CNS Drugs

, Volume 29, Issue 3, pp 245–252 | Cite as

Serotonin–Norepinephrine Reuptake Inhibitor and Selective Serotonin Reuptake Inhibitor Use and Risk of Fractures: A New-User Cohort Study Among US Adults Aged 50 Years and Older

  • Amy Lanteigne
  • Yi-han Sheu
  • Til Stürmer
  • Virginia Pate
  • Deb Azrael
  • Sonja A. Swanson
  • Matthew MillerEmail author
Original Research Article



Antidepressants may increase the risk of fractures by disrupting sensory-motor function, thereby increasing the risk of falls, and by decreasing bone mineral density and consequently increasing the fall- or impact-related risk of fracture. Selective serotonin reuptake inhibitor (SSRI) antidepressants appear to increase fracture risk relative to no treatment, while less is known about the effect of serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants, despite SNRIs being prescribed with increasing frequency. No prior study has directly examined how fracture risk differs among patients initiating SNRIs versus those initiating SSRIs.


The objective of this study was to assess the effect of SNRI versus SSRI initiation on fracture rates.

Data Source

Data were derived from a PharMetrics claims database, 1998–2010, which is comprised of commercial health plan information obtained from managed care plans throughout the US.


We constructed a cohort of patients aged 50 years or older initiating either of the two drug classes (SSRI, N = 335,146; SNRI, N = 61,612). Standardized mortality weighting and Cox proportional hazards regression were used to estimate hazard ratios (HRs) for fractures by antidepressant class.


In weighted analyses, the fracture rates were approximately equal in SNRI and SSRI initiators: HRs for the first 1- and 5-year periods following initiation were 1.11 [95 % confidence interval (CI) 0.92–1.36] and 1.06 (95 % CI 0.90–1.26), respectively. For the subgroup of patients with depression who initiated on either SNRIs or SSRIs, those initiating SNRIs had a modestly, but not significantly, elevated fracture risk compared with those who initiated on SSRIs [HR 1.31 (95 % CI 0.95–1.79)].


We found no evidence that initiating SNRIs rather than SSRIs materially influenced fracture risk among a cohort of middle-aged and older adults.


Fracture Risk Selective Serotonin Reuptake Inhibitor Norepinephrine Reuptake Inhibitor Depression Diagnosis Decrease Bone Mineral Density 
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.



Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01 MH085021. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Stürmer receives investigator-initiated research funding and support as Principal Investigator (R01 AG023178) and Co-Investigator (R01 AG042845) from the National Institute on Aging, and as Co-Investigator (R01 CA174453) from the National Cancer Institute at the National Institutes of Health, and also as Principal Investigator of a Pilot Project from the Patient-Centered Outcomes Research Institute (PCORI). Dr. Stürmer does not accept personal compensation of any kind from any pharmaceutical company, although he receives salary support from the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Merck) and research support from pharmaceutical companies (Amgen, Merck) to the Department of Epidemiology, University of North Carolina at Chapel Hill. Drs. Miller, Sheu, Azrael, and Swanson, as well as Ms. Lanteigne and Ms. Pate, have no conflicts of interest.


  1. 1.
    Uchida N, Chong MY, Tan CH, Nagai H, Tanaka M, Lee MS, et al. International study on antidepressant prescription pattern at 20 teaching hospitals and major psychiatric institutions in East Asia: analysis of 1898 cases from China, Japan, Korea, Singapore and Taiwan. Psychiatry Clin Neurosci. 2007;61(5):522–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Bauer M, Monz BU, Montejo AL, Quail D, Dantchev N, Demyttenaere K, et al. Prescribing patterns of antidepressants in Europe: results from the Factors Influencing Depression Endpoints Research (FINDER) study. Eur Psychiatry. 2008;23(1):66–73.CrossRefPubMedGoogle Scholar
  3. 3.
    Bakken MS, Engeland A, Engesæter LB, Ranhoff AH, Hunskaar S, Ruths S. Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry. Age Ageing. 2013;42(4):514–20.CrossRefPubMedGoogle Scholar
  4. 4.
    Eom CS, Lee HK, Ye S, Park SM, Cho KH. Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis. J Bone Miner Res. 2012;27(5):1186–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Gorman JM, Kent JM. SSRIs and SNRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry. 1999;60:33–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Artigas F. Selective serotonin/noradrenaline reuptake inhibitors (SNRIs): pharmacology and therapeutic potential in the treatment of depressive-disorders. CNS Drugs. 1995;4(2):79–89.CrossRefGoogle Scholar
  7. 7.
    Cummings SR, Kelsey JL, Nevitt MC, O’Dowd KJ. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev. 1985;7:178–208.PubMedGoogle Scholar
  8. 8.
    Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int. 2006;17(6):807–16.CrossRefPubMedGoogle Scholar
  9. 9.
    Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007;167(12):1246–51.CrossRefPubMedGoogle Scholar
  11. 11.
    Hanyu R, Wehbi VL, Hayata T, Moriya S, Feinstein TN, Ezura Y, et al. Anabolic action of parathyroid hormone regulated by the β(2)-adrenergic receptor. Proc Natl Acad Sci USA. 2012;109(19):7433–8.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Ma Y, Krueger JJ, Redmon SN, Uppuganti S, Nyman JS, Hahn MK, et al. Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis. J Biol Chem. 2013;288(42):30105–13.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Vestergaard P, Rejnmark L, Mosekilde L. Selective serotonin reuptake inhibitors and other antidepressants and risk of fracture. Calcif Tissue Int. 2008;82(2):92–101.CrossRefPubMedGoogle Scholar
  14. 14.
    Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD. Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol. 2008;28(4):384–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Schneeweiss S, Wang PS. Association between SSRI use and hip fractures and the effect of residual confounding bias in claims database studies. J Clin Psychopharmacol. 2004;24(6):632–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ. 2011;343:d4551.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Sturmer T, Rothman KJ, Glynn RJ. Insights into different results from different causal contrasts in the presence of effect-measure modification. Pharmacoepidemiol Drug Saf. 2006;15(10):698–709.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Shelton RC. Serotonin norepinephrine reuptake inhibitors: similarities and differences. Prim Psychiatry. 2009;16:25–35.Google Scholar
  19. 19.
    Wu Q, Magnus JH, Liu J, Bencaz AF, Hentz JG. Depression and low bone mineral density: a meta-analysis of epidemiologic studies. Osteoporos Int. 2009;20(8):1309–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Erez HB, Weller A, Vaisman N, Kreitler S. The relationship of depression, anxiety and stress with low bone mineral density in post-menopausal women. Arch Osteoporos. 2012;7(1–2):247–55.CrossRefPubMedGoogle Scholar
  21. 21.
    Bab I, Yirmiya R. Depression, selective serotonin reuptake inhibitors, and osteoporosis. Curr Osteoporos Rep. 2010;8(4):185–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Williams LJ, Pasco JA, Jacka FN, Henry MJ, Dodd S, Berk M. Depression and bone metabolism: a review. Psychother Psychosom. 2009;78(1):16–25.CrossRefPubMedGoogle Scholar
  23. 23.
    Demyttenaere K, Enzlin P, Dewe W, Boulanger B, De Bie J, De Troyer W, et al. Compliance with antidepressants in a primary care setting, 1: beyond lack of efficacy and adverse events. J Clin Psychiatry. 2001;62(Suppl 22):30–3.PubMedGoogle Scholar
  24. 24.
    Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications? Innov Clin Neurosci. 2012;9(5–6):41–6.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Amy Lanteigne
    • 1
  • Yi-han Sheu
    • 2
  • Til Stürmer
    • 3
  • Virginia Pate
    • 3
  • Deb Azrael
    • 4
    • 5
  • Sonja A. Swanson
    • 2
  • Matthew Miller
    • 2
    • 5
    Email author
  1. 1.Department of Social and Behavioral SciencesHarvard University, Harvard School of Public HealthBostonUSA
  2. 2.Department of EpidemiologyHarvard University, Harvard School of Public HealthBostonUSA
  3. 3.Department of EpidemiologyUniversity of North Carolina at Chapel Hill, Gillings School of Global Public HealthChapel HillUSA
  4. 4.Department of Health Policy and ManagementHarvard University, Harvard School of Public HealthBostonUSA
  5. 5.Department of Health SciencesBouvé College of Health Sciences, Northeastern UniversityBostonUSA

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