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Adherence to Treatment with Selective Serotonin Reuptake Inhibitors and the Risk for Fractures and Bone Loss

A Population-Based Cohort Study

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Abstract

Background

Selective serotonin reuptake inhibitors (SSRIs) are suspected of increasing the risk of bone loss and osteoporotic fractures.

Objective

The aim of this study was to investigate the association between adherence to SSRI treatment and the risk of bone loss-related events.

Methods

The data used in this retrospective cohort study are part of the ongoing medical documentation routinely collected in a large health maintenance organization in Israel. Specifically, we used the information collected between January 2004 and April 2010. The study cohort included 10 621 women who were new users of SSRIs. Bone loss-related events were defined as fractures or initiation of bisphosphonate treatment. Adherence level was assessed by calculating the proportion of days covered (PDC) with an SSRI from the date of first dispensed SSRI (index date) to the end of follow-up and was categorized as low (PDC ≤20%), intermediate (PDC 21–79%) and high (PDC ≥80%). To validate the study model, we conducted a similar analysis on patients using antiepileptic drugs, which are known to be positively associated with an increased risk of osteoporotic fractures.

Results

Higher adherence to SSRI treatment was significantly associated with an increased risk of bone loss-related events in a dose-response manner. The adjusted hazard ratio for bone loss-related events adjusted for age, physician visits and body mass index in patients who were covered with an SSRI for 21–79% of the time and 80% or more of the time was 1.15 (95% CI 0.97, 1.37) and 1.40 (95% CI 1.14, 1.73) compared with patients who were covered for less than 21% of the follow-up period.

Conclusion

Exposure to SSRI treatment is associated with an increased risk of bone loss-related events. Further studies are required to determine the causality of the association and its relevance to the clinical use of SSRIs.

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References

  1. Becker DJ, Kilgore ML, Morrisey MA. The societal burden of osteoporosis. Curr Rheumatol Rep 2010 Jun; 12(3): 186–91

    Article  PubMed  Google Scholar 

  2. Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 2010 Oct; 123(10): 877–84

    Article  PubMed  CAS  Google Scholar 

  3. Bolton JM, Targownik LE, Leung S, et al. Risk of low bone mineral density associated with psychotropic medications and mental disorders in postmenopausal women. J Clin Psycopharmacol 2011 Feb; 31(1): 56–60

    Article  Google Scholar 

  4. Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int 2006; 17(6): 807–16

    Article  PubMed  CAS  Google Scholar 

  5. Ensrud KE, Blackwell T, Mangione CM, et al. Central nervous system active medications and risk for fracture in older women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 2003 Apr 28; 163(8): 949–57

    Article  PubMed  Google Scholar 

  6. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Canadian Multicentre Osteoporosis Study Research Group. Arch Intern Med 2007 Jan 22; 167(2): 188–94

    Article  PubMed  CAS  Google Scholar 

  7. Bolton JM, Metge C, Lix L, et al. Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychophramcol 2008 Aug; 28(4): 384–91

    Article  Google Scholar 

  8. Hubbard R, Farrington P, Smith C, et al. Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol 2003 Jul 1; 158(1): 77–84

    Article  PubMed  Google Scholar 

  9. van den Brand MW, Pouwels S, Samson MM, et al. Use of anti-depressants and the risk of fracture of the hip or femur. Osteoporos Int 2009 Oct; 20(10): 1705–13

    Article  PubMed  CAS  Google Scholar 

  10. Verdel BM, Souverein PC, Egberts TC, et al. Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures. Bone 2010 Sep; 47(3): 604–9

    Article  PubMed  CAS  Google Scholar 

  11. Prozac: highlights of prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018936s075s077lbl.pdf [Accessed 2011 Feb 21]

  12. Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry 2009 Aug; 66(8): 848–56

    Article  PubMed  Google Scholar 

  13. Bliziotes MM, Eshleman AJ, Zhang XW, et al. Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone 2001 Nov; 29(5): 477–86

    Article  PubMed  CAS  Google Scholar 

  14. Westbroek I, van der Plas A, de Rooij KE, et al. Expression of serotonin receptors in bone. J Biol Chem 2001 Aug 3; 276(31): 28961–8

    Article  PubMed  CAS  Google Scholar 

  15. Battaglino R, Fu J, Späte U, et al. Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res 2004 Sep; 19(9): 1420–31

    Article  PubMed  CAS  Google Scholar 

  16. Bliziotes M, Gunness M, Eshelman A, et al. The role of dopamine and serotonin in regulating bone mass and strength: studies on dopamine and serotonin transporter null mice. J Musculoskelet Neuronal Interact 2002 Mar; 2(3): 291–5

    PubMed  CAS  Google Scholar 

  17. Warden SJ, Robling AG, Sanders MS, et al. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 2005 Feb; 146(2): 685–93

    Article  PubMed  CAS  Google Scholar 

  18. Warden SJ, Nelson IR, Fuchs RK, et al. Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency. Menopause 2008; 15(6): 1176–83

    Article  PubMed  Google Scholar 

  19. Haney EM. Balancing bone health and mental health: a new clinical dilemma?. Expert Rev Endocrinol Metab 2008; 3(1): 1–3

    Article  Google Scholar 

  20. Diem SJ, Blackwell TL, Stone KY, et al. Use of antidepressants and rates of hip bone loss in older women. Arch Intern Med 2007 Jun 25; 167(12): 1240–5

    Article  PubMed  Google Scholar 

  21. Haney EM, Chan BK, Diem SJ, et al., for the Osteoporotic Fractures in Men Study Group. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 2007 Jun 25; 167(12): 1246–51

    Article  PubMed  Google Scholar 

  22. Spangler L, Scholes D, Brunner RL, et al. Depressive symptoms, bone loss and fractures in postmenopausal women. J Gen Intern Med 2008 May; 23(5): 567–74

    Article  PubMed  Google Scholar 

  23. Michelson D, Stratakis C, Hill L, et al. Bone mineral density in women with depression. N Eng J Med 1996 Oct 17; 335(16): 1176–81

    Article  CAS  Google Scholar 

  24. Cizza G, Primma S, Csako G. Depression as a risk factor for osteoporosis. Trends Endocrinol Metab 2009 Oct; 20(8): 367–73

    Article  PubMed  CAS  Google Scholar 

  25. Ali II, Schuh L, Berkley GL, et al. Antiepileptic drugs and reduced bone mineral density. Epilpesy Behav 2004 Jun; 5(3): 296–300

    Article  Google Scholar 

  26. Weng MY, Lane NE. Medication-induced osteoporosis. Curr Osteoporos Rep 2007 Dec; 5(4): 139–45

    Article  PubMed  Google Scholar 

  27. Kinjo M, Setoguchi S, Schneeweiss S, et al. Bone mineral density in subjects using central nervous system-active medications. Am J Med 2005 Dec; 118(12): 1414, e7–12

    Article  Google Scholar 

  28. Karve S, Cleves MA, Helm M, et al. Prospective validation of eight different adherence measures for use with administrative claims data among patients with schizophrenia. Value Health 2009 Sep; 12(6): 989–95

    Article  PubMed  Google Scholar 

  29. Peterson AM, Nau DP, Cramer JA, et al. A checklist for medication compliance and persistence studies using retrospective databases. Value Health 2007 Jan-Feb; 10(1): 3–12

    Article  PubMed  Google Scholar 

  30. Sleath B, Domino ME, Wiley-Exley E, et al. Antidepressant and antipsychotic use and adherence among Medicaid youths: differences by race. Community Ment Health J 2010 Jun; 46(3): 265–72

    Article  PubMed  Google Scholar 

  31. Israel Central Bureau of Statistics. 1995 Census population and housing. Jerusalem: Israel Central Bureau of Statistics, 1998

    Google Scholar 

  32. WHO. BMI classification [online]. Available from URL: http://apps.who.int/bmi/index.jsp?introPage=intro_3.html. [Accessed 2012 Apr 30]

  33. Cox DR. Regression models and life tables. J R Stat Soc B Stat Methodol 1972; 34(2): 187–220

    Google Scholar 

  34. Diem SJ, Blackwell TL, Stone KL, et al., for the Study of Osteoporotic Fractures Research Group. Use of antidepressant medications and risk of fracture in older women. Calcif Tissue Int 2011 June; 88(6): 476–84

    Article  PubMed  CAS  Google Scholar 

  35. Vestergaard P, Rejmnark L, Mosekilde L. Selective serotonin reuptake inhibitors and other antidepressants and risk of fracture. Calcif Tissue Int 2008 Feb; 82(2): 92–101

    Article  PubMed  CAS  Google Scholar 

  36. Ziere G, Dieleman JP, van der Cammen TJ, et al. Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol 2008 Aug; 28(4): 411–7

    Article  PubMed  CAS  Google Scholar 

  37. Schwan S, Hallberg P. SSRIs, bone mineral density and risk of fractures: a review. Eur Nueropsychopharmacol 2009 Oct; 19(10): 683–92

    Article  CAS  Google Scholar 

  38. Cherin P, Colvez A, Deville de Periere G, et al. Risk of syncope in the elderly and consumption of drugs: a case-control study. J Clin Epidemiol 1997 Mar; 50(3): 313–20

    Article  PubMed  CAS  Google Scholar 

  39. Laursen AL, Mikkelsen PL, Rasmussen S, et al. Paroxetine in the treatment of depression-a randomized comparison with amitriptyline. Acta Psychiatr Scand 1985 Mar; 71(3): 249–55

    Article  PubMed  CAS  Google Scholar 

  40. Lee RH, Lyles KW, Colon-Emeric C. A review of the effect of anticonvulsant medication on bone mineral density and fracture risk. Am J Geriatr Pharmacother 2010 Feb; 8(1): 34–46

    Article  PubMed  CAS  Google Scholar 

  41. Souverein PC, Webb DG, Weil JG, et al. Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy. Neurology 2006 May 9; 66(9): 1318–24

    Article  PubMed  CAS  Google Scholar 

  42. Wu Q, Liu J, Gallegos-Orozco JF, et al. Depression, fracture risk and bone loss: a meta-analysis of cohort studies. Osteoporos Int 2010 Oct; 21(10): 1627–35

    Article  PubMed  CAS  Google Scholar 

  43. Joling KJ, van Marwijk HW, der Horst HE, et al. Do GPs’ medical records demonstrate a good recognition of depression? A new perspective on case extraction. J Affect Disord 2011 Oct; 133(3): 522–7

    Article  PubMed  Google Scholar 

  44. Lee MS, Lee HY, Kang SG, et al. Variables influencing antidepressant medication adherence for treatning outpatients with depressive disorders. J Affect Disord 2010 Jun; 123(1–3): 216–21

    Article  PubMed  CAS  Google Scholar 

  45. Milea D, Guelfucci F, Bent-Ennakhil N, et al. Antidepressant monotherapy: A claims database analysis of treatment changes and treatment duration. Clin Ther 2010 Nov; 32(12): 2057–72

    Article  PubMed  CAS  Google Scholar 

  46. Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol 2007 Aug 1; 166(3): 348–54

    Article  PubMed  Google Scholar 

  47. Sheehan DV, Keene MS, Eaddy M, et al. Differences in medication adherence and healthcare resource utilization patterns: older vesrus newer antidepressant agents in patients with depression and/or anxiety disorders. CNS Drugs 2008; 22(11): 963–73

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors have no conflict of interest to declare. This study was conducted by the research department in MHS with no external funding.

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Correspondence to Inbar Zucker.

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Zucker, I., Chodick, G., Grunhaus, L. et al. Adherence to Treatment with Selective Serotonin Reuptake Inhibitors and the Risk for Fractures and Bone Loss. CNS Drugs 26, 537–547 (2012). https://doi.org/10.2165/11633300-000000000-00000

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