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Semin Plast Surg 2021; 35(03): 198-203
DOI: 10.1055/s-0041-1732334
Review Article

Bone Healing and Inflammation: Principles of Fracture and Repair

Hassan ElHawary
1   Division of Plastic and Reconstructive Surgery, McGill University Health Centre, Montreal, Quebec, Canada
,
Aslan Baradaran
1   Division of Plastic and Reconstructive Surgery, McGill University Health Centre, Montreal, Quebec, Canada
,
Jad Abi-Rafeh
1   Division of Plastic and Reconstructive Surgery, McGill University Health Centre, Montreal, Quebec, Canada
,
Joshua Vorstenbosch
1   Division of Plastic and Reconstructive Surgery, McGill University Health Centre, Montreal, Quebec, Canada
,
Liqin Xu
1   Division of Plastic and Reconstructive Surgery, McGill University Health Centre, Montreal, Quebec, Canada
,
Johnny Ionut Efanov
2   Division of Plastic and Reconstructive Surgery, Centre Hospitalier de l'Université de Montréal, Quebec, Canada
› Author Affiliations Funding None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript.
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Abstract

Bones comprise a significant percentage of human weight and have important physiologic and structural roles. Bone remodeling occurs when healthy bone is renewed to maintain bone strength and maintain calcium and phosphate homeostasis. It proceeds through four phases: (1) cell activation, (2) resorption, (3) reversal, and (4) bone formation. Bone healing, on the other hand, involves rebuilding bone following a fracture. There are two main types of bone healing, primary and secondary. Inflammation plays an integral role in both bone remodeling and healing. Therefore, a tightly regulated inflammatory response helps achieve these two processes, and levels of inflammation can have detrimental effects on bone healing. Other factors that significantly affect bone healing are inadequate blood supply, biomechanical instability, immunosuppression, and smoking. By understanding the different mechanisms of bone healing and the factors that affect them, we may have a better understanding of the underlying principles of bony fixation and thereby improve patient care.

Keywords

bone healing - fracture repair - bone inflammation - osteomyelitis


Publication History

Article published online:
10 September 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton III LJ. Trends in fracture incidence: a population-based study over 20 years. J Bone Miner Res 2014; 29 (03) 581-589
    CrossrefPubMedSearch in Google Scholar
  • 2 Bergh C, Wennergren D, Möller M, Brisby H. Fracture incidence in adults in relation to age and gender: a study of 27,169 fractures in the Swedish Fracture Register in a well-defined catchment area. PLoS One 2020; 15 (12) e0244291
    CrossrefPubMedSearch in Google Scholar
  • 3 Abtahi S, Driessen JH, Vestergaard P. et al. Secular trends in major osteoporotic fractures among 50+ adults in Denmark between 1995 and 2010 (retraction of Vol 13, art no 91, 2018). Arch Osteoporos 2019; 14 (01) 91
    CrossrefPubMedSearch in Google Scholar
  • 4 Christensen L, Iqbal S, Macarios D, Badamgarav E, Harley C. Cost of fractures commonly associated with osteoporosis in a managed-care population. J Med Econ 2010; 13 (02) 302-31
    CrossrefPubMedSearch in Google Scholar
  • 5 Leslie WD, Metge CJ, Azimaee M. et al. Direct costs of fractures in Canada and trends 1996-2006: a population-based cost-of-illness analysis. J Bone Miner Res 2011; 26 (10) 2419-2429
    CrossrefPubMedSearch in Google Scholar
  • 6 Katsoulis M, Benetou V, Karapetyan T. et al. Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project. J Intern Med 2017; 281 (03) 300-310
    CrossrefPubMedSearch in Google Scholar
  • 7 Kim JN, Lee JY, Shin KJ, Gil YC, Koh KS, Song WC. Haversian system of compact bone and comparison between endosteal and periosteal sides using three-dimensional reconstruction in rat. Anat Cell Biol 2015; 48 (04) 258-261
    CrossrefPubMedSearch in Google Scholar
  • 8 Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 2008; 3 (Suppl. 03) S131-S139
    CrossrefPubMedSearch in Google Scholar
  • 9 Office of the Surgeon General (US). Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville (MD): Office of the Surgeon General (US); 2004
    Search in Google Scholar
  • 10 Young MF. Bone matrix proteins: their function, regulation, and relationship to osteoporosis. Osteoporos Int 2003; 14 (Suppl. 03) S35-S42
    CrossrefPubMedSearch in Google Scholar
  • 11 Zhao W, Byrne MH, Wang Y, Krane SM. Osteocyte and osteoblast apoptosis and excessive bone deposition accompany failure of collagenase cleavage of collagen. J Clin Invest 2000; 106 (08) 941-949
    CrossrefPubMedSearch in Google Scholar
  • 12 Green J, Schotland S, Stauber DJ, Kleeman CR, Clemens TL. Cell-matrix interaction in bone: type I collagen modulates signal transduction in osteoblast-like cells. Am J Physiol 1995; 268 (5, pt 1): C1090-C1103
    CrossrefPubMedSearch in Google Scholar
  • 13 Lynch MP, Stein JL, Stein GS, Lian JB. The influence of type I collagen on the development and maintenance of the osteoblast phenotype in primary and passaged rat calvarial osteoblasts: modification of expression of genes supporting cell growth, adhesion, and extracellular matrix mineralization. Exp Cell Res 1995; 216 (01) 35-45
    CrossrefPubMedSearch in Google Scholar
  • 14 Waddington RJ, Roberts HC, Sugars RV, Schönherr E. Differential roles for small leucine-rich proteoglycans in bone formation. Eur Cell Mater 2003; 6: 12-21 , discussion 21
    CrossrefPubMedSearch in Google Scholar
  • 15 Bonewald LF, Mundy GR. Role of transforming growth factor-beta in bone remodeling. Clin Orthop Relat Res 1990; (250) 261-276
    PubMedSearch in Google Scholar
  • 16 Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008; 29 (05) 535-559
    CrossrefPubMedSearch in Google Scholar
  • 17 Frost HMA. A 2003 update of bone physiology and Wolff's law for clinicians. Angle Orthod 2004; 74 (01) 3-15
    PubMedSearch in Google Scholar
  • 18 Plochocki JH, Rivera JP, Zhang C, Ebba SA. Bone modeling response to voluntary exercise in the hindlimb of mice. J Morphol 2008; 269 (03) 313-318
    CrossrefPubMedSearch in Google Scholar
  • 19 Roodman GD. Cell biology of the osteoclast. Exp Hematol 1999; 27 (08) 1229-1241
    CrossrefPubMedSearch in Google Scholar
  • 20 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423 (6937): 337-342
    CrossrefPubMedSearch in Google Scholar
  • 21 Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 2005; 11 (02) 76-81
    CrossrefPubMedSearch in Google Scholar
  • 22 Anderson HC. Matrix vesicles and calcification. Curr Rheumatol Rep 2003; 5 (03) 222-226
    CrossrefPubMedSearch in Google Scholar
  • 23 Kaderly RE. Primary bone healing. Semin Vet Med Surg (Small Anim) 1991; 6 (01) 21-25
    PubMedSearch in Google Scholar
  • 24 Greenbaum MA, Kanat IO. Current concepts in bone healing. Review of the literature. J Am Podiatr Med Assoc 1993; 83 (03) 123-129
    CrossrefPubMedSearch in Google Scholar
  • 25 Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res 1998; (355, suppl): S7-S21
    CrossrefPubMedSearch in Google Scholar
  • 26 Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 2003; 88 (05) 873-884
    CrossrefPubMedSearch in Google Scholar
  • 27 Granero-Moltó F, Weis JA, Miga MI. et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells 2009; 27 (08) 1887-1898
    CrossrefPubMedSearch in Google Scholar
  • 28 Breur GJ, VanEnkevort BA, Farnum CE, Wilsman NJ. Linear relationship between the volume of hypertrophic chondrocytes and the rate of longitudinal bone growth in growth plates. J Orthop Res 1991; 9 (03) 348-359
    CrossrefPubMedSearch in Google Scholar
  • 29 Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 2008; 87 (02) 107-118
    CrossrefPubMedSearch in Google Scholar
  • 30 Reikerås O, Shegarfi H, Wang JE, Utvåg SE. Lipopolysaccharide impairs fracture healing: an experimental study in rats. Acta Orthop 2005; 76 (06) 749-753
    CrossrefPubMedSearch in Google Scholar
  • 31 Toben D, Schroeder I, El Khassawna T. et al. Fracture healing is accelerated in the absence of the adaptive immune system. J Bone Miner Res 2011; 26 (01) 113-124
    CrossrefPubMedSearch in Google Scholar
  • 32 Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol 2012; 8 (03) 133-143
    CrossrefPubMedSearch in Google Scholar
  • 33 Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P. Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br 2000; 82 (05) 655-658
    CrossrefPubMedSearch in Google Scholar
  • 34 Pountos I, Georgouli T, Calori GM, Giannoudis PV. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. ScientificWorldJournal 2012; 2012: 606404
    CrossrefPubMedSearch in Google Scholar
  • 35 Wheatley BM, Nappo KE, Christensen DL, Holman AM, Brooks DI, Potter BK. Effect of NSAIDs on bone healing rates: a meta-analysis. J Am Acad Orthop Surg 2019; 27 (07) e330-e336
    CrossrefPubMedSearch in Google Scholar
  • 36 Hak DJ, Fitzpatrick D, Bishop JA. et al. Delayed union and nonunions: epidemiology, clinical issues, and financial aspects. Injury 2014; 45 (Suppl. 02) S3-S7
    CrossrefPubMedSearch in Google Scholar
  • 37 Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury 2006; 37 (Suppl. 02) S59-S66
    CrossrefPubMedSearch in Google Scholar
  • 38 Croes M, van der Wal BCH, Vogely HC. Impact of bacterial infections on osteogenesis: evidence from in vivo studies. J Orthop Res 2019; 37 (10) 2067-2076
    CrossrefPubMedSearch in Google Scholar
  • 39 Fritz JM, McDonald JR. Osteomyelitis: approach to diagnosis and treatment. Phys Sportsmed 2008; 36 (01) a116823
    CrossrefPubMedSearch in Google Scholar
  • 40 Lee YJ, Sadigh S, Mankad K, Kapse N, Rajeswaran G. The imaging of osteomyelitis. Quant Imaging Med Surg 2016; 6 (02) 184-198
    CrossrefPubMedSearch in Google Scholar
  • 41 Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997; 336 (14) 999-1007
    CrossrefPubMedSearch in Google Scholar
  • 42 Cortés-Penfield NW, Kulkarni PA. The history of antibiotic treatment of osteomyelitis. Open Forum Infect Dis 2019; 6 (05) ofz181
    CrossrefPubMedSearch in Google Scholar
  • 43 Buckley R, Moran C, Apivatthakakul T. AO Principles of Fracture Management. Available at: https://www.scribbr.com/apa-examples/website/ https://pfxm3.aoeducation.org/start.html. Accessed July 19, 2021
    PubMed
  • 44 Mukhopadhaya J, Jain AK. AO principles of fracture management. Indian J Orthop 2019; 53 (01) 217-218
    CrossrefPubMedSearch in Google Scholar
  • 45 Cunningham BP, Brazina S, Morshed S, Miclau III T. Fracture healing: a review of clinical, imaging and laboratory diagnostic options. Injury 2017; 48 (Suppl. 01) S69-S75
    CrossrefPubMedSearch in Google Scholar
  • 46 Klotch DW, Gilliland R. Internal fixation vs. conventional therapy in midface fractures. J Trauma 1987; 27 (10) 1136-1145
    CrossrefPubMedSearch in Google Scholar
  • 47 Patel RA, Wilson RF, Patel PA, Palmer RM. The effect of smoking on bone healing: a systematic review. Bone Joint Res 2013; 2 (06) 102-111
    CrossrefPubMedSearch in Google Scholar
  • 48 Sloan A, Hussain I, Maqsood M, Eremin O, El-Sheemy M. The effects of smoking on fracture healing. Surgeon 2010; 8 (02) 111-116
    CrossrefPubMedSearch in Google Scholar
  • 49 Clark D, Nakamura M, Miclau T, Marcucio R. Effects of aging on fracture healing. Curr Osteoporos Rep 2017; 15 (06) 601-608
    CrossrefPubMedSearch in Google Scholar
  • 50 Meesters DM, Wijnands KAP, Brink PRG, Poeze M. Malnutrition and fracture healing: are specific deficiencies in amino acids important in nonunion development?. Nutrients 2018; 10 (11) E1597
    CrossrefPubMedSearch in Google Scholar
  • 51 Gao F, Lv TR, Zhou JC, Qin XD. Effects of obesity on the healing of bone fracture in mice. J Orthop Surg Res 2018; 13 (01) 145
    CrossrefPubMedSearch in Google Scholar
  • 52 Thorud JC, Mortensen S, Thorud JL, Shibuya N, Maldonado YM, Jupiter DC. Effect of obesity on bone healing after foot and ankle long bone fractures. J Foot Ankle Surg 2017; 56 (02) 258-262
    CrossrefPubMedSearch in Google Scholar
  • 53 Liu YZ, Akhter MP, Gao X. et al. Glucocorticoid-induced delayed fracture healing and impaired bone biomechanical properties in mice. Clin Interv Aging 2018; 13: 1465-1474
    CrossrefPubMedSearch in Google Scholar
  • 54 Victoria G, Petrisor B, Drew B, Dick D. Bone stimulation for fracture healing: what's all the fuss?. Indian J Orthop 2009; 43 (02) 117-120
    CrossrefPubMedSearch in Google Scholar
  • 55 Rutten S, van den Bekerom MP, Sierevelt IN, Nolte PA. Enhancement of bone-healing by low-intensity pulsed ultrasound: a systematic review. JBJS Rev 2016; 4 (03) 01874474 -201603000-00006
    CrossrefPubMedSearch in Google Scholar
  • 56 Schandelmaier S, Kaushal A, Lytvyn L. et al. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ 2017; 356: j656
    CrossrefPubMedSearch in Google Scholar
  • 57 Griffin M, Bayat A. Electrical stimulation in bone healing: critical analysis by evaluating levels of evidence. Eplasty 2011; 11: e34
    PubMedSearch in Google Scholar
  • 58 Kuzyk PR, Schemitsch EH. The science of electrical stimulation therapy for fracture healing. Indian J Orthop 2009; 43 (02) 127-131
    CrossrefPubMedSearch in Google Scholar
  • 59 Poolman RW, Agoritsas T, Siemieniuk RA. et al. Low intensity pulsed ultrasound (LIPUS) for bone healing: a clinical practice guideline. BMJ 2017; 356: j576
    CrossrefPubMedSearch in Google Scholar