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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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There are still some concerns about the safety of high doses of inhaled glucocorticosteroids (ICS). We compared the safety and efficacy of fluticasone propionate (FP) and beclomethasone dipropionate (BDP) in 306 patients with moderate to severe asthma in a double-blind, multicenter, cross-over study of 12 mo duration. During the 1-mo run-in period, bronchodilators were replaced by salmeterol 50 µg twice daily, increasing morning peak expiratory flow rate (PEFR) by 28 L/min (p < 0.001) and FEV1 by 6.2% predicted (p < 0.001). At randomization the current ICS was replaced by 500 µg BDP or 250 µg FP in accordance with previously taken 500 µg BDP or 400 µg budesonide (BUD). No significant differences between the two treatments regarding morning plasma cortisol, urinary excretion of calcium and hydroxyproline, FEV1, and PEFR were observed at any time point during the study. Osteocalcin and bone mineral density (BMD) were improved over baseline in the FP group, resulting in higher serum osteocalcin levels (mean difference 0.28 ng/ml; p < 0.001) and higher BMD in the spine (1.0%; p = 0.05), femoral neck (1.6; p < 0.01), and Ward's triangle (3.6%; p = 0.01) as compared with BDP. We conclude that chronic treatment with FP, at half the dose of BDP, results in a similar antiasthma effect but a more favorable safety profile with respect to bone metabolism and mineral density.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Inhaled glucocorticosteroids (ICS) are recognized as the most effective anti-inflammatory therapy available for the chronic treatment of asthma. There are, however, still some concerns that long-term treatment with high doses of ICS might result in significant systemic side effects such as growth suppression and osteoporosis (1). High doses of ICS have been shown to cause systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis and bone metabolism (1, 3, 4), but the long-term clinical significance of these findings is not clear (3).
The mechanisms of toxicity of oral corticosteroids on bone are well documented (2, 5). Oral corticosteroids directly and indirectly inhibit bone formation (1, 2) and stimulate bone resorption (1). Furthermore, they reduce calcium absorption from the gut and increase calcium loss from the kidney. The effects of ICS on bone turnover are less well documented (1, 2, 6). ICS have been shown to inhibit parameters of bone formation and to increase bone resorption, and hence may increase the risk of osteoporosis (6). Studies on the effect of ICS on bone mineral density (BMD) are, however, scanty (7) and their results are conflicting. Some studies found only a decrease in osteocalcin, especially at high doses of ICS, but no effect on BMD (7). Others found a decrease in BMD (8, 9) but these studies were open to criticism because many patients were also treated by oral corticosteroids.
Fluticasone propionate (Flixotide/Flovent; FP) is a highly potent and topically active ICS, with an oral bioavailability of less than 1% (10, 11). Studies over a wide range of doses have indicated that FP has at least twice the potency of beclomethasone dipropionate (BDP) in the control of asthma (12). Studies including the monitoring of adrenal function indicate that FP has fewer systemic effects than BDP at equipotent doses (13, 15).
The aim of this study was to test the hypothesis that FP at half the dose of BDP would have the same antiasthma effect but less systemic effects. HPA axis, bone metabolism, and BMD were assessed as parameters of systemic activity.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
A total of 391 Caucasian patients ranging in age from 18 to 75 yr, with
a clinical history of moderate to severe asthma and reversible airflow
obstruction, were recruited in 36 centers. Reversibility in airflow obstruction was defined by an increase of the FEV1 of 
15% predicted
15 min after the inhalation of 200 µg salbutamol or by a variation in
FEV1 of 15% of predicted within the preceding year. All were outpatients on a regular treatment with BDP or budesonide (BUD) in a
dose range of 800 to 2,000 µg daily. They had not received oral corticosteroids for more than 6 wk during the preceding year or within the
last month prior to the study. Patients using drugs affecting bone metabolism, or having concomitant bone disease were excluded. Patients
who changed their asthma medication, were hospitalized for asthma, or had an upper and/or lower respiratory tract infection during the
month prior to the trial were excluded. After a 1-mo run-in period,
patients were randomized if their FEV1 was 40% predicted and if
they still fulfilled the inclusion criteria. The study was approved by the
local ethics committees. All patients gave written informed consent
and the study was carried out in accordance with the provisions of the
Declaration of Helsinki and in accordance with local regulations.
Study Design
During the 1-mo run-in period, patients continued to take their current ICS at an unchanged dose. All bronchodilator medication except for theophylline was replaced by salmeterol powder formulation, 50 µg twice daily, administered via the Diskhaler (Glaxo Wellcome, Greenford, UK). At the end of the run-in period, patients were randomized to replace their current ICS with an equipotent dose of either BDP or FP. Patients on daily treatment with 1,000 µg BDP or 800 µg BUD were randomized to 1,000 µg BDP or 500 µg FP, 1,500 µg BDP or 1,200 µg BUD to 1,500 µg BDP or 750 µg FP, 2,000 µg BDP or 1,600 µg BUD to 2,000 µg BDP or 1,000 µg FP. The study medication was crossed-over after 6 mo. Throughout the duration of the study, patients continued to take their salmeterol. Salbutamol administered via a pressurized metered dose inhaler was permitted as rescue medication. A large volume spacer device (Volumatic) could be used provided it was used throughout the whole study. Mouth rinsing after the inhalation of the study drug was recommended.
Measurements
At the beginning and end of the run-in period, and after 1, 3, and 6 mo of both treatment periods, patients attended the clinic. Three measurements of FEV1 and FVC were made, and the best of the three measurements was recorded. Where possible, measurements were made at the same time of day and no rescue inhaled bronchodilator (salbutamol) was used for 4 h before attending the clinic.
During the study, patients measured their peak expiratory flow rate (PEFR) in the morning (7:00 to 8:00 A.M.) and in the evening (7:00 to 8:00 P.M.) using a mini Wright peak flow meter, preferably not within 4 h after rescue bronchodilator use. On each occasion they made three readings and entered the highest one on a diary card. Patients were instructed to use the inhaled salbutamol only for the relief of breakthrough symptoms. The use of "rescue salbutamol" was noted on the diary card as well as the severity of asthma symptoms during the day and night time using a four-point rating scale: day time rating scores: 0 = very well, no symptoms, 1 = few symptoms (not troublesome), 2 = troublesome, 3 = bad asthma, unable to carry out usual activities as normal; night time scores: 0 = slept through the night, 1 = slept well, woke up early or once by asthma, 2 = woke up 2 or 3 times by cough or asthma, 3 = bad night, awake most of the night due to asthma. The diary cards were filled in during the entire run-in period, and during 15 d after randomization, 15 d after 1 and 3 mo of treatment, and 15 d before the end of each treatment period of 6 mo. Quality of life (QOL) benefits were assessed using Hyland's Living with Asthma questionnaire (19), and filled in by the patient before and after the run-in period and the end of each treatment period.
Blood samples for osteocalcin and cortisol measurements, as well as second morning fasting urine samples for the analysis of hydroxyproline, creatinine, and calcium were taken between 8:00 and 10:00 A.M. at the start and at Months 1 and 6 of each treatment period. The serum cortisol assay was carried out using a competitive coated tube radioimmunoassay (Coat-A-Count Cortisol; DPC, Los Angeles, CA; less than 1% interference by beclomethasone or fluticasone). Serum osteocalcin was measured by radioimmunoassay using a human osteocalcin antibody (Nichols Institute, San Juan Capistrano, CA). Urinary hydroxyproline and calcium were determined by standard methods and related to the urinary concentration of creatinine. All blood and urine samples were analyzed by a central laboratory.
At randomization and at the end of the first treatment period of 6 mo, BMD was measured in vertebra L2 to L4 (lumbar spine [LS]) and in the hip (femoral neck [FN]), femoral trochanter [FT], and femoral Ward's triangle [FW]) by dual energy X-ray absorptiometry (DEXA). As the study was multicentric, several measuring devices were used. In 15 centers (n = 242) BMD was measured by DEXA using a Hologic QDR 1000 (Hologic, Waltham, MA) (9 centers, n = 61), Hologic QDR 2000 (1 center, n = 36), Lunar DPX (Lunar, Madison, WI) (2 centers, n = 49), Norland XR26 (Norland, Fort Atkinson, WI) (5 centers, n = 75), or a Sophos XR (Hologic) (1 center, n = 21) device. Measurements were performed according to the manufacturers' instructions. All BMD data were centrally collected for final quality control. Differences in BMD assessments between several devices have been documented (20). Therefore a single spine phantom (Hologic, Inc.) was measured on all devices for cross-calibration. The coefficient of variation between the QDR devices was 0.9%, between the DPX devices 0.5%, and between the XR26 devices 0.8%. BMD data generated by Sophos were excluded as the phantom measurements revealed significantly different values as compared with QDR, DPX, and XR26. Results of QDR and XR26 were converted to DPX values to ensure compatibility and consistency in interpretation (22). In order to compare the BMD baseline results of the asthmatic population with those of healthy subjects, BMD values of DPX and converted values of QDR and XR26 were expressed in Z-scores. One Z-score corresponds with one standard deviation (SD) compared with the mean value of age- and sex-matched control subjects, as provided by the manufacturer (Lunar, Inc).
For quality control of longitudinal data, the regularly performed calibration results of each device were collected to control the stability of each device during the study. All devices were stable during the study, as the coefficient of variation of each device was < 0.45% during the study. The effect of therapy was expressed in percent changes from BMD baseline values after cross-calibration.
Monitoring of Adverse Events
Safety assessments were performed at each clinic visit. The patient was visually examined for the presence of oral candidiasis and was asked whether asthma exacerbations occurred between clinic visits. An asthma exacerbation was defined as any worsening of asthma symptoms sufficient to require a change in medication. The procedure to be followed in the event of an exacerbation was detailed in the protocol. Patients experiencing a worsening of symptoms were instructed to increase their use of rescue salbutamol and to report to the investigator within 24 h. Exacerbation treatment was then at the discretion of the investigator (a short period of systemic steroids was allowed). The patients were not required to be withdrawn from the study if there was a return to their pre-exacerbation medication within 3 wk. All serious and minor adverse events were recorded irrespective of their apparent relation to the study drug.
Statistics
The sample size was calculated on the primary variable, i.e., morning serum cortisol levels. We needed 380 evaluable patients to detect with 90% power a treatment difference (FP versus BDP) in morning cortisol of 40 nmol/L (1.43 µg%) assuming a standard deviation on cortisol concentrations of 170 nmol/L (6.07 µg%).
The mean morning and evening PEFR, percentage of symptom-free days and nights, and percentage of rescue salbutamol-free days were calculated for both the FP and BDP groups providing these variables were available for both treatment periods and for at least half of the days that the diary cards had to be completed (86.3 and 85.2% of the patients at 1 and 6 mo). Percentage of predicted FEV1 was calculated based on predicted values with respect to sex, age, and height (23). Results of serum cortisol, osteocalcin, and urinary hydroxyproline and calcium were not included in the parametric (t test) statistical analysis if systemic steroids had been taken within 1 mo before sampling. Analyses were based on the cross-over technique described by Hills and Armitage (24). Analysis of variance (ANOVA) was used to assess prognostic factors such as dose effect of ICS on blood and urine variables.
BMD was only measured during the first treatment period, hence BMD data were analyzed as a parallel group design. Parametric tests were used to examine differences from baseline and differences between BDP and FP. An ANOVA was used to assess the effect of different DEXA devices on BMD changes from baseline. With respect to the reported adverse events, all patients who took FP (n = 325) and/or BDP (n = 325) have been considered. All statistical methods were performed two-tailed at the 5% level using SPSS/PC+ or SPSSWIN programs and procedures. Results are expressed as mean ± SEM (or SD if indicated) and changes are expressed as mean percent difference (95% confidence interval [CI], p value).
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
Of the 391 patients recruited, 51 patients were not randomized owing to failure to meet the inclusion criteria. A total of 340 patients (145 women and 195 men, 297 on BDP, 43 on BUD) were randomized to start treatment with FP (n = 167) or BDP (n = 173). We allocated 25%, 39%, and 36% of the randomized patients to the low, mid, or high dose of ICS, respectively, (Table 1). Both groups were well matched for sex, age, race, and duration of asthma. The group starting with BDP had used ICS for a longer time (p = 0.014) and had a higher incidence of seasonal rhinitis (p = 0.005) and of history of eczema (p = 0.041). The use of spacer was comparable in the two groups (93% in the group starting with BDP and 92% in the group starting with FP).
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Of the 340 patients randomized, 306 and 291 patients completed both treatment periods for 1 and 6 mo, respectively, and were eligible for the evaluation of safety (blood and urine variables and BMD) and efficacy (QOL, lung function tests at the clinic and on diary cards).
Safety
Morning cortisol and bone markers. No differences in treatment effect of FP and BDP on urinary calcium/creatinine, hydroxyproline/creatinine, and morning serum cortisol were found after 1 and 6 mo treatment. Moreover, these parameters did not change significantly during the treatment period on either FP or BDP. As compared with BDP, more patients were found on FP elevating their morning serum cortisol from below to above the lower normal limit (12 versus 5 and 17 versus 13 at 1 and 6 mo, respectively; NS) and fewer patients on FP exhibited a shift from above to below the lower limit (10 versus 11 and 6 versus 11 at 1 and 6 mo, respectively; NS). Serum osteocalcin values were in the lower normal range (1.5 to 6.6 ng/ml; Figure 1). Serum osteocalcin, however, was significantly higher after 1 mo (mean difference 0.15 ng/ml; 0.01 to 0.29, p = 0.041) and 6 mo (mean difference 0.28 ng/ml; 0.12 to 0.44, p < 0.001) of FP treatment as compared with BDP (Table 2). The dose of the ICS had no significant effect on the outcome of serum cortisol, serum osteocalcin, or on urinary excretion of hydroxyproline or calcium per creatinine.
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Bone density measurement. Of the 340 randomized patients, 133 were excluded or not available for the evaluation of BMD: 13 for the use of bone-affecting drugs, five for BMD measurements out of time schedule, 31 for missing data at randomization or at 6 mo, 17 for inadequate delineation at the BMD assessment or other technical errors, 35 for changes of devices or software between the two measurements, and 32 patients recruited in centers where a DEXA device was not available. Ten patients in the FP group received 11 courses of oral glucocorticosteroids during the first 6 mo compared with six patients and 9 courses (five patients with 1 course, one patient with 3 courses) in the BDP group. The remaining 207 patients (105 on FP and 102 on BDP) were available for the assessment of BMD. The group of patients excluded from the longitudinal evaluation of bone density and turnover were comparable to the study group with regard to gender, percentage of postmenopausal women, duration and dose of inhaled steroid treatment, use of oral steroids, lung function, morning cortisol, baseline serum osteocalcin and BMD. The treatment effects on lung function and symptom scores were similar between patients excluded and included for BMD analysis. ANOVA of the effect of DEXA device on changes in BMD after treatment revealed no significant device effect.
At randomization, the asthmatic patients eligible for bone
assessment showed a significantly lowered baseline of converted Z-score as compared with healthy control subjects in
the spine (
0.68 ± 0.09, p < 0.001) and in FN (0.18 ± 0.07, p = 0.01). The baseline Z-scores were not different between
patients randomized to FP or BDP (mean difference FP BDP:
0.03, 0.33 to 0.39 in the spine and 0.04, 0.23 to 0.32 in the
femoral neck).
After 6 mo of FP treatment, BMD increased significantly in the LS with 1.0% (p < 0.001) and in FW with 2.9% (p < 0.01) as compared with baseline values (Table 3). No changes in LS and FW were found after BDP treatment. No change from baseline in BMD was found in the FN after FP compared with a significant loss after BDP (p < 0.01). No significant changes were found in the FT after FP and BDP.
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FP and BDP had significantly different effects on BMD (Figure 2) as reflected by the difference in mean percentage change from baseline in the LS of 1.0% (0.00 to 1.9, p = 0.05), in the FN of 1.6% (0.4 to 2.7, p < 0.01), and in the FW of 3.6% (0.9 to 6.4, p = 0.01). BMD in FT showed the same trend in favor of FP but failed to reach statistical significance.
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Adverse Events
In both FP- and BDP-treated patients, a similar number of adverse events (217 and 215, respectively) was found (Table 4). Differences in frequencies between both ICS were statistically not significant. During the treatment period 28 patients (FP 9, BDP 19) discontinued the study owing to an adverse event (lack of efficacy: FP 2, BDP 4; hoarseness: FP 2, BDP 1; miscellaneous: FP 2, BDP 7). Exacerbation of asthma was reported as the reason for withdrawal in 10 of these 28 patients and was more frequent under BDP than under FP (7 versus 3, NS).
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Efficacy
PEFR, FEV1 percentage of predicted, and FVC as well as QOL (Table 5) were all significantly increased (p < 0.001) at randomization as compared with the start of the run-in period (mean differences PEFR of 28 L/min [18.7 to 37.7], FEV1 percentage of predicted of 6.2% [4.5 to 7.9], FVC of 0.19 L [0.13 to 0.25], and QOL of 0.10 [0.08 to 0.12]).
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After randomization, no differences were found between the two treatment modalities in lung function (FEV1 percentage of predicted, PEFR, and FVC; Figure 3) recorded at each clinic visit. Morning and evening PEFR as recorded on diary cards were, however, significantly (p < 0.05) higher at the end of the FP treatment period as compared with the BDP treatment period (mean difference morning of 5.02 L/min [0.06 to 9.98] and evening of 5.37 L/min [0.66 to 10.08]). The percentage of symptom-free days and nights, and the use of rescue salbutamol did not differ significantly between FP and BDP (Table 6). Over the entire treatment period, 64 of 325 (19.7%) and 66 of 325 patients (20.3%) who were treated with FP and BDP, respectively, reported temporary worsening of asthma (NS).
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The QOL score after 6 mo FP (1.22 ± 0.02) was also significantly better than after BDP (1.20 ± 0.02). The mean difference was 0.02 (0.00 to 0.04, p < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was designed to test the hypothesis that long-term treatment of asthma with FP at half the dose of BDP would result in a comparable antiasthma effect but a better safety profile. The results show indeed that FP, at half the dose of BDP, results in a similar efficacy in the control of moderate to severe asthma. This was evident from the PEFR, FVC, and FEV1 percentage of predicted recorded at each clinic visit and from the percentage of symptom-free days and nights, of days free from rescue medication and from the rate of asthma exacerbations. After 6 mo treatment the diary morning and evening PEFR measurements as well as the QOL were significantly higher in the FP group. All these findings confirm the 1:2 efficacy ratio in favor of FP as reported in other studies using doses appropriate to the severity of asthma being treated (12).
During the run-in period, the current maintenance bronchodilator treatment was replaced by the long-acting 
2-agonist, salmeterol 50 µg twice daily, for all patients in order to
improve symptom control and lung function so that retention
would be optimal for the 1-yr study period (25, 26). The lung
function tests and the QOL were significantly increased at randomization as compared with the start of the run-in. During
the subsequent treatment period, the combination of salmeterol with either FP or BDP was not associated with a decline
in lung function. This argues for a persistent improvement of
asthma during long-term treatment with salmeterol in combination with FP or BDP. Furthermore, variations between morning and evening PEFR were very small during the whole treatment period of both combination treatments.
All mean morning cortisol levels for both ICS remained unchanged within normal upper and lower limits (28 and 7 µg%). No differences in morning cortisol were found between both treatments. As compared with BDP, more patients were found on FP exhibiting a shift from below to above the lower normal limit of morning serum cortisol (12 versus 5 and 17 versus 13 at 1 and 6 mo, respectively) and fewer patients on FP exhibited a shift from above to below the lower limit (10 versus 11 and 6 versus 11 at 1 and 6 mo, respectively).
Serum osteocalcin levels were in the lower normal range, as expected in patients with chronic corticosteroid therapy. Bone metabolism during BDP and FP treatments was significantly different. Osteocalcin levels at Months 1 and 6 were higher on FP treatment as compared with BDP. This suggests a relatively higher bone formation on FP. Parameters of bone resorption were similar on both treatments as indicated by a similar urinary excretion of hydroxyproline and calcium. FP exerts therefore less suppression on bone formation as compared with BDP, whereas metabolism of bone resorption did not differ between both ICS. It has been found that ICS only decrease bone formation, while oral corticosteroids are associated with an additional increase in bone resorption (6). Since the use of oral steroids was not allowed in this study, our results are in agreement with these findings so that differences in effects on bone metabolism between FP and BDP appear in osteocalcin concentrations and not in urinary hydroxyproline or calcium. These findings on bone formation and resorption are in accordance with another study comparing the effect on bone metabolism of 750 µg/d FP and 1,500 µg/d BDP over a period of 6 wk and referring to type 1 collagen carboxyterminal telopeptide (1CTP) and deoxypyridinoline for bone resorption and to osteocalcin and procollagen type 1 carboxyterminal propeptide (P1CP) for bone formation (18). In association with the favorable effect of FP on markers of bone formation, BMD in the spine, FN, and FW was found to increase significantly when patients were switched from BDP or BUD to FP. During FP treatment no bone loss occurred in the femoral neck, whereas it continued in patients treated with BDP. This is an important clinical finding as it has been demonstrated that patients on corticosteroids are affected by a persistent and continuous bone loss in the femoral neck (27).
The bone protective profile of FP has been confirmed in a 2-yr study comparing a daily dose of 1,000 µg FP with 2,000 µg BDP using the quantitative computed tomography (QCT) BMD assessment (28). Changes from baseline QTC were significantly different between FP and BDP at 12 and 24 mo as a result of an unchanged BMD on FP and a decrease of BMD on BDP. The increase in BMD within 6 mo of therapy with FP are compatible with the observation that in corticoid-induced osteoporosis, bone loss is more the result of thinning of trabeculae than loss of connectivity (29). Therefore, using medication that stimulates osteoblasts, or, as is the case for FP, using an ICS that is less suppressive for osteoblasts, will have immediate positive effects on BMD. We conclude that chronic treatment with FP, at half the dose of BDP, results in a similar antiasthma effect but with a more favorable safety profile with respect to bone metabolism and BMD, conferring to FP a superior therapeutic index.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Prof. R. A. Pauwels, Department of Respiratory Diseases, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
(Received in original form October 3, 1996 and in revised form November 4, 1997).
Acknowledgments: We thank the physicians at the following centers for their assistance with this study: Dr. J. Aumann (Hasselt), Dr. J. Bockaert (Mechelen), Dr. Y. Bogaerts (Brugge), Dr. D. Coolen (Antwerpen), Dr. L. Croonenborghs (Veurne), Dr. R. Cordier (Bruxelles), Prof. W. De Backer (Antwerpen), Dr. M. De Jonghe (Jumet), Dr. W. Demedts (Oudenaarde), Dr. Ph. De Rudder (Torhout), Dr. J. P. De Bruyne (Ronse), Dr. P. De Vuyst (Bruxelles), Dr. M. De Vos (Gent), Dr. J. L. Doyen (Bruxelles), Dr. M. Estenne (Bruxelles), Dr. L. Gepts (Aalst), Dr. N. Impens (Aalst), Dr. L. Lousberg (Verviers), Dr. M. Mairesse (Bouge), Dr. S. Mariën (Lier), Dr. J. B. Martinot (Namur), Dr. P. Mary (Bruxelles), Dr. G. Nuttin (Tournai), Dr. M. Noppen (Jette), Dr. P. Ortmanns (Reet), Dr. P. Prigogine (Bruxelles), Dr. M. Richez (Ghlin), Dr. R. Ryckaert (Sint-Niklaas), Dr. L. Siemons (Sint-Truiden), Dr. R. Simons (Marche-En-Famenne), Dr. R. Stevigny (Tournai), Dr. P. Van Den Brande (Duffel), Dr. B. Van De Maele (Oostende), Dr. A. Van Meerhaeghe (Montigny-Le-Tilleul), Dr. G. Vandermoten (Namur), Dr. L. Van Moorter (Aalst), Dr. D. Van Renterghem (Brugge), Dr. P. Verhoye (Kortrijk), Prof. P. Vermeire (Antwerpen), Dr. P. Verstraeten (Aalst), Prof. W. Vincken (Jette). Bone Densitometry Centers: Dr. F. Adam (Gosselies), Prof. P. Bergmann (Bruxelles), Prof. P. Blockx (Edegem), Dr. L. Boeckx (Sint-Niklaas), Dr. R. Crombez (Assebroek), Prof. J. Dequeker (Leuven), Dr. H. De Winter (Aalst), Dr. M. Durez (Hornu), Dr. L. Doalto (Tournai), Dr. N. Dorny (Aalst), Prof. G. Geusens (Leuven and Diepenbeek), Prof. J. M. Kaufman (Gent), Dr. L. Lamberigts (Brugge), Dr. E. Morimont (Namur), Prof. M. Osteaux (Jette), Prof. J. Y. Reginster (Liège), Prof. A. Schoutens (Anderlecht), Dr. L. Van Der Schueren (Kortrijk).
Supported by a grant from Glaxo Wellcome N.V., Belgium.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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