Effects of long-term inhaled corticosteroid treatment on fragility fractures in older women: the Manitoba BMD registry study

Abstract

Summary

The effects of inhaled corticosteroids (ICS) on fracture risk in older women with chronic respiratory diseases are not well established. Our results indicate long-term ICS use in this population does not increase the risk of major osteoporotic fracture. This finding further elucidates the long-term safety of ICS in older women.

Introduction

Inhaled corticosteroids (ICS) are frequently used in older women with chronic respiratory diseases. There is insufficient evidence regarding the association between long-term ICS use and the risk of fragility fractures in this population.

Methods

We used linked Manitoba health administrative databases and the provincial bone mineral density (BMD) registry (1996–2013) to identify women ≥ 40 years of age with asthma and/or chronic obstructive pulmonary disease (COPD) within 3 years preceding the baseline BMD test. We followed them until the first major osteoporotic fracture or end of study, whichever came first. ICS use, stratified by exposure tertiles, was measured within the 12-month period following the baseline BMD test (by total days and quantity, primary outcome), and over the entire follow-up period (by medication possession ratio (MPR) and average annual dose, secondary outcome). The hazard ratio of fracture with ICS use was estimated using a Cox proportional hazards model, controlling for baseline determinants of fracture.

Results

Of 6880 older women with asthma (38%) or COPD (62%), 810 (12%) experienced a major osteoporotic fracture over a mean follow-up of 7.7 years (SD = 3.9). ICS use at any tertile was not associated with an increased risk of fracture (dispensed days, p = 0.90; dispensed quantity, p = 0.67). Similarly, ICS use at any tertile during the entire follow-up period was not associated with an increased risk of fracture (MPR, p = 0.62; average annual dose, p = 0.58).

Conclusion

Our findings do not support an increased risk of major osteoporotic fracture in older women with chronic respiratory diseases due to long-term ICS use.

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References

  1. 1.

    World Health Organization (2018) Global health estimates 2016 summary tables: global death by cause, age and sex, 2000–2016. World Health Organization, Geneva https://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html. Accessed 5 July 2019

    Google Scholar 

  2. 2.

    World Health Organization (2018) Global health estimates 2016 summary tables: global DALY estimates by cause, age and sex, 2000–2016. World Health Organization, Geneva https://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html. Accessed 5 July 2019

    Google Scholar 

  3. 3.

    Wouters EFM, Reynaert NL, Dentener MA, Vernooy JHJ (2009) Systemic and local inflammation in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 6:638–647. https://doi.org/10.1513/pats.200907-073DP

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Lehouck A, Boonen S, Decramer M, Janssens W (2011) COPD, bone metabolism, and osteoporosis. CHEST 139:648–657. https://doi.org/10.1378/chest.10-1427

    Article  PubMed  Google Scholar 

  5. 5.

    Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention 2018 Global Initiative for Asthma (GINA). https://ginasthma.org/gina-reports. Accessed 5 July 2019

  6. 6.

    Watz H, Tetzlaff K, Wouters EFM, Kirsten A, Magnussen H, Rodriguez-Roisin R, Vogelmeier C, Fabbri LM, Chanez P, Dahl R, Disse B, Finnigan H, Calverley PM (2016) Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med 4:390–398. https://doi.org/10.1016/S2213-2600(16)00100-4

    Article  PubMed  Google Scholar 

  7. 7.

    Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD). https://goldcopd.org/gold-reports. Accessed 5 July 2019

  8. 8.

    Toogood JH, Baskerville JC, Markov AE, Hodsman AB, Fraher LJ, Jennings B, Haddad RG, Drost D (1995) Bone mineral density and the risk of fracture in patients receiving long-term inhaled steroid therapy for asthma. J Allergy Clin Immunol 96:157–166. https://doi.org/10.1016/S0091-6749(95)70003-X

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Loke YK, Cavallazzi R, Singh S (2011) Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 66:699 LP–699708. https://doi.org/10.1136/thx.2011.160028

    Article  Google Scholar 

  10. 10.

    Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17:1726–1733. https://doi.org/10.1007/s00198-006-0172-4

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Garnero P, Sornay-Rendu E, Chapuy M-C, Delmas PD (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 11:337–349. https://doi.org/10.1002/jbmr.5650110307

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Canalis E, Delany AM (2002) Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 966:73–81. https://doi.org/10.1111/j.1749-6632.2002.tb04204.x

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Loke YK, Gilbert D, Thavarajah M, Blanco P, Wilson AM (2015) Bone mineral density and fracture risk with long-term use of inhaled corticosteroids in patients with asthma: systematic review and meta-analysis. BMJ Open 5:e008554. https://doi.org/10.1136/bmjopen-2015-008554

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gonzalez AV, Coulombe J, Ernst P, Suissa S (2018) Long-term use of inhaled corticosteroids in COPD and the risk of fracture. CHEST 153:321–328. https://doi.org/10.1016/j.chest.2017.07.002

    Article  PubMed  Google Scholar 

  15. 15.

    Government of Canada SC (2014) Population by sex and age group, by province and territory (number, both sexes). Government of Canada SC. https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1710000501. Accessed 5 July 2019

  16. 16.

    Roos NP, Black C, Roos LL, Frohlich N, DeCoster C, Mustard C, Brownell MD, Shanahan M, Fergusson P, Toll F, Carriere KC, Burchill C, Fransoo R, MacWilliam L, Bogdanovic B, Friesen D (1999) Managing health services: how the population health information system (POPULIS) works for policymakers. Med Care 37:JS27–JS41. https://doi.org/10.1097/00005650-199906001-00007

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kozyrskyj AL, Mustard CA (1998) Validation of an electronic, population-based prescription database. Ann Pharmacother 32:1152–1157. https://doi.org/10.1345/aph.18117

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lix LM, Kuwornu JP, Kroeker K, Kephart G, Sikdar KC, Smith M, Quan H (2016) Estimating the completeness of physician billing claims for diabetes case ascertainment using population-based prescription drug data. Health Promot Chronic Dis Prev Can 36:54–60. https://doi.org/10.24095/hpcdp.36.3.02

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Leslie WD, Caetano PA, Macwilliam LR, Finlayson GS (2005) Construction and validation of a population-based bone densitometry database. J Clin Densitom 8:25–30. https://doi.org/10.1385/jcd:8:1:025

    Article  Google Scholar 

  20. 20.

    Leslie WD, Metge C (2003) Establishing a regional bone density program: lessons from the Manitoba experience. J Clin Densitom 6:275–282. https://doi.org/10.1385/jcd:6:3:275

    Article  Google Scholar 

  21. 21.

    Epp R, Alhrbi M, Ward L, Leslie W (2018) Radiological validation of fracture definitions from administrative data. J Bone Miner Res 33(Supp 1):S275

    Google Scholar 

  22. 22.

    Kelly HW (1998) Comparison of inhaled corticosteroids. Ann Pharmacother 32:220–232. https://doi.org/10.1345/aph.17014

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Andrade SE, Kahler KH, Frech F, Chan KA (2006) Methods for evaluation of medication adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf 15:565–574. https://doi.org/10.1002/pds.1230

    Article  PubMed  Google Scholar 

  24. 24.

    Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E (2008) FRAX™ and the assessment of fracture probability in men and women from the UK. Osteoporos Int 19:385–397. https://doi.org/10.1007/s00198-007-0543-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Chen W, Johnson KM, FitzGerald JM, Sadatsafavi M, Leslie WD (2018) Long-term effects of inhaled corticosteroids on bone mineral density in older women with asthma or COPD: a registry-based cohort study. Arch Osteoporos 13:116. https://doi.org/10.1007/s11657-018-0537-2

    Article  PubMed  Google Scholar 

  26. 26.

    Etminan M, Sadatsafavi M, Ganjizadeh Zavareh S, Takkouche B, FitzGerald J (2008) Inhaled corticosteroids and the risk of fractures in older adults: a systematic review and meta-analysis. Drug Saf 31:409–414. https://doi.org/10.2165/00002018-200831050-00005

    Article  PubMed  Google Scholar 

  27. 27.

    Yanik B, Ayrim A, Ozol D, Koktener A, Gokmen D (2009) Influence of obesity on bone mineral density in postmenopausal asthma patients undergoing treatment with inhaled corticosteroids. Clinics 64:313–318. https://doi.org/10.1590/S1807-59322009000400008

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Manitoba Population Research Data Repository under HIPC Project Number 2011/2012-31). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, or other data providers is intended or should be inferred. Data used in this study are from the Manitoba Population Research Data Repository housed at the Manitoba Centre for Health Policy, University of Manitoba and were derived from data provided by Manitoba Health. This article has been reviewed and approved by the members of the Manitoba Bone Density Program. BCN wrote the first draft of the manuscript. WDL was responsible for conception, design, data access, and analysis. All authors critically revised the article for important intellectual content and gave final approval of the version to be published. WDL had full access to all the data in the study and takes the responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

MS received salary support from the Canadian Institutes of Health Research and Michael Smith Foundation for Health Research.

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Correspondence to W.D. Leslie.

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The study was approved by the Human Research Ethics Board of the University of Manitoba.

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Ng, B., Leslie, W., Johnson, K. et al. Effects of long-term inhaled corticosteroid treatment on fragility fractures in older women: the Manitoba BMD registry study. Osteoporos Int 31, 1155–1162 (2020). https://doi.org/10.1007/s00198-020-05361-9

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Keywords

  • Asthma
  • Chronic obstructive pulmonary disease
  • Fracture
  • Inhaled corticosteroids
  • Osteoporosis
  • Women