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 D ₃ 200 000 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: ACTRN 12611000402943.

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.

The relationship between vitamin D status or supplementation and cancer outcomes has been examined in several meta‐analyses. To address remaining knowledge gaps, we conducted a systematic overview and critical appraisal of pertinent meta‐analyses. For meta‐analyses of trials, we assessed their quality using AMSTAR‐2 (A Measurement Tool to Assess Systematic Reviews), strength of associations using umbrella review methodology and credibility of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria. Meta‐analyses of observational studies reported inverse associations of 25OHD with risk of cancer incidence and cancer mortality and, particularly for colorectal cancer, fulfilled some of Bradford‐Hill's causation criteria. In meta‐analyses of trials, vitamin D supplementation did not affect cancer incidence. However, we found credible evidence that vitamin D supplementation reduced total cancer mortality risk, with five out of six meta‐analyses reporting a relative risk (RR) reduction of up to 16%: RR, 0.84 (95% CI, 0.74–0.95). The strength of the association, however, was classified as weak. This was true among meta‐analyses of high, moderate, and lower quality (AMSTAR‐2–rated). Trials did not include large numbers of vitamin D‐deficient participants; many tested relatively low doses and lacked sufficiently powered data on site‐specific cancers. In conclusion, meta‐analyses show that, although observational evidence indicates that low vitamin D status is associated with a higher risk of cancer outcomes, randomized trials show that vitamin D supplementation reduces total cancer mortality, but not cancer incidence. However, trials with larger proportions of vitamin D‐insufficient participants and longer durations of follow‐up, plus adequately powered data on site‐specific common cancers, would provide further insight into the evidence base. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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.

Scientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25‐hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (n > 2000 participants in each) of vitamin D supplementation giving higher doses than previously used. The intervention periods in these trials collectively started in 2009 and continued to 2020. They have recruited participants, mostly of both sexes and over the age of 50 years, from many countries and have given either daily or monthly doses of vitamin D. Collectively, the trials have a wide range of outcomes with the main focus on the prevention of cancer, cardiovascular disease, and fractures, besides many other outcomes. The findings of four trials have been published, and they have shown that vitamin D supplementation does not prevent hard‐disease endpoints, such as cardiovascular disease, cancer, fractures, or falls, aside from a possible beneficial effect against cancer mortality. In contrast, beneficial effects were seen for intermediate outcomes such as BMD of spine and hips, arterial function, and lung function, especially in people with vitamin D deficiency. The finding of a benefit primarily in people with vitamin D deficiency, if confirmed by the other trials, would support a population approach to preventing vitamin D deficiency using fortification rather than the high‐risk approach of screening for deficiency combined with supplementation. The findings on other outcomes from the three published trials, along with the findings from the four unpublished trials, are expected within the next 2 to 3 years to clarify the role of vitamin D supplementation in preventing nonskeletal disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Evidence is still emerging on the relationships of arterial stiffness with cardiac autonomic neuropathy (CAN) and peripheral neuropathy (PN). To our knowledge no systematic reviews or meta-analyses of these associations have been published. The purpose of our review was to assess the association of arterial stiffness with each type of neuropathy. Medline and Embase were systematically searched for observational studies of arterial stiffness and neuropathy. The systematic review of 60 studies (25 for CAN and 37 for PN), 59 including people with diabetes, showed arterial stiffness overall was higher in people with neuropathy than people without neuropathy. Forty-three studies were included in the meta-analysis. For CAN (19 studies), arterial stiffness was increased in people with neuropathy compared with without, as measured by pulse wave velocity (PWV) (mean difference: 1.32 m/s, 95% CI 0.82 to 1.81, p<0.00001), pulse pressure (PP) (mean difference: 6.25 mmHg, 95% CI 4.51 to 7.99, p<0.00001) or augmentation index (mean difference: 5.52%, 95% CI 3.46 to 7.58, p<0.0001). For PN (26 studies), arterial stiffness was increased in people with neuropathy compared with those without, as measured by PWV (mean difference: 1.22 m/s, 95% CI 0.87 to 1.58, p<0.00001) or PP (mean difference: 4.59 mmHg, 95% CI 2.96 to 6.22, p<0.00001). Only two cohort studies were located so the temporality of the association between arterial stiffness and neuropathy remains unclear. Increased arterial stiffness is associated with CAN and PN. PROSPERO registration number: CRD42019129563.