The effect of three years of vitamin D supplementation on erectile dysfunction: Results from the randomized placebo-controlled D-Health Trial.

BACKGROUND & AIMS: Erectile dysfunction is common among older men and has been associated with low serum 25-hydroxy vitamin D concentration. However, this association may be due to uncontrolled confounding, and there is a paucity of evidence from interventional studies. We aimed to examine the effect of vitamin D supplementation on the prevalence of erectile dysfunction, in an exploratory analysis using data from a large randomized controlled trial. METHODS: The D-Health Trial recruited Australians aged 60-84 years between January 2014 and May 2015 and randomly assigned them to supplementation with 60,000 IU of vitamin D or placebo per month for up to 5 years. Blood samples were collected annually from randomly selected participants (total N = 3943). We assessed erectile dysfunction at the end of the third year of follow-up. We used log-binomial regression to examine the effect of vitamin D on the prevalence of erectile dysfunction overall, and within sub-groups. RESULTS: Of the 11,530 men enrolled, 8920 (77.4 %) completed the erectile dysfunction question and were included in the analysis. After three years of supplementation, the mean serum 25-hydroxy vitamin D concentration was 76 nmol/L (standard deviation (SD) 24.94) in the placebo group and 106 nmol/L (SD 26.76) in the vitamin D group (p < 0.0001). The prevalence of erectile dysfunction was 58.8 % and 59.0 % in the vitamin D and placebo groups, respectively (prevalence ratio 1.00, 95 % CI 0.97, 1.03); there was no evidence of an effect of vitamin D in any subgroup analyses. CONCLUSION: Supplementing older men with vitamin D is unlikely to prevent or improve erectile dysfunction. CLINICAL TRIALS REGISTRY: (ACTRN12613000743763).

Association between unstable diabetes mellitus and risk of pancreatic cancer.

BACKGROUND: Deterioration of glycaemic control in people with long-standing diabetes mellitus (diabetes) may be a possible indicator of pancreatic cancer. However, the magnitude of the association between diabetes deterioration and pancreatic cancer has received little attention. METHODS: We conducted a matched cohort study, nested within a population-based cohort of Australian women with diabetes. Women with unstable diabetes, defined as a change in medication after a 2-year period of stable medication use, were matched by birth year to those with stable diabetes, in a 1:4 ratio. We used flexible parametric survival models to estimate hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: We included 134,954 and 539,789 women in the unstable and stable diabetes cohorts, respectively (mean age 68 years). In total, 1,315 pancreatic cancers were diagnosed. Deterioration of stable diabetes was associated with a 2.5-fold increased risk of pancreatic cancer (HR 2.55; 95% CI 2.29-2.85). The risk was particularly high within the first year after diabetes deteriorated. HRs at 3 months, 6 months and 1 year were: 5.76 (95% CI 4.72-7.04); 4.56 (95% CI 3.81-5.46); and 3.33 (95% CI 2.86-3.89), respectively. The risk was no longer significantly different after 7 years. CONCLUSIONS: Deterioration in glycaemic control in people with previously stable diabetes may be an indicator of pancreatic cancer, suggesting investigations of the pancreas may be appropriate. The weaker longer-term (3-7 years) association between diabetes deterioration and pancreatic cancer may indicate that poor glycaemic control can be a risk factor for pancreatic cancer.

The Effect of Vitamin D Supplementation on Hypothyroidism in the Randomized Controlled D-Health Trial.

Background: Hypothyroidism is common, and in iodine-sufficient areas, it is primarily caused by autoimmune destruction of the thyroid gland. Observational studies have consistently shown an inverse association between serum 25-hydroxyvitamin D concentration and autoimmune diseases; however, there is a lack of evidence from randomized controlled trials to support a benefit of vitamin D supplementation, particularly for autoimmune thyroid diseases. We, therefore, aimed to assess the effect of vitamin D supplementation on the incidence of hypothyroidism. Methods: We analyzed data from the D-Health Trial (n = 21,315), a randomized double-blind placebo-controlled trial of 60,000 international units per month of supplemental vitamin D3 among Australians aged 60 years and over. Hypothyroidism, a tertiary outcome of the D-Health Trial, was defined by treatment with levothyroxine, ascertained through linkage with the Australian Pharmaceutical Benefits Scheme. The outcome was time to first prescription of levothyroxine. We began follow-up at 12 months after randomization; people who had died or who had been dispensed levothyroxine during the first year were excluded. Flexible parametric survival models were used to assess the effect of vitamin D supplementation on hypothyroidism, overall and within strata defined by age, sex, body mass index, and predicted baseline vitamin D status. Results: We included 17,851 participants in the main analysis (vitamin D = 8939; placebo = 8912). During a median follow-up of 4.1 years (interquartile range 4.1-4.1), 293 participants developed hypothyroidism (vitamin D = 138 [1.5%]; placebo = 155 [1.7%]). Vitamin D supplementation did not significantly reduce the incidence of hypothyroidism (overall hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.71-1.12). There was some suggestion of an effect in females (overall HR 0.78; CI 0.58-1.06) but not in males (overall HR 1.06; CI 0.74-1.50; p interaction 0.20). Conclusions: Vitamin D supplementation did not reduce the incidence of hypothyroidism overall; however, the possible beneficial effect observed in females warrants further investigation. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763.

Serum 25(OH)D Concentration, Vitamin D Supplementation, and Risk of Cardiovascular Disease and Mortality in Patients with Type 2 Diabetes or Prediabetes: a Systematic Review and Dose-Response Meta-Analysis.

BACKGROUND: Evidence is uncertain about the association between serum 25-hydroxyvitamin D (25(OH)D) concentration and health outcomes in people with type 2 diabetes. OBJECTIVES: We aimed to assess the association between vitamin D status and all-cause mortality and cardiovascular disease in people with type 2 diabetes. METHODS: We did a systematic search in PubMed, Scopus, CENTRAL, and Web of Science until May 2022. We selected 1) cohort studies investigating the association between serum 25(OH)D concentration and mortality or cardiovascular disease in people with type 2 diabetes or prediabetes and 2) randomized trials of vitamin D supplementation in these patients. We used random-effects pairwise meta-analyses to calculate summary relative risks (RRs) and 95% confidence intervals (CI). RESULTS: 21 cohort studies and 6 randomized trials were included. Compared with sufficient vitamin D status (≥50 nmol/L), the RR of all-cause mortality was 1.36 (95% CI: 1.23, 1.49; n = 11 studies, GRADE = moderate) for vitamin D insufficiency (25 to <50 nmol/L), and 1.58 (1.33, 1.83; n = 16, GRADE = moderate) for deficiency (<25 nmol/L). Similar findings were observed for cardiovascular mortality and morbidity but not for cancer mortality. The certainty of evidence ranged from very low to moderate. Dose-response meta-analyses indicated nonlinear associations, with the lowest risk at 25(OH)D ∼60 nmol/L for all-cause and cardiovascular mortality. Supplementation with vitamin D did not reduce the risk of all-cause mortality (RR: 0.96, 95% CI: 0.79, 1.16; risk difference per 1000 patients: 3 fewer, 95% CI: 16 fewer, 12 more; n = 6 trials with 7316 participants; GRADE = low) or the risk of cardiovascular mortality and morbidity (very low- to low-certainty evidence). CONCLUSIONS: Vitamin D deficiency and insufficiency are associated with a higher risk of all-cause and cardiovascular mortality in patients with type 2 diabetes or prediabetes. Vitamin D deficiency should be corrected in patients with type 2 diabetes to reach normal serum 25(OH)D concentrations, preferably 60 nmol/L. SYSTEMATIC REVIEW REGISTRATION: This systemic review was registered at PROSPERO as CRD42022326429 (=https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=326429).

The effect of vitamin D supplementation on the gut microbiome in older Australians - Results from analyses of the D-Health Trial.

Observational studies suggest a link between vitamin D and the composition of the gut microbiome, but there is little evidence from randomized controlled trials of vitamin D supplementation. We analyzed data from the D-Health Trial, a randomized, double-blind, placebo-controlled trial. We recruited 21,315 Australians aged 60-84 y and randomized them to 60,000 IU of vitamin D3 or placebo monthly for 5 y. Stool samples were collected from a sample of 835 participants (417 in the placebo and 418 in the vitamin D group) approximately 5 y after randomization. We characterized the gut microbiome using 16S rRNA gene sequencing. We used linear regression to compare alpha diversity indices (i.e. Shannon index (primary outcome), richness, inverse Simpson index), and the ratio of Firmicutes to Bacteroidetes between the two groups. We analyzed between-sample (beta) diversity (i.e. Bray Curtis distance and UniFrac index) using principal coordinate analysis and used PERMANOVA to test for significant clustering according to randomization group. We also assessed the difference in the abundance of the 20 most abundant genera between the two groups using negative binomial regression model with adjustment for multiple testing. Approximately half the participants included in this analysis were women (mean age 69.4 y). Vitamin D supplementation did not alter the Shannon diversity index (mean 3.51 versus 3.52 in the placebo and vitamin D groups, respectively, p = 0.50). Similarly, there was little difference between the groups for other alpha diversity indices, the abundance of different genera, and the Firmicutes-to-Bacteroidetes ratio. We did not observe clustering of bacterial communities according to randomization group. In conlusion, monthly doses of 60,000 IU of vitamin D supplementation for 5 y did not alter the composition of the gut microbiome in older Australians.

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial.

OBJECTIVE: To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events. DESIGN: Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments. SETTING: Australia from 2014 to 2020. PARTICIPANTS: 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment. INTERVENTION: 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%). MAIN OUTCOME MEASURES: The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was -5.8 events per 1000 participants (95% confidence interval -12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23). CONCLUSIONS: Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease. TRIAL REGISTRATION: ACTRN12613000743763.

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 %.

The effect of monthly vitamin D supplementation on fractures: a tertiary outcome from the population-based, double-blind, randomised, placebo-controlled D-Health trial.

BACKGROUND: Low serum 25-hydroxy vitamin D concentration is associated with increased fracture risk. It is uncertain whether vitamin D supplementation reduces fractures, or whether intermittent doses are harmful. We aimed to investigate if supplementing adults living in Australia with monthly doses of 60 000 international units (IU) vitamin D3 for 5 years or less altered the rate of fractures. METHODS: We did a population-based, double-blind, randomised, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) for up to 5 years in adults aged 60-84 years living in Australia. We randomly assigned (1:1) 21 315 participants to either vitamin D or placebo. We ascertained fractures through linkage with administrative datasets. The main outcome was total fractures. Additional outcomes were non-vertebral, major osteoporotic (hip, wrist, proximal humerus, and spine), and hip fractures. We excluded participants (989 [4·6%]) without linked data, and estimated hazard ratios (HRs) and 95% CIs using flexible parametric survival models. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763, and the trial intervention ended in February, 2020. FINDINGS: Between Feb 14, 2014, and June 17, 2015, we recruited 21 315 participants. For the current analysis, we included 20 326 participants (vitamin D 10 154 [50·0%]; placebo 10 172 [50·0%]). 9295 (45·7%) of 20 326 participants were women and the mean age was 69·3 years (SD 5·5). Over a median follow-up of 5·1 years (IQR 5·1-5·1), 568 (5·6%) participants in the vitamin D group and 603 (5·9%) in the placebo group had one or more fractures. There was no effect on fracture risk overall (HR 0·94 [95% CI 0·84-1·06]), and the interaction between randomisation group and time was not significant (p=0·14). However, the HR for total fractures appeared to decrease with increasing follow-up time. The overall HRs for non-vertebral, major osteoporotic, and hip fractures were 0·96 (95% CI 0·85-1·08), 1·00 (0·85-1·18), and 1·11 (0·86-1·45), respectively. INTERPRETATION: These findings do not support concerns that bolus doses of vitamin D administered monthly increase fracture risk. Long-term supplementation might reduce the incidence of total fractures, but additional research is needed to clarify this effect. FUNDING: Australian National Health and Medical Research Council.

Vitamin D and Sun Exposure: A Community Survey in Australia.

Sun exposure carries both harms and benefits. Exposing the skin to the sun is the main modifiable cause of skin cancers, which exert a considerable health and economic burden in Australia. The most well-established benefit of exposure to ultraviolet (UV) radiation is vitamin D production. Australia has the highest incidence of skin cancer in the world but, despite the high ambient UV radiation, approximately one quarter of the population is estimated to be vitamin D deficient. Balancing the risks and benefits is challenging and requires effective communication. We sought to provide a snapshot of public knowledge and attitudes regarding sun exposure and vitamin D and to examine the associations between these factors and sun protective behaviors. In 2020 we administered an online survey; 4824 participants with self-reported fair or medium skin color were included in this analysis. Only 25% and 34% of participants were able to identify the amount of time outdoors needed to maintain adequate vitamin D status in summer and winter, respectively and 25% were concerned that sunscreen use inhibits vitamin D synthesis. This lack of knowledge was associated with suboptimal sun protection practices. Public education is warranted to prevent over-exposure, while supporting natural vitamin D production.

Vitamin D supplementation and hospitalization for infection in older adults: A post-hoc analysis of data from the Australian D-Health Trial.

BACKGROUND: Evidence suggests that vitamin D influences the immune system. Recent studies indicate that vitamin D supplementation may reduce the severity of infections, but this has not been confirmed. OBJECTIVES: The objective of this study was to assess the effect of vitamin D supplementation on hospitalization for infection. METHODS: The D-Health Trial was a randomized, double-blind, placebo-controlled trial of monthly 60,000 international units of vitamin D3 for 5 y among 21,315 Australians aged 60-84 y. Hospitalization for infection, ascertained through linkage with hospital admitted patient data, is a tertiary outcome of the trial. The primary outcome for this post-hoc analysis was hospitalization for any infection. Secondary outcomes were extended hospitalization for infection (length of stay >3 d and >6 d) and hospitalization for respiratory tract, skin, and gastrointestinal infections. We used negative binomial regression to estimate the effect of vitamin D supplementation on outcomes. RESULTS: Participants (46% women, mean age: 69 y), were followed up for a median of 5 y. Vitamin D supplementation had little or no effect on the incidence of hospitalization for any infection [incidence rate ratio (IRR): 0.95; 95% CI: 0.86, 1.05], respiratory tract (IRR: 0.93; 95% CI: 0.81, 1.08), skin (IRR: 0.95; 95% CI: 0.76, 1.20), gastrointestinal infections (IRR: 1.03; 95% CI: 0.84, 1.26), or hospitalizations lasting >3 d (IRR: 0.94; 95% CI: 0.81, 1.09), with all CIs consistent with a null finding. People supplemented with vitamin D had fewer hospitalizations lasting >6 d (IRR: 0.80; 95% CI: 0.65, 0.99). CONCLUSIONS: We did not find a protective effect of vitamin D on hospitalization for infection, but it reduced the number of extended hospitalizations. In populations where few people are vitamin D deficient, the effect of population-wide supplementation is likely to be small, but these findings support previous studies suggesting that vitamin D plays a role in infectious disease. The D-Health Trial is registered at the Australian New Zealand Clinical Trials Registry as ACTRN12613000743763.

Vitamin D supplementation and cognition-Results from analyses of the D-Health trial.

BACKGROUND: Observational studies have consistently found a link between low serum 25-hydroxyvitamin D concentration and higher risk of cognitive impairment. Results from randomized controlled trials have been mixed, and few have been conducted in the general population. METHODS: We recruited 21,315 community-dwelling Australians aged between 60 and 84 years to participate in the D-Health Trial, a randomized, double-blind, placebo-controlled trial. The intervention was monthly oral doses of 60,000 international units of vitamin D or placebo for 5 years. We assessed cognitive function in a randomly sampled group of participants aged ≥70 years using the Telephone Interview for Cognitive Status (TICS) at 2 and 5 years after randomization. The primary outcome for this analysis was TICS score; the secondary outcome was the proportion of people who had cognitive impairment (defined as TICS score ≤25). We analyzed data using mixed models (linear and logistic). RESULTS: We interviewed 3887 participants at year 2 and 3614 participants at year 5. The mean TICS score at these time points was 32.3 and 32.2, respectively. Vitamin D supplementation did not affect cognitive function as measured by TICS score (mean difference between vitamin D and placebo groups 0.04; 95% CI -0.14 to 0.23), or alter risk of cognitive impairment (odds ratio 1.00; 95% CI 0.75 to 1.33). CONCLUSIONS: Monthly bolus doses of vitamin D supplementation neither enhanced nor hindered cognitive function among older adults. Population-wide vitamin D supplementation of older adults that are largely vitamin D replete is unlikely to substantially benefit cognition.

Vitamin D Supplementation and the Incidence of Cataract Surgery in Older Australian Adults.

PURPOSE: Observational studies suggest that higher serum 25-hydroxy vitamin D (25(OH)D) concentration may be associated with lower risk of cataract. However, no randomized controlled trials have assessed the effect of vitamin D supplementation on the incidence of cataract. We aimed to assess whether vitamin D supplementation reduces the incidence of cataract surgery. DESIGN: We conducted an ancillary study of the D-Health Trial, a randomized, double-masked, placebo-controlled trial of monthly vitamin D conducted from 2014 through 2020 within the Australian general population. PARTICIPANTS: We invited 421 207 men and women 60 to 84 years of age to participate; including an additional 1896 volunteers, 40 824 expressed interest. Those with hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis or those who were taking more than 500 international units (IU) supplemental vitamin D per day were excluded. A total of 21 315 were randomized, and 1390 participants did not fulfil the eligibility criteria for this analysis (linked data available, no cataract within first 6 months), leaving 19 925 included. The median follow-up was 5 years. METHODS: Participants took 60 000 IU of vitamin D3 (n = 10 662) or placebo (n = 10 653) orally once per month for a maximum of 5 years. MAIN OUTCOME MEASURES: The primary outcome for this analysis was the first surgical treatment for cataract, ascertained through linkage to universal health insurance records and hospital data. RESULTS: Among 19 925 participants eligible for this analysis (mean age, 69.3 years; 46% women) 3668 participants (18.4%) underwent cataract surgery during follow-up (vitamin D: n = 1841 [18.5%]; placebo: n = 1827 [18.3%] ). The incidence of cataract surgery was similar between the two groups (incidence rate, 41.6 and 41.1 per 1000 person-years in the vitamin D and placebo groups, respectively; hazard ratio, 1.02; 95% confidence interval, 0.95-1.09). In prespecified subgroup analyses, the effect of vitamin D supplementation on the incidence of cataract surgery was not modified by age, sex, body mass index, predicted serum 25(OH)D concentration, or ambient ultraviolet radiation. CONCLUSIONS: Routinely supplementing older adults who live in an area with a low prevalence of vitamin D deficiency with high-dose vitamin D is unlikely to reduce the need for cataract surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effect of vitamin D supplementation on depression in older Australian adults.

OBJECTIVES: To investigate whether vitamin D supplementation reduces depressive symptoms and incidence of antidepressant use. METHODS: We used data from the D-Health Trial (N = 21,315), a randomized double-blind placebo-controlled trial of monthly vitamin D3 for the prevention of all-cause mortality. Participants were Australians aged 60-84 years. Participants completed the Patient Health Questionnaire (PHQ-9) at 1, 2 and 5 years after randomization to measure depressive symptoms; national prescribing records were used to capture antidepressant use. We used mixed models and survival models. RESULTS: Analyses of PHQ-9 scores included 20,487 participants (mean age 69·3 years, 46% women); the mean difference (MD) in PHQ-9 score (vitamin D vs. placebo) was 0·02 (95% CI -0·06, 0·11). There was negligible difference in the prevalence of clinically relevant depression (PHQ-9 score ≥10) (odds ratio 0·99; 95% CI 0·90, 1·08). We included 16,670 participants in the analyses of incident antidepressant use (mean age 69·4 years, 43% women). Incidence of antidepressant use was similar between the groups (hazard ratio [HR] 1·04; 95% CI 0·96, 1·12). In subgroup analyses, vitamin D improved PHQ-9 scores in those taking antidepressants at baseline (MD -0·25; 95% CI -0·49, -0·01; p-interaction = 0·02). It decreased risk of antidepressant use in participants with predicted 25(OH)D concentration <50 nmol/L (HR 0·88; 95% CI 0·75, 1·02; p-interaction = 0·01) and increased risk in those with predicted 25(OH)D ≥ 50 nmol/L (HR 1·10; 95% CI 1·01, 1·20). CONCLUSION: Monthly supplementation with high-dose vitamin D3 was not of benefit for measures of depression overall, but there was some evidence of benefit in subgroup analyses. CLINICAL TRIAL REGISTRATION: The trial is registered on the Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/.

The effect of vitamin D supplementation on pain: an analysis of data from the D-Health randomised controlled trial.

Observational studies suggest that 25-hydroxy vitamin D (25(OH)D) concentration is inversely associated with pain. However, findings from intervention trials are inconsistent. We assessed the effect of vitamin D supplementation on pain using data from a large, double-blind, population-based, placebo-controlled trial (the D-Health Trial). 21 315 participants (aged 60-84 years) were randomly assigned to a monthly dose of 60 000 IU vitamin D3 or matching placebo. Pain was measured using the six-item Pain Impact Questionnaire (PIQ-6), administered 1, 2 and 5 years after enrolment. We used regression models (linear for continuous PIQ-6 score and log-binomial for binary categorisations of the score, namely 'some or more pain impact' and 'presence of any bodily pain') to estimate the effect of vitamin D on pain. We included 20 423 participants who completed ≥1 PIQ-6. In blood samples collected from 3943 randomly selected participants (∼800 per year), the mean (sd) 25(OH)D concentrations were 77 (sd 25) and 115 (sd 30) nmol/l in the placebo and vitamin D groups, respectively. Most (76 %) participants were predicted to have 25(OH)D concentration >50 nmol/l at baseline. The mean PIQ-6 was similar in all surveys (∼50·4). The adjusted mean difference in PIQ-6 score (vitamin D cf placebo) was 0·02 (95 % CI (-0·20, 0·25)). The proportion of participants with some or more pain impact and with the presence of bodily pain was also similar between groups (both prevalence ratios 1·01, 95 % CI (0·99, 1·03)). In conclusion, supplementation with 60 000 IU of vitamin D3/month had negligible effect on bodily pain.

The effect of vitamin D supplementation on risk of keratinocyte cancer: an exploratory analysis of the D-Health randomized controlled trial.

BACKGROUND: Vitamin D may play a role in prevention of keratinocyte cancer (KC), but observational studies examining the association between serum 25-hydroxy vitamin D concentration and KC are largely uninformative because sun exposure causes both KC and vitamin D production. There is scant evidence from clinical trials of supplementary vitamin D. OBJECTIVES: To examine the effect of vitamin D supplementation on the risk of developing KC. METHODS: We used data from the D-Health Trial, a randomized placebo-controlled trial of vitamin D supplementation (60 000 international units monthly for 5 years) among Australians aged ≥60 years. KC outcomes were captured through linkage to a national administrative dataset for those who consented (N = 20 334; 95%). We used negative binomial regression to analyse the incidence of KC excisions and the incidence of actinic lesions treated using cryotherapy or serial curettage, and flexible parametric survival models for analysis of time to first KC excision. RESULTS: Randomization to vitamin D supplementation did not reduce the incidence of KC lesions treated by excision [incidence rate ratio (IRR) 1·04; 95% confidence interval (CI) 0·98-1·11], the incidence of actinic lesions treated using other methods (IRR 1·01; 95% CI 0·95-1·08) or time to first histologically confirmed KC excision (hazard ratio 1·02; 95% CI 0·97-1·08). However, in subgroup analysis vitamin D increased the incidence of KC excisions in adults aged ≥ 70 years (IRR 1·13, 95% CI 1·04-1·23; P-value for interaction = 0·01). CONCLUSIONS: Vitamin D supplementation did not reduce the incidence of KC or other actinic lesions. What is already known about this topic? Laboratory studies have suggested possible protective effects of vitamin D on skin cancer. Observational studies investigating the association between vitamin D and risk of keratinocyte cancer are largely uninformative as ultraviolet radiation both causes skin cancer and is the primary source of vitamin D. The evidence from randomized controlled trials of vitamin D is limited and inconclusive. What does this study add? This population-based, randomized controlled trial suggests that supplementing older adults with a high monthly dose of vitamin D for 5 years does not affect the incidence of keratinocyte cancer.

Vitamin D Supplementation and Antibiotic Use in Older Australian Adults: An Analysis of Data From the D-Health Trial.

BACKGROUND: Vitamin D supplementation may reduce the risk or severity of infection, but this has been investigated in few large population-based trials. We analyzed data from the D-Health Trial, using prescription of antibiotics as a surrogate for infection. METHODS: The D-Health Trial is a randomized, double-blind, placebo-controlled trial in which 21 315 Australians aged 60-84 years were randomized to 60 000 IU of supplementary vitamin D3 or placebo monthly for 5 years. For this analysis, the primary outcome was the number of antibiotic prescription episodes; secondary outcomes were total number of prescriptions, repeat prescription episodes, and antibiotics for urinary tract infection. We estimated incidence rate ratios (IRRs) using negative binomial regression, and odds ratios using logistic regression. RESULTS: Vitamin D supplementation slightly reduced the number of prescription episodes (IRR, 0.98; 95% confidence interval [CI], .95-1.01), total prescriptions (IRR, 0.97; 95% CI, .93-1.00), and repeat prescription episodes (IRR, 0.96; 95% CI, .93-1.00). There was stronger evidence of benefit in people predicted to have insufficient vitamin D at baseline (prescription episodes IRR, 0.93; 95% CI, .87-.99). CONCLUSIONS: Vitamin D may reduce the number of antibiotic prescriptions, particularly in people with low vitamin D status. This supports the hypothesis that vitamin D has a clinically relevant effect on the immune system. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/.

The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality.

BACKGROUND: The effect of supplementing unscreened adults with vitamin D3 on mortality is unclear. We aimed to determine whether monthly doses of vitamin D3 influenced mortality in older Australians. METHODS: We did a randomised, double-blind, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) in Australians 60 years or older who were recruited across the country via the Commonwealth electoral roll. Participants were randomly assigned (1:1), using automated computer-generated permuted block randomisation, to receive one oral gel capsule of either 60 000 IU vitamin D3 or placebo once a month for 5 years. Participants, staff, and investigators were blinded to study group allocation. The primary endpoint was all-cause mortality assessed in all participants who were randomly assigned. We also analysed mortality from cancer, cardiovascular disease, and other causes. Hazard ratios (HRs) and 95% CIs were generated using flexible parametric survival models. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. FINDINGS: Between Feb 14, 2014, and June 17, 2015, we randomly assigned 21 315 participants, including 10 662 to the vitamin D group and 10 653 to the placebo group. In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 77 (SD 25) in the placebo group and 115 (SD 30) nmol/L in the vitamin D group. Following 5 years of intervention (median follow-up 5·7 years [IQR 5·4-6·7]), 1100 deaths were recorded (placebo 538 [5·1%]; vitamin D 562 [5·3%]). 10 661 participants in the vitamin D group and 10 649 participants in the placebo group were included in the primary analysis. Five participants (one in the vitamin D group and four in the placebo group) were not included as they requested to be withdrawn and their data to be destroyed. The HR of vitamin D3 effect on all-cause mortality was 1.04 [95% CI 0·93 to 1·18]; p=0·47)and the HR of vitamin D3 effect on cardiovascular disease mortality was 0·96 (95% CI 0·72 to 1·28; p=0·77). The HR for cancer mortality was 1·15 (95% CI 0·96 to 1·39; p=0·13) and for mortality from other causes it was 0·83 (95% CI 0·65 to 1·07; p=0·15). The odds ratio for the per-protocol analysis was OR 1·18 (95% CI 1·00 to 1·40; p=0·06). In exploratory analyses excluding the first 2 years of follow-up, those randomly assigned to receive vitamin D had a numerically higher hazard of cancer mortality than those in the placebo group (HR 1·24 [95% CI 1·01-1·54]; p=0·05). INTERPRETATION: Administering vitamin D3 monthly to unscreened older people did not reduce all-cause mortality. Point estimates and exploratory analyses excluding the early follow-up period were consistent with an increased risk of death from cancer. Pending further evidence, the precautionary principle would suggest that this dosing regimen might not be appropriate in people who are vitamin D-replete. FUNDING: The D-Health Trial is funded by National Health and Medical Research Council.

Predicting obesity and smoking using medication data: A machine-learning approach.

PURPOSE: Administrative health datasets are widely used in public health research but often lack information about common confounders. We aimed to develop and validate machine learning (ML)-based models using medication data from Australia's Pharmaceutical Benefits Scheme (PBS) database to predict obesity and smoking. METHODS: We used data from the D-Health Trial (N = 18 000) and the QSkin Study (N = 43 794). Smoking history, and height and weight were self-reported at study entry. Linkage to the PBS dataset captured 5 years of medication data after cohort entry. We used age, sex, and medication use, classified using anatomical therapeutic classification codes, as potential predictors of smoking (current or quit <10 years ago; never or quit ≥10 years ago) and obesity (obese; non-obese). We trained gradient-boosted machine learning models using data for the first 80% of participants enrolled; models were validated using the remaining 20%. We assessed model performance overall and by sex and age, and compared models generated using 3 and 5 years of PBS data. RESULTS: Based on the validation dataset using 3 years of PBS data, the area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI] 0.68-0.71) for predicting obesity and 0.71 (95% CI 0.70-0.72) for predicting smoking. Models performed better in women than in men. Using 5 years of PBS data resulted in marginal improvement. CONCLUSIONS: Medication data in combination with age and sex can be used to predict obesity and smoking. These models may be of value to researchers using data collected for administrative purposes.

Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial.

BACKGROUND: Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high-dose vitamin D supplementation reduces risk and incidence of falls. METHODS: We used data from the randomized, double-blind, placebo-controlled D-Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60-84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25-hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3-month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention-to-treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013. RESULTS: Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%). Vitamin D had no effect on falling in the past month (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.95-1.10). There was an interaction with body mass index (BMI) (P-interaction = 0.001); vitamin D increased risk in participants with BMI < 25 kg/m2 (OR 1.25, 95% CI 1.09-1.43), but there was no effect in those with BMI ≥ 25 kg/m2 (OR 0.95, 95% CI 0.87-1.04). Analyses of diary data were consistent with these findings. The incidence of hypercalcaemia and kidney stones did not differ between groups. CONCLUSIONS: Monthly high-dose vitamin D supplementation did not reduce risk of falling. A possible increased risk of falling with vitamin D supplementation in people with normal BMI warrants further investigation.