Vitamin D for the management of chronic obstructive pulmonary disease.

BACKGROUND: COPD is a common, preventable and treatable airway disease, and is currently the third leading cause of death worldwide. About one billion people worldwide are estimated to have vitamin D deficiency or insufficiency. Vitamin D deficiency is common among people with COPD, and has been reported to be associated with reduced lung function and increased risk of acute exacerbations of COPD. Several clinical trials of vitamin D to prevent acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and improve COPD control have been conducted, but an up-to-date meta-analysis of all double-blind, randomised, placebo-controlled trials of this intervention is lacking. OBJECTIVES: To assess the effects of vitamin D for the management of acute exacerbations and symptoms for people with COPD. SEARCH METHODS: We searched the Cochrane Airways Trials Register and reference lists of articles. We also searched trial registries directly, and contacted the authors of studies in order to identify additional trials. The date of the last search was 24 August 2022. SELECTION CRITERIA: We included double-blind, randomised, placebo-controlled trials of vitamin D or its hydroxylated metabolites, for adults with a clinical diagnosis of chronic obstructive pulmonary disease based on the presence of characteristic symptoms and irreversible airflow obstruction. We did not impose restrictions regarding disease severity or baseline vitamin D status, in order to maximise generalisability. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The primary outcome was the rate of moderate or severe exacerbations (requiring systemic corticosteroids, antibiotics or both). We also performed subgroup analyses to determine whether the effect of vitamin D on the rate of moderate or severe exacerbations was modified by baseline vitamin D status, COPD severity or regular inhaled corticosteroid use. The main secondary outcomes of interest were the proportion of participants experiencing one or more exacerbations (moderate or severe), the change in forced expiratory volume in one second (FEV1, % predicted) and the proportion of participants with one or more serious adverse events of any cause, mortality (all-cause) and quality of life. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 10 double-blind, randomised, placebo-controlled trials in this review, involving a total of 1372 adults. Five studies contributed to the primary outcome analysis of the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both. The duration of studies ranged from six weeks to 40 months, and all investigated the effects of administering cholecalciferol (vitamin D3). One study included two intervention arms, one where vitamin D3 was given and one where calcitriol (1,25-dihydroxyvitamin D) was given. The majority of participants had mild to moderate COPD, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare (123 participants contributing data to subgroup analysis). Administration of vitamin D or its hydroxylated metabolites results in little to no change in the overall rate of exacerbations requiring systemic corticosteroids, antibiotics or both (rate ratio (RR) 0.98, 95% CI 0.86 to 1.11; 5 studies, 980 participants; high-certainty evidence). Vitamin D supplementation did not influence any meta-analysed secondary outcomes. These were all based on moderate- or high-certainty evidence aside from adverse events and quality of life, which were based on low-certainty evidence. We observed little to no change in the proportion of participants experiencing one or more moderate or severe exacerbations (odds ratio (OR) 0.94, 95% CI 0.72 to 1.24; 5 studies, 980 participants; high-certainty evidence). Additionally, vitamin D probably results in little to no difference in the inter-arm mean change in FEV1 (% predicted) (mean difference 2.82 higher in intervention arm, 95% CI -2.42 to 8.06; 7 studies, 1063 participants; moderate-certainty evidence). There was also probably no effect of vitamin D on the incidence of serious adverse events due to any cause; although we identified an anticipated absolute effect of 36 additional adverse events per 1000 people, the confidence interval included the null hypothesis of no effect (OR 1.19, 95% CI 0.82 to 1.71; 5 studies, 663 participants; moderate-certainty evidence). Vitamin D may have little to no effect on mortality (OR 1.13, 95% CI 0.57 to 2.21; 6 studies, 1019 participants; low-certainty evidence). It also may have little to no effect on quality of life as measured by validated instruments (narrative findings; 5 studies, 663 participants; low-certainty evidence). We assessed one study as being at high risk of bias in at least one domain; this did not contribute data to the meta-analysis of the primary outcome reported above. Sensitivity analysis that excluded this study from the meta-analysed outcome to which it contributed, the inter-arm mean change in FEV1, did not change the findings. AUTHORS' CONCLUSIONS: We found that administration of vitamin D results in little to no effect on the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both or the proportion of participants experiencing one or more exacerbations (moderate or severe) (both high-certainty evidence). Further, vitamin D probably has no effect on the inter-arm difference in change in lung volumes and the proportion of participants with one or more serious adverse event of any cause (both moderate-certainty evidence), and may make little to no difference to mortality or quality of life (both low-certainty evidence). We recommend further research on the balance of benefits and harms of vitamin D supplements in COPD for those with very low or very high starting vitamin D levels, because we assessed the available evidence as low-certainty for these groups.

Adiposity is a confounding factor which largely explains the association of serum vitamin D concentrations with C-reactive protein, leptin and adiponectin.

OBJECTIVE: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C-reactive protein (CRP), leptin and adiponectin and the role of adiposity in this relationship. METHODS: This is a cross-sectional analysis of The Netherlands Epidemiology of Obesity Study (NEO), a population-based cohort study in men and women aged 45 to 65 years. Main outcome measures were CRP, leptin and adiponectin. In the linear regression analyses we adjusted for age, sex, ethnicity, creatinine, education, alcohol use, smoking status, physical activity, number of chronic diseases, season, total body fat and waist circumference. RESULTS: Of the 6287 participants, 21% were vitamin D deficient (serum 25(OH)D < 50 nmol/L). Mean (SD) age and BMI were 56 (6) years and 26.3 (4.4) kg/m2, respectively. Although after adjustment for most examined potential confounders, each 10 nmol/L increase in serum 25(OH)D was associated with 2.3% (95%CI: -4.0 to -0.5) lower CRP, 3.5% (-4.7 to -2.2) lower leptin, and 0.13 ng/mL (0.04-0.21) higher adiponectin, most of these associations seemed to largely stem from an additional potential confounder - adiposity - as they either disappeared (leptin and CRP) or were largely diminished (adiponectin) upon further adjustment for adiposity indices (total body fat and waist circumference). CONCLUSION: We found that measures of adiposity largely explained the negative association of serum 25(OH)D with the pro-inflammatory CRP and leptin, and the positive association with the anti-inflammatory adiponectin. These results suggest that future studies should take the effect of adiposity into account.

Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials.

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.

Prevention of exacerbations in patients with COPD and vitamin D deficiency through vitamin D supplementation (PRECOVID): a study protocol.

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: 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. TRIAL REGISTRATION: This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.

Vitamin D supplementation in chronic obstructive pulmonary disease patients with low serum vitamin D: a randomized controlled trial.

BACKGROUND: 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. OBJECTIVES: We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD. METHODS: We performed a multicenter, double-blind, randomized controlled trial. COPD patients with ≥1 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 16,800 International Units (IU) vitamin D3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, 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. RESULTS: The intention-to-treat population consisted of 155 participants. Mean ± SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 ± 34 nmol/L in the vitamin D group, compared with 42 ± 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 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 groups in terms of secondary outcomes. CONCLUSIONS: Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency.This trial was registered at clinicaltrials.gov as NCT02122627.

Associations of different body fat deposits with serum 25-hydroxyvitamin D concentrations.

BACKGROUND & AIMS: Obesity is a well-established risk factor of vitamin D deficiency. However, it is unclear which fat deposit is most strongly related to serum 25-hydroxyvitamin D (25(OH)D) concentrations. Our aim was to distinguish the specific contributions of total body fat (TBF), abdominal subcutaneous adipose tissue (aSAT), visceral adipose tissue (VAT) and hepatic fat on 25(OH)D concentrations. METHODS: We performed a cross-sectional analysis of the Netherlands Epidemiology of Obesity study, a population-based cohort study. We used linear regression analyses to examine associations of TBF, aSAT, VAT (n = 2441) and hepatic fat (n = 1980) with 25(OH)D concentrations. Standardized values were used to compare the different fat deposits. RESULTS: Mean (SD) age and 25(OH)D concentrations of the study population was 56 (6) years and 70.8 (24.2) nmol/L, respectively. TBF was inversely associated with 25(OH)D concentrations in women, but not in men. One percent higher TBF was associated with 0.40 nmol/L (95%CI: -0.67 to -0.13) lower 25(OH)D. aSAT was not associated with 25(OH)D concentrations. One cm2 higher VAT was associated with 0.05 nmol/L (-0.09 to -0.02) lower 25(OH)D in men, and 0.06 nmol/L (-0.10 to -0.01) lower 25(OH)D in women. Hepatic fat was only associated with 25(OH)D in men. A tenfold increase in hepatic fat was associated with 6.21 nmol/L (-10.70 to -1.73) lower 25(OH)D. Regressions with standardized values showed VAT was most strongly related to 25(OH)D. CONCLUSIONS: In women, TBF and VAT were inversely related to 25(OH)D concentrations. In men, VAT and hepatic fat were inversely related to 25(OH)D concentrations. In both groups, VAT was most strongly associated with 25(OH)D concentrations.

Associations of Serum 25(OH)D Concentrations with Lung Function, Airway Inflammation and Common Cold in the General Population.

Vitamin D is hypothesized to have a beneficial effect on lung function and respiratory infections. The aim of this study was to assess the relationship of serum 25-hydroxyvitamin D (25(OH)D) concentrations with lung function, airway inflammation and common colds. We performed a cross-sectional analysis in the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort study. We included participants with measurements of serum 25(OH)D, Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), Fractional Exhaled Nitric Oxide (FeNO), and data on self-reported common colds (n = 6138). In crude associations, serum 25(OH)D was positively associated with FEV1 and FVC, and negatively with FeNO and the occurrence of a common cold. After adjustment for confounders, however, these associations disappeared. Stratified analyses showed that Body Mass Index (BMI) was an effect modifier in the relationship between serum 25(OH)D and FEV1, FVC and FeNO. In obese participants (BMI ≥ 30 kg/m²), 10 nmol/L higher 25(OH)D was associated with 0.46% predicted higher FEV1 (95% Confidence Interval: 0.17 to 0.75), 0.46% predicted higher FVC (0.18 to 0.74), and 0.24 ppb lower FeNO (-0.43 to -0.04). Thus, in the total study population, 25(OH)D concentrations were not associated with lung function, airway inflammation and common colds. In obese participants, however, higher 25(OH)D concentrations were associated with a better lung function and lower airway inflammation.

Effects of daily vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients: a pilot trial.

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.