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Severe Vitamin D Deficiency: A Prerequisite for COPD Responsiveness to Vitamin D Supplementation?

Diane R. Gold, MD, MPH; and JoAnn E. Manson, MD, DrPH
[+] Article, Author, and Disclosure Information

From Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, MA 02215.

Grant Support: The authors' work on vitamin D, COPD, and asthma is funded by the National Institutes of Health (R01 HL101932 and U01 CA138962).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2794.

Requests for Single Reprints: JoAnn E. Manson, MD, DrPH, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215; e-mail, jmanson@rics.bwh.harvard.edu.

Current Author Addresses: Dr. Gold: Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115.

Dr. Manson: Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215.

Ann Intern Med. 2012;156(2):156-157. doi:10.7326/0003-4819-156-2-201201170-00013
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In this issue, Lehouck and colleagues found no overall benefit of vitamin D supplementation on time to COPD exacerbation or exacerbation rates, except among a few participants who had very low vitamin D levels at baseline. The editorialists discuss the study and how it and other ongoing studies will help to elucidate the balance of benefits and risks of vitamin D supplementation among patients with respiratory dysfunction.

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Vitamin D and pulmonary disease
Posted on February 2, 2012
AndrewGrey, Physician, Mark Bolland, Ian R Reid
University of Auckland
Conflict of Interest: None Declared

The randomized, placebo-controlled trial reported by Lehouck et al found that vitamin D supplementation did not improve any of a series of clinically important outcomes over 1 year in patients with moderately severe chronic obstructive pulmonary disease (COPD) (1) . It adds to an expanding body of clinical trial evidence that vitamin D supplementation does not favourably alter outcomes for many of the diseases that have been associated with lower vitamin D levels in observational studies (2). Collectively, these emerging data raise significant doubts as to the role of vitamin D in the pathogenesis and management of non-skeletal disease. It was disappointing, therefore, that the authors of the paper, in their Abstract, and the accompanying editorial, in its title and text, placed undue emphasis on the positive findings of a post-hoc analysis of a secondary endpoint in a subgroup of 30 participants with low baseline 25- hydroxyvitamin D levels (3). Such analyses should be treated with considerable caution, as there is a high probability that they produce erroneous findings.

As is frequently observed in the vitamin D literature, the editorialists were reluctant to consider the possibility that vitamin D is an ineffective intervention, instead offering disease heterogeneity and vitamin D receptor polymorphisms as explanations for the null result. In skeletal biology, considerable resource was invested in evaluating the influence of vitamin D receptor polymorphisms, to no avail. Finally, we are less confident than the editorialists that the VITAL trial will provide definitive evidence of the risks and benefits of vitamin D. In that trial, participants are permitted to take non-protocol vitamin D supplements up to 800 IU/day (4), potentially rendering it a comparison of low dose vs moderate dose vitamin D, rather than vitamin D vs placebo. A similar design in the Women's Health Initiative trial of calcium and vitamin D, in which >50% of participants took non-protocol calcium supplements, obscured adverse cardiovascular effects of calcium supplements (5).


1. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease. Annals of Internal Medicine. 2012;156(2):105-14.

2. Grey A, Bolland M. Vitamin D: A place in the sun? Arch Intern Med. 2010;170:1099-100.

3. Gold DR, Manson JE. Severe vitamin D deficiency: a prerequisite for COPD responsiveness to vitamin D supplementation? Annals of Internal Medicine. 2012;156(2):156-7.

4. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, et al. The VITamin D and OmegA-3 TriaL (VITAL): Rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemporary Clinical Trials. 2012;33(1):159-71.

5. Bolland M, Grey A, Gamble G, Reid I. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.

Conflict of Interest:

None declared

Author's Response
Posted on March 23, 2012
JoAnn E.Manson, MD, DrPH, Diane R. Gold, MD, MPH, Brigham and Women's Hospital, Harvard Medical School, Harvard School of Public Health
Brigham and Women's Hospital, Harvard Medical School, Harvard School of Public Health
Conflict of Interest: None Declared

There was no overall benefit of vitamin D for time to COPD exacerbation or exacerbation rates in the clinical trial by Lehouck and colleagues. However, when a post-hoc analysis suggests a possible clinical benefit of vitamin D supplementation, with reduced exacerbations for the 20 percent of the population with severe vitamin deficiency at baseline (30 of the 150 patients followed for a year in the Lehouck trial), it would be worthwhile evaluating whether these findings stand up internally to further statistical scrutiny, and whether they are replicable. As we discussed in our editorial, the evolving pulmonary literature gives credence to the hypothesis that baseline level of vitamin D, genetic variation, variability in disease expression, as well as variability in dose and timing of vitamin D supplementation may result in heterogeneity in COPD responses. There will be no single magic bullet for treatment of COPD, and smoking cessation remains the most effective starting point to improve prognosis. However as the scientific community awaits findings from other ongoing clinical trials, it would be premature to conclude that for all patients there will be no benefit of vitamin D for either the pulmonary or extrapulmonary manifestations of this systemic and clinically heterogeneous disease. Finally, while clinicians caring for COPD patients await the results of ongoing clinical trials addressing pulmonary and other nonskeletal outcomes, it will be important to take into account the potential benefits of vitamin D supplementation for reducing the risk of fractures, which can contribute to COPD morbidity in this frail population with high rates of vitamin D deficiency.

Diane R. Gold, MD, MPH Brigham and Women's Hospital Harvard Medical School, Harvard School of Public Health

JoAnn E. Manson, MD, DrPH Brigham and Women's Hospital Harvard Medical School Harvard School of Public Health

Conflict of Interest:

None declared

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