Skip to main content

Advertisement

Log in

Diabetes and Impaired Fracture Healing: A Narrative Review of Recent Literature

  • Bone and Diabetes (A Schwartz and P Vestergaard, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

Diabetes mellitus is a chronic metabolic disorder commonly encountered in orthopedic patients. Both type 1 and type 2 diabetes mellitus increase fracture risk and impair fracture healing. This review examines complex etiology of impaired fracture healing in diabetes.

Recent Findings

Recent findings point to several mechanisms leading to orthopedic complications in diabetes. Hyperglycemia and chronic inflammation lead to increased formation of advanced glycation end products and generation of reactive oxygen species, which in turn contribute to the disruption in osteoblast and osteoclast balance leading to decreased bone formation and heightening the risk of nonunion or delayed union as well as impaired fracture healing. The mechanisms attributing to this imbalance is secondary to an increase in pro-inflammatory mediators leading to premature resorption of callus cartilage and impaired bone formation due to compromised osteoblast differentiation and their apoptosis. Other mechanisms include disruption in the bone’s microenvironment supporting different stages of healing process including hematoma and callus formation, and their resolution during bone remodeling phase. Complications of diabetes including peripheral neuropathy and peripheral vascular disease also contribute to the impairment of fracture healing. Certain diabetic drugs may have adverse effects on fracture healing.

Summary

The pathophysiology of impaired fracture healing in diabetic patients is complex. This review provides an update of the most recent findings on how key mediators of bone healing are affected in diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

AGE:

Advanced glycation end products

ROS:

Reactive oxygen species

PTHrP:

Parathyroid hormone related protein

PGE2:

Prostaglandin E2

NF-κB:

Nuclear factor-κB

References

  1. Wukich DK. Diabetes and its negative impact on outcomes in orthopaedic surgery. World journal of orthopedics. 2015;6(3):331–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Centers for Disease Control and Prevention. National Diabetes Statistics Report website. January 18, 2022 2/27/2022]; Available from: https://www.cdc.gov/diabetes/data/statistics-report/index.html.

  3. Jiao H, Xiao E, Graves DT. Diabetes and its effect on bone and fracture healing. Current osteoporosis reports. 2015;13(5):327–35.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ding ZC, et al. Do patients with diabetes have an increased risk of impaired fracture healing? A systematic review and meta-analysis. ANZ J Surgery. 2020;90(7-8):1259–64.

    Article  Google Scholar 

  5. Zura R, Xiong Z, Einhorn T, Watson JT, Ostrum RF, Prayson MJ, Della Rocca GJ, Mehta S, McKinley T, Wang Z, Steen RG. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg. 2016;151(11):e162775.

    Article  PubMed  Google Scholar 

  6. Lecka-Czernik B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 2017;60(7):1163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schwartz AV. Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia. 2017;60(7):1170–9.

    Article  CAS  PubMed  Google Scholar 

  8. Laurent MR, et al. Lower bone turnover and relative bone deficits in men with metabolic syndrome: a matter of insulin sensitivity? The European Male Ageing Study. Osteoporosis International. 2016;27(11):3227–37.

    Article  CAS  PubMed  Google Scholar 

  9. Hygum K, Starup-Linde J, Harsløf T, Vestergaard P, Langdahl BL. Mechanisms in endocrinology: diabetes mellitus, a state of low bone turnover–a systematic review and meta-analysis. European journal of endocrinology. 2017;176(3):R137–57.

    Article  CAS  PubMed  Google Scholar 

  10. Dhaliwal R, Ewing SK, Vashishth D, Semba RD, Schwartz AV. Greater carboxy-methyl-lysine is associated with increased fracture risk in type 2 diabetes. Journal of Bone and Mineral Research. 2022;37(2):265–72.

    Article  CAS  PubMed  Google Scholar 

  11. Samakkarnthai P, Sfeir JG, Atkinson EJ, Achenbach SJ, Wennberg PW, Dyck PJ, Tweed AJ, Volkman TL, Amin S, Farr JN, Vella A, Drake MT, Khosla S. Determinants of bone material strength and cortical porosity in patients with type 2 diabetes mellitus. The Journal of Clinical Endocrinology & Metabolism. 2020;105(10):e3718–29.

    Article  Google Scholar 

  12. Henderson S, Ibe I, Cahill S, Chung YH, Lee FY. Bone quality and fracture-healing in type-1 and type-2 diabetes mellitus. JBJS. 2019;101(15):1399–410.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Lafage-Proust M-H, Roche B, Langer M, Cleret D, vanden Bossche A, Olivier T, Vico L. Assessment of bone vascularization and its role in bone remodeling. BoneKEy reports. 2015;4:662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bragdon BC, Bahney CS. Origin of reparative stem cells in fracture healing. Current osteoporosis reports. 2018;16(4):490–503.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Doherty L, Wan M, Kalajzic I, Sanjay A. Diabetes impairs periosteal progenitor regenerative potential. Bone. 2021;143:115764.

    Article  PubMed  Google Scholar 

  17. Zhang E, Miramini S, Patel M, Richardson M, Ebeling P, Zhang L. Role of TNF-α in early-stage fracture healing under normal and diabetic conditions. Computer Methods and Programs in Biomedicine. 2022;213:106536.

    Article  PubMed  Google Scholar 

  18. Marin C, Luyten FP, van der Schueren B, Kerckhofs G, Vandamme K. The impact of type 2 diabetes on bone fracture healing. Frontiers in Endocrinology. 2018;9:6.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Alharbi MA, Zhang C, Lu C, Milovanova TN, Yi L, Ryu JD, Jiao H, Dong G, O’Connor JP, Graves DT. FOXO1 deletion reverses the effect of diabetic-induced impaired fracture healing. Diabetes. 2018;67(12):2682–94.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sundararaghavan V, Mazur MM, Evans B, Liu J, Ebraheim NA. Diabetes and bone health: latest evidence and clinical implications. Therapeutic advances in musculoskeletal disease. 2017;9(3):67–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sun N, Ning B, Hansson KM, Bruce AC, Seaman SA, Zhang C, Rikard M, DeRosa CA, Fraser CL, Wågberg M, Fritsche-Danielson R, Wikström J, Chien KR, Lundahl A, Hölttä M, Carlsson LG, Peirce SM, Hu S. Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing. Scientific reports. 2018;8(1):1–11.

    Article  Google Scholar 

  22. Ko KI, Syverson AL, Kralik RM, Choi J, DerGarabedian BP, Chen C, Graves DT. Diabetes-induced NF-κB dysregulation in skeletal stem cells prevents resolution of inflammation. Diabetes. 2019;68(11):2095–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kalyanaraman H, Schwaerzer G, Ramdani G, Castillo F, Scott BT, Dillmann W, Sah RL, Casteel DE, Pilz RB. Protein kinase G activation reverses oxidative stress and restores osteoblast function and bone formation in male mice with type 1 diabetes. Diabetes. 2018;67(4):607–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schall N, Garcia JJ, Kalyanaraman H, China SP, Lee JJ, Sah RL, Pfeifer A, Pilz RB. Protein kinase G1 regulates bone regeneration and rescues diabetic fracture healing. JCI Insight. 2020;5(9):e135355.

  25. Xu MT, Sun S, Zhang L, Xu F, Du SL, Zhang XD, Wang DW. Diabetes mellitus affects the biomechanical function of the callus and the expression of TGF-beta1 and BMP2 in an early stage of fracture healing. Braz J Med Biol Res. 2016;49(1):e4736.

  26. Jiang H, Wang Y, Meng J, Chen S, Wang J, Qiu Y, Zhao J, Guo T. Effects of transplanting bone marrow stromal cells transfected with CXCL13 on fracture healing of diabetic rats. Cellular Physiology and Biochemistry. 2018;49(1):123–33.

    Article  CAS  PubMed  Google Scholar 

  27. Hoff P, Gaber T, Strehl C, Schmidt-Bleek K, Lang A, Huscher D, Burmester GR, Schmidmaier G, Perka C, Duda GN, Buttgereit F. Immunological characterization of the early human fracture hematoma. Immunologic research. 2016;64(5):1195–206.

    Article  CAS  PubMed  Google Scholar 

  28. Liuni FM, Rugiero C, Feola M, Rao C, Pistillo P, Terracciano C, Giganti MG, Tarantino U. Impaired healing of fragility fractures in type 2 diabetes: clinical and radiographic assessments and serum cytokine levels. Aging Clinical and Experimental Research. 2015;27(1):37–44.

    Article  Google Scholar 

  29. Guo Q, Wang W, Abboud R, Guo Z. Impairment of maturation of BMP-6 (35 kDa) correlates with delayed fracture healing in experimental diabetes. Journal of Orthopaedic Surgery and Research. 2020;15(1):1–11.

    Article  Google Scholar 

  30. Takahara S, Lee SY, Iwakura T, Oe K, Fukui T, Okumachi E, Arakura M, Sakai Y, Matsumoto T, Matsushita T, Kuroda R, Niikura T. Altered microRNA profile during fracture healing in rats with diabetes. Journal of Orthopaedic Surgery and Research. 2020;15(1):1–9.

    Article  Google Scholar 

  31. Wang Z, Tang J, Li Y, Wang Y, Guo Y, Tu Q, Chen J, Wang C. AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes. Experimental cell research. 2020;387(2):111757.

    Article  CAS  PubMed  Google Scholar 

  32. Choy MHV, Wong RMY, Chow SKH, Li MC, Chim YN, Li TK, Ho WT, Cheng JCY, Cheung WH. How much do we know about the role of osteocytes in different phases of fracture healing? A systematic review. Journal of orthopaedic translation. 2020;21:111–21.

    Article  PubMed  Google Scholar 

  33. Shimizu T, Fujita N, Tsuji-Tamura K, Kitagawa Y, Fujisawa T, Tamura M, Sato M. Osteocytes as main responders to low-intensity pulsed ultrasound treatment during fracture healing. Scientific reports. 2021;11(1):1–15.

    Article  Google Scholar 

  34. García-Martín A, Rozas-Moreno P, Reyes-García R, Morales-Santana S, García-Fontana B, García-Salcedo JA, Muñoz-Torres M. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. The journal of clinical endocrinology & metabolism. 2012;97(1):234–41.

    Article  Google Scholar 

  35. Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, Salimi-Moosavi H, Asuncion FJ, Li C, Sun B, Tan HL, Zhang L, Han CY, Case R, Duguay AN, Grisanti M, Stevens J, Pretorius JK, Pacheco E, et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nature communications. 2016;7(1):1–14.

    Article  Google Scholar 

  36. Alzahrani MM, Rauch F, Hamdy RC. Does sclerostin depletion stimulate fracture healing in a mouse model? Clin Orthop Res. 2016;474(5):1294–302.

    Article  Google Scholar 

  37. Kruck B, Zimmermann EA, Damerow S, Figge C, Julien C, Wulsten D, Thiele T, Martin M, Hamdy R, Reumann MK, Duda GN, Checa S, Willie BM. Sclerostin neutralizing antibody treatment enhances bone formation but does not rescue mechanically induced delayed healing. Journal of Bone and Mineral Research. 2018;33(9):1686–97.

    Article  CAS  PubMed  Google Scholar 

  38. Morse A, McDonald MM, Schindeler A, Peacock L, Mikulec K, Cheng TL, Liu M, Ke HZ, Little DG. Sclerostin antibody increases callus size and strength but does not improve fracture union in a challenged open rat fracture model. Calcified Tissue International. 2017;101(2):217–28.

    Article  CAS  PubMed  Google Scholar 

  39. Bhandari M, Schemitsch EH, Karachalios T, Sancheti P, Poolman RW, Caminis J, Daizadeh N, Dent-Acosta RE, Egbuna O, Chines A, Miclau T. Romosozumab in skeletally mature adults with a fresh unilateral tibial diaphyseal fracture: a randomized phase-2 study. JBJS. 2020;102(16):1416–26.

    Article  Google Scholar 

  40. Schemitsch EH, et al. A randomized, placebo-controlled study of romosozumab for the treatment of hip fractures. J Bone Joint Surg Am. 2020;102(8):693.

    Article  PubMed  Google Scholar 

  41. Leder BZ. Parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis therapy. Current osteoporosis reports. 2017;15(2):110–9.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Baroi S, Czernik PJ, Chougule A, Griffin PR, Lecka-Czernik B. PPARG in osteocytes controls sclerostin expression, bone mass, marrow adiposity and mediates TZD-induced bone loss. Bone. 2021;147:115913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rasmussen NH, Dal J. Falls and fractures in diabetes—more than bone fragility. Current osteoporosis reports. 2019;17(3):147–56.

    Article  PubMed  Google Scholar 

  44. Komorita Y, Ohkuma T, Iwase M, Fujii H, Oku Y, Higashi T, Oshiro A, Sakamoto W, Yoshinari M, Nakamura U, Kitazono T. Polypharmacy and bone fracture risk in patients with type 2 diabetes: the Fukuoka Diabetes Registry. Diabetes research and clinical practice. 2021;181:109097.

    Article  PubMed  Google Scholar 

  45. Poiana C, Capatina C. Fracture risk assessment in patients with diabetes mellitus. Journal of Clinical Densitometry. 2017;20(3):432–43.

    Article  PubMed  Google Scholar 

  46. Hofbauer LC, Busse B, Eastell R, Ferrari S, Frost M, Müller R, Burden AM, Rivadeneira F, Napoli N, Rauner M. Bone fragility in diabetes: novel concepts and clinical implications. Lancet Diabetes Endocrinol. 2022;10(3):207-220.

  47. Rathmann W, Kostev K. Fracture risk in patients with newly diagnosed type 2 diabetes: a retrospective database analysis in primary care. Journal of Diabetes and its Complications. 2015;29(6):766–70.

    Article  PubMed  Google Scholar 

  48. Wang H, Ba Y, Xing Q, du JL. Diabetes mellitus and the risk of fractures at specific sites: a meta-analysis. BMJ open. 2019;9(1):e024067.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Compston J. Type 2 diabetes mellitus and bone. Journal of internal medicine. 2018;283(2):140–53.

    Article  CAS  PubMed  Google Scholar 

  50. Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE, Donaldson MG, Cauley JA, Harris TB, Koster A, Womack CR, Palermo L, Black DM, Study of Osteoporotic Fractures (SOF) Research Group, Osteoporotic Fractures in Men (MrOS) Research Group, Health, Aging, and Body Composition (Health ABC) Research Group. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. Jama. 2011;305(21):2184–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schacter GI, Leslie WD. DXA-based measurements in diabetes: can they predict fracture risk? Calcified tissue international. 2017;100(2):150–64.

    Article  CAS  PubMed  Google Scholar 

  52. Champakanath A, Keshawarz A, Pyle L, Snell-Bergeon JK, Shah VN. Fracture risk assessment (FRAX) without BMD and risk of major osteoporotic fractures in adults with type 1 diabetes. Bone. 2021;143:115614.

    Article  PubMed  Google Scholar 

  53. Sihota P, Yadav RN, Dhaliwal R, Bose JC, Dhiman V, Neradi D, Karn S, Sharma S, Aggarwal S, Goni VG, Mehandia V, Vashishth D, Bhadada SK, Kumar N. Investigation of mechanical, material, and compositional determinants of human trabecular bone quality in type 2 diabetes. The Journal of Clinical Endocrinology & Metabolism. 2021;106(5):e2271–89.

    Article  Google Scholar 

  54. Baleanu F, Bergmann P, Hambye AS, Dekelver C, Iconaru L, Cappelle SI, Moreau M, Paesmans M, Karmali R, Body JJ. Assessment of bone quality with trabecular bone score in type 2 diabetes mellitus: A study from the FRISBEE cohort. International journal of clinical practice. 2019;73(5):e13347.

    Article  PubMed  Google Scholar 

  55. Yamamoto M, Yamauchi M, Sugimoto T. Prevalent vertebral fracture is dominantly associated with spinal microstructural deterioration rather than bone mineral density in patients with type 2 diabetes mellitus. Plos one. 2019;14(9):e0222571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Janghorbani M, van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. American journal of epidemiology. 2007;166(5):495–505.

    Article  PubMed  Google Scholar 

  57. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporosis international. 2007;18(4):427–44.

    Article  CAS  PubMed  Google Scholar 

  58. Dytfeld J, Michalak M. Type 2 diabetes and risk of low-energy fractures in postmenopausal women: meta-analysis of observational studies. Aging clinical and experimental research. 2017;29(2):301–9.

    Article  PubMed  Google Scholar 

  59. Moayeri A, Mohamadpour M, Mousavi S, Shirzadpour E, Mohamadpour S, Amraei M. Fracture risk in patients with type 2 diabetes mellitus and possible risk factors: a systematic review and meta-analysis. Therapeutics and clinical risk management. 2017;13:455–68.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Koromani F, Ghatan S, van Hoek M, Zillikens MC, Oei EHG, Rivadeneira F, Oei L. Type 2 Diabetes Mellitus and Vertebral Fracture Risk. Curr Osteoporos Rep. 2021;19(1):50–57.

  61. Zhukouskaya VV, Eller-Vainicher C, Vadzianava VV, Shepelkevich AP, Zhurava IV, Korolenko GG, Salko OB, Cairoli E, Beck-Peccoz P, Chiodini I. Prevalence of morphometric vertebral fractures in patients with type 1 diabetes. Diabetes care. 2013;36(6):1635–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Koromani F, Oei L, Shevroja E, Trajanoska K, Schoufour J, Muka T, Franco OH, Ikram MA, Zillikens MC, Uitterlinden AG, Krestin GP, Anastassiades T, Josse R, Kaiser SM, Goltzman D, Lentle BC, Prior JC, Leslie WD, McCloskey E, et al. Vertebral fractures in individuals with type 2 diabetes: more than skeletal complications alone. Diabetes Care. 2020;43(1):137–44.

    Article  PubMed  Google Scholar 

  63. Hayrapetyan A, Jansen JA, van den Beucken JJ. Signaling pathways involved in osteogenesis and their application for bone regenerative medicine. Tissue Engineering Part B: Reviews. 2015;21(1):75–87.

    Article  Google Scholar 

  64. Thompson WR, Rubin CT, Rubin J. Mechanical regulation of signaling pathways in bone. Gene. 2012;503(2):179–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fatima N, Faisal SM, Zubair S, Ajmal M, Siddiqui SS, Moin S, Owais M. Role of pro-inflammatory cytokines and biochemical markers in the pathogenesis of type 1 diabetes: correlation with age and glycemic condition in diabetic human subjects. PloS one. 2016;11(8):e0161548.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Devaraj S, Venugopal SK, Singh U, Jialal I. Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and-β. Diabetes. 2005;54(1):85–91.

    Article  CAS  PubMed  Google Scholar 

  67. Kumar P, Natarajan K, Shanmugam N. High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. Cellular signalling. 2014;26(3):528–39.

    Article  CAS  PubMed  Google Scholar 

  68. Bastard J-P, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. The Journal of Clinical Endocrinology & Metabolism. 2000;85(9):3338–42.

    CAS  Google Scholar 

  69. Harmer D, Falank C, Reagan MR. Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma. Front Endocrinol (Lausanne). 2019;9:788.

  70. Wu Q, Zhou X, Huang D, JI Y, Kang F. IL-6 enhances osteocyte-mediated osteoclastogenesis by promoting JAK2 and RANKL activity in vitro. Cellular Physiology and Biochemistry. 2017;41(4):1360–9.

    Article  CAS  PubMed  Google Scholar 

  71. Peruzzi B, Cappariello A, del Fattore A, Rucci N, de Benedetti F, Teti A. c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nature communications. 2012;3(1):1–10.

    Article  Google Scholar 

  72. Kaneshiro S, Ebina K, Shi K, Higuchi C, Hirao M, Okamoto M, Koizumi K, Morimoto T, Yoshikawa H, Hashimoto J. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. Journal of bone and mineral metabolism. 2014;32(4):378–92.

    Article  CAS  PubMed  Google Scholar 

  73. Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes. 2005;54(Suppl 2):S114–24.

    Article  CAS  PubMed  Google Scholar 

  74. Marahleh A, Kitaura H, Ohori F, Kishikawa A, Ogawa S, Shen WR, Qi J, Noguchi T, Nara Y, Mizoguchi I. TNF-α Directly Enhances Osteocyte RANKL Expression and Promotes Osteoclast Formation. Front Immunol. 2019;10:2925.

  75. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature medicine. 2011;17(10):1231–4.

    Article  CAS  PubMed  Google Scholar 

  76. Ding Y, Wei J, Hettinghouse A, Li G, Li X, Einhorn TA, Liu CJ. Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus. Annals of the New York Academy of Sciences. 2021;1490(1):77–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wei J, Zhang L, Ding Y, Liu R, Guo Y, Hettinghouse A, Buza J, de la Croix J, Li X, Einhorn TA, Liu CJ. Progranulin promotes diabetic fracture healing in mice with type 1 diabetes. Annals of the New York Academy of Sciences. 2020;1460(1):43–56.

    Article  CAS  PubMed  Google Scholar 

  78. Tanaka N, Yonekura H, Yamagishi SI, Fujimori H, Yamamoto Y, Yamamoto H. The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-α through nuclear factor-κB, and by 17β-estradiol through Sp-1 in human vascular endothelial cells. Journal of Biological Chemistry. 2000;275(33):25781–90.

    Article  CAS  PubMed  Google Scholar 

  79. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal transduction and targeted therapy. 2017;2(1):1–9.

    Article  CAS  Google Scholar 

  80. Weinberg E, Maymon T, Weinreb M. AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFa production and oxidative stress. J Mol Endocrinol. 2014;52(1):67–76.

    Article  CAS  PubMed  Google Scholar 

  81. Tanaka K, Yamagata K, Kubo S, Nakayamada S, Sakata K, Matsui T, Yamagishi SI, Okada Y, Tanaka Y. Glycolaldehyde-modified advanced glycation end-products inhibit differentiation of human monocytes into osteoclasts via upregulation of IL-10. Bone. 2019;128:115034.

    Article  CAS  PubMed  Google Scholar 

  82. Xu LX, Kukita T, Kukita A, Otsuka T, Niho Y, Iijima T. Interleukin-10 selectively inhibits osteoclastogenesis by inhibiting differentiation of osteoclast progenitors into preosteoclast-like cells in rat bone marrow culture system. Journal of cellular physiology. 1995;165(3):624–9.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang Q, Chen B, Yan F, Guo J, Zhu X, Ma S, Yang W. Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases. Biomed Res Int. 2014;2014:284836.

  84. Nakano N, Fukuhara-Takaki K, Jono T, Nakajou K, Eto N, Horiuchi S, Takeya M, Nagai R. Association of advanced glycation end products with A549 cells, a human pulmonary epithelial cell line, is mediated by a receptor distinct from the scavenger receptor family and RAGE. Journal of biochemistry. 2006;139(5):821–9.

    Article  CAS  PubMed  Google Scholar 

  85. Schmidt AM, et al. The biology of the receptor for advanced glycation end products and its ligands. Biochim et Biophys Acta (BBA)-Molecul Cell Res. 2000;1498(2-3):99–111.

    Article  CAS  Google Scholar 

  86. Takeuchi M, Yamagishi S-i. Involvement of toxic AGEs (TAGE) in the pathogenesis of diabetic vascular complications and Alzheimer's disease. Journal of Alzheimer's Disease. 2009;16(4):845–58.

    Article  PubMed  Google Scholar 

  87. Ohashi K, Takahashi HK, Mori S, Liu K, Wake H, Sadamori H, Matsuda H, Yagi T, Yoshino T, Nishibori M, Tanaka N. Advanced glycation end products enhance monocyte activation during human mixed lymphocyte reaction. Clinical immunology. 2010;134(3):345–53.

    Article  CAS  PubMed  Google Scholar 

  88. Figarola JL, Shanmugam N, Natarajan R, Rahbar S. Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90 in human monocytes. Diabetes. 2007;56(3):647–55.

    Article  CAS  PubMed  Google Scholar 

  89. Okazaki K, Yamaguchi T, Tanaka KI, Notsu M, Ogawa N, Yano S, Sugimoto T. Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcified tissue international. 2012;91(4):286–96.

    Article  CAS  PubMed  Google Scholar 

  90. Takahashi HK, Mori S, Wake H, Liu K, Yoshino T, Ohashi K, Tanaka N, Shikata K, Makino H, Nishibori M. Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. Journal of Pharmacology and Experimental Therapeutics. 2009;330(1):89–98.

    Article  CAS  PubMed  Google Scholar 

  91. Lee E-J, Kang MK, Kim YH, Kim DY, Oh H, Kim SI, Oh SY, Na W, Kang YH. Coumarin ameliorates impaired bone turnover by inhibiting the formation of advanced glycation end products in diabetic osteoblasts and osteoclasts. Biomolecules. 2020;10(7):1052.

    Article  CAS  PubMed Central  Google Scholar 

  92. Saito M, Kida Y, Kato S, Marumo K. Diabetes, collagen, and bone quality. Current osteoporosis reports. 2014;12(2):181–8.

    Article  PubMed  Google Scholar 

  93. Turecek C, Fratzl-Zelman N, Rumpler M, Buchinger B, Spitzer S, Zoehrer R, Durchschlag E, Klaushofer K, Paschalis EP, Varga F. Collagen cross-linking influences osteoblastic differentiation. Calcified tissue international. 2008;82(5):392–400.

    Article  CAS  PubMed  Google Scholar 

  94. Schwartz AV, Sellmeyer DE. Diabetes, fracture, and bone fragility. Current osteoporosis reports. 2007;5(3):105–11.

    Article  PubMed  Google Scholar 

  95. Khosravi R, Sodek KL, Faibish M, Trackman PC. Collagen advanced glycation inhibits its discoidin domain receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone. 2014;58:33–41.

    Article  CAS  PubMed  Google Scholar 

  96. Luc K, et al. Oxidative stress and inflammatory markers in prediabetes and diabetes. J. Physiol. Pharmacol. 2019;70(6):809–24.

    CAS  Google Scholar 

  97. Rehman K, Akash MSH. Mechanism of generation of oxidative stress and pathophysiology of type 2 diabetes mellitus: how are they interlinked? Journal of cellular biochemistry. 2017;118(11):3577–85.

    Article  CAS  PubMed  Google Scholar 

  98. Callaway DA, Jiang JX. Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. Journal of Bone and Mineral Metabolism. 2015;33(4):359–70.

    Article  CAS  PubMed  Google Scholar 

  99. Almeida M, O’Brien CA. Basic biology of skeletal aging: role of stress response pathways. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences. 2013;68(10):1197–208.

    Article  CAS  Google Scholar 

  100. Bartell SM, Kim HN, Ambrogini E, Han L, Iyer S, Serra Ucer S, Rabinovitch P, Jilka RL, Weinstein RS, Zhao H, O’Brien CA, Manolagas SC, Almeida M. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nature communications. 2014;5(1):1–12.

    Article  Google Scholar 

  101. Wang Y, Dong G, Jeon HH, Elazizi M, la LB, Hameedaldeen A, Xiao E, Tian C, Alsadun S, Choi Y, Graves DT. FOXO1 mediates RANKL-induced osteoclast formation and activity. The Journal of Immunology. 2015;194(6):2878–87.

    Article  CAS  PubMed  Google Scholar 

  102. Guo T-Y, Liu LJ, Xu LZ, Zhang JC, Li SX, Chen C, He LG, Chen YM, Yang HD, Lu L, Hashimoto K. Alterations of the daily rhythms of HPT axis induced by chronic unpredicted mild stress in rats. Endocrine. 2015;48(2):637–43.

    Article  CAS  PubMed  Google Scholar 

  103. Hyeon S, Lee H, Yang Y, Jeong W. Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radical Biology and Medicine. 2013;65:789–99.

    Article  CAS  PubMed  Google Scholar 

  104. Simpson C, Jayaramaraju D, Agraharam D, Gudipati S, Shanmuganathan R, Giannoudis PV. The effects of diabetes medications on post-operative long bone fracture healing. Eur J Orthop Surg Traumatol. 2015;25(8):1239–43.

    Article  CAS  PubMed  Google Scholar 

  105. Mu W, Wang Z, Ma C, Jiang Y, Zhang N, Hu K, Li L, Wang Z. Metformin promotes the proliferation and differentiation of murine preosteoblast by regulating the expression of sirt6 and oct4. Pharmacol Res. 2018;129:462–74.

    Article  CAS  PubMed  Google Scholar 

  106. Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C, Goodship A, Roux JP, Pierre M, Chenu C. The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int. 2013;24(10):2659–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Smieszek A, Tomaszewski KA, Kornicka K, Marycz K. Metformin Promotes Osteogenic Differentiation of Adipose-Derived Stromal Cells and Exerts Pro-Osteogenic Effect Stimulating Bone Regeneration. J Clin Med. 2018;7(12):482.

  108. Lecka-Czernik B. Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep. 2010;8(4):178–84.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Lebovitz HE. Thiazolidinediones: the forgotten diabetes medications. Curr Diab Rep. 2019;19(12):151.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Liu L, Aronson J, Lecka-Czernik B. Rosiglitazone disrupts endosteal bone formation during distraction osteogenesis by local adipocytic infiltration. Bone. 2013;52(1):247–58.

    Article  CAS  PubMed  Google Scholar 

  111. Liu L, Aronson J, Huang S, Lu Y, Czernik P, Rahman S, Kolli V, Suva LJ, Lecka-Czernik B. Rosiglitazone inhibits bone regeneration and causes significant accumulation of fat at sites of new bone formation. Calcif Tissue Int. 2012;91(2):139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Stechschulte LA, Czernik PJ, Rotter ZC, Tausif FN, Corzo CA, Marciano DP, Asteian A, Zheng J, Bruning JB, Kamenecka TM, Rosen CJ, Griffin PR, Lecka-Czernik B. PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine. 2016;10:174–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Harrison SA, Alkhouri N, Davison BA, Sanyal A, Edwards C, Colca JR, Lee BH, Loomba R, Cusi K, Kolterman O, Cotter G, Dittrich HC. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study. J Hepatol. 2020;72(4):613–26.

    Article  CAS  PubMed  Google Scholar 

  114. Gehling DJ, Lecka-Czernik B, Ebraheim NA. Orthopedic complications in diabetes. Bone. 2016;82:79–92.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Karen Bach for her support with preparation and review of this article.

Funding

BLC was supported by grants from NIH R01AG071332 and American Diabetes Association Innovative Basic Science Award #1-19-IBS-029.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mina Tanios or Beata Lecka-Czernik.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Bone and Diabetes

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanios, M., Brickman, B., Cage, E. et al. Diabetes and Impaired Fracture Healing: A Narrative Review of Recent Literature. Curr Osteoporos Rep 20, 229–239 (2022). https://doi.org/10.1007/s11914-022-00740-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-022-00740-z

Keywords

Navigation