An Lehouck, PhD; Chantal Mathieu, MD, PhD; Claudia Carremans, MS; Femke Baeke, PhD; Jan Verhaegen, MD, PhD; Johan Van Eldere, MD, PhD; Brigitte Decallonne, MD, PhD; Roger Bouillon, MD, PhD; Marc Decramer, MD, PhD; Wim Janssens, MD, PhD
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: A Randomized Trial. Ann Intern Med. 2012;156:105-114. doi: 10.7326/0003-4819-156-2-201201170-00004
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Published: Ann Intern Med. 2012;156(2):105-114.
Low serum 25-hydroxyvitamin D (25-[OH]D) levels have been associated with lower FEV1, impaired immunologic control, and increased airway inflammation. Because many patients with chronic obstructive pulmonary disease (COPD) have vitamin D deficiency, effects of vitamin D supplementation may extend beyond preventing osteoporosis.
To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations.
Randomized, single-center, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00666367)
University Hospitals Leuven, Leuven, Belgium.
182 patients with moderate to very severe COPD and a history of recent exacerbations.
100 000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year.
The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalization, time to second exacerbation, FEV1, quality of life, and death.
Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV1, hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042).
This was a single-center study with a small sample size.
High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations.
Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM).
The association between low serum vitamin D levels and more severe chronic obstructive pulmonary disease (COPD) suggests that vitamin D supplementation might be beneficial for COPD treatment.
In this randomized trial, supplementation with vitamin D did not reduce the number of acute exacerbations of COPD nor improve lung function, compared with placebo. A post hoc analysis suggested possible benefit in patients with the lowest baseline vitamin D levels.
Vitamin D supplementation does not seem to be beneficial for COPD, although further study may be warranted to assess whether it might help certain patient groups.
ITT = intention-to-treat.
25-(OH)D = 25-hydroxyvitamin D; ANOVA = analysis of variance; COPD = chronic obstructive pulmonary disease; RR = rate ratio. Top. Kaplan–Meier plots of time to first exacerbation in the on-treatment population. Middle. Mean serum 25-(OH)D levels in the on-treatment population, excluding patients who started low-dose vitamin D supplementation during the trial. Bottom. COPD exacerbations per patient-year in the on-treatment population. Two-way ANOVA statistics for between-group differences in serum 25-(OH)D levels and interaction are given. For exacerbation rates, Poisson regression statistics are given. P values are unadjusted.
Linear mixed-model analysis showed no significant differences between the groups and study visits (P = 0.87).
Appendix Table 1.
Two-way analysis-of-variance statistics for between-group differences in serum 25-(OH)D levels and Poisson regression statistics for exacerbation rates are given. P values are unadjusted. Severe vitamin D deficiency was defined as having serum 25-(OH)D levels <10 ng/mL. To convert values to nmol/L, multiply by 2.5. 25-(OH)D = 25-hydroxyvitamin D; COPD = chronic obstructive pulmonary disease; ITT = intention-to-treat; RR = rate ratio.
Appendix Table 2.
Appendix Table 3.
25-(OH)D = 25-hydroxyvitamin D; ITT = intention-to-treat. Top. Relationship between plasma cathelicidin and serum 25-(OH)D levels at baseline. Spearman r = 0.027; P = 0.04. Bottom. Plasma cathelicidin levels during the study in the ITT population. Linear mixed-model analysis showed no significant differences between the groups and study visits (P = 0.85).
ITT = intention-to-treat. Top. Percentage of monocytes positive for phagocytosis at the end of the study in the ITT population. Bottom. Percentage of monocytes positive for phagocytosis at the end of the study in the subgroup of participants with severe vitamin D deficiency (serum 25-hydroxyvitamin D levels <10 ng/mL).
Appendix Table 4.
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GoranKrstic, PhD, Human Health Risk Assessment Specialist
January 26, 2012
A functional vitamin D status is more than a simple serum 25-hydroxyvitamin D concentration
Considering that there is evidence in the published literature, as referenced in this article by Lehouck et al. , that low serum 25- hydroxyvitamin D (25-[OH]D or calcidiol) levels are associated with the impaired forced expiratory volume in 1 second (FEV1), and that vitamin D deficiency, defined by the Institute of Medicine as serum 25-[OH]D levels <20 ng/mL, is present in 60% to 75% of patients with severe chronic obstructive pulmonary disease (COPD), it is interesting that vitamin D supplementation does appear to have very little or no effect on the incidence of COPD exacerbations in the studied group of patients. Although the acknowledged small sample size may explain in part the observed absence of a significant effect, it is also important to take into account the uncertainties potentially associated with establishing the vitamin D status on the basis of serum 25-[OH]D rather than the active and functional form of vitamin D (i.e., 1,25[OH]2D or calcitriol). It would be interesting to observe if treatment of the same group of patients with 1,25[OH]2D would show different results.
In addition, some genes and polymorphisms directly or indirectly associated with the function of vitamin D are implicated in the pathogenesis of COPD . Hence, it may be beneficial to focus further research in this field on the genetic polymorphism of loci encoding, for example, the vitamin D-binding protein (VDBP), the vitamin D receptor (VDR), and the enzyme responsible for transforming 25-[OH]D to 1,25[OH]2D, 1-alpha hydroxylase (CYP27B1) . Controlling for these and other vitamin D associated polymorphisms in a larger study group may provide the basis for confirming or ruling out the effects of a functional vitamin D status on the development/exacerbation of COPD.
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: a randomized trial. Ann Intern Med. 2011;155:827-838.
2. Joos L, Par? PD, Sandford AJ. Genetic risk factors of chronic obstructive pulmonary disease. Swiss Med Wkly. 2002;132(3-4):27-37.
3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-81.
FranciscoRamirez Lafita MD, PhD, FACP, Rheumatologist, Belinda Garcia MD
Clinica Monegal. Tarragona, Spain
January 29, 2012
Vitamin D beyond healthy bones
Interest in extra bone effects of vitamin D have been renewed in the past decade. Vitamin D deficiency is frequently found even in industrialized countries. Recently, the term vitamin D insufficiency has been used to describe suboptimal levels of serum 25(OH)D that could be associated with other disease outcomes (extra-skeletal conditions). Cutoff value for optimal vitamin D status has been established in 30 ng/mL. On this basis, patients can be diagnosis with vitamin D insufficiency or deficiency when most have not evidence of disease1. In a recent publication in Annals, Lehouck et al2 found that high doses of vitamin D supplementation in a sample of patients with COPD failed to reduce the incidence of exacerbations and to improve secondary outcomes such as FEV1, quality of life and death rate. However, in a small sample of 30 patients with severe vitamin D deficiency (serum 25-OH-D levels less of 10 ng/mL) an important reduction of COPD exacerbations per patient-year was observed in the group of only 15 patients supplemented with high doses of vitamin D (p 0.042). Vitamin D deficiency has been linked to accelerated decline in lung function, increased inflammation and reduced immunity in chronic lung diseases. The exact mechanism by which vitamin D plays a protective role on lung health is not clearly underlined but, vitamin D appears to modulate inflammatory and structural cells (dendritic cells, lymphocytes, monocytes, and epithelial cells)3 Recently, some papers on the role of vitamin D receptor (VDR) on lung health have been published. Experimental VDR knock out in mice induced an increased presence of inflammatory cells and mediators (phosphoacetylation of NF-?B and up-regulation of matrix metalloproteinases 2, 9 and 12) as a declining in lung function. 4 More recently, other authors have found that variant in gene polymorphism in VDR, was associated with the development of COPD in men 5. Vitamin D effects on health could be related not only to serum 25(OH)D levels but to an effective signal process on cell receptors. Extra bone effect of vitamin D deserves further studies.
1. Thatcher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86(1):50-60
2. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, van Eldere JV, Decallonne B, Boluillon R, Decramer M, Janssens W. High doses of Vitamin D to reduce exacerbations in chronic obstructive pulmonary disease. Ann Intern Med. 2012;156:105-114
3. Greulich HC, Koczulla RA, Meyer S, Zakharkina T, Bransheidt M, Eschmann R, Blas R. The role of vitamin D in pulmonary disease: COPD, asthma, infection and cancer. Respir Res. 2011;12:31
4. Sundar IK, Hwang JW, Wu S, Sun J, Rahman I. Deletion of vitamin D receptors leads to premature emphysema/COPD by increased matrix metalloproneinases and lymphoid aggregates formation. Biochem Biophys Res Commun. 2011;406(1):127-133
5. Poon A, Cho MH, Sparrow D, Litonjua AA. A variant in the vitamin D receptor gene (vdr) is associated with time to the onset of chronic obstructive pulmonary disease in men. Am J Respir Crit Care Med. 2011;183:A2655
Victor O.Kolade, MD, FACP, Meena Sunil, MD
Department of Medicine, University of Tennessee College of Medicine Chattanooga
February 15, 2012
Vitamin D for COPD: Better than the Alternative?
We believe the report of Lehouck et al on Vitamin D supplementation and reduction of exacerbations of chronic obstructive pulmonary disease (COPD) (1) is very timely. Although Vitamin D deficiency has been associated with increasing severity of COPD (2), current guidelines on evaluation of Vitamin D deficiency do not call for screening of persons with most forms of chronic lung disease (3). Indeed, the guidelines do not identify predictors of severe Vitamin D deficiency, in which guideline- appropriate therapy appeared to confer a benefit in terms of reduction of COPD exacerbations, per Lehouck et al; no significant side effects of therapy would be anticipated at the dose used - which is recommended for replacement (3). If these findings are replicated in larger studies, vitamin D supplementation would likely be a safer alternative to daily azithromycin - which has been shown to prevent COPD exacerbations while increasing the risk of hearing loss (4). Additionally, this study should provoke a closer look into the effects of severe Vitamin D deficiency, for which there is yet no consensus definition. ? References
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: a randomized trial. Ann Intern Med. 2012;156(2):105-14.
2. Janssens W, Bouillon R, Claes B, Carremans C, Lehouck A, Buysschaert I, et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax. 2010;65(3):215-20.
3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-30.
4. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98.
Chronic Obstructive Airway Disease, Hospital Medicine, Prevention/Screening, Pulmonary/Critical Care.
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