Correspondence
Bone Loss and Inhaled Glucocorticoids
N Engl J Med 2002; 346:533-535February 14, 2002
- Article
To the Editor:
The study by Israel et al. (Sept. 27 issue)1 of bone thinning in women with asthma did not effectively control for the critical variables of the level of physical activity and the severity of asthma.
Comparisons between patients with mild asthma and those with persistent asthma who are receiving high doses of inhaled glucocorticoids must include a careful evaluation of base-line characteristics.2 Table 2 of the article shows that the 28 women who did not use inhaled glucocorticoids weighed less than the 42 women who required more than eight puffs of inhaled glucocorticoids per day (mean [±SD], 140±20 vs. 154±40 lb), had nearly twice the level of physical activity (98±54 vs. 55±71 metabolic hours per week), had a lower incidence of past or current use of inhaled glucocorticoids (14±36 percent vs. 62±49 percent), and were less likely to have a history of oral-glucocorticoid use (36± 49 percent vs. 79±42 percent). All of these base-line differences appear to be statistically significant. It is as if we compared the bones of a busload of women soccer players with those of a busload of sedentary women.
A relative lack of gravitational exercise can obviously contribute to bone loss, as shown most clearly in astronauts returning from zero gravity. Because the presence of persistent asthma limits one's ability to exercise, the resulting inactivity and other changes in variables reflecting the severity of asthma (e.g., weight, prednisone use, and airway inflammation) invalidate any reliable analysis of the effects of inhaled glucocorticoids on bone loss in groups that were so dissimilar at base line in the absence of a randomized scheme of treatment allocation.
2 ReferencesEdward Kerwin, M.D.
Clinical Research Institute, Medford, OR 975041
Israel E ,Banerjee TR ,Fitzmaurice GM ,Kotlov TV ,Lattive K ,LeBoff MS . Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 2001;345:941-947
Full Text | Web of Science | Medline2
Kaiser DL. Statistical concepts in infection control. In: Wenzel RP, ed. Prevention and control of nosocomial infections. Baltimore: Williams & Wilkins, 1987:591-600.
To the Editor:
Israel et al. observed a dose-related decline in bone density at the hip among users of inhaled glucocorticoids. We conducted a large cohort study and found a dose-related increase in the risk of fracture among adult users of inhaled glucocorticoids.1 However, patients who used bronchodilator drugs had similar degrees of risk. Our conclusion was that this excess risk is more likely to be related to the presence of underlying respiratory disease than to treatment.
Israel et al. found that pulmonary function was similar among the three groups and inferred that there was no confounding related to differences in the severity of asthma. Since treatment was not randomly assigned, the high-dose group most likely had more severe asthma. Despite having similar pulmonary function, more patients in the high-dose group than in the other groups were excluded because they had received more than 30 days of oral or parenteral glucocorticoid therapy. Inhaled glucocorticoids can suppress the symptoms of bronchoconstriction, but they do not cure the disease. Their effects on the natural history of asthma are not clearly understood.2 Complications may thus occur independently of the level of bronchoconstriction.
The bone loss associated with the use of oral glucocorticoids is principally trabecular, with a greater loss in the lumbar spine and less of a loss in the proximal femur. The spine is associated with the largest increases in the risk of fracture.3 The pattern of effect on bone density at the spine and hip reported by Israel et al. does not support the hypothesis that inhaled glucocorticoids influence bone in a fashion similar to that of oral glucocorticoids.
We agree that patients using inhaled glucocorticoids have an increased risk of fracture. The potential role of asthma in increasing this risk should not be underestimated.
3 ReferencesTjeerd-Pieter van Staa, M.D., Ph.D.
University of Southampton, Southampton SO16 6YD, United KingdomBert Leufkens, Ph.D.
Utrecht University, 3508 TB Utrecht, the NetherlandsCyrus Cooper, D.M.
University of Southampton, Southampton SO16 6YD, United Kingdom
cc@mrc.soton. ac. uk 1
van Staa TP ,Leufkens HGM ,Cooper C . Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 2001;16:581-588
CrossRef | Web of Science | Medline2
Tavakkoli A ,Rees PJ . Drug treatment of asthma in the 1990s: achievements and new strategies. Drugs 1999;57:1-8
CrossRef | Web of Science | Medline3
van Staa TP ,Leufkens HGM ,Abenhaim L ,Zhang B ,Cooper C . Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000;15:993-1000
CrossRef | Web of Science | Medline
To the Editor:
Israel et al. report that inhaled glucocorticoids lead to a dose-related decline in bone density at the hip in premenopausal women. However, the authors never comment on the control group in the study, which was not exposed to glucocorticoids. The loss of bone mineral density in women older than 25 years of age is well documented, and Israel et al. have given us no means of distinguishing physiologic changes from those resulting from medication.
That there is a normal decline in bone mineral density with age also calls into question the data from the study's bone densitometers. Data from the femoral neck and lumbar spine do not correspond to the expected base-line loss of 0.7 percent per year.1 Such measuring error calls into question the small changes in density that Israel et al. report as statistically significant. More analysis of the control group and more data are necessary to understand the consequences of this widespread treatment approach.
1 ReferencesJames L. Glazer, M.D.
Maine–Dartmouth Family Practice Residency, Augusta, ME 04330
jamesglazer@hotmail.com 1
Lindsay R . Prevention and treatment of osteoporosis. Lancet 1993;341:801-805
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Author/Editor Response
The authors reply:
To the Editor: In response to Dr. Kerwin: the “busloads” of women we compared were well matched. There were no statistically significant differences among the groups in weight or the level of physical activity. The apparent difference in the level of physical activity was due to a typographical error in Table 2. The mean level of physical activity in the group of women who did not take inhaled glucocorticoids was 48 metabolic hours per week, not 98. In addition, analyses that also adjusted for weight and level of physical activity did not affect our quantitative conclusions about the dose-related loss in bone density at the hip and trochanter.
Naturally, our groups differed with respect to the use of inhaled glucocorticoids. This was the independent variable used to assemble the groups. We also expected the incidence of a history of oral-glucocorticoid use before the study to differ among the groups. However, the data obtained during the study were not confounded by the use of oral glucocorticoids, which was prospectively monitored; we performed an a priori analysis that was restricted to patients who did not receive oral glucocorticoids during the study. Furthermore, data from van Staa et al.,1 among others, suggest that the presence of a history of glucocorticoid use before the study was unlikely to affect our outcome, since there is a rapid offset of the effects of oral glucocorticoids on bone density once therapy is stopped.
Since we did not examine any patients without asthma, we cannot confirm the observation of van Staa et al. regarding bronchodilator users and controls. However, when van Staa and colleagues compared users of high-dose inhaled glucocorticoids with those who used bronchodilators alone (an analysis similar to ours), their findings were remarkably similar to ours.2 They observed an increased rate of hip fracture with the use of high-dose inhaled glucocorticoids. The rate was not a function of the underlying population, since it declined toward base line once the treatment was discontinued. Furthermore, there was an increased rate of hip fracture and not of spinal fracture. Why inhaled glucocorticoids produce a pattern of accelerating bone loss that differs from that reported with oral glucocorticoids is unclear.
Dr. Glazer misunderstands our analysis. Patients who did not use inhaled glucocorticoids were very much part of the analysis (as indicated by the points superimposed on the ordinate in each panel of Figure 2 of our article). In fact, the yearly decline in bone density per puff of inhaled glucocorticoid that we report is the supplementary decline, which would occur in addition to any physiologic change in bone density that would be occurring in the group that was not using inhaled glucocorticoids. We used a very precise technique for measuring bone mass — dual x-ray absorptiometry — and the results were interpreted by one observer. However, as we noted in the article, on the basis of the results of dietary screening, patients received supplemental calcium, vitamin D, or both. This supplementation may have influenced the yearly rate of bone loss in our subjects, including the rate in the group that did not use inhaled glucocorticoids. Nonetheless, we found that inhaled glucocorticoids were associated with a dose-related decrease in bone density that was superimposed on any positive effect that may have resulted from dietary supplementation.
2 ReferencesElliot Israel, M.D.
Brigham and Women's Hospital, Boston, MA 02115
eisrael@partners.org Garrett M. Fitzmaurice, Sc.D.
Harvard School of Public Health, Boston, MA 02115Meryl S. LeBoff, M.D.
Brigham and Women's Hospital, Boston, MA 021151
van Staa TP ,Leufkens HGM ,Abenhaim L ,Zhang B ,Cooper C . Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000;15:993-1000
CrossRef | Web of Science | Medline2
van Staa TP ,Leufkens HGM ,Cooper C . Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 2001;16:581-588
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Binmiao Liang, Yulin Feng. (2011) The association of low bone mineral density with systemic inflammation in clinically stable COPD. Endocrine
CrossRef2
Mahyar Etminan, Mohsen Sadatsafavi, Saeedreza Ganjizadeh Zavareh, Bahi Takkouche, J Mark FitzGerald. (2008) Inhaled Corticosteroids and the Risk of Fractures in Older Adults. Drug Safety 31:5, 409-414
CrossRef3
T. P. Staa. (2006) The Pathogenesis, Epidemiology and Management of Glucocorticoid-Induced Osteoporosis. Calcified Tissue International 79:3, 129-137
CrossRef4
(2002) Current Awareness. Pharmacoepidemiology and Drug Safety 11:5, 421-436
CrossRef
