Normal and Delayed Fracture Healing: Symphony and Cacophony

S. Jha; J. E. Blau; T. Bhattacharyya

doi:10.1055/s-0042-117636

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2016; 48(11): 779-784
DOI: 10.1055/s-0042-117636

Review

Normal and Delayed Fracture Healing: Symphony and Cacophony

S. Jha

¹National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

,

J. E. Blau

²Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA

,

T. Bhattacharyya

¹National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

› Institutsangaben

Abstract

The incidence of any fracture in the US is estimated to be 2 704 fractures per 100,000 person-years. Approximately 10 percent of these fractures develop complications of healing. The processes that occur during fracture healing mimic the processes that take place in the growth plate during development. The study of fracture healing represents a window to enhance our understanding of the processes of growth and development of bones and its reparative biology. This review is aimed for clinicians evaluating non-unions as an overview of different factors that inhibit fracture healing.

Key words

skeletal injury - bone repair - callus formation

Volltext

Referenzen

References
1 Einhorn T. The cell and molecular biology of fracture healing. Clin Orthop Rel Res. 1998 355. Suppl S7-S21
2 McKibbin B. The biology of fracture healing in long bones. J Bone Joint Surg Br 1978; 60 B: 150-162
3 Marsell R, Einhorn TA. The biology of fracture healing. Injury 2011; 42: 551-555
4 Remedios A. Bone and bone healing. Vet Clin North Am Small Anim Pract 1999; 29: 1029-1044 v
5 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: 873-884
6 Frost HM. The biology of fracture healing. An overview for clinicians. Part I. Clin Orthop Rel Res 1989; 248: 283-293
7 Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, Nakano M, Fujii N, Nagasawa T, Nakamura T. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum 2009; 60: 813-823
8 Utvåg SE, Iversen KB, Grundnes O, Reikerås O. Poor muscle coverage delays fracture healing in rats. Acta Orthop Scand 2002; 73: 471-474
9 Colnot C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res 2009; 24: 274-282
10 Liu R, Birke O, Morse A, Peacock L, Mikulec K, Little DG, Schindeler A. Myogenic progenitors contribute to open but not closed fracture repair. BMC Musculoskel Disord 2011; 12: 1
11 Bais MV, Wigner N, Young M, Toholka R, Graves DT, Morgan EF, Gerstenfeld LC, Einhorn TA. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells. Bone 2009; 45: 254-266
12 Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 2006; 38: 1424-1429
13 Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O’Keefe RJ. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 2002; 109: 1405-1415
14 Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 2002; 17: 513-520
15 Phillips AM. Overview of the fracture healing cascade. Injury 2005; 36 (Suppl. 03) S5-S7
16 Keramaris NC, Calori GM, Nikolaou VS, Schemitsch EH, Giannoudis PV. Fracture vascularity and bone healing: a systematic review of the role of VEGF. Injury 2008; 39 (Suppl. 02) S45-S57
17 Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dental Res 2008; 87: 107-118
18 Rundle CH, Wang H, Yu H, Chadwick RB, Davis EI, Wergedal JE, Lau KH, Mohan S, Ryaby JT, Baylink DJ. Microarray analysis of gene expression during the inflammation and endochondral bone formation stages of rat femur fracture repair. Bone 2006; 38: 521-529
19 Yu-Yahiro JA, Michael RH, Dubin NH, Fox KM, Sachs M, Hawkes WG, Hebel JR, Zimmerman SI, Shapiro J, Magaziner J. Serum and urine markers of bone metabolism during the year after hip fracture. J Am Geriatr Soc 2001; 49: 877-883
20 Melnyk M, Henke T, Claes L, Augat P. Revascularisation during fracture healing with soft tissue injury. Arch Orthop Trauma Surg 2008; 128: 1159-1165
21 Simmons DJ. Fracture healing perspectives. Clin Orthop Rel Res 1985; 200: 100-113
22 Fischer MD, Gustilo RB, Varecka T. The timing of flap coverage, bone-grafting, and intramedullary nailing in patients who have a fracture of the tibial shaft with extensive soft-tissue injury. J Bone Joint Surgery Am 1991; 73: 1316-1322
23 Rhinelander FW. Tibial blood supply in relation to fracture healing. Clin Orthop Rel Res 1974; 105: 34-81
24 Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Eng J Med 2005; 352: 1959-1966
25 Rumi MN, Deol GS, Singapuri KP, Pellegrini Jr. VD. The origin of osteoprogenitor cells responsible for heterotopic ossification following hip surgery: an animal model in the rabbit. J Orthop Res 2005; 23: 34-40
26 Wilkins KE. Principles of fracture remodeling in children. Injury 2005; 36 (Suppl. 01) A3-A11
27 Schottel PC, O’Connor DP, Brinker MR. Time trade-off as a measure of health-related quality of life: long bone nonunions have a devastating impact. J Bone Joint Surg Am 2015; 97: 1406-1410
28 Claes L, Augat P, Suger G, Wilke HJ. Influence of size and stability of the osteotomy gap on the success of fracture healing. J Orthop Res 1997; 15: 577-584
29 Augat P, Margevicius K, Simon J, Wolf S, Suger G, Claes L. Local tissue properties in bone healing: influence of size and stability of the osteotomy gap. J Orthop Res 1998; 16: 475-481
30 Claes L, Wolf S, Augat P. Mechanical modification of callus healing. Chirurg 2000; 71: 989-994
31 Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br 2007; 89: 1553-1560
32 Castillo RC, Bosse MJ, MacKenzie EJ, Patterson BM. Group LS . Impact of smoking on fracture healing and risk of complications in limb-threatening open tibia fractures. J Orthop Trauma 2005; 19: 151-157
33 Kyrö A, Usenius J, Aarnio M, Kunnamo I, Avikainen V. Are smokers a risk group for delayed healing of tibial shaft fractures?. Ann Chirurg Gynaecol 1992; 254-262
34 Schmitz MA, Finnegan M, Natarajan R, Champine J. Effect of smoking on tibial shaft fracture healing. Clin Orthop Rel Res 1999; 365: 184-200
35 Campanile G, Hautmann G, Lotti T. Cigarette smoking, wound healing, and face-lift. Clin Dermatol 1998; 16: 575-578
36 Raikin SM, Landsman JC, Alexander VA, Froimson MI, Plaxton NA. Effect of nicotine on the rate and strength of long bone fracture healing. Clinical Orthop Rel Res 1998; 353: 231-237
37 Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR. Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using The Health Improvement Network (THIN). Diabetes Care 2015; 38: 1913-1920
38 Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes–a meta-analysis. Osteop Int 2007; 18: 427-444
39 Cozen L. Does diabetes delay fracture healing?. Clin Orthop Rel Res 1972; 82: 134-140
40 Macey LR, Kana SM, Jingushi S, Terek RM, Borretos J, Bolander ME. Defects of early fracture-healing in experimental diabetes. J Bone Joint Surg Am 1989; 71: 722-733
41 Boddenberg U. Healing time of foot and ankle fractures in patients with diabetes mellitus: literature review and report on own cases. Zentralbl Chir 2004; 129: 453-459
42 Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005; 366: 1736-1743
43 Cavo MJ, Fox JP, Markert R, Laughlin RT. Association Between Diabetes, Obesity, and Short-Term Outcomes Among Patients Surgically Treated for Ankle Fracture. J Bone Joint Surg Am 2015; 97: 987-994
44 Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 2002; 17: 963-976
45 Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of nonsteroidal antiinflammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma 1995; 9: 392-400
46 Davis T, Ackroyd C. Non-steroidal anti-inflammatory agents in the management of Colles’ fractures. Br J Clin Pract 1988; 42: 184-189
47 Adolphson P, Abbaszadegan H, Jonsson U, Dalen N, Sjöberg H, Kalén S. No effects of piroxicam on osteopenia and recovery after Colles’ fracture. Arch Orthop Trauma Surg 1993; 112: 127-130
48 Høgevold HE, Grøgaard B, Reikerås O. Effects of short-term treatment with corticosteroids and indomethacin on bone healing: a mechanical study of osteotomies in rats. Acta Orthop Scand 1992; 63: 607-611
49 LoCascio V, Bonucci E, Imbimbo B, Ballanti P, Adami S, Milani S, Tartarotti D, DellaRocca C. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990; 8: 39-51
50 Huddleston P, Steckelberg J, Hanssen A, Rouse M, Bolander M, Patel R. Ciprofloxacin Inhibition of Experimental Fracture-Healing. J Bone Joint Surg Am 2000; 82: 161-173
51 Isefuku S, Joyner CJ, Simpson AH. Gentamicin may have an adverse effect on osteogenesis. J Orthop Trauma 2003; 17: 212-216
52 Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE. Bone toxicity of locally applied aminoglycosides. J Orthop Trauma 1995; 9: 401-406
53 Perry AC, Prpa B, Rouse MS, Piper KE, Hanssen AD, Steckelberg JM, Patel R. Levofloxacin and trovafloxacin inhibition of experimental fracture-healing. Clin Orthop Rel Res 2003; 414: 95-100
54 Isefuku S, Joyner C, Simpson A. Toxic effect of rifampicin on human osteoblast-like cells. J Orthop Res 2001; 19: 950-954
55 Street JT, McGrath M, O’Regan K, Wakai A, McGuinness A, Redmond HP. Thromboprophylaxis using a low molecular weight heparin delays fracture repair. Clin Orthop Relat Res 2000; 381: 278-289
56 Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Eng J Med 2008; 358: 2765-2775
57 Namkung-Matthai H, Appleyard R, Jansen J, Lin JH, Maastricht S, Swain M, Mason R, Murrell G, Diwan A, Diamond T. Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 2001; 28: 80-86
58 Kubo T, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, Kitajima I, Semba I, Hirasawa Y. Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol 1999; 68: 197-202
59 Peichl P, Holzer LA, Maier R, Holzer G. Parathyroid hormone 1–84 accelerates fracture-healing in pubic bones of elderly osteoporotic women. J Bone Joint Surg 2011; 93: 1583-1587
60 Peter CP, Cook WO, Nunamaker DM, Provost MT, Seedor JG, Rodan GA. Effect of alendronate on fracture healing and bone remodeling in dogs. J Orthop Res 1996; 14: 74-79
61 Li J, Mori S, Kaji Y, Mashiba T, Kawanishi J, Norimatsu H. Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats. J Bone Miner Res 1999; 14: 969-979
62 Colón-Emeric C, Nordsletten L, Olson S, Major N, Boonen S, Haentjens P, Mesenbrink P, Magaziner J, Adachi J, Lyles K. Association between timing of zoledronic acid infusion and hip fracture healing. Osteop Int 2011; 22: 2329-2336
63 Gerstenfeld LC, Sacks DJ, Pelis M, Mason ZD, Graves DT, Barrero M, Ominsky MS, Kostenuik PJ, Morgan EF, Einhorn TA. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 2009; 24: 196-208
64 Day SM, DeHeer DH. Reversal of the detrimental effects of chronic protein malnutrition on long bone fracture healing. J Orthop Trauma 2001; 15: 47-53
65 Schurch MA, Rizzoli R, Slosman D, Vadas L, Vergnaud P, Bonjour JP. Protein supplements increase serum insulin-like growth factor-I levels and attenuate proximal femur bone loss in patients with recent hip fracture. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128: 801-809
66 Goldring MB, Goldring SR. Skeletal tissue response to cytokines. Clin Orthop Rel Res 1990; 258: 245-278
67 Einhorn T, Bonnarens F, Burstein A. The contributions of dietary protein and mineral to the healing of experimental fractures. A biomechanical study. J Bone Joint Surg 1986; 68: 1389-1395
68 Pourfeizi HH, Tabriz A, Elmi A, Aslani H. Prevalence of vitamin D deficiency and secondary hyperparathyroidism in nonunion of traumatic fractures. Acta Med Iran 2013; 51: 705-710
69 Komnenou A, Karayannopoulou M, Polizopoulou ZS, Constantinidis TC, Dessiris A. Correlation of serum alkaline phosphatase activity with the healing process of long bone fractures in dogs. Vet Clin Pathol 2005; 34: 35-38
70 Rothman RH, Klemek JS, Toton JJ. The effect of iron deficiency anemia on fracture healing. Clin Orthop Rel Res 1971; 77: 276-283
71 Jänicke-Lorenz J, Lorenz R. Alcoholism and fracture healing. Arch Orthop Trauma Surg 1984; 103: 286-289
72 Kristensson H, Lunden A, Nilsson BE. Fracture incidence and diagnostic roentgen in alcoholics. Acta Orthop Scand 1980; 51: 205-207
73 Bikle DD, Genant HK, Cann C, Recker RR, Halloran BP, Strewler GJ. Bone disease in alcohol abuse. Ann Intern Med 1985; 103: 42-48
74 Brinker MR, O’Connor DP, Monla YT, Earthman TP. Metabolic and endocrine abnormalities in patients with nonunions. J Orthop Trauma 2007; 21: 557-570
75 Bauer DC, Ettinger B, Nevitt MC, Stone KL. Study of Osteoporotic Fractures Research G. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med 2001; 134: 561-568
76 Chrastil J, Sampson C, Jones KB, Higgins TF. Evaluating the affect and reversibility of opioid-induced androgen deficiency in an orthopaedic animal fracture model. Clin Orthop Relat Res 2014; 472: 1964-1971
77 Maus U, Andereya S, Schmidt H, Zombory G, Gravius S, Ohnsorge JA, Niedhart C. Therapy effects of testosterone on the recovery of bone defects. Z Orthop Unfall 2008; 146 59-63
78 Cheng BH, Chu TM, Chang C, Kang HY, Huang KE. Testosterone delivered with a scaffold is as effective as bone morphologic protein-2 in promoting the repair of critical-size segmental defect of femoral bone in mice. PloS One 2013; 8: e70234
79 Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 2015; 11: 45-54