The aim of our study was to assess the effects of long-term treatment with inhaled budesonide (BUD) on total body bone mineral density (BMD), total body bone mineral capacity (BMC), total bone calcium (TBC), and body composition in children with asthma. Dual energy X-ray absorptiometry (DEXA scan) was performed in 157 asthmatic children treated with inhaled BUD at a mean daily dose of 504 μ g (range, 189 to 1,322 μ g) for 3 to 6 yr (mean, 4.5 yr). Measurements were compared with those of 111 age-matched children also suffering from asthma but who had never been treated with exogenous corticosteroids for more than 14 d (control group). There were no statistically significant differences between the two groups in BMD (BUD = 0.915 g/cm2, controls = 0.917 g/cm2), BMC (BUD = 1,378 g, controls = 1,367 g), TBC (BUD = 524 g, controls = 519 g), or body composition (lean body weight = 27,600 g [BUD] and 26,923 g [control], % body fat = 20.1% [BUD] and 20.3% [control]). Furthermore, there was no correlation between any of these parameters and duration of treatment, accumulated or current dose of budesonide. Three to six years of treatment with inhaled budesonide at an average daily dose of 504 μ g has no adverse effect on total BMD, total BMC, TBC, or body composition in children with chronic asthma.
New advances in our understanding of the pathophysiology of asthma have made us aware of the inflammatory nature of this disease. Inflammation is present even in patients with mild disease and, hence, the early use of inhaled corticosteroids has been advocated for optimal treatment of both adults and children (1, 2). Several controlled clinical trials have established the efficacy of inhaled corticosteroids in asthma. Virtually all asthma outcome parameters are improved to a greater extent with inhaled corticosteroids than with any other antiasthma treatment (2). The change-over to inhaled steroid therapy has occurred more rapidly among adults than among children, mainly because many pediatricians are still concerned about potential adverse effects of long-term treatment with inhaled corticosteroids. In a growing child there is particular concern over the possible negative effects on bone.
Several studies have evaluated the influence of inhaled corticosteroids on markers of bone formation and bone degradation (3-6). Overall, the results from these studies have been reassuring. Doses of inhaled corticosteroids producing optimal disease control in the majority of patients have not been associated with any detectable effect on these markers, whereas subtle changes have sometimes been reported with high dose therapy. Whether or not these small changes in markers of bone formation and/or degradation are clinically important remains to be established.
Measurement of bone mineral density in adults has been shown to be of some value in predicting the risk of fracture caused by osteoporosis (7-10). At present, our knowledge about bone mineral density in children receiving continuous long-term treatment with inhaled steroids is limited. Therefore, the aim of the present cross-sectional study was to measure total body bone mineral density (BMD), total body bone calcium (TBC), total body bone mineral capacity (BMC), and measures of body composition in children with asthma treated for at least 3 yr with the inhaled corticosteroid budesonide and to compare these measurements with those of asthmatic children who had never received continuous treatment with exogenous steroids.
Children with persistent asthma and no other chronic disease were studied. The patients were well-known to our clinic as participants in an ongoing prospective, long-term (several years), controlled study on the effect of budesonide on growth and lung function (1). The present cross-sectional investigation was added as a part of the recordings made in the prospective study at a time when all children had been followed for at least 3 yr.
The children had been seen at our clinic at least each sixth month for 3 to 6 yr at the time of study initiation. The following recordings are routinely made at each visit: number of hospital admissions because of acute severe asthma during the previous 6 mo, age, height (Harpenden stadiometer, mean of three measurements), weight, lung function (Vitalograph, Buckingham, UK) (best of three measurements), stage of puberty (11), use of concurrent medicine, dose of inhaled budesonide, and inhalation device. Furthermore, adjustments of the dose of inhaled steroid are made based upon the assessment of the clinical control of the disease in an attempt to always treat the child with the minimal effective dose of budesonide.
Between clinic visits, changes in budesonide dose or other asthma medications are always made under the supervision of the clinic so that transient changes in treatment during periods of increased asthma symptoms are always recorded. These recordings make it possible to accurately calculate the average dose of exogenous corticosteroid during each previous 6-mo period and the accumulated dose of budesonide over the years.
Compliance with the asthma medication was checked at each visit by asking the child and the family about their compliance. In addition, the frequency of renewal of prescriptions was measured once a year for each child. Finally, the child was given an inhaler at the clinic whenever the inhaler strength was changed. In such situations the child was asked to return to the clinic for another visit 6 to 8 wk later and to bring the inhaler at that visit. These measures allowed an assessment of compliance by measuring the number of doses taken (weighing canisters [pMDI] or counting the number of doses left [Turbuhaler]) in relation to the prescribed dose.
Any asthma medication required to maintain asthma control (except systemic steroids for more than 2 wk per year) is allowed in the study. If a child receives systemic steroid for more than 2 wk per year he or she is excluded from the study.
In addition to children treated with inhaled budesonide, the ongoing prospective study also includes a “control group” of children with asthma whose parents have not allowed their children to be treated with inhaled corticosteroids (because of concerns about side effects). These “control” children have been followed in exactly the same manner as the children receiving budesonide (similar recordings at least every 6 mo at our clinic for a number of years). Children in the control group receive a variety of asthma medications, excepting inhaled or systemic steroids, for more than 2 wk per year. In addition to these children the control group of the present study also included some newly referred children with asthma. These were included in order to obtain a sufficient number of control patients for comparison. None of the newly referred children have ever received oral or inhaled steroids for more than 2 wk.
All children from the ongoing prospective study who had received inhaled budesonide continuously for ⩾ 3 yr were included in the present cross-sectional study on bone mineral density and body composition. To avoid the confounding influence of systemic steroids, the following exclusion criteria were used in the present study:
More than 14 d of treatment with systemic glucocorticosteroids ever (both groups of children).
Inhaled glucocorticosteroids for more than 2 wk ever (control group).
Topical (skin) glucocorticosteroids after 2 yr of age ever applied to more than 25% of the body surface (both groups).
Use of nasal corticosteroids, except for the treatment of seasonal rhinitis < 1 mo per year (both groups).
Total body bone mineral density was measured by dual energy photon absorptiometry (DEXA), using a Lunar DP3 densitometer (Lunar Corp., Madison, WI). The results are reported as absolute densities (in grams per square centimeter). All measurements and analyses were performed by the same experienced investigator who was blinded with respect to treatment group. The children in the prospective study met up for one visit to record bone density; the seasonal distribution of measurements over the year was similar between the two groups.
The DEXA scan also allowed measurement of total body bone mineral capacity (BMC), total bone calcium (TBC), body composition (total fat tissue [gram and percent] and total lean body weight [gram]).
An assessment of each patient's physical activity was made with the aid of a visual analog scale and a standardized questionnaire about daily activities, including participation in sports (number of times per week) at the time of the DEXA scan. The visual analog scale (0 to 10) scored the children's participation in play and daily physical activities within the previous month (0 = none at all, 10 = very high level). In addition, each family was asked about the child's estimated daily consumption of dairy products (milk, cheese, etc.) and vitamin tablets.
The study was approved by the local ethics committee, and all families had given verbal and written informed consent to participation.
For comparison, DEXA scans were also performed on three children with asthma, who had been receiving a cow-milk-free diet for at least 2 yr without sufficient supplementary calcium intake at the time of the study. In addition, serial DEXA scans were performed in two children (one with nephrotic syndrome and one with allergic alveolitis) receiving continuous treatment with prednisolone during the study period. One of these patients also had a scan done 1 yr after stopping prednisolone.
DEXA scan data were analyzed using ANOVA with group, sex, and group-by-sex interaction as factors. Estimates obtained from the ANOVA were used in the group comparison. The relationship between the various data and accumulated dose of budesonide used the log of the accumulated dose as a covariate in a model with the factors sex and age as a covariate.
Prediction intervals were obtained through simple linear regression analysis for the independent variables height and age separately. All tests were two-sided, and p < 0.05 were considered statistically significant.
A total of 208 children from the prospective study fulfilled the inclusion criteria and none of the exclusion criteria: 157 in the budesonide group and 51 in the control group. The addition of 60 newly referred children to the control group increased the total in this group to 111 children. Patient characteristics are shown in Table 1. The two groups were comparable with respect to age, height, and weight. The proportion of boys was somewhat higher and the mean duration of asthma at the time of study initiation was longer in the budesonide group than in the control group. Children treated with budesonide had higher FEV1% predicted than did the children in the control group.
|Control Group (n = 111 )||Budesonide Group (n = 157 )|
|Age, yr||9.9 (5–16)||10.3 (5–16)|
|Height, cm||142.1 (107–177)||142.7 (104–182)|
|Weight, kg||37.4 (16–75)||38.1 (16–90)|
|Asthma duration, yr||4.5 (0.5–12)||8.3 (4–16)|
|FEV1, % pred||81 (60–97)||97 (76–106)|
|Tanner stage I, %||55.9||55.4|
|Tanner stage II, %||36.9||35.0|
|Tanner stage III, %||5.4||7.7|
|Tanner stage IV, %||1.8||1.9|
Eight percent of the children in the budesonide group used inhaled long-acting β2-agonists and 2% theophylline. In the control group, 15% used inhaled long-acting β2-agonists, 22% used theophylline, 20% used sodium cromoglycate, and 1% used oral β2-agonists. All children in both groups used inhaled short-acting β2-agonists as needed.
Mean compliance with inhaled budesonide was assessed to be 78% (range, 42 to 110%).
The mean total accumulated dose of budesonide for children in the budesonide group was 813.1 mg (range, 249 to 2,800 mg) and the mean treatment duration was 1,603 d (4.4 yr; range, 3 to 6 yr), giving a mean average daily dose of 504 μg (range, 189 to 1,322 μg).
BMD, BMC, and TBC values are given in Table 2. No statistically significant difference in any of these parameters was seen between the two groups or between boys and girls.
|Treatment Group||Factor||Group-by-Sex Interaction||Estimated Difference|
The individual measurements for BMD, BMC, and TBC were plotted against age and height (Figure 1) in order to compare the measured values in children treated with budesonide with those obtained from children in the control group. All three parameters varied significantly with age and height of the children. Few children in the budesonide group fell outside the 95% prediction interval calculated upon the basis of the measurements in the control group. The age- and height-dependent variation was nearly identical in budesonide-treated and control children so that the mean regression lines for the two groups yielding were virtually superimposed (Figure 1). The accumulated dose of budesonide also varied significantly with age, with older children having received higher accumulated doses of budesonide. However, no statistically significant influence of accumulated dose of budesonide was found on BMD (ANOVA; p = 0.97). The parameter estimates from the analysis suggested that doubling the accumulated dose would result in a BMD decrease of 0.0004 g/cm2. This figure should be related to an annual estimated increase in BMD of 0.029 g/cm2 in the control children in the study.
The measurements from the three children receiving a cow-milk-free diet, and the children who had received systemic steroids, are presented as individual values in Figure 1 for the sake of comparison. For the children receiving a cow-milk-free diet all measurements from the bone scans were below the 95% prediction interval. It was estimated that these children received 40 to 80% (mean, 62%) of the recommended daily calcium intake for children in their age groups. The first measurements from the prednisolone-treated children were within the 95% prediction interval, but they decreased during the treatment period. Apparent catch-up was seen in the bone scan of the child in whom treatment with prednisolone had been stopped for a year.
The lean body mass and percent body fat mass differed significantly between boys and girls, but not between the two groups of children, and no group-by-sex interaction was found (Table ). Lean body mass and percent fat also varied significantly with age and height of the children (Figure 2). As for the bone density parameters, few children in the budesonide group fell outside the 95% prediction interval calculated upon the basis of the values of the control group. The mean regression lines of the two groups were virtually superimposed (Figure 2).
There was no difference between the two groups in the number of times per week that the children participated in sports activities (1.46 [BUD] and 1.40 [control]). However, based upon the visual analog scale results, the children in the budesonide group were physically more active than the children in the control group (spent more hours outside playing, more frequently biked or walked to school, etc.). The mean scores in the two groups were 8.3 (BUD) and 5.7 (control) (p < 0.01).
Physical activity and participation in sports activities were found to increase with age, and the analysis suggested an association between increasing physical activity and increased bone mineral density. However, the interrelationship was very complex, and it was difficult to find a statistical model that closely fitted the data. Therefore, firm conclusions about the influence of physical activity upon BMD should be made with caution because of the complexity of the interrelationship.
There was no difference in daily consumption of dairy products and vitamin tablets between the two groups. The mean daily calcium intake from dairy products in the BUD group was 712 mg and in the control group it was 720 mg. None of the children participating in the study was receiving a cow-milk-free diet.
Peak bone density attained during childhood may be a critical determinant of risk of fracture in adulthood. For this reason it is important to fully understand the factors influencing peak bone mineral density in children. These include diet, physical activity, growth, and genetic predisposition (12-19). Some chronic diseases have also been reported to be associated with reduced peak bone mass in children (3, 20).
High doses of oral steroids have been shown to adversely affect bone mineral density in adults and in children (10, 12). However, when given to patients with severe disease such treatment may sometimes increase bone mineral density (22), probably because of changes in physical activity or diet and/or improvement in disease control. This makes prediction of the effects of exogenous steroids on the asthma disease difficult.
When designing the present study, we tried to anticipate some of the problems in interpreting the results obtained in the budesonide-treated children. Therefore, we included a control group of children with asthma who had not received continuous exogenous corticosteroids. This allowed a clinically more relevant comparison than a comparison with healthy children because children with chronic asthma often demonstrate a growth pattern different from that of healthy children (23– 26). Many asthmatic children experience a prepubertal growth retardation and delayed onset of puberty as compared with healthy control children (23-26). Therefore their Tanner stages would lag behind their chronologic age compared with healthy children. Because growth and puberty are very important for increase in bone mineral density (17, 18, 27) it is desirable to compare groups of children with similar growth patterns and pubertal development. In the present study, there was no statistically significant difference between the two groups in height, weight, or distribution of Tanner stages, indicating that we succeeded in controlling for these confounding factors. Further studies are required to assess how the findings in asthmatic children compare with healthy Danish children. Some studies have suggested that children with asthma may differ from normal healthy children with respect to plasma levels of osteocalcin (3).
It would have been desirable to have electronic monitoring of compliance to accurately assess the actual dose taken. That was not possible, mainly because we could not get a Turbuhaler with an electronic recording of the number of doses taken. Therefore, we had to monitor compliance in a less accurate way. However, during a 1-yr period we were able to electronically monitor the actual number of doses taken in some of the patients. These measures were in reasonably good agreement with our other recordings (the mean compliance was the same). This suggests that our compliance estimate was fairly accurate. This assumption is indirectly supported by the excellent clinical results seen in the budesonide group (1).
We tried to make the study as sensitive as possible by having all DEXA scans and analyses performed by the same person, who was blinded to the treatment. Furthermore, we included only children who had been receiving budesonide for a long time in a controlled prospective study so that we could make an accurate estimate of the total accumulated dose of budesonide after several years of treatment. Finally, we studied only children who had received systemic steroids < 15 d ever. These precautions were taken to facilitate the analysis and the interpretation of the results, which may otherwise have become very complex. A recent study in adults found an apparent beneficial effect of high accumulated doses of inhaled corticosteroids on BMD, probably because of the oral steroid sparing effect of high doses (10).
The total body BMD of the children in our study treated for 3 to 6 yr with continuous inhaled budesonide at an average daily dose of around 500 μg was not different from the BMD of the control group. These findings corroborate those reported in previously published cross-sectional studies of much smaller groups of children treated for shorter periods of time with inhaled steroids (3, 28-30). Moreover, two longitudinal studies assessing the development of bone mineral density over a period of 6 mo in 14 children (31) and 1 yr in 21 children (32) found normal growth of BMD during treatment with inhaled corticosteroids. Although these studies may have been underpowered, the results support the findings of the present study: long-term treatment with budesonide is unlikely to adversely affect total bone mineral density in children with chronic asthma when the dose is regularly tailored to the severity of the disease.
The various inhaled corticosteroids may differ with respect to systemic activity (2, 33) and hence the risk of systemic side effects. Thus recent studies have reported growth retardation in children treated with inhaled beclomethasone propionate at a daily dose of 400 μg (33). This has not been reported with budesonide (1, 34). Therefore, the observations in the present study may not be extrapolated to other inhaled corticosteroids.
The budesonide group differed from the control group with respect to duration of asthma at the time of study and to the proportion of boys and girls. Gender was not found to influence bone mineral density, in agreement with the findings of others (15, 17). So, the small difference in boy/girl ratio between the two groups is unlikely to have influenced the results. Moreover, even when the influence of sex was taken into account in the statistical assessment, there still was no trend toward an adverse effect of the inhaled corticosteroid treatment on any of the outcome parameters studied.
The extent to which duration of asthma affects bone mineral density is unknown. It is most unlikely that the longer duration of asthma seen in the budesonide group would have increased the bone mineral density in this group, thereby balancing any possible negative effect of budesonide on bone mineral density. On the contrary, the long duration of disease could conceivably have had an adverse effect on BMD. We therefore do not believe that the difference in asthma duration at the study onset could account for the lack of difference in bone mineral density between the two groups. Although no direct comparison was possible, the children in the budesonide group probably had more severe disease than the children in the control group. As for the duration of asthma it is most unlikely that a more severe disease should be associated with a higher BMD and thereby mask a possible negative effect of the budesonide on BMD.
Because our study did not detect a difference between the two groups, it is important to consider the sensitivity of the methods used and their ability to detect the influence of other conditions reported to affect bone mineral density. In this respect the measurements of the children receiving a cow-milk-free diet with insufficient dietary calcium supplement and those of the children treated with oral steroids indicate that the methods used were sensitive enough to detect adverse effects of such regimens. Our findings suggest, then, that a mean of 4.5 yr of treatment with inhaled budesonide had less effect on bone mineral density and the other measured bone parameters than either an insufficient diet or the use or oral steroids.
The apparent accelerated increase in BMD seen in the child who stopped prednisolone supports previous findings that indicate that steroid-induced osteoporosis can be reverted in young patients when treatment with exogenous steroids is stopped (35).
To the best of our knowledge, the influence of inhaled steroids on body composition has not previously been studied in children. Oral steroids are known to reduce muscle mass (lean body mass) and increase the amount of fat tissue. In the present study, no statistically significant difference in body composition between the two groups was seen. Indeed there seemed to be a trend toward a higher lean body mass and a lower percent of body fat with increasing age in the budesonide group as compared with the control children. This finding is the opposite of what one would expect to find from studies of children treated with systemic steroids. For this reason it is most unlikely that this trend was due to an adverse systemic effect caused by the budesonide treatment. A much more plausible explanation for this finding would be the higher level of physical activity recorded by the older children. This increased level of physical activity seemed to be more marked in the children who were treated with budesonide, probably because their asthma was better controlled.
The results of our study are in agreement with the results of studies of markers of bone formation and bone degradation, which suggest that only high daily doses of inhaled steroids (equivalent to 800 μg budesonide) have a detectable effect on these markers in children (3-6). Measures of markers of bone formation and degradation have always been done in short-term studies on patients with quite mild disease; these conditions are very different from those detailed in the present study.
Elective measurements of bone mineral density at sites with mainly trabecular bone such as the L2-L4 lumbar spine or the femoral neck, may be more sensitive in detecting adverse effects of exogenous corticosteroids in adults. However, a reduction in total bone mineral density has also been found to be a good predictor of risk of fracture; many studies find it to have a predictive value similar to that of bone mineral density measurements at other sites (7-9). As mentioned earlier, the total body scan was also sensitive enough to detect effects of diet and oral steroids.
The similar heights between the two groups of children agrees with findings of previous prospective studies, suggesting that long-term treatment with budesonide does not adversely affect statural growth when the dose is tailored to the severity of the disease (1, 34).
In conclusion, a mean of 4.5 yr of treatment with inhaled budesonide at an average daily dose of 504 μg has no detectable adverse effect on total bone mineral density, total bone mineral capacity, total bone calcium, or body composition in children with chronic asthma when the dose is tailored to the severity of the disease.
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