Chronic obstructive pulmonary disease (COPD) exacerbations and secondary COPD outcomes showed no improvement with high-dose vitamin D, according to a small, single-center randomized trial — the first such trial of vitamin D and COPD. However, the study probably will not put the concept to rest that vitamin D merits further scientific study for patients with moderate to severe COPD. The trial was published in the January 17 issue of the Annals of Internal Medicine.
"Particularly for COPD, the vitamin D pathway is an attractive target for intervention studies because vitamin D deficiency may enhance chronic airway and systemic inflammation, reduce bacterial clearance, and increase the risk for infectious exacerbations at the same time," write lead author An Lehouk, PhD, from the Department of Medical Sciences, University Hospitals Leuven, Belgium, and colleagues.
There was no significant improvement in several exacerbation outcomes, including time to the first exacerbation (the primary outcome), time to the second exacerbation, annual rate of exacerbations, and median time to first hospitalization for an exacerbation.
The investigators randomly assigned 182 patients who had moderate to severe COPD, all of whom were current or former smokers who were older than 50 years, to monthly supplementation with 100,000 IU of vitamin D or placebo. In the intention-to-treat analysis, vitamin D yielded no benefit in survival, dyspnea, emotional, mastery, fatigue scores, Chronic Respiratory Questionnaire scores, or forced expiratory volume in 1 second.
"Vitamin D supplementation resulted in a steep and significant increase in serum25-(OH)D levels that remained stable during the study (52 ng/mL [SD, 16]) (mean between-group difference, 30 ng/mL [(confidence interval [CI]), 27 to 33 ng/mL]; P < .001)," the authors write.
A post hoc subgroup analysis of patients with the most severe vitamin D deficiency showed that the rate of exacerbations per patient year declined by 43% (rate ratio, 0.57; CI, 0.33 - 0.98; P = .042). Hypercalciuria occurred in a small number of patients, but it was transient.
The authors suggest that it may be difficult to disentangle a benefit for vitamin D because patients often were getting maximum inhalation therapy. Further, they point out that high-dose vitamin D may be more valuable earlier in the disease course, "consistent with the idea that such milder stages are also more sensitive to disease modification." Further, they contend that the post hoc analysis, although only hypothesis-generating, raises the importance of looking more closely at patients with COPD who have the most severe levels of vitamin D deficiency.
In an accompanying editorial, Diane R. Gold, MD, MPH, and JoAnn E. Manson, MD, DrPH, from the Division of Preventive Medicine at Harvard Medical School in Boston, Massachusetts, urge larger and longer-term trials. "Variability in the physiology, immunology, and genetics underpinning the final common pathway of chronic airflow obstruction and risk for exacerbation is likely to modify the pulmonary responses to vitamin D supplementation in patients with COPD."
"Such trials should probably study daily dosing," they conclude. They also call attention to randomized trials of vitamin D only ramping up recently, noting that daily vitamin D will be tested rigorously in 2 National Institutes of Health trials.
Several of the authors disclosed grant support, writing assistance, consultancies, board membership, advisory board membership, payment for lectures, travel and meeting expenses, owning patents, and receiving royalties from Altana, AstraZeneca, Boerhinger Ingelheim, Dompé, GSK, Hybrigenix, Laboratoires SMB, Lilly, Novartis, Nycomed, and/or Pfizer.The editorialists have disclosed no relevant financial relationships.
Ann Intern Med. 2012;156:105-114, 156-157. Article full text, Editorial extract
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