Pediatric Pulmonology
Inhaled Corticosteroids and Bone Mineral Density at School Age: A Follow-up Study After Early Childhood Wheezing Virpi H. Sidoroff, MD,1,2* Mari K. Ylinen, MD, PhD,3 Liisa M. Kro¨ger, MD, PhD,3 Heikki P.J. Kro¨ger, MD, PhD,4 and Matti O. Korppi, MD, PhD1,5 Summary. Objective: The aim of the study was to evaluate the association between previous use of ICS and bone mineral density (BMD) at school age in a cohort followed after early childhood wheezing. Methods: As part of a prospective follow-up study after hospitalization for wheezing at 6 months at age 2.0 SD. Fifteen (23.1%) boys and 9 (37.5%) girls were at puberty (M/G3-5). In the lumbar spine, BMDareal and aBMDvol were lower in boys than in girls and lower in prepubertal than in pubertal children (Table 1). In the femoral neck, BMDareal was lower in pre-pubertal children than in pubertal children (Table 1). There were no statistically significant differences between the BMD of obese, overweight and normal weight (BMI-SDS < 1.3) children (data not shown). The mean cumulative dose of systemic corticosteroids during the follow-up period was 161 mg. Systemic corticosteroids were analysed as continuous and categorized parameters (at the 10th, 50th, and 90th percentiles) and had no significant association with BMD (data not shown). The mean cumulative dose of ICS expressed as budesonide equivalents during the whole follow-up period was 517 mg (SD 424, range 31–1,813) in those 68 children who have received ICS medication. Twenty one of the children did not receive any ICS medication during the follow-up. There was a significant association between increasing cumulative ICS dose and decreasing BMDareal (adjusted P ¼ 0.000) and decreasing aBMDvol (adjusted P ¼ 0.006) in the femoral neck. However, the correlation was weak: for BMDareal r ¼ 0.32, r2 ¼ 0.10,
TABLE 1— The Association Between Bone Mineral Density, Gender and Pubertal Stage at the Median Age of 12.3 Years in 89 Children After Early Childhood Wheezing Gender
Bone mineral density (mean, 95% CI)3 BMDareal1 Lumbar spine L2–4 Femoral neck aBMDvol2 Lumbar spine L2–4 Femoral neck
Pubertal stage
Female, N ¼ 24
Male, N ¼ 65
Pre- and early pubertal4, N ¼ 63
Pubertal,4 N ¼ 24
0.95 (0.88–1.02) 0.91 (0.84–0.98)
0.83 (0.80–0.85) 0.91 (0.89–0.94)
0.82 (0.80–0.85) 0.88 (0.86–0.91)
0.97 (0.91–1.03) 1.00 (0.95–1.06)
0.33 (0.31–0.35) 0.41 (0.39–0.44)
0.29 (0.28–0.30) 0.39 (0.38–0.41)
0.29 (0.28–0.30) 0.40 (0.38–0.41)
0.32 (0.30–0.34) 0.42 (0.39–0.44)
1
Areal BMD (g/cm2) measured by dual energy X-ray absorptiometry (DXA). Apparent volumetric BMD(g/cm3) calculated from DXA measurements. 3 95% Confidence interval. 4 Tanner stage M1–2 and G1–2 as pre- and early pubertal, M3–5 and G3–5 pubertal. Two independent samples t-test P < 0.05, between males and females or pre-/early pubertal and pubertal children. 2
Pediatric Pulmonology
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and for aBMDvol r ¼ 0.28, r2 ¼ 0.08 (Fig. 1A and B). There was no association between the cumulative ICS dose and BMD in the lumbar spine (Fig. 2A and B). Both BMDareal and aBMDvol in lumbar spine were significantly lower in the 12 children who had used regular ICS medication only at 6 months before 6 years of age. The results were robust to adjustments for known confounding factors, such as age, gender, pubertal stage, height and weight status, and the use of systemic corticosteroids. However, no definitive conclusions can be drawn regarding the clinical impact of the findings. On the other hand, the clinical complications associated with decreased BMD in childhood may not arise until adulthood.
Inhaled Steroids and Bone Density
5
2
TABLE 2— Bone Mineral Density at the Median Age of 12.3 Years in Children Who Had Regularily Used Inhaled Corticosteroids (ICS) Before School Age and at School Age, Compared to Children Who Had Never Used ICSs BMDareal1 (mean, 95% CI)3 Regular use of ICS during childhood4
Lumbar spine L2–4
Only at 0–6 years of age N ¼ 12 0.81 (0.74–0.90) Only at 6–12.3 years of age N ¼ 12 0.88 (0.77–0.99) No ICS use during the 12.3 years follow-up N ¼ 21 0.85 (0.82–0.93)
aBMDvol1 (mean, 95% CI)3
P-value4
Femoral neck
P-value4
Lumbar spine L2–4
P-value4
Femoral neck
P-value4
0.010
0.91 (0.83–1.00)
0.059
0.27 (0.25–0.30)
0.006
0.38 (0.36–0.40)
0.031
0.514
0.96 (0.86–1.05)
0.784
0.31 (0.28–0.35)
0.454
0.42 (0.38–0.46)
0.886
0.94 (0.90–0.98)
0.30 (0.28–0.31)
0.41 (0.39–0.44)
1
BMD measured by dual energy X-ray absorptiometry (DXA), apparent volumetric BMD calculated. Regular use; over 6 months use of ICS during the 6-year age period. 3 95% Confidence interval. 4 The analysis of variance adjusted for the cumulative dose of systemic corticosteroids (mg) classified with cut-off points at the 10th, 50th, and 90th percentiles), gender, pubertal stage (Tanner stage M1–2 and G1–2 as pre- and early pubertal, M3–5 and G3–5 pubertal), age and weight as BMI-SDS (normal, overweight, obesity). Height (cm) was included in the model for analysis of areal BMD. 2
Preliminary evidence indicated that the critical age for the emergence of reduced BMD may be between 0 and 6 years, seen more prominently in the lumbar spine. The lumbar spine consists mainly of trabecular bone that has a rapid turnover, and the femoral neck consists mainly of cortical bone that has a slower turnover; in addition, trabecular bone is more susceptible to hormonal and metabolic effects.25 Most previous studies of children have focused on the lumbar spine or whole body BMD, thus mainly reflecting the effects on trabecular bone.3,9,12 Earlier long-term studies have not revealed any significant differences in areal BMD between children treated and not treated with ICS.3,9,12 In the CAMP study, 1,041 children aged 5–12 years with mild to moderate asthma were randomized to receive budesonide 200 mg, nedocromil or a placebo twice a day.12 Lumbar spine BMD was measured recurrently with DXA, and annual bone mineral accretion was calculated. The use of ICS had no detrimental effect on the mineral accretion in girls during a follow-up of 4–7 years. However, the cumulative ICS dose was associated with decreased bone mineral accretion in boys.12 Oral corticosteroids were allowed when necessary and produced a dose-dependent reduction in bone mineral accretion in boys but not in girls.12 In a Danish study, 157 asthmatic children with and 111 without ICS were monitored for 3–6 years. Total body BMD was measured by DXA, and no significant differences were observed in BMD, bone mineral content, or total body calcium between the groups.9 In a French study, 174 children aged 6–14 years with persistent asthma were randomized to receive or not to receive inhaled fluticasone propionate.3 BMD was measured by DXA in the lumbar spine and femoral neck at baseline and
at 12 and 24 months later, and no significant differences were found between the groups.3 However, ICS therapy with an average daily dose of 670 mg for 9–20 months reduced BMD in pre-pubertal children compared to controls in an Australian study,11 suggesting a potentially harmful role for regular treatment with high ICS doses. Unfortunately, long-term follow-up results were not available. The results are in line with the observations of the present long-term study that high cumulative ICS doses were associated with reduced BMD. In the randomized, controlled, double-blind study from Helsinki, Finland, including 136 children aged 5–10 years with recently diagnosed asthma,28 the intervention was budesonide 200 mg daily for 18 months or budesonide 200 mg daily as required or disodium cromoglycate daily for 18 months. Areal BMD in the lumbar spine was measured by DXA before and after intervention. Daily treatment with budesonide, but not treatment on-demand, reduced both BMD and height growth velocity when compared with the group treated with daily disodium cromoglycate. However, the findings were not robust to adjustment for height. The authors concluded that changes in BMD interact with changes in height, which means that monitoring children’s heights gives an approximation of the effects of ICS on bone.28 The most recent crosssectional study including retrospective follow-up time did not find a difference in lumbar BMD in pre-pubertal children using intermitted fluticasone with 200 mg mean daily dose for 5 years compared with newly diagnosed asthmatic children with no history of ICS medication.29 Due to the long follow-up time, the median cumulative ICS dose in the present study was higher than in two previous French and Finnish studies.3,28 In the CAMP Pediatric Pulmonology
6
Sidoroff et al.
study, Danish study and recent Turkish study the ICS dose was higher than the median dose of this study.9,12,29 The high accrual dose up to 1,800 mg of ICS and long followup time might be the reason for positive results in the present study compared with other studies. In the early years of the study, used ICS doses were higher than the doses currently recommended for childhood asthma, which might have influenced the results concerning ICS use before school age. DXA scanners, as used in the present and previous studies, measure areal BMD (in g/cm2), and thus the size of the bone influences the BMD values obtained; smaller bones have a lower areal BMD than larger ones. Calculated volumetric BMD values are similar in large and small bones.30 The interaction between height and BMD requires special attention in long-term follow-up studies, since measured areal BMD increases with the growth of the bones without any actual increase in BMD.25 The calculation of volumetric BMD values has been used to counteract this artificial increase in areal BMD values. In the present study, aBMDvol confirmed the changes in femoral neck associated with ICS-use in early childhood. The main strengths of the present study are the long prospective follow-up time from infancy to school age and a high participation rate. Though data on the use of ICS were collected retrospectively, they were recorded relatively accurately, due to participation in the prospective follow-up study. Age, gender and pubertal stage were significant confounding factors, and the analyses were adjusted for all of them and additionally for systemic corticosteroids. However, bone age was not studied by radiology, and since the Tanner classification is not sufficiently exact in the estimation of pubertal stage in growth studies, we were not able to evaluate the effects of ICS on growth in height. In addition, physical activities and diets were not systematically recorded, which is a clear shortcoming of the study. In conclusion, the use of ICS during childhood may reduce the BMD measured at late school age. High cumulative doses during childhood were associated with changes in the femoral neck. There might be a critical period for changes in the BMD, and this critical period seems to be before 6 years of age. These preliminary results emphasize the importance of using the lowest possible ICS dose that maintains adequate asthma control. ACKNOWLEDGMENTS
Kuopio University Hospital, Kuopio, and NorthKarelia Central Hospital, Joensuu, Finland, The National Graduation School of Clinical Investigations and Tampere Tuberculosis Foundation are acknowledged for financial support. Pediatric Pulmonology
REFERENCES 1. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol 2005;115:897, 909; quiz 910. 2. Wennergren G. The prevalence of asthma has reached a plateau. Acta Paediatr 2011;100:938–939. 3. Roux C, Kolta S, Desfougeres JL, Minini P, Bidat E. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma. Pediatrics 2003;111: e706–e713. 4. Castro-Rodriguez JA, Rodrigo GJ. The role of inhaled corticosteroids and montelukast in children with mild-moderate asthma: results of a systematic review with meta-analysis. Arch Dis Child 2010;95:365–370. 5. Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ. Inhaled corticosteroids: past lessons and future issues. J Allergy Clin Immunol 2003;112:S1–S40. 6. Leone FT, Fish JE, Szefler SJ, West SL. Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: Collaboration of American college of chest physicians, American academy of allergy, asthma, and immunology, and American college of allergy, asthma, and immunology. Chest 2003;124:2329–2340. 7. Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904–912. 8. Martinati LC, Bertoldo F, Gasperi E, Micelli S, Boner AL. Effect on cortical and trabecular bone mass of different anti-inflammatory treatments in preadolescent children with chronic asthma. Am J Respir Crit Care Med 1996;153:232–236. 9. Agertoft L, Pedersen S. Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide. Am J Respir Crit Care Med 1998;157:178–183. 10. Allen DB. Inhaled steroids for children: effects on growth, bone, and adrenal function. Endocrinol Metab Clin North Am 2005;34: 555–564. 11. Allen HD, Thong IG, Clifton-Bligh P, Holmes S, Nery L, Wilson KB. Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma. Pediatr Pulmonol 2000;29:188–193. 12. Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green P, Strunk RC, CAMP Research Group. Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood asthma management program (CAMP) study. Pediatrics 2008;122:53–61. 13. Leonard MB, Elmi A, Mostoufi-Moab S, Shults J, Burnham JM, Thayu M, Kibe L, Wetzsteon RJ, Zemel BS. Effects of sex, race, and puberty on cortical bone and the functional muscle bone unit in children, adolescents, and young adults. J Clin Endocrinol Metab 2010;95:1681–1689. 14. Zemel BS, Leonard MB, Kelly A, Lappe JM, Gilsanz V, Oberfield S, et al. Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J Clin Endocrinol Metab 2010;95:1265–1273. 15. Rocher E, Chappard C, Jaffre C, Benhamou CL, Courteix D. Bone mineral density in prepubertal obese and control children: relation to body weight, lean mass, and fat mass. J Bone Miner Metab 2008;26:73–78. 16. Reijonen T, Korppi M, Kuikka L, Remes K. Anti-inflammatory therapy reduces wheezing after bronchiolitis. Arch Pediatr Adolesc Med 1996;150:512–517. 17. Kotaniemi-Syrjanen A, Reijonen TM, Korhonen K, Korppi M. Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up. Pediatr Allergy Immunol 2002;13:418–425.
Inhaled Steroids and Bone Density 18. Hyvarinen MK, Kotaniemi-Syrjanen A, Reijonen TM, Korhonen K, Korppi MO. Teenage asthma after severe early childhood wheezing: an 11-year prospective follow-up. Pediatr Pulmonol 2005;40:316–323. 19. Northwest institute for bio-health informatics. Child obesity calculator using British 1990 growth reference data [homepage on the Internet]. 20. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 2000;320:1240–1243. 21. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23. 22. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303. 23. Kroger H, Kotaniemi A, Kroger L, Alhava E. Development of bone mass and bone density of the spine and femoral neck—a prospective study of 65 children and adolescents. Bone Miner 1993;23:171–182. 24. Kroger H, Kotaniemi A, Vainio P, Alhava E. Bone densitometry of the spine and femur in children by dual-energy x-ray absorptiometry. Bone Miner 1992;17:75–85.
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25. Bianchi ML. Osteoporosis in children and adolescents. Bone 2007;41:486–495. 26. Kelly TL, Wilson KE, Heymsfield SB. Dual energy X-ray absorptiometry body composition reference values from NHANES. PLoS ONE 2009;4:e7038. 27. Griffiths AL, Sim D, Strauss B, Rodda C, Armstrong D, Freezer N. Effect of high-dose fluticasone propionate on bone density and metabolism in children with asthma. Pediatr Pulmonol 2004;37: 116–121. 28. Turpeinen M, Pelkonen AS, Nikander K, Sorva R, Selroos O, Juntunen-Backman K, Haahtela T. Bone mineral density in children treated with daily or periodical inhaled budesonide: the Helsinki early intervention childhood asthma study. Pediatr Res 2010;68:169–173. 29. Ozkaya E, Nursoy MA, Uzuner S, Erenberk U, Cakir E. Osteocalcin, cortisol levels, and bone mineral density in prepubertal children with asthma treated with long-term fluticasone propionate. Horm Res Paediatr 2012;77:351–357. 30. Binkovitz LA, Henwood MJ, Pediatric DXA. Technique and interpretation. Pediatr Radiol 2007;37:21–31.
Pediatric Pulmonology
Inhaled Corticosteroids and Bone Mineral Density at School Age: A Follow-up Study After Early Childhood Wheezing Virpi H. Sidoroff, MD,1,2* Mari K. Ylinen, MD, PhD,3 Liisa M. Kro¨ger, MD, PhD,3 Heikki P.J. Kro¨ger, MD, PhD,4 and Matti O. Korppi, MD, PhD1,5 Summary. Objective: The aim of the study was to evaluate the association between previous use of ICS and bone mineral density (BMD) at school age in a cohort followed after early childhood wheezing. Methods: As part of a prospective follow-up study after hospitalization for wheezing at 6 months at age 2.0 SD. Fifteen (23.1%) boys and 9 (37.5%) girls were at puberty (M/G3-5). In the lumbar spine, BMDareal and aBMDvol were lower in boys than in girls and lower in prepubertal than in pubertal children (Table 1). In the femoral neck, BMDareal was lower in pre-pubertal children than in pubertal children (Table 1). There were no statistically significant differences between the BMD of obese, overweight and normal weight (BMI-SDS < 1.3) children (data not shown). The mean cumulative dose of systemic corticosteroids during the follow-up period was 161 mg. Systemic corticosteroids were analysed as continuous and categorized parameters (at the 10th, 50th, and 90th percentiles) and had no significant association with BMD (data not shown). The mean cumulative dose of ICS expressed as budesonide equivalents during the whole follow-up period was 517 mg (SD 424, range 31–1,813) in those 68 children who have received ICS medication. Twenty one of the children did not receive any ICS medication during the follow-up. There was a significant association between increasing cumulative ICS dose and decreasing BMDareal (adjusted P ¼ 0.000) and decreasing aBMDvol (adjusted P ¼ 0.006) in the femoral neck. However, the correlation was weak: for BMDareal r ¼ 0.32, r2 ¼ 0.10,
TABLE 1— The Association Between Bone Mineral Density, Gender and Pubertal Stage at the Median Age of 12.3 Years in 89 Children After Early Childhood Wheezing Gender
Bone mineral density (mean, 95% CI)3 BMDareal1 Lumbar spine L2–4 Femoral neck aBMDvol2 Lumbar spine L2–4 Femoral neck
Pubertal stage
Female, N ¼ 24
Male, N ¼ 65
Pre- and early pubertal4, N ¼ 63
Pubertal,4 N ¼ 24
0.95 (0.88–1.02) 0.91 (0.84–0.98)
0.83 (0.80–0.85) 0.91 (0.89–0.94)
0.82 (0.80–0.85) 0.88 (0.86–0.91)
0.97 (0.91–1.03) 1.00 (0.95–1.06)
0.33 (0.31–0.35) 0.41 (0.39–0.44)
0.29 (0.28–0.30) 0.39 (0.38–0.41)
0.29 (0.28–0.30) 0.40 (0.38–0.41)
0.32 (0.30–0.34) 0.42 (0.39–0.44)
1
Areal BMD (g/cm2) measured by dual energy X-ray absorptiometry (DXA). Apparent volumetric BMD(g/cm3) calculated from DXA measurements. 3 95% Confidence interval. 4 Tanner stage M1–2 and G1–2 as pre- and early pubertal, M3–5 and G3–5 pubertal. Two independent samples t-test P < 0.05, between males and females or pre-/early pubertal and pubertal children. 2
Pediatric Pulmonology
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Sidoroff et al.
and for aBMDvol r ¼ 0.28, r2 ¼ 0.08 (Fig. 1A and B). There was no association between the cumulative ICS dose and BMD in the lumbar spine (Fig. 2A and B). Both BMDareal and aBMDvol in lumbar spine were significantly lower in the 12 children who had used regular ICS medication only at 6 months before 6 years of age. The results were robust to adjustments for known confounding factors, such as age, gender, pubertal stage, height and weight status, and the use of systemic corticosteroids. However, no definitive conclusions can be drawn regarding the clinical impact of the findings. On the other hand, the clinical complications associated with decreased BMD in childhood may not arise until adulthood.
Inhaled Steroids and Bone Density
5
2
TABLE 2— Bone Mineral Density at the Median Age of 12.3 Years in Children Who Had Regularily Used Inhaled Corticosteroids (ICS) Before School Age and at School Age, Compared to Children Who Had Never Used ICSs BMDareal1 (mean, 95% CI)3 Regular use of ICS during childhood4
Lumbar spine L2–4
Only at 0–6 years of age N ¼ 12 0.81 (0.74–0.90) Only at 6–12.3 years of age N ¼ 12 0.88 (0.77–0.99) No ICS use during the 12.3 years follow-up N ¼ 21 0.85 (0.82–0.93)
aBMDvol1 (mean, 95% CI)3
P-value4
Femoral neck
P-value4
Lumbar spine L2–4
P-value4
Femoral neck
P-value4
0.010
0.91 (0.83–1.00)
0.059
0.27 (0.25–0.30)
0.006
0.38 (0.36–0.40)
0.031
0.514
0.96 (0.86–1.05)
0.784
0.31 (0.28–0.35)
0.454
0.42 (0.38–0.46)
0.886
0.94 (0.90–0.98)
0.30 (0.28–0.31)
0.41 (0.39–0.44)
1
BMD measured by dual energy X-ray absorptiometry (DXA), apparent volumetric BMD calculated. Regular use; over 6 months use of ICS during the 6-year age period. 3 95% Confidence interval. 4 The analysis of variance adjusted for the cumulative dose of systemic corticosteroids (mg) classified with cut-off points at the 10th, 50th, and 90th percentiles), gender, pubertal stage (Tanner stage M1–2 and G1–2 as pre- and early pubertal, M3–5 and G3–5 pubertal), age and weight as BMI-SDS (normal, overweight, obesity). Height (cm) was included in the model for analysis of areal BMD. 2
Preliminary evidence indicated that the critical age for the emergence of reduced BMD may be between 0 and 6 years, seen more prominently in the lumbar spine. The lumbar spine consists mainly of trabecular bone that has a rapid turnover, and the femoral neck consists mainly of cortical bone that has a slower turnover; in addition, trabecular bone is more susceptible to hormonal and metabolic effects.25 Most previous studies of children have focused on the lumbar spine or whole body BMD, thus mainly reflecting the effects on trabecular bone.3,9,12 Earlier long-term studies have not revealed any significant differences in areal BMD between children treated and not treated with ICS.3,9,12 In the CAMP study, 1,041 children aged 5–12 years with mild to moderate asthma were randomized to receive budesonide 200 mg, nedocromil or a placebo twice a day.12 Lumbar spine BMD was measured recurrently with DXA, and annual bone mineral accretion was calculated. The use of ICS had no detrimental effect on the mineral accretion in girls during a follow-up of 4–7 years. However, the cumulative ICS dose was associated with decreased bone mineral accretion in boys.12 Oral corticosteroids were allowed when necessary and produced a dose-dependent reduction in bone mineral accretion in boys but not in girls.12 In a Danish study, 157 asthmatic children with and 111 without ICS were monitored for 3–6 years. Total body BMD was measured by DXA, and no significant differences were observed in BMD, bone mineral content, or total body calcium between the groups.9 In a French study, 174 children aged 6–14 years with persistent asthma were randomized to receive or not to receive inhaled fluticasone propionate.3 BMD was measured by DXA in the lumbar spine and femoral neck at baseline and
at 12 and 24 months later, and no significant differences were found between the groups.3 However, ICS therapy with an average daily dose of 670 mg for 9–20 months reduced BMD in pre-pubertal children compared to controls in an Australian study,11 suggesting a potentially harmful role for regular treatment with high ICS doses. Unfortunately, long-term follow-up results were not available. The results are in line with the observations of the present long-term study that high cumulative ICS doses were associated with reduced BMD. In the randomized, controlled, double-blind study from Helsinki, Finland, including 136 children aged 5–10 years with recently diagnosed asthma,28 the intervention was budesonide 200 mg daily for 18 months or budesonide 200 mg daily as required or disodium cromoglycate daily for 18 months. Areal BMD in the lumbar spine was measured by DXA before and after intervention. Daily treatment with budesonide, but not treatment on-demand, reduced both BMD and height growth velocity when compared with the group treated with daily disodium cromoglycate. However, the findings were not robust to adjustment for height. The authors concluded that changes in BMD interact with changes in height, which means that monitoring children’s heights gives an approximation of the effects of ICS on bone.28 The most recent crosssectional study including retrospective follow-up time did not find a difference in lumbar BMD in pre-pubertal children using intermitted fluticasone with 200 mg mean daily dose for 5 years compared with newly diagnosed asthmatic children with no history of ICS medication.29 Due to the long follow-up time, the median cumulative ICS dose in the present study was higher than in two previous French and Finnish studies.3,28 In the CAMP Pediatric Pulmonology
6
Sidoroff et al.
study, Danish study and recent Turkish study the ICS dose was higher than the median dose of this study.9,12,29 The high accrual dose up to 1,800 mg of ICS and long followup time might be the reason for positive results in the present study compared with other studies. In the early years of the study, used ICS doses were higher than the doses currently recommended for childhood asthma, which might have influenced the results concerning ICS use before school age. DXA scanners, as used in the present and previous studies, measure areal BMD (in g/cm2), and thus the size of the bone influences the BMD values obtained; smaller bones have a lower areal BMD than larger ones. Calculated volumetric BMD values are similar in large and small bones.30 The interaction between height and BMD requires special attention in long-term follow-up studies, since measured areal BMD increases with the growth of the bones without any actual increase in BMD.25 The calculation of volumetric BMD values has been used to counteract this artificial increase in areal BMD values. In the present study, aBMDvol confirmed the changes in femoral neck associated with ICS-use in early childhood. The main strengths of the present study are the long prospective follow-up time from infancy to school age and a high participation rate. Though data on the use of ICS were collected retrospectively, they were recorded relatively accurately, due to participation in the prospective follow-up study. Age, gender and pubertal stage were significant confounding factors, and the analyses were adjusted for all of them and additionally for systemic corticosteroids. However, bone age was not studied by radiology, and since the Tanner classification is not sufficiently exact in the estimation of pubertal stage in growth studies, we were not able to evaluate the effects of ICS on growth in height. In addition, physical activities and diets were not systematically recorded, which is a clear shortcoming of the study. In conclusion, the use of ICS during childhood may reduce the BMD measured at late school age. High cumulative doses during childhood were associated with changes in the femoral neck. There might be a critical period for changes in the BMD, and this critical period seems to be before 6 years of age. These preliminary results emphasize the importance of using the lowest possible ICS dose that maintains adequate asthma control. ACKNOWLEDGMENTS
Kuopio University Hospital, Kuopio, and NorthKarelia Central Hospital, Joensuu, Finland, The National Graduation School of Clinical Investigations and Tampere Tuberculosis Foundation are acknowledged for financial support. Pediatric Pulmonology
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