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What is the relationship between steroids and bone mineral density in people with COPD?



Conclusion Statement

Twelve studies regarding the relationship between steroids and bone mineral density in people with COPD were reviewed. Four studies report significant associations of cumulative corticosteroid use (both oral and inhaled, >1000 mg) with changes in biochemical bone markers, decreased bone mineral density, and increased fracture risk. However, six studies based on inhaled corticosteroid use for at least one year report conflicting findings. Two studies support a significant association between COPD and bone mineral density and/or fracture risk independent of steroid use. Further research on the relationship among the type, dose and duration of corticosteroid use, confounding variables and bone mineral density is needed.

Evidence Summary

Twelve studies were reviewed regarding the relationship between steroids and bone mineral density in people with COPD: four randomized controlled trials, one retrospective cohort study, one case-control study, five cross-sectional studies, and one meta-analysis.

Significant Associations between Cumulative Corticosteroid Treatment and Bone Density

In a neutral-quality retrospective cohort study by Melton et al (2004), the medical records of 226 subjects with adult-onset asthma were reviewed to evaluate fracture risk. In multivariate analysis, the predictors of a moderate trauma vertebral fracture were older age (hazard ratio 1.6, 95% confidence interval 1.3 to 2.1), concomitant COPD (hazard ratio 2.4, 95% confidence interval 1.2 to 4.9), cigarette smoking (hazard ratio 2.3, 95% confidence interval 1.2 to 4.8), and cumulative corticosteroid dose (both oral and inhaled) greater than the median (hazard ratio 2.6, 95% confidence interval 1.4 to 5.0). A 70% increase in overall fracture risk in subjects with adult-onset asthma was confined to the subset that had COPD and was influenced by corticosteroid use.

In a neutral-quality case-control study by de Vries et al (2005), 108,754 patients with osteoporotic fractures were compared with 108,754 control subjects without a history of fracture, matched for age, sex, medical practice and calendar time. Higher doses of inhaled corticosteroids were associated with greater risks of fracture; the crude odds ratio of fracture among patients exposed to >1,600 µg beclomethasone equivalents per day was 1.95 (95% confidence interval 1.68 to 2.27). However, when adjusted for disease severity and use of bronchodilators, the initial dose-response relationship between inhaled corticosteroids and fracture risk disappeared (adjusted odds ratio of 1.19, 95% confidence interval 1.01 to 1.41). In the high-dose group (>1,600 µg beclomethasone equivalents per day), approximately half had not been exposed to oral corticosteroids in the previous 6 months, and these patients did not have an increased risk of osteoporotic fracture. The risk of fracture was increased in patients who were exposed to both oral corticosteroids and high-dose inhaled corticosteroids; in these patients, the median number of prior oral corticosteroid prescriptions was 14.

In a neutral-quality cross-sectional analysis of a cohort by Walsh et al (2002), the effect of cumulative oral corticosteroid use on bone mineral density and vertebral fracture was evaluated in 117 male and female subjects with COPD. The cumulative prednisolone dose ranged from 3.4 to 175 g and was significantly related to reduced bone mineral density at the femoral neck and Ward's triangle, as well as strongly associated with vertebral fracture (odds ratio between highest and lowest quartiles 4.4, 95% confidence interval 1.04 to 18.8).

In a neutral-quality cross-sectional study by DuBois et al (2002), the bone mineral density outcomes of 86 men with COPD were compared. 10 patients received oral prednisolone daily, 11 patients were treated for several exacerbations with multiple prednisolone courses, up to a period of 2 weeks per course with a cumulative dose of >1000 mg, 28 patients were treated with multiple systemic prednisolone courses, but with a cumulative dose < 1000 mg, and 37 patients had never been treated with systemic prednisolone and partly with inhaled corticosteroids. Bone mineral density outcomes at any site were lower in patients receiving multiple systemic prednisolone courses > 1000 mg cumulatively, compared to the other groups.

Significant Associations between Inhaled Corticosteroid Treatment (for at Least 1 Year) and Bone Density

In a neutral-quality randomized controlled trial by the Lung Health Study Group (2000), Scanlon et al (2004), 1116 people with COPD were assigned to receive inhaled triamcinolone acetonide (600 µg twice daily) or placebo for 3 years. 1050 subjects completed the trial and bone density was measured in a substudy of 412 subjects. After 3 years, the bone density of the lumbar spine (P = 0.007) and the femur (P < 0.001) was significantly lower in the group receiving triamcinolone compared to placebo.

In a neutral-quality randomized controlled trial by Struijs and Mulder (1997), 39 patients with COPD were assigned to 1 of 3 groups: 200 µg beclomethasone 4 times daily, 200 µg budesonide 4 times daily, or no inhaled glucocorticoids. 33 completed the 1-year trial. Both inhaled corticosteroids had a significant effect on serum concentrations of biochemical bone markers compared to the control group. Mean bone mineral density decreased similarly over 1 year in all groups, however, the decrease in lumbar and hip bone mineral density was only statistically significant in the beclomethasone group (-1.1% in the spine, -1.7% in the hip, P < 0.05).

In a neutral-quality cross-sectional study by Dinc et al (2001), the effect of long-term inhaled beclomethasone diproprionate (for at least 12 months) on markers of bone formation was assessed in 65 men with COPD. Serum osteocalcin levels in patients using beclomethasone were significantly lower than that of controls, while there were no significant differences between groups for serum alkaline phosphatase, total serum calcium or inorganic phosphate.


No Association between Inhaled Corticosteroid Treatment (for at Least 1 Year) and Bone Density

In a neutral-quality randomized controlled trial by Johnell et al (2002), 912 patients with COPD received inhaled budesonide (400 µg) or placebo twice daily for 3 years. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin, but there was no difference in serum osteocalcin concentrations between the groups after 3 years. There were no significant changes in bone mineral density at any site in the budesonide-treated patients, compared with placebo.

In a positive-quality meta-analysis by Halpern et al (2004), 14 studies were analyzed to evaluate the impact of long-term inhaled corticosteroid use (at least 1 year) on bone mineral density. Among inhaled corticosteroid users, annual changes from baseline in lumbar (-0.23%), femoral neck (-0.17%) and major trochanter bone mineral density (+1.46%) were not statistically significant; mean changes in lumbar bone mineral density were also not significantly different from controls (-0.02%). In addition, annual changes in lumbar bone mineral density were not statistically significant for subgroups of patients with asthma or COPD.

Independent Effects of COPD on Bone Mineral Density

In a neutral-quality cross-sectional analysis by Yeh et al (2002) of 39 men at a high risk for falls in a Veterans Administration Medical Center, only 21% were found to have normal lumbar spine and right hip bone mineral density. There was a significant association between COPD and osteoporosis which was independent of oral corticosteroid use (P = 0.00045).

In a neutral-quality cross-sectional study by McEvoy et al (1998), the association between corticosteroid use and vertebral fracture prevalence was determined in 312 older men with COPD. The subjects were divided into 3 groups: 117 were Never Steroid Users, 70 were Inhaled Steroid Users, and 125 were Systemic Steroid Users. Systemic corticosteroid users were twice as likely to have vertebral fractures than inhaled steroid users and those who have never used steroids, but vertebral fractures were found to be prevalent in white men with COPD independent of steroid use. Significant independent predictors of one or more vertebral fractures were increasing age (P < 0.02), earlier age of smoking initiation (P < 0.03), and greater weight (P < 0.02).

Summary of research regarding steroids and bone mineral density in people with COPD

listed in order of class and rating

Author/Year

Rating

Study Type

Intervention

Population

Outcomes

Limitations

Lung Study Health Group, 2000, Scanlon et al, 2004

A, ø RCT Assigned to receive inhaled triamcinolone acetonide (600 µg twice daily) or placebo for 3 years. 1116 people with COPD; 1050 subjects completed the trial and bone density was measured in a substudy of 412 subjects. After 3 years, the bone density of the lumbar spine (P = 0.007) and the femur (P < 0.001) was significantly lower in the group receiving triamcinolone compared to placebo. Groups had statistically significant differences at baseline. Bone density measured in subset. Other factors affecting bone mineral density not measured.
Johnell et al, 2002 A, ø RCT Assigned to inhaled budesonide (400 µg) or placebo twice daily for 3 years. 912 patients with COPD completed the 3-year trial. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin, but there was no difference in serum osteocalcin concentrations between the groups after 3 years. There were no significant changes in BMD at any site in the budesonide-treated patients, compared with placebo. Original enrolllment unclear. Not all measurements made in all patients.
Struijs and Mulder, 1997 A, ø RCT Assigned to 1 of 3 groups for 1 year: 200 µg beclomethasone 4 times daily, 200 µg budesonide 4 times daily, or no inhaled glucocorticoids. 39 patients with COPD; 33 completed the 1-year trial. Both inhaled corticosteroids had a significant effect on serum concentrations of biochemical bone markers compared to the control group. Mean BMD decreased similarly over 1 year in all groups, however, the decrease in lumbar and hip BMD was only statistically significant in the beclomethasone group (-1.1% in the spine, -1.7% in the hip, P < 0.05). Small sample size. Baseline differences between groups not statistically analyzed. Statistical methods may not have been appropriate.
Melton et al, 2004 B; ø Retrospective Cohort Study Not applicable 226 subjects with adult-onset asthma Predictors of a moderate trauma vertebral fracture were older age (HR 1.6, 95% CI 1.3 to 2.1), concomitant COPD (HR 2.4, 95% CI 1.2 to 4.9), cigarette smoking (HR 2.3, 95% CI 1.2 to 4.8), and cumulative corticosteroid dose (both oral and inhaled) greater than the median (HR 2.6, 95% CI 1.4 to 5.0). A 70% increase in overall fracture risk in subjects with adult-onset asthma was confined to the subset that had COPD and was influenced by corticosteroid use. Population limited to Rochester, MN residents.
de Vries et al, 2005 C; ø Case-Control Study Not applicable. 108,754 patients with osteoporotic fractures were compared with 108,754 control subjects without a history of fracture, matched for age, sex, medical practice and calendar time. Higher doses of inhaled corticosteroids were associated with greater risks of fracture; the crude OR of fracture among patients exposed to >1,600 µg beclomethasone equivalents per day was 1.95 (95% CI 1.68 to 2.27). However, when adjusted for disease severity and use of bronchodilators, the initial dose-response relationship between inhaled corticosteroids and fracture risk disappeared (adjusted OR of 1.19, 95% CI 1.01 to 1.41). In the high-dose group (>1,600 µg beclomethasone equivalents per day), approximately half had not been exposed to oral corticosteroids in the previous 6 months, and these patients did not have an increased risk of osteoporotic fracture. The risk of fracture was increased in patients who were exposed to both oral corticosteroids and high-dose inhaled corticosteroids; in these patients, the median number of prior oral corticosteroid prescriptions was 14. Baseline differences between cases and controls not statistically analyzed. Authors note that data on physical activity, smoking and loss of fat free mass were not available.
McEvoy et al, 1998 D; ø Cross-Sectional Study Subjects were divided into 3 groups: 117 were Never Steroid Users, 70 were Inhaled Steroid Users, and 125 were Systemic Steroid Users. 312 older men with COPD Systemic corticosteroid users were twice as likely to have vertebral fractures than inhaled steroid users and those who have never used steroids, but vertebral fractures were found to be prevalent in white men with COPD independent of steroid use. Significant independent predictors of one or more vertebral fractures were increasing age (P < 0.02), earlier age of smoking initiation (P < 0.03), and greater weight (P < 0.02). Authors note that study lacked power to rule out type II error, as well as ability to control for all confounders.
Walsh et al, 2002 D; ø Cross-Sectional Study Cumulative oral prednisolone dose ranged from 3.4 to 175 g. 117 male and female subjects with COPD Cumulative prednisolone dose was significantly related to BMD at the femoral neck and Ward's triangle, as well as strongly associated with vertebral fracture (OR between highest and lowest quartiles 4.4, 95% CI 1.04 to 18.8). Authors did not provide odds ratios for all quartiles.
DuBois et al, 2002 D; ø Cross-Sectional Study 10 patients received oral prednisolone daily, 11 patients were treated for several exacerbations with multiple prednisolone courses, up to a period of 2 weeks per course with a cumulative dose of >1000 mg, 28 patients were treated with multiple systemic prednisolone courses, but with a cumulative dose < 1000 mg, and 37 patients had never been treated with systemic prednisolone and partly with inhaled corticosteroids. 86 men with COPD BMD outcomes at any site were lower in patients receiving multiple systemic prednisolone courses > 1000 mg cumulatively, compared to the other groups. Other factors affecting bone mineral density were not measured.
Dinc et al, 2001 D; ø Cross-Sectional Study Not applicable 65 men with COPD Serum osteocalcin levels in patients using beclomethasone were significantly lower than that of controls, while there were no significant differences between groups for serum alkaline phosphatase, total serum calcium or inorganic phosphate. Recruitment methods unclear.
Yeh et al, 2002 D; ø Cross-Sectional Analysis Not applicable 39 men at a high risk for falls in a Veterans Administration Medical Center 21% were found to have normal lumbar spine and right hip BMD. There was a significant association between COPD and osteoporosis which was independent of oral corticosteroid use (P = 0.00045). Small sample size and limited generalizability. High falling risk not described. Measurements not made in all subjects.
Halpern et al, 2004 M; + Meta-analysis Inhaled corticosteroid use for at least 1 year 14 studies evaluated Among inhaled corticosteroid users, annual changes from baseline in lumbar (-0.23%), femoral neck (-0.17%) and major trochanter BMD (+1.46%) were not statistically significant; mean changes in lumbar BMD were also not significantly different from controls (-0.02%). In addition, annual changes in lumbar BMD were not statistically significant for subgroups of patients with asthma or COPD. Authors note limitation of only 14 studies meeting inclusion criteria.




Quality Rating Summary
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Worksheets
de Vries F, van Staa TP, Bracke MSGM, Cooper C, Leufkens HGM, Lammers JWJ. Severity of obstructive airway disease and risk of osteoporotic fracture. Eur Respir J 2005;25:879-884.

Dinc M, Tchugunova Y, Dinc S, Cinarli B, Atasever T, Oz M.  Decreased osteocalcin levels in patients with chronic obstructive pulmonary disease using long-term inhaled beclomethosone diproprionate.  Metabolism 2001, 11:1336-1339.


DuBois EF, Roder E, Dekhuijzen PN, Zwinderman AE, Schweitzer DH.  Dual energy x-ray absorptiometry outcomes in male COPD patients after treatment with different glucocorticoid regimens.  Chest 2002;121(5):1456-63.

Halpern MT, Schmier JK, Van Kerkhove MD, Watkins M, Kalberg CJ.  Impact of long-term inhaled corticosteroid therapy on bone mineral density:  results of a meta-analysis.  Ann Allergy Asthma Immunol 2004;92(2):201-7.

Johnell O, Pauwels R, Lofdahl CG, Laitinen LA, Postma DS, Pride NB, Ohlsson SV.  Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler.  Eur Respir J 2002;19(6):1058-63.

Lung Health Study Group.  Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.  N Engl J Med 2000;343(26):1902-9. 

McEvoy CE, Ensrud KE, Bender E, Genant HK, Yu W, Griffith JM, and Niewoehner DE.  Association between Corticosteroid Use and Vertebral Fractures in Older Men with Chronic Obstructive Pulmonary Disease. American Journal of Respiratory Critical Care Medicine 1998;157:704–709.

Melton LJ, Patel A, Achenbach SJ, Oberg AL, Yunginger JW.  Long-term fracture risk following adult-onset asthma:  a population-based study.  Osteoporosis International 2004;15:311-316.

Scanlon PD, Connett JE, Wise RA, Tashkin DP, Madhok T, Skeans M, Carpenter PC, Bailey WC, Buist AS, Eichenhorn M, Kanner RE, Weinmann G, The Lung Health Study Research Group.  Loss of bone density with inhaled triamcinolone in Lung Health Study II.  American Journal of Respiratory and Critical Care Medicine 2004;170:1302-1309.


Struijs A, Mulder H.  The effects of inhaled glucocorticoids on bone mass and biochemical markers of bone homeostasis:  a 1-year study of beclomethasone versus budesonide.  Netherlands Journal of Medicine 1997;50:233-237.


Walsh LJ, Lewis SA, Wong CA, Cooper S, Oborne J, Cawte SA, Harrison T, Green DJ, Pringle M, Hubbard R, Tattersfield AE.  The Impact of Oral Corticosteroid Use on Bone Mineral Density and Vertebral Fracture. American Journal of Respiratory and Critical Care Medicine  2002;166:691-695. 

Yeh SS, Phanumas D, Hafner A, Schuster MW.  Risk factors for osteoporosis in a subgroup of elderly men in a Veterans Administration nursing home.  J Investigative Med 2002;50(6):452-7.

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