Osteoporosis International

, Volume 24, Issue 5, pp 1741–1749 | Cite as

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

  • M. L. O. Shea
  • L. D. Garfield
  • S. Teitelbaum
  • R. Civitelli
  • B. H. Mulsant
  • C. F. ReynoldsIII
  • D. Dixon
  • P. Doré
  • E. J. Lenze
Original Article



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.


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.


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.


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.


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.


Antidepressants Bone loss Bone turnover Depression Elderly Serotonin 



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.


  1. 1.
    Olfson M, Marcus SC (2009) National patterns in antidepressant medication treatment. Arch Gen Psychiatry 66:848–856PubMedCrossRefGoogle Scholar
  2. 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 9:109–119PubMedCrossRefGoogle Scholar
  3. 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 46:985–992PubMedCrossRefGoogle Scholar
  4. 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 15:1176–1183PubMedCrossRefGoogle Scholar
  5. 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 221:111–118PubMedCrossRefGoogle Scholar
  6. 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 146:685–693PubMedCrossRefGoogle Scholar
  7. 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 8:121–132PubMedGoogle Scholar
  8. 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 46:4–12PubMedCrossRefGoogle Scholar
  9. 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 100:1387–1394PubMedCrossRefGoogle Scholar
  10. 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 98:139–151PubMedCrossRefGoogle Scholar
  11. 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 22:418–427PubMedCrossRefGoogle Scholar
  12. 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 103:16876–16881PubMedCrossRefGoogle Scholar
  13. 13.
    Haney EM, Warden SJ (2008) Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies. J Musculoskelet Neuronal Interact 8:133–145PubMedGoogle Scholar
  14. 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 167:1246–1251PubMedCrossRefGoogle Scholar
  15. 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 167:188–194PubMedCrossRefGoogle Scholar
  16. 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 167:1240–1245PubMedCrossRefGoogle Scholar
  17. 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 16:1525–1537PubMedCrossRefGoogle Scholar
  18. 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 23:84–87PubMedCrossRefGoogle Scholar
  19. 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 31:56–60PubMedCrossRefGoogle Scholar
  20. 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 63:1410–1415PubMedCrossRefGoogle Scholar
  21. 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 335:1176–1181PubMedCrossRefGoogle Scholar
  22. 22.
    Kinjo M, Setoguchi S, Schneeweiss S, Solomon DH (2005) Bone mineral density in subjects using central nervous system-active medications. Am J Med 118:1414PubMedCrossRefGoogle Scholar
  23. 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 23:567–574PubMedCrossRefGoogle Scholar
  24. 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 163:949–957PubMedCrossRefGoogle Scholar
  25. 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 88:476–484PubMedCrossRefGoogle Scholar
  26. 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 22:211–219CrossRefGoogle Scholar
  27. 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 ResearchGoogle Scholar
  28. 28.
    Eskandari F, Martinez PE, Torvik S et al (2007) Low bone mass in premenopausal women with depression. Arch Intern Med 167:2329–2336PubMedCrossRefGoogle Scholar
  29. 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 16:610–615PubMedCrossRefGoogle Scholar
  30. 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 12:88–91PubMedCrossRefGoogle Scholar
  31. 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 49:732–736PubMedCrossRefGoogle Scholar
  32. 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 46:29–35PubMedCrossRefGoogle Scholar
  33. 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 34:140–144PubMedGoogle Scholar
  34. 34.
    Mussolino ME (2005) Depression and hip fracture risk: the NHANES I epidemiologic follow-up study. Public Health Rep 120:71–75PubMedGoogle Scholar
  35. 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. 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 65:1634–1641PubMedCrossRefGoogle Scholar
  37. 37.
    Szulc P, Delmas PD (2008) Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis. Osteoporos Int 19:1683–1704PubMedCrossRefGoogle Scholar
  38. 38.
    Civitelli R, Armamento-Villareal R, Napoli N (2009) Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporos Int 20:843–851PubMedCrossRefGoogle Scholar
  39. 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, WashingtonGoogle Scholar
  40. 40.
    Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry: J Ment Sci 134:382–389Google Scholar
  41. 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 12:189–198PubMedCrossRefGoogle Scholar
  42. 42.
    Hannon R, Eastell R (2000) Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 11(Suppl 6):S30–S44PubMedCrossRefGoogle Scholar
  43. 43.
    Randolph C (1998) Repeatable battery for the assessment of neuropsychological status manual. The Psychological Corporation, San Antonio, TXGoogle Scholar
  44. 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 41:237–248PubMedCrossRefGoogle Scholar
  45. 45.
    Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122PubMedGoogle Scholar
  46. 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 YorkGoogle Scholar
  47. 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 19:1420–1431PubMedCrossRefGoogle Scholar
  48. 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 1018:99–104PubMedCrossRefGoogle Scholar
  49. 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 ResGoogle Scholar
  50. 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 18:230–233PubMedCrossRefGoogle Scholar
  51. 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 45:1316–1320PubMedCrossRefGoogle Scholar
  52. 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 175:439–443PubMedCrossRefGoogle Scholar
  53. 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 53:603–608PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  • M. L. O. Shea
    • 1
  • L. D. Garfield
    • 1
  • S. Teitelbaum
    • 2
    • 3
  • R. Civitelli
    • 3
  • B. H. Mulsant
    • 5
    • 6
  • C. F. ReynoldsIII
    • 7
  • D. Dixon
    • 1
  • P. Doré
    • 1
    • 4
  • E. J. Lenze
    • 1
  1. 1.Department of PsychiatryWashington University School of MedicineSt. LouisUSA
  2. 2.Department of PathologyWashington University School of MedicineSt. LouisUSA
  3. 3.Department of Internal MedicineWashington University School of MedicineSt. LouisUSA
  4. 4.School of Social WorkWashington UniversitySt. LouisUSA
  5. 5.Centre for Addiction and Mental HealthTorontoCanada
  6. 6.Department of PsychiatryUniversity of TorontoTorontoCanada
  7. 7.Department of Psychiatry and Department of Behavioral and Community Health SciencesUniversity of Pittsburgh School of Medicine and Graduate School of Public HealthPittsburghUSA

Personalised recommendations