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Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case–control studies

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Abstract

Summary

Studies on use of selective serotonin reuptake inhibitors (SSRIs) and risk of fracture have yielded inconsistent results. This meta-analysis, which pooled results from 13 qualifying cohort and case–control studies, found that SSRIs were associated with a significantly increased risk of fractures.

Introduction

This study was conducted to assess whether people who take SSRIs are at an increased risk of fracture.

Methods

We conducted a meta-analysis of observational studies. Relevant studies published by February 2010 were identified through literature searches using MEDLINE (from 1966), EMBASE (from 1988), PsycINFO (from 1806), and manual searching of reference lists. Only cohort or case–control studies that examined the association of SSRIs and risk of fracture and bone loss were included. Data were abstracted independently by two investigators using a standardized protocol; disagreements were resolved by consensus. Random effects models were used for pooled analysis due to heterogeneity in the studies.

Results

Thirteen studies met inclusion criteria. Overall, SSRI use was associated with a significantly increased risk of fracture (relative risk, RR, 1.72; 95% CI [1.51, 1.95]; P < 0.001). An increased fracture risk associated with SSRIs also was observed in the three studies that adjusted for bone mineral density (RR, 1.70; 95% CI [1.28, 2.25]; P < 0.001) and in the four studies that adjusted for depression (RR 1.74; 95% CI [1.28, 2.36]; P < 0.001). SSRI use was not associated with bone loss in the two cohort studies of women (P = 0.29). The overall association between SSRI use and fracture risk was weaker (RR, 1.40; 95% CI [1.22, 1.61]), though still significant (P < 0.001) in analyses that accounted for apparent publication bias.

Conclusions

Use of SSRIs is associated with increased risk of fracture. The SSRIs may exert an increased risk of fracture independent of depression and bone mineral density.

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Abbreviations

BMD:

Bone mineral density

CI:

Confidence interval

HR:

Hazard ratio

MOOSE:

Meta-analysis of Observational Studies in Epidemiology

OR:

Odds ratio

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-analyses

RR:

Relative risk

SSRI:

Selective serotonin reuptake inhibitor

References

  1. Department of Health and Human Services (2004) Bone health and osteoporosis: a report of the surgeon general. US Department of Health and Human Services, Office of the Surgeon General, Rockville. At http://www.surgeongeneral.gov/library/bonehealth/index.html. Accessed 18 Dec 2010

  2. Gehlbach SH, Avrunin JS, Puleo E (2007) Trends in hospital care for hip fractures. Osteoporos Int 18(5):585–591

    Article  PubMed  CAS  Google Scholar 

  3. Chevalley T, Guilley E, Herrmann FR, Hoffmeyer P, Rapin CH, Rizzoli R (2007) Incidence of hip fracture over a 10-year period (1991–2000): reversal of a secular trend. Bone 40(5):1284–1289

    Article  PubMed  CAS  Google Scholar 

  4. Leslie WD, O'Donnell S, Jean S, Lagacé C, Walsh P, Bancej C, for the Osteoporosis Surveillance Expert Working Group et al (2009) Trends in hip fracture rates in Canada. JAMA 302(8):883–889

    Article  PubMed  CAS  Google Scholar 

  5. Melton LJ III, Cooper C (2001) Magnitude and impact of osteoporosis and fractures. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic, San Diego, pp 557–567

    Chapter  Google Scholar 

  6. Pacher P, Ungvari Z (2001) Selective serotonin-reuptake inhibitor antidepressants increase the risk of falls and hip fractures in elderly people by inhibiting cardiovascular ion channels. Med Hypotheses 57:469–471

    Article  PubMed  CAS  Google Scholar 

  7. Liu B, Anderson G, Mittmann N, To T, Axcell T, Shear N (1998) Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 351:1303–1307

    Article  PubMed  CAS  Google Scholar 

  8. Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A et al (2003) Central nervous system active medications and risk for fractures in older women. Arch Intern Med 8:949–957

    Article  Google Scholar 

  9. Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC et al (2007) Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 167:188–194

    Article  PubMed  CAS  Google Scholar 

  10. Ziere G, Dieleman JP, van der Cammen TJ, Hofman A, Pols HA, Stricker BH (2008) Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol 28:411–417

    Article  PubMed  CAS  Google Scholar 

  11. Lewis CE, Ewing SK, Taylor BC, Shikany JM, Fink HA, Ensrud KE et al (2007) Predictors of non-spine fracture in elderly men: the MrOS study. J Bone Miner Res 22(2):211–219

    Article  PubMed  Google Scholar 

  12. Hubbard R, Farrington P, Smith C, Smeeth L, Tattersfield A (2003) Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol 158:77–84

    Article  PubMed  Google Scholar 

  13. Vestergaard P, Rejnmark L, Mosekilde L (2006) Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int 17:807–816

    Article  PubMed  CAS  Google Scholar 

  14. Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD (2008) Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol 28:384–391

    Article  PubMed  Google Scholar 

  15. van den Brand MW, Samson MM, Pouwels S, van Staa TP, Thio B, Cooper C et al (2009) Use of anti-depressants and the risk of fracture of the hip or femur. Osteoporos Int 20:1705–1713

    Article  PubMed  CAS  Google Scholar 

  16. French DD, Campbell R, Spehar A, Cunningham F, Foulis P (2005) Outpatient medications and hip fractures in the US: a national veterans study. Drugs Aging 22:877–885

    Article  PubMed  Google Scholar 

  17. Karasu TB, Gelenberg A, Merriam A, Wang P (2000) American Psychiatric Association practice guideline for the treatment of patients with major depressive disorder (second edition). At http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=MDD2e_05-15-06. Accessed 9 Dec 2010

  18. Pirraglia PA, Stafford RS, Singer DE (2003) Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiatry 5:153–157

    Article  PubMed  Google Scholar 

  19. Schneeweiss S, Wang PS (2004) Association between SSRI use and hip fractures and the effect of residual confounding bias in claims database studies. J Clin Psychopharmacol 24(6):632–638

    Article  PubMed  Google Scholar 

  20. Spangler L, Scholes D, Brunner RL, Robbins J, Reed SD, Newton KM et al (2008) Depressive symptoms, bone loss, and fractures in postmenopausal women. J Gen Intern Med 23(5):567–574

    Article  PubMed  Google Scholar 

  21. Verdel BM, Surverein PC, Egberts TCG, van Staa VP, Leufkens HG, de Vries F (2010) Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures. Bone 47(3):604–609

    Article  PubMed  CAS  Google Scholar 

  22. Schwan S, Hallberg P (2009) SSRIs, bone mineral density, and risk of fractures—a review. Eur Neuropsychopharmacol 19:10683–10692

    Article  Google Scholar 

  23. Vestergaard P (2009) Fracture risks of antidepressants. Expert Rev Neurother 9(1):137–141

    Article  PubMed  Google Scholar 

  24. Ginzburg R, Rosero E (2009) Risk of fractures with selective serotonin reuptake inhibitors or tricyclic antidepressants. Ann Pharmacother 43:98–103

    Article  PubMed  Google Scholar 

  25. Bab I, Yirmiya R (2010) Depression, selective serotonin reuptake inhibitors, and osteoporosis. Curr Osteoporos Rep 8(4):185–191

    Article  PubMed  Google Scholar 

  26. Haney EM, Bliziotes MM (2007) Selective serotonin reuptake inhibitors and bone health. Future Rheumatol 2(2):213–222

    Article  CAS  Google Scholar 

  27. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al (2000) Meta-analysis of observational studies in epidemiology—a proposal for reporting. JAMA 283:2008–2012

    Article  PubMed  CAS  Google Scholar 

  28. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:W65–W94

    PubMed  Google Scholar 

  29. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM et al (2007) Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med 167(12):1240–1245

    Article  PubMed  Google Scholar 

  30. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ (2002) Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288:728–737

    Article  PubMed  Google Scholar 

  31. Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Meth Med Res 8:135–160

    Article  CAS  Google Scholar 

  32. Etminan M, Takkouche B, Isorna FC, Samii A (2005) Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 330:63

    Article  PubMed  Google Scholar 

  33. Walter SD, Cook RJ (1991) A comparison of several point estimators of the odds ratio in a single 2 × 2 contingency table. Biometrics 47(3):795–811

    Article  PubMed  CAS  Google Scholar 

  34. Kahn HA, Sempos CT (1989) Statistical methods in epidemiology. Monogr epidemiol biostat 12:292

    Google Scholar 

  35. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  36. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  Google Scholar 

  37. Furukawa TA, Guyatt GH, Griffith LE (2002) Can we individualize the ‘number needed to treat’? An empirical study of summary effect measures in meta-analyses. Int J Epidemiol 31(1):72–76

    Article  PubMed  Google Scholar 

  38. Sterne JA, Gavaghan D, Egger M (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53:1119–1129

    Article  PubMed  CAS  Google Scholar 

  39. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  PubMed  CAS  Google Scholar 

  40. Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56:455–463

    Article  PubMed  CAS  Google Scholar 

  41. Thapa PB, Gideon P, Cost TW, Milam AB, Ray WA (1998) Antidepressants and the risk of falls among nursing home residents. N Engl J Med 339:875–882

    Article  PubMed  CAS  Google Scholar 

  42. Arfken CL, Wilson JG, Aronson SM (2001) Retrospective review of selective serotonin reuptake inhibitors and falling in older nursing home residents. Int Psychogeriatr 13(1):85–91

    Article  PubMed  CAS  Google Scholar 

  43. Darowski A, Chambers S, Chambers D (2009) Antidepressants and falls in the elderly. Drugs Aging 26(5):381–394

    Article  PubMed  CAS  Google Scholar 

  44. Wu Q, Liu J, Gallegos-Orozco J, Hentz JG (2010) Depression, fracture risk, and bone loss: a meta-analysis of cohort studies. Osteoporos Int 21(10):1627–1635

    Article  PubMed  CAS  Google Scholar 

  45. Wu Q, Magnus JH, Liu J, Bencaz AF, Hentz JG (2009) Depression and bone mineral density: meta-analysis of epidemiological studies. Osteoporos Int 20(8):1309–1320

    Article  PubMed  CAS  Google Scholar 

  46. Kinjo M, Setoguchi S, Schneeweiss S, Solomon DH (2005) Bone mineral density in subjects using central nervous system-active medications. Am J Med 118(12):1414

    Article  PubMed  Google Scholar 

  47. Romas E (2005) Bone loss in inflammatory arthritis: mechanisms and therapeutic approaches with bisphosphonates. Best Pract Res Clin Rheumatol 19(6):1065–1079

    Article  PubMed  CAS  Google Scholar 

  48. Harpavat M, Keljo DJ, Regueiro MD (2004) Metabolic bone disease in inflammatory bowel disease. J Clin Gastroenterol 38(3):218–224

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Kay E. Wellik for her consultation on literature search.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. College of Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA

    Q. Wu, J. G. Hentz & M. D. Crowell

  2. School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    A. F. Bencaz

Authors
  1. Q. Wu
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  2. A. F. Bencaz
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  3. J. G. Hentz
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  4. M. D. Crowell
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Corresponding author

Correspondence to Q. Wu.

Appendix

Appendix

Search strategy for MEDLINE (OVID)

001 exp Serotonin Uptake Inhibitors/

002 serotonin uptake inhibitor#.mp.

003 exp Antidepressive Agents/

004 antidepressant#.mp.

005 exp Fluoxetine/or fluoxetine.mp.

006 ssri#.mp.

007 fluvoxamine.mp. or exp Fluvoxamine/

008 sertraline.mp. or exp Sertraline/

009 citalopram.mp. or Citalopram/

010 escitalopram.mp. or exp Citalopram/

011 paroxetine.mp. or exp Paroxetine/

012 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11

013 exp Fractures, Bone/

014 fracture#.mp.

015 exp Osteoporosis/or osteoporosis.mp.

016 osteopenia.mp. or exp Bone Diseases, Metabolic/

017 bone mineral density.mp. or exp Bone Density/

018 bone density.mp.

019 bone loss.mp.

020 bone#.mp.

021 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

022 12 and 21

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Wu, Q., Bencaz, A.F., Hentz, J.G. et al. Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case–control studies. Osteoporos Int 23, 365–375 (2012). https://doi.org/10.1007/s00198-011-1778-8

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  • DOI: https://doi.org/10.1007/s00198-011-1778-8

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