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image of The Effect of Tricyclic Antidepressants on Fracture Healing: An Experimental Study

Abstract

Introduction

Disorders of mood and post-traumatic stress disorder (PTSD) are common after major trauma, and one of the treatments used is Tricyclic Antidepressants (TCA). These medications work by inhibiting the re-uptake of neurotransmitters like serotonin and noradrenaline. Serotonin is known to have measurable effects on bone tissue due to the presence of specific receptors on bone cells. However, there are conflicting reports about how serotonin signaling affects bone tissue and the process of fracture healing. This study aimed to evaluate the effect of TCAs on fracture healing.

Method

Twelve skeletally mature Wistar rats were used in the study. All rats underwent intra-medullary pinning of the right tibia, and a complete mid-diaphyseal fracture was created. The rats were then randomly split into two groups: a control group and a study group. For twenty-eight days, the study group received a daily dose of 10 mg/kg of amitriptyline intraperitoneal infusion, while the control group received an equal volume of plain saline the same route. On day twenty-eight, five hours after the final dose, all rats were euthanized to assess fracture healing using radiological, microscopic, and histological methods.

Results

The study found a significant difference in the total volume of new bone formation between the two groups on day twenty-eight. The control group had a mean bone formation volume of 1.077 mm3, whereas the amitriptyline-treated group had a significantly higher mean volume of 1.824 mm3 (<0.01).

Discussion

The results suggest that TCAs positively influence the early phases of fracture healing. The increased new bone formation observed in the amitriptyline group indicates a potential therapeutic benefit beyond their known psychiatric effects. This finding adds to the existing literature on the complex relationship between serotonin signaling and bone metabolism, providing evidence that this class of antidepressants may enhance the process of bone repair.

Conclusion

Tricyclic Antidepressants, specifically amitriptyline, significantly increase new bone formation in the early stages of fracture healing in Wistar rats.

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2025-10-10
2025-11-04
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References

  1. Radell M.L. Hamza E.A. Moustafa A.A. Depression in post-traumatic stress disorder. Rev. Neurosci. 2020 31 7 703 722 10.1515/revneuro‑2020‑0006 32866132
    [Google Scholar]
  2. Ogłodek E.A. Changes in the serum concentration levels of serotonin, tryptophan and cortisol among stress-resilient and stress-susceptible individuals after experiencing traumatic stress. Int. J. Environ. Res. Public Health 2022 19 24 16517 10.3390/ijerph192416517 36554398
    [Google Scholar]
  3. Bakshi A. Tadi P. Biochemistry, serotonin. Treasure Island StatPearls Publishing 2020
    [Google Scholar]
  4. Kayabaşı Y. Güneş B. Erbaş O. Serotonin receptors and depression. J Exp and Basic Med Sci 2021 2 2 240 246
    [Google Scholar]
  5. Pourhamzeh M. Moravej F.G. Arabi M. The roles of serotonin in neuropsychiatric disorders. Cell. Mol. Neurobiol. 2022 42 6 1671 1692 10.1007/s10571‑021‑01064‑9 33651238
    [Google Scholar]
  6. Paul N. Glucocorticoid-induced, rapid serotonin release by serotonergic neurons in vitro. Dissertation 2023
    [Google Scholar]
  7. Bhatt S. Devadoss T. Manjula S.N. Rajangam J. 5-HT3 receptor antagonism a potential therapeutic approach for the treatment of depression and other disorders. Curr. Neuropharmacol. 2021 19 9 1545 1559 10.2174/1570159X18666201015155816 33059577
    [Google Scholar]
  8. Wu Q. Xu Y. Bao Y. Alvarez J. Gonzales M.L. Tricyclic antidepressant use and risk of fractures: A meta-analysis of cohort studies through the use of both frequentist and Bayesian approaches. J. Clin. Med. 2020 9 8 2584 10.3390/jcm9082584 32785030
    [Google Scholar]
  9. Schweiger J.U. Schweiger U. Hüppe M. The use of antidepressive agents and bone mineral density in women: A meta-analysis. Int. J. Environ. Res. Public Health 2018 15 7 1373 10.3390/ijerph15071373 29966324
    [Google Scholar]
  10. Na I. Seo J. Park E. Lee J. Risk of falls associated with long-acting benzodiazepines or tricyclic antidepressants use in community-dwelling older adults: A nationwide population-based case–crossover study. Int. J. Environ. Res. Public Health 2022 19 14 8564 10.3390/ijerph19148564 35886415
    [Google Scholar]
  11. Yao Q. Liang H. Huang B. Beta-adrenergic signaling affect osteoclastogenesis via osteocytic MLO-Y4 cells’ RANKL production. Biochem. Biophys. Res. Commun. 2017 488 4 634 640 10.1016/j.bbrc.2016.11.011 27823934
    [Google Scholar]
  12. Agarwal S. Germosen C. Kil N. Current anti-depressant use is associated with cortical bone deficits and reduced physical function in elderly women. Bone 2020 140 115552 10.1016/j.bone.2020.115552 32730935
    [Google Scholar]
  13. Al Saedi A. Sharma S. Summers M.A. Nurgali K. Duque G. The multiple faces of tryptophan in bone biology. Exp. Gerontol. 2020 129 110778 10.1016/j.exger.2019.110778 31705966
    [Google Scholar]
  14. Weerasinghe D.K. Hodge J.M. Pasco J.A. Samarasinghe R.M. Azimi Manavi B. Williams L.J. Antipsychotic-induced bone loss: The role of dopamine, serotonin and adrenergic receptor signalling. Front. Cell Dev. Biol. 2023 11 1184550 10.3389/fcell.2023.1184550 37305679
    [Google Scholar]
  15. Franco R. Matteo A. Gianfreda F. Miranda M. Bollero P. Barlattani A. The effects of serotonin inhibitors on bone metabolism: Literature review. Czas. Stomatol. 2020 73 3 136 141 10.5114/jos.2020.96942
    [Google Scholar]
  16. Ji C.X. Fan D.S. Li W. Evaluation of the anti-ulcerogenic activity of the antidepressants duloxetine, amitriptyline, fluoxetine and mirtazapine in different models of experimental gastric ulcer in rats. Eur. J. Pharmacol. 2012 691 1-3 46 51 10.1016/j.ejphar.2012.06.041 22789173
    [Google Scholar]
  17. Dineshbhai V.S. Biomechanical and clinical evaluation of indigenously designed double threaded intramedullary pin for the stabilization of canine tibial and femoral fractures. In: The Indian Journal of Animal Sciences 2022 92 (7) 819 824
    [Google Scholar]
  18. Vorontsov P. Maltseva V.Y. A review of animal models for bone fracture nonunion and their role in studying biological therapy efficacy. Ortho Traumato Prosthet 2024 2 81 87 10.15674/0030‑59872024281‑87
    [Google Scholar]
  19. Say G.N. Önger M.E. Say F. Yontar O. Yapıcı O. Effects of methylphenidate on femoral bone growth in male rats. Hum. Exp. Toxicol. 2023 42 09603271231210970 10.1177/09603271231210970 37903444
    [Google Scholar]
  20. Göl E.B. Özkan N. Bereket C. Önger M.E. Extracorporeal shock-wave therapy or low-level laser therapy: Which is more effective in bone healing in bisphosphonate treatment? J. Craniofac. Surg. 2020 31 7 2043 2048 10.1097/SCS.0000000000006506 32371691
    [Google Scholar]
  21. Weibel E.R. Morphometry: Stereological theory and practical methods. Models of Lung Disease. CRC Press 2020 54 10.1201/9781003066248‑8
    [Google Scholar]
  22. Knudsen L. Brandenberger C. Ochs M. Stereology as the 3D tool to quantitate lung architecture. Histochem. Cell Biol. 2021 155 2 163 181 10.1007/s00418‑020‑01927‑0 33051774
    [Google Scholar]
  23. Xiang K. Wang P. Xu Z. Causal effects of gut microbiome on systemic lupus erythematosus: A two-sample Mendelian randomization study. Front. Immunol. 2021 12 667097 10.3389/fimmu.2021.667097 34557183
    [Google Scholar]
  24. Özkan E. Şenel E. Bereket M.C. Önger M.E. The effect of shock waves on mineralization and regeneration of distraction zone in osteoporotic rabbits. Ann. Med. 2023 55 1 1346 1354 10.1080/07853890.2023.2192958 36995151
    [Google Scholar]
  25. Søndergaard N. Nyengaard J.R. Bloch S.L. Stereologic investigation of mastoid air cell geometry: Volume, surface area, and anisotropy. Otol. Neurotol. 2020 41 5 e630 e637 10.1097/MAO.0000000000002583 32032296
    [Google Scholar]
  26. Blomquist M.B. Roth J.D. Ultrasound‐based bone tracking using cross‐correlation enables dynamic measurements of knee kinematics during clinical assessments. J. Exp. Orthop. 2024 11 3 e12050 10.1002/jeo2.12050 38846378
    [Google Scholar]
  27. Cakmak G. Soyguder Z. Calculation of the lumbosacral segment volume of the spinal cord in ducks (Anas) using the stereological method. Vet. Med. Sci. 2025 11 2 e70289 10.1002/vms3.70289 40116539
    [Google Scholar]
  28. Pannu A. K Goyal R. Serotonin and depression: Scrutiny of new targets for future anti-depressant drug development. Curr. Drug Targets 2023 24 10 816 837 10.2174/1389450124666230425233727 37170981
    [Google Scholar]
  29. Levenson J.L. Ferrando S.J. Clinical manual of psychopharmacology in the medically ill. American Psychiatric Pub. 2023
    [Google Scholar]
  30. Guaiana G. Pharmacological treatments in panic disorder in adults: A network meta-analysis. Protocol 2020
    [Google Scholar]
  31. Lee S. Vigoureux T.F.D. Hyer K. Small B.J. Prevalent insomnia concerns among direct-care workers JAG. J. Appl. Gerontol. 2020 41 1
    [Google Scholar]
  32. Zhou W. Jia L. Deng Q. Role of serum amitriptyline concentration and CYP2C19 polymorphism in predicting the response to low-dose amitriptyline in irritable bowel syndrome. Dig. Liver Dis. 2021 53 11 1422 1427 10.1016/j.dld.2021.02.020 33753003
    [Google Scholar]
  33. Obermanns J. Krawczyk E. Juckel G. Emons B. Analysis of cytokine levels, T regulatory cells and serotonin content in patients with depression. Eur. J. Neurosci. 2021 53 10 3476 3489 10.1111/ejn.15205 33768559
    [Google Scholar]
  34. Unnissa Z. Ammaarah A. Fatima S.S. Prophylactic role of amitriptyline after major lower limb fractures and in orthopedic surgeries in preventing post operative depression. RJPT 2024 17 5 2289 2295 10.52711/0974‑360X.2024.00359
    [Google Scholar]
  35. Power C. Duffy R. Mahon J. McCarroll K. Lawlor B.A. Bones of contention: A comprehensive literature review of non-SSRI antidepressant use and bone health. J. Geriatr. Psychiatry Neurol. 2020 33 6 340 352 10.1177/0891988719882091 31665962
    [Google Scholar]
  36. Warden S.J. Fuchs R.K. Do selective serotonin reuptake inhibitors (SSRIs) cause fractures? Curr. Osteoporos. Rep. 2016 14 5 211 218 10.1007/s11914‑016‑0322‑3 27495351
    [Google Scholar]
  37. Bradaschia-Correa V. Josephson A.M. Mehta D. The selective serotonin reuptake inhibitor fluoxetine directly inhibits osteoblast differentiation and mineralization during fracture healing in mice. J. Bone Miner. Res. 2017 32 4 821 833 10.1002/jbmr.3045 27869327
    [Google Scholar]
  38. Hart X.M. Update lessons from PET imaging Part II:AA systematic critical review on therapeutic plasma concentrations of antidepressants. Ther. Drug Monit. 2022 46 2 155 169 10.1097/FTD.0000000000001142
    [Google Scholar]
  39. Yuan S. Chen J. Zeng L. Zhou C. Yu S. Fang L. Association of bone mineral density and depression in different bone sites and ages: A meta‐analysis. Food Sci. Nutr. 2021 9 9 4780 4792 10.1002/fsn3.2379 34531991
    [Google Scholar]
  40. Guo W. Li F. Zhu C. Effect of hypercortisolism on bone mineral density and bone metabolism: A potential protective effect of adrenocorticotropic hormone in patients with Cushing’s disease. J. Int. Med. Res. 2018 46 1 492 503 10.1177/0300060517725660 28851260
    [Google Scholar]
  41. Rosenblat J.D. Gregory J.M. Carvalho A.F. McIntyre R.S. Depression and disturbed bone metabolism: A narrative review of the epidemiological findings and postulated mechanisms. Curr. Mol. Med. 2016 16 2 165 178 10.2174/1566524016666160126144303 26812918
    [Google Scholar]
  42. Speer K.E. Semple S. Naumovski N. D’Cunha N.M. McKune A.J. HPA axis function and diurnal cortisol in post-traumatic stress disorder: A systematic review. Neurobiol. Stress 2019 11 100180 10.1016/j.ynstr.2019.100180 31236437
    [Google Scholar]
  43. Güler-Yüksel M. Hoes J.N. Bultink I.E.M. Lems W.F. Glucocorticoids, inflammation and bone. Calcif. Tissue Int. 2018 102 5 592 606 10.1007/s00223‑017‑0335‑7 29313071
    [Google Scholar]
  44. Hansen C.H. Larsen L.W. Sørensen A.M. Halling-Sørensen B. Styrishave B. The six most widely used selective serotonin reuptake inhibitors decrease androgens and increase estrogens in the H295R cell line. Toxicol. In Vitro 2017 41 1 11 10.1016/j.tiv.2017.02.001 28179152
    [Google Scholar]
  45. Altiparmak B. Uysal A.I. Demirbilek S. The analysis of patients under mechanical ventilation support in ıntensive care unit with the diagnosis of H1N1 infection: Retrospective study. Medicine 2017 6 3 389 392
    [Google Scholar]
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