Key messages
This Cochrane review does not find that vitamin D offers protection against acute flare-ups of chronic obstructive pulmonary disease (COPD), a chronic, inflammatory lung disease that causes breathing difficulties. It also does not find that vitamin D improves symptoms overall in people with COPD.
Why did we think that vitamin D might benefit people with COPD?
Low blood levels of vitamin D (the 'sunshine vitamin') have been linked to an increased risk of severe COPD flare-ups. In these flare-ups, patients experience breathing difficulty and increased cough - severe flare-ups are defined as those requiring steroid tablets or injections. Thus, we thought that supplementation to ensure good vitamin D levels might help to prevent flare-ups and improve control of symptoms.
What did we want to find out?
We wanted to find out if vitamin D supplementation:
• reduces the risk of COPD flare-ups;
• improves control of COPD symptoms;
• leads to any negative side effects.
What did we do?
We searched for research studies that compared the effect of vitamin D against matching placebo (dummy medication) on the risk of acute flare-ups of COPD and COPD symptom control. We did not place any limitations based on the dose of vitamin D given, the way it was delivered or the duration of the study. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods.
We also analysed whether the effects of vitamin D supplementation differed according to participants' vitamin D levels before taking supplements (baseline levels), how badly participants were affected by COPD initially and regular steroid medication use.
What did we find?
We included data from 10 studies in this review, which involved a total of 1372 people. Of these, five studies reported data on the rate of severe flare-ups. The studies lasted between six weeks and 40 months, and all investigated a particular form of vitamin D called cholecalciferol or vitamin D3. This is the most common form of vitamin D tablet. One also investigated another form, called calcitriol. The majority of participants had mild/moderate COPD, and a minority had severe COPD.
• Overall, giving people vitamin D supplements makes little to no difference to the risk of COPD flare-ups compared to those given placebo (dummy medication).
• Vitamin D also makes little to no difference to the proportion of people who had one or more flare-ups during the study time period.
• Vitamin D supplementation probably makes little to no difference to lung capacity, or to the risk of serious harmful side effects.
• Vitamin D supplementation may have little to no effect on the risk of death, or on the quality of life of participants.
What are the limitations of the evidence?
• We are confident that vitamin D has no effect on COPD flare-ups, and moderately confident that it probably has little to no effect on lung capacity and the risk of serious harmful side effects.
• However, we have little confidence in the evidence for risk of death from COPD because it is based on studies with small numbers of participants. We also have little confidence in the evidence for quality of life because different studies used a range of measurements that could not be compared easily.
• We have little confidence in the results of one study, because it depended on participants remembering their day-to-day symptoms over the previous two months without use of a diary. This study contributed data to one of the main outcomes, lung function of people with COPD. However, when we repeated the analysis excluding this study, the overall result did not change - vitamin D supplementation had no effect in either case.
Future research
We recommend further research on the balance of the benefits and harms of vitamin D supplements in COPD for those with very low or very high starting vitamin D levels, because we found little evidence to help us answer our questions for these groups.
How up-to-date is this evidence?
The evidence is up-to-date to 24 August 2022.
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.
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.
To assess the effects of vitamin D for the management of acute exacerbations and symptoms for people with COPD.
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.
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.
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.
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.