The comparison of the effects of fluticasone propionate and budesonide on clinical indices and on bone mineral density in the asthmatic patients: a one year treatment study

The comparison of the effects of fluticasone propionate and budesonide on clinical indices and on bone mineral density in the asthmatic patients: a one year treatment study

E. Harmancž*, Î. Ak**, N. Özdemir*, E. Vardareli**, O. Elbek* and Î. Uçgun

Departments of Pulmonary Diseases* and Nuclear Medicine**. Osmangazi University. Faculty of Medicine. Eskisehir. Turkey.

Correspondence:

Emel Harmancž

Hamamyolu 76/6

26010

Eskisehir

Turkey

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SUMMARY

Background: it is well accepted that the inhaled administration of steroids is efficacious and has fewer side effects than the systemic use. Among them fluticasone propionate (FP) has been said to cause the similar antiasthma effect without unfavorable side effect at half the dose of the other ICS. The aim of the study was to compare the effects of FP 500 µg/day and budesonide (BUD) 800 µg/day as a pressurized metered dose inhaler (pMDI) for one year on clinical indices determined by FEV₁ and diurnal variation of PEFR (peak expiratory flow rates) and on laboratory indices determined by serum cortisol and bone mineral density (BMD).

Methods: a total of 30 nonsmoking mild to moderate asthmatic patients were recruited the study. 15 patients were given 800 µg/day BUD and 15 patients were given 500 µg/day FP as a pMDI. BMD measurements were done with dual energy X-ray absorbtiometry (DEXA) before and after the treatment at the lumbar area of the spine (L1-4) and left hip (trocanter major, neck of femur, intertrocanteric region and Ward''s triangle). 10 patients of BUD group and 13 of FP group completed the study. After a year of treatment period, patients were compared on the basis of clinical indices (FEV₁ and variability of PEFR), on serum cortisol levels and on BMD in both groups.

Results: after the treatment, variability of PEFR (in BUD group p < 0,01, in FP group p < 0,001) and FEV₁ (in BUD group p < 0,05, in FP group p < 0,05) were both improved in the groups. Serum cortisol levels and BMD of the patients in both groups were not changed significantly (p > 0,05).

Conclusions: the results suggested that FP 500 µg/d and BUD 800 µg/d as a pMDI results in a similar antiasthma effect without causing any adverse effect on BMD in mild and moderate asthmatics after one year treatment period.

Key words: Asthma. Inhaled corticosteroids. Fluticasone propionate. Bone mineral density. Budesonide.

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INTRODUCTION

Inhaled corticosteroids (ICS) are recommended in the treatment of asthmatic patients (1, 2). Osteoporosis is a well known side effect of long term systemic use of steroids (3). There is growing concern about the possible effects of inhaled corticosteroids on bone. Previous studies has confirmed that ICS may cause depressed bone formation (4), increased bone resorption (5) and osteoporosis (6). Fluticasone propionate is relatively new ICS with a higher topical antiinflammatory effect. FP was said to have the same clinical potency at half the dose of budesonide (BUD) (7). The aim of this study was to compare the effects of 500 µg/d and BUD 800 µg/d for one year period on clinical parameters determined by variability of peak expiratory flow rate (PEFR) and FEV₁ and to compare the effects on bone mineral density (BMD) and on serum cortisol values.

METHODS

Patiens

A total of 30 nonsmoking subjects (5 males) aged 20 to 55 (mean, 39.9 ± 1.4) were recruited from the outpatient department. The patients were selected on the basis of symptoms and lung function parameters compatible with the diagnosis of asthma according to the American Thoracic Society. All women were premenopausal. No patient had any other pulmonary or serious systemic disease and not using drugs effecting bone metabolism and concomitant bone disease. No patient reported bone fractures in the preceding 3 years. Patients had been receiving regular treatment with fluticasone propionate or beclomethasone dipropionate except two. Any patient did not have a history of chronic systemic steroid use (defined as any dose taken for more than 1 month continously), more than 4 booster courses of systemic steroids in the past or in systemic steroid use in the previous 6 months. All subjects gave informed consent for entering to the study.

Protocol

After a 2 week placebo run in period 15 patients were given 500 µg/d FP and 15 patients were given 800 µg/d BUD by pressurized metered dose inhaler (pMDI) as divided by two doses. They used salbutamol 100 µg pMDI as rescue medication. Only two patients were given long acting 2 agonist (salmeterol) as a pMDI regularly to control the symptoms from beginning. Patients were instructed how to use their pMDI correctly. No other pulmonary medication was allowed. Patients were withdrawn from the study if a change in the dose of their current antiasthma medication proved necessary, or if any additional medication including oral corticosteroids was required. Throughout the study period patients continued using their asthma medication at a constant dose.

During the placebo run in period patients were recorded their peak expiratory flow rate (PEFR) in the morning (7.00 to 8.00 AM) and in the evening (7.00 to 8.00 PM) using a mini Wright peak flow meter, preferably not within 4 hours after rescue bronchodilator use. On each occasion they made three readings and entered the highest one on a diary card. The diary cards were filled in during the run-in period and 15 day before the end of treatment period of one year. Three measurements of FEV₁ were made and the best one was recorded. FEV₁ measurements were made with dry-bellows spirometry (Model S; Vitalograph, Ltd. Buckingham, UK).

Bone mass and serum cortisol levels

Bone mineral density (BMD) measurements were done with dual energy X- ray absorbtiometry using a fan beam X-ray bone densitometer (QDR 4500 W, Hologic, USA). Regions of interest that were assessed included lumbar area of the spine (L1-4) and left hip (trochanter major, neck of femur, intertrochanteric region and Ward''s triangle). BMD was automatically calculated from bone area (cm²) and the bone mineral content (g) and expressed in absolute values (g/cm²). Values were also expressed as Z-scores of sex and age matched weight adjusted normal controls.

Serum cortisol levels were determined with radioimmunassay (cortisol; DPC; Los Angelos, CA) in the fasting blood taken between 8:00 and 10:00 AM at the end of placebo and treatment period to assess effects on adrenal function.

Statistical analyses

The comparisons between groups were done using Mann Whitney U test and within the same group using Wilcoxon t-test. The level of significance for all analyses was taken at p < 0.05. A personal computer program SPSS.WIN was used for all calculations.

RESULTS

5 patients of BUD group and 2 patients of FP group had been out of the study because of poor compliance (5 patients) and hospitalisation due to acute asthma attack (2 patients). The characteristics of the remaining 23 patients are summarized in table I. As shown in table I baseline characteristics were not different in both groups. i.e.; age, variability of PEFR, FEV₁, duration of ICS use, duration of asthma and baseline serum cortisol levels (p > 0.05).

 

Table I Baseline characteristics of the patients in the two groups
	BUD*	FP*	p
Subjects,n	10	13
Male/Female	1/9	2/11
Age, yr (range)	41.2 ± 1.9 (34-50)	39.5 ± 2.4 (23-55)	NS
Duration of asthma,yr	17.7 ± 1.5	16.5 ± 1.5	NS
Duration of ICS use, mo	14.9 ± 4.0	16.6 ± 5.0	NS
Baseline FEV1, % pred.	68.0 ± 3.1	75.8 ± 3.8	NS
Variability of PEFR, %	19.5 ± 2.6	15.8 ± 2.4	NS
Serum cortisol, g/dl	13.9 ± 1.8	15.4 ± 1.5	NS
*Values are mean ± SEM. Definitions of abbreviations: yr: year; PEFR: peak expiratory flow rate; CIS: inhaled corticosteroids; FEV1: forced expiratory volume in one second; pred: predicted; BUD: budesonide; FP: fluticasone propionate; NS: non significant.

Table II shows the mean values of FEV₁, variation of PEFR, and serum cortisol levels after treatment in each group. After the treatment, variability of PEFR and FEV₁ were both improved in both of the groups. In BUD group mean values of FEV₁ were increased from % 68.0 ± 3.1 to 73.8 ± 3.2 (p < 0.05) and the mean values of variability of PEFR were decreased from % 19.5 ± 2.6% to % 11.6 ± 1.0 (p < 0.01). In FP group mean values of FEV₁ were increased from 75.8 ± 3.8% to 84.3 ± 4.3% (p < 0.05) and the mean values of variability of PEFR were decreased from 15.8 ± 2.4% to 10.7 ± 1.8% (p < 0.001). The mean values of serum cortisol levels were not changed in both group after treatment (p > 0.05). In BUD group mean values of serum cortisol changed from 13.9 ± 1.8 to 13.7 ± 1.7 g/dl and FP group it changed from 15.4 ± 1.5 to 14.5 ± 1.6 g/dl.

 

Table II The mean values of percentages of FEV1, diurnal variation of PEFR and serum cortisol levels of the two group before and after the treatment
		Baseline*	Posttreatment*	p
FEV1 (%)	BUD	68.0 ± 3.1	73.8 ± 3.2	§
	FP	75.8 ± 3.8	84.3 ± 4.3	§
PEFR, %	BUD	19.5 ± 2.6	11.6 ± 1.0	÷
	FP	15.8 ± 2.4	10.7 ± 1.8	¶
Serum cortisol, g/dl	BUD	13.9 ± 1.8	13.7 ± 1.7	NS
	FP	15.4 ± 1.5	14.5 ± 1.6	NS
*Values are mean ± SEM. Definitions of abbreviations: FEV1: forced expiratory volume in one second; BUD: budesonide; FP: fluticasone propionate; PEFR: peak expiratory flow rate; §: p < 0.05, ÷: p < 0,01; ¶: p < 0.01; NS: non significant.

The mean values of BMD absolute values before and after one year treatment with both FP and BUD are in table III. The BMD absolute values of the lumbar area of the spine (L1-4), neck of femur, trochanter major, inertrocanteric region and Ward''s triangle were all not different after the treatment with both BUD and FP (p > 0,05).

 

Table III The mean values of BMD absolute values before and after treatment in the groups
Bone data*	Treatment	Baseline	After treatment	p
Spine BMD, g/cm^2 L1-4,	BUD	0.920 ± 0.03	0.705 ± 0.19	NS
	FP	0.920 ± 0.028	0.911 ± 0.023	NS
Hip BMD, g/cm^2 Neck of femur,	BUD	0.773 ± 0.03	0.802 ± 0.03	NS
	FP	0.769 ± 0.024	0.760 ± 0.027	NS
Trochanter,	BUD	0.692 ± 0.04	0.712 ± 0.03	NS
	FP	0.698 ± 0.025	0.694 ± 0.024	NS
Intertroc. reg.,	BUD	0.977 ± 0.04	1.034 ± 0.05	NS
	FP	1.031 ± 0.034	1.053 ± 0.033	NS
Ward''s,	BUD	0.679 ± 0.04	0.714 ± 0.05	NS
	FP	0.687 ± 0.04	0.669 ± 0.036	NS
*Values are mean ± SEM. Definitions of abbreviations: BMD: bone mineral density; BUD: budesonide; FP: fluticasone propionate; intertroc reg: intteric region; NS: non significant.

The BMD z scores were also not changed after the both FP and BUD (p > 0,05). The mean values of z scores before and after the treatment in both group are in table IV.

 

Table IV BMD z scores of the groups before and after the treatment
Bone data*	Treatment	Baseline	After one year	p
Spine, L1-4	BUD	­0.36 ± 0.48	­0.75 ± 0.30	NS
	FP	­0.89 ± 0.21	­0.93 ± 0.18	NS
Hip
Neck,	BUD	­0.56 ± 0.29	­0.36 ± 0.38	NS
	FP	­0.77 ± 0.23	­0.81 ± 0.25	NS
Trochanter,	BUD	­0.28 ± 0.26	­0.16 ± 0.38	NS
	FP	­0.09 ± 0.26	­0.11 ± 0.25	NS
Intertrochanter,	BUD	­0.84 ± 0.28	­0.49 ± 0.38	NS
	FP	­0.65 ± 0.24	­0.53 ± 0.26	NS
Ward''s,	BUD	­0.08 ± 0.30	0.08 ± 0.40	NS
	FP	­0.003 ± 0.30	­0.093 ± 0.27	NS
*Values are mean ± SEM. Definitions of abbreviations: NS: non significant; BUD: budesonide; FP: fluticasone propionate.

DISCUSSION

The present study shows that Budesonide (BUD) 800 µg/d and FP 400 µg/d for one year would result in a similar antiasthma effect without affecting bone density. After 1 year treatment diurnal variation of PEFR and FEV₁ percentage of predicted were improved significantly in both group. We used pMDI (pressurized metered dose inhaler) in this study. Different results were reported according to the preperation type of drugs used. Although dry powdered form of BUD is suggested as being equipotent with the other forms of FP, it has been accepted that FP pMDI is more potent than BUD pMDI (8). The recommended FP: BUD potency ratio is about 2:1 (7). In a study, it has been reported that FP pMDI is as effective as at half the dose of BUD pMDI (9): That''s why we used FP pMDI at the half dose of BUD.

We demonstrated that FP 400 µg/d pMDI and BUD 800 µg/d have no adverse effect on bone density in the long term. Osteoporosis is a well known side effect of systemic steroid use (10). There have been conflicting results about the effects of inhaled corticosteroids (ICS) on bone density. Reduction in bone density has been reported in patients with asthma treated with high doses of inhaled corticosteroids in the long term (11). In another study, Ip and collagues (6) also reported the decrease in bone density but mainly in women. But in some other studies inhaled steroids have been shown to exert no change on bone density as used with higher doses at least for one year (12, 13). Certainly, there are several factors affecting bone density such as age, sex, physical activity, oral corticosteroids taken before. Most studies compare BMD of asthmatic patients treated with ICS with BMD of healty adults and in some others confounding factors couldnt''t be exluded. In our study, the characteristics of patients in each group were not different from each other with respect to age, premenopausal- nonsmoking status, prior use of ICS and clinical severity which may itself affect BMD causing less physical activity. Number of women is higher in both group and there is no difference between the groups in that respect. Perhaps we could use a placebo drug to see the effects of the confounding factors in the subjects but we couldn''t use a placebo due to the ethical limitations. Because in some pharmacologic studies, delayed onset of treatment with inhaled glucocorticoids has been shown to be associated with a reduced improvement of lung function and may lead to develop chronic airway limitation causing irreversible remodeling of the airways (14, 15). Our patients also required antiinflammatory therapy and we didn''t think to follow up any of the patients without antiinflammatory therapy. Most studies compares the effects of FP and BDP on BMD. And FP has been shown to exert less effect than beclomethasone dipropionate (BDP) (13, 16). In addition Pauwels et al (16) also found that FP increased bone density in contrast to BDP and said FP has a more favorable safety profile with respect to BMD. There were small increases in some indices in our patients also but they were not significant. We couldn''s found such an increase in our patients. Also it has been said that inhaled steroid therapy may have a protective effect on bone density in the long term use wiht a reduction of oral steroid use (17). Most of our patients were taking inhaled steroid before and none of them had received systemic steroid at least 1,5 years before the study. Our patients were well controlled with these lower doses of ICS and no additional OCS was given. It has been reported that the daily dose, but not the lifetime cumulative dose of inhaled steroid therapy may adversely affect bone density (18). If so, it should be said that the dose which our patients taken is not efficient to exert some effects on BMD.

In addition all morning cortisol levels were within normal upper and lower limits (5-25 g/dl in both treatment group. And there were no differences in morning cortisol between the values before and after the treatment as in some other studies published previously (14, 19).

The results suggest that FP 500 µg/d and BUD 800 µg/d results in a similar antiasthma effect without an important adverse effect on bone density in mild and moderate asthmatics during one year treatment period. It may be of potential interest in the long term with higher doses.

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RESUMEN

Antecedentes: está bien aceptado que la administración inhalada de esteroides es eficaz y tiene menos efectos colaterales que su uso sistémico. Entre estos esteroides, el propionato de fluticasona (PF) parece producir un efecto antiasmático similar a los otros esteroides, sin efectos colaterales desfavorables y a la mitad de dosis. El objetivo del estudio era comparar durante un año los efectos de la administración de 500 µg/día de FP y 800 µg/día de budesonida (BUD) utilizando un inhalador presurizado de dosis medida (MDIp) sobre los índices clínicos determinados mediante el FEV₁ (volumen espiratorio forzado en un segundo) y la variación diurna de los PEF (flujo espiratorio forzado) y sobre los índices analíticos, consistentes en la determinación del cortisol sérico y de la densidad mineral ósea (DMO).

Método: se incluyeron en el estudio un total de 30 pacientes no fumadores con asma de leve a moderada. Se administraron 800 µg/día de BUD a 15 pacientes y 500 µg/día de PF a 15 pacientes en forma de MDIp. Las determinaciones de DMO se realizaron mediante absorbimetría de rayos X de energía doble (DEXA) antes y después de los tratamientos en la zona lumbar de la columna (L1-4) y en la cadera izquierda (trocánter mayor, cuello del fémur, región intertrocantérea y triángulo de Ward). Completaron el estudio 10 pacientes del grupo BUD y 13 del grupo PF. Después de un año de tratamiento, se compararon los pacientes en función de los índices clínicos (FEV₁ y variabilidad de PEF), sobre los niveles de cortisol sérico y sobre la DMO en los dos grupos.

Resultados: después del tratamiento, mejoraron en los grupos de variabilidad del PEF (en el grupo BUD p < 0,01, en el grupo PF p < 0,001) y el FEV₁ (en el grupo BUD p < 0,05). Los niveles séricos de cortisol y la DMO de los pacientes de los dos grupos no cambiaron de manera significativa (p > 0,05).

Conclusiones: según parecen sugerir los resultados, 500 µg/d de MDIp tiene un efecto antiasmático similar sin causar efectos adversos sobre la DMO en pacientes con asma de ligera a moderada después de un período de un año de tratamiento.

Palabras clave: Asma. Corticosteroides inhalados. Propionato de fluticasona. Densidad mineral ósea. Budesonida.

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