Skip to main content

Advertisement

SpringerLink
Log in

Association between use of benzodiazepines and risk of fractures: a meta-analysis

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

Abstract

Summary

Benzodiazepines (BZDs) are some of the most commonly prescribed drugs in the world. It has been shown that BZD use could be associated with increased fracture risk. However, studies on the use of BZDs and fracture risk have yielded inconsistent results. Results from the present meta-analysis show that BZD use is associated with a moderate and clinically significant increase in the risk of fractures.

Introduction

The relationship between the use of BZDs and fracture risk has been neither well identified nor summarized. This meta-analysis reports on the use of BZDs, especially short-acting BZDs, and their correlation with a moderate and clinically significant increase in fracture risk. This analysis will provide evidence for clinicians to consider fracture risk when prescribing BZDs among the elderly population. This study was conducted to determine whether people who take BZDs are at an increased fracture risk.

Methods

A systematic search of studies published through January 2013 was conducted using MEDLINE, EMBASE, OVID, and ScienceDirect. Case–control and cohort studies that assessed the relationship between BZD use and the risk of fractures were identified. Literature searches, study selections, methodological assessments, and data mining were independently conducted by two reviewers. Disagreements were resolved by consensus. STATA 12.0 software was used for the meta-analysis. Random effects models were used for pooled analysis due to heterogeneity among the studies.

Results

There were 25 studies, including 19 case–control studies and 6 cohort studies, that met the inclusion criteria. Overall, the results of the meta-analysis indicated that BZD use was associated with a significantly increased fracture risk (relative risk (RR) = 1.25; 95 % confidence intervals (CI), 1.17–1.34; p < 0.001). Increased fracture risk associated with BZD use was observed in participants aged ≥65 years old (RR = 1.26; 95 % CI, 1.15–1.38; p < 0.001). When only hip fractures were included as the outcome measure, the RR increased to 1.35. However, subgroup meta-analyses showed that there was no significant association between BZD use and fracture risk in Eastern countries (RR = 1.27; 95 % CI, 0.76–2.14; p = 0.362) as well as between long-acting BZD use and risk of fractures (RR = 1.21; 95 % CI, 0.95–1.54; p = 0.12). After accounting for publication bias, we observed that the overall association between BZD use and fracture risk to be slightly weaker (RR = 1.21; 95 % CI, 1.13–1.30) but still significant.

Conclusion

The results of this meta-analysis demonstrate that the use of BZD, especially short-acting BZD, is associated with a moderate and clinically significant increase in fracture risk. However, large prospective studies that minimize selection bias are necessary to determine a more accurate fracture risk associated with BZD use.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lin PC, Lu CM (2005) Hip fracture: family caregivers' burden and related factors for older people in Taiwan. J Clin Nurs 14(6):719–726

    Article  PubMed  Google Scholar 

  2. Shyu YI, Chen MC, Liang J, Lu JF, Wu CC, Su JY (2004) Changes in quality of life among elderly patients with hip fracture in Taiwan. Osteoporos Int 15(2):95–102

    Article  PubMed  Google Scholar 

  3. Leibson CL, Tosteson AN, Gabriel SE, Ransom JE, Melton LJ (2002) Mortality, disability, and nursing home use for persons with and without hip fracture: a population-based study. J Am Geriatr Soc 50(10):1644–1650

    Article  PubMed  Google Scholar 

  4. [No authors listed] (2003) Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 916 (1–149)

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

    Article  CAS  PubMed  Google Scholar 

  6. Wu Q, Qu W, Crowell MD, Hentz JG, Frey KA (2012) Tricyclic antidepressant use and risk of fractures: a meta-analysis of cohort and case–control studies. J Bone Miner Res 28(4):753–763

    Article  Google Scholar 

  7. Rabenda V, Nicolet D, Beaudart C, Bruyere O, Reginster JY (2013) Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporos Int 24(1):121–137

    Article  CAS  PubMed  Google Scholar 

  8. Jette N, Lix LM, Metge CJ, Prior HJ, McChesney J, Leslie WD (2011) Association of antiepileptic drugs with nontraumatic fractures: a population-based analysis. Arch Neurol 68(1):107–112

    Article  PubMed  Google Scholar 

  9. Zint K, Haefeli WE, Glynn RJ, Mogun H, Avorn J, Sturmer T (2010) Impact of drug interactions, dosage, and duration of therapy on the risk of hip fracture associated with benzodiazepine use in older adults. Pharmacoepidemiol Drug Saf 19(12):1248–1255

    Article  CAS  PubMed  Google Scholar 

  10. Nurminen J, Puustinen J, Piirtola M, Vahlberg T, Kivela SL (2010) Psychotropic drugs and the risk of fractures in old age: a prospective population-based study. BMC Public Health 10:396

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chang CM, Wu EC, Chang IS, Lin KM (2008) Benzodiazepine and risk of hip fractures in older people: a nested case–control study in Taiwan. Am J Geriatr Psychiatry 16(8):686–692

    Article  PubMed  Google Scholar 

  12. 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(4):384–391

    Article  PubMed  Google Scholar 

  13. Kang DY, Park S, Rhee CW, Kim YJ, Choi NK, Lee J, Park BJ (2012) Zolpidem use and risk of fracture in elderly insomnia patients. J Prev Med Public Health 45(4):219–226

    Article  PubMed  Google Scholar 

  14. Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA (2003) Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163(8):949–957

    Article  PubMed  Google Scholar 

  15. Pierfitte C, Macouillard G, Thicoipe M, Chaslerie A, Pehourcq F, Aissou M, Martinez B, Lagnaoui R, Fourrier A, Begaud B et al (2001) Benzodiazepines and hip fractures in elderly people: case–control study. BMJ 322(7288):704–708

    Article  CAS  PubMed  Google Scholar 

  16. Ray WA, Griffin MR, Downey W (1989) Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 262(23):3303–3307

    Article  CAS  PubMed  Google Scholar 

  17. Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J (2001) Zolpidem use and hip fractures in older people. J Am Geriatr Soc 49(12):1685–1690

    Article  CAS  PubMed  Google Scholar 

  18. Wagner AK, Zhang F, Soumerai SB, Walker AM, Gurwitz JH, Glynn RJ, Ross-Degnan D (2004) Benzodiazepine use and hip fractures in the elderly: who is at greatest risk? Arch Intern Med 164(14):1567–1572

    Article  PubMed  Google Scholar 

  19. Brown MJ, Mezuk B (2012) Brains, bones, and aging: psychotropic medications and bone health among older adults. Curr Osteoporos Rep 10(4):303–311

    Article  PubMed  PubMed Central  Google Scholar 

  20. Smith AJ, Tett SE (2010) Improving the use of benzodiazepines—is it possible? A non-systematic review of interventions tried in the last 20 years. BMC Health Serv Res 10:321

    Article  PubMed  PubMed Central  Google Scholar 

  21. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283(15):2008–2012

    Article  CAS  PubMed  Google Scholar 

  22. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006–1012

    Article  PubMed  Google Scholar 

  23. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    Article  PubMed  Google Scholar 

  24. 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 

  25. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  PubMed  Google Scholar 

  26. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  Google Scholar 

  27. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  28. 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(11):1119–1129

    Article  CAS  PubMed  Google Scholar 

  29. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    Article  CAS  PubMed  Google Scholar 

  30. Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed  Google Scholar 

  31. 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(2):455–463

    Article  CAS  PubMed  Google Scholar 

  32. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2007) Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Stat Med 26(25):4544–4562

    Article  PubMed  Google Scholar 

  33. Perreault S, Dragomir A, Blais L, Moride Y, Rossignol M, Ste-Marie LG, Fernandes JC (2008) Population-based study of the effectiveness of bone-specific drugs in reducing the risk of osteoporotic fracture. Pharmacoepidemiol Drug Saf 17(3):248–259

    Article  CAS  PubMed  Google Scholar 

  34. Schlienger RG, Kraenzlin ME, Jick SS, Meier CR (2004) Use of beta-blockers and risk of fractures. JAMA 292(11):1326–1332

    Article  CAS  PubMed  Google Scholar 

  35. Vestergaard P, Rejnmark L, Mosekilde L (2004) Fracture risk associated with use of antiepileptic drugs. Epilepsia 45(11):1330–1337

    Article  CAS  PubMed  Google Scholar 

  36. Sgadari A, Lapane KL, Mor V, Landi F, Bernabei R, Gambassi G (2000) Oxidative and nonoxidative benzodiazepines and the risk of femur fracture. The Systematic Assessment of Geriatric Drug Use Via Epidemiology Study Group. J Clin Psychopharmacol 20(2):234–239

    Article  CAS  PubMed  Google Scholar 

  37. Vestergaard P, Tigaran S, Rejnmark L, Tigaran C, Dam M, Mosekilde L (1999) Fracture risk is increased in epilepsy. Acta Neurol Scand 99(5):269–275

    Article  CAS  PubMed  Google Scholar 

  38. Guo Z, Wills P, Viitanen M, Fastbom J, Winblad B (1998) Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study. Am J Epidemiol 148(9):887–892

    Article  CAS  PubMed  Google Scholar 

  39. Jacqmin-Gadda H, Fourrier A, Commenges D, Dartigues JF (1998) Risk factors for fractures in the elderly. Epidemiology 9(4):417–423

    Article  CAS  PubMed  Google Scholar 

  40. Herings RM, Stricker BH, de Boer A, Bakker A, Sturmans F (1995) Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life. Arch Intern Med 155(16):1801–1807

    Article  CAS  PubMed  Google Scholar 

  41. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332(12):767–773

    Article  CAS  PubMed  Google Scholar 

  42. Lichtenstein MJ, Griffin MR, Cornell JE, Malcolm E, Ray WA (1994) Risk factors for hip fractures occurring in the hospital. Am J Epidemiol 140(9):830–838

    CAS  PubMed  Google Scholar 

  43. Cumming RG, Klineberg RJ (1993) Psychotropics, thiazide diuretics and hip fractures in the elderly. Med J Aust 158(6):414–417

    CAS  PubMed  Google Scholar 

  44. Jensen J, Nielsen LH, Lyhne N, Hallas J, Brosen K, Gram LF (1991) Drugs and femoral neck fracture: a case–control study. J Intern Med 229(1):29–33

    Article  CAS  PubMed  Google Scholar 

  45. Stevens A, Mulrow C (1989) Drugs affecting postural stability and other risk factors in the hip fracture epidemic—case–control study. Community Med 11(1):27–34

    CAS  PubMed  Google Scholar 

  46. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LR (1987) Psychotropic drug use and the risk of hip fracture. N Engl J Med 316(7):363–369

    Article  CAS  PubMed  Google Scholar 

  47. Ray WA (1992) Psychotropic drugs and injuries among the elderly: a review. J Clin Psychopharmacol 12(6):386–396

    CAS  PubMed  Google Scholar 

  48. Olkkola KT, Ahonen J (2008) Midazolam and other benzodiazepines. Handb Exp Pharmacol 182:335–360

    Article  CAS  PubMed  Google Scholar 

  49. Leipzig RM, Cumming RG, Tinetti ME (1999) Drugs and falls in older people: a systematic review and meta-analysis: I. Psychotropic drugs J Am Geriatr Soc 47(1):30–39

    CAS  Google Scholar 

  50. Campbell AJ, Robertson MC, Gardner MM, Norton RN, Buchner DM (1999) Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 47(7):850–853

    CAS  PubMed  Google Scholar 

  51. Koopmans R, Dingemanse J, Danhof M, Horsten GP, van Boxtel CJ (1991) The influence of dosage time of midazolam on its pharmacokinetics and effects in humans. Clin Pharmacol Ther 50(1):16–24

    Article  CAS  PubMed  Google Scholar 

  52. Albrecht S, Ihmsen H, Hering W, Geisslinger G, Dingemanse J, Schwilden H, Schuttler J (1999) The effect of age on the pharmacokinetics and pharmacodynamics of midazolam. Clin Pharmacol Ther 65(6):630–639

    Article  CAS  PubMed  Google Scholar 

  53. Cumming RG, Le Couteur DG (2003) Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs 17(11):825–837

    Article  CAS  PubMed  Google Scholar 

  54. Petitjean S, Ladewig D, Meier CR, Amrein R, Wiesbeck GA (2007) Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies. Int Clin Psychopharmacol 22(5):292–298

    Article  PubMed  Google Scholar 

  55. Esposito E, Barbui C, Patten SB (2009) Patterns of benzodiazepine use in a Canadian population sample. Epidemiol Psichiatr Soc 18(3):248–254

    PubMed  Google Scholar 

  56. Swift CG, Swift MR, Hamley J, Stevenson IH, Crooks J (1984) Side-effect ‘tolerance’ in elderly long-term recipients of benzodiazepine hypnotics. Age Ageing 13(6):335–343

    Article  CAS  PubMed  Google Scholar 

  57. Eto F, Saotome I, Furuichi T, Ogasawara M (1998) Effects of long-term use of benzodiazepines on gait and standing balance in the elderly. Ann N Y Acad Sci 860:543–545

    Article  CAS  PubMed  Google Scholar 

  58. Bribes E, Bourrie B, Esclangon M, Galiegue S, Vidal H, Casellas P (2002) Involvement of the peripheral benzodiazepine receptor in the development of rheumatoid arthritis in Mrl/lpr mice. Eur J Pharmacol 452(1):111–122

    Article  CAS  PubMed  Google Scholar 

  59. Casellas P, Galiegue S, Basile AS (2002) Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int 40(6):475–486

    Article  CAS  PubMed  Google Scholar 

  60. Takkouche B, Montes-Martinez A, Gill SS, Etminan M (2007) Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf 30(2):171–184

    Article  PubMed  Google Scholar 

  61. Jorgensen NR, Schwarz P, Holme I, Henriksen BM, Petersen LJ, Backer V (2007) The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease: a cross sectional study. Respir Med 101(1):177–185

    Article  CAS  PubMed  Google Scholar 

  62. Vrieze A, de Greef MH, Wijkstra PJ, Wempe JB (2007) Low bone mineral density in COPD patients related to worse lung function, low weight and decreased fat-free mass. Osteoporos Int 18(9):1197–1202

    Article  CAS  PubMed  Google Scholar 

  63. Uretmen S, Gol M, Cimrin D, Irmak E (2005) Effects of chronic liver disease on bone mineral density and bone metabolism markers in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 123(1):67–71

    Article  CAS  PubMed  Google Scholar 

  64. Strotmeyer ES, Cauley JA (2007) Diabetes mellitus, bone mineral density, and fracture risk. Curr Opin Endocrinol Diabetes Obes 14(6):429–435

    Article  PubMed  Google Scholar 

  65. Nurminen J, Puustinen J, Piirtola M, Vahlberg T, Lyles A, Kivela SL (2012) Opioids, antiepileptic and anticholinergic drugs and the risk of fractures in patients 65 years of age and older: a prospective population-based study. Age Ageing 42(3):318–324

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. van Staa TP, Leufkens HG, Cooper C (2000) Use of nonsteroidal anti-inflammatory drugs and risk of fractures. Bone 27(4):563–568

    Article  PubMed  Google Scholar 

  68. 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(6):993–1000

    Article  PubMed  Google Scholar 

  69. 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 

Download references

Acknowledgments

The authors thank Professor Edmund Y.S. Chao for his great advice regarding researching unpublished literature. This study was supported by grants from the National Natural Science Foundation of China (no. 81102607), the National Natural Science Foundation of Tianjin (043111411, 993607711), the Key Technologies & Program of Tianjin (no. 11ZCGYSY01800), the Scientific and Technological Project of Tianjin Public Security Bureau (no. 2013KYSGAY033), and the Scientific and Technological Project of Tianjin Public Health Bureau (no. 11KG137 and 12KG120).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Orthopaedics Institute, Tianjin Hospital, 406 Jiefang Nan Street, Hexi District, Tianjin, 300211, China

    D. Xing, X. L. Ma, Y. Yang & Y. Chen

  2. Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China

    X. L. Ma, J. X. Ma & J. Wang

Authors
  1. D. Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X. L. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. X. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X. L. Ma.

Additional information

The first two authors contributed equally to this work.

Appendix

Appendix

Search strategy for MEDLINE (OVID).

  1. 1.

    exp Benzodiazepines/or benzodiazepine#.mp.

  2. 2.

    diazepam.mp. or exp Diazepam/

  3. 3.

    clonazepam.mp. or exp Clonazepam/

  4. 4.

    chlordiazepoxide.mp. or exp Chlordiazepoxide/

  5. 5.

    medazepam.mp. or exp Medazepam/

  6. 6.

    nitrazepam.mp. or exp Nitrazepam/

  7. 7.

    lorazepam.mp. or exp Lorazepam/

  8. 8.

    oxazepam.mp. or exp Oxazepam/

  9. 9.

    Temazepam.mp. or exp Temazepam/

  10. 10.

    1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9

  11. 11.

    exp Fractures, Bone/

  12. 12.

    fracture#.mp.

  13. 13.

    exp Osteoporosis/or osteoporosis.mp.

  14. 14.

    osteopenia.mp. or exp Bone Diseases, Metabolic/

  15. 15.

    bone mineral density.mp. or exp Bone Density/

  16. 16.

    bone density.mp.

  17. 17.

    bone loss.mp.

  18. 18.

    bone#.mp.

  19. 19.

    bone mass.mp.

  20. 20.

    fall$.tw.

  21. 21.

    11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xing, D., Ma, X.L., Ma, J.X. et al. Association between use of benzodiazepines and risk of fractures: a meta-analysis. Osteoporos Int 25, 105–120 (2014). https://doi.org/10.1007/s00198-013-2446-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-013-2446-y

Keywords

Search

Navigation