Download Inhaled Steroids Do Not Decrease Bone Mineral Density But

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. Ebeling PR, Erbas B, Hopper JL, Wark JD, Rubinfeld AR. 1998
Bone mineral density and bone turnover in asthmatics treated
with long-term inhaled or oral glucocorticoids. J Bone Miner
Res 13:1283–1289.
5. Tug T, Kamanli A, Tug E. 2001 Effects of long-term inhaled steroid use on bone mineral density in asthma patients. J Investig
Allergol Clin Immunol 11:300–302.
6. Harmanci E, Colak O, Metintas M, Alatas O, Yurdasiper A.
2001 Fluticasone propionate and budesonide do not influence
bone metabolism in the long term treatment of asthma. Allergol
Immunopathol (Madr) 29:22–27.
7. Sivri A, Coplu L. 2001 Effect of the long-term use of inhaled
corticosteroids on bone mineral density in asthmatic women.
Respirology 6:131–134.
8. Fujita K, Kasayama S, Hashimoto J, et al. 2001 Inhaled corticosteroids reduce bone mineral density in early postmenopausal but not
premenopausal asthmatic women. J Bone Miner Res 16:782–787.
Volume 9, 2006
158
9. 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. Ionescu AA, Schoon E. 2003 Osteoporosis in chronic obstructive
pulmonary disease. Eur Respir J 46(Suppl):64s–75s.
16. Sin DD, Man JP, Man SF. 2003 The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J
Med 114:10–14.
17. Ishizuka T, Yoshii A, Hisada T, et al. 2002 Effects of fluticasone
propionate on bone mineral density in patients with persistent
bronchial asthma. Intern Med 41:798–804.
18. Reid DM, Nicoll JJ, Smith MA, Higgins B, Tothill P, Nuki G.
1986 Corticosteroids and bone mass in asthma: comparisons
with rheumatoid arthritis and polymyalgia rheumatica. Br Med
J 293:1463–1466.
19. Packe GE, Douglas JG, McDonald AF, Robins SP, Reid DM.
1992 Bone density in asthmatic patients taking high dose inhaled
beclomethasone dipropionate and intermittent systemic corticosteroids. Thorax 47:414–417.
Journal of Clinical Densitometry
Sosa et al.
20. 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