Calcified Tissue International

, Volume 82, Issue 1, pp 34–43

Anxiolytics and Sedatives and Risk of Fractures: Effects of Half-life



To study the risk of fractures associated with anxiolytics, sedatives, and hypnotics, we conducted a case-control study. Cases were all subjects with any fracture during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The exposure was use of any anxiolytic, sedative, or hypnotics. Adjustments were made for a number of potential confounders. Most anxiolytics, sedatives, and hypnotics were associated with a limited increase in the risk of fractures. There was a dose-response relationship, and drugs with a half-life longer than 24 h were associated with a trend toward a higher relative risk of fractures than drugs with a shorter half-life. Both current use (last use <1 year ago) and past use (last use more than one year ago) were associated with an increased risk of fractures. We conclude that anxiolytics, sedatives, and hypnotics are associated with a limited increase in the risk of fractures. For most drugs a dose-response relationship was present, and drugs with a half-life >24 h tended to be associated with a higher risk of fractures than drugs with a shorter half-life. This points to a dose-dependent risk of, for example, falls leading to fractures. However, the increased risk of fractures with past use may suggest an effect of the condition for which the drug was prescribed rather than the drug per se (confounding by indication).


Fracture Hypnotics Anxiolytics Sedatives Benzodiazepine 


  1. 1.
    Cummings SR, Nevitt MC, Browner WS et al. (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767–773Google Scholar
  2. 2.
    Ray WA, Griffin MR, Downey W (1989) Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 262:3303–3307PubMedCrossRefGoogle Scholar
  3. 3.
    Cumming RG, Klineberg RJ (1993) Psychotropics, thiazide diuretics and hip fractures in the elderly. Med J Aust 158:414–417PubMedGoogle Scholar
  4. 4.
    Tamblyn R, Abrahamowicz M, du BR et al. (2005) A 5-year prospective assessment of the risk associated with individual benzodiazepines and doses in new elderly users. J Am Geriatr Soc 53:233–241PubMedCrossRefGoogle Scholar
  5. 5.
    Hoffmann F, Glaeske G (2006) [New use of benzodiazepines and the risk of hip fracture: a case-crossover study]. Z Gerontol Geriatr 39:143–148PubMedCrossRefGoogle Scholar
  6. 6.
    Ensrud KE, Blackwell TL, Mangione CM, et al. (2002) Central nervous system-active medications and risk for falls in older women. J Am Geriatr Soc 50:1629–1637PubMedCrossRefGoogle Scholar
  7. 7.
    Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD (2005) Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 53:955–962PubMedCrossRefGoogle Scholar
  8. 8.
    Kinjo M, Setoguchi S, Schneeweiss S, et al. (2005) Bone mineral density in subjects using central nervous system-active medications. Am J Med 118:1414PubMedCrossRefGoogle Scholar
  9. 9.
    Pierfitte C, Macouillard G, Thicoipe M, et al. (2001) Benzodiazepines and hip fractures in elderly people: case-control study. BMJ 322:704–708PubMedCrossRefGoogle Scholar
  10. 10.
    Vestergaard P, Rejnmark L, Mosekilde L (2006) Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporosis Int 17:807–816CrossRefGoogle Scholar
  11. 11.
    Frank L (2000) Epidemiology. When an entire country is a cohort. Science 287:2398–2399Google Scholar
  12. 12.
    Andersen TF, Madsen M, Jørgensen J, et al. (1999) The Danish National Hospital Register. Danish Med Bull 46:263–268PubMedGoogle Scholar
  13. 13.
    Vestergaard P, Mosekilde L (2002) Fracture risk in patients with celiac disease, Crohn’s disease, and ulcerative colitis: a nation-wide follow-up study in 16,416 patients in Denmark. Am J Epidemiol 156:1–10PubMedCrossRefGoogle Scholar
  14. 14.
    Wacholder S, McLaughlin JK, Silverman DT, et al. (1992) Selection of controls in case-control studies. I. Principles. Am J Epidemiol 135:1019–1028Google Scholar
  15. 15.
    Capella D (1993) Descriptive tools and analysis. In: Dukes MNG (ed) Drug utilization studies: methods and uses. WHO Regional Publications, European Series No. 45. WHO, Copenhagen, pp 55–78Google Scholar
  16. 16.
    Nielsen GL, Sørensen HT, Zhou W et al. (1997) The pharmaco-epidemiologic prescription database of North Jutland. Int J Risk Saf Med 10:203–205Google Scholar
  17. 17.
    Rosenberg R, Sparle Christensen K, Jepsen PW (2007) Benzodiazepiner. In: Pedersen C, Bjerrum L, Dalhoff KP, Damkier P, Friis H, Hendel J (eds) 2007. Infomatum A/S, Copenhagen, pp 368–371Google Scholar
  18. 18.
    Munk-Jørgensen P, Mortensen PB (1997) The Danish Psychiatric Central Register. Danish Med Bull 44:82–84PubMedGoogle Scholar
  19. 19.
    Miettinen OS (1985) Theoretical epidemiology: principles of occurrence research in medicine. Wiley & Sons, New YorkGoogle Scholar
  20. 20.
    Sidik K, Jonkman JN (2005) A note on variance estimation in random effects meta-regression. J Biopharm Stat 15:823–838PubMedCrossRefGoogle Scholar
  21. 21.
    Knapp G, Hartung J (2003) Improved tests for a random effects meta-regression with a single covariate. Stat Med 22:2693–2710PubMedCrossRefGoogle Scholar
  22. 22.
    Larsen ER, Mosekilde L, Foldspang A (2004) Correlates of falling during 24 h among elderly Danish community residents. Prev Med 39:389–398PubMedCrossRefGoogle Scholar
  23. 23.
    O’Neill TW, Varlow J, Reeve J et al. (1995) Fall frequency and incidence of distal forearm fracture in the UK. J Epidemiol Commun Health 49:597–598CrossRefGoogle Scholar
  24. 24.
    Herings RM, Stricker BH, de Boer A et al. (1995) Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life. Arch Intern Med 155:1801–1807Google Scholar
  25. 25.
    Vestergaard P (2005) Epilepsy, osteoporosis and fracture risk—a meta-analysis. Acta Neurol Scand 112:277–286PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Peter Vestergaard
    • 1
    • 2
  • Lars Rejnmark
    • 1
  • Leif Mosekilde
    • 1
  1. 1.Department of Endocrinology and Metabolism CAarhus University Hospital, Aarhus UniversityAarhusDenmark
  2. 2.The Osteoporosis Clinic, Aarhus AmtssygehusAarhus CDenmark

Personalised recommendations