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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 6/2017

01-12-2017 | Orthopedic Management of Fractures (S Bukata and L Gerstenfeld, Section Editors)

Effects of Aging on Fracture Healing

Authors: Dan Clark, Mary Nakamura, Ted Miclau, Ralph Marcucio

Published in: Current Osteoporosis Reports | Issue 6/2017

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Abstract

Purpose of Review

This review summarizes research on the physiological changes that occur with aging and the resulting effects on fracture healing.

Recent Findings

Aging affects the inflammatory response during fracture healing through senescence of the immune response and increased systemic pro-inflammatory status. Important cells of the inflammatory response, macrophages, T cells, mesenchymal stem cells, have demonstrated intrinsic age-related changes that could impact fracture healing. Additionally, vascularization and angiogenesis are impaired in fracture healing of the elderly. Finally, osteochondral cells and their progenitors demonstrate decreased activity and quantity within the callus.

Summary

Age-related changes affect many of the biologic processes involved in fracture healing. However, the contributions of such changes do not fully explain the poorer healing outcomes and increased morbidity reported in elderly patients. Future research should address this gap in understanding in order to provide improved and more directed treatment options for the elderly population.
Literature
1.
Iorio R, Robb WJ, Healy WL, Berry DJ, Hozack WJ, Kyle RF, et al. Orthopaedic surgeon workforce and volume assessment for total hip and knee replacement in the United States: preparing for an epidemic. J Bone Joint Surg Am. 2008;90:1598–605.CrossRefPubMed
2.
3.
Rose S, Maffulli N. Hip fractures: an epidemiological review. Bull Hosp Jt Dis. 1999;58:197–201.PubMed
4.
Green E, Lubahn JD, Evans J. Risk factors, treatment, and outcomes associated with nonunion of the midshaft humerus fracture. J Surg Orthop Adv. 2005;14:64–72.PubMed
5.
Cauley JA, Thompson DE, Ensrud KC, Scott J, Black D. Risk of mortality following clinical fractures. Osteoporos Int. 2000;11:556–61.CrossRefPubMed
6.
Nieminen S, Nurmi M, Satokari K. Healing of femoral neck fractures; influence of fracture reduction and age. Ann Chir Gynaecol. 1981;70:26–31.PubMed
7.
Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA, et al. Prevention of venous thromboembolism. Chest. 2001;119:132S–75S.CrossRefPubMed
8.
Little DG, Ramachandran M, Schindeler A. The anabolic and catabolic responses in bone repair. J Bone Joint Surg Br. 2007;89:425–33.CrossRefPubMed
9.
Hankenson KD, Zmmerman G, Marcucio R. Biological perspectives of delayed fracture healing. Injury. 2014;45:S8–S15.
10.
Phillips AM. Overview of the fracture healing cascade. Injury. 2005;36:55–7.CrossRef
11.
Kurdy NM, Weiss JB, Bate A. Endothelial stimulating angiogenic factor in early fracture healing. Injury. 1996;27:143–5.CrossRefPubMed
12.
Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, et al. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;15:221–34.CrossRef
13.
Bahney CS, Hu DP, Taylor AJ, Ferro F, Britz HM, Hallgrimsson B, et al. Stem cell-derived endochondral cartilage stimulates bone healing by tissue transformation. J Bone Miner Res. 2014;29:1269–82.CrossRefPubMedPubMedCentral
14.
Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11:45–54.CrossRefPubMed
15.
Lopas LA, Belkin NS, Mutyaba PL, Gray CF, Hankenson KD, Ahn J. Fracture in geriatric mice show decreased callus expansion and bone volume. Clin Orthop Relat Res. 2014;472:3523–32.CrossRefPubMedPubMedCentral
16.
Meyer RA, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res. 2001;19:428–35.CrossRefPubMed
17.
Bak B, Andreassen TT. The effect of aging on fracture healing in the rat. Calcif Tissue Int. 1989;45:292–7.CrossRefPubMed
18.
Bergman RJ, et al. Age-related changes in osteogenic stem cells in mice. J Bone Miner Res. 1996;11:568–77.CrossRefPubMed
19.
Gruber R, Koch H, Doll BA, Tegtmeier F, Einhorn TA, Hollinger JO. Fracture healing in the elderly patient. Exp Gerontol. 2006;41:1080–93.CrossRefPubMed
20.
Baxter M, et al. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells. 2004;22:675–82.CrossRefPubMed
21.
Nakahara H, Goldberg VM, Caplan AI. Culture-expanded human periosteal-derived cells exhibit osteochondral potential in vivo. J Orthop Res. 1991;9:465–76.CrossRefPubMed
22.
O'Driscoll SW, Saris DB, Ito Y, Fitzimmons JS. The chondrogenic potential of periosteum decreases with age. J Orthop Res. 2001;19:95–103.CrossRefPubMed
23.
Ferretti C, Lucarini G, Andreoni C, Salvolini E, Bianchi N, Vozzi G, et al. Human periosteal derived stem cell potential: the impact of age. Stem Cell Rev. 2015;11:487–500.CrossRefPubMed
24.
25.
Abou-Khalil R, et al. Role of muscle stem cells during skeletal regeneration. Stem Cells. 2015;33:1501–11.CrossRefPubMed
26.
27.
Marecic O, Tevlin R, McArdle A, et al. Identification and characterization of an injury-induced skeletal progenitor. Proc Natl Acad Sci U S A. 2015;112:9920–5.CrossRefPubMedPubMedCentral
28.
Tevlin R, Walmsley GG, Marecic O, Hu MS, Wan DC, Longaker MT. Stem and progenitor cells: advancing bone tissue engineering. Drug Deliv Transl Res. 2016;6:159–73.CrossRefPubMedPubMedCentral
29.
Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 2003;33:919–26.CrossRefPubMed
30.
Sebastian S, Andrew S, Alexandra S. Aging of mesenchymal stem cells. Ageing Res Rev. 2006;5:91–116.CrossRef
31.
Ode A, Duda GN, Geissler S, Pauly S, Ode JE, Perka C, et al. Interaction of age and mechanical stability on bone defect healing: an early transcriptional analysis of fracture hematoma in rat. PLoS One. 2014;9:e106462.CrossRefPubMedPubMedCentral
32.
Meyer RA, Meyer MH, Tenholder M, Wondracek S, Wasserman R, et al. Gene expression in older rats with delayed union of femoral fractures. J Bone Joint Surg Am. 2003;85:1243–54.CrossRefPubMed
33.
Desai BJ, Meyer MH, Porter S, Kellam JF, Meyer RA Jr. The effect of age on gene expression in adult and juvenile rats following femoral fracture. J Orthop Trauma. 2003;17:689–98.CrossRefPubMed
34.
Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Cruceta J, Graves BD, et al. Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-alpha signaling. Cells Tissues Organs. 2001;169:285–94.CrossRefPubMed
35.
Schmidt-Bleek K, Schell H, Schulz N, Hoff P, Perka C, Buttgereit F, et al. Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res. 2012;347:567–73.CrossRefPubMed
36.
37.
Dishowitz MI, Mutyaba PL, Takacs JD, Barr AM, Engiles JB, Ahn J, et al. Systemic inhibition of canonical notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing. PLoS One. 2013;8:e68726.CrossRefPubMedPubMedCentral
38.
Lim JC, Ko KI, Mattos M, Fang M, Zhang C, Feinberg D, et al. TNFα contributes to diabetes impaired angiogenesis in fracture healing. Bone. 2017;99:26–38.CrossRefPubMed
39.
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.CrossRefPubMed
40.
Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, et al. Inflammaging as a prodrome to Alzheimer’s disease. J Neuroinflammation. 2008;5:51.CrossRefPubMedPubMedCentral
41.
Boren E, Gershwin ME. Inflamm-aging: autoimmunity, and the immune-risk phenotype. Autoimmun Rev. 2004;3:401–6.CrossRefPubMed
42.
Lencel P, Magne D. Inflammaging: the driving force in osteoporosis? Med Hypotheses. 2011;76:317–21.CrossRefPubMed
43.
• Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, Wu J, et al. An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res. 2016;2016:8426874. This is an updated and an in-depth review that covers the breadth of the inflamm-aging field. CrossRefPubMedPubMedCentral
44.
45.
46.
47.
48.
Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Ann Rev Immunol. 2000;18:529–60.CrossRef
49.
50.
Melton DW, Roberts AC, Wang H, Sarwar Z, Wetzel MD, Wells JT, et al. Absence of CCR2 results in an inflammaging environment in young mice with age-independent impairments in muscle regeneration. J Leukoc Biol. 2016;100:1011–25.CrossRefPubMedPubMedCentral
51.
Xing Z, Lu C, Hu D, Miclau T 3rd, Marcucio RS. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice. J Orthop Res. 2010;28:1000–6.PubMedPubMedCentral
52.
• Baht GS, Silkstone D, Vi L, Nadesan P, Amani Y, Whetstone H, et al. Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nat Commun. 2015;6:7131. This study demonstrated the significance of hematopoietic cells on fracture healing and the ability to improve healing in old mice with exposure to young hematopoietic cells. CrossRefPubMedPubMedCentral
53.
Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;25:445–55.CrossRef
54.
Ferrante CJ, Leibovich SJ. Regulation of macrophage polarization and wound healing. Adv Wound Care. 2012;1:10–6.CrossRef
55.
Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593.CrossRefPubMed
56.
Sebastian C, Herrero C, Serra M, Lloberas J, Blasco MA, Celada A. Telomere shortening and oxidative stress in aged macrophages results in impaired STAT5a phosphorylation. J Immunol. 2009;183:2356–64.CrossRefPubMed
57.
Ramanathan R, Kohli A, Ingaramo MC, Jain A, Leng SX, Punjabi NM, et al. Serum chitotriosidase, a putative marker of chronically activated macrophages, increases with normal aging. J Gerontol A Biol Sci Med Sci. 2013;68:1303–9.CrossRefPubMedPubMedCentral
58.
• Duscher D, Rennert RC, Januszyk M, Anghel E, Maan ZN, Whittam AJ, et al. Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells. Sci Rep. 2014;4:7144. This paper thoroughly showed age-related disruption of MSC function specifically related to a compromise of angiogenesis in wound healing, via in vitro, in vivo, and single-cell transcriptional analysis. CrossRefPubMedPubMedCentral
59.
Slade Shantz JA, YY Y, Andres W, Miclau T, Marcucio R. Modulation of macrophage activity during fracture repair has differential effects in young adult and elderly mice. J Orthop Trauma. 2014;28:S10–4.CrossRefPubMedPubMedCentral
60.
• Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, et al. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol. 2008;181:1232–44. This study was the first to demonstrate a resident tissue macrophage population, osteomacs that are involved in bone homeostasis and regulate osteoblast function. CrossRefPubMed
61.
Alexander KA, Chang MK, Maylin ER, Kohler T, Müller R, Wu AC, et al. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res. 2011;26:1517–32.CrossRefPubMed
62.
Ono T, Takayanagi H. Osteoimmunology in bone fracture healing. Curr Osteoporos Rep. 2017;15:367–75.CrossRefPubMed
63.
Könnecke I, Serra A, El Khassawna T, et al. T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone. 2014;64:155–65.CrossRefPubMed
64.
Sun G, Wang Y, Ti Y, Wang J, Zhao J, Qian H. Regulatory B cell is critical in bone union process through suppressing proinflammatory cytokines and stimulating Foxp3 in Treg cells. Clin Exp Pharmacol Physiol. 2017;44:455–62.CrossRefPubMed
65.
Al-Sebaei MO, Daukss DM, Belkina AC, et al. Role of Fas and Treg cells in fracture healing as characterized in the Fas-deficient (lpr) mouse model of lupus. J Bone Miner Res. 2014;29:1478–91.CrossRefPubMedPubMedCentral
66.
67.
Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. 2012;20:14–20.CrossRefPubMed
68.
69.
Caplan A, Dennis J. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.CrossRefPubMed
70.
Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499–506.CrossRefPubMed
71.
72.
Shabbir A, Zisa D, Suzuki G, Lee T. Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen. Am J Physiol Heart Circ Physiol. 2009;296:1888–97.CrossRef
73.
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–32.CrossRefPubMed
74.
Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, et al. Treatment of severe acute graft versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–41.CrossRefPubMed
75.
Tögel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31–42.CrossRefPubMed
76.
Colnot C, Lu C, Hu D, Helms JA. Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. Dev Biol. 2004;269:55–69.CrossRefPubMed
77.
78.
Jacobsen KA, et al. Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. J Bone Miner Res. 2008;23:596–609.CrossRefPubMedPubMedCentral
79.
Prisby RD, Ramsey MW, Behnke BJ, Dominguez JM 2nd, Donato AJ, Allen MR, et al. Aging reduces skeletal blood flow, endothelium-dependent vasodilation, and NO bioavailability in rats. J Bone Miner Res. 2007;22:1280–8.CrossRefPubMed
80.
81.
Frenkel-Denkberg G, Gershon D, Levy AP. The function of hypoxia-inducible factor 1 (HIF-1) is impaired in senescent mice. FEBS Lett. 1999;462:341–4.CrossRefPubMed
82.
Wagatsuma A. Effect of aging on expression of angiogenesis-related factors in mouse skeletal muscle. Exp Gerontol. 2006;41:49–54.CrossRefPubMed
83.
Kosaki N, et al. Impaired bone fracture healing in matrix metalloproteinase-13 deficient mice. Biochem Biophys Res Commun. 2007;354:846–51.CrossRefPubMed
Metadata
Title
Effects of Aging on Fracture Healing
Authors
Dan Clark
Mary Nakamura
Ted Miclau
Ralph Marcucio
Publication date
01-12-2017
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 6/2017
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-017-0413-9

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