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(Chest. 2001;120:1468-1473.)
© 2001 American College of Chest Physicians

Effects of Inhaled Corticosteroid and Short Courses of Oral Corticosteroids on Bone Mineral Density in Asthmatic Patients*

A 4-Year Longitudinal Study

Hisako Matsumoto, MD; Kyosuke Ishihara, MD; Tsuyoshi Hasegawa, MD; Bun-ichi Umeda, MD; Akio Niimi, MD and Megumu Hino, MD

* From the Department of Respiratory Diseases (Drs. Ishihara, Hasegawa, and Umeda) and Nuclear Medicine (Dr. Hino), Kobe City General Hospital, Kobe, Japan; and the Department of Respiratory Medicine (Drs. Matsumoto and Niimi), Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to: Hisako Matsumoto, MD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; e-mail: hmatsumo{at}kuhp.kyoto-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: It is not certain whether inhaled corticosteroid (ICS) therapy reduces bone mineral density (BMD) in asthmatic patients. In addition, the potential risk of osteoporosis associated with the rescue use of short courses of oral corticosteroids (SC-OCS) is unclear.

Objective: To evaluate the effect of inhaled beclomethasone dipropionate (BDP) and SC-OCS on BMD in asthmatic patients.

Design: A 4-year longitudinal study.

Method: Lumbar BMD was measured twice by dual-energy x-ray absorptiometry at a mean (± SD) interval of 4.2 ± 0.1 years in 35 asthmatic adults (15 men and 20 postmenopausal women; mean age at the second evaluation, 60.6 ± 11.5 years) who had been treated with BDP and SC-OCS.

Results: The average period of BDP treatment was 7.7 ± 2.2 years (range, 4.8 to 13.0 years) at the second evaluation. During the study period, the daily dose of BDP was 765 ± 389 µg (range, 100 to 1,730 µg), and the frequency of SC-OCS was 1.9 ± 2.7 courses per year (range, 0.0 to 8.9 courses per year). As a whole, lumbar BMD was unchanged during the course of the study, whereas the Z score (ie, the percentage of normal value predicted from age and sex) increased significantly. Changes in BMD and Z scores in patients receiving high doses of BDP (ie, > 1,000 µg/d; n = 9) were not significantly different from those of patients receiving lower doses (ie, <= 1,000 µg/d; n = 26). However, patients receiving frequent SC-OCS (ie, > 2.5 courses per year; n = 9) showed a significantly greater loss in BMD and Z score compared with those receiving sporadic courses (ie, <= 2.5 courses per year; n = 26) (p = 0.002 and p = 0.035, respectively).

Conclusions: ICS therapy per se does not affect BMD, whereas frequent SC-OCS may do so.

Key Words: adverse effect • beclomethasone dipropionate • bone mineral density • bronchial asthma • inhaled corticosteroids • short courses of oral corticosteroids


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory treatment for asthma and are currently considered to be the first-line therapy for persistent disease.1 Since ICS treatment can control asthma but does not usually lead to a cure for the disease, the long-term use of ICSs is often required.2 3 Furthermore, higher doses of ICSs may be needed in patients with severe asthma.4 However, the effects of the long-term use of ICSs on bone metabolism and the associated risk of osteoporosis remain controversial.

There have been several studies reporting the effect of ICS therapy on markers of bone metabolism. Cross-sectional or short-term longitudinal studies5 6 7 have indicated that ICS treatment may cause a reduction in bone formation. However, one study8 with a longer observation period (ie, > 2.5 years) did not detect any detrimental effects of beclomethasone dipropionate (BDP) (dose, 800 µg/d) on bone formation or resorption. The results of the latter study suggest that long-term changes in bone turnover during treatment with ICSs should not be deduced from short-term studies.

Previous studies of the effect of ICS on bone mineral density (BMD) yielded conflicting results. Although some studies7 9 10 11 12 13 14 show a reduction in BMD associated with ICSs, others15 16 17 18 19 20 21 22 do not. However, most of these studies7 9 10 11 12 13 14 15 16 20 have been conducted in a cross-sectional fashion. In fact, there are only a few longitudinal studies18 19 21 that have reported on the effects of high doses of ICSs, and among these the longest study period has been 3 years.21 Studies evaluating the change in BMD in asthmatic patients over longer periods are therefore needed to clarify the risk of the prolonged use of ICSs.

In addition to ICSs, patients with asthma sometimes require rescue short courses of oral corticosteroids (SC-OCS) for exacerbations of the disease.23 Although the continuous use of systemic corticosteroids is a well-known risk factor for osteoporosis,24 the association between SC-OCS and bone loss has not been clarified.

The aim of this study, therefore, was to investigate the effects of long-term (ie, 4 years) use of ICSs and of SC-OCS on bone mass.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Of 130 asthmatic patients who took part in our previous cross-sectional evaluation of BMD in 1993,16 17 patients were excluded based on their use of oral corticosteroids (OCSs) for >= 3 consecutive months during the study period because of the known deleterious effects of continuous OCS treatment on bone.16 24 Of the remaining 113 patients, 35 patients (15 men and 20 postmenopausal women) who visited two physicians (K.I. and B.U.) for a regular visit during the 3 months (from November 1997 to January 1998) set for the second evaluation, and who consented to the reassessment of BMD and other clinical indexes, participated in this study. The remaining 78 patients who did not participate in this study consisted of the following: one patient who died of advanced pancreatic cancer before the second measurement; two patients who had received calcium supplements since the first measurement; and 25 patients we were unable to locate for follow-up after the 4-year study period. The maintenance dose of BDP that had been prescribed around 1993 for these 25 patients was significantly lower than that of the 35 active participants, suggesting more mild disease in these patients (data not shown). The remaining 50 patients consisted of those who refused the second measurement (n = 16) and those who were under the care of other respiratory physicians who were not involved in this longitudinal study (n = 34). However, the latter group was similar to the 35 active participants in terms of their compliance with medical regimens and in terms of having been treated with smaller or similar maintenance doses of BDP (data not shown). Taken together, the 35 active participants neither were the healthiest patients from the original group nor did they exhibit greater compliance with their medical regimen than did the other patients. In the previous cross-sectional study in 1993,16 patients suffering from additional disorders or taking medication that is known to contribute to osteoporosis were excluded, as were those with apparent arthrosis. The absence of these conditions in the 35 patients was reconfirmed during the second measurement.

Asthma was defined according to the American Thoracic Society criteria.25 All the patients in this study had been inhaling BDP. The patients were classified into the following two groups according to the mean daily dose of BDP during the study period (from 1993 to 1997): the high-dose group consisted of patients who inhaled > 1,000 µg/d BDP (n = 9); and the low-dose group consisted of patients who inhaled <= 1,000 µg/d (n = 26). All patients used a spacer device (InspirEase; Schering-Plough; Kenilworth, NJ) and were monitored to ensure that they were following the correct inhalation procedure and maintaining compliance.

In the 35 patients studied, there were 14 patients who had received continuous OCS therapy (prednisolone, 5 to 10 mg/d, in 9 patients and dexamethasone, 0.5 to 1 mg/d, in 5 patients) for a mean (± SD) period of 3.6 ± 3.8 years (duration range, 0.6 to 15 years) but had discontinued it for > 1.5 years prior to the first BMD measurement, owing to the benefits of BDP therapy. During the study period, no patient was given OCSs continuously. However, 27 patients were given SC-OCS (prednisolone, 20 to 40 mg, for 3 to 14 days; 1 to 39 courses) during the study period. All patients were fully ambulatory, carrying on an independent, active lifestyle, and none were engaged in vigorous exercise programs. None of the patients were receiving medications that are known to cause alterations in BMD, such as calcium supplements, vitamin D, calcitonin, diuretics, estrogens, androgens, or anticonvulsants. The study was approved by the ethics committee at our institution, and written informed consent was obtained from all patients.

BMD
The BMD of the lumbar spine (L2 to L4) was measured with a dual-energy x-ray densitometry using a densitometer (model QDR 1000; Hologic Corp; Boston, MA). The absolute value of BMD was expressed as grams per square centimeter. The percentage of bone mass of young adult mean was expressed as a T score (%). According to the diagnostic criteria proposed by the Japanese Society for Bone and Mineral Research, 26 osteoporosis was defined by a T score of < 70% and osteopenia was defined by a T score between 70% and 80%. The percentage of the normal value predicted from age and sex was expressed as a Z score (%). The scanner was calibrated daily using a phantom according to the recommendations of the manufacturer. All measurements were carried out by a single technician following the same procedure. The reproducibility of the densitometry was good, and the coefficient of variation (CV) was 0.5%.

Peak Expiratory Flow
Patients were instructed to record their peak expiratory flow (PEF) values twice daily using a peak flowmeter (Assess; Healthscan Products Inc; Cedar Grove, NJ). The morning PEF values were analyzed as the mean and SD of all values obtained over a 1-week period immediately prior to the first and second evaluation.

Statistical Analysis
Variables were expressed as the mean ± SD, unless otherwise stated. The paired t test was used to analyze the changes in variables within groups, and the Mann-Whitney U test was used to analyze the differences between groups. A p value of < 0.05 was considered to be significant. A multivariate analysis was not performed because of the small sample size.27


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Demographic Data
The demographic data for the 35 patients participating in the second evaluation are shown in Table 1 . Since the first evaluation, the average daily BDP dose had increased by 41 ± 268 µg, and the PEF values had increased by 0.9 ± 16.7% predicted.


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  		Table 1. Patients’ Characteristics at the Second Evaluation*

 
BMD
The BMD measured at the lumbar spine on the second evaluation (0.893 ± 0.123 g/cm2) was not significantly different from baseline values (0.899 ± 0.125 g/cm2; p = 0.484). The Z score significantly increased from 95.8 ± 17.8% to 98.3 ± 18.4% (p = 0.001). There were no significant differences between men and women in the change in BMD or Z score. The prevalence of osteoporosis (8.5%; 3 patients) and osteopenia (25.7%; 9 patients) as defined by the T score did not change between the first measurement and the second measurement. More specifically, the three patients who had received diagnoses of osteoporosis and six of the nine patients with osteopenia at baseline remained in the same categories on the second evaluation. The three remaining patients originally considered to have osteopenia had returned to normal, and three originally healthy patients were classified as osteopenic on the second evaluation.

Table 2 shows patient characteristics classified by BDP dose (ie, doses of <= or > 1,000 µg/d). No significant differences were found in the baseline or follow-up values nor were any changes in BMD or Z score detected between the two groups. When patients were classified according to the frequency of SC-OCS, patients with frequent treatments (ie, > 2.5 courses per year; n = 9) showed a significantly greater loss of BMD and had a significantly reduced Z score compared to patients with sporadic SC-OCS (ie, <= 2.5 courses per year) (Table 3 ). There was no significant difference in the mean duration of BDP treatment between groups when patients were classified either by the dose of BDP or by the frequency of SC-OCS (data not shown).


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  		Table 2. Characteristics of Patients Divided by Mean BDP Dose*

 

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  		Table 3. Characteristics of Patients Divided by Frequency of SC-OCS*

 
The 14 patients who previously had received continuous OCS therapy that had been discontinued due to the benefits of BDP therapy showed a significant increase in the Z score (increase, 91.6 ± 16.6% to 96.0 ± 17.8%; p = 0.0006) during the study period, whereas no significant changes were observed in BMD (from 0.856 ± 0.111 g/cm2 to 0.863 ± 0.120 g/cm2; p = 0.564) during the study period. There were no significant changes either in the Z score or in BMD (Z score change, 98.6 ± 18.4% to 99.9 ± 19.0% [p = 0.186]; BMD change, 0.927 ± 0.128 g/cm2 to 0.914 ± 0.124 g/cm2 [p = 0.159]) in the 21 patients who had not been treated previously with continuous OCS therapy. Although the increase in Z score for the former 14 patients (4.4 ± 3.6%) was significantly larger than that of the latter 21 patients (1.2 ± 4.1%) (p = 0.012), the exclusion of these patients did not alter the main results. No significant difference was found in the magnitude of the changes in either BMD or the Z scores between the low-dose and high-dose BDP groups (data not shown). On the contrary, a significant increase in bone loss was found in patients receiving frequent SC-OCS (mean change, 0.056 ± 0.041 g/cm2; n = 5) compared to those receiving sporadic SC-OCS (mean change, 0.0003 ± 0.031 g/cm2; n = 16; p = 0.010).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study investigated the effects of the long-term use of ICSs and periods of SC-OCS on lumbar BMD in asthmatic patients. The observation period (4.2 ± 0.1 years) was the longest ever among similar studies reported.18 19 21 As a whole, BDP treatment (dose, 765 ± 389 µg/d) and SC-OCS (1.9 ± 2.7 courses per year) did not accelerate bone mass loss in the lumbar spine. Patients treated with higher doses of BDP (ie, > 1,000 µg/d) showed no difference in the change of BMD compared with patients treated with lower doses (ie, <= 1,000 µg/d). However, patients who experienced frequent SC-OCS (ie, > 2.5 courses per year) showed significantly greater loss of BMD compared with patients who had more sporadic SC-OCS (ie, <= 2.5 courses per year).

Several studies have investigated the effect of ICS on BMD. Low doses of BDP (mean doses, 326 µg/d15 and 462 µg/d17 ) had no effect on bone mass according to a cross-sectional study15 or a 1-year longitudinal study.17 Cross-sectional studies investigating the effects of higher doses of ICSs have yielded conflicting results. Boulet and coworkers20 have reported a lack of adverse effects for BDP or budesonide (BUD) (mean dose, 1,140 µg/d for an average period of 34.2 months) on BMD. In contrast, Ip and coworkers10 have reported a trend toward a negative correlation (r = -0.46; p = 0.054) between spinal BMD and the daily dose of BDP or BUD (mean dose, 1,100 µg/d for an average period of 40 months). Toogood and coworkers28 have suggested that the daily dose (mean dose, 1,300 µg/d), but not the duration, of ICS therapy (mean duration, 10.1 years) may adversely affect BMD. Ebeling and coworkers13 have observed that high doses of BDP (mean dose, 2,131 µg/d for an average period of 3 years) are associated with low lumbar BMD in asthmatic men. Patients who receive ICS therapy for COPD also have been examined. The results of the study by Iqbal et al14 that looked at subjects with both COPD (n = 96) and asthma (n = 24) suggested that ICS therapy offers no protection from systemic steroid-induced bone loss. The results of another study29 surveying patients with COPD (n = 312) suggested that ICS therapy may increase the risk of vertebral fracture, although the relationship did not reach significance. Although the latter two studies suggest a negative effect of ICS therapy on BMD, the results cannot be extrapolated to patients with asthma because COPD itself is a substantial risk for osteoporosis.29

In contrast to the cross-sectional studies that have yielded controversial results, longitudinal studies17 18 19 22 have consistently negated the adverse effect of ICS therapy on BMD. A 1-year prospective study18 reported that 1,000 µg/d BDP did not affect BMD in middle-aged or elderly women. In another 1-year prospective study,19 it was shown that 1,000 µg/d fluticasone propionate and 1,600 µg/d BUD did not result in any decreases in spinal BMD or femoral neck BMD, irrespective of gender or age. Boulet and coworkers21 investigated the effects of 3-year treatment with BDP or BUD (dose, >= 800 µg/d) on BMD in asthmatic patients. They found no significant differences in those patients in comparison to those receiving either no ICSs or lower doses of ICS (ie, < 500 µg/d BDP or BUD).21 We have investigated the effect of longer-term ICS treatment on BMD and have confirmed the results of the four studies described above. No significant difference was found in the rate of reduction of lumbar BMD between the low-dose and high-dose ICS groups.

The use of SC-OCS for asthma exacerbations is recommended by asthma treatment guidelines.4 23 This treatment modality is unique to asthma and COPD, and therefore very little is known about the risk of osteoporosis associated with the use of SC-OCS. Packe and coworkers11 found a reduction in BMD in patients treated with high doses of BDP (ie, 1,000 to 2,000 µg/d for an average period of 3 years) coupled with SC-OCS. In the study by Packe et al,11 the frequency of previous SC-OCS, which may influence the results, is not described. In our previous study,16 there was no significant difference between patients treated with BDP (mean dose, 885 µg/d for an average period of 42 months) in conjunction with SC-OCS (7.5 courses per year) from patients treated with BDP alone (mean dose, 480 µg/d for an average period of 35 months) in terms of either lumbar BMD or Z score. In the present longitudinal study, we found that patients who received only sporadic SC-OCS showed significantly less bone loss in the spine than those who received frequent SC-OCS. Furthermore, patients given sporadic SC-OCS, but not those given frequent SC-OCS, actually showed a significant increase in Z score during the study period. These findings suggest that treatment with sporadic SC-OCS in addition to BDP may not accelerate natural bone loss, while frequent SC-OCS may do so. Consistent with our results, Luengo and coworkers22 found in a shorter study that there was no difference in the rate of bone loss in patients receiving BDP or BUD (mean dose, 662 ± 278 µg/d), irrespective of the use of sporadic SC-OCS (ie, 1 to 6 courses per 2 years). Taken together, it appears that the sporadic use of SC-OCS is safe with regard to bone loss.

A possible limitation of our study is that we did not measure the lateral view of the lumbar spine, which may have decreased the potential confounding factors such as arthrosis.30 With the densitometer used in this study (model QDR 1000; Hologic), the subjects have to be held in the lateral decubitus position in order to obtain the lateral view. While the CV for measurements in the lateral view using a spine phantom are relatively good, the use of these measurements in vivo results in high CV values, varying from 1.6 to 15.7%.31 32 33 With the densitometer that we used, therefore, lateral BMD measurements might not be suitable for longitudinal assessments. Recognizing the limitation of the anteroposterior projection, we had excluded patients with apparent arthrosis at the entry of our cross-sectional study in 199316 and made every effort to avoid the overestimation of BMD that could be associated with our methodology.

In this study, the Z score unexpectedly showed a significant increase during the study period. The densitometer was calibrated every day using a phantom, and the CV was smaller than 0.5%. Furthermore, the method of measurement itself was unchanged throughout the study period. The increase in Z score was therefore unlikely to have resulted from inadequate measurement precision. The increase was significantly more prominent in the 14 patients who had previously received continuous OCS therapy compared with those who had not received continuous OCS. The increase in Z score might therefore be explained in the former subset of patients by the restitution of previously osteopenic bone with the discontinuation of OCS therapy.34 Toogood and coworkers28 have shown that increased lifetime exposure to ICSs is associated with the decreased prevalence of vertebral fractures and higher lumbar Z scores. They proposed that this might be an indirect effect associated with the withdrawal of prednisone after the commencement of ICS therapy. Another possible reason for the increase in Z score might be an improvement in asthma control. However, the 14 patients who had ceased continuous OCS therapy had been in good control for > 1.5 years prior to the first BMD measurement. Regardless, the exclusion of the 14 patients did not alter our main results. Changes in BMD and Z scores in patients treated with high doses of BDP were not significantly different from those in patients treated with lower doses, whereas patients receiving frequent SC-OCS showed significantly more loss of BMD compared with those patients receiving sporadic SC-OCS.

In conclusion, we have shown that ICS treatment per se does not affect BMD, whereas frequent SC-OCS may. Our findings may reassure physicians and patients about the safety of the treatment approach in which ICS is supplemented with sporadic SC-OCS, although longer follow-up studies of ICS might be needed.


   Acknowledgements
 
Authors thank Hiroyuki Otsuka for the measurement of BMDs.


   Footnotes
 
Abbreviations: BDP = beclomethasone dipropionate; BMD = bone mineral density; BUD = budesonide; CV = coefficient of variation; ICS = inhaled corticosteroid; OCS = oral corticosteroids; PEF = peak expiratory flow; SC-OCS = short courses of oral corticosteroids

Received for publication August 2, 2000. Accepted for publication May 16, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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