Personal view in Lancet Respiratory Medicine:
Vitamin D and COPD: hype or reality.
Wim Janssens*, Marc Decramer*, Chantal Mathieu£, Hannelie Korf£
*Laboratory of Pneumology, Department of Experimental and Clinical Medicine, KULeuven,
Leuven, Belgium
£
Laboratory of Clinical and Experimental Endocrinology, Department of Experimental and
Clinical Medicine, KULeuven, Leuven, Belgium
WJ, CM and HK are supported by the Flemish Research Funds (FWO Vlaanderen)
Address of correspondence:
Wim Janssens, MD, PhD
Respiratory Medicine, UZ Leuven, Herestraat 49, 3000 Leuven, Belgium
Tel: +32 16 34 68 00
Fax: + 32 16 34 68 03
Email: wim.janssens@uzleuven.be
Keywords: vitamin D, COPD, VDR, supplementation, exacerbation
Search strategy and selection criteria:
PubMed was searched for English reports before March 1, 2013 with the terms ‘vitamin D’ in
combination with ‘smoking’, ‘COPD’, ‘airways disease’, ‘lung function’ or ‘exacerbations’.
References from identified papers were also searched for relevant articles.
Abstract
Abundant evidence from laboratory studies is supporting an important role for vitamin D in
the innate and adaptive immune system. In humans, observational studies have associated
vitamin D deficiency to an increased risk for different inflammatory, infectious and autoimmune diseases. With regard to chronic obstructive pulmonary disease, conflicting data have
been reported. Most epidemiological studies have been limited by their design so that larger
longitudinal studies of population based samples and of cohorts with COPD are warranted.
An alternative explanation for the discordant observations in COPD may be found in the
complexity of the intracellular vitamin signaling pathway, which is not reflected in systemic
levels of precursor 25-hydroxyvitamin D. For COPD in particular, we speculate that local
down-regulation of vitamin D signaling from and beyond the receptor may clarify why proinflammatory processes in the airways are not or insufficiently countered by vitamin D
dependent control mechanisms. In a disease already characterized by glucocorticoid
resistance, the potential (re)activation of an intrinsic comprehensive immune control system
should attract more attention in order to design appropriate interventions with promising
therapeutic potential.
2
1. Introduction
Increasing but conflicting evidence is currently arising on the role of the vitamin D pathway
in chronic obstructive pulmonary disease (COPD). Although several studies have highlighted
associations between vitamin D deficiency, pulmonary function and disease characteristics,
others have failed to confirm these findings. A recent placebo controlled intervention trial did
not support clinical benefits of vitamin D supplementation on exacerbations in a severe COPD
population.1 Moreover, the claim that vitamin D deficiency would be rather consequence than
cause of the disease, has dampened the enthusiasm for new clinical studies on vitamin D in
COPD.2;3 This is surprising since most mechanistic studies in cell culture systems and animal
models clearly point to important anti-inflammatory, anti-infectious and anti-proliferative
effects of vitamin D.4 Similarly, large cross-sectional and prospective studies have shown
associations between low levels of vitamin D or polymorphisms in the vitamin D receptor
with increased risk for asthma and poor asthma control, suggesting that the vitamin D
pathway has anti-inflammatory effects in the human respiratory system.5-7 Here, we aim to
review the current literature on vitamin D and COPD with a focus on epidemiological
findings, underlying mechanisms, missing links and future challenges. We are aware of the
role vitamin D may have in common comorbidities of COPD such as osteoporosis, muscle
dysfunction, cardiovascular disease, diabetes and cancer8, but the focus of this review will be
strictly on the respiratory involvement.
2. Vitamin D deficiency and COPD: epidemiologic associations
The majority of vitamin D3 (cholecalciferol) is synthesized in the skin by solar UVB exposure
but an alternative source is derived from dietary intake, mainly fish oils, dairy products,
fortified grains or oral supplements. Cholecalciferol is hydroxylated in the liver by 25hydroxylase (CYP2R1) into 25-hydroxyvitamin D (25(OH)D3) that serves as a substrate for
generation of the bioactive ligand, 1,25-dihydroxyvitaminD3 (1,25(OH)2D3), which is
synthesized in the kidney or locally in immune and epithelial cells by 1α-hydroxylase
(CYP27B1). Circulating 25(OH)D3 is mainly bound to its carrier protein, vitamin D binding
protein (DBP), and because of its relative stability and long half-life, is often used to
determine vitamin D status.9 Based on skeletal benefits, a recent report of the Institute of
Medicine (IOM) has defined the cut-off for deficiency at serum 25(OH)D3 levels < 20 ng/ml,
3
as there was no conclusive evidence for extra-skeletal benefits nor for the need of higher
serum levels in humans.10
Low 25(OH)D3 levels have been associated with a variety of diseases including infections,
auto-immune disease, cardiovascular diseases, diabetes and cancer.9 When focusing on
pulmonary function, Black and colleagues were the first to describe associations with
25(OH)D3 in 14,091 subjects from the Third National Health and Nutrition Survey
(NHANESIII).11 After multiple adjustments for confounders including intake of supplements
and outdoors activity, the mean FEV1 was 106 mL (SE, 24 mL), and the mean FVC was 142
mL (SE, 29 mL) greater for the highest quintile of serum 25(OH)D3 levels compared with the
lowest quintile (p < 0·0001). However, the authors did not find any relationship with
FEV1/FVC ratio, indicating that the cross-sectional observation could also be determined by
impaired lung growth or reduced respiratory muscle force rather than lung function decline
per se. Moreover, a more recent analysis in 2,997 adults of the Hertfordshire Cohort found
positive associations between lung function variables (FEV1, FVC, FEV1/FVC ratio) and
vitamin D intake but failed to confirm the findings of NHANESIII with serum 25(OH)D3
levels.3 It was therefore concluded that vitamin D status did not influence adult lung function
but that other (dietary) factors closely linked to vitamin D, could presumably explain the
positive associations.
To address causality, Lange and colleagues performed a longitudinal study to investigate
vitamin D status and lung function decline in 626 healthy community-based elderly men over
20 years. Multivariable-adjusted analysis revealed that vitamin D status alone was not
associated with spirometric measurements but that a significant vitamin D status-by-smoking
interaction for all measures of lung function was present. In addition, faster rates of lung
function decline per pack-year of smoking were found in subjects with vitamin D deficiency
compared with non-deficient subjects.12 The study indicated that in the general population
smoking individuals are particularly at risk for developing COPD if being deficient for
vitamin D. As a Belgian Cohort study showed that vitamin D deficiency was more prevalent
in mild COPD (39%) compared to smoking controls (31%), these latter findings indirectly
supported such a hypothesis.13 However, the study of Lange et al. did not adjust for physical
activity nor for sun exposure, which are main determinants of vitamin D status. Physical
inactivity is an independent risk for lung function decline and COPD onset14, and additional
research is needed to unravel how these conditions interact with respect to COPD.
4
Several cross-sectional studies have described poor vitamin D status in patients with
established COPD.13;15;16 For instance, in the Belgian cohort of 414 individuals not taking
vitamin D supplements, mean 25(OH)D3 levels were significantly lower in the COPD group
compared to the smoking controls (19·9 ± 8·2 vs. 24·6 ± 8·7 ng/ml) with respectively 39, 47,
60 and 77% of the GOLD stage I, II, III and IV exhibiting vitamin D deficiency.13
Multivariate analysis retained FEV1, obesity, smoking and winter season as main
determinants of low vitamin D status. The Belgian study also confirmed previous reports that
polymorphisms in genes encoding for DBP (GC) were independent determinants of
25(OH)D3 levels.17 Interestingly, genotypes that associated with lower 25(OH)D3 levels also
depicted an increased risk of COPD in the Belgian study. In other studies the same genetic
variants of GC also associated with COPD and diffuse pan-bronchiolitis.18;19 Although DBP
has pleiotropic functions and may activate macrophages in COPD20, the association of the
same risk variants with lower 25(OH)D3 levels may offer an alternative explanation for the
underlying biological mechanism. Overall, these cross-sectional studies highlight that vitamin
D deficiency is prevalent in COPD. Notwithstanding the fact that lower serum levels in
certain genotypes may exist long before disease onset, impaired intake and reduced synthesis
capacity because of low outdoors activities and accelerated skin ageing, are likely the main
causes for such deficiency. As such, vitamin D deficiency can be considered as a direct
consequence of COPD which does not exclude that deficiency once established, may
accelerate disease onset or progression.8
Currently, only few longitudinal studies have explored relationships between 25(OH)D3 and
disease outcomes in patients with COPD. One nested matched case-control study in a limited
sample of 196 COPD patients of the Lung Health Study, did not find lower mean 25(OH)D3
levels in rapid decliners compared to non-decliners over a 6-year follow-up period.21 A larger
secondary analysis of a randomized intervention trial with Azithromycin in 1,117 COPD
patients at risk for exacerbations, found no relationship between baseline 25(OH)D3 levels
and incident exacerbations over 1 year follow-up.2 Unfortunately, patients taking supplements
were not excluded from this analysis. As supplementation in particular is often started in more
severe COPD for reasons of osteoporosis, it may explain why the quintile with the highest
25(OH)D3 levels (>40ng/ml) presented with a higher number of exacerbations per patient year
(1·79 ± 1·96 exacerbations per year). Notably, patients from the same trial with lowest
25(OH)D3 titers (<10ng/ml) exhibited the highest risk for relapse (2·2 ± 5·3 exacerbations per
5
year), suggesting that severe vitamin D deficiency is a useful biomarker for future
exacerbation risk.22 Indeed, a recent analysis in 402 cases of non-cystic fibrosis bronchiectasis
demonstrated an inverse relationship of 25(OH)D3 with exacerbations23, although similar
associations were not retrieved in a small London cohort of 97 COPD patients with 3 years
follow-up24. Finally, Holmgaard and colleagues found no association between vitamin D
status and all-cause mortality in 462 COPD patients followed for 10 years.25 Again, their
design was limited by small sample size including patients on supplementation. Taken
together, new longitudinal studies in large population-based samples or patient cohorts with
COPD, are urgently needed to investigate if 25(OH)D3 levels determine risk of COPD, lung
function decline, exacerbation frequency and even all-cause mortality.26
3. Potential mechanisms
It should be emphasized that epidemiological associations between vitamin D status and
clinical outcomes are currently based on 25(OH)D3 serum levels. These measures are reliable
markers for vitamin D synthesis or intake. The cutoffs for deficiency determine hazards for
disease, particularly in the bone but possibly also in other organs.10 However, 25(OH)D3
serum levels conceptually reduce the entire signaling pathway to a single substrate which is
not the active compound and which does not reflect local activation or activity. Therefore,
lack of associations between substrate and clinical outcomes does not exclude vitamin D
signaling being involved in the underlying pathophysiological process. One could even
speculate that in COPD local or general alterations in the signaling cascade beyond 25(OH)D3
are critically determining vitamin D mediated actions. We will first review the main
mechanisms of vitamin D relevant to the lung and then discuss how some of these may be
downregulated.
3.1. Epigenetic regulation of vitamin D pathway
Upon binding of 1,25(OH)2D3 to the VDR, a heterodimer is formed with the retinoid X
receptor (RXR) and this VDR/RXR complex further binds to specific genomic sequences in
the promoter region of target genes (vitamin D response elements) thereby affecting gene
transcription. To regulate transcription, the VDR/RXR dimer interacts with histone
acetyltransferases (HATs) which are known as transcriptional activators. Binding of the
VDR/RXR complex to negative VDREs with recruitment of histone deacetylases (HDACs),
6
reverses HAT activity by making chromatin more condensed thereby promoting gene
repression and transcriptional inactivation. 27 Histone modification enzymes may act alone or
in concert to facilitate the activation or repression of chromatin-mediated gene expression in
various inflammatory mediators, genes for cell cycle arrest, apoptosis, senescence,
antioxidants and growth factors - notably, all disease processes involved in COPD.28;29 It is
therefore plausible that epigenetic chromatin remodeling events important in COPD might be
co-regulated by VDR-dependent signaling events (Figure 1). In fact, abnormalities in
acetylation and methylation patterns on histones resulting from imbalance of HAT/HDAC and
HMT/demethylases, are associated with alteration in gene expression and/or disease severity
in COPD.30 Ligand activation of VDR may restore such imbalance by recruitment of
HDAC2/SIRT1 deacetylases31;32, with the down-regulation of pro-inflammatory factors
including NF-κB and IL-17 as well as the upregulation of the anti-inflammatory cytokine IL10.33;34
3.2 Anti- inflammatory effects
In COPD, lung destruction is mediated in part through inflammation, oxidative stress and
increased release of proteases and many of these processes are modulated by vitamin D.4;35
An overview of pathological processes and the interaction with VDR-dependent pathways, is
depicted in Figure 2. Briefly, direct injury of airway epithelial cells by toxic and noxious
gases activates pattern-recognition receptors such as Toll-like receptors on epithelial cells and
alveolar macrophages, inducing NF- dependent inflammatory responses with subsequent
recruitment of neutrophils, monocytes and dendritic cells to orchestrate the immune
response.36 Interestingly, epithelial cells and macrophages express VDR at high levels and
possess the enzymatic machinery to produce 1,25(OH)2D3 locally in the lung (CYP27B1).37;38
Macrophages in particular, respond to 1,25(OH)2D3 by preventing excessive expression of
inflammatory cytokines and chemokines. VDR signaling may engage counter-regulatory
mechanisms including the anti-inflammatory cytokine IL-10, the transrepression of NF-mediated responses or the targeting of MAPK phosphatase.32;39;40 In addition, dendritic cells
in COPD portray elevated expression of co-stimulatory molecules to promote CD4+ cell
differentiation and CD8+ cytotoxicity against antimicrobial or self-antigens. It is well
established that 1,25(OH)2D3 inhibits dendritic cell maturation by lowering expression of
MHC
class
II
molecules,
co-stimulatory
molecules
and
pro-inflammatory
cytokines/chemokines.41 With respect to T cells, 1,25(OH)2D3 can either directly or indirectly
7
influence T cell reactivity by suppressing cytokines such as IFNand IL-17 while enhancing
the regulatory markers FOXP3, CTLA4 and IL-10.33;42;43 As the efficacy of 1,25(OH)2D3 in
vivo models of autoimmunity and asthma has been demonstrated repeatedly44;45, tapering
down Th1/Th17 reactivity while promoting regulatory T cell responses may also protect
against uncontrolled inflammation in COPD.36 Moreover, 1,25(OH)2D3 can attenuate MMP9
release thereby limiting tissue destruction46. Finally, either directly or indirectly via
inflammatory cells, vitamin D may also modulate inflammation, muscle contraction and
remodeling in airway smooth muscle cells. 47
3.3 Anti-infectious effects
Viral and bacterial infections are the main cause of acute COPD exacerbations which
accelerate disease progression and increase the risk of death.48 Chronic infection or
colonization of the lower airways may also amplify and perpetuate airway inflammation.49
Interestingly, genes encoding for antimicrobial polypeptides are driven by VDRE-containing
promoters (Figure 2).50 TLR activation of monocytes and macrophages results in the
upregulation of VDR and other VDR-target genes thereby inducing cathelicidin antimicrobial
peptide (CAMP) with subsequent intracellular eradication of Mycobacterium tuberculosis.51
CAMP may also kill a number of antibiotic-resistant strains such as Pseudomonas aeruginosa
and Staphylococcus aureus, different viruses, and chlamydia.51;52 Besides CAMP, the gene
encoding for the antimicrobial defensin-β2, is also direct and indirect target for
1,25(OH)2D3.50 Exposure to 1,25(OH)2D3 results in a strong induction of these peptides with
enhanced antimicrobial activity in various cell types, including myeloid cells, neutrophils, and
bronchial epithelial cells. Other signaling pathways have been proposed to participate in the
anti-infectious activities of 1,25(OH)2D3. For example, phosphatidylinositol 3-kinase was
found to regulate the anti-mycobacterial activity of 1,25(OH)2D3 via the enhanced generation
of reactive oxygen species (ROS) in monocytes and macrophages.53 1,25(OH)2D3 was shown
to induce an NF- inhibitor in airway epithelium with subsequent dampening of chemokine
and IFNβ release upon viral infection.54 1,25(OH)2D3 also induces autophagy and mediates
co-localization of M. tuberculosis with antimicrobial peptides facilitating the destruction of
these bacteria.55 Finally, 1,25(OH)2D3 enhances chemotactic and phagocytic capacity of
macrophages which is severely impaired in patients with COPD.56;57 To summarize, it is clear
that in addition to antibiotic treatment for acute bacterial infections, appropriate ligand
activation of VDR may offer a powerful tool for boosting-up host innate immune defenses
against low grade, smoldering bacterial and viral infections in COPD.
8
3.4 Impaired signaling in the vitamin D pathway
Impaired signaling in the vitamin D pathway is not only dependent on levels of 25(OH)D 3.
Deficient signaling may also comprise of reduced 25(OH)D3 activation (1α-hydroxylase,
CYP27B1), increased catabolism of the active 1,25(OH)2D3 (24-hydroxylase, CYP24A) or
impaired functioning of the receptor (VDR) with its complex regulation. The expression and
functionality of these critical enzymes and receptor may depend on factors other than vitamin
D intake or synthesis, in particular on smoking, chronic inflammation and (epi)genetic
determinants which may even be organ or cell-specific.28 First, smoking can trigger increased
expression of CYP24A in macrophages, resulting in increased catabolism and reduced
bioavailability of the active compound.58 In dendritic cells for instance, the local activation of
25(OH)D3 is crucial for mediating the anti-inflammatory effects of vitamin D 43 and not only
determined by absolute 25(OH)D3 levels but also by the concentration and genetic variant of
its carrier protein DBP.59 Secondly, smoking may inhibit VDR translocation from the nucleus
to the cell membrane.60 In mice, absence of VDR results in an abnormal lung phenotype with
characteristics of COPD, including airspace enlargement, decline in lung function, increased
lung inflammatory cellular influx and immune-lymphoid aggregates formation.61 Similar
mechanisms may occur in patients as VDR expression in alveolar macrophages and airway
epithelial cells was shown to be critically down-regulated by Aspergillus Fumigatus toxins in
cystic fibrosis, a process which could be reversed by antifungal treatment.62 Finally,
multifunctional enhancers including 1,25(OH)2D3 increase VDR gene transcription with local
accumulation of VDR and increased signaling.27 Together, these data suggest that a downregulation of critical intracellular enzymes and receptors in the vitamin D/VDR signaling
cascade may occur in patients with COPD thereby creating a pro-inflammatory environment.
If so, an important question arises whether environmental risk factors (including long-term
vitamin D deficiency) may dampen or inactivate local VDR signaling and whether oral
supplementation of the precursor 25(OH)D3, at low or high dose, will be able to overcome
this.
3.4
Vitamin D irresponsiveness, steroid resistance and ageing
Pulmonary emphysema and cellular ageing or senescence share features in the sense that for
both conditions cells enter in a non-proliferative and pro-inflammatory state. Cigarette smoke
and oxidative stress promote senescence and as such, COPD is often referred to as a disease
9
causing accelerated ageing of the lung.63 It is well established that 1,25(OH)2D3 signals
through the nuclear vitamin D receptor (VDR) to regulate target genes involved in cellular
senescence.64 A recent study has implicated the interaction of VDR with downstream FoxO
proteins and its regulator SIRT1 (another member of the HDAC family), as one of the
underlying molecular mechanisms.31 The activation of SIRT1, which is reduced in lungs of
patients with COPD, may therefore offer a potential target to alleviate cellular senescence in
COPD.65;66 However, posttranslational modifications by cigarette smoke and oxidative stress,
critically down-regulate HDAC2 activity in COPD resulting in the activation of proinflammatory pathways and the insensitivity to corticosteroids.29;67 Upon intracellular
translocation of glucocorticoid receptors, impaired recruitment of HDAC2 will result in
insufficient gene repression, less transcriptional inactivation and subsequently, persistent proinflammatory responses. It is not known to what extent anti-inflammatory VDR signaling
which is also HDAC dependent68, is abrogated by impaired HDAC2 activity in COPD. If
present, it would mean that similar to glucocorticoid resistance, vitamin D resistance may
occur which is in line with the recent negative supplementation trial in COPD patients.1;69 On
the other hand, in vitro experiments in steroid-resistant asthma demonstrated that
1,25(OH)2D3 restored the capacity of CD4+ T cells to produce IL-10 when exposed to
dexamethasone.70 It remains to be further explored how vitamin D interacts with impaired
corticosteroid signaling in COPD. Overall, stimulation of HDAC2 and SIRT1 by drugs (e.g.
resveratrol, SRT1720), caloric restriction or physical activity seem appealing strategies which,
in conjunction with anti-inflammatory mediators such as corticosteroids and ligands of the
VDR may offer powerful anti-inflammatory effects in COPD.71
4. Intervention studies for causality
At this stage, there is no direct proof that vitamin D deficiency or impaired vitamin D
signaling is causally involved in the pathogenesis of COPD. Similarly, it remains to be
explored if activation of the vitamin D pathway, by supplementation or other strategies, may
alter the disease course. In animal models the absence of VDR expression results in airspace
enlargement, increased lung inflammation and immune-lymphoid aggregate formation61,
whereas vitamin D deficiency by dietary intervention results in decreased lung growth72. Yet,
it is not known whether similar conditions may enhance emphysema and airway inflammation
in smoke-induced models of COPD. In patients up to date, only one randomized controlled
10
intervention study has investigated the effect of vitamin D supplementation on exacerbation
risk.1 In this single center study, 182 subjects with moderate to very severe COPD were
randomized to monthly doses of 100,000 IU of cholecalciferol or placebo for one year.
Although the study did not demonstrate any difference in exacerbation risk, a statistically
significant interaction was found between baseline 25(OH)D3 levels and the intervention.
Subsequent subgroup analysis in 30 patients with severe vitamin D deficiency (< 10ng/ml)
revealed a significant reduction in number of exacerbations in the vitamin D intervention arm
(rate ratio: 0·57; CI: 0·33 – 0·98). Moreover, the study found a relative improvement of
monocyte phagocytosis capacity in subjects who were supplemented, particularly in the
deficient subgroup. Because of low sample size, limited follow-up and the specific setting of
severe disease under maximal therapy, the trial was not able to refute the potential of longterm vitamin D intervention for reducing exacerbations or lung function decline in patient
cohorts with mild disease.73 Moreover, the intriguing question whether the lack of
effectiveness of supplementation rather relates to intracellular vitamin D resistance than to an
inefficient treatment per se, was left unanswered. To a certain extent the observed benefit of
high dose supplementation in the most deficient subgroup of the trial indicates that antiinflammatory effects of vitamin D signaling can be enhanced by ligand supplementation but
only to a certain plateau level. Finally, the study was not designed to address potential adverse
effects of high doses or dose swings of cholecalciferol on the immune system. These concerns
are particularly relevant as recent studies have shown adverse effects on the skeleton with
high loading doses74, as well as an increased mortality with high serum levels.26 Interestingly,
stratification according to baseline 25(OH)D3 levels of all patients who participated in the
intervention trial, suggested that for the subgroup with highest baseline titers supplementation
with 100,000 IU may have opposite effects on exacerbation rate (Figure 3).1 These differences
were not significant due to small sample sizes, but they support the idea that peak serum
concentrations may also have adverse effects on the immune system. New trials in COPD or
other respiratory diseases will need to include pharmacokinetic analyses to better determine
an optimal dose regimen and a preferred route of administration.75;76 Future studies may also
include the use of non-calcemic vitamin D analogues eventually through inhalation.77
5. Clinical recommendations in COPD
Based on a comprehensive review of the scientific data, an expert committee of the Institute
of Medicine recently updated the recommendations for calcium and vitamin D dietary intakes
11
in the North American population.10 The committee advocated dietary reference intakes by
life stage and gender to cover the needs of 97.5 % of the population in conditions of minimal
sun exposure. These needs are strictly defined on bone health and correspond to the required
25(OH)D3 serum levels of 20ng/ml. To summarize, dietary intakes of 600 IU/d were
estimated to be sufficient for all adult individuals with exception of the group aged 71 or
older, especially if not physically active, for whom 800 IU /day were recommended. It should
be mentioned that these recommendations are made for the general population and may not
pertain to patients with established disease including COPD. Indeed, in the majority of
healthy subjects a balanced diet and sufficient sun exposure may result in adequate 25OHD
levels, whilst most experts agree that subjects at risk for deficiency, including patients, may
benefit from a vitamin D supplement especially during winter at northern latitudes.78 As long
as specific evidence for supplementation in patients with COPD is missing, we advocate to
follow the IOM recommendations in clinical practice. One alternative but more expensive
approach would be to measure 25(OH)D3 routinely, but we prefer to restrict this assay to the
subgroup of COPD patients at high risk for severe deficiency (<10ng/ml) and suspect of
concomitant bone disease.79 In this particular group higher supplementation doses and
retesting of serum 25(OH)D3 levels may be needed to reach the minimal skeletal
requirements. When addressing extra-skeletal outcomes in COPD, we follow the IOM
statement that there is currently insufficient evidence to recommend high dose
supplementation and even danger when targeting serum 25(OH)D3 levels above 50ng/ml
because of a potentially higher mortality.
6. Conclusions
Whether or not the vitamin D pathway has a role in the pathogenesis of COPD, is still an
ongoing debate. Despite many mechanistic studies highlighting important anti-inflammatory
and anti-infectious effects of vitamin D in laboratory experiments, the clinical evidence in
cohorts of COPD patients remains contradictory. This is partly explained by the suboptimal
design of current observational studies and the lack of large population-based and COPD
cohort studies with sufficient longitudinal follow-up. An alternative reason may be found in
the complexity of the vitamin D/VDR signaling pathway which is not reflected by serum
25(OH)D3 levels alone. Future research in COPD should therefore focus on mechanisms
beyond systemic levels of 25(OH)D3 in animal models and patients with particular attention to
12
the role of locally produced 1,25(OH)2D3 and VDR signaling in immune and structural airway
cells. An improved understanding of the intrinsic regulatory functions of the vitamin D
pathway in COPD may then identify subgroups that can benefit from treatment. We assume
that future studies will not only target therapeutic thresholds of serum 25(OH)D3 but that
alternatives will be designed which may act directly on the pathway, irrespectively of serum
levels. At this stage, minimal 25(OH)D3 serum levels of 20ng/ml compose an objective
endpoint for optimal bone health in the COPD population at risk for osteoporosis. With regard
to the respiratory system however, there is still insufficient evidence to recommend
supplementation and even caution on high dose interventions.
13
Key messages

Large population based studies and clinical COPD cohort studies with longitudinal
follow-up are needed to investigate if 25(OH)D3 levels determine risk of COPD, lung
function decline, exacerbation frequency and all-cause mortality.

The role of vitamin D pathway in the pathogenesis of COPD is complex and should
not be reduced to serum 25(OH)D3 levels alone. Reduced activation or impaired
signaling in airway and immune cells may be responsible for uncontrolled
inflammation and reduced immune defense in COPD.

There is insufficient evidence to recommend general vitamin D supplementation and
even caution on high dose interventions for improving respiratory health in patients
with COPD. A better mechanistic insight is needed before new intervention trials with
vitamin D supplements or related drugs are undertaken.
14
Authors contribution
WJ and HK contributed equally to the design and writing of the manuscript. After input from
MD and CM, all authors edited and approved the final version. WJ took responsibility for
submission
Role of funding source
WJ, MD and CM have received funding from the Flemish Research Institute (FWO) and
Flemish institute of Science and Technology (IWT) for previous and current research projects
on vitamin D.
Conflicts of interest
None of the authors report conflicts of interest relevant to the content of the manuscript.
15
Table 1. Overview of all observational studies that report associations between 25(OH)D3
levels and clinical outcomes in patients with or at risk for COPD .
Figure 1. Histone deactetylases (HDACs) enable condensed chromatin to prevent binding of
transcription factors. During activation, chromatin is acetylated by histone acetylases (HATs)
thereby opening up binding sites for transcription factors. Retinoid X receptor (RXR), vitamin
D response elements (VDRE).
Figure 2. Common cellular mechanisms triggered by smoke-induced airway inflammation
and vitamin D/VDR signaling pathways.
Figure 3. Effects of a monthly dose of 100.000 IU of vitamin D during one year on
exacerbations1. Participants are stratified according to baseline 25(OH)D3, n represents the
number of individuals per block.
16
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