Abstract
Our aim was to study fracture risk in users of various antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and the group of other antidepressants including monoamine oxidase B inhibitors and drugs with effect on the norepinephrine system) and its relationship with effects on inhibition of the cholinergic and serotonin transporter system. We conducted a case-control study with 124,655 fracture cases and 373,962 age- and gender-matched controls. The exposure was use of antidepressants and a number of confounders. Among the tricyclic antidepressants, amitriptyline and clomipramine were associated with a dose-dependent increase in fracture risk, while imipramine and nortriptyline were not. Amityriptyline was associated with an increased risk of fractures at low doses, while the other tricyclic antidepressants were not. Among the selective serotonin reuptake inhibitors, citalopram, fluoxetine, and sertraline were associated with a dose-dependent increase in fracture risk, while the increase was borderline statistically insignificant for paroxetine. The group of other antidepressants was not associated with fracture risk. The increase in fracture risk was significantly associated with the pharmacodynamic effect on the serotonin transporter system but not on other signaling systems. The effect of antidepressants on the risk of fractures may be linked to their effect on the serotonin transporter system. While selective serotonin receptor uptake inhibitors were associated with an increased fracture risk, tricyclic antidepressants and the group of other antidepressants were not systematically associated with fracture risk.
Similar content being viewed by others
References
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 SY, Lau EM, Lynn H, Leung PC, Woo J, Cummings SR, Orwoll E (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
Konstantynowicz J, Kadziela-Olech H, Kaczmarski M, Zebaze RM, Iuliano-Burns S, Piotrowska-Jastrzebska J, Seeman E (2005) Depression in anorexia nervosa: a risk factor for osteoporosis. J Clin Endocrinol Metab 90:5382–5385
Videbech P, Sparle Christensen K, Buchholtz Hansen PE (2007) Antidepressiva. In: Pedersen C, Bjerrum L, Dalhoff KP, Damkier P, Friis H, Hendel J (eds) Medicin.dk 2007. Infomatum A/S, Copenhagen, pp 373–386
Pollock BG (1999) Adverse reactions of antidepressants in elderly patients. J Clin Psychiatry 20(60 Suppl):4–8
Rodriguez de la Torres B, Dreher J, Malevany I, Bagli M, Kolbinger M, Omran H, Luderitz B, Rao ML (2001) Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients. Ther Drug Monit 23:435–440
Christensen P, Thomsen HY, Pedersen OL, Gram LF, Kragh-Sorensen P (1985) Orthostatic side effects of clomipramine and citalopram during treatment for depression. Psychopharmacology (Berl) 86:383–385
Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM, Ensrud KE (2007) Use of antidepressants and rates of hip bone loss in older women: the Study of Osteoporotic Fractures. Arch Intern Med 167:1240–1245
Haney EM, Chan BKS, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes MM; for the Osteoporotic Fractures in Men Study Group (2007) Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 167:1246–1251
Vestergaard P, Rejnmark L, Mosekilde L (2006) Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int 17:807–816
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
Liu B, Anderson G, Mittmann N, To T, Axcell T, Shear N (1998) Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 351:1303–1307
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
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 (eds) Drug utilization studies: methods and uses. WHO Regional Publications, European Series 45. WHO, 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
Miettinen OS (1985) Theoretical epidemiology: principles of occurrence research in medicine. Wiley, New York
Sidik K, Jonkman JN (2005) A note on variance estimation in random effects meta-regression. J Biopharm Stat 15:823–838
Knapp G, Hartung J (2003) Improved tests for a random effects meta-regression with a single covariate. Stat Med 22:2693–2710
Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254–1259
Acknowledgments
P. V. designed the study, analyzed the data, raised the funds, and drafted the paper. L. M. and L. R. were involved in designing the study, analyzing and interpreting the data, and drafting and revising the paper. All authors have accepted the final version. P. V. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. 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 22-04-0495).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Vestergaard, P., Rejnmark, L. & Mosekilde, L. Selective Serotonin Reuptake Inhibitors and Other Antidepressants and Risk of Fracture. Calcif Tissue Int 82, 92–101 (2008). https://doi.org/10.1007/s00223-007-9099-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-007-9099-9