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Sex-Based Difference in Bone Healing: A Review of Recent Pre-clinical Literature

  • Updates in Spine Surgery - Techniques, Biologics, and Non-Operative Management (B Feeley, Section Editor)
  • Published:
Current Reviews in Musculoskeletal Medicine Aims and scope Submit manuscript

Abstract

Purpose of Review

Recent literature has sought to understand differences in fusion failure, specifically considering how patient sex may play a role. Overall, there exists inconclusive data regarding any sex-based differences in bone healing.

Recent Findings

In vitro studies examining the roles of sex hormones, 5-LO, IGF-1, VEGF, osteoclasts, and OPCs seem to show sexually dimorphic actions. Additionally, donor characteristics and stem cell environment seem to also determine osteogenic potential. Building on this biomolecular basis, in vivo work investigates the aforementioned elements. Broadly, males tend to have a more robust healing compared to females. Taking these findings together, differences in sex hormones levels, their timing and action, and composition of the inflammatory milieu underlie variations in bone healing by sex.

Summary

Clinically, a robust understanding of bone healing mechanics can inform care of the transgender patient. Transgender patients undergoing hormone therapy present a clinically nuanced scenario for which limited long-term data exist. Such advances would help inform treatment for sports-related injury due to hormonal changes in biomechanics and treatment of transgender youth. While recent advances provide more clarity, conclusive answers remain elusive.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Bechmann N, Barthel A, Schedl A, Herzig S, Varga Z, Gebhard C, Mayr M, Hantel C, Beuschlein F, Wolfrum C, Perakakis N, Poston L, Andoniadou CL, Siow R, Gainetdinov RR, Dotan A, Shoenfeld Y, Mingrone G, Bornstein SR. Sexual dimorphism in COVID-19: potential clinical and public health implications. The Lancet Diabetes & Endocrinology. 2022;10:221–30.

    Article  CAS  Google Scholar 

  2. Umiker BR, Andersson S, Fernandez L, Korgaokar P, Larbi A, Pilichowska M, Weinkauf CC, Wortis HH, Kearney JF, Imanishi-Kari T. Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus. European journal of immunology. 2014;44(5):1503–16.

    Article  CAS  Google Scholar 

  3. O’Driscoll DN, De Santi C, McKiernan PJ, McEneaney V, Molloy EJ, Greene CM. Expression of X-linked Toll-like receptor 4 signaling genes in female vs. male neonates. Pediatric Research. 2017;81(5):831–7.

    Article  Google Scholar 

  4. Berghöfer B, Frommer T, Haley G, Fink L, Bein G, Hackstein H. TLR7 ligands induce higher IFN-α production in females. The Journal of Immunology. 2006;177(4):2088–96.

    Article  Google Scholar 

  5. Pinzan CF, Ruas LP, Casabona-Fortunato AS, Carvalho FC, Roque-Barreira M-C. Immunological basis for the gender differences in murine Paracoccidioides brasiliensis infection. PloS One. 2010;5(5):e10757.

    Article  Google Scholar 

  6. Lotter H, Helk E, Bernin H, Jacobs T, Prehn C, Adamski J, González-Roldán N, Holst O, Tannich E. Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNγ secretion in natural killer T cells. PLoS One. 2013;8(2):e55694.

    Article  CAS  Google Scholar 

  7. Amur S, Parekh A, Mummaneni P. Sex differences and genomics in autoimmune diseases. Journal of autoimmunity. 2012;38(2-3):J254–J65.

    Article  CAS  Google Scholar 

  8. Schurz H, Salie M, Tromp G, Hoal EG, Kinnear CJ, Möller M. The X chromosome and sex-specific effects in infectious disease susceptibility. Human genomics. 2019;13(1):1–12.

    Article  Google Scholar 

  9. Rajaee SS, Bae HW, Kanim LE, Delamarter RB. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine. 2012;37(1):67–76.

    Article  Google Scholar 

  10. Mannion AF, Brox J-I, Fairbank JC. Consensus at last! Long-term results of all randomized controlled trials show that fusion is no better than non-operative care in improving pain and disability in chronic low back pain. The Spine Journal. 2016;16(5):588–90.

    Article  Google Scholar 

  11. Hedlund R, Johansson C, Hägg O, Fritzell P, Tullberg T, Group SLSS. The long-term outcome of lumbar fusion in the Swedish lumbar spine study. The Spine Journal. 2016;16(5):579–87.

    Article  Google Scholar 

  12. Ekman P, Möller H, Hedlund R. Predictive factors for the outcome of fusion in adult isthmic spondylolisthesis. Spine. 2009;34(11):1204–10.

    Article  Google Scholar 

  13. Peolsson A, Hedlund R, Vavruch L, Öberg B. Predictive factors for the outcome of anterior cervical decompression and fusion. European spine journal. 2003;12(3):274–80.

    Article  Google Scholar 

  14. Gehrchen MP, Dahl B, Katonis P, Blyme P, Tøndevold E, Kiær T. No difference in clinical outcome after posterolateral lumbar fusion between patients with isthmic spondylolisthesis and those with degenerative disc disease using pedicle screw instrumentation: a comparative study of 112 patients with 4 years of follow-up. European Spine Journal. 2002;11(5):423–7.

    Article  Google Scholar 

  15. Schmitt PJ, Kelleher JP, Ailon T, Heller JE, Kasliwal MK, Shaffrey CI, Smith JS. Long-segment fusion for adult spinal deformity correction using low-dose recombinant human bone morphogenetic protein-2: a retrospective review of fusion rates. Neurosurgery. 2016;79(2):212–21.

    Article  Google Scholar 

  16. Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: a review of principles and methods. Bone reports. 2017;6:87–100.

    Article  Google Scholar 

  17. Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nature Reviews Rheumatology. 2012;8(3):133–43.

    Article  CAS  Google Scholar 

  18. Chang MA, Bishop AT, Moran SL, Shin AY. The outcomes and complications of 1, 2-intercompartmental supraretinacular artery pedicled vascularized bone grafting of scaphoid nonunions. The Journal of hand surgery. 2006;31(3):387–96.

    Article  Google Scholar 

  19. Tian R, Zheng F, Zhao W, Zhang Y, Yuan J, Zhang B, Li L. Prevalence and influencing factors of nonunion in patients with tibial fracture: systematic review and meta-analysis. Journal of Orthopaedic Surgery and Research. 2020;15(1):1–16.

    Article  Google Scholar 

  20. Hussain HM, Roth AL, Sultan AA, Anis HK, Stern PJ. Nonunion and reoperation following proximal interphalangeal joint arthrodesis and associated patient factors. HAND. 2022;17(3):566–71.

    Article  Google Scholar 

  21. Patel S, Baker L, Perez J, Vulcano E, Kaplan J, Aiyer A. Risk factors for nonunion following ankle arthrodesis: a systematic review and meta-analysis. Foot Ankle Specialist. 2021:1938640021998493. https://pubmed.ncbi.nlm.nih.gov/33660542/.

  22. Khosla S, Melton L, Riggs B, Melton 3rd L. Estrogens and bone health in men. Calcif Tissue Int. 2001;69(4). https://pubmed.ncbi.nlm.nih.gov/11730247/.

  23. Hammes SR, Levin ER. Impact of estrogens in males and androgens in females. The Journal of clinical investigation. 2019;129(5):1818–26.

    Article  Google Scholar 

  24. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis research & therapy. 2007;9(1):1–7.

    Article  Google Scholar 

  25. Väänänen HK, Härkönen PL. Estrogen and bone metabolism. Maturitas. 1996;23:S65–S9.

    Article  Google Scholar 

  26. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. New England Journal of Medicine. 1994;331(16):1056–61.

    Article  CAS  Google Scholar 

  27. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of testosterone and estradiol in a man with aromatase deficiency. New England Journal of Medicine. 1997;337(2):91–5.

    Article  CAS  Google Scholar 

  28. Callewaert F, Sinnesael M, Gielen E, Boonen S, Vanderschueren D. Skeletal sexual dimorphism: relative contribution of sex steroids, growth hormone-insulin-like growth factor-I (GH-IGF-I) and mechanical loading. Journal of Endocrinology. 2010;207(2):127–34.

    Article  CAS  Google Scholar 

  29. Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH, et al. Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-α. The FASEB Journal. 2009;23(1):232–40.

    Article  CAS  Google Scholar 

  30. Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV, et al. Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. Journal of Bone and Mineral Research. 2006;21(4):576–85.

    Article  CAS  Google Scholar 

  31. Juul A. The effects of oestrogens on linear bone growth. Apmis. 2001;109(S103):S124–S34.

    Article  Google Scholar 

  32. Sims NA, Brennan K, Spaliviero J, Handelsman DJ, Seibel MJ. Perinatal testosterone surge is required for normal adult bone size but not for normal bone remodeling. American Journal of Physiology-Endocrinology and Metabolism. 2006;290(3):E456–E62.

    Article  CAS  Google Scholar 

  33. Chang C, Yeh S, Lee SO, Chang T-M. Androgen receptor (AR) pathophysiological roles in androgen related diseases in skin, metabolism syndrome, bone/muscle and neuron/immune systems: lessons learned from mice lacking AR in specific cells. Nucl Recept Signal. 2013;11(1):nrs. 11001.

    Article  Google Scholar 

  34. Dhatariya KK, Nair KS. Dehydroepiandrosterone: is there a role for replacement? Mayo Clinic Proceedings: Elsevier; 2003. p. 1257–73.

    Google Scholar 

  35. Lamberts S. The endocrinology of gonadal involution: menopause and andropause. Annales d’endocrinologie 2003. p. 77-81. https://pubmed.ncbi.nlm.nih.gov/12773935/.

  36. Jankowski CM, Wolfe P, Schmiege SJ, Nair KS, Khosla S, Jensen M, von Muhlen D, Laughlin GA, Kritz-Silverstein D, Bergstrom J, Bettencourt R, Weiss EP, Villareal DT, Kohrt WM. Sex-specific effects of dehydroepiandrosterone (DHEA) on bone mineral density and body composition: a pooled analysis of four clinical trials. Clinical endocrinology. 2019;90(2):293–300.

    Article  CAS  Google Scholar 

  37. Wang L, Wang Y-D, Wang W-J, Zhu Y, Li D-J. Dehydroepiandrosterone improves murine osteoblast growth and bone tissue morphometry via mitogen-activated protein kinase signaling pathway independent of either androgen receptor or estrogen receptor. Journal of molecular endocrinology. 2007;38(4):467–79.

    Article  Google Scholar 

  38. Moon TC, Befus AD, Kulka M. Mast cell mediators: their differential release and the secretory pathways involved. Frontiers in immunology. 2014;5:569.

    Article  Google Scholar 

  39. • Cottrell J, Keshav V, Mitchell A, O’Connor J. Local inhibition of 5-lipoxygenase enhances bone formation in a rat model. Bone Joint Res. 2013;2(2):41–50 Novel study that shows clinical potential for a small molecule inhibition for bone healing in vivo.

    Article  CAS  Google Scholar 

  40. Pace S, Pergola C, Dehm F, Rossi A, Gerstmeier J, Troisi F, Pein H, Schaible AM, Weinigel C, Rummler S, Northoff H, Laufer S, Maier TJ, Rådmark O, Samuelsson B, Koeberle A, Sautebin L, Werz O. Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males. The Journal of clinical investigation. 2017;127(8):3167–76.

    Article  Google Scholar 

  41. Hartman ML, Veldhuis JD, Thorner MO. Normal control of growth hormone secretion. Hormone Research in Paediatrics. 1993;40(1-3):37–47.

    Article  CAS  Google Scholar 

  42. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocrine reviews. 2008;29(5):535–59.

    Article  CAS  Google Scholar 

  43. Hobbs CJ, Plymate SR, Rosen CJ, Adler RA. Testosterone administration increases insulin-like growth factor-I levels in normal men. The Journal of Clinical Endocrinology & Metabolism. 1993;77(3):776–9.

    CAS  Google Scholar 

  44. Weissberger AJ, Ho K. Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization. The Journal of Clinical Endocrinology & Metabolism. 1993;76(6):1407–12.

    CAS  Google Scholar 

  45. Veldhuis JD, Frystyk J, Iranmanesh A, Ørskov H. Testosterone and estradiol regulate free insulin-like growth factor I (IGF-I), IGF binding protein 1 (IGFBP-1), and dimeric IGF-I/IGFBP-1 concentrations. The Journal of Clinical Endocrinology & Metabolism. 2005;90(5):2941–7.

    Article  CAS  Google Scholar 

  46. Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges EL, Ungvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience. 2017;39(2):129–45.

    Article  CAS  Google Scholar 

  47. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T. Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus. Osteoporosis International. 2007;18(12):1675–81.

    Article  CAS  Google Scholar 

  48. Locatelli V, Bianchi VE. Effect of GH/IGF-1 on bone metabolism and osteoporsosis. Int J Endocrinol. 2014;2014:235060. https://doi.org/10.1155/2014/235060.

    Article  CAS  Google Scholar 

  49. Liu Y, Olsen BR. Distinct VEGF functions during bone development and homeostasis. Archivum immunologiae et therapiae experimentalis. 2014;62(5):363–8.

    Article  CAS  Google Scholar 

  50. Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone. 2016;91:30–8.

    Article  CAS  Google Scholar 

  51. Goring A, Sharma A, Javaheri B, Smith RC, Kanczler JM, Boyde A, et al. Regulation of the bone vascular network is sexually dimorphic. Journal of Bone and Mineral Research. 2019;34(11):2117–32.

    Article  Google Scholar 

  52. Lorenzo J, Canalis E, Raisz L. Metabolic bone disease in Williams text book of endocrinology. Saunders-Elsevier, Philadelphia. 2008:1269–310.

  53. Ikeda K, Takeshita S. The role of osteoclast differentiation and function in skeletal homeostasis. The Journal of Biochemistry. 2016;159(1):1–8.

    Article  CAS  Google Scholar 

  54. Lorenzo J. Sexual dimorphism in osteoclasts. Cells. 2020;9(9):2086.

    Article  CAS  Google Scholar 

  55. Mun SH, Jastrzebski S, Kalinowski J, Zeng S, Oh B, Bae S, Eugenia G, Khan NM, Drissi H, Zhou P, Shin B, Lee SK, Lorenzo J, Park-Min KH. Sexual dimorphism in differentiating osteoclast precursors demonstrates enhanced inflammatory pathway activation in female cells. Journal of Bone and Mineral Research. 2021;36(6):1104–16.

    Article  CAS  Google Scholar 

  56. Maniar H, Tawari A, Suk M, Horwitz D. The current role of stem cells in orthopaedic surgery. Malaysian orthopaedic journal. 2015;9(3):1–7.

    Article  CAS  Google Scholar 

  57. Mafi R, Hindocha S, Mafi P, Griffin M, Khan W. Suppl 2: sources of adult mesenchymal stem cells applicable for musculoskeletal applications-a systematic review of the literature. The open orthopaedics journal. 2011;5:242–8.

    Article  Google Scholar 

  58. Corsi KA, Pollet JB, Phillippi JA, et al. Osteogenic potential of postnatal skeletal muscle-derived stem cells is influenced by donor sex. J Bone Miner Res. 2007;22:1592–602.

    Article  Google Scholar 

  59. Strube P, Mehta M, Baerenwaldt A, Trippens J, Wilson CJ, Ode A, Perka C, Duda GN, Kasper G. Sex-specific compromised bone healing in female rats might be associated with a decrease in mesenchymal stem cell quantity. Bone. 2009;45(6):1065–72.

    Article  CAS  Google Scholar 

  60. Mehta M, Duda GN, Perka C, Strube P. Influence of gender and fixation stability on bone defect healing in middle-aged rats: a pilot study. Clin Orthop Relat Res. 2011;469(11):3102–10.

    Article  Google Scholar 

  61. Haffner-Luntzer M, Fischer V, Ignatius A. Differences in fracture healing between female and male C57BL/6J mice. Frontiers in Physiology. 2021:1227. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381649/.

  62. • Foley JP, Fred EJ, Minardi S, Yamaguchi JT, Greene AC, Furman AA, et al. Sex-based difference in response to recombinant human bone morphogenetic protein-2 in a rat posterolateral fusion model. Spine. 2022. https://pubmed.ncbi.nlm.nih.gov/35943241/. Provided the background for the undertaking of a sexually dimorphic response to bone healing.

  63. Komrakova M, Nagel J, Hoffmann DB, Lehmann W, Schilling AF, Sehmisch S. Effect of selective androgen receptor modulator enobosarm on bone healing in a rat model for aged male osteoporosis. Calcified tissue international. 2020;107(6):593–602.

    Article  CAS  Google Scholar 

  64. Komrakova M, Furtwängler J, Hoffmann DB, Lehmann W, Schilling AF, Sehmisch S. The selective androgen receptor modulator ostarine improves bone healing in ovariectomized rats. Calcified Tissue International. 2020;106(2):147–57.

    Article  CAS  Google Scholar 

  65. Manigrasso MB, O’Connor JP. Accelerated fracture healing in mice lacking the 5-lipoxygenase gene. Acta orthopaedica. 2010;81(6):748–55.

    Article  Google Scholar 

  66. Cottrell JA, O’Connor JP. Pharmacological inhibition of 5-lipoxygenase accelerates and enhances fracture-healing. JBJS. 2009;91(11):2653–65.

    Article  Google Scholar 

  67. Ashpole NM, Herron JC, Mitschelen MC, Farley JA, Logan S, Yan H, Ungvari Z, Hodges EL, Csiszar A, Ikeno Y, Humphrey MB, Sonntag WE. IGF-1 regulates vertebral bone aging through sex-specific and time-dependent mechanisms. Journal of Bone and Mineral Research. 2016;31(2):443–54. https://doi.org/10.1002/jbmr.2689.

    Article  CAS  Google Scholar 

  68. Ueno M, Zhang N, Hirata H, Barati D, Utsunomiya T, Shen H, Lin T, Maruyama M, Huang E, Yao Z, Wu JY, Zwingenberger S, Yang F, Goodman SB. Sex differences in mesenchymal stem cell therapy with gelatin-based microribbon hydrogels in a murine long bone critical-size defect model. Frontiers in Bioengineering and Biotechnology. 2021;9.

  69. Meszaros LB, Usas A, Cooper GM, Huard J. Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. Tissue Engineering Part A. 2012;18(17-18):1751–9.

    Article  CAS  Google Scholar 

  70. • Ramsey DC, Lawson MM, Stuart A, Sodders E, Working ZM. Orthopaedic care of the transgender patient. JBJS. 2021;103(3):274–81 Clinical applications of sexually dimorphic bone healing have incredible ramifications for the transgender population.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 1350, Chicago, IL, 6061, USA

    Steven S. Kurapaty & Wellington K. Hsu

  2. Simpson Querrey Institute, Center for Regenerative Nanomedicine, Northwestern University, Chicago, IL, USA

    Steven S. Kurapaty & Wellington K. Hsu

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Correspondence to Steven S. Kurapaty.

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Kurapaty, S.S., Hsu, W.K. Sex-Based Difference in Bone Healing: A Review of Recent Pre-clinical Literature. Curr Rev Musculoskelet Med 15, 651–658 (2022). https://doi.org/10.1007/s12178-022-09803-1

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