Loss of Bone Density with Inhaled Triamcinolone in Lung Health Study II Paul D. Scanlon, John E. Connett, Robert A. Wise, Donald P. Tashkin, Thelma Madhok, Melissa Skeans, Paul C. Carpenter, William C. Bailey, A. Sonia Buist, Michael Eichenhorn, Richard E. Kanner, Gail Weinmann, and the Lung Health Study Research Group
Mayo Clinic, Rochester; University of Minnesota Coordinating Center, Minneapolis, Minnesota; Johns Hopkins University School of Medicine,Baltimore; National Heart, Lung, and Blood Institute, Bethesda, Maryland; University of California, Los Angeles, California; University ofAlabama at Birmingham, Birmingham, Alabama; Oregon Health Sciences University, Portland, Oregon; Henry Ford Hospital, Detroit,Michigan; and University of Utah, Salt Lake City, Utah
Inhaled glucocorticosteroids (ICS) are commonly prescribed for
unproven effects of ICS include cataracts (13–15), glaucoma (16,
chronic obstructive pulmonary disease. No adverse effect on bone
17), adrenal suppression (18), and skin bruising (2, 15, 18–20). mineral density (BMD) has been proven. In a randomized double-
Studies of the effect of ICS on bone metabolism in adults with
blind, placebo-controlled trial at seven centers in North America,
asthma show mixed results (18, 21–25, 56). One uncontrolled
we recruited 412 current smokers or recent quitters with mild to
longitudinal study over 3 years showed a dose-related decline
moderate chronic obstructive pulmonary disease. They used inhaled
in bone density at the hip in premenopausal women with asthma
triamcinolone acetonide, 600 mcg, or placebo, twice daily. We mea-
using ICS (26). In the only long-term controlled study of patients
sured femoral neck and lumbar spine BMD at baseline and after 1
with COPD treated with budesonide, no adverse effect on BMD
and 3 years, and serum osteocalcin at baseline, 3 months, 1 year,
was found (2). Two systematic reviews have concluded that the
and 3 years. After 3 years, BMD at the femoral neck decreased 1.78%
long-term use of ICS is not proven to cause significant changes
more with ICS than with placebo (p Ͻ 0.001). More participants in
in BMD (27, 28). This issue remains controversial, however,
the ICS group experienced 6% or more loss of femoral neck BMD
and several recent studies address the evidence of nonvertebral
(p ϭ 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p ϭ 0.007). Changes in osteocalcin did not correlate with
Many patients with COPD have risk factors for osteoporosis,
changes in BMD. Fractures, lost height, or osteoporosis diagnoses
including older age, female sex, impaired nutritional status, low
were not increased among ICS users compared with placebo users.
exercise levels, and tobacco smoking (33–35). The Lung Health
In summary, the use of inhaled triamcinolone acetonide was associ-
Study II (LHS II) was designed to study the efficacy of inhaled
ated with loss of BMD at the femoral neck and lumbar spine after
triamcinolone (1,200 g/day Azmacort ) in slowing the decline
3 years of treatment.
of FEV1 in current smokers and recent quitters with mild tomoderate COPD. This trial afforded the opportunity to examine
Keywords: bone density; obstructive lung diseases; osteoporosis; ran-
the effect of the long-term use of ICS on bone metabolism in
domized controlled trials; triamcinolone acetonide
COPD. We performed serial measurements of BMD and serumosteocalcin over 3 years in a subgroup of 412 participants (1).
Inhaled glucocorticosteroids (ICS) are commonly used for thetreatment of chronic obstructive pulmonary disease (COPD),
although their effectiveness has not been established. Severalrecent large multicenter randomized trials investigated the effi-
cacy of ICS in COPD (1–5). None found a difference between
LHS II recruited 1,116 participants with COPD (ages 40–69 years).
ICS and placebo in the rate of decline of FEV1 over 2 to 3.5
Based on a sample size estimate for this ancillary study, we recruited
years. Several studies have found a reduction in exacerbations
412 participants from the LHS II for measurements of BMD and osteo-
and symptoms associated with ICS (1, 2, 4, 6–8). A subsequent
calcin. Willing participants were recruited sequentially until the recruit-
nonrandomized study of patients dismissed from hospital after
ment goal was met. Women were recruited in equal numbers to men.
exacerbation of COPD showed lower rates of rehospitalization
Of the potential LHS II recruits, five were excluded because of use of
and death among those prescribed ICS (9).
glucocorticosteroids (OCS) and two for use of ICS in the previous 6
The adverse effects of long-term use of systemic glucocorticoste-
months. Exclusion criteria for the BMD study included known osteopo-
roids include loss of bone mineral density (BMD) (10, 11), fractures
rosis, other disorders of calcium metabolism, or a condition that might
(12), adrenal suppression, glaucoma and cataracts, diabetes, myopa-
interfere with participation. Participants were randomized to triamcino-lone acetonide (Azmacort) six puffs twice a day (1,200 g/day) or
thy, hypertension, and loss of skin integrity (12). Reported but
placebo. We obtained written consent, approved by the institutionalreview board at each center. Methods for the LHS II have been de-scribed (1, 36). BMD Measurements
(Received in original form October 1, 2003; accepted in final form September 13, 2004)
BMD scans of the hip and lumbar spine were performed using dual-
Supported by a cooperative agreement with NIH-NHLBI-5U01-HL50267-05 andby Rho
ˆne-Poulenc Rorer, Inc. (now Aventis Pharmaceuticals, Inc.) (Collegeville,
energy X-ray absorptiometry at baseline and the end of the first and
PA), who provided the study medication, the placebo, and support for ancillary
third years with Hologic model 1000, 1000W, or 2000 pencil-beam
scanner. We used the same equipment for the entire study. Scannerswere calibrated at the beginning and annually with a single standard
Correspondence and requests for reprints should be addressed to John E. Connett,Ph.D., Lung Health Study Coordinating Center, 2221 University Ave SE, Suite
spine model. Scanners were calibrated against local standards on each
200, Minneapolis, MN 55414. E-mail: [email protected]
day of testing. Digitized data were analyzed without knowledge oftreatment assignment at a central reading center. Hip data are presented
Am J Respir Crit Care Med Vol 170. pp 1302–1309, 2004 Originally Published in Press as DOI: 10.1164/rccm.200310-1349OC on September 16, 2004
only for the femoral neck and lumbar spine data for L2 to L4. Hologic
Internet address: www.atsjournals.org
Scanlon, Connett, Wise, et al.: Loss of Bone Density in LHS II
Serum osteocalcin levels were drawn before 10:00 a.m. at baseline and at
The longitudinal analyses of BMD included participants with
3, 12, and 36 months of treatment. Samples were stored at Ϫ70ЊC until
technically satisfactory scans at all three study visits (328 lumbar
shipped for batch processing using radioimmuno assay (ELSA-OSTEO;
spine and 359 femoral neck). Technically, inadequate spinal
CIS US Inc., Bedford, MA). The laboratory was unaware of treatment
scans were mostly due to degenerative joint disease or scoliosis.
assignment. A two-level calibration against standard samples was per-
Follow-up rates and technically satisfactory scan rates were simi-
lar in the two treatment groups. The average weight gain over
3 years was 0.41 Ϯ 5.8 kg (mean Ϯ SD). There was no differencebetween the groups in this regard (p ϭ 0.54).
Descriptions of data were based on counts for categorical data or meansand SDs for continuous variables. Bivariate comparisons between the
treatment groups used chi-square statistics (for categorical variables)or unpaired t tests (for continuous variables). Controlled comparisons of
Adherence was monitored by inhaler canister weight at 3-month
outcome variables were done with multivariate linear regression using
visits. Good adherence (у 9 puffs/day averaged over 3 years)
PROC GLM in SAS (SAS version 6.12; SAS, Inc., Cary, NC) (37). No
was observed in 46.6% of participants; 21.2% had satisfactory
adjustment was made for multiple comparisons; nominal p values are
adherence (6–8.99 puffs/day); 13.2% had less than satisfactory
adherence (3–5.99 puffs/day); 8.3% had poor adherence (1–2.99
Changes in BMD were analyzed separately for baseline to Year 1,
puffs/day), and 10.7% had very poor adherence (Ͻ 1 puff/day).
baseline to Year 3, and Year 1 to Year 3. Baseline characteristicsincluded treatment group, age, sex, race, smoking status, baseline BMD
Baseline Bone Density
of the femoral neck and lumbar spine, use of calcium or vitamins,
Table 2 shows bone densities for lumbar spine and femoral neck
use of estrogen and self-reported menopausal status in women, FEV1percentage predicted before and after bronchodilator, methacholine
by treatment assignment with sexes combined and separated.
responsiveness, number of cigarettes per day, body mass index, activity
We found no differences between the active drug and placebo
level, and weight change. The results are summarized in terms of per-
group for any of the baseline measurements. A baseline femoral
centage changes in BMD associated with each significant predictor or
neck BMD below the fifth percentile (10) was observed in 15 men
specified increments in the predictor.
and 21 women. A baseline lumbar spine BMD below the fifth
Baseline data were available for all of the 412 participants. Femoral
percentile was observed in 26 men and 9 women.
neck BMD results are reported for those with three technically accept-able measurements (baseline, Year 1, and Year 2) from the hip (n ϭ
Change in Femoral Neck BMD
359; 8 [2%] had technically inadequate data, and 45 [11%] had missing
Femoral neck BMD showed no change and no difference be-
data). Lumbar spine BMD results are reported for those with threetechnically acceptable measurements from the spine (n ϭ 328; 45 [11%]
tween the ICS and placebo groups during the first year of treat-
had technically inadequate data, and 39 [9%] had missing data). Other
ment (Table 2 and Figure 1). Between Year 1 and Year 3, there
follow-up data are reported for all participants who belonged to one
was a Ϫ1.66 Ϯ 4.40% change in femoral neck BMD in the active
treatment group but no change (0.1 Ϯ 4.01%) in the placebogroup (p Ͻ 0.001, ICS vs. placebo). At Year 3, the active treat-
ment group was significantly lower than baseline (Ϫ2.00 Ϯ4.67%) and significantly lower than the placebo group, which
was unchanged from baseline (Ϫ0.22 Ϯ 4.36%). This resulted
The baseline characteristics of participants are shown in Table 1.
in a 1.78% difference between the two groups in femoral neck
The ICS group participants were slightly younger and had a slightly
BMD change from baseline to Year 3 (p Ͻ 0.001). When sexes
higher FEV1, and fewer reported taking calcium supplements.
were analyzed separately, the ICS–placebo difference was
TABLE 1. BASELINE CHARACTERISTICS OF STUDY PARTICIPANTS Definition of abbreviations: BD ϭ bronchodilator; ICS ϭ inhaled glucocorticosteroids; N/A ϭ not applicable; PLAC ϭ placebo. Users of estrogen replacement therapy are calculated among women who are perimenopausal or postmenopausal. Results are presented as mean Ϯ SD. * p Values comparing ICS and PLAC groups for all participants are calculated using the Fisher’s exact test (2-tail) for categorical data and the t test for quantitative
† Percentage of female participants who are currently menopausal and postmenopausal.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
TABLE 2. BONE MINERAL DENSITIES (MEANS Ϯ SD): BASELINE VALUES, PERCENTAGE CHANGES FROM BASELINE TO YEARS 1 AND 3 AND FROM YEAR 1 TO YEAR 3, Z SCORES AT BASELINE AND YEAR 3, AND Z SCORE CHANGES Definition of abbreviations: BMD ϭ bone mineral density; ICS ϭ inhaled glucocorticosteroids; PLAC ϭ placebo. Bone mineral densities of femoral neck and lumbar spine in g/cm2 at baseline, percentage changes between different time points, Z scores of femoral neck and
lumbar spine, and Z score changes between different time points. ICS users and placebo users are shown separately. Data are expressed as mean Ϯ SD. No significantdifferences were found at baseline; p values are for comparisons of changes between the ICS and the placebo group for the various time comparisons.
significant for men (Ϫ2.22%, p Ͻ 0.001) but not for women
men and women combined (p ϭ 0.002) and for women (p ϭ
(Ϫ1.28%, p ϭ 0.087). In terms of femoral neck Z scores, at Year
0.008) but not for men (p ϭ 0.091). In the ICS group, 20 partici-
3, there was a small increase from baseline among placebo users
pants (6 men and 14 women) had a femoral neck BMD below the
(0.13 Ϯ 0.34, p Ͻ 0.001), but among ICS users, the increase was
fifth percentile at 3 years; in the placebo group, 15 participants (7
smaller and not different from zero (0.008 Ϯ 0.35, p ϭ 0.76;
men and 8 women) had a femoral neck BMD below the fifth
Table 2). The difference between ICS and placebo users was
We analyzed the results by adherence level (Table 3). The
Change in Lumbar Spine BMD
difference in femoral neck BMD between the ICS group and
Between baseline and Year 1, there was no change in spine BMD
the placebo group was significant only for those who used nine
for either treatment group, and the difference between groups was
or more inhalations per day (Ϫ1.92%, p ϭ 0.003).
not significant (Table 2 and Figure 2). Between Year 1 and Year
A multivariate analysis was performed (Table 4) to determine
3 the active treatment group showed a Ϫ0.30 Ϯ 3.49% decrease
whether other factors contributed to the loss of femoral neck
in BMD, and the placebo group showed a 1.52 Ϯ 4.15% increase
BMD and whether there was any subgroup that might be at
in BMD (p Ͻ 0.001 between groups). At the end of the third year,
particular risk. In addition to the effect of the study medication,
the difference between the two treatment groups in the change
age of more than 56 years (the median age among our partici-
from baseline in lumbar spine BMD was significant, with the ICS
pants) was associated with a greater loss of femoral neck BMD.
group showing a 1.33% lower BMD compared with the placebo
Sex, baseline femoral BMD, cigarette smoking, and the use of
group (p ϭ 0.007). The results were similar for men and women.
estrogen, calcium supplements, vitamin D, or multivitamins were
For women, the treatment effect was significant from baseline to
not significant predictors of change in femoral BMD.
Year 3 (p ϭ 0.027) and from Year 1 to Year 3 (p ϭ 0.001). For
At Year 3, in the ICS group, 31 (16 men and 15 women) had
men, the treatment effect was significant between Year 1 and Year
a more than 6% decrease in femoral neck BMD compared with
3 (p ϭ 0.005) but not between baseline and Year 3 (p ϭ 0.082).
baseline. In the placebo group, 13 (8 men and 5 women) had a
In terms of Z scores, for men and women combined, the placebo
more than 6% decrease in femoral neck BMD. The difference
group increased by 0.25 from baseline at Year 3 (p Ͻ 0.001 com-
between the ICS group and placebo group was significant for
pared with baseline), whereas the ICS group increased by only
Scanlon, Connett, Wise, et al.: Loss of Bone Density in LHS II
TABLE 4. RESULTS OF MULTIVARIATE ANALYSES* OF DRUG EFFECTS ON PERCENT CHANGES IN BONE DENSITY FROM BASELINE TO YEAR 3 Figure 1. Changes in bone mineral density (BMD) of femoral neck at
Year 1 and Year 3, expressed as percentage change from baseline. ErrorDefinition of abbreviations: ICS ϭ inhaled glucocorticosteroids. bars represent 2 SEs. Closed circles indicate inhaled glucocorticosteroids
Multivariate analysis of effects of various characteristics on percent changes in
(ICS) group; closed triangles indicate placebo group.
bone mineral density of femoral neck and lumbar spine from baseline to Year 3. The model was calculated as a stepwise regression using treatment assignment,age group, sex, cigarettes per day, calcium use, vitamin D use, and multivitaminuse. Significant predictors are shown with effect size expressed as percentage
0.11 (p Ͻ 0.001 compared with baseline, p ϭ 0.004 compared with
change in bone mineral density; p values are for comparisons shown.
* Results of General Linear Model procedure.
We analyzed the effect of drug adherence on changes in
lumbar spine BMD (Table 3). The ICS participants who usednine or more puffs per day showed a significantly lower lumbarspine BMD (Ϫ2.15%, p ϭ 0.003). The numbers of participants
given short courses of OCS as part of their medical care (34 ICS
in the lower adherence subgroups were small, and no significant
and 34 placebo). We found no difference between those who
used OCS and those who did not. After controlling for OCS,
A multivariate analysis (Table 4) showed that in addition to
the medication effect of ICS on BMD was significant at both
the effect of the medication, women had a greater loss of spine
the femoral neck (p Ͻ 0.001) and the spine (p ϭ 0.011).
BMD than men did. Participants who were older than the median
More participants in the ICS group than the placebo group
age of 56 years had a greater increase in spine BMD. Smoking
(11 ICS vs. 2 placebo) used thyroid replacement. Participants
appeared to have a deleterious effect in proportion to number
in the ICS group who used thyroid replacement had a slightly
of cigarettes smoked at baseline (p ϭ 0.056). Baseline spine
(but not significantly) greater BMD loss in both femur and spine
BMD and the use of estrogen, vitamin D, calcium, and multivita-
than those who did not. When we reanalyzed the changes in
mins were not predictors of change in spine BMD.
femoral and spinal BMD excluding participants using thyroid
No difference was observed between the ICS group and the
replacement therapy, the results were unchanged, and the differ-
placebo group in the number of participants with spine BMD below
ences from baseline to Year 3 remained significant (p Ͻ 0.001
the fifth percentile or with a decline of 6% or more at 3 years.
for femoral neck, p ϭ 0.0121 for spine).
Self-reported physical activity levels (no regular exercise,
Other Factors Considered in Analysis of BMD
moderate, vigorous) had no effect on femoral or spinal BMD.
At the beginning of the study, we excluded potential participants
After controlling for baseline physical activity, the effect of ICS
who reported recent use of oral or systemic glucocorticosteroids
on BMD was unchanged and still significant (p Ͻ 0.001 for
(OCS). During the course of the study, some participants were
femoral neck and p ϭ 0.016 for spine). TABLE 3. PERCENTAGE CHANGES IN BONE MINERAL DENSITY FROM BASELINE TO YEAR 3 BY DRUG GROUP AND BY AVERAGE PUFFS PER DAY Definition of abbreviations: BMD ϭ bone mineral density; ICS ϭ inhaled glucocorticosteroids; PLAC ϭ placebo. Percentage changes in bone mineral density of femoral neck and lumbar spine among participants with different levels of treatment adherence from baseline to Year
3. Data are expressed as mean Ϯ SD; p values compare ICS and placebo users.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
in the number of participants who lost 2 cm or more of height(17 men and 9 women in the ICS group and 14 men and 11women in the placebo group, p ϭ NS). A small number ofparticipants reported fractures of the spine or hip during thestudy: five men and one woman in the ICS group and seven menand eight women in the placebo group (p ϭ NS, p ϭ 0.23). Fracture of any bone was reported by 14 participants in the ICSgroup (seven men and seven women) and 21 participants in theplacebo group (6 men and 15 women, p ϭ 0.29 for ICS vs. placebo). The number of participants who reported a diagnosisof osteoporosis during the study was not different between theICS group (no men and 11 women) and the placebo group (2men and 12 women, p ϭ NS). DISCUSSION
The primary end-point result of this randomized controlled clini-cal trial is that participants with COPD assigned to use 1,200 g/
Figure 2. Changes in BMD of lumbar spine at Year 1 and Year 3, ex-
day of inhaled triamcinolone for 3 years demonstrated reduced
pressed as percentage change from baseline. Error bars represent 2 SEs.
BMD of both the lumbar spine and the femoral neck compared
Closed circles indicate ICS group; closed triangles indicate placebo group.
with participants assigned to placebo: a mean deficit of 1.78%in femoral neck BMD and 1.33% in lumbar spine BMD. Thesedifferences in BMD occurred in both men and women. In addi-tion, more users of triamcinolone than users of placebo experi-
enced a 6% or more decline in femoral neck BMD. On the other
The osteocalcin levels were similar at baseline between groups
hand, there was no difference in complications attributable to
(Figure 3). The ICS group had lower osteocalcin levels than the
loss of BMD (e.g., fractures, loss of height, diagnoses of osteopo-
placebo group after 3 months of treatment (p ϭ 0.002). This
difference between treatment groups persisted but was smaller
We cannot determine whether the change in BMD observed
at Year 1 (p ϭ 0.031). The difference had disappeared by Year
at 3 years would continue, level off, or accelerate with continued
3 (p ϭ 0.675). Osteocalcin levels were lower in both treatment
use of ICS. Although the magnitude of loss of BMD observed
groups at Year 1 and Year 3 compared with baseline and 3
would not cause serious morbidity in healthy persons, it could
months. The differences between treatment groups were signifi-
contribute to the risk of fracture among people with pre-existing
cant at both 3 months and Year 1. We found no association
osteoporosis. If the observed loss of BMD, a surrogate indicator
between changes in osteocalcin levels and changes in BMD at
of fracture risk, were to persist for many years of ICS treatment,
it might contribute to development of osteoporosis and fracturesin susceptible individuals. The effects of ICS on other elements
Clinical Indicators of Osteoporosis
of fracture risk, such as bone architecture, are not known. Studies
We found no difference in the number of participants who lost
of postmenopausal osteoporosis indicate that the relative risk
1 cm or more of height during the course of the study (36 men
of fracture approximately doubles for every 1 SD (approximately
and 18 women in the ICS group and 28 men and 27 women in
10%) decrease in BMD below the age-adjusted mean for the
the placebo group, p ϭ NS). Likewise, there was no difference
hip and spine (10, 38–40). A large number of persons with COPDcurrently use, or at some point may use, ICS. The results of thisstudy support and extend other evidence that ICS have systemiceffects. Many persons with COPD have risk factors for osteopo-rosis, including older age, smoking, poor nutrition, and sedentarylifestyle (33–35).
The strengths of this study, in comparison with most previous
studies of ICS on BMD, include a randomized, placebo-con-trolled design, larger number of participants, a high rate and longduration of follow-up, inclusion of large numbers of susceptibleindividuals (women, smokers, older individuals), rigorous cen-tralized quality control of BMD scans, and objective monitoringof drug adherence. These factors may account for the positivefindings in this study in comparison to previous negative studies,most of which were smaller and had shorter follow-up times.
An important and unexpected finding of this study was the
delay in the decline in BMD, which was not apparent duringthe first year of the study. There was little or no change in BMDduring the first year, although osteocalcin levels indicate thatthe metabolic effect of the ICS began early. The losses in BMDoccurred during the second and third years of the trial. Figure 3. Changes in osteocalcin levels at 3 months, Year 1, and Year
Therefore, short-term studies of the effect of ICS on bone
3, expressed as percentage change from baseline. Participants with at
density cannot be used to predict longer term effects (41). These
least three measurements are included. Error bars represent 2 SEs. Closed
findings contrast with findings in studies using OCS, in which
circles indicate ICS group; closed triangles indicate placebo group.
the loss of BMD is greater and occurs within the first 6 to 12
Scanlon, Connett, Wise, et al.: Loss of Bone Density in LHS II
months of the start of therapy followed by slower subsequent
risks, including the risk of osteoporosis. Monitoring of BMD
and the use of agents that may reduce bone loss (e.g., calcium
An additional contrast with other studies is the larger effect
supplementation, vitamin D supplementation, or bisphospho-
in the femoral neck than in the lumbar spine, although similar
nates) should be considered for patients with an increased risk
findings have been reported (46). Histomorphometric studies
show a greater effect of OCS on trabecular bone than on corticalbone so that one might expect a greater impact on the lumbar
Conflict of Interest Statement : P.D.S. received funding support for this study from Rhone Poulenc Rorer (now Aventis) and also received (during 2001–2004)
spine (11, 47), although both lumbar spine and femoral neck
research funding from Boehringer Ingelheim, Dey Pharmaceuticals, GlaxoSmith-
contain both trabecular and cortical bone. No study has analyzed
Kline, LaRoche, and ONO Pharmaceuticals, and he received an honorarium from
the localization of bone loss with ICS, and the predominant site
Boehringer Ingelheim for a lecture 2001; J.E.C. was Principal Investigator of agrant from Rhone Poulenc Rorer to support an ancillary study on bone density
of bone loss in this study cannot be determined from our data.
changes associated with the use of triamcinolone acetonide; R.A.W. received
Is the effect that we observed limited to triamcinolone or
consulting fees from Pfizer between July 1, 2001 and July 1, 2004, and received
applicable to other ICS? Some newer formulations of ICS such
consulting fees from GlaxoSmithKline in 2003 and 2004 for serving on a mortality
as budesonide and fluticasone have more rapid first-pass hepatic
review committee and has received research grants from Boehringer Ingelheimbetween 2002 and 2004 and from Otsuka Medical Research Institute in 2003
metabolism and thus may have less systemic effect. On the other
and 2004 and from Pfizer in 2003, and he also has pending research grants from
hand, these agents may be more potent or may be used in higher
AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; D.P.T. does not have
doses that may enhance systemic side effects. These newer agents
a financial relationship with a commercial entity that has an interest in the subjectof this manuscript; T.M. does not have a financial relationship with a commercial
have not been thoroughly tested for long-term effects on BMD
entity that has an interest in the subject of this manuscript; M.S. does not have
(48, 49). Similarly, a lower dose may reduce the risk of loss of
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript; P.C.C. does not have a financial relationship with a commercial
The effect of continued smoking on the rate of decline in
entity that has an interest in the subject of this manuscript; W.C.B. has receivedresearch contracts from drug companies as sponsors of investigational drug re-
spine BMD was significant in this study. Other studies support
search projects and has received honoraria from pharmaceutical companies for
this observation. Smoking prevalence is high in persons with
delivering lectures as part of Continuing Medical Education programs for physi-
COPD; therefore, if ICS are prescribed, smoking cessation
cians with appropriate disclosure and has grants from the American Lung Associa-
should be encouraged for this reason among others.
tion for an Asthma Clinical Research Center and others from the National Institutesof Health, which may occasionally use a therapy/drug from pharmaceutical com-
In addition to the primary finding, we found that older partici-
panies, some of which are GlaxoSmithKline, Schering-Plough, Merck, Inspire,
pants had greater ICS-related loss of BMD at the hip but para-
Rhone Poulenc Rorer, Pharmaceutical Dev, Aventis, and Boehringer Ingelheim;
doxically increased BMD at the lumbar spine. The increase in
A.S.B. does not have a financial relationship with a commercial entity that has aninterest in the subject of this manuscript; M.E. does not have a financial relationship
spine BMD is not predicted by reference equations but has been
with a commercial entity that has an interest in the subject of this manuscript;
documented to occur in population studies of men. It may be
R.E.K. does not have a financial relationship with a commercial entity that has an
due to the effects of degenerative osteoarthritis (50, 51). Alterna-
interest in the subject of this manuscript; G.W. does not have a financial relation-
tively, it could be related to the large number of participants
ship with a commercial entity that has an interest in the subject of this manuscript.
who used supplemental estrogen, calcium, vitamin D, and multi-
Acknowledgment : The authors thank Steven Cummings, M.D., Dennis Black,
vitamins (10). The positive trend in Z scores of all groups from
Ph.D., Kristine Ensrud, M.D., and Marc Hochberg, M.D., for assistance in interpre-
baseline to Year 3 suggests that the LHS II cohort had a slower
tation of bone density results; Mary F. Hauser, M.D., and Heinz W. Wahner,M.D., for assistance with bone density measurements; and Patricia Muldrow for
decline in BMD than the reference population (10). This does
assistance in preparation of the article.
not alter the observed differences between the ICS-treated andthe placebo groups, which are independent of the changes in Z
The principal investigators and senior staff of the clinical and coordinating centers,
scores. Osteocalcin levels indicated the presence of a systemic
the National Heart, Lung, and Blood Institute, and members of the Safety andData Monitoring Board are as follows: Case Western Reserve University, Cleveland,
effect of ICS therapy but were not predictive in individual pa-
OH: M.D. Altose, M.D. (Principal Investigator), S. Redline, M.D. (Co-Principal
Investigator), C.D. Deitz, Ph.D., K.J. Quinlan; Henry Ford Hospital, Detroit, MI:
Whereas recent studies have better defined the potential ben-
M.S. Eichenhorn, M.D., (Principal Investigator), W.A. Conway, M.D. (Co-Principal
efits of ICS in persons with COPD, this study indicates that ICS
Investigator), R.L. Jentons, M.A., K. Braden, M. Ketchum; Johns Hopkins UniversitySchool of Medicine, Baltimore, MD: R.A. Wise, M.D. (Principal Investigator), S.
may contribute to accelerated decline in BMD in this population.
Permutt, M.D. (Co-Principal Investigator), C.S. Rand, Ph.D. (Co-Principal Investi-
Consensus recommendations suggest they be limited to persons
gator), M. Daniel, V. Santopietro, K.A. Weeks; Mayo Clinic, Rochester, MN: P.D.
with moderate to severe COPD and frequent exacerbations (52,
Scanlon, M.D. (Principal Investigator), A.M. Patel, M.D. (Co-Principal Investiga-
53). When prescribing moderate or higher doses of ICS to patients
tor), J.P. Utz, M.D. (Co-Principal Investigator), D.E. Williams, M.D. (Co-PrincipalInvestigator), G.M. Caron, K.S. Mieras, L.C. Walters (Bone Density Quality Control
with COPD, it may be prudent to consider the recommendations
Coordinator); Oregon Health Sciences University, Portland, OR: A.S. Buist, M.D.
of the American College of Rheumatology for the prevention
(Principal Investigator), L.R. Johnson, Ph.D. (LHS Pulmonary Function Coordina-
of steroid-induced osteoporosis (54, 55). Smoking cessation, limi-
tor), V.J. Bortz, S.L. Persons, H.A. Schueler; University of Alabama at Birmingham,AL: W.C. Bailey, M.D. (Principal Investigator), C.M. Brooks, Ed.D. (Co-Principal
tation of alcohol consumption, and regular exercise should be
Investigator), L.B. Gerald, Ph.D., M.S.P.H. (Co-Principal Investigator), S. Erwin;
encouraged. It has been recommended that patients with asthma
University of California, Los Angeles, CA: D.P. Tashkin, M.D. (Principal Investiga-
with lifetime “cumulative doses of 5,000 mg [equivalent to 11.4
tor), A.H. Coulson, Ph.D. (Co-Principal Investigator), E.C. Kleerup, M.D. (Co-
years at the dose used in the present study] should be monitored
Principal Investigator), V.C. Li, Ph.D., M.P.H. (Co-Principal Investigator), M.A. Nides, Ph.D., I.P. Zuniga, Y.E. Lee; University of Manitoba, Winnipeg, Manitoba,
by bone densitometry and considered for active intervention to
Canada: N.R. Anthonisen, M.D. (Principal Investigator), J. Manfreda, M.D. (Co-
reduce the risk of osteoporotic fracture in later life” (56). In this
Principal Investigator), S.C. Rempel-Rossum, J.M. Stoyko; University of Minnesota
population, that recommendation seems prudent. In contrast,
Coordinating Center, Minneapolis, MN: J.E. Connett, Ph.D. (Principal Investiga-tor), M.O. Kjelsberg, Ph.D. (Co-Principal Investigator), M.T. Bollenbeck, M.S., K.J.
measurement of osteocalcin does not appear to be helpful in
Kurnow, M.S., P.L. Lindgren, M.S., T.C. Madhok, Ph.D., M.A. Skeans, M.S., H.T.
identifying persons likely to experience greater loss of BMD.
Voelker; University of Pittsburgh, Pittsburgh, PA: R.M. Rogers, M.D. (Principal
In summary, we found that in persons with mild to moderate
Investigator), G.R. Owens, M.D. (Principal Investigator, deceased), F.M. Vitale,
COPD, the use of moderate to high dose inhaled triamcinolone
M.A., M.E. Pusateri; University of Utah, Salt Lake City, UT: R.E. Kanner, M.D. (Principal Investigator), G.M. Villegas, C. Esplin, R.S. Stayner; Safety and Data
was associated with accelerated loss of spinal and femoral BMD
Monitoring Board: R. Bascom, M.D., J.R. Landis, Ph.D., J.R. Maurer, M.D., Y.
after 3 years. We did not observe an increase in clinical indicators
Phillips, M.D., S.I. Rennard, M.D., J.K. Stoller, M.D., I. Tager, M.D., A. Thomas,
of osteoporosis during the time course of the study. In the ab-
Jr., M.D.; National Heart, Lung, and Blood Institute, Bethesda, MD: J.P. Kiley,Ph.D. (Director, Division of Lung Diseases), G. Weinmann, M.D. (Director, Airway
sence of longer term (Ͼ 3 years) safety data, the expected bene-
Biology & Disease Program; former Project Officer), M.C. Wu, Ph.D. (Division of
fits of ICS therapy in COPD must be weighed against potential
Epidemiology and Clinical Applications).
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European Journal of Obstetrics & Gynecology andReproductive Biology 110 (2003) 190–195Stress relief after infertility treatment—spontaneous conception,aFertility Workgroup—Reproduction Medicine & Endocrinology, Munich University Hospital—City Centre,Ludwig-Maximilian-University, Maistrasse 11, D-80337 Muenchen, GermanybDepartment of Gynecological Endocrinology and Reprod