CHEST

Recent Advances in Chest Medicine

COPD, Bone Metabolism, and Osteoporosis

An Lehouck, MSc; Steven Boonen, MD, PhD; Marc Decramer, MD, PhD;
and Wim Janssens, MD, PhD

COPD and osteoporosis are strongly associated because of common risk factors such as age,
smoking, and inactivity. In addition, COPD-related systemic inflammation, vitamin D deficiency,
and the use of systemic corticosteroids enhance ongoing bone destruction. Osteoporosis, in turn,
may cause fragility fractures, which further impair mobility and increase morbidity and mortality.
Vertebral compression fractures and rib cage fractures in patients with COPD may also reduce
pulmonary function or enhance exacerbations. Early prevention and treatment of osteoporosis in
COPD is, therefore, important and should be based on integrated risk assessment tools such as FRAX,
which take bone mineral density, history of fragility fractures, and population-specific clinical
factors into account. As long as intervention studies focusing on the bone in COPD are lacking, a
more rigorous application of existing treatment guidelines of osteoporosis in general is mandatory.
CHEST 2011; 139(3):648657
Abbreviations: 1,25(OH)2D 5 1,25 dihydroxyvitamin D; 25-OHD 5 25 hydroxyvitamin D; BMD 5 bone mineral density;
DXA 5 dual-energy x-ray absorptiometry; GCS 5 glucocorticosteroid; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; ICS 5 inhaled corticosteroid; OPG 5 osteoprotegerin; PTH 5 parathyroid hormone; RANK 5 receptor
activator of nuclear factor-kB; RANKL 5 receptor activator of nuclear factor-kB ligand

is a major cause of chronic morbidity and

COPD
mortality worldwide. The Global Initiative for

Chronic Obstructive Lung Disease (GOLD) has

defined COPD as a preventable and treatable disease
that is primarily characterized by progressive airflow
limitation. This airflow limitation is not fully reversible and is associated with an abnormal inflammatory
response of the lung to noxious particles or gases,
most often cigarette smoke.1 COPD is often associated with different comorbidities and systemic consequences, which further impair functional status, reduce

Manuscript received June 18, 2010; revision accepted September

3, 2010.
Affiliations: From the Respiratory Division (Ms Lehouck and
Drs Decramer and Janssens) and the Center of Metabolic Bone
Diseases (Dr Boonen), University Hospital Gasthuisberg, Katholieke
Universiteit Leuven, Leuven, Belgium.
Funding/Support: This study was supported by the Funds for
Scientific Research-Flanders [Grant 059809N] and the Institute
for Promotion of Innovation Through Science and TechnologyFlanders [Grant 335102].
Correspondence to: Wim Janssens, MD, PhD, Respiratory Division, University Hospital Gasthuisberg, KUL, Herestraat 49,
3000 Leuven, Belgium; e-mail: wim.janssens@uz.kuleuven.be
2011 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.10-1427
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quality of life, and increase mortality.2 Of these, osteoporosis is increasingly being appreciated as an important target for therapeutic intervention.
Osteoporosis is a systemic skeletal disorder that is
characterized by compromised bone strength due to
an impaired bone quality, leading to increased fracture risk. Bone strength depends on the structural and
material properties of bone, both of which are influenced by the rate of bone turnover. Not all determinants of bone strength are well represented by a bone
mineral density (BMD) measurement, but BMD provides a very useful estimate of fracture risk.3 BMD is
measured accurately by dual-energy x-ray absorptiometry (DXA) and is used to define osteoporosis.
DXA measures BMD by dividing bone mineral content by bone area. The T score is calculated by subtracting the mean BMD of a young-adult reference
population from the patients BMD and dividing
by the SD of the reference population. Z scores are
used to compare the patients BMD to a population of peers. According to the World Health Organization, a T score . 21 is accepted as normal, and
T scores between 21 and 22.5 are considered to
be osteopenia, whereas T scores of , 22.5 are
defined as osteoporosis, at least in postmenopausal
women.4 Osteoporosis-related fractures are divided
Recent Advances in Chest Medicine

into vertebral fractures (predominantly at the thoracolumbar spine) and nonvertebral or peripheral
fractures, including hip fractures. Hip bone density is
slightly more predictive of hip fracture risk than BMD
measured at the spine; for other fracture types, DXA
measurements at the spine and hip have similar predictive value. In this regard, hip bone density is preferred for estimating fracture risk, whereas for treatment monitoring, spine bone density is often selected
because the trabecular bone of the spine is more rapidly affected by treatment. Measures of bone turnover, on the other hand, like C-terminal cross-linked
telopeptide of type 1 collagen, or bone alkaline phosphatase, are less predictive of fracture risk, at least
in the individual. As a result, such markers are not
used routinely in clinical practice to identify patients
at risk. However, in osteoporotic patients receiving
treatment, biochemical markers are more sensitive
than BMD to therapeutic interventions, allowing early
feedback and, potentially, enhanced compliance.5
Because of pain and decreased mobility, osteoporotic fractures frequently cause significant morbidity in
older individuals. At this stage in life, hip fractures
and other types of nonvertebral fractures are associated with increased mortality, functional decline, loss
of quality of life, and need for institutionalization.6 In
disabled patients with COPD who are more at risk of
osteoporosis, the impact of such events may be even
worse. Furthermore, vertebral compression fractures
may also lead to increased kyphosis and reduced rib
cage mobility, leading to a further deterioration of pulmonary function.7 Finally, fragility fractures of the rib
may cause hypoventilation and reduce sputum evacuation, which may lead to, or aggravate, exacerbations.8
Hence, more attention should be attributed to the intimate relationship between COPD and osteoporosis.
Prevalence of Osteoporosis
and Fractures in COPD
Prevalence of Osteoporosis in COPD
The prevalence of osteoporosis in COPD varies
between 4% and 59%, depending on the diagnostic
methods used, the population studied, and the severity of the underlying respiratory disease.9 Table 1 summarizes the most important studies. Overall, a higher
prevalence of osteoporosis is generally found in patients
with COPD when compared with healthy control
subjects. In addition, the majority of studies report
an increased risk of osteoporosis with lower FEV1.10-16
Prevalence of Vertebral Compression
Fractures in COPD
Several studies, summarized in Table 1, have explored
by radiograph the prevalence of vertebral compreswww.chestpubs.org

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sion fractures in COPD, which may vary from 24%

to 63%, depending on the population studied.17-20
Vertebral compression fractures should be of major
concern in COPD, even when remaining asymptomatic. Different studies have shown that, besides back
pain, they can result in significant performance
impairments and decline of pulmonary function.21,22
Moreover, a previous fracture is a well-known risk factor for new vertebral and nonvertebral fractures, indicating that their diagnosis is important. In fact, within
1 year after sustaining a vertebral compression fracture,
the rate of new vertebral fractures is close to 20%.23
Prevalence of Hip Fractures in COPD
Although hip fractures are generally considered to be
the most dramatic complication of osteoporosis in terms
of morbidity, mortality, and economic cost,24 their
exact prevalence in patients with COPD has not been
studied in detail. Walsh et al25 reported an increased
prevalence of hip fractures in a population of patients
with miscellaneous lung diseases, 52% of whom were
patients with COPD, when compared with age-matched
control subjects. More recently, the Osteoporosis
Fractures in Men (MrOS) research group demonstrated that a reported history of COPD or asthma
was associated with a lower BMD at the spine and hip,
even when adjusting for confounders such as corticosteroid use, age, hospital site, BMI, and smoking.26
Pathogenesis of Osteoporosis in COPD
Bone is generally classified into two types. Cortical
bone is a dense and strong bone found primarily in
the shaft of long bones. Trabecular bone is more
porous or weak and typically occurs at the ends of long
bones and within the interior of vertebrae and flat
bones. Bone tissue is continuously renewed throughout life and it is estimated that in adults, approximately 25% of trabecular bone and 3% of cortical bone
is replaced every year. After reaching peak bone mass at
the age of 25 to 30 years, remodeling is associated
with an imbalance between formation and resorption,
resulting in a mean annual bone loss of 0.5% to 1%,
which differs by sex, skeletal site, and age. Key determinants of the rate of bone remodeling and bone loss
are parathyroid hormone (PTH), vitamin D, and sex
hormones.27-29 At the cellular level, bone remodeling
is a complex interplay in which osteoblasts, osteoclasts, and osteocytes work together (Fig 1). Basically,
osteoclasts resorb bone and osteoblasts replace bone
by forming an osteoid protein matrix that subsequently
mineralizes, whereas osteocytes and their canicular
network serve as sensors to adjust bone response
to mechanical stimuli. On their surface, osteoblasts
constitutively express the receptor activator of nuclear
CHEST / 139 / 3 / MARCH, 2011

649

Table 1Prevalence of Osteoporosis and Vertebral Compression Fractures in COPD

Study

Patient Group

Osteoporosis
Graat-Verboom et al10 COPD patients
(GOLD I-IV) referred
for PR
Ferguson et al11
COPD patients
(GOLD II-IV)
Sin et al12
COPD patients
(GOLD I-IV)
COPD patients awaiting
Forli et al13
LTX
Patients with chronic
Iqbal et al14
lung disease
Sabit et al15
COPD patients
(GOLD I-IV)
Respiratory outpatients
Bolton et al16
referred for PR
Compression fractures
Ambulatory COPD
Jorgensen et al17
outpatients
(GOLD III-IV)
Ambulatory COPD
Nuti et al18
outpatients
(GOLD I-IV)
Papaioannou et al19
COPD patients
(GOLD not reported)
Male COPD patients
McEvoy et al20
(GOLD not reported)

Prevalence of
Osteoporosis,
Subjects BMD Measurements
%

RX diagnosis of VCF

Prevalence of
VCF, %

554

Whole-body BMD
(DXA)

21

658

BMD LS and hip

(DXA)
BMD total femur
(DXA)
BMD LS and FN
(DXA)
BMD LS and hip
(DXA)
BMD LS and hip
(DXA)
BMD total body, LS,
and hip (DXA)

24

4-33

59

36

24

32

5215
40
130
75
81

62

Thoracic and lumbar spine

radiographs

24

2981

Lateral chest radiograph

41

127

Lateral chest radiograph

27

312

Lateral lumbar and thoracic

radiograph

49-63

BMD 5 bone mineral density; DXA 5 dual-energy x-ray absorptiometry; FN 5 femoral neck; GOLD 5 Global Initiative for Chronic Obstructive
Lung Disease; LS 5 lumbar spine; LTX 5 lung transplant; PR 5 pulmonary rehabilitation; RX 5 radiograph; VCF 5 vertebral compression fractures.

factor-kB ligand (RANKL). When binding to its receptor (receptor activator of nuclear factor-kB [RANK])
on the surface of preosteoclast cells, the latter differentiate into mature and activated osteoclasts. Additionally, osteoblasts but also stromal cells secrete a
soluble decoy receptor, osteoprotegerin (OPG), which
blocks the RANK/RANKL interaction, thereby acting
as a physiologic regulator of bone turnover.30 Imbalance between RANKL and OPG results in excessive
activity of osteoclasts and is considered a major cause
of osteoporosis.31 Another pathway that is less well
understood is the Wnt/b-catenin signaling cascade
downstream of a number of osteoblast-activating proteins and receptors. Wnt signaling activates osteoblasts and bone formation, whereas reduced Wnt
signaling may lead to osteoporosis.32 Several factors
that have often been described in COPD patients
(ie, systemic inflammation, use of corticosteroids,
and vitamin D deficiency) clearly interact with these
pathways and are discussed in the following sections.
Systemic Inflammation
Systemic inflammation is thought to play an important role in the development of osteoporosis in
COPD.33 Key inflammatory cytokines such as tumor
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necrosis factor a and IL-6 are known to induce

expression of RANKL and RANKL-mediated bone
resorption.34 In addition, many other cytokines have
been found to interact with the OPG/RANKL system, supporting the concept that inflammatory mediators contribute to the regulation of bone remodeling.35
In line with this concept, recent data from the arthritis field demonstrate that inflammation can also trigger the Wnt/b-catenin pathway.36
Use of Corticosteroids
Several in vitro and in vivo studies have demonstrated profound effects of glucocorticosteroids (GCSs)
on bone turnover by different mechanisms. GCSs
preferentially affect trabecular bone because of
its higher metabolic activity, but with prolonged
use, cortical bone is also affected.37 Briefly, GCSs
rapidly increase the expression of RANKL and macrophage colony-stimulating factor, while decreasing
the expression of OPG. Along with reduced apoptosis of mature osteoclasts, enhanced and prolonged
resorption occurs, which gradually slows down during
continued use of GCSs because of the inhibition of
osteoclast precursors.38 In a second phase, inhibition
of proliferation, differentiation, and maturation of
Recent Advances in Chest Medicine

72. Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary rehabilitation in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med. 2005;172(1):19-38.
73. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and
calcium to prevent hip fractures in the elderly women. N Engl
J Med. 1992;327(23):1637-1642.
74. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect
of withdrawal of calcium and vitamin D supplements on
bone mass in elderly men and women. Am J Clin Nutr.
2000;72(3):745-750.
75. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention
of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch
Intern Med. 2009;169(6):551-561.
76. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA,
Vanderschueren D, Haentjens P. Need for additional calcium
to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab. 2007;92(4):
1415-1423.
77. Avenell A, Gillespie WJ, Gillespie LD, OConnell D. Vitamin D
and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.
Cochrane Database Syst Rev. 2009;(2):CD000227.
78. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al.
Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ.
2009;339:b3692:1-11.
79. Janssens W, Lehouck A, Carremans C, Bouillon R, Mathieu C,
Decramer M. Vitamin D beyond bones in chronic obstructive
pulmonary disease: time to act. Am J Respir Crit Care Med. 2009;
179(8):630-636.
80. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms
of action of bisphosphonates: similarities and differences and
their potential influence on clinical efficacy. Osteoporos Int.
2008;19(6):733-759.

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81. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med. 2009;
122(2 Suppl):S14-S21.
82. Smith BJ, Laslett LL, Pile KD, et al. Randomized controlled
trial of alendronate in airways disease and low bone mineral
density. Chron Respir Dis. 2004;1(3):131-137.
83. Langdahl BL, Marin F, Shane E, et al. Teriparatide versus
alendronate for treating glucocorticoid-induced osteoporosis:
an analysis by gender and menopausal status. Osteoporos Int.
2009;20(12):2095-2104.
84. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J
Med. 2007;357(20):2028-2039.
85. Lim LS, Hoeksema LJ, Sherin K; ACPM Prevention Practice
Committee. Screening for osteoporosis in the adult U.S.
population: ACPM position statement on preventive practice.
Am J Prev Med. 2009;36(4):366-375.
86. Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F,
Oden A; National Osteoporosis Guideline Group. Case finding
for the management of osteoporosis with FRAXassessment
and intervention thresholds for the UK. Osteoporos Int.
2008;19(10):1395-1408.
87. Compston J. US and UK guidelines for glucocorticoid-induced
osteoporosis: similarities and differences. Curr Rheumatol Rep.
2004;6(1):66-69.
88. Devogelaer JP, Goemaere S, Boonen S, et al. Evidence-based
guidelines for the prevention and treatment of glucocorticoidinduced osteoporosis: a consensus document of the Belgian
Bone Club. Osteoporos Int. 2006;17(1):8-19.
89. Bell KJ, Hayen A, Macaskill P, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate
treatment: secondary analysis of trial data. BMJ. 2009;338:
b2266:1-5.
90. Watts NB, Lewiecki EM, Bonnick SL, et al. Clinical value
of monitoring BMD in patients treated with bisphosphonates
for osteoporosis. J Bone Miner Res. 2009;24(10):1643-1646.

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Use of Corticosteroids

Figure 2. COPD-related risk factors for osteoporosis and its

functional consequences.

25 hydroxyvitamin D (25-OHD) levels and BMD has

been described in different populations, including
COPD patients.47,48 Lower 25-OHD levels are also
associated with muscle weakness and an increased
risk of falls.49 The prevalence of vitamin D deficiency is rising. According to data from the National
Health and Nutrition Examination Survey in the
United States, population mean 25-OHD levels
decreased from 30 ng/mL to 24 ng/mL over the
last 15 years.50 In elderly patients, it is estimated
that vitamin D deficiency may even occur in up to
40% to 70% of the population.51,52 Some controversy still exists about which cutoffs are appropriate for defining optimal vitamin D levels, but
nowadays most experts agree on a 25-OHD level
below 20 ng/mL (50 nmol/L) to define low circulating vitamin D levels. With respect to this 20-ng/mL
threshold, a cross-sectional analysis of 25-OHD
levels in 414 smokers revealed that compared with
31% of the healthy smokers, 39%, 47%, and as many
as 60% and 77% of the patients with GOLD I to IV
exhibited vitamin D deficiency. 25-OHD levels were
independently determined by season and disease
severity, but also by genetic variation in the vitamin
D binding gene,53 supporting a role for standard
supplementation in the majority of patients. The
currently recommended supplementation dose of
800 International Units/d is an estimated average
requirement for older adults to reach 25-OHD levels of 30 ng/mL, a serum concentration well above
the cutoff for deficiency and certainly sufficient
for adequate bone protection. However, the effective repletion dose for an individual patient varies
according to the initial level of deficiency, BMI, effective sun exposure, and genetic and other unidentified factors. Each 100 International Units/d is
estimated to increase the serum 25-OHD level by
1.0 ng/mL (range 0.7-1.1 ng/mL) and when using
such calculated repletion doses in high risk patients,
25-OHD should be retested after 3 months of
therapy.54
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Systemic GCSs are used as evidence-based treatment of COPD exacerbations despite their deleterious effect on BMD and fracture incidence. A survey
of seven studies in 42,500 subjects concluded that
prior and current exposure to GCSs is correlated
with an increased risk of fractures.55 A meta-analysis
by van Staa et al56 showed a strong inverse correlation between bone density and total cumulative
dose of GCSs. A significant correlation was also
found between the daily dose of GCSs and the risk
of fractures. Even oral doses as low as 2.5 to 5 mg
prednisone equivalent daily were associated with an
increase in fracture risk. The risk of fracture increased
rapidly after the start of oral corticosteroid therapy
(within 3 to 6 months) but most of the excess risk
of fracture disappeared within 1 year after stopping
therapy. For COPD patients in particular, different
studies demonstrate that patients receiving oral GCS
are more likely to have one or more vertebral fractures.20,25 The effect of inhaled corticosteroids (ICSs)
on bone loss and fracture risk, on the other hand, is less
clear, with several cross-sectional studies reporting
mild effects of high doses of ICSs on bone turnover.57
In a meta-analysis, Drummond et al58 included three
large randomized controlled trials on ICSs in COPD
with fractures as secondary outcome and could not
find any statistically significant difference between
groups. Similarly, a recent substudy of Towards a
Revolution in COPD Health (TORCH) in 658 patients
revealed no significant effect of ICS on BMD over
the course of 3 years.11 Because the follow-up in most
of these studies was relatively short compared with
the need for long-term treatment of COPD patients
in real life and because high doses have been associated with increased rates of bone turnover,59 further
studies are needed and further care should be given
to prescribe the lowest dose of ICSs possible.
Gonadal Sex Steroids
Sex steroids and their receptors play a crucial role
in skeletal growth and maturation but are also important for the maintenance of skeletal integrity at later
stages in life. It is well established that a decrease
in bioavailable sex steroid hormones is related to
bone loss not only in postmenopausal women, but
also in elderly men.60,61 Although estrogen concentrations (17b-estradiol) are linked with bone turnover, bone loss, and even fracture risk in both postmenopausal women and elderly men, the evidence
for androgens is less convincing.62,63 Testosterone
may have direct effects on the bone via androgen
receptors, but it may also act on estrogen receptors
after aromatization to estradiol in vivo.64 Hypogonadism in men is an accepted risk factor for osteoporosis,
Recent Advances in Chest Medicine

Figure 3. Flow diagram summarizing risk assessment, diagnosis, and therapy of osteoporosis in COPD
*25-OHD , 10 ng/mL: start high dose vitamin D supplements with control of 25-OHD after 3 months.
25-OHD 5 25 hydroxyvitamin D; DXA 5 dual-energy x-ray absorptiometry; Vit D 5 vitamin D.

but testosterone-replacement studies have yielded

conflicting results with only beneficial bone effects
below a testosterone serum threshold of 200 ng/dL.65,66
In COPD, low 17b-estradiol levels have been associated with an increased risk of osteoporosis.14 Men
with COPD exhibit reduced testosterone levels when
compared with healthy control subjects,67,68 but different intervention trials with androgens demonstrated only modest effects on muscle mass and
strength, especially in combination with rehabilitation. They did not report beneficial effects on the
bone.69,70 A crossover study in asthmatic men on longterm GCS, however, indicated that testosterone could
also increase BMD.71 Not in the least because of side
effects and increased cancer risk, more research is
needed to define the role of sex steroids and analogs
in the treatment of COPD and osteoporosis.
Prevention and Treatment of
Osteoporosis in COPD Patients
Nonpharmacologic Interventions
Cross-sectional and epidemiologic evidence suggests a strong association between several lifestyle factors in COPD patients and the risk of osteoporotic
fragility fractures. Physical inactivity, smoking, and
poor diet are accepted as important domains for interwww.chestpubs.org

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vention in COPD patients, and the benefits of multidisciplinary rehabilitation in symptomatic patients
have been clearly established.72 However, although
several training methods have demonstrated positive
effects on bone density in a healthy general population, studies in COPD patients are lacking. Randomized controlled trials are definitely required to
determine which training modalities, from a skeletal
perspective, are most efficient in the context of COPD.
Indirectly, training benefits on skeletal muscle force,
balance impairment, and self-confidence may also
reduce the risk of falling and prevent osteoporosis
from causing symptoms. Furthermore, the beneficial
effects of other lifestyle modifications, such as smoking cessation and healthy diet, on osteoporosis and
osteoporotic fracture occurrence in established COPD
should still be confirmed with intervention studies.
Calcium and Vitamin D Supplementation
Supplementation of calcium and vitamin D enhances
bone density, suppresses bone remodeling, and
reduces fracture risk in older individuals.73 However,
compliance with supplements is essential, with no
long-lasting benefits once calcium and vitamin D have
been discontinued.74 In a recent meta-analysis, BischoffFerrari et al75 studied the efficacy of oral vitamin D
supplements on nonvertebral fractures in an elderly
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653

population aged older than 65 years. They concluded

that, compared with calcium or placebo, vitamin D
was able to reduce fracture risk and that this effect
was dose dependent. Higher doses of vitamin D
(800 International Units/d) reduced nonvertebral
fractures by approximately 20% and hip fractures
by approximately 18%, whereas 400 International
Units/d was not effective. To address the potential
benefit of calcium in individuals treated with vitamin D,
Boonen et al76 performed a comparative meta-analysis
and found that the risk of hip fractures was reduced
only when calcium was added to vitamin D. Similar
findings were reported by a recent Cochrane review.77
Particularly appealing about calcium and vitamin D
is that supplements not only reduce bone loss but
also prevent falls. Bischoff-Ferrari and colleagues78
demonstrated that vitamin D (800 International
Units/d) reduced the risk of falling in older individuals
by 19%. This fall-preventive effect does not require
calcium but is related to vitamin D-induced improvements in muscle function and postural stability.
Specific data for COPD patients are currently lacking, but the fact that the majority of COPD patients are
of older age, have many additional risk factors for
osteoporosis, and are more likely to have at least some
degree of vitamin D deficiency supports the need for
standard supplementation (800 International Units/d)
in most of these risk patients. We recommend an even
more aggressive repletion regimen when 25-OHD
levels are below 10 ng/mL.54 Moreover, we and others have suggested that the effect of high doses of
vitamin D supplementation might extend beyond
the protection of bone because 1,25-(OH)2D may
directly affect inflammation and interfere with other
comorbidities.79
Antiresorptive Therapy
Bisphosphonates are the most widely used drugs
for osteoporosis. They have a high affinity for bone
mineral and impair bone resorption by blocking key
enzymes of osteoclasts.80 Numerous studies have
demonstrated a protective effect of bisphosphonates
in postmenopausal and glucocorticoid-induced osteoporosis.81 but few trials have specifically addressed the
effect of antiresorptive agents in COPD. One exception is a randomized controlled trial by Smith et al82
demonstrating a significant improvement in lumbar
spine BMD through daily intake of alendronate. For
glucocorticoid-induced osteoporosis in particular,
teriparatide, a more potent anabolic drug, was found
to be superior to alendronate in increasing bone density and reducing vertebral (but not nonvertebral)
fracture risk.83,84 Although more studies are needed
to determine its exact place in the current treatment,
in high-risk patients receiving GCS (eg, those with
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multiple existing deformities), teriparatide may be a

preferred alternative.
To take into account independent clinical determinants of fracture risk (such as corticosteroid use),
FRAX was developed recently. FRAX is a computerbased algorithm (http://www.shef.ac.uk/FRAX) that
provides models for assessment of fracture probability in men and women from the information provided
from clinical risk factors such as age, sex, BMI, prior
fragility fracture, smoking status, ethanol abuse, and
prior use of GCS. With FRAX, the 10-year fracture
probability can be derived from these clinical risk
factors for fractures, alone or with femoral neck
BMD, to enhance fracture risk prediction and to identify patients who will benefit most from treatment.85,86
FRAX will likely become an increasingly useful tool
for defining intervention thresholds in patients receiving corticosteroids, including patients with COPD.
However, for the time being, the identification of
patients who need antiresorptive treatment continues to be based on bone density and prevalent fracture status. Trials in osteoporosis have typically used
DXA-defined T scores below 22.5 SD or existing
(vertebral) fractures to enroll patients and define
intervention thresholds. However, it is recognized
that these thresholds are different for high-risk patients
receiving long-term GCS treatment (. 3 months)
because corticosteroid treatment enhances fracture
probability, independently of age or bone density. In
this regard, numerous guidelines, including those of
the Royal College of Physicians and the American
College of Rheumatology, recommend antiresorptive
treatment in corticosteroid-treated patients with
DXA-defined osteopenia (T score between 21 and
22.5), even in the absence of existing fragility fractures.87,88 Because these guidelines predated PTH
therapy and have not yet integrated multiple riskassessment tools, an update in the nearby future will
be required. The controversy on repetitive BMD measurements and/or the use of biochemical markers to
monitor treatment effects may then be tackled as well.89
At present, clinicians should consider a follow-up
DXA scan 1 year after starting pharmacologic therapy
and thereafter at intervals determined by the individual situation.90
Conclusions
Osteoporosis is common in COPD and should be a
major concern in the diagnostic and therapeutic
approach to COPD patients, who should be regarded
as individuals at risk benefiting from osteoporosis
assessment and therapy. A clinical guidance to a more
aggressive approach is summarized in a flowchart, which
integrates risk assessment, diagnosis, and therapeutic
interventions (Fig 3). Briefly, early diagnosis is important,
Recent Advances in Chest Medicine

even in COPD patients with no symptoms. In this

regard, identification of vertebral compression fractures on radiograph, measurement of 25-OHD levels, and DXA scan are recommended in all patients
with an obvious risk profile for osteoporosis. Standard
supplementation with vitamin D and calcium must
be considered in all these patients at risk and, in line
with established guidelines, COPD patients receiving
GCS should be started with antiresorptive treatment
not only when osteoporotic (T score , 22.5 or existing fragility fracture) but even when having DXAdefined osteopenia (T score , 21).
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Decramer has
received grant monies from AstraZeneca. He has been a consultant to Dompe, GlaxoSmithKline, Boehringer, and Nycomed and
has received monies from Pfizer. Drs Lehouck, Boonen, and Janssens
have reported that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.

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