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Journal of Clinical Densitometry, vol. 9, no. 2, 154–158, 2006 Ó Copyright 2006 by The International Society for Clinical Densitometry 1094-6950/06/9:154–158/$32.00 DOI: 10.1016/j.jocd.2005.11.005 Original Article Inhaled Steroids Do Not Decrease Bone Mineral Density But Increase Risk of Fractures: Data from the GIUMO Study Group M. Sosa,* P. Saavedra, C. Valero, N. Guañabens, X. Nogue´s, J. del Pino-Montes, J. Mosquera, J. Alegre, C. Gómez-Alonso, M. Muñoz-Torres, M. Quesada, R. Pe´rez-Cano, E. Jódar, A. Torrijos, C. Lozano-Tonkin, M. Dı´az-Curiel, and the GIUMO Study Groupy Canary Islands, Spain Abstract Although the negative effect of systemic steroids on bone is well documented, there is not clear evidence about possible adverse effects of inhaled steroids on bone metabolism and fractures. A cross-sectional study was performed on 105 women suffering from bronchial asthma treated with inhaled steroids and 133 controls. Bone mineral density (BMD) was measured by quantitative ultrasonography (QUS) at the calcaneus and by dual X-ray absorptiometry (DXA), at both the lumbar spine and proximal femur. Patients suffering from bronchial asthma showed no statistically significant changes in BMD as measured by DXA or QUS, compared with controls. A higher prevalence of fractures was found in the group of women with bronchial asthma, with an age-adjusted odds ratio of 2.79 (95% CI: 1.1926.54). Inhaled steroids do not appear to decrease BMD, but are associated with an increased risk of fracture in women. Key Words: Asthma; bone mineral density; fractures; inhaled steroids; quantitative ultrasonography; women. can control asthma but does not cure the disease, long-term use of ICS is often required (2,3). However, the effects of long-term use of ICS on bone metabolism, and the associated risk of osteoporosis, remain controversial. The deleterious effect of systemic steroids on patients suffering from asthma has been described previously (4), but no consistent association has been found between inhaled corticosteroids use and bone loss (5–8). Moreover, it is unclear to what extent inhaled corticosteroids cause clinical fractures (9,10). The lack of definitive conclusions about the possible negative effect of ICSs on bone metabolism of patients suffering for asthma relates to several methodological problems, including small sample sizes, referral bias, short follow-up or confounding by previous or intermittent use of systemic corticosteroids. Also, few studies have used quantitative ultrasonography systems (QUS) to assess bone status. The aim of the present study was to assess the prevalence of fractures and bone density by QUS and Introduction Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma, and are currently considered the first-line therapy for persistent disease, as suggested by international treatment consensuses (1,2). Because ICS treatment Received: 07/22/05; Revised: 10/25/05; Accepted: 11/27/05. *Address correspondence to: Manuel Sosa, University of Las Palmas de Gran Canaria, Hospital University Insular, Bone Metabolic Unit, Apartado 550, 35080 Las Palmas de Gran Canaria, Canary Islands, Spain. E-mail: [email protected] yOther members of the GIUMO Group: J. González-Macı́as, J. M. Olmos, A. Dı́ez, L. Corral, A. Castro, B. Alvarez, J. Cannata, A. Rodrı́guez, M. Rodrı́guez, G. Alonso, P. Mezquita, M. A. Lara, B. Garcı́a, M. J. Gómez de Tejada, R. Pérez Temprano, F. Hawkins, G. Martı́nez Dı́az-Guerra, C. Villasante, E. Hernández, D. Hernández, and J. Sarmiento. 154 Inhaled Steroids and Bone Mineral Density 155 DXA in Caucasian European (Spanish) women on chronic ICS therapy because of asthma. a record existed for each patient, with the exception of childhood fractures, which were excluded. Methods Statistical Analysis Patients Patients included women who were suffering from stable bronchial asthma and were treated with ICS for at least 1 yr, with a median of 10 yr, and who did not receive oral or parenteral steroids. The control group was composed by women of similar weight who did not suffer from bronchial asthma and did not receive steroids in any form. They were usually friends or neighbors of the patients and came along with them to the study. All participants were informed about the aims of the study and gave written consent. The study was approved by the Ethics Committee of the Hospital University Insular. Physical Examination A complete physical examination was performed. Height and weight were measured to obtain body mass index (BMI; calculated as weight [kg]/height [m]2) of each subject. Height was measured without shoes, and weight with light clothes was estimated on a balance scale. Postmenopausal women were defined as those who had their last menstrual period at least 1 yr before, in accordance with the clinical definition of the World Health Organization (11). Measurements QUS All subjects had calcaneus’s QUS measurement. These were performed using the Sahara clinical sonometer (Hologic, Bedford, MA). The system consists of two unfocused transducers mounted coaxially on a monitor calliper. One transducer acts as the transmitter and the other as a receiver. The transducers are acoustically coupled to the heel using soft rubber pads and an oil-based coupling gel. The Sahara device measures both broadband ultrasound attenuation (BUA) and speed of sound (SOS) at a fixed region of interest in the mid-calcaneus. The BUA and SOS results are combined to provide the quantitative ultrasound index (QUI) using the formula: QUI 5 0:41 ðBUA 1 SOSÞ2571. DXA Bone mineral density of the lumbar spine and the proximal femur was measured by DXA (Hologic QDR-1000, Bedford, MA) at the lumbar spine (L2–L4) and the femoral neck of all patients. Precision of the techniques and reference values in the Spanish population have been published elsewhere (12,13). Fractures were recorded from written reports from radiologists, emergency reports, and X-rays provided by the patients, and after examining their medical records. In both patients and controls, fractures were recorded only if properly documented and occurred with a minor trauma, as long as Journal of Clinical Densitometry For asthma cases and controls, the categorical variables were summarized as frequencies and percentages, and the continuous variables as means and standard deviations. The percentages were compared between groups using c2 test and means by t-test. When the comparison of the percentages showed statistical significance, crude and adjusted-for-age odds ratios were estimated. For QUS and DXA markers, means were adjusted using the generalized additive models, where the effects of age were modeled with cubic splines. Estimated means were plotted against the age and by group for DXA markers. In order to evaluate the possible diminution in BMD, 95% confidence intervals for the difference mC–mA were obtained, where mC and mA denote the adjusted means in the control and asthmatic women, respectively. Average diminution percentage was calculated by 100(mC–mA)/mC and maximum diminution percentage as 100 U/mC, where U is the upper extreme of the 95% confidence interval for mC–mA. The analysis was carried out using the statistical package R version 1.9.1 (The R Foundation for Statistical Computing). Results Table 1 shows characteristics of the population enrolled in the study. The patient group was composed of 105 women suffering from asthma and controls was composed of 133 women. Patients were older than controls (53 6 13.7 yr vs 49.7 6 11.2 yr, p 5 0.044). Because of this, all statistically Table 1 Basal Characteristics of the Populations Studied Asthmatics receiving inhaled steroids (n 5 105) Age (yr)a Weight (kg)a Height (cm)a BMI (kg/m2)a Current smokersb Nonsmokersb Ex-smokersb Menopause, yesb Fractures, yesb 53.0 70.3 156.4 28.8 (13.7) (13.7) (6.4) (5.7) 3 (2.9) 86 16 65 22 (81.9) (15.2) (61.9) (21.0) Controls (n 5 133) 49.7 68.4 158.0 27.5 p Value (11.2) (13.1) (6.7) (5.4) 0.044 0.280 0.065 0.068 25 (19.5) !0.001 89 14 74 9 (69.5) (10.9) (57.8) (7.0) 0.544 0.002 Abbr: BMI, body mass index. a Values expressed as mean (standard deviation). b Frequencies expressed as total number (%). Volume 9, 2006 156 Sosa et al. Discussion Systemic corticosteroid therapy leads to excessive bone loss and increased fracture risk, especially with high doses and prolonged use (4). Detrimental effects on bone metabolism are assumed to be lower with inhaled corticosteroids, ,40 Group Asthmatic ,35 Control ,30 Estimated prevalence FX studies were adjusted for age. We found similar weight, height, and BMI in the two groups. There was a higher prevalence of current smokers in controls than asthmatics (19.5% vs 2.9%, p ! 0.001). The proportion of menopausal women was similar in both groups (61.9% vs 57.8%, p 5 0.526). As shown in Fig. 1, asthmatic women had a higher prevalence of fractures than controls (21% vs 7%, p 5 0.002). The crude odds ratio for fracture in the asthmatic women was 3.50 (95% CI: 1.54–7.99) and the age adjusted odds ratio was 2.79 (95% CI: 1.19–6.54). Table 2 shows the comparison of quantitative ultrasonography measurements at the calcaneus and BMD at the lumbar spine and femoral neck by DXA between asthmatic women (on inhaled steroids therapy) and controls. We found no statistically significant differences in any of the QUS measurements (BUA, SOS, QUI) between asthmatic patients and controls, either by performing crude comparisons or after adjusting for age. Asthmatic women had lower BMD values than controls in the lumbar spine (0.924 6 0.158 g/cm2 vs 0.982 6 0.157 g/cm2 , p 5 0.005), but this difference was not significant when adjusted for age ( p 5 0.098). The estimated percentage diminution in mean lumbar spine BMD was 3.1% being the upper bound for this percentage of 6.8%. There were no statistically significant differences between BMD values at the femoral neck in both groups. ,25 ,20 ,15 ,10 ,05 0,00 30 40 50 60 70 Age Fig. 1. Prevalence of fractures in asthmatic patients and controls. given their limited systemic absorption (14). However, patients with chronic obstructive airway disease have other risk factors that may predispose them to accelerated bone loss and osteoporosis: As airflow obstruction worsens, risk of osteoporosis increases because patients become more debilitated, less mobile and nutritionally depleted (15,16). Table 2 Comparison of Quantitative Ultrasound Measurements at the Calcaneus and Bone Mineral Density at the Lumbar Spine and Femoral Neck by DXA in Asthmatic Women Receiving Inhaled Steroids and Controls Group Asthmatics receiving inhaled steroids BUA (dB/mHz) SOS (m/s) QUI-stiffness DXA L2-L4 (g/cm2) DXA femoral neck (g/cm2) 72.0 72.8b 1546 1548 92.7 93.7 0.924 0.960 0.750 (18.6)a (69.4–76.2) (31.8) (1542–1554) (20.0) (90.1–97.3) (0.158) (0.925–0.995) (0.132) 0.776 (0.750–0.802) % Diminution Controls 72.1 71.6 1552 1551 95.0 94.2 0.982 0.991 0.775 p Value (17.2) (68.6–74.6) (32.3) (1546–1556) (19.3) (91.1–97.4) (0.157) (0.960–1.022) (0.118) 0.966 0.598 0.158 0.468 0.788 0.832 0.005 0.098 0.131 0.780 (0.758–0.803) 0.779 Two-tailed 95% CI for mC 2 mA Mean Maximum 21.7 4.5 24.91–10.70 0.2 0.7 25.34–4.29 0.6 4.6 20.006–0.067 3.1 6.8 20.025–0.033 0.5 4.2 25.69–3.27 Abbr: BUA, broadband ultrasound attenuation; DXA, dual X-ray absorptiometry; QUI, quantitative ultrasound index; SOS, speed of sound. a Crude mean (standard deviation). b Adjusted means for age (95% CI). Journal of Clinical Densitometry Volume 9, 2006 Inhaled Steroids and Bone Mineral Density Studies performed in asthmatic patients receiving inhaled steroids have been controversial. Ishizuka et al. (17) found that in 128 patients that inhaled steroids did not produce bone loss measured by DXA when administered alone, but increased the rate of bone loss at 6 months when combined with oral steroids. Reid et al. (18) and Packe et al. (19) described a reduction in bone mass in patients receiving inhaled steroids, and Israel et al. (20) found that ICS led to dose-related loss of bone in the hip in premenopausal women. On the other hand, other studies have found no changes in BMD. Medici et al. (21) did not find bone loss after 1 yr of follow-up, in a multicentric, double-blind prospective study, but the patients enrolled were young (mean age: 39 yr) and all the women were premenopausal. Similar results have been described by Luengo et al. (22). Two recent meta-analyses concluded that long-term use of ICS in patients with asthma or chronic obstructive pulmonary disease was not associated with significant changes in BMD (23,24), suggesting that inhaled steroids for the treatment of asthma can be considered safe with respect to their effect on bone loss. Nevertheless, our study shows that without changes in BMD, the risk of fractures seems to be greater in patients receiving inhaled steroids. BMD is one component of bone strength, and it has been well established that every SD reduction in T-score doubles the risk of fracture (25). However, in our study, there were no differences either in lumbar spine or in femoral neck BMD between cases and controls, despite the 14% higher prevalence of fractures in the asthmatic women. According to our results, van Staa et al. (26) reported on the effects of inhaled steroids on fracture rates in the UK General Practice Research Database. In this study of 450,000 subjects, they concluded that users of inhaled corticosteroids have an increased risk of fracture, particularly at the hip and spine. However, that they consider this risk excess may be related more to the underlying respiratory disease than to inhaled corticosteroid. Melton et al. (27) found similar results in a population-based retrospective cohort study and concluded that a 70% increase in overall fracture risk among unselected community patients with adult onset asthma was mainly confined to the subset that also had chronic obstructive pulmonary disease and was influenced by substantial corticosteroid use. There was a 1.8-fold increase in risk of developing a new vertebral fracture due to moderate trauma with the use of ICS. Recently, Melton et al. (28) found no substantial increase in overall fracture risk among children with asthma followed for up to four decades. There was, however, an increase in hand and finger fractures in males with asthma as compared with their age- and sex-matched controls; and a general increase in fracture risk among males compared with females, attributable mostly to recreational injuries. They suggested a relationship with impaired development of a biomechanically competent skeleton. On the other hand, some studies have found no association between ICS and fracture prevalence. Johnell et al. (29) did not find statistically significant changes either in BMD or in the fracture rate in 912 patients with mild chronic obstructive Journal of Clinical Densitometry 157 pulmonary disease, with similar mean age to our study (age 5 52 yr). Similar results were found by Suissa et al. (30), who performed a case-control study nested within a population-based cohort of all Quebec elderly dispensed respiratory medications and followed for at least 4 yr during 1988–2001. They concluded that long-term use of inhaled and nasal corticosteroids at the usual recommended doses is not associated with a risk of fracture in older patients with respiratory disease. A limitation of the study is the number of patients and controls included. With a higher number we would probably have shown statistically significant differences in DXA values at the lumbar spine. We would have liked to perform the study with a third group, composed of patients with asthma and without inhaled steroids, but after the pilot study, we realized that these patients were very much younger than patients and controls and used short courses of inhaled steroids when their symptoms worsened, so we decided to exclude them. In conclusion, women treated with inhaled steroids seem to have a higher prevalence of fractures independent of their BMD values, measured either by DXA or QUS. This finding suggests the possibility that ICS produce derangements in bone quality more than in bone mass. Additional studies with larger number of patients should be performed to ascertain this finding. Acknowledgments This work was supported by a grant from Italfármaco Laboratories, Spain. References 1. Lemiere C, Bai T, Balter M, et al. 2003 2004 Adult Asthma Consensus Guidelines Update. Can Respir J 11(Suppl A): 9A–18A. 2. Leone FT, Fish JE, Szefler SJ, West SL. 2003 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 124:2329–2340. 3. Nelson HS. 2005 Combination therapy of long-acting beta agonists and inhaled corticosteroids in the management of chronic asthma. Curr Allergy Asthma Rep 5:123–129. 4. 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Sambrook PN. 2000 Inhaled corticosteroids, bone density, and risk of fracture. Lancet 355:1385. 10. Smith BJ, Phillips PJ, Heller RF. 1999 Asthma and chronic obstructive airway diseases are associated with osteoporosis and fractures: a literature review. Respirology 4:101–109. 11. World Health Organisation Scientific Group Research on the menopause. 1998 WHO Technical Services Report Series 670. WHO, Geneva. 12. Dı́az Curiel M, Carrasco de la Peña JL, Honorato Pérez J, Pérez Cano R, Rapado A, Ruiz Martı́nez I. 1997 Study of bone mineral density in lumbar spine and femoral neck in a Spanish population. Osteoporos Int 7:59–64. 13. Sosa M, Saavedra P, Muñoz-Torres M, et al. 2002 Quantitative ultrasound calcaneus measurements: normative data and precision in Spanish population. Osteoporos Int 13:487– 492. 14. Lipworth BJ. 1999 Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 159:941–955. 15. 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Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS. 2001 Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 345:941–947. 21. Medici TC, Grebski E, Hacki M, Ruegsegger P, Maden C, Efthimiou J. 2000 Effect of one year treatment with inhaled fluticasone propionate or beclomethasone dipropionate on bone density and bone metabolism: a randomised parallel group study in adult asthmatic subjects. Thorax 55:375–382. 22. Luengo M, del Rio L, Pons F, Picado C. 1997 Bone mineral density in asthmatic patients treated with inhaled corticosteroids: a case-control study. Eur Respir J 10:2110–2113. 23. Lipworth BJ. 1999 Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 159:941–955. 24. Halpern MT, Schmier JK, Van Kerkhove MD, Watkins M, Kalberg CJ. 2004 Impact of long-term inhaled corticosteroid therapy on bone mineral density: results of a meta-analysis. Ann Allergy Asthma Immunol 92:201–207. 25. Cummings SR, Black D. 1995 Bone mass measurements and risk of fracture in Caucasian women: a review of findings from prospective studies. Am J Med 98(2A):24S–28S. 26. van Staa TP, Dennison EM, Leufkens HG, Cooper C. 2001 Epidemiology of fractures in England and Wales. Bone 29:517–522. 27. Melton LJ III, Patel A, Achenbach SJ, Oberg AL, Yunginger JW. 2004 Long-term fracture risk following adult-onset asthma: a population-based study. Osteoporos Int 15:311–316. 28. Melton LJ III, Patel A, Achenbach SJ, Oberg AL, Yunginger JW. 2005 Long-term fracture risk among children with asthma: a population-based study. J Bone Miner Res 20:564–570. 29. Johnell O, Pauwels R, Löfdahl C-G, et al. 2002 Bone mineral density in patients with chronic onstructive pulmonary disease treated with budesonide TurbuhalerÒ. Eur Respir J 19:1058–1063. 30. Suissa S, Baltzan M, Kremer R, Ernst P. 2004 Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 169:83–88. Volume 9, 2006