With all the talk about vitamins on here recently this seems appropriate.
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Vitamin D and COPD: who benefits from supplementation?
Much attention has been focused on the potential role of vitamin D deficiency on both the development and exacerbations of obstructive lung diseases. Vitamin D has immunomodulatory functions and anti-inflammatory properties, reduces oxidative stress, and acts as an epigenetic regulator of genes associated with lung disease.1 Research into the link between vitamin D and asthma, including a large multicentre randomised trial, has been focused mainly on the potential for vitamin D supplementation to improve the effectiveness of inhaled corticosteroids by enhancing their anti-inflammatory effects and reversing steroid resistance.2 By contrast, research into the link between vitamin D and chronic obstructive pulmonary disease (COPD) has been focused largely on the antimicrobial and anti-inflammatory effects of vitamin D and its ability to stimulate the innate immune response and ward off upper respiratory infections, thereby reducing the frequency of COPD exacerbations.3
In The Lancet Respiratory Medicine, Adrian Martineau and colleagues present the results of a double-blind, multicentre placebo-controlled trial of the effect of vitamin D3 (colecalciferol) supplementation on exacerbations and upper respiratory tract infections in adults with COPD in London, UK.4 240 participants with COPD (aged ≥40 years) were followed up every 2 months, by telephone or in person, over 1 year. Individuals in the intervention group were given an oral bolus dose of 3 mg (120 000 IU) of vitamin D3 every 2 months. Martineau and colleagues enrolled participants with a broad range of 25-hydroxyvitamin D serum levels. Overall, they found that supplementation did not affect the time to a moderate-to-severe exacerbation or time to first upper respiratory tract infection. However, the investigators noted that supplementation with vitamin D3 led to a lower incidence of moderate-to-severe exacerbations in participants with baseline serum 25-hydroxyvitamin D level of less than 50 nmol/L, which, though not universally accepted, is the current standard cutoff for vitamin D deficiency. Additionally, Martineau and colleagues found that the intervention reduced mean peak symptom score for exacerbation, suggesting that supplementation might ameliorate exacerbation symptoms. They concluded that supplementation should be provided to individuals with COPD and 25-hydroxyvitamin D levels of less than 50 nmol/L.
This study is the first multicentre trial to assess the effect of vitamin D supplementation on COPD outcomes. The finding that vitamin D supplementation increased the time to first exacerbation in participants who had vitamin D deficiency (25-hydroxyvitamin D levels < 50 nmol/L) could have important implications, especially because of the high prevalence of this in individuals with COPD.5 However, the results of the subgroup analysis should not be taken as conclusive evidence for the effectiveness of supplementation in patients with deficiency, although supplementation should be assessed on an individual basis for people with deficiency irrespective of the direct effect on COPD outcomes. The results should instead be regarded as exploratory and hypothesis-generating because of the small size of the subgroup (n=148). Also, the benefits of randomisation are lost in subgroup analyses, thereby precluding the ability to ascertain causality. The investigators point out that the results from another small, randomised controlled trial also showed a benefit of vitamin D3 supplementation on time to exacerbation in participants with COPD and severe deficiency (ie, <25 nmol/L).6 However, this trial had similar limitations to the current trial. Although the results of subgroup analyses in these trials are promising, additional randomised trials are needed in which only individuals with COPD and 25-hydroxyvitamin D levels of less than 50 nmol/L, or perhaps less than 75 nmol/L, the current accepted definition of vitamin D insufficiency, are enrolled.
Martineau and colleagues also noted that one potential reason for the absence of an effect on COPD outcomes could be related to the intermittent bolus dosing regimen in this trial. Improved studies are needed to assess the differences in daily versus intermittent dosing regimens because dose frequency could affect the physiological effects and therapeutic benefits of vitamin D supplementation on COPD. Because of the important relation between COPD and obesity and the anti-inflammatory effects of vitamin D,7 the interaction between vitamin D supplementation and obesity should be studied.
Similar to the findings reported by Martineau and colleagues,4 the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) investigators reported that vitamin D3 supplementation in adult individuals with asthma did not reduce the rate of first treatment failure compared with placebo. However, in a subgroup of VIDA participants who responded to supplementation, each 10 ng/mL (25 nmol/L) increase in serum concentrations of vitamin D3 was associated with a significant reduction in the rate of treatment failures and exacerbations,2 which suggests that there might be a dose-response relation between vitamin D and outcomes in patients with asthma and COPD. 85% of circulating levels of vitamin D metabolites are bound to vitamin D binding protein and 15% to albumin (the bioavailable fraction), with less than 1% in the free or unbound form.8 Polymorphisms in GC, the gene that codes for vitamin D binding protein, might contribute to the variability in levels of vitamin D binding protein between individuals.9, 10 Because of the variability in vitamin D binding protein concentrations, the use of total levels of vitamin D as a biomarker of vitamin D insufficiency has been recently questioned in favour of quantifying bioavailable or free vitamin D concentrations, which are unaffected by differences in vitamin D binding protein concentrations.11, 12, 13 Therefore, future studies of vitamin D levels as a biomarker of disease should include the measurement of vitamin D binding protein and estimation of bioavailable or free concentrations.