 2037). The prediction model was developed using clinical characteristics in a logistic regression analysis with deseasonalised serum 25OHD (DS-25OHD) as the dependent variable. RESULTS: DS-25OHD < 40 nmol/L was found in 8.2% of European participants, 18.8% of Maori participants, 23.1% of Pacific participants and 52.2% of South Asian participants. Predictors for DS-25OHD < 40 nmol/L in the European sub-cohort included increasing age, female sex, higher body mass index, current smoking, no alcohol intake, lower self-reported general health status, lower physical activity hours, lower outdoor hours and no use of vitamin D-containing supplementation. The area under the curve in the discovery dataset was 0.73, and in the validation dataset was 0.71. Of those with a prediction score ≥ 10 (total risk score range 0-21.5), the sensitivity and specificity for predicting vitamin D deficiency was 0.90 and 0.41, respectively. CONCLUSION: Non-European ethnicity is an important risk factor for vitamin D deficiency. Our vitamin D deficiency prediction model performed well and demonstrates its potential as a tool that can be integrated into clinical practice for the prediction of vitamin D deficiency.

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

BACKGROUND: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. METHODS AND FINDINGS: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. CONCLUSIONS: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.

What factors modify the effect of monthly bolus dose vitamin D supplementation on 25-hydroxyvitamin D concentrations?

The increasing use of vitamin D supplements has stimulated interest in identifying factors that may modify the effect of supplementation on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Such information is of potential interest to researchers, clinicians and patients when deciding on bolus dose of vitamin D supplementation. We carried out a large randomized controlled trial of 5110 adults aged 50-84 years, of European/Other (84%), Polynesian (11%) and Asian (5%) ethnicity, to whom we gave a standard dose of vitamin D3 supplements (200,000 IU initially, then 100,000 IU monthly) which was taken with high adherence. All participants provided a baseline blood sample, and follow-up blood samples were collected at 6 months and annually for 3 years in a random sample of 441 participants, and also at 2 years in 413 participants enrolled in a bone density sub-study. Serum 25(OH)D was measured by LC/MSMS. Mixed model analyses were carried out on all 854 participants providing follow-up blood samples in multivariable models that included age, sex, ethnicity, body mass index (kg/m2), tobacco smoking, alcohol intake, physical activity, sun exposure, season, medical prescription of high-dose vitamin D3 (Cal.D.Forte tablets), asthma/COPD and the study treatment (vitamin D or placebo). The adjusted mean difference in 25(OH)D in the follow-up points between vitamin D supplementation and placebo groups was inversely related (all p for interaction <0.05) to baseline 25(OH)D, BMI, and hours of sun exposure, and higher in females, elders, and those with high frequency of alcohol, medical prescription of vitamin D, and asthma/COPD. The mean difference was not significantly related to ethnicity (p = 0.12), tobacco (p = 0.34), and vigorous activity (p = 0.33). In summary, these data show that vitamin D status, BMI, sun exposure hours, sex and asthma/COPD modify the 25(OH)D response to vitamin D supplementation. By contrast, ethnicity, tobacco smoking, and vigorous activity do not.

Self-Reported Fatigue Predicts Incident Stroke in a General Population: EPIC-Norfolk Prospective Population-Based Study.

Background and Purpose- Fatigue is a common symptom among stroke survivors and in general practice. However, the clinical significance of fatigue and its relationship to incident stroke is unclear. The aim of this study was to examine the relationship between self-reported fatigue and the incidence of stroke in a general population. Methods- This was a prospective, population-based study. The study population was 15 654 men and women aged 39 to 79 years recruited in 1993 to 1997 and followed till March 2016. Fatigue was assessed at 18 months after baseline using the vitality domain of the Short Form 36 questionnaire. Cox proportional hazard models were constructed to describe the prospective relationship between baseline fatigue and incident stroke adjusting for age, sex, systolic blood pressure, cholesterol, physical activity, smoking status, alcohol consumption, fruit and vegetable consumption, diabetes mellitus, body mass index, vitamin supplement use, education level, Townsend deprivation index, and occupational social class. Incident stroke was ascertained using death certificates and hospital record linkage data. Results- Through 249 248 person-years of follow-up, 1509 incident strokes occurred. Participants who reported the highest level of fatigue (quartile 4) were more likely to be women, to be multimorbid, and to perceive their health as fair or poor. We observed ≈50% relative risk increase in stroke risk (hazard ratio, 1.49 [95% CI, 1.29-1.71]) in those who reported the highest level of fatigue compared with those who reported the lowest level of fatigue (Q4 versus Q1). This relationship remained unaltered regardless of anemia status, the presence or absence of chronic bronchitis, thyroid dysfunction, or depression. Conclusions- Self-report fatigue assessed by the vitality domain of the Short Form 36 questionnaire predicts the risk of future stroke at the general population level. Identifying and addressing stroke risk factors in those who report fatigue in general practice may have substantial benefit at the population level.

Effect of Monthly High-Dose Vitamin D Supplementation on Acute Respiratory Infections in Older Adults: A Randomized Controlled Trial.

BACKGROUND: Although adults with low vitamin D status are at increased risk of acute respiratory infection (ARI), randomized controlled trials of vitamin D supplementation have provided inconsistent results. METHODS: We performed a randomized, double-blinded, placebo-controlled trial of 5110 adults aged 50-84 years. In 2011-2012, participants were randomized to an initial oral dose of 200 000 IU vitamin D3 followed by 100 000 IU monthly (n = 2558) or placebo (n = 2552) until late 2013 (median follow-up, 1.6 years). Participants reported upper and lower ARIs on monthly questionnaires. Cox models analyzed time to first ARI (upper or lower) by treatment group. RESULTS: Participants' mean age was 66 years and 58% were male; 83% were of European/other ethnicity, with the rest Maori, Polynesian, or South Asian. Mean (SD) baseline blood 25-hydroxyvitamin D [25(OH)D] level was 63 (24) nmol/L; 25% were <50 nmol/L. In a random sample (n = 441), vitamin D supplementation increased mean 25(OH)D to 135 nmol/L at 3 years, while those on placebo remained at 63 nmol/L. During follow-up, 3737 participants reported ≥1 ARI: 74.1% in the vitamin D group versus 73.7% in the placebo group. The hazard ratio for vitamin D compared with placebo was 1.01 (95% CI, 0.94, 1.07). Similar results were seen in most subgroups, including those with baseline 25(OH)D <50 nmol/L and in analyses of the upper/lower components of the ARI outcome. CONCLUSIONS: Monthly high-dose vitamin D supplementation does not prevent ARI in older adults with a low prevalence of profound vitamin D deficiency at baseline. Whether effects of daily or weekly dosing differ requires further study. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry, identifier ACTRN12611000402943.

Estimated Substitution of Tea or Coffee for Sugar-Sweetened Beverages Was Associated with Lower Type 2 Diabetes Incidence in Case-Cohort Analysis across 8 European Countries in the EPIC-InterAct Study.

INTRODUCTION: Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another. OBJECTIVE: The aim of this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992-2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D. RESULTS: Mean ± SD of estimated consumption of SSB was 55 ± 105 g/d. Means ± SDs for the other beverages were as follows: fruit juice, 59 ± 101 g/d; milk, 209 ± 203 g/d; coffee, 381 ± 372 g/d; and tea, 152 ± 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was -12.0 (95% CI: -20.0, -5.0) per 10,000 person-years among adults consuming SSBs ≥250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or -11.0 (95% CI: -20.0, -2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly. CONCLUSIONS: These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations.

Monthly high-dose vitamin D supplementation does not increase kidney stone risk or serum calcium: results from a randomized controlled trial.

BACKGROUND: A growing number of randomized controlled trials (RCTs) are investigating the potential health benefits of high-dose vitamin D supplementation. However, there are limited RCT data on the safety of calcium-related adverse effects. OBJECTIVE: We investigated the incidence of kidney stone and hypercalcemia events in a large, population-based RCT of vitamin D supplementation. DESIGN: The Vitamin D Assessment (ViDA) study was a randomized, double-blind, placebo-controlled trial of vitamin D supplementation in 5110 participants in Auckland, New Zealand. This trial investigated the impact of monthly 100,000 IU vitamin D3 supplementation over several years on cardiovascular events, respiratory infections, and falls/fractures. Participants provided information about recent kidney stone events in regular questionnaires sent to them with study capsules. Hospitalization data for kidney stones were collected from health authorities. Serum calcium was measured in an 8% subsample of participants who returned annually for blood tests. HRs of time to the first kidney stone event were calculated by Cox regression. RESULTS: During a median follow-up of 3.3 y, 158 participants reported a kidney stone event (76 vitamin D, 82 placebo). The HR of reporting the first kidney stone event was 0.90 (95% CI: 0.66, 1.23; P = 0.51) for participants in the vitamin D arm compared with the placebo arm. There were 18 urolithiasis events in the hospitalization records: 7 in the vitamin D arm and 11 from the placebo arm. The HR to the first hospitalization urolithiasis event was 0.62 (95% CI: 0.24, 1.26; P = 0.30) in the vitamin D arm compared with the placebo arm. From the subsample annual blood test, there was no case of hypercalcemia in the vitamin D arm, compared with 1 in the placebo arm. CONCLUSION: Over a median of 3.3 y, monthly supplementation with 100,000 IU vitamin D3 did not affect the incidence rate of kidney stone events, or hypercalcemia. This study was registered at clinicaltrials.gov as ACTRN12611000402943.

Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status.

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

Cross-sectional associations of vitamin D status with asthma prevalence, exacerbations, and control in New Zealand adults.

BACKGROUND: Previous studies, mostly with children, have reported inconsistent findings on the associations of vitamin D status with asthma prevalence, exacerbations, and control. Because of limited research with adults, we examined these associations in a large community-based sample of New Zealand adults. METHODS: 5110 participants, aged 50-84 years, were recruited from the community into a clinical trial of vitamin D supplementation. The current analysis is based on baseline blood sample collection to measure serum 25-hydroxyvitamin D (25(OH)D), which was deseasonalized for data analyses; and baseline asthma assessment, which included questions on asthma prevalence, urgent medical care for asthma in the previous 12 months, and control of asthma symptoms in the previous 4 weeks. RESULTS: 702 (13.2%) of 5088 participants reported having doctor-diagnosed asthma. There was no difference in mean (SE) 25(OH)D concentration between participants with and without asthma: 66 (0.9) and 66 (0.4) nmol/L, respectively, adjusting for sex (p = 0.71). However, in multivariable analyses restricted to participants who reported having asthma, mean (SE) 25(OH)D concentration was 6.3 (2.6) nmol/L lower in those who reported having urgent medical care for asthma in the previous 12 months compared to others (p = 0.02), and 10.4 (3.9) nmol/L lower in those with very poor asthma control compared to those who were well-controlled (p = 0.03). CONCLUSION: These cross-sectional results suggest that asthmatic adults with lower vitamin D status are more likely to receive urgent asthma medical care and to experience poor asthma control. Clinical trials are needed to determine the role of vitamin D supplementation in asthma management.

Association between serum 25-hydroxyvitamin D levels and self-reported chronic pain in older adults: A cross-sectional analysis from the ViDA study.

Chronic pain is a major contributor to the global burden of disability. Prior studies on the association between serum 25-hydroxyvitamin D (25(OH)D) levels and chronic pain have yielded mixed results. The Vitamin D Assessment study, a large randomized controlled trial from New Zealand, offered the opportunity to examine this association in data collected at baseline in all participants, and among those with arthritis or depression. A total of 5110 participants aged 50-84 years were recruited from community general practices. Chronic pain (lasting ≥6 months) and other baseline characteristics were collected at baseline interview. Serum 25(OH)D concentration was measured by liquid chromatography-tandem mass spectrometry. Associations between 25(OH)D levels and chronic pain were explored using multivariable log-binomial regression to estimate relative risks (RRs). Out of 5049 participants with complete data, 871 (17%) reported having this clinical outcome, and 1254 (25%) had a 25(OH)D concentration <50 nmol/L. There was no significant association between 25(OH)D and chronic pain, with vitamin D status categorized in four groups: <25.0, 25.0-49.9, 50.0-74.9, and ≥75.0 nmol/L (the highest group as reference). The unadjusted RRs were 1.09, 1.10, and 1.08, respectively (Ptrend = 0.24). Adjustment for demographics, lifestyle, BMI, medical history, prescription of analgesics and vitamin D supplements did not change this finding. Similar non-significant results were observed in participants with arthritis (n = 1732) or depression (n = 528). In this multi-ethnic, community-selected sample of older adults in New Zealand, serum 25(OH)D levels were not associated with chronic pain. These results do not support a role for low vitamin D status in the prevalence of chronic pain in older adults.

Coffee and tea consumption and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

The epidemiological evidence regarding the association of coffee and tea consumption with prostate cancer risk is inconclusive, and few cohort studies have assessed these associations by disease stage and grade. We examined the associations of coffee (total, caffeinated and decaffeinated) and tea intake with prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 142,196 men, 7,036 incident prostate cancer cases were diagnosed over 14 years of follow-up. Data on coffee and tea consumption were collected through validated country-specific food questionnaires at baseline. We used Cox proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (CI). Models were stratified by center and age, and adjusted for anthropometric, lifestyle and dietary factors. Median coffee and tea intake were 375 and 106 mL/day, respectively, but large variations existed by country. Comparing the highest (median of 855 mL/day) versus lowest (median of 103 mL/day) consumers of coffee and tea (450 vs. 12 mL/day) the HRs were 1.02 (95% CI, 0.94-1.09) and 0.98 (95% CI, 0.90-1.07) for risk of total prostate cancer and 0.97 (95% CI, 0.79-1.21) and 0.89 (95% CI, 0.70-1.13) for risk of fatal disease, respectively. No evidence of association was seen for consumption of total, caffeinated or decaffeinated coffee or tea and risk of total prostate cancer or cancer by stage, grade or fatality in this large cohort. Further investigations are needed to clarify whether an association exists by different preparations or by concentrations and constituents of these beverages.

Dietary folate intake and pancreatic cancer risk: Results from the European prospective investigation into cancer and nutrition.

Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (≥353 µg/day) compared to the lowest (<241 µg/day) was 0.81 (95% CI: 0.51, 1.31; ptrend = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for ≥353 µg/day vs. <241 µg/day, ptrend = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (pinteraction = 0.99). We found no association between dietary folate intake and PC risk in this large European study.

Monthly high-dose vitamin D3 supplementation and self-reported adverse events in a 4-year randomized controlled trial.

BACKGROUND: The use of high-dose vitamin D supplementation has increased in recent years. However, relatively little is known about the safety of long-term high doses. AIMS: To investigate the safety of a monthly high-dose of vitamin D3 supplementation taken for up to 4 years. METHODS: Data were collected in a randomized, double blind, placebo-controlled trial of 5108 adults aged 50-84 years old from Auckland, New Zealand. Participants were given monthly doses of 100,000 IU vitamin D3 or placebo, for a median of 3.3 years (range 2.5-4.2 years). They answered an open-ended question in a monthly questionnaire about any adverse events they attributed to the study capsules, which were coded blindly. Incidence rates per person months were calculated for categories of adverse events. Cox regression model used to calculate hazard ratio of time to first adverse-event. RESULTS: In total, 419 (16.5%) participants taking vitamin D and 399 (15.8%) taking placebo reported ≥1 adverse event. Compared to placebo, the hazard ratio (HR) of reporting first adverse event in the vitamin D group was 1.03 (95% CI: 0.90, 1.18; p = 0.63). Despite a slightly higher incidence of recurrent adverse events in vitamin D arm, the incidence rate ratio (1.17) was not significantly higher in vitamin D (95% CI: 0.97, 1.41; p = 0.10). All regression results were adjusted for age, sex, and ethnicity. There was no difference between study arms in terms of participants' allocation perception (p = 0.52). CONCLUSION: Monthly supplementation of 100,000 IU vitamin D3 for a median of 3.3 years did not affect participant-reported adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ACTRN12611000402943; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12611000402943.

Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial.

Importance: Previous randomized 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 randomized, double-blind, placebo-controlled trial that recruited participants from family practices and community groups in Auckland, New Zealand, 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 practices and 163 from community groups, 5110 participants were randomized 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 randomization 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 random 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: ACTRN12611000402943.

Circulating isoflavone and lignan concentrations and prostate cancer risk: a meta-analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls.

Phytoestrogens may influence prostate cancer development. This study aimed to examine the association between prediagnostic circulating concentrations of isoflavones (genistein, daidzein, equol) and lignans (enterolactone and enterodiol) and the risk of prostate cancer. Individual participant data were available from seven prospective studies (two studies from Japan with 241 cases and 503 controls and five studies from Europe with 2,828 cases and 5,593 controls). Because of the large difference in circulating isoflavone concentrations between Japan and Europe, analyses of the associations of isoflavone concentrations and prostate cancer risk were evaluated separately. Prostate cancer risk by study-specific fourths of circulating concentrations of each phytoestrogen was estimated using multivariable-adjusted conditional logistic regression. In men from Japan, those with high compared to low circulating equol concentrations had a lower risk of prostate cancer (multivariable-adjusted OR for upper quartile [Q4] vs. Q1 = 0.61, 95% confidence interval [CI] = 0.39-0.97), although there was no significant trend (OR per 75 percentile increase = 0.69, 95 CI = 0.46-1.05, ptrend = 0.085); Genistein and daidzein concentrations were not significantly associated with risk (ORs for Q4 vs. Q1 = 0.70, 0.45-1.10 and 0.71, 0.45-1.12, respectively). In men from Europe, circulating concentrations of genistein, daidzein and equol were not associated with risk. Circulating lignan concentrations were not associated with the risk of prostate cancer, overall or by disease aggressiveness or time to diagnosis. There was no strong evidence that prediagnostic circulating concentrations of isoflavones or lignans are associated with prostate cancer risk, although further research is warranted in populations where isoflavone intakes are high.

Effects of vitamin D supplementation on adherence to and persistence with long-term statin therapy: Secondary analysis from the randomized, double-blind, placebo-controlled ViDA study.

BACKGROUND AND AIMS: Long-term statin use increases survival. However, the adherence to and persistence with statin use are challenging and this influences the success of statin treatment. Our aim was to explore if monthly vitamin D supplementation (100,000-IU) improves the adherence to and persistence with long-term statin use in older adults. METHODS: We conducted a secondary analysis of a trial comparing data on dispensed statin prescriptions, between participants allocated to vitamin D supplementation or placebo, for those taking statin therapy. Primary outcomes were defined as adherence to (proportion of days covered by prescriptions ≥80%) and persistence (non-discontinuation of the statin therapy following an allowed 30 days gap between refills) with all statins over a 24-month measurement period of statin therapy. Secondary outcomes were defined as adherence and persistence at other measurement periods for all types of statins and for individual statins. RESULTS: Overall, 2494 participants were on long-term statins at follow-up (vitamin D = 1243, placebo = 1251). Compared with placebo, monthly vitamin D supplementation did not improve the proportion with adherence (risk ratio: 1.01, p=0.62), but improved the persistence probability of taking all statins after 24 months (hazard ratio: 1.15, p=0.02). In further analyses, significant differences were observed in the adherence to simvastatin, the first-line statin therapy. CONCLUSIONS: Monthly vitamin D supplementation improved persistence with statins use over a 24-month measurement period in older adults on long-term statin therapy, especially for participants on simvastatin. The role of vitamin D supplementation as an adjunct therapy for patients on long-term statins merits further investigation.