Background: Randomised controlled trials (RCTs) of vitamin D to prevent COPD exacerbations have yielded conflicting results.Individual participant data meta-analysis could identify factors that explain this variation.Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial.Results: Four eligible RCTs (total 560 participants) were identified; individual participant data were obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels <25 nmol/L (aIRR 0.55, 95% CI 0.36 to 0.84) but not in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (aIRR 1.04, 95% CI 0.85 to 1.27; p for interaction=0.015). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted OR 1.16, 95% CI 0.76 to 1.75).Conclusions: Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels <25 nmol/L but not in those with higher levels.Trial registration number: CRD42014013953.

Background: Although vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function. In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections. As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients. Objective: To assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients. Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life. Methods: We performed a randomized, double-blind, placebo-controlled pilot trial. Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months. Study visits were conducted at baseline, and at 3 and 6 months after randomization. During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed. In addition, participants kept a diary card in which they registered respiratory symptoms. Results: At baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group. Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P<0.001). Primary outcomes, respiratory muscle strength and physical performance, did not differ between the groups after 6 months. In addition, no differences were found in the 6-minute walking test results, handgrip strength, pulmonary function, exacerbation rate, or quality of life. Conclusion: Vitamin D supplementation did not affect (respiratory) muscle strength or physical performance in this pilot trial in vitamin D-deficient COPD patients.

Vitamin D deficiency is frequently found in patients with Chronic Obstructive Pulmonary Disease (COPD). Vitamin D has antimicrobial, anti-inflammatory and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients. To assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD We performed a multi-center, double-blind, randomized controlled trial. COPD patients with one or more exacerbations in the preceding year and a vitamin D deficiency (15–50 nmol/L) were randomly allocated in a 1:1 ratio to receive either vitamin D3 16.800 IU or placebo once a week during 1 year. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbation, time to first and second hospitalization, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life. The intention-to-treat population consisted of 155 participants. Mean (SD) serum 25-hydroxyvitamine D (25(OH)D) concentrations after one year was 112 (34) nmol/L in the vitamin D group, compared to 42 (17) nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate (incidence rate ratio (IRR):0.90; 95%-confidence interval (95%-CI): 0.67,1.21). In a prespecified subgroup analysis in participants with 25(OH)D levels 15–25 nmol/L (n = 31) no effect of vitamin D supplementation was found (IRR:0.91; 95%-CI:0.43,1.93). No relevant differences were found between the intervention and placebo group in secondary outcomes. Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.

Context: Vitamin D deficiency has been associated with impaired physical functioning, depression, and several chronic diseases and might thereby affect quality of life and self-rated health. Objective: The aim of this study was to assess relationships of serum 25-hydroxyvitamin D [25(OH)D] with quality of life and self-rated health and to examine whether physical performance, depressive symptoms, and number of chronic diseases mediate these relationships. Design: We analyzed data from the Longitudinal Aging Study Amsterdam, an ongoing population-based cohort study of older Dutch individuals. Main Outcome Measures: Serum 25(OH)D was classified into the following categories: less than 25, 25–50, and 50 nmol/L or greater. We assessed quality of life (QOL) using the Short Form-12 Health Survey (SF-12; n = 862) and self-rated health (SRH) with a single question, dichotomized into good vs poor SRH (n = 1248). Results: Individuals with serum 25(OH)D less than 25 nmol/L scored lower on the physical component score of the SF-12 and had a lower odds on good SRH score compared with individuals with serum 25(OH)D greater than 50 nmol/L (β (95% confidence interval) −3.9 (−6.5 to −1.3) for SF-12, and odds ratio [95% confidence interval) 0.50 (0.33–0.76) for SRH]. Physical performance, depressive symptoms, and the number of chronic diseases were associated with vitamin D status, QOL, and SRH. Adding all these potential mediators to regression models attenuated associations of 25(OH)D less than 25 nmol/L with QOL with 78% and SRH with 32%. Conclusion: Lower 25(OH)D status is related to lower scores on QOL and SRH. A large part of the association with QOL can statistically be explained by physical performance, depressive symptoms, and the number of chronic diseases.

Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect of vitamin D on exacerbation rate in COPD patients. However, subgroup analyses suggested protective effects in vitamin D deficient patients. Our objective is to assess the effect of vitamin D supplementation on exacerbation rate specifically in vitamin D deficient COPD patients. We will perform a randomised, multi-center, double-blind, placebo-controlled intervention study. The study population consists of 240 COPD patients aged 40 years and older with vitamin D deficiency (25-hydroxyvitamin D concentration < 50 nmol/L). Participants will be recruited after an exacerbation and will be randomly allocated in a 1:1 ratio to receive vitamin D3 16800 IU or placebo orally once a week during 1 year. Participants will receive a diary card to register the incidence of exacerbations and changes in medication during the study period. Visits will be performed at baseline, at 6 months and at 12 months after randomisation. Participants will undergo spirometry, measurement of total lung capacity and assessment of maximal respiratory mouth pressure. Several physical performance and hand grip strength tests will be performed, questionnaires on quality of life and physical activity will be filled in, a nasal secretion sample and swab will be obtained and blood samples will be taken. The primary outcome will be exacerbation rate. This study will be the first RCT aimed at the effects of vitamin D supplementation on exacerbation rate in vitamin D deficient COPD patients. Also, in contrast to earlier studies that used infrequent dosing regimens, our trial will study effects of a weekly dose of vitamin D supplementation. Secondly, the immunomodulatory effects of vitamin D on host immune response of COPD patients and underlying mechanisms will be studied. Finally, the effects on physical functioning will be examined. This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.