Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Serum 25-hydroxyvitamin D concentrations and lung cancer risk in never-smoking postmenopausal women.

PURPOSE: Vitamin D has been implicated in lowering lung cancer risk, but serological data on the association among never-smoking women are limited. We report results examining the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with lung cancer risk among female never smokers. We also examined whether the association was modified by vitamin D supplementation and serum vitamin A concentrations. METHODS: In the Women's Health Initiative, including the calcium/vitamin D (CaD) Trial, we selected 298 incident cases [191 non-small cell lung cancer (NSCLC) including 170 adenocarcinoma] and 298 matched controls of never smokers. Baseline serum 25(OH)D was assayed by a chemiluminescent method. Logistic regression was used to estimate odds ratios (ORs) for quartiles and predefined clinical cutoffs of serum 25(OH)D concentrations. RESULTS: Comparing quartiles 4 versus 1 of serum 25(OH)D concentrations, ORs were 1.06 [95% confidence interval (CI) 0.61-1.84] for all lung cancer, 0.94 (95% CI 0.52-1.69) for NSCLC, and 0.91 (95% CI 0.49-1.68) for adenocarcinoma. Comparing serum 25(OH)D ≥ 75 (high) versus <30 nmol/L (deficient), ORs were 0.76 (95% CI 0.31-1.84) for all lung cancer, 0.71 (95% CI 0.27-1.86) for NSCLC, and 0.81 (95% CI 0.31-2.14) for adenocarcinoma. There is suggestive evidence that CaD supplementation (1 g calcium + 400 IU D3/day) and a high level of circulating vitamin A may modify the associations of 25(OH)D with lung cancer overall and subtypes (p interaction <0.10). CONCLUSIONS: In this group of never-smoking postmenopausal women, the results did not support the hypothesis of an association between serum 25(OH)D and lung cancer risk.

Association of Serum Level of Vitamin D at Diagnosis With Breast Cancer Survival: A Case-Cohort Analysis in the Pathways Study.

IMPORTANCE: There are long-standing interests in the potential benefits of vitamin D for preventing breast cancer recurrence and mortality, yet data from prospective cohort studies are limited. OBJECTIVE: To investigate a serum biomarker of vitamin D status, 25-hydroxyvitamin D (25OHD) measured at the time of breast cancer diagnosis, to determine the association with prognosis. DESIGN, SETTING, AND PARTICIPANTS: The Pathways Study is a prospective cohort study of breast cancer survivors established in 2006. Enrollment was completed in 2013; follow-up is ongoing. The cohort was established in Kaiser Permanente Northern California, a large integrated health care delivery system in northern California. Women with a diagnosis of incident invasive breast cancer were typically consented and enrolled within 2 months of diagnosis. The overall enrollment rate was 46% (4505 of 9820). Participants are followed for health outcomes and comorbidities at 12, 24, 48, 72, and 96 months after baseline interview. A case-cohort design was used for efficiency assay of 25OHD, selecting 1666 cohort members with serum samples and ensuring representation in the subcohort of races and clinical subtypes. The data analysis was performed from January 5, 2014, to March 15, 2015. MAIN OUTCOMES AND MEASURES: Primary outcomes are breast cancer recurrence, second primary cancer, and death. RESULTS: Mean (SD) age was 58.7 (12.4) years. Serum 25OHD concentrations were lower in women with advanced-stage tumors, and the lowest in premenopausal women with triple-negative cancer. Levels were also inversely associated with hazards of disease progression and death. Compared with the lowest tertile, women with the highest tertile of 25OHD levels had superior overall survival (OS). This association remained after adjustment for clinical prognostic factors (hazard ratio [HR], 0.72; 95% CI, 0.54-0.98). Among premenopausal women, the association with OS was stronger, and there were also associations with breast cancer-specific survival and invasive disease-free survival (OS: HR, 0.45; 95% CI, 0.21-0.96; breast cancer-specific survival: HR, 0.37; 95% CI, 0.15-0.93; invasive disease-free survival: HR, 0.58; 95% CI, 0.34-1.01; all after full adjustment). CONCLUSIONS AND RELEVANCE: Serum 25OHD levels were independently associated with breast cancer prognostic characteristics and patient prognosis, most prominently among premenopausal women. Our findings from a large, well-characterized prospective cohort provide compelling observational evidence on associations of vitamin D with lower risk of breast cancer morbidity and mortality.

Estimated intake of vitamin D and its interaction with vitamin A on lung cancer risk among smokers.

Data are very limited on vitamin D and lung cancer prevention in high-risk populations. The authors investigated whether estimated vitamin D intake was associated with lung cancer risk and whether effect modification by vitamin A existed among current/former heavy smokers and workers with occupational exposure to asbestos. A case-cohort study selected 749 incident lung cancers and 679 noncases from the Carotene and Retinol Efficacy Trial (CARET), 1988-2005. The active intervention was supplementation of 30 mg ß-carotene + 25,000 IU retinyl palmitate/day. Baseline total intake including both diet (from food frequency questionnaire) and personal supplements (from brand names linked to the labeled potencies) was assessed. Hazard ratios (HRs) were estimated by Cox proportional hazard models. No significant association of total vitamin D intake with lung cancer was observed overall. However, total vitamin D intake ≥600 versus <200 IU/day was associated with a lower risk of non-small cell lung cancer among former smokers [HR = 0.36, 95% confidence interval (CI) = 0.13-0.96]. Total vitamin D intake ≥400 versus <400 IU/day was associated with a lower risk of total lung cancer among participants who received the CARET active intervention (HR = 0.56, 95% CI = 0.32-0.99) and among those who had total vitamin A intake ≥1,500 µg/day retinol activity equivalent (RAE; HR = 0.46, 95% CI = 0.23-0.91). The beneficial associations were attenuated among those who did not receive the CARET active intervention or who had total vitamin A intake <1,500 µg/day RAE (p-interaction = 0.02 for current smokers). Our observation suggests that vitamin A may assist vitamin D in preventing lung cancer among smokers.

Vitamin D intake determines vitamin d status of postmenopausal women, particularly those with limited sun exposure.

Few detailed data are available on the wide range of determinants of vitamin D status among postmenopausal women, and it is also unclear whether there may be undiscovered determinants. The objective of this study was to comprehensively evaluate determinants of serum 25-hydroxyvitamin D [25(OH)D] concentrations in a large cohort of postmenopausal women. Data from a subset of the Women's Health Initiative Observational Study were analyzed (50-79 y; n = 3345). Information on diet, lifestyle behaviors, secondhand smoke, use of dietary supplements and medication, chronic diseases, and anthropometry was collected at baseline (1993-1998) and on sun exposure at year 4 follow-up. Linear regression was performed to estimate regression coefficients (ß). Significant determinants were total vitamin D intake (food plus supplements per 100 IU/d, ß = 2.08), years of supplemental vitamin D use (ß = 0.15), total fat intake (grams per day, ß = -0.03), smoking status (ß = -2.64, current vs. never), regional solar irradiance (ß = 6.26, 475-500 vs. 300-325 Langleys), daylight time spent outdoors in summer (ß = 5.15, >2 h vs. <30 min/d), recreational physical activity (metabolic equivalent task per hour per week, ß = 0.13), waist circumference (centimeters, ß = -0.26), and race/ethnicity (ß = -11.94, black vs. white). Total vitamin D intake (partial R(2) = 0.09) explained the most variance in serum 25(OH)D concentrations (total R(2) = 0.29). The association between total vitamin D intake and serum 25(OH)D concentrations was stronger among participants who spent less rather than more daylight time outdoors in summer (P-interaction = 0.026). History and medications for hypertension, hyperlipidemia, and type 2 diabetes and secondhand smoke exposure were not associated with serum 25(OH)D. In conclusion, dietary factors and sun exposure remain important determinants of vitamin D status in postmenopausal women. Vitamin D intake should be emphasized for those with limited sun exposure.

Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort.

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994-1995), peri- (1996-1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.

Vitamin D intake and lung cancer risk in the Women's Health Initiative.

BACKGROUND: Prior research suggests that vitamin D protects against lung cancer only among certain subgroups. OBJECTIVES: We investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association. DESIGN: Prospective cohort data from 128,779 postmenopausal women, including 1771 incident lung cancers in the Women's Health Initiative (Clinical Trials and Observational Study) 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g Ca + 400 IU vitamin D3/d) in the Calcium/Vitamin D Trial. Baseline total intake included both dietary intake (from food-frequency questionnaires) and supplement intake (from bottle labels). HRs were estimated by Cox proportional hazard models. RESULTS: No significant association was observed overall. Among never smokers, a total vitamin D intake ≥400 IU/d was significantly associated with lower risks of lung cancer (HR: 0.37; 95% CI: 0.18, 0.77 for ≥800 compared with <100 IU/d; P-trend = 0.01). No significant effect modification of total vitamin A intake on the association between total vitamin D intake and lung cancer was found. However, the Calcium/Vitamin D Trial active intervention was significantly associated with a lower lung cancer risk only among women with a vitamin A intake <1000 µg/d retinol activity equivalents (HR: 0.69; 95% CI: 0.50, 0.96; P-interaction = 0.09). CONCLUSIONS: Vitamin D intake was associated with a lower lung cancer risk in never-smoking, postmenopausal women. Lower vitamin A intake may be important for a beneficial association of 1 g Ca + 400 IU vitamin D3 supplementation with lung cancer. This trial was registered at clinicaltrials.gov as NCT00000611.

B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort.

BACKGROUND: The role of one-carbon metabolism nutrients in colorectal carcinogenesis is not fully understood. Associations might be modified by mandated folic acid (FA) fortification or alcohol intake. OBJECTIVE: We investigated associations between intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and colorectal cancer (CRC) in the Women's Health Initiative Observational Study, stratified by time exposed to FA fortification and alcohol intake. DESIGN: A total of 88,045 postmenopausal women were recruited during 1993-1998; 1003 incident CRC cases were ascertained as of 2009. Quartiles of dietary intakes were compared; HRs and 95% CIs were estimated by Cox proportional hazards models. RESULTS: Dietary and total intakes of vitamin B-6 in quartile 4 compared with quartile 1 (HR: 0.80; 95% CI: 0.66, 0.97 and HR: 0.80; 95% CI: 0.66, 0.99, respectively) and total intakes of riboflavin (HR: 0.81; 95% CI: 0.66, 0.99) were associated with reduced risk of CRC overall and of regionally spread disease. In current drinkers who consumed <1 drink (13 g alcohol)/wk, B vitamin intakes were inversely associated with CRC risk (P-interaction < 0.05). Dietary folate intake was positively associated with CRC risk among women who had experienced the initiation of FA fortification for 3 to <9 y (P-interaction < 0.01). CONCLUSIONS: Vitamin B-6 and riboflavin intakes from diet and supplements were associated with a decreased risk of CRC in postmenopausal women. Associations of B vitamin intake were particularly strong for regional disease and among women drinkers who consumed alcohol infrequently. Our study provides new evidence that the increased folate intake during the early postfortification period may have been associated with a transient increase in CRC risk.

Serum 25-hydroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient-nutrient interaction.

OBJECTIVE: Excess vitamin A may interrupt vitamin D-mediated transcription of target genes. This study investigated whether serum 25-hydroxyvitamin D [25(OH)D] concentrations were associated with lung cancer mortality, and whether this association varied by excess circulating vitamin A and vitamin A/ß-carotene supplement use. METHOD: We analyzed 16,693 men and women in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Lung cancer mortality (n = 258, 104 were former smokers and 23 were never smokers) were identified through National Death Index as of 2006. Serum 25(OH)D was measured by a radioimmunoassay. Vitamin A biomarkers including serum retinol, ß-carotene, and retinyl esters were measured by HPLC. Supplement use for the past month was obtained by self-report. Multivariate-adjusted hazard ratios (HR) were estimated by Cox proportional hazard models. RESULTS: There was no association of serum 25(OH)D with overall lung cancer mortality. Among nonsmokers, ≥44 vs. <44 nmol/L of serum 25(OH)D was associated with a decreased risk (HR = 0.53, 95 % CI = 0.31-0.92, former/never smokers and HR = 0.31, 95 % CI = 0.13-0.77, distant-former [quit ≥20 years]/never smokers). The associations were not observed among participants with excess circulating vitamin A (serum retinyl esters ≥7.0 µg/dL or the ratio of retinyl esters to retinol ≥0.08) or vitamin A/ß-carotene supplement users. However, statistical evidence to support effect modification of vitamin A was less clear. CONCLUSIONS: Serum 25(OH)D concentrations were inversely associated with lung cancer mortality in nonsmokers. The beneficial association was diminished among those with excess circulating vitamin A or vitamin A/ß-carotene supplement users.

All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan.

BACKGROUND: Both end-stage renal disease and chronic kidney disease are increasing worldwide; however, the full effect of chronic kidney disease is unknown because mortality risks for all five stages are unavailable. We assessed prevalence and mortality risks for all stages of chronic kidney disease and quantified its attributable mortality in Taiwan. METHODS: The cohort consisted of 462 293 individuals aged older than 20 years who participated in a standard medical screening programme since 1994. As of Dec 31, 2006, we identified 14 436 deaths. Chronic kidney disease was determined by glomerular filtration rate and urinary protein. We estimated national prevalence in Taiwan from the cohort by adjusting age and educational levels. Hazard ratios (HRs) were calculated with Cox proportionate hazards model. We calculated mortality attributable to chronic kidney disease for national population and for low socioeconomic status. FINDINGS: The national prevalence of chronic kidney disease was 11.93% (95% CI 11.66-12.28), but only 3.54% (3.37-3.68) of participants in the cohort were aware of their disorder. Prevalence was substantially higher in the group with low socioeconomic status than in the high status group (19.87% [19.84-19.91] vs 7.33% [7.31-7.35]). 56 977 (12%) of cohort participants had chronic kidney disease; those with disease had 83% higher mortality for all cause (HR 1.83 [1.73-1.93]) and 100% higher for cardiovascular diseases (2.00 [1.78-2.25]), in a cohort that was observed for 13 years with median follow-up of 7.5 years (IQR 4.0-10.1). 10.3% (95% CI 9.57-11.03) of deaths in the entire population were attributable to chronic kidney disease, but 17.5% (16.27-18.67) of deaths in the low socioeconomic status population. 2350 (39%) deaths occurred before 65 years of age in those with chronic kidney disease. Regular users of Chinese herbal medicines had a 20% (odds ratio 1.20 [1.16-1.24]) increased risk of developing chronic kidney disease. INTERPRETATION: The high prevalence of chronic kidney disease and its associated all-cause mortality, especially in people with low socioeconomic status, make reduction of this disorder a public-health priority. Promotion of its recognition through the general public knowing their glomerular filtration rate and testing their urine is crucial to reduce premature deaths from all causes and to attenuate this global epidemic.