Abstract
Introduction: Our objective was to study the association between fracture risk and the use of anxiolytics and sedatives (benzodiazepines, etc.), neuroleptics and antidepressants. Subjects and methods: This was a case control study. All cases consisted of subjects who had sustained a fracture during the year 2000 (n=124,655). For each case, three controls (n=373,962) matched for age and gender were randomly drawn from the background population. Exposure was defined as the use of neuroleptics, antidepressants and anxiolytics/sedatives, psychiatric disease (manic depressive states, schizophrenia, other psychoses), and other confounders. The effect of dose was examined as a defined daily dose per day (DDD/day). The values referred to are confounder-adjusted. Results: For anxiolytics and sedatives, there was a small increase in overall fracture risk (OR: around 1.1) even with limited doses (<0.1 DDD/day). No dose-response relationship was observed for anxiolytics and sedatives. For neuroleptics, a limited increase in overall fracture risk was observed (OR: around 1.2 from <0.05 DDD/day with no dose-response relationship). For antidepressants, a dose-response relationship was observed for fracture risk (OR: increasing from 1.15, 95% CI: 1.11–1.19 at <0.15 DDD/day to 1.40, 95% CI: 1.35–1.46 for ≥0.75 DDD/day). The risk of fracture was higher with selective serotonin re-uptake inhibitors than with tricyclic antidepressants. Conclusions: Small increases in fracture risk were seen with the use of anxiolytics and sedatives and neuroleptics without a dose-response relationship. The increase may be linked to an increased risk of falls. For antidepressants, a dose-response relationship was found, with a higher fracture risk for selective serotonin re-uptake inhibitors.
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References
Cumming RG, Klineberg RJ (1993) Psychotropics, thiazide diuretics and hip fractures in the elderly. Med J Aust 158:414–417
Ensrud KE, Blackwell T, Mangione CM et al. (2003) Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163:949–957
Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ III (1987) Psychotropic drug use and the risk of hip fracture. N Engl J Med 316:363–369
Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J (2001) Zolpidem use and hip fractures in older people. J Am Geriatr Soc 49:1685–1690
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 50:1629–1637
Ataya K, Mercado A, Kartaginer J, Abbasi A, Moghissi KS (1988) Bone density and reproductive hormones in patients with neuroleptic-induced hyperprolactinemia. Fertil Steril 50:876–881
Higuchi T, Komoda T, Sugishita M et al (1987) Certain neuroleptics reduce bone mineralization in schizophrenic patients. Neuropsychobiology 18:185–188
Whooley MA, Kip KE, Cauley JA et al. (1999) Depression, falls, and risk of fracture in older women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 159:484–490
Mussolino ME, Jonas BS, Looker AC (2004) Depression and bone mineral density in young adults: results from NHANES III. Psychosom Med 66:533–537
Wong SYS, Lau EMC, Lynn H et al. (2005) Depression and bone mineral density: is there a relationship in elderly Asian men? Results from Mr. Os (Hong Kong). Osteoporos Int 16:610–615
Sogaard AJ, Joakimsen RM, Tverdal A et al. (2005) Long-term mental distress, bone mineral density and non-vertebral fractures. The Tromsø Study. Osteoporos Int 16:887–897
Frank L (2000) Epidemiology. When an entire country is a cohort. Science 287:2398–2399
Andersen TF, Madsen M, Jørgensen J, Mellemkjær L, Olsen JH (1999) The Danish National Hospital register. Dan Med Bull 46:263–268
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 156:1–10
Wacholder S, McLaughlin JK, Silverman DT, Mandel JS (1992) Selection of controls in case-control studies. I. Principles. Am J Epidemiol 135:1019–1028
Capella D (1993) Descriptive tools and analysis. In: Dukes MNG (ed) Drug utilization studies: methods and uses. WHO Regional Publications, European Series No. 45,Copenhagen, pp 55–78
Nielsen GL, Sørensen HT, Zhou W, Steffensen FH, Olsen J (1997) The pharmaco-epidemiologic prescription database of North Jutland. Int J Risk Saf Med 10:203–205
Munk-Jørgensen P, Mortensen PB (1997) The Danish psychiatric central register. Dan Med Bull 44:82–84
Vestergaard P, Emborg C, Støving RK et al (2002) Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disorders - a nation-wide register study. Int J Eating Disord 32:301–308
Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–383
de Groot V, Beckerman H, Lankhorst GJ, Bouter LM (2003) How to measure comorbidity. a critical review of available methods. J Clin Epidemiol 56:221–229
Miettinen OS (1985) Theoretical epidemiology: principles of occurrence research in medicine, 1st edn. Wiley & Sons, New York
Vestergaard P, Mollerup CL, Frøkjær VG et al (2000) Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 321:598–602
Bliziotes M, Gunness M, Eshleman A, Wiren K (2002) The role of dopamine and serotonin in regulating bone mass and strength: studies on dopamine and serotonin transporter null mice. J Musculoskelet Neuronal Interact 2:291–295
Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH (2005) Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146:685–693
Christensen P, Thomsen HY, Pedersen OL, Gram LF, Kragh-Sorensen P (1985) Orthostatic side effects of clomipramine and citalopram during treatment for depression. Psychopharmacology 86:383–385
Arfken CL, Wilson JG, Aronson SM (2001) Retrospective review of selective serotonin reuptake inhibitors and falling in older nursing home residents. Int Psychogeriatr 13:85–91
Hoidrup S, Grønbæk M, Gottschau A, Lauritzen JB, Schroll M (1999) Alcohol intake, beverage preference, and risk of hip fracture in men and women. Am J Epidemiol 149:993–1001
Acknowledgements
Danmarks Statistik (Statistics Denmark) is acknowledged for the help without which this project would not have been possible. Research Librarian ms. Edith Clausen is acknowledged for invaluable help with the references.
The Danish Medical Research Council granted financial support (Grant number 22-04-0495).
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Appendix: Codes used
Appendix: Codes used
ATC codes
Anxiolytics and sedatives: N05BA01, N05BA02, N05BA04, N05BA06, N05BA08, N05BA09, N05BA12, N05BB01, N05BE01, N05CC01, N05CD02, N05CD03, N05CD05, N05CD06, N05CD08, N05CD09, N05CF01, N05CF02, N05CF03, N05CM02
Neuroleptics: N05AA01, N05AA02, N05AA04, N05AB02, N05AB03, N05AB04, N05AC01, N05AC02, N05AD01, N05AD03, N05AD05, N05AE05, N05AF01, N05AF03, N05AF05, N05AG02, N05AG03, N05AH02, N05AH03, N05AH04, N05AK01, N05AL01, N05AL05, N05AX08
Antidepressants: N06AA09, N06AA04, N06AA16, N06AA12, N06AA02, N06AA10, N06AA06, N06AA21, N06AX03, N06AX16, N06AX11, N06AB04, N06AB10, N06AB03, N06AB08, N06AB05, N06AB06, N06AX18, N06AF01, N06AG02
ICD8 and 10 codes for psychiatric disorders:
Manic depressive states: ICD8 codes 29609, 29619, 29629, 29639, 29689, 29699, IDC10 codes F300, F301, F302, F308, F309, F310–F319, F320–F329, F330–F339
Schizophrenia: ICD8 codes 29509, 29519, 29529, 29539, 29549, 29559, 29569, 29579, 29589, 29599, IDC10 codes F200–F209
Other psychoses: ICD8 codes 29209, 29219, 29229, 29239, 29299, 29309, 29319, 29329, 29339, 29349, 29359, 29399, 29409, 29419, 29429, 29430, 29438, 29439, 29449, 29489, 29499, 29709, 29719, 29799, 29809, 29819, 29829, 29839, 29889, 29899, 29900, 29901, 29902, 29903, 29904, 29905, 29909, IDC10 codes F220, F228, F229, F230–F233, F238, F239, F249, F250, F251, F252, F258, F259, F289, F299, F340, F341, F348, F349, F380, F381, F388, F399
Eating disorders: ICD8 codes 30658, 30659, IDC10 codes F502, F503, F504, F505, F508, F509
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Vestergaard, P., Rejnmark, L. & Mosekilde, L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int 17, 807–816 (2006). https://doi.org/10.1007/s00198-005-0065-y
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DOI: https://doi.org/10.1007/s00198-005-0065-y