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.

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.

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.

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.

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.

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.

Adverse events from large dose vitamin D supplementation taken for one year or longer.

In recent years, clinical trials increasingly have given large doses of vitamin D supplements to investigate possible health benefits beyond bone at high 25-hydroxyvitamin D levels. However, there are few publications on the safety of high-dose vitamin D given long term. The study objective was to investigate the cumulative relative risk (RR) of total adverse events, kidney stones, hypercalcemia and hypercalciuria from ≥2800 IU/d vitamin D2 or D3 supplementation, followed for one year or more in randomized controlled trials (RCTs). A systematic review was conducted in Medline Ovid, EMBASE and Cochrane in March 2018 to update results of studies published since a previous review in October 2015. RCTs were included if they gave vitamin D2 or D3 at ≥2800 IU/d for at least one year and reported on total adverse events or at least one calcium-related adverse event. There were a total of 32 studies that met the inclusion criteria. Of these, only 15 studies (3150 participants) reported one or more event of the outcomes of interest. Long-term high-dose vitamin D supplementation did not increase total adverse events compared to placebo in 1731 participants from 10 studies (RR = 1.05; 95% CI = 0.88, 1.24; p = 0.61), nor kidney stones in 1336 participants from 5 studies (RR = 1.26; 95% CI = 0.35, 4.58; p = 0.72). However, there was a trend for vitamin D to increase risk of hypercalcemia in 2598 participants from 10 studies (RR = 1.93; 95% CI = 1.00, 3.73; p = 0.05); while its effect on hypercalciuria in only 276 participants from 3 studies was inconclusive (RR = 1.93; 95% CI = 0.83, 4.46; p = 0.12). In conclusion, one year or longer supplementation with a large daily, weekly or monthly dose of vitamin D2 /D3 did not significantly increase a risk of total adverse events or kidney stones, although there was a trend towards increased hypercalcemia, and possibly for hypercalciuria.

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.

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.

Monthly vitamin D supplementation, pain, and pattern of analgesic prescription: secondary analysis from the randomized, double-blind, placebo-controlled Vitamin D Assessment study.

Observational studies suggest that vitamin D deficiency is associated with higher risk of pain. However, evidence on the effect of vitamin D supplementation on pain is limited and contradictory. The aim of this study was to compare the effect of monthly high-dose vitamin D supplementation on a pain impact questionnaire (PIQ-6) score and prescription of analgesics in the general population. We performed a randomized, double-blind, placebo-controlled trial of 5108 community-dwelling participants, aged 50 to 84 years, who were randomly assigned to receive monthly 100,000-IU capsules of vitamin D3 (n = 2558) or placebo (n = 2550) for a median of 3.3 years. The PIQ-6 was administered at baseline, year 1, and final follow-up. Analgesic prescription data were collected from Ministry of Health. There was no difference in mean PIQ-6 score at the end of follow-up (adjusted mean difference: 0.06; P = 0.82) between the vitamin D (n = 2041) and placebo (n = 2014) participants. The proportion of participants dispensed one or more opioids was similar in the vitamin D group (n = 559, 21.9%) compared with placebo (n = 593, 23.3%); the relative risk (RR) adjusted for age, sex, and ethnicity was 0.94 (P = 0.24). Similar results were observed for dispensing of nonsteroidal anti-inflammatory drugs (RR = 0.94; P = 0.24) and other nonopioids (RR = 0.98; P = 0.34). Focusing on vitamin D deficient participants (<50 nmol/L, 24.9%), there was a lower risk of dispensing nonsteroidal anti-inflammatory drugs in the vitamin D group compared with placebo (RR = 0.87; P = 0.009); all other subgroup analyses were not significant. Long-term monthly high-dose vitamin D supplementation did not improve mean PIQ-6 score or reduce analgesic dispensing in the general population.

Effect of Monthly, High-Dose, Long-Term Vitamin D on Lung Function: A Randomized Controlled Trial.

Although observational studies suggest positive vitamin D-lung function associations, randomized trials are inconsistent. We examined effects of vitamin D supplementation on lung function. We recruited 442 adults (50-84 years, 58% male) into a randomized, double-blinded, placebo-controlled trial. Participants received, for 1.1 years (median; range = 0.9-1.5 years), either (1) vitamin D3 200,000 IU, followed by monthly 100,000 IU doses (n = 226); or (2) placebo monthly (n = 216). At baseline and follow-up, spirometry yielded forced expiratory volume in 1 s (FEV1; primary outcome). Mean (standard deviation) 25-hydroxyvitamin D increased from 61 (24) nmol/L at baseline to 119 (45) nmol/L at follow-up in the vitamin D group, but was unchanged in the placebo group. There were no significant lung function improvements (vitamin D versus placebo) in the total sample, vitamin D-deficient participants or asthma/chronic obstructive pulmonary disease (COPD) participants. However, among ever-smokers (n = 217), the mean (95% confidence interval) FEV1 increase in the vitamin D versus placebo was 57 (4, 109) mL (p = 0.03). FEV1 increases were larger among vitamin D-deficient ever-smokers (n = 54): 122 (8, 236) mL (p = 0.04). FEV1 improvements were largest among ever-smokers with asthma/COPD (n = 60): 160 (53, 268) mL (p = 0.004). Thus, vitamin D supplementation did not improve lung function among everyone, but benefited ever-smokers, especially those with vitamin D deficiency or asthma/COPD.

Effect of Monthly, High-Dose, Long-Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy.

BACKGROUND: The effects of monthly, high-dose, long-term (≥1-year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. METHODS AND RESULTS: A total of 517 adults (58% male, aged 50-84 years) were recruited into a double-blinded, placebo-controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9-1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000-IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow-up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25-hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow-up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were -5.3 mm Hg (95% confidence interval [CI], -11.8 to 1.3) for brachial systolic BP (P=0.11), -2.8 mm Hg (95% CI, -6.2 to 0.7) for brachial diastolic BP (P=0.12), -7.5 mm Hg (95% CI, -14.4 to -0.6) for aortic systolic BP (P=0.03), -5.7 mm Hg (95% CI, -10.8 to -0.6) for augmentation index (P=0.03), -0.3 m/s (95% CI, -0.6 to -0.1) for pulse wave velocity (P=0.02), -8.6 mm Hg (95% CI, -15.4 to -1.9) for peak reservoir pressure (P=0.01), and -3.6 mm Hg (95% CI, -6.3 to -0.8) for backward pressure amplitude (P=0.01). CONCLUSIONS: Monthly, high-dose, 1-year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943.

Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial.

BACKGROUND: Adults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls. METHODS: The Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200 000 IU (5·0 mg) colecalciferol (vitamin D3) followed by monthly 100 000 IU (2·5 mg) colecalciferol or equivalent placebo dosing. The prespecified primary outcome was cardiovascular disease and secondary outcomes were respiratory illness and fractures. Here, we report secondary outcome data for fractures and post-hoc outcome data for falls. Cox proportional hazards models were used to estimate hazard ratios (HRs) for time to first fracture or time to first fall in individuals allocated vitamin D compared with placebo. The analysis of fractures included all participants who gave consent and was by intention-to-treat; the analysis of falls included all individuals who returned one or more questionnaires. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000402943. FINDINGS: Between April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65·9 years (SD 8·3) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3·4 years (SD 0·4, range 2·5-4·2). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0·99 (95% CI 0·92-1·07; p=0·82) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1·19 (95% CI 0·94-1·50; p=0·15) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant. INTERPRETATION: High-dose bolus vitamin D supplementation of 100 000 IU colecalciferol monthly over 2·5-4·2 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium. FUNDING: Health Research Council of New Zealand and Accident Compensation Corporation of New Zealand.

Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial.

Importance: Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. Objective: To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. Design, Setting, and Participants: The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults 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 retracted consent, and all others (n = 5108) were included in the primary analysis. Interventions: Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later 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: The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Results: Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Conclusions and Relevance: Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. Trial Registration: clinicaltrials.gov Identifier: ACTRN12611000402943.

The Vitamin D Assessment (ViDA) Study: design of a randomized controlled trial of vitamin D supplementation for the prevention of cardiovascular disease, acute respiratory infection, falls and non-vertebral fractures.

Observational studies have shown that low vitamin D status is associated with an increased risk of cardiovascular disease, acute respiratory infection, falls and non-vertebral fractures. We recruited 5110 Auckland adults, aged 50-84 years, into a randomized, double-blind, placebo-controlled trial to test whether vitamin D supplementation protects against these four major outcomes. The intervention is a monthly cholecalciferol dose of 100,000IU (2.5mg) for an estimated median 3.3 years (range 2.5-4.2) during 2011-2015. Participants were recruited primarily from family practices, plus community groups with a high proportion of Maori, Pacific, or South Asian individuals. The baseline evaluation included medical history, lifestyle, physical measurements (e.g. blood pressure, arterial waveform, lung function, muscle function), and a blood sample (stored at -80°C for later testing). Capsules are being mailed to home addresses with a questionnaire to collect data on non-hospitalized outcomes and to monitor adherence and potential adverse effects. Other data sources include New Zealand Ministry of Health data on mortality, hospitalization, cancer registrations and dispensed pharmaceuticals. A random sample of 438 participants returned for annual collection of blood samples to monitor adherence and safety (hypercalcemia), including repeat physical measurements at 12 months follow-up. The trial will allow testing of a priori hypotheses on several other endpoints including: weight, blood pressure, arterial waveform parameters, heart rate variability, lung function, muscle strength, gait and balance, mood, psoriasis, bone density, and chronic pain.

The global burden of hemorrhagic stroke: a summary of findings from the GBD 2010 study.

This report summarizes the findings of the GBD 2010 (Global Burden of Diseases, Injuries, and Risk Factors) study for hemorrhagic stroke (HS). Multiple databases were searched for relevant studies published between 1990 and 2010. The GBD 2010 study provided standardized estimates of the incidence, mortality, mortality-to-incidence ratios (MIR), and disability-adjusted life years (DALY) lost for HS (including intracerebral hemorrhage and subarachnoid hemorrhage) by age, sex, and income level (high-income countries [HIC]; low- and middle-income countries [LMIC]) for 21 GBD 2010 regions in 1990, 2005, and 2010. In 2010, there were 5.3 million cases of HS and over 3.0 million deaths due to HS. There was a 47% increase worldwide in the absolute number of HS cases. The largest proportion of HS incident cases (80%) and deaths (63%) occurred in LMIC countries. There were 62.8 million DALY lost (86% in LMIC) due to HS. The overall age-standardized incidence rate of HS per 100,000 person-years in 2010 was 48.41 (95% confidence interval [CI]: 45.44 to 52.13) in HIC and 99.43 (95% CI: 85.37 to 116.28) in LMIC, and 81.52 (95% CI: 72.27 to 92.82) globally. The age-standardized incidence of HS increased by 18.5% worldwide between 1990 and 2010. In HIC, there was a reduction in incidence of HS by 8% (95% CI: 1% to 15%), mortality by 38% (95% CI: 32% to 43%), DALY by 39% (95% CI: 32% to 44%), and MIR by 27% (95% CI: 19% to 35%) in the last 2 decades. In LMIC countries, there was a significant increase in the incidence of HS by 22% (95% CI: 5% to 30%), whereas there was a significant reduction in mortality rates of 23% (95% CI: -3% to 36%), DALY lost of 25% (95% CI: 7% to 38%), and MIR by 36% (95% CI: 16% to 49%). There were significant regional differences in incidence rates of HS, with the highest rates in LMIC regions such as sub-Saharan Africa and East Asia, and lowest rates in High Income North America and Western Europe. The worldwide burden of HS has increased over the last 2 decades in terms of absolute numbers of HS incident events. The majority of the burden of HS is borne by LMIC. Rates for HS incidence, mortality, and DALY lost, as well as MIR decreased in the past 2 decades in HIC, but increased significantly in LMIC countries, particularly in those patients ≤75 years. HS affected people at a younger age in LMIC than in HIC. The lowest incidence and mortality rates in 2010 were in High Income North America, Australasia, and Western Europe, whereas the highest rates were in Central Asia, Southeast Asia, and sub-Saharan Africa. These results suggest that reducing the burden of HS is a priority particularly in LMIC. The GBD 2010 findings may be a useful resource for planning strategies to reduce the global burden of HS.

The global burden of ischemic stroke: findings of the GBD 2010 study.

This study sought to summarize the findings of the GBD 2010 (Global Burden of Diseases, Injuries, and Risk Factors) study for ischemic stroke (IS) and to report the impact of tobacco smoking on IS burden in specific countries. The GBD 2010 searched multiple databases to identify relevant studies published between 1990 and 2010. The GBD 2010 analytical tools were used to calculate region-specific IS incidence, mortality, mortality-to-incidence ratio, and disability-adjusted life years (DALY) lost, including 95% uncertainty intervals (UI). In 2010, there were approximately 11,569,000 incident IS events (63% in low- and middle-income countries [LMIC]), approximately 2,835,000 deaths from IS (57% in LMIC), and approximately 39,389,000 DALY lost due to IS (64% in LMIC). From 1990 to 2010, there was a significant increase in global IS burden in terms of absolute number of people with incident IS (37% increase), deaths from IS (21% increase), and DALY lost due to IS (18% increase). Age-standardized IS incidence, DALY lost, mortality, and mortality-to-incidence ratios in high-income countries declined by about 13% (95% UI: 6% to 18%), 34% (95% UI: 16% to 36%), and 37% (95% UI: 19% to 39%), 21% (95% UI: 10% to 27%), respectively. However, in LMIC there was a modest 6% increase in the age-standardized incidence of IS (95% UI: -7% to 18%) despite modest reductions in mortality rates, DALY lost, and mortality-to-incidence ratios. There was considerable variability among country-specific estimates within broad GBD regions. China, Russia, and India were ranked highest in both 1990 and 2010 for IS deaths attributable to tobacco consumption. Although age-standardized IS mortality rates have declined over the last 2 decades, the absolute global burden of IS is increasing, with the bulk of DALY lost in LMIC. Tobacco consumption is an important modifiable risk factor for IS, and in both 1990 and 2010, the top ranked countries for IS deaths that could be attributed to tobacco consumption were China, Russia, and India. Tobacco control policies that target both smoking initiation and smoking cessation can play an important role in the prevention of IS. In China, Russia, and India, even modest reductions in the number of current smokers could see millions of lives saved due to prevention of IS alone.

Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.

BACKGROUND: Although stroke is the second leading cause of death worldwide, no comprehensive and comparable assessment of incidence, prevalence, mortality, disability, and epidemiological trends has been estimated for most regions. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the global and regional burden of stroke during 1990-2010. METHODS: We searched Medline, Embase, LILACS, Scopus, PubMed, Science Direct, Global Health Database, the WHO library, and WHO regional databases from 1990 to 2012 to identify relevant studies published between 1990 and 2010.We applied the GBD 2010 analytical technique (DisMod-MR), based on disease-specific, pre-specified associations between incidence, prevalence, and mortality, to calculate regional and country-specific estimates of stroke incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) lost by age group (<75 years, ≥ 75 years, and in total)and country income level (high-income, and low-income and middle-income) for 1990, 2005, and 2010. FINDINGS: We included 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). From 1990 to 2010, the age-standardised incidence of stroke significantly decreased by 12% (95% CI 6-17)in high-income countries, and increased by 12% (-3 to 22) in low-income and middle-income countries, albeit nonsignificantly. Mortality rates decreased significantly in both high income (37%, 31-41) and low-income and middle income countries (20%, 15-30). In 2010, the absolute numbers of people with fi rst stroke (16・9 million), stroke survivors (33 million), stroke-related deaths (5・9 million), and DALYs lost (102 million) were high and had significantly increased since 1990 (68%, 84%, 26%, and 12% increase, respectively), with most of the burden (68・6% incident strokes, 52・2% prevalent strokes, 70・9% stroke deaths, and 77・7% DALYs lost) in low-income and middle-income countries. In 2010, 5・2 million (31%) strokes were in children (aged <20 years old) and young and middle-aged adults(20-64 years), to which children and young and middle-aged adults from low-income and middle-income countries contributed almost 74 000 (89%) and 4・0 million (78%), respectively, of the burden. Additionally, we noted significant geographical differences of between three and ten times in stroke burden between GBD regions and countries. More than 62% of new strokes, 69・8% of prevalent strokes, 45・5% of deaths from stroke, and 71・7% of DALYs lost because of stroke were in people younger than 75 years. INTERPRETATION: Although age-standardised rates of stroke mortality have decreased worldwide in the past two decades,the absolute number of people who have a stroke every year, stroke survivors, related deaths, and the overall global burden of stroke (DALYs lost) are great and increasing. Further study is needed to improve understanding of stroke determinants and burden worldwide, and to establish causes of disparities and changes in trends in stroke burden between countries of different income levels. FUNDING: Bill & Melinda Gates Foundation.

The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis.

BACKGROUND: The effects of systolic blood pressure (SBP), serum total cholesterol (TC), fasting plasma glucose (FPG), and body mass index (BMI) on the risk of cardiovascular diseases (CVD) have been established in epidemiological studies, but consistent estimates of effect sizes by age and sex are not available. METHODS: We reviewed large cohort pooling projects, evaluating effects of baseline or usual exposure to metabolic risks on ischemic heart disease (IHD), hypertensive heart disease (HHD), stroke, diabetes, and, as relevant selected other CVDs, after adjusting for important confounders. We pooled all data to estimate relative risks (RRs) for each risk factor and examined effect modification by age or other factors, using random effects models. RESULTS: Across all risk factors, an average of 123 cohorts provided data on 1.4 million individuals and 52,000 CVD events. Each metabolic risk factor was robustly related to CVD. At the baseline age of 55-64 years, the RR for 10 mmHg higher SBP was largest for HHD (2.16; 95% CI 2.09-2.24), followed by effects on both stroke subtypes (1.66; 1.39-1.98 for hemorrhagic stroke and 1.63; 1.57-1.69 for ischemic stroke). In the same age group, RRs for 1 mmol/L higher TC were 1.44 (1.29-1.61) for IHD and 1.20 (1.15-1.25) for ischemic stroke. The RRs for 5 kg/m(2) higher BMI for ages 55-64 ranged from 2.32 (2.04-2.63) for diabetes, to 1.44 (1.40-1.48) for IHD. For 1 mmol/L higher FPG, RRs in this age group were 1.18 (1.08-1.29) for IHD and 1.14 (1.01-1.29) for total stroke. For all risk factors, proportional effects declined with age, were generally consistent by sex, and differed by region in only a few age groups for certain risk factor-disease pairs. CONCLUSION: Our results provide robust, comparable and precise estimates of the effects of major metabolic risk factors on CVD and diabetes by age group.