Skip to main content

Serotonin–norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption

Osteoporosis International volume 24, pages 1741–1749 (2013)Cite this article

Abstract

Summary

Antidepressants are associated with bone loss and fractures in older adults. We treated depressed older adults with an antidepressant and examined its effects on bone turnover by comparing blood samples before and after treatment. Bone resorption increased after antidepressant treatment, which may increase fracture risk.

Introduction

Antidepressants have been associated with increased bone loss and fractures in older adults in observational studies, but the mechanism is unclear. We examined the effects of a serotonin–norepinephrine reuptake inhibitor, venlafaxine, on biomarkers of bone turnover in a prospective treatment study of late-life depression.

Methods

Seventy-six individuals aged 60 years and older with current major depressive disorder received a 12-week course of venlafaxine XR 150–300 mg daily. We measured serum C-terminal cross-linking telopeptide of type I collagen (β-CTX) and N-terminal propeptide of type I procollagen (P1NP), measures of bone resorption and formation, respectively, before and after treatment. We then analyzed the change in β-CTX and P1NP within each participant. Venlafaxine levels were measured at the end of the study. We assessed depression severity at baseline and remission status after treatment.

Results

After 12 weeks of venlafaxine, β-CTX increased significantly, whereas P1NP did not significantly change. The increase in β-CTX was significant only in participants whose depression did not remit (increase by 10 % in non-remitters vs. 4 % in remitters). Change in β-CTX was not correlated with serum levels of venlafaxine or norvenlafaxine.

Conclusion

Our findings suggest that the primary effect of serotonergic antidepressants is to increase bone resorption. However, such an increase in bone resorption seemed to depend on whether or not participants’ depression remitted. Our results are in agreement with prior observational studies reporting increased bone loss in older adults taking serotonergic antidepressants. These negative effects on bone homeostasis could potentially contribute to increased fracture risk in older adults.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Olfson M, Marcus SC (2009) National patterns in antidepressant medication treatment. Arch Gen Psychiatry 66:848–856

    PubMed  Article  Google Scholar 

  2. Karkare SU, Bhattacharjee S, Kamble P, Aparasu R (2011) Prevalence and predictors of antidepressant prescribing in nursing home residents in the United States. Am J Geriatr Pharmacother 9:109–119

    PubMed  Article  Google Scholar 

  3. Warden SJ, Hassett SM, Bond JL et al (2010) Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels. Bone 46:985–992

    PubMed  Article  CAS  Google Scholar 

  4. Warden SJ, Nelson IR, Fuchs RK, Bliziotes MM, Turner CH (2008) Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency. Menopause 15:1176–1183

    PubMed  Article  Google Scholar 

  5. Bonnet N, Bernard P, Beaupied H, Bizot JC, Trovero F, Courteix D, Benhamou CL (2007) Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling. Toxicol Appl Pharmacol 221:111–118

    PubMed  Article  CAS  Google Scholar 

  6. 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

    PubMed  Article  CAS  Google Scholar 

  7. Warden SJ, Haney EM (2008) Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies. J Musculoskelet Neuronal Interact 8:121–132

    PubMed  CAS  Google Scholar 

  8. Warden SJ, Robling AG, Haney EM, Turner CH, Bliziotes MM (2010) The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Bone 46:4–12

    PubMed  Article  CAS  Google Scholar 

  9. Battaglino R, Vokes M, Schulze-Spate U, Sharma A, Graves D, Kohler T, Muller R, Yoganathan S, Stashenko P (2007) Fluoxetine treatment increases trabecular bone formation in mice. J Cell Biochem 100:1387–1394

    PubMed  Article  CAS  Google Scholar 

  10. Gustafsson BI, Thommesen L, Stunes AK, Tommeras K, Westbroek I, Waldum HL, Slordahl K, Tamburstuen MV, Reseland JE, Syversen U (2006) Serotonin and fluoxetine modulate bone cell function in vitro. J Cell Biochem 98:139–151

    PubMed  Article  CAS  Google Scholar 

  11. Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC (2008) The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J 22:418–427

    PubMed  Article  CAS  Google Scholar 

  12. Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tam J, Trembovler V, Csernus V, Shohami E, Bab I (2006) Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci U S A 103:16876–16881

    PubMed  Article  CAS  Google Scholar 

  13. Haney EM, Warden SJ (2008) Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies. J Musculoskelet Neuronal Interact 8:133–145

    PubMed  CAS  Google Scholar 

  14. Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes MM (2007) Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 167:1246–1251

    PubMed  Article  Google Scholar 

  15. Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, Goltzman D (2007) Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 167:188–194

    PubMed  Article  CAS  Google Scholar 

  16. 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

    PubMed  Article  Google Scholar 

  17. Cauley JA, Fullman RL, Stone KL, Zmuda JM, Bauer DC, Barrett-Connor E, Ensrud K, Lau EM, Orwoll ES (2005) Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 16:1525–1537

    PubMed  Article  Google Scholar 

  18. Williams LJ, Henry MJ, Berk M, Dodd S, Jacka FN, Kotowicz MA, Nicholson GC, Pasco JA (2008) Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol 23:84–87

    PubMed  Article  Google Scholar 

  19. Bolton JM, Targownik LE, Leung S, Sareen J, Leslie WD (2011) Risk of low bone mineral density associated with psychotropic medications and mental disorders in postmenopausal women. J Clin Psychopharmacol 31:56–60

    PubMed  Article  Google Scholar 

  20. Mezuk B, Eaton WW, Golden SH, Wand G, Lee HB (2008) Depression, antidepressants, and bone mineral density in a population-based cohort. J Gerontol A Biol Sci Med Sci 63:1410–1415

    PubMed  Article  Google Scholar 

  21. Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, Chrousos G, Gold P (1996) Bone mineral density in women with depression. N Engl J Med 335:1176–1181

    PubMed  Article  CAS  Google Scholar 

  22. Kinjo M, Setoguchi S, Schneeweiss S, Solomon DH (2005) Bone mineral density in subjects using central nervous system-active medications. Am J Med 118:1414

    PubMed  Article  Google Scholar 

  23. Spangler L, Scholes D, Brunner RL, Robbins J, Reed SD, Newton KM, Melville JL, Lacroix AZ (2008) Depressive symptoms, bone loss, and fractures in postmenopausal women. J Gen Intern Med 23:567–574

    PubMed  Article  Google Scholar 

  24. Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA (2003) Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163:949–957

    PubMed  Article  Google Scholar 

  25. Diem SJ, Blackwell TL, Stone KL, Cauley JA, Hillier TA, Haney EM, Ensrud KE (2011) Use of antidepressant medications and risk of fracture in older women. Calcif Tissue Int 88:476–484

    PubMed  Article  CAS  Google Scholar 

  26. Lewis CE, Ewing SK, Taylor BC, Shikany JM, Fink HA, Ensrud KE, Barrett-Connor E, Cummings SR, Orwoll E (2007) Predictors of non-spine fracture in elderly men: the MrOS study. Research J Bone Miner Res Off J Am Soc Bone Miner Res 22:211–219

    Article  Google Scholar 

  27. Eom CS, Lee HK, Ye S, Park SM, Cho KH (2012) Use of selective serotonin reuptake inhibitors and risk of fracture: a systematic review and meta-analysis. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research

  28. Eskandari F, Martinez PE, Torvik S et al (2007) Low bone mass in premenopausal women with depression. Arch Intern Med 167:2329–2336

    PubMed  Article  Google Scholar 

  29. 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

    PubMed  Article  Google Scholar 

  30. Jacka FN, Pasco JA, Henry MJ, Kotowicz MA, Dodd S, Nicholson GC, Berk M (2005) Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study. Menopause 12:88–91

    PubMed  Article  Google Scholar 

  31. Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T (2001) The association of bone mineral density and depression in an older population. J Am Geriatr Soc 49:732–736

    PubMed  Article  CAS  Google Scholar 

  32. Coelho R, Silva C, Maia A, Prata J, Barros H (1999) Bone mineral density and depression: a community study in women. J Psychosom Res 46:29–35

    PubMed  Article  CAS  Google Scholar 

  33. Silverman SL, Shen W, Minshall ME, Xie S, Moses KH (2007) Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study. J Rheumatol 34:140–144

    PubMed  Google Scholar 

  34. Mussolino ME (2005) Depression and hip fracture risk: the NHANES I epidemiologic follow-up study. Public Health Rep 120:71–75

    PubMed  Google Scholar 

  35. Diem SJ, Harrison SL, Haney E, Cauley JA, Stone KL, Orwoll E, Ensrud KE (2012) Depressive symptoms and rates of bone loss at the hip in older men. Osteoporos Int. doi:10.1007/s00198-012-1975-0

  36. Whyte EM, Basinski J, Farhi P, Dew MA, Begley A, Mulsant BH, Reynolds CF (2004) Geriatric depression treatment in nonresponders to selective serotonin reuptake inhibitors. J Clin Psychiatry 65:1634–1641

    PubMed  Article  CAS  Google Scholar 

  37. Szulc P, Delmas PD (2008) Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis. Osteoporos Int 19:1683–1704

    PubMed  Article  CAS  Google Scholar 

  38. Civitelli R, Armamento-Villareal R, Napoli N (2009) Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporos Int 20:843–851

    PubMed  Article  CAS  Google Scholar 

  39. First MB, Spitzer RL, Gibbon M (1996) Structured clinical interview for DSM-IV axis i disorders (SCID), clinician version: administration booklet. Amer Psychiatric Pub Inc, Washington

    Google Scholar 

  40. Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry: J Ment Sci 134:382–389

    Google Scholar 

  41. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    PubMed  Article  CAS  Google Scholar 

  42. Hannon R, Eastell R (2000) Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 11(Suppl 6):S30–S44

    PubMed  Article  Google Scholar 

  43. Randolph C (1998) Repeatable battery for the assessment of neuropsychological status manual. The Psychological Corporation, San Antonio, TX

  44. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, Mulsant B, Reynolds CF 3rd (1992) Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 41:237–248

    PubMed  Article  CAS  Google Scholar 

  45. Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122

    PubMed  Google Scholar 

  46. O'Donnell JM, Shelton RC (2011) Drug Therapy of depression and anxiety disorders. In Laurence L. Brunton BAC, Bjorn C. Knollmann (ed) Goodman & Gilman's the pharmacological basis of therapeutics, 12th edition. McGraw-Hill, New York

  47. Battaglino R, Fu J, Spate U, Ersoy U, Joe M, Sedaghat L, Stashenko P (2004) Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res 19:1420–1431

    PubMed  Article  CAS  Google Scholar 

  48. Tjurmina OA, Armando I, Saavedra JM, Li Q, Murphy DL (2004) Life-long serotonin reuptake deficiency results in complex alterations in adrenomedullary responses to stress. Ann N Y Acad Sci 1018:99–104

    PubMed  Article  CAS  Google Scholar 

  49. Beluche I, Chaudieu I, Norton J, Carriere I, Boulenger JP, Ritchie K, Ancelin ML (2008) Persistence of abnormal cortisol levels in elderly persons after recovery from major depression. J Psychiatr Res

  50. Simon NM, McNamara K, Chow CW, Maser RS, Papakostas GI, Pollack MH, Nierenberg AA, Fava M, Wong KK (2008) A detailed examination of cytokine abnormalities in Major Depressive Disorder. Eur Neuropsychopharmacol 18:230–233

    PubMed  Article  CAS  Google Scholar 

  51. Aydin H, Mutlu N, Akbas NB (2011) Treatment of a major depression episode suppresses markers of bone turnover in premenopausal women. J Psychiatr Res 45:1316–1320

    PubMed  Article  Google Scholar 

  52. Wilson KC, Copeland JR, Taylor S, Donoghue J, McCracken CF (1999) Natural history of pharmacotherapy of older depressed community residents. The MRC-ALPHA Study. Br J Psychiatry 175:439–443

    PubMed  Article  CAS  Google Scholar 

  53. Leon AC, Heo M (2009) Sample sizes required to detect interactions between two binary fixed-effects in a mixed-effects linear regression model. Comput Stat Data Anal 53:603–608

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

This study was supported by MH083648 to all three sites, P30 MH090333 (University of Pittsburgh), the UPMC Endowment in Geriatric Psychiatry (University of Pittsburgh), and the John A. Hartford Center of Excellence in Geriatric Psychiatry (University of Pittsburgh). Additionally, Pfizer provided venlafaxine XR for the study. Dr. Lenze had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflicts of interest

Drs. Shea, Garfield, Teitelbaum, and Dixon and Peter Dore have no financial disclosures. Dr. Mulsant currently receives research support from the Canadian Institutes of Health Research, the US National Institute of Health (NIH); he directly own stocks of General Electric (less than $5,000); within the past 5 years, he has also received some grant support from Eli Lilly and Janssen and some travel support from Roche. Dr. Civitelli owns stock of Amgen, Merck & Co., and Eli Lilly; he has also received consultant fees from Amgen and has been on the speaker bureau for Amgen and Novartis. Dr. Lenze currently receives research support from Forest, Lundbeck, Johnson & Johnson, and Roche; within the past 5 years he has also been a consultant for Fox Learning Systems.

Author information

Affiliations

  1. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    M. L. O. Shea, L. D. Garfield, D. Dixon, P. Doré & E. J. Lenze

  2. Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA

    S. Teitelbaum

  3. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    S. Teitelbaum & R. Civitelli

  4. School of Social Work, Washington University, St. Louis, MO, USA

    P. Doré

  5. Centre for Addiction and Mental Health, Toronto, ON, Canada

    B. H. Mulsant

  6. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    B. H. Mulsant

  7. Department of Psychiatry and Department of Behavioral and Community Health Sciences, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, PA, USA

    C. F. Reynolds III

Authors
  1. M. L. O. Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. D. Garfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Teitelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Civitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. H. Mulsant
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. F. Reynolds III
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Doré
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E. J. Lenze
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. L. O. Shea.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shea, M.L.O., Garfield, L.D., Teitelbaum, S. et al. Serotonin–norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption. Osteoporos Int 24, 1741–1749 (2013). https://doi.org/10.1007/s00198-012-2170-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-012-2170-z

Keywords

  • Antidepressants
  • Bone loss
  • Bone turnover
  • Depression
  • Elderly
  • Serotonin