A hip fracture epidemic is occurring in developed countries in association with population aging. The increasing number of people with a hip fracture has major implications for clinicians and health service managers. More importantly, a hip fracture is a devastating event in the life of an older person, as it often leads to loss of independence and death. Identification of risk factors for hip fracture is an essential first step towards prevention.
The use of psychotropic medications is an established risk factor for hip fracture. The purpose of this article is to systematically review epidemiological studies of the relationship between use of benzodiazepines and risk of hip fracture and, then, to see how the findings of these studies fit with what is known about the pharmacology of benzodiazepines.
Eleven primary epidemiological studies were identified. The results of these studies were not consistent; however, the inconsistency appeared to be almost entirely explained by research design. The studies that did not show an association between increased hip fracture risk and benzodiazepine use were nearly all hospital-based case-control studies, a type of study that often lacks validity because of the difficulty of finding an appropriate control group. After excluding the hospital-based case-control studies, all but one of the remaining seven studies found that use of benzodiazepines was associated with an increased risk of hip fracture that varied between 50% and 110%. The only higher quality study that did not find an association between benzodiazepine use and hip fracture was also the only study conducted entirely in nursing homes.
There was no evidence that the risk of hip fracture differed between short- and long-acting benzodiazepines. People using higher doses of benzodiazepines and those who had recently started using benzodiazepines were at the highest risk of hip fracture. In very old people, there was some preliminary evidence that benzodiazepines that undergo oxidation in the liver may be associated with a higher risk of hip fracture than other benzodiazepines.
The epidemiological evidence strongly suggests that the use of benzodiazepines by older people increases their risk of hip fracture by at least 50%. The benefits of benzodiazepines for older people are unclear. Given the high morbidity and mortality of hip fracture, it can be concluded that older people should rarely be prescribed benzodiazepines and that many older people already taking these drugs should have them withdrawn under appropriate supervision.
Nursing Home Psychotropic Medication Nursing Home Resident Temazepam Observational Epidemiological Study
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.
Sanders KM, Nicholson GC, Ugoni AM, et al. Health burden of hip and other fractures in Australia beyond 2000: projections based on the Geelong Osteoporosis Study. Med J Aust 1999; 170: 467–70PubMedGoogle Scholar
MacDonald JB, MacDonald ET. Nocturnal femoral fracture and continuing widespread use of barbiturate hypnotics. BMJ 1977; 2: 483–5PubMedCrossRefGoogle Scholar
Ray WA, Griffin MR, Schaffner W, et al. Psychotropic drug use and the risk of hip fracture. New Engl J Med 1987; 316: 363–9PubMedCrossRefGoogle Scholar
Liu B, Anderson G, Mittmann N, et al. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998; 351: 1303–7PubMedCrossRefGoogle Scholar
Jorm AF, Grayson D, Creasey H, et al. Long-term benzodiazepine use by elderly people living in the community. Aust N Z J Public Health 2000; 24: 7–10PubMedCrossRefGoogle Scholar
Kirby M, Denihan A, Bruce I, et al. Benzodiazepine use among the elderly in the community. Int J Geriatr Psychiatry 1999; 14: 280–4PubMedCrossRefGoogle Scholar
Tu K, Mamdani MM, Hux JE, et al. Progressive trends in the prevalence of benzodiazepine prescribing in older people in Ontario, Canada. J Am Geriatr Soc 2001; 49: 1341–5PubMedCrossRefGoogle Scholar
Fourrier A, Letenneur L, Dartigues JF, et al. Benzodiazepine use in an elderly community-dwelling population: characteristics of users and factors associated with subsequent use. Eur J Clin Pharmacol 2001; 57: 419–25PubMedCrossRefGoogle Scholar
Egan M, Moride Y, Wolfson C, et al. Long-term continuous use of benzodiazepines by older adults in Quebec: prevalence, incidence and risk factors. J Am Geriatr Soc 2000; 48: 811–6PubMedGoogle Scholar
Ramesh M, Roberts G. Use of night-time benzodiazepines in an elderly inpatient population. J Clin Pharm Ther 2002; 27: 93–7PubMedCrossRefGoogle Scholar
Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and meta-analysis. I: psychotropic drugs. J Am Geriatr Soc 1999; 47: 30–9Google Scholar
Campbell A, Robertson M, Gardner M, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized controlled trial. J Am Geriatr Soc 1999; 47: 850–3PubMedGoogle Scholar
Weintraub M, Handy BM. Benzodiazepines and hip fracture: the New York State experience. Clin Pharmacol Ther 1993; 54: 252–6PubMedCrossRefGoogle Scholar
Moore N, Pierfitte C, Pehourcq F, et al. Comparison of patient questionnaires, medical records, and plasma assays in assessing exposure to benzodiazepines in elderly subjects. Clin Pharmacol Ther 2001; 69: 445–50PubMedCrossRefGoogle Scholar
Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women: Study of Osteoporotic Fractures Research Group. New Engl J Med 1995; 332: 767–73PubMedCrossRefGoogle Scholar
Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 1989; 262: 3303–7PubMedCrossRefGoogle Scholar
Cumming RG, Klineberg RJ. Psychotropics, thiazide diuretics and hip fractures in the elderly. Med J Aust 1993; 158: 414–7PubMedGoogle Scholar
Herings RM, Stricker BH, de Boer A, et al. Benzodiazepines and the risk of falling leading to femur fractures: dosage more important than elimination half-life. Arch Intern Med 1995; 155: 1801–7PubMedCrossRefGoogle Scholar
Wang PS, Bohn RL, Glynn RJ, et al. Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture. Am J Psychiatr 2001; 158: 892–8PubMedGoogle Scholar
Sgadari A, Lapane K, Mor V, et al. Oxidative and nonoxidative benzodiazepines and the risk of femur fracture. J Clin Psychopharmacol 2000; 20: 234–9PubMedCrossRefGoogle Scholar
Lichtenstein MJ, Griffin MR, Cornell JE, et al. Risk factors for hip fractures occurring in the hospital. Am J Epidemiol 1994; 140: 830–8PubMedGoogle Scholar
Stevens A, Mulrow C. Drugs affecting postural stability and other risk factors in the hip fracture epidemic: case-control study. Community Med 1989; 11: 27–34PubMedGoogle Scholar
Grisso JA, Kelsey JL, Strom BL, et al. Risk factors for falls as a cause of hip fracture in women: the Northeast Hip Fracture Study Group. New Engl J Med 1991; 324: 1326–31PubMedCrossRefGoogle Scholar
Schwab M, Roder F, Alekar T, et al. Psychotropic drug use, falls and hip fracture in the elderly. Aging Clin Exp Res 2000; 12: 234–9Google Scholar
Pierfitte C, Macouillard G, Thicoipe M, et al. Benzodiazepines and hip fractures in elderly people: case-control study. BMJ 2001; 322: 704–8PubMedCrossRefGoogle Scholar
Thapa PB, Brockman KG, Gideon P, et al. Injurious falls in nonambulatory nursing home residents: a comparative study of circumstances, incidence, and risk factors. J Am Geriatr Soc 1996; 44: 273–8PubMedGoogle Scholar
Studenski S, Duncan PW, Chandler J, et al. Predicting falls: the role of mobility and nonphysical factors. J Am Geriatr Soc 1994; 42: 297–302PubMedGoogle Scholar
Grisso JA, Kelsey JL, Strom BL, et al. Risk factors for hip racture in black women: the Northeast Hip Fracture Study Group. N Engl J Med 1994; 330: 1555–9PubMedCrossRefGoogle Scholar
Wysowski DK, Baum C, Ferguson WJ, et al. Sedative-hypnotic drugs and the risk of hip fracture. J Clin Epidemiol 1996; 49: 111–3PubMedCrossRefGoogle Scholar
Ray WA, Thapa PB, Gideon P. Benzodiazepines and the risk of falls in nursing home residents. J Am Geriatr Soc 2000; 48: 682–5PubMedGoogle Scholar
Passaro A, Volpato S, Romagnoni F, et al. Benzodiazepines with different half-life and falling in a hospitalized population: the GIFA study: Gruppo Italiano di Farmacovigilanza nell’Anziano. J Clin Epidemiol 2000; 53: 1222–9PubMedCrossRefGoogle Scholar
Ryynanen OP, Kivela SL, Honkanen R, et al. Medications and chronic diseases as risk factors for falling injuries in the elderly. Scand J Soc Med 1993; 21: 264–71PubMedGoogle Scholar
Le Couteur DG, McLean AJ. The aging liver: drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34: 359–73PubMedCrossRefGoogle Scholar
Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (part I). Clin Pharmacokinet 1991; 21: 165–77PubMedCrossRefGoogle Scholar
Neutel CI, Hirdes JP, Maxwell CJ, et al. New evidence on benzodiazepine use and falls: the time factor. Age Ageing 1996; 25: 273–8PubMedCrossRefGoogle Scholar
Stephens MD, Talbot JC, Routledge PA, editors. Detection of new adverse drug reactions. New York: Grove’s Dictionaries Inc., 1998Google Scholar
Fujimori S, Hinoi E, Yoneda Y. Functional GABA(B) receptors expressed in cultured calvarial osteoblasts. Biochem Biophys Res Commun 2002; 293: 1445–52PubMedCrossRefGoogle Scholar
Rico H, Gervas JJ, Hernandez ER, et al. Effects of alprazolam supplementation on vertebral and femoral bone mass in rats on strenuous treadmill training exercise. Calcif Tissue Int 1999; 65: 139–42PubMedCrossRefGoogle Scholar
Casellas P, Galiegue S, Basile AS. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int 2002;40: 475–86PubMedCrossRefGoogle Scholar
Pomara N, Tun H, DaSilva D, et al. The acute and chronicperformance effects of alprazolam and lorazepam in the elderly:relationship to duration of treatment and self-rated sedation.Psychopharmacol Bull 1998; 34: 139–53PubMedGoogle Scholar
Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology zzof Vascular Aging Study. J Clin Psychopharmacol 2002; 22: 285–93PubMedCrossRefGoogle Scholar
Swift CG, Swift MR, Hamley J, et al. Side-effect ‘tolerance’ in elderly long-term recipients of benzodiazepine hypnotics. Age Ageing 1984; 13: 335–43PubMedCrossRefGoogle Scholar
Eto F, Saotome I, Furuichi T, et al. Effects of long-term use of benzodiazepines on gait and standing balance in the elderly. Ann N Y Acad Sci 1998; 860: 543–5PubMedCrossRefGoogle Scholar
Speeg-Schatz C, Giersch A, Boucart M, et al. Effects of lorazepam on vision and oculomotor balance. Binocul Vis Strabismus Q 2001; 16: 99–104PubMedGoogle Scholar
Albrecht S, Ihmsen H, Hering W, et al. The effect of age on the pharmacokinetics and pharmacodynamics of midazolam. Clin Pharmacol Ther 1999; 65: 630–9PubMedCrossRefGoogle Scholar
Koopmans R, Dingemanse J, Danhof M, et al. The influence of dosage time of midazolam on its pharmacokinetics and effects in humans. Clin Pharmacol Ther 1991; 50: 16–24PubMedCrossRefGoogle Scholar
Tuk B, Herben VM, Mandema JW, et al. Relevance of arteriovenous concentration differences in pharmacokinetic-pharmacodynamic modeling of midazolam. J Pharmacol Exp Ther 1998; 284: 202–7PubMedGoogle Scholar
Kanto J, Kangas L, Aaltonen L, et al. Effect of age on the pharmacokinetics and sedative of flunitrazepam. Int J Clin Pharmacol Ther Toxicol 1981; 19: 400–4PubMedGoogle Scholar
Katelaris AG, Cumming RG. Health status before and mortality after hip fracture. Am J Pub Health 1996; 86: 557–60CrossRefGoogle Scholar
Banazak DA. Anxiety disorders in elderly patients. J Am Board Fam Pract 1997; 10: 280–9PubMedGoogle Scholar
Nowell PD, Mazumdar S, Buysse DJ, et al. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997; 278: 2170–7PubMedCrossRefGoogle Scholar
Grad RM. Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk. J Fam Pract 1995; 41: 473–81PubMedGoogle Scholar
Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999; 281: 991–9PubMedCrossRefGoogle Scholar