Mechanisms of Disease: molecular insights into aseptic loosening of orthopedic implants

Abstract

Despite the success of treating rheumatic disorders with biologic therapies, joint replacement surgery still remains the final treatment option in many cases. Approximately 1.5 million joint arthroplastic operations are performed annually worldwide. Implant failure due to massive bone loss and aseptic loosening of prostheses, however, is a major complication of joint replacement, which can lead to high socioeconomic burdens both for the individual patient and for health-care systems. To date, there is no approved drug therapy to prevent or inhibit periprosthetic osteolysis, and aseptic loosening of prostheses can only be overcome by surgical revision. Research during the past decade, however, has unravelled much of the pathogenesis of aseptic prosthesis loosening and preclinical studies have identified potential targets for pharmaceutical treatments. This article highlights the importance of a cooperative interaction between rheumatologists and orthopedic surgeons, and presents novel insights into the molecular mechanisms behind aseptic loosening of prostheses. In addition, we outline potential perspectives for the development of future therapeutic strategies for this devastating complication.

Key Points

  • Prosthesis loosening without concurrent infection or trauma is called aseptic loosening

  • Over 10% of implants require surgical revision within 15 years of the initial operation, mostly because of aseptic prosthesis loosening

  • The pathogenesis of aseptic loosening shows substantial overlap with the pathogenesis of inflammatory disorders of the joint, such as rheumatoid arthritis; similarities include histopathology (i.e. the periprosthetic membrane) and the molecular signaling pathways involved

  • Key cells in bone destruction include multinucleated osteoclasts, macrophages and mesenchymal cells (prosthesis-loosening fibroblasts)

  • Preclinical studies have identified molecular targets that might lead to potential pharmaceutical therapies for aseptic prosthesis loosening

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Figure 1: Immunogold–silver staining of wear debris particles
Figure 2: Wear debris induces interplay between prosthesis-loosening fibroblasts, multinucleated osteoclasts and macrophages
Figure 3: Signaling pathways involved in aseptic prosthesis loosening

References

  1. 1

    Teeny SM et al. (2003) Long-term follow-up care recommendations after total hip and knee arthroplasty: results of the American Association of Hip and Knee Surgeons' member survey. J Arthroplasty 18: 954–962

  2. 2

    Fender D et al. (2000) The Trent regional arthroplasty study. Experiences with a hip register. J Bone Joint Surg Br 82: 944–947

  3. 3

    Nelson CL et al. (2005) Is aseptic loosening truly aseptic? Clin Orthop Relat Res 437: 25–30

  4. 4

    Karrholm J et al. (1994) Does early micromotion of femoral stem prostheses matter? 4–7-year stereoradiographic follow-up of 84 cemented prostheses. J Bone Joint Surg Br 76: 912–917

  5. 5

    Emerson RH Jr (2004) Proximal ingrowth components. Clin Orthop Relat Res 420: 130–134

  6. 6

    Eckardt A et al. (2003) Biological fixation of hydroxyapatite-coated versus grit-blasted titanium hip stems: a canine study. Arch Orthop Trauma Surg 123: 28–35

  7. 7

    Schmalzried TP et al. (1997) The role of access of joint fluid to bone in periarticular osteolysis. A report of four cases. J Bone Joint Surg Am 79: 447–452

  8. 8

    Freund E (1940) The pathological significance of intra-articular pressure. Edinburgh Med J 47

  9. 9

    Jayson MI et al. (1970) Intra-articular pressure and rheumatoid geodes (bone 'cysts'). Ann Rheum Dis 29: 496–502

  10. 10

    van der Vis HM et al. (1998) Fluid pressure causes bone resorption in a rabbit model of prosthetic loosening. Clin Orthop Relat Res 350: 201–208

  11. 11

    Hirakawa K et al. (2004) Mechanisms of failure of total hip replacements: lessons learned from retrieval studies. Clin Orthop Relat Res 420: 10–17

  12. 12

    Nieuwenhuis JJ et al. (2005)Unsatisfactory results with the cementless Omnifit acetabular component due to polyethylene and severe osteolysis. Acta Orthop Belg 71: 294–302

  13. 13

    Bauer TW (2002) Particles and peri-implant bone resorption. Clin Orthop Relat Res 405: 138–143

  14. 14

    Goldring SR et al. (1983) The synovial-like membrane at the bone-cement interface in loose total hip replacements and its proposed role in bone lysis. J Bone Joint Surg Am 65: 575–584

  15. 15

    Lafyatis R et al. (1989) Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-β and retinoids. J Clin Invest 83: 1267–1276

  16. 16

    Grimbacher B et al. (1998) TNF-alpha induces the transcription factor Egr-1, pro-inflammatory cytokines and cell proliferation in human skin fibroblasts and synovial lining cells. Rheumatol Int 17: 185–192

  17. 17

    Pap T et al. (2000) Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum 43: 1226–1232

  18. 18

    Franz JK et al. (2000) Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 43: 599–607

  19. 19

    Pap T et al. (2003) Osteoclast-independent bone resorption by fibroblast-like cells. Arthritis Res Ther 5: R163–R173

  20. 20

    Morawietz L et al. (2006) Proposal for a histopathological consensus classification of the periprosthetic interface membrane. J Clin Pathol 59: 591–597

  21. 21

    Hansen T et al. (2002) New aspects in the histological examination of polyethylene wear particles in failed total joint replacements. Acta Histochem 104: 263–269

  22. 22

    Charnley J (2005) The long-term results of low-friction arthroplasty of the hip performed as a primary intervention. 1970. Clin Orthop Relat Res 430: 3–11

  23. 23

    Tarasevicius S et al. (2006) Femoral head diameter affects the revision rate in total hip arthroplasty: an analysis of 1,720 hip replacements with 9–21 years of follow-up. Acta Orthop 77: 706–709

  24. 24

    Bradford L et al. (2004) Wear and surface cracking in early retrieved highly cross-linked polyethylene acetabular liners. J Bone Joint Surg Am 86 (pt A): 1271–1282

  25. 25

    McKellop HA (1994) Wear modes, mechanisms, damage and debris, separating cause from effect in the wear of total hip replacements. In Total Hip Revision Surgery, 21–39 (Eds Galante JO et al.). New York: Raven Press

  26. 26

    McKellop HA (2001) Bearing surfaces in total hip replacements: state of the art and future developments. Instr Course Lect 50: 165–179

  27. 27

    Shanbhag AS et al. (1994) Macrophage/particle interactions: effect of size, composition and surface area. J Biomed Mater Res 28: 81–90

  28. 28

    Gelb H et al. (1994) In vivo inflammatory response to polymethylmethacrylate particulate debris: effect of size, morphology, and surface area. J Orthop Res 12: 83–92

  29. 29

    Green TR et al. (1998) Polyethylene particles of a 'critical size' are necessary for the induction of cytokines by macrophages in vitro. Biomaterials 19: 2297–2302

  30. 30

    Wilkinson JM et al. (2005) Polyethylene wear rate and osteolysis: critical threshold versus continuous dose–response relationship. J Orthop Res 23: 520–525

  31. 31

    Greenfield EM et al. (2005) Does endotoxin contribute to aseptic loosening of orthopedic implants? J Biomed Mater Res B Appl Biomater 72: 179–185

  32. 32

    Neale SD et al. (1999) Macrophage colony-stimulating factor and interleukin-6 release by periprosthetic cells stimulates osteoclast formation and bone resorption. J Orthop Res 17: 686–694

  33. 33

    Ingham E and Fisher J (2005) The role of macrophages in osteolysis of total joint replacement. Biomaterials 26: 1271–1286

  34. 34

    Zaidi M et al. (2001) Cathepsin K, osteoclastic resorption, and osteoporosis therapy. J Bone Miner Res 16: 1747–1749

  35. 35

    Corisdeo S et al. (2001) New insights into the regulation of cathepsin K gene expression by osteoprotegerin ligand. Biochem Biophys Res Commun 285: 335–339

  36. 36

    Schlesinger PH et al. (1994) Osteoclastic acid transport: mechanism and implications for physiological and pharmacological regulation. Miner Electrolyte Metab 20: 31–39

  37. 37

    Zaidi M et al. (2003) Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics. J Bone Miner Res 18: 599–609

  38. 38

    Dean DD et al. (1999) Ultrahigh molecular weight polyethylene particles have direct effects on proliferation, differentiation, and local factor production of MG63 osteoblast-like cells. J Orthop Res 17: 9–17

  39. 39

    DeLaSalle H et al. (2006) The effects of PMMA particle number on MG-63 osteoblast cell function. Biomed Sci Instrum 42: 48–53

  40. 40

    Astrand J and Aspenberg P (2004) Topical, single dose bisphosphonate treatment reduced bone resorption in a rat model for prosthetic loosening. J Orthop Res 22: 244–249

  41. 41

    Wedemeyer C et al. (2005) Stimulation of bone formation by zoledronic acid in particle-induced osteolysis. Biomaterials 26: 3719–3725

  42. 42

    Schwarz EM et al. (2000) Anti-TNF-alpha therapy as a clinical intervention for periprosthetic osteolysis. Arthritis Res 2: 165–168

  43. 43

    Pollice PF et al. (2001) Oral pentoxifylline inhibits release of tumor necrosis factor α from human peripheral blood monocytes: a potential treatment for aseptic loosening of total joint components. J Bone Joint Surg Am 83 (pt A): 1057–1061

  44. 44

    Arora A et al. (2003) The role of the TH1 and TH2 immune responses in loosening and osteolysis of cemented total hip replacements. J Biomed Mater Res A 64: 693–697

  45. 45

    Anandarajah AP and Schwarz EM (2006) Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications. J Cell Biochem 97: 226–232

  46. 46

    McClung MR (2006) Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies. Curr Osteoporos Rep 4: 28–33

  47. 47

    Ulrich-Vinther M et al. (2002) Recombinant adeno-associated virus-mediated osteoprotegerin gene therapy inhibits wear debris-induced osteolysis. J Bone Joint Surg Am 84 (pt A): 1405–1412

  48. 48

    Yang SY et al. (2004) Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis. Gene Ther 11: 483–491

  49. 49

    Kobayashi K et al. (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL–RANK interaction. J Exp Med 191: 275–286

  50. 50

    Tanabe N et al. (2005) IL-1 alpha stimulates the formation of osteoclast-like cells by increasing M-CSF and PGE2 production and decreasing OPG production by osteoblasts. Life Sci 77: 615–626

  51. 51

    Wiktor-Jedrzejczak W et al. (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832

  52. 52

    Dossing DA and Stern PH (2005) Receptor activator of NF-κB ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol. J Cell Biochem 95: 1029–1041

  53. 53

    Kitazawa S et al. (2003) Vitamin D3 supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter. J Cell Biochem 89: 771–777

  54. 54

    Toraldo G et al. (2003) IL-7 induces bone loss in vivo by induction of receptor activator of NF-κB ligand and tumor necrosis factor α from T cells. Proc Natl Acad Sci USA 100: 125–130

  55. 55

    Thirunavukkarasu K et al. (2002) Analysis of regulator of G-protein signaling-2 (RGS-2) expression and function in osteoblastic cells. J Cell Biochem 85: 837–850

  56. 56

    Nagasawa T et al. (2002) LPS-stimulated human gingival fibroblasts inhibit the differentiation of monocytes into osteoclasts through the production of osteoprotegerin. Clin Exp Immunol 130: 338–344

  57. 57

    Ikeda F et al. (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114: 475–484

  58. 58

    Takayanagi H (2005) Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med 83: 170–179

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Correspondence to Philipp Drees.

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Drees, P., Eckardt, A., Gay, R. et al. Mechanisms of Disease: molecular insights into aseptic loosening of orthopedic implants. Nat Rev Rheumatol 3, 165–171 (2007). https://doi.org/10.1038/ncprheum0428

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