Correspondence
Inhaled Triamcinolone and Chronic Obstructive Pulmonary Disease
N Engl J Med 2001; 344:1553-1556May 17, 2001
- Article
To the Editor:
The findings of the Lung Health Study Research Group (Dec. 28 issue)1 with regard to bone density should be interpreted with caution. The participants in the triamcinolone group had a nonsignificant 0.35 percent decrease in lumbar bone density between base line and 36 months, whereas there was a 0.98 percent increase in lumbar bone density in the participants in the placebo group. The increase is rather difficult to explain and would not be expected in patients in this age group. Moreover, this increase was not mirrored in the femoral neck, where there was a concomitant 0.22 percent decrease in bone density in the participants in the placebo group.
In contrast to the usual pattern of corticosteroid-induced bone loss, the magnitude of the decrease in bone density with triamcinolone was greater in cortical bone (femoral neck) than in trabecular bone (lumbar spine). In order to quantify the risk of osteoporotic fracture, the bone density should be expressed as a standard-deviation z score normalized to the age-matched mean2 to see whether at-risk patients with low bone mass who started with a z score of less than 1 SD at base line also had the greatest decline after three years.
All inhaled corticosteroids have dose-related systemic adverse effects.3 Inhaled fluticasone (1000 μg per day) in patients with chronic obstructive pulmonary disease (COPD) was associated with higher levels of adrenal suppression and skin bruising than placebo, although bone density was not measured.4 It should also be noted that the effects of high-dose triamcinolone (1200 μg daily) on the bone density of patients with COPD should not be extrapolated to younger patients with asthma, in whom lower doses are commonly used.
4 ReferencesBrian J. Lipworth, M.D.
Catherine M. Jackson, M.R.C.G.P.
Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom1
The Lung Health Study Research Group
Full Text | Web of Science | Medline2
Wasnich R . Bone mass measurement: prediction of risk. Am J Med 1993;95:Suppl 5A:6S-10S
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Lipworth BJ . Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159:941-955
CrossRef | Web of Science | Medline4
Burge PS ,Calverley PM ,Jones PW ,Spencer S ,Anderson JA ,Maslen TK . Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-1303
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To the Editor:
The mean age, particularly in women, at which osteoporosis may cause pain from vertebral fractures or disability due to fractures of the femoral neck is much higher than the age at which patients entered the Lung Health Study.1 Inhaled corticosteroids are currently used as a long-term treatment for COPD and may be prescribed over a span of several years or even for the rest of the patient's life. In addition, the authors do not mention the proportion of women analyzed in the substudy of bone mineral density. If the proportion was high (more than 40 percent), then the fact that the bone mineral density decreased 10 times as much after three years of inhaled triamcinolone therapy as it did with placebo would very likely be reflected in considerable long-term (e.g., 10-year) disability and health-related costs because of vertebral or femoral neck fractures.1
The relatively short-term benefits of the prolonged administration of inhaled corticosteroids in COPD — which do not modify the pattern of disease progression — could be outweighed by the considerable risk of their long-term effects on bone demineralization, particularly in postmenopausal women.
1 ReferencesAndrea De Maria, M.D.
G. Walter Canonica, M.D.
University of Genoa, Genoa 16132, Italy1
Liberman UA ,Weiss SR ,Broll J , et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1443
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To the Editor:
We have recruited patients for a number of COPD studies. After we had excluded those with any suggestion of asthma, 60 percent of the 160 volunteers in our study data base were already receiving inhaled corticosteroids. These patients are frequently reluctant to cease corticosteroid treatment because of its perceived benefit. Selection bias may have been introduced into the study by the Lung Health Study Research Group through the exclusion of patients taking inhaled corticosteroids who may be precisely those in whom the medications are most efficacious. The adherence to corticosteroid treatment was also extremely poor, which could have significantly altered the findings.
Furthermore, there was no mention of bronchodilator reversibility in the triamcinolone group, nor of any relation to benefit. Again, experience with our volunteers suggests that the use of a bronchodilator results in an improvement of 15 percent or more in forced expiratory volume in one second in 30 percent of patients with COPD. Such patients are also usually excluded from studies of COPD because they are thought to have asthma, although this diagnosis may be spurious.1-3 Finally, 90 percent of the patients in the triamcinolone group were current smokers; this may partially explain the negative findings, which may not apply to former smokers.4
4 ReferencesDavid William Reid, M.R.C.P., F.R.A.C.P.
Amir Soltani, M.D.
Haydn Walters, D.M., F.R.C.P., F.R.A.C.P.
Alfred Hospital, Melbourne, VIC 3181, Australia1
Paggiaro PL ,Dahle R ,Bakran I ,Frith L ,Hollingworth K ,Efthimiou J . Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998;14:351:773-780[Erratum, Lancet 1998;351:1968.]
CrossRef | Web of Science2
Vestbo J ,Sorensen T ,Lange P ,Brix A ,Torre P ,Viskum K . Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999;353:1819-1823
CrossRef | Web of Science | Medline3
Burge PS ,Calverley PM ,Jones PW ,Spencer S ,Anderson JA ,Maslen TK . Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-1303
CrossRef | Web of Science | Medline4
Pedersen B ,Dahl R ,Karlstrom R ,Peterson CG ,Venge P . Eosinophil and neutrophil activity in asthma in a one-year trial with inhaled budesonide: the impact of smoking. Am J Respir Crit Care Med 1996;153:1519-1529
Web of Science | Medline
To the Editor:
I think that Mapp in her editorial is clutching at straws to find a benefit of inhaled corticosteroids in patients with COPD.1 The report of the Lung Health Study Research Group had basically negative findings about the effects of inhaled corticosteroids in COPD. There were benefits in the rates of hospitalization and outpatient visits for respiratory conditions, but given that one would need to treat approximately 100 patients for one year to prevent 1 hospitalization and 1 outpatient visit, this benefit is extremely small. Benefits were also noted in reported symptoms. These were similarly small, and from the broader perspective of well-being (the health-related quality of life), there was no difference between inhaled corticosteroids and placebo except that the scores on the mental health subscale were worse in those treated with inhaled corticosteroids.
It may be biologically plausible that a decrease in bronchial reactivity resulting from the use of inhaled corticosteroids might result in a reduced death rate, but no clinical trial or meta-analysis has demonstrated such a relation. If it did exist, one would have to assume that the number needed to treat to avoid one death would be enormous. If this supposed benefit is going to be factored into arguments for using inhaled corticosteroids in patients with COPD, the more plausible outcome of an increased rate of fractures resulting from the demineralization of bone should be factored in as well.
1 ReferencesSimon O'Connor, M.B., B.S., F.R.A.C.P.
104 Calala Lane, Tamworth, NSW 2340, Australia1
Mapp CE . Inhaled glucocorticoids in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1960-1961
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Author/Editor Response
The authors reply:
To the Editor: Lipworth and Jackson raise questions about the interpretation of our findings on bone mineral density after treatment with inhaled triamcinolone. An increase in lumbar density is a recognized phenomenon, particularly in men in the age range of our study population,1 and is often attributed to osteoarthritis. Although demineralization resulting from corticosteroids is more rapid in trabecular than in cortical bone, both the spine and hip contain both types of bone, and systemic corticosteroids demineralize bone in both regions.2 It is possible that the response to inhaled triamcinolone differs from the response to systemic steroids, since we found that the demineralization is delayed with the inhaled agent.3 We provide data in the form of z scores in Table 1Table 1
Bone-Density z Scores and Changes in z Scores in the Triamcinolone and Placebo Groups.. Finally, we would characterize 1200 μg of triamcinolone daily as a moderate dose of inhaled steroid — equivalent to about 600 μg of beclomethasone.4 Although we share the concern of De Maria and Canonica that the prolonged use of inhaled steroids may cause clinical osteoporosis in susceptible persons, the effects of steroids on bone might eventually decrease. Until we know more, a prudent strategy for high-risk patients undergoing long-term therapy with inhaled steroids might include the monitoring of bone density and the use of such preventive treatments as hormone replacement and calcium and vitamin D supplementation.
Reid et al. question whether the study population was representative, because we excluded persons who were using inhaled steroids. Since our goal was to prevent the progression of early COPD, we did not want to include persons with asthma. We might have found greater improvement in respiratory symptoms if we had included persons who had used inhaled steroids. Although adherence to therapy with inhaled steroids in this study was imperfect, it was similar to that among most persons with asthma, which is about 50 percent.
The mean response to bronchodilators in terms of the change in forced expiratory volume in one second was 6.6 percent at base line. We did not exclude persons with a response to a bronchodilator of 15 percent or greater, which occurred in 11.5 percent of participants. Furthermore, we found no reduction in the decline in forced expiratory volume in one second in subgroups defined according to bronchodilator response, methacholine reactivity, or history of asthma (but the study was not powered for these subgroup analyses).
We agree with O'Connor that our results do not justify treating asymptomatic COPD with inhaled corticosteroids. The evidence from our study and others may be used to justify the treatment of selected patients with COPD for the relief of symptoms or reduction of exacerbations.
4 ReferencesRobert Wise, M.D.
John Connett, Ph.D.
Paul Scanlon, M.D.
University of Minnesota, Minneapolis, MN 55455for the Lung Health Study Research Group
1
Dennison E ,Yoshimura N ,Hashimoto T ,Cooper C . Bone loss in Great Britain and Japan: a comparative longitudinal study. Bone 1998;23:379-382
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Reid IR ,Evans MC ,Wattie DJ ,Ames R ,Cundy TF . Bone mineral density of the proximal femur and lumbar spine in glucocorticoid-treated asthmatic patients. Osteoporos Int 1992;2:103-105
CrossRef | Web of Science | Medline3
LoCascio V ,Bonucci E ,Imbimbo B , et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990;8:39-51
CrossRef | Medline4
National Asthma Education and Prevention Program. Expert Panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, Md.: National Institutes of Health, 1998:88. (NIH publication no. 98-4051.)
Author/Editor Response
The editorialist replies:
To the Editor: O'Connor raises important questions about the use of inhaled corticosteroids in patients with COPD. His concern about administering these drugs underscores the need for caution in considering the beneficial effects of a therapy. There are, however, important differences among corticosteroids with regard to the risk of adverse effects, and the lower-risk medications should be chosen. O'Connor correctly highlights the fact that the effects of inhaled corticosteroids on the secondary outcomes (use of health care services, respiratory symptoms, and airway reactivity) in the study by the Lung Health Study Research Group are small. However, since symptoms and abnormalities of lung function in patients with COPD are poorly reversible or irreversible, an effect that is additive to that of bronchodilators, even if it is small, may be beneficial, particularly in patients with severe COPD. The reduction in airway reactivity (hyperresponsiveness to methacholine) is interesting despite its limited extent, given the predictive value of airway reactivity for mortality from COPD independent of pulmonary function.1 Additional data from other cohorts would be helpful.
I believe O'Connor underestimates the value of fewer unscheduled visits to physicians and hospitalizations for respiratory conditions in the triamcinolone group. In addition to the costs of hospitalization, outpatient care, and drug consumption during acute exacerbations, an exacerbation is an important event in the progression of the disease, since it is related to reduced survival2 and a decrease in the quality of life.3 In other studies of inhaled corticosteroids in patients with COPD, moderate or severe exacerbations occurred more frequently in the placebo group than in the corticosteroid group4; thus, the patients who were taking inhaled corticosteroids most likely required fewer hospitalizations. At present, inhaled corticosteroids are an option for physicians in preventing an acute exacerbation of COPD, especially in patients with severe disease.
4 ReferencesCristina Elisabetta Mapp, M.D.
University of Ferrara, 44100 Ferrara, Italy1
Hospers JJ ,Postma DS ,Rijcken B ,Weiss ST ,Schouten JP . Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study. Lancet 2000;356:1313-1317
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Connors AF Jr ,Dawson NV ,Thomac C , et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. Am J Respir Crit Care Med 1996;154:959-967[Erratum, Am J Respir Crit Care Med 1997;155:386.]
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Seemungal TAR ,Donaldson GC ,Paul EA ,Bestall JC ,Jeffries DJ ,Wedzicha JA . Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-1422
Web of Science | Medline4
Paggiaro PL ,Dahle R ,Bakran I ,Frith L ,Hollingworth K ,Efthimiou J . Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998;351:773-780[Erratum, Lancet 1998;351:1968.]
CrossRef | Web of Science | Medline
