Skip to main content

Advertisement

SpringerLink
Log in

Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Little data exist on the frequency of fracture among oral glucocorticoid users. We examined the effect of oral glucocorticoids on fracture incidence using data from randomized controlled trials. Patients starting glucocorticoids had a higher probability of fracture and decline in bone mineral density compared to chronic glucocorticoid users.

Introduction

Oral glucocorticoids (GCs) are the leading cause of secondary osteoporosis. However, there have been few studies that quantify the rate of fracture among GC users. We sought to provide a pooled estimate of fracture risk from randomized controlled trials (RCTs) of GC-treated patients.

Methods

We updated a MEDLINE search published by the American College of Rheumatology through to March 2015 and identified RCTs of osteoporosis therapies that reported fracture and bone mineral density (BMD) among oral GC users. We restricted the analysis to placebo or control arms. RCT arms were stratified by GC exposure at enrolment to GC initiators (≤6 months) and chronic GC users (>6 months). Bayesian meta-regression was used to estimate the annual probability of vertebral fracture (primary), non-vertebral fracture and percentage change in lumbar spine and femoral neck BMD.

Results

The annual incidence of vertebral and non-vertebral fracture was 5.1 % (95 % CrI = 2.8–8.2) and 2.5 % (95 % CrI = 1.2–-4.2) among GC initiators, and 3.2 % (95 % CrI = 1.8–5.0) and 3.0 % (95 % CrI = 0.8–5.9) among chronic GC users. Our meta-regression identified a non-significant effect of group-level variables (mean age, mean BMD, mean GC daily dose, patients with previous vertebral fractures, proportion of women and adjuvant used) on vertebral fracture rate.

Conclusion

Our study found higher vertebral fracture incidence among GC initiators, yet a relative decline in fracture incidence with longer exposure. Our findings suggest that fracture incidence among oral GC users may be more common than previously estimated. Optimizing GC-induced osteoporosis management during early exposure to GC is essential to prevent fractures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

GC:

Glucocorticoid

BMD:

Bone mineral density

RCT:

Randomized controlled trial

MCMC:

Markov Chain Monte Carlo

CrI:

Credible interval

References

  1. Van Staa TP (2006) The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 79:129–137

    Article  CAS  PubMed  Google Scholar 

  2. Grossman JM, Gordon R, Ranganath VK et al (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 62:1515–1526

    Article  Google Scholar 

  3. Nawata H, Soen S, Takayanagi R et al (2005) Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research (2004). J Bone Miner Metab 23:105–109

    Article  PubMed  Google Scholar 

  4. Devogelaer J-P, Goemaere S, Boonen S et al (2006) Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian bone club. Osteoporos Int 17:8–19

    Article  CAS  PubMed  Google Scholar 

  5. Gourlay M, Franceschini N, Sheyn Y (2007) Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures. Clin Rheumatol 26:144–153

    Article  PubMed  Google Scholar 

  6. Papaioannou A, Morin S, Cheung AM et al (2010) 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 182:1864–1873

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lekamwasam S, Adachi JD, Agnusdei D et al (2012) A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 23:2257–2276

    Article  CAS  PubMed  Google Scholar 

  8. de Nijs RNJ, Jacobs JWG, Lems WF et al (2006) Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. NEJM 355:675–684

    Article  PubMed  Google Scholar 

  9. Ismail AA, Pye SR, Cockerill WC et al (2002) Incidence of limb fracture across Europe: results from the European prospective osteoporosis study (Epos). Osteoporos Int 13:565–571

    Article  CAS  PubMed  Google Scholar 

  10. Adachi JD, Saag KG, Delmas PD et al (2001) Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 44:202–211

    Article  CAS  PubMed  Google Scholar 

  11. Jenkins EA, Walker-Bone KE, Wood A et al (1999) The prevention of corticosteroid-induced bone loss with intermittent cyclical etidronate. Scand J Rheumatol 28:152–156

    Article  CAS  PubMed  Google Scholar 

  12. Cortet B, Hachulla E, Barton I, Bonvoisin B, Roux C (1999) Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. A randomized study. Rev Rhum Engl Ed 66:214–219

    CAS  PubMed  Google Scholar 

  13. Cohen S, Levy RM, Keller M et al (1999) Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42:2309–2318

    Article  CAS  PubMed  Google Scholar 

  14. Roux C, Oriente P, Laan R et al (1998) Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. Ciblos study group. J Clin Endocrinol Metab 83:1128–1133

    Article  CAS  PubMed  Google Scholar 

  15. van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13:777–787

    Article  PubMed  Google Scholar 

  16. Kanis JA, Johansson H, Oden A et al (2004) A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 19:893–899

    Article  PubMed  Google Scholar 

  17. Canalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328

    Article  CAS  PubMed  Google Scholar 

  18. den Uyl D, Bultink IE, Lems WF (2011) Advances in glucocorticoid-induced osteoporosis. Curr Rheumatol Rep 13:233–240

    Article  CAS  Google Scholar 

  19. Dore RK (2013) Long-term safety, efficacy, and patient acceptability of teriparatide in the management of glucocorticoid-induced osteoporosis. Patient Prefer Adherence 7:435–446

    Article  PubMed  PubMed Central  Google Scholar 

  20. Panday K, Gona A, Humphrey MB (2014) Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Disord 6:185–202

    Article  CAS  Google Scholar 

  21. Angeli A, Guglielmi G, Dovio A et al (2006) High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone 39:253–259

    Article  CAS  PubMed  Google Scholar 

  22. Amin S, Lavalley MP, Simms RW, Felson DT (2002) The comparative efficacy of drug therapies used for the management of corticosteroid-induced osteoporosis: a meta-regression. J Bone Miner Res 17:1512–1526

    Article  CAS  PubMed  Google Scholar 

  23. Homik JE, Cranney A, Shea B et al (1999) A meta-analysis on the use of bisphosphonates in corticosteroid induced osteoporosis. J Rheumatol 26:1148–1157

    CAS  PubMed  Google Scholar 

  24. Rizzoli R, Biver E (2015) Glucocorticoid-induced osteoporosis: who to treat with what agent? Nat Rev Rheumatol 11:98–109

    Article  CAS  PubMed  Google Scholar 

  25. Seibel MJ, Cooper MS, Zhou H (2013) Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. Lancet Diabetes Endocrinol 1:59–70

    Article  CAS  PubMed  Google Scholar 

  26. Sutton AJ, Abrams KR (2001) Bayesian methods in meta-analysis and evidence synthesis. Stat Methods Med Res 10:277–303

    Article  CAS  PubMed  Google Scholar 

  27. Dias S, Welton NJ, Sutton AJ, Ades AE (2013) Evidence synthesis for decision making 5: the baseline natural history model. Med Decis Mak 33:657–670

    Article  Google Scholar 

  28. Hamra G, MacLehose R, Richardson D (2013) Markov chain Monte Carlo: an introduction for epidemiologists. Int J Epidemiol 42:627–634

    Article  PubMed  PubMed Central  Google Scholar 

  29. Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JP (2012) Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane database of systematic reviews. Int J Epidemiol 41:818–827

    Article  PubMed  PubMed Central  Google Scholar 

  30. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15:993–1000

    Article  PubMed  Google Scholar 

  31. Kalpakcioglu BB, Engelke K, Genant HK (2011) Advanced imaging assessment of bone fragility in glucocorticoid-induced osteoporosis. Bone 48:1221–1231

    Article  PubMed  Google Scholar 

  32. Rüegsegger P, Medici TC, Anliker M (1983) Corticosteroid-induced bone loss. A longitudinal study of alternate day therapy in patients with bronchial asthma using quantitative computed tomography. Eur J Clin Pharmacol 25:615–620

    Article  PubMed  Google Scholar 

  33. Albaum JM, Lévesque LE, Gershon AS, Liu G, Cadarette SM (2015) Glucocorticoid-induced osteoporosis management among seniors, by year, sex, and indication, 1996–2012. Osteoporos Int 26:2845–2852

    Article  CAS  PubMed  Google Scholar 

  34. Majumdar SR, Lix LM, Morin SN et al (2013) The disconnect between better quality of glucocorticoid-induced osteoporosis preventive care and better outcomes: a population-based cohort study. J Rheumatol 40:1736–1741

    Article  CAS  PubMed  Google Scholar 

  35. LoCascio V, Bonucci E, Imbimbo B et al (1990) Bone loss in response to long-term glucocorticoid therapy. Bone Miner 8:39–51

    Article  CAS  PubMed  Google Scholar 

  36. Reid DM, Devogelaer JP, Saag K et al (2009) Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (horizon): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 373:1253–1263

    Article  CAS  PubMed  Google Scholar 

  37. Ringe JD, Dorst A, Faber H, Schacht E, Rahlfs VW (2004) Superiority of alfacalcidol over plain vitamin D in the treatment of glucocorticoid-induced osteoporosis. Rheumatol Int 24:63–70

    Article  CAS  PubMed  Google Scholar 

  38. Teramukai S, Matsuyama Y, Mizuno S, Sakamoto J (2004) Individual patient-level and study-level meta-analysis for investigating modifiers of treatment effect. Jpn J Clin Oncol 34:717–721

    Article  PubMed  Google Scholar 

  39. Dias S, Sutton AJ, Welton NJ, Ades AE (2013) Evidence synthesis for decision making 3: heterogeneity--subgroups, meta-regression, bias, and bias-adjustment. Med Decis Mak 33:618–640

    Article  Google Scholar 

  40. van Houwelingen HC, Arends LR, Stijnen T (2002) Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 21:589–624

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

MAA is supported by the CAnadian Network for Advanced Interdisciplinary Methods for Comparative Effectiveness Research (CAN-AIM) training scholarship and the Leslie Dan Faculty of Pharmacy Dean’s Entrance Scholarship and was supported by the Drug Safety and Effectiveness Cross-Disciplinary Training scholarship. The funding agencies did not have any role in the design and conduct of the study; analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Author information

Authors and Affiliations

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada

    M. A. Amiche, J. M. Albaum, M. Tadrous, P. Pechlivanoglou & S. M. Cadarette

  2. St. Michael’s Hospital, Toronto, ON, Canada

    M. Tadrous

  3. Department of Public Health Sciences, Queens University, Kingston, ON, Canada

    L. E. Lévesque

  4. Department of Medicine, McMaster University, Hamilton, ON, Canada

    J. D. Adachi

Authors
  1. M. A. Amiche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. M. Albaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Tadrous
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Pechlivanoglou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. E. Lévesque
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. D. Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. M. Cadarette
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. A. Amiche.

Ethics declarations

Conflicts of interest

JDA reports having participated in clinical trials sponsored by Procter & Gamble, Amgen and by Merck for the prevention and treatment of glucocorticoid-induced osteoporosis. JDA also reports having received consulting fees and research grants from Actavis, Amgen, Eli Lilly, Merck, and Novartis. MAA, JMA, MT, PP, LEL, and SMC state that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 79 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amiche, M.A., Albaum, J.M., Tadrous, M. et al. Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials. Osteoporos Int 27, 1709–1718 (2016). https://doi.org/10.1007/s00198-015-3455-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-015-3455-9

Keywords

Search

Navigation