037092u349

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- Participants
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 Osteocalcin
Follow-up
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 Data Analysis
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 Adherence
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 Participant Characteristics
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. Error Definition 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- Osteocalcin
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).
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE References
Bone mineral density in asthmatic women on high-dose inhaled beclo-methasone dipropionate. Bone 1994;15:621–623.
1. The Lung Health Study Research Group. Effect of inhaled triamcinolone 24. Struijs A, Mulder H. The effects of inhaled glucocorticoids on bone on the decline in pulmonary function in chronic obstructive pulmonary mass and biochemical markers of bone homeostasis: a 1-year study of disease. N Engl J Med 2000;343:1902–1909.
beclomethasone versus budesonide. Neth J Med 1997;50:233–237.
2. Pauwels RA, Lofdahl C-G, Laitinen LA, Schouten JP, Postma DS, Pride 25. McEvoy CE, Ensrud KE, Bender E, Genant HK, Yu W, Griffith JM.
NB, Ohlsson SV. Long-term treatment with inhaled budesonide in Niewoehner DE. Association between corticosteroid use and vertebral persons with mild chronic obstructive pulmonary disease who continue fractures in older men with chronic obstructive pulmonary disease.
smoking. N Engl J Med 1999;340:1948–1953.
Am J Respir Crit Care Med 1998;157:704–709.
3. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term 26. Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff effect of inhaled budesonide in mild and moderate chronic obstructive MS. Effects of inhaled glucocorticoids on bone density in premeno- pulmonary disease: a randomised controlled trial. Lancet 1999;353: pausal women. N Engl J Med 2001;345:941–947.
27. Jones A, Fay JK, Burr M, Stone M, Hood K, Robert G. Inhaled corticoste- 4. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen roid effects on bone metabolism in asthma and mild chronic obstructive TK. Randomised, double blind, placebo controlled study of fluticason pulmonary disease. Cochrane Database Syst Rev 2002;CD003537.
propionate in patients with moderate to severe chronic obstructive 28. Halpern MT, Schmier JK, Van Kerkhove MD, Watkins M, Kalberg CJ.
pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297–1303.
Impact of long-term inhaled corticosteroid therapy on bone mineral 5. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J.
density: results of a meta-analysis. Ann Allergy Asthma Immunol Multicentre randomised placebo-controlled trial of inhaled fluticasone 2004;92:201–207; quiz 207–208, 267.
propionate in patients with chronic obstructive pulmonary disease.
29. Hubbard RB, Smith CJ, Smeeth L, Harrison TW, Tattersfield AE. In- International COPD Study Group. Lancet 1998;351:773–780.
haled corticosteroids and hip fracture: a population-based case-control 6. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids study. Am J Respir Crit Care Med 2002;166(12 Pt 1):1563–1566.
in chronic obstructive pulmonary disease: a systematic review of ran- 30. Lee TA, Weiss KB. Fracture risk associated with inhaled corticosteroid domized placebo-controlled trials. Am J Med 2002;13:59–65.
use in chronic obstructive pulmonary disease. Am J Respir Crit Care 7. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination 31. Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid delivered via the Diskus device in the treatment of chronic obstructive use and the risk of fracture. Am J Respir Crit Care Med 2004;169:83–88.
pulmonary disease. Am J Respir Crit Care Med 2002;166:1084–1091.
32. Pauwels RA, Yernault JC, Demedts MG, Geusens P. Safety and efficacy 8. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson of fluticasone and beclomethasone in moderate to severe asthma: J, Maden C. Trial of Inhaled Steroids and long-acting beta2 agonists Belgian Multicenter Study Group. Am J Respir Crit Care Med study group: combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.
33. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM. Risk factors for hip fracture in white 9. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and women: study of Osteoporotic Fractures Research Group. N Engl J readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:580–584.
34. Law MR, Hackshaw AK. A meta-analysis of cigarette smoking, bone 10. Bonnick SL. Bone densitometry in clinical practice: application and inter- mineral density and risk of hip fracture: recognition of a major effect.
pretation. Totowa, NJ: Humana Press; 1998.
11. Dubois EF, Roder E, Dekhuijzen PN, Zwinderman AE, Schweitzer DH.
35. Biskobing DM. COPD and osteoporosis. Chest 2002;121:609–620.
Dual energy X-ray absorptiometry outcomes in male COPD patients 36. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist after treatment with different glucocorticoid regimens. Chest 2002;121: AS, Conway WA Jr, Enright PL, Kanner RE, O’Hara P, et al. Effects of smoking intervention and the use of an inhaled anticholinergic 12. McEvoy CE, Niewoehner DE. Adverse effects of corticosteroid therapy bronchodilator on the rate of decline of FEV1. JAMA 1994;272:1497–1505.
for COPD: a critical review. Chest 1997;111:732–743.
37. SAS Institute Inc. SAS/STAT software 1999; version 8.0. Cary, NC: SAS 13. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997;337:8–14.
38. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures 14. Garbe E, Suissa S, LeLorier J. Association of inhaled corticosteroids of bone mineral density predict occurrence of osteoporotic fractures.
with cataract extraction in elderly patients. JAMA 1998;280:539–543.
15. Agertoft L, Larsen FE, Pedersen S. Posterior subcapsular cataracts, 39. Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med bruises and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide. Eur Respir J 1998;12:130–135.
40. Ross P, Davis J. Vagel J, Wasnich RD. A critical review of bone mass and 16. Garbe E, LeLorier J, Boivin JF, Suissa S. Inhaled and nasal glucocorti- the risk of fractures in osteoporosis. Calcif Tissue Int 1990;46:149–161.
coids and the risks of ocular hypertension or open-angle glaucoma.
41. Allen DB. Limitations of short-term studies in predicting long-term ad- verse effects of inhaled corticosteroids. Allergy 1999;54:29–34.
17. Opatowsky I, Feldman RM, Gross R, Feldman ST. Intraocular pressure 42. Laan RF, van Riel PL, van de Putte LB, van Erning LJ, van’t Hof MA, elevation associated with inhalation and nasal corticosteroids. Oph- Lemmens JA. Low-dose prednisone induces rapid reversible axial thalmology 1995;102:177–179.
bone loss in patients with rheumatoid arthritis: a randomized, con- 18. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: trolled study. Ann Intern Med 1993;119:963–968.
a systematic review and meta-analysis. Arch Intern Med 1999;159:941– 43. Saito JK, Davis JW, Wasnich RD, Ross PD. Users of low dose glucocorti- coids have increased bone loss rates: a longitudinal study. Calcif Tissue 19. Malo JL, Cartier A, Ghezzo H, Mark S, Brown J, Laviolette M, Boulet LP. Skin bruising, adrenal function and markers of bone metabolism in 44. Lo Cascio V, Bonucci E, Imbimbo B, Ballanti P, Adami S, Milani S, asthmatics using inhaled beclomethasone and fluticasone. Eur Respir Tartarotti D, DellaRocca C. Bone loss in response to long-term gluco- corticoid therapy. Bone Miner 1990;8:39–51.
20. Roy A, Leblanc C, Paquette L, Ghezzo H, Cote J, Cartier A, Malo JL.
45. Reid IR, Heap SW. Determinants of vertebral mineral density in patients Skin bruising in asthmatic subjects treated with high doses of inhaled receiving long term glucocorticoid therapy. Arch Intern Med 1990;150: steroids: frequency and association with adrenal function. Eur Respir 46. Hanania NA, Chapman KR, Sturtridge WC, Szalai JP, Kesten S. Dose- 21. Wong CA, Walsh LJ, Smith CJP, Wisniewski AF, Lewis SA, Hubbard related decrease in bone density among asthmatic patients treated R, Cawte S, Green DJ, Pringle M, Tattersfield AE. Inhaled corticoste- with inhaled corticosteroids. J Allergy Clin Immunol 1995;96(5 Pt roid use and bone-mineral density in patients with asthma. Lancet 47. Seeman E, Wahner HW, Offord KP, Kumar R, Johnson WJ, Riggs BL.
22. Luengo M, del Rio L, Pons F, Picado C. Bone mineral density in asthmatic Differential effects of endocrine dysfunction on the axial and the patients treated with inhaled corticosteroids: a case-control study. Eur appendicular skeleton. J Clin Invest 1982;69:1302–1309.
Respir J 1997;10:2110–2113.
48. Lipworth BJ. Airway and systemic effects of inhaled corticosteroids in 23. Herrala J, Puolijoki H, Impivaara O, Liippo K, Tala E, Nieminen MM.
asthma: dose response relationship. Pulm Pharmacol 1996;9:19–27.
Scanlon, Connett, Wise, et al.: Loss of Bone Density in LHS II 49. Brown PH, Matusiewicz SP, Shearing C, Tibi L, Greening AP, Crompton WHO Global Initiative for Chronic Obstructive Lung Disease GK. Systemic effects of high dose inhaled steroids: comparison of (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001;163: beclomethasone dipropionate and budesonide in healthy subjects.
53. American Thoracic Society/European Respiratory Society. Standards for 50. Liu G, Peacock M, Eilam O, Dorulla G, Braunstein E, Johnston CC.
the diagnosis and management of patients with COPD: American Effect of osteoarthritis in the lumbar spine and hip on bone mineral Thoracic Society/European Respiratory Society COPD Guidelines,2004. http://www.thoracic.org/copd/ (Accessed June 1, 2004) density and diagnosis of osteoporosis in elderly men and women.
54. Smith BJ, Phillips PJ, Heller RF. Asthma and chronic obstructive airway Osteoporos Int 1997;7:564–569.
diseases are associated with osteoporosis and fractures: a literature 51. Peacock DJ, Egger P, Taylor P, Cawley MI, Cooper C. Lateral bone review. Respirology 1999;4:101–109.
density measurements in osteoarthritis of the lumbar spine. Ann 55. American College of Rheumatology Task Force on Osteoporosis Guide- lines. Recommendations for the prevention and treatment of glucocor- 52. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, GOLD ticoid-induced osteoporosis. Arthritis Rheum 1996;39:1791–1801.
Scientific Committee. Global strategy for the diagnosis, management, 56. Sambrook PN. Commentary: inhaled corticosteroids, bone density, and and prevention of chronic obstructive pulmonary disease: NHLBI/ the risk of fracture. Lancet 2000;355:1385.

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