**10. References**


mechanism of aseptic loosening is not complete. Understanding of the mechanisms of wearinduced osteolysis will help control undesirable processes at the implant-bone interface and

Our study provided further insight into the mechanism of aseptic loosening of hip arthroplasty. The most interesting aspect of this study is the evidence of elevated production of ROS, which are known to cause tissue fibrosis and may help explain the initiation of aseptic loosening. We feel that the thick pseudocapsule around loose prostheses is not an adaptive but a reactive tissue as a result of decreased degradation and increased formation of collagen matrix and proliferation of fibroblasts due to high oxidative stress. Furthermore, we demonstrated that elevated oxidative stress is associated with aseptic loosening of hip arthroplasty, suggesting that oxidative stress might induce periprosthetic osteolysis and subsequent loosening. Research in this line may help introducing new strategies for therapeutic prevention and/or treatment of osteolysis and subsequent aseptic loosening of

Aitken, C., Hodge, J., Nishinaka, Y., Vaughan, T., Yodoi, J., Day, C., Morrison, N. &

Antoniou, J., Zukor, D.J., Mwale, F., Minarik, W., Petit, A. & Huk, O.L. (2008). Metal ion

Aspenberg, P. & Herbertsson, P. (1996). Periprosthetic bone resorption. Particles versus

Aspenberg, P. & Van der Vis, H. (1998). Fluid pressure may cause periprosthetic osteolysis.

Bai, X.C., Lu, D., Bai, J., Zheng, H., Ke, Z.Y., Li, X.M. & Luo, S.Q. (2004). Oxidative stress

Bai, X.C., Lu, D., Liu, A.L., Zhang, Z.M., Li, X.M., Zou, Z.P., Zeng, W.S., Cheng, B.L. & Luo,

Basu, S., Michaëlsson, K., Olofsson, H., Johansson, S. & Melhus, H. (2001). Association

Bechtold, J.E., Kubic, V. & Sobale, K. (2002). Bone ingrowth in the presence of particulate

Particles are not the only thing, *Acta Orthop Scand* Vol.69(No.1):1-4.

ligand expression in osteoblast, *J Biol Chem* Vol.280:17497–17506.

metal hip resurfacing arthroplasty, *J Arthroplasty* Vol.26:198-208.

Nicholson, G. (2004). Regulation of human osteoclast differentiation by thioredoxin binding protein-2 and redoxsensitive signaling, *J Bone Miner Res* Vol.19:2057–2064. Albrektsson, T. (1990). Biological factors of importance for bone integration of implanted devices, *in* Older MWJ (ed.), *Implant bone interface*, Springer-Velag, London. Amstutz, H., Wisk, L. & Le Duff, M. (2011). Sex as a patient selection criterion for metal-on-

levels in the blood of patients after hip resurfacing: a comparison between twentyeight and thirty-six-millimeter-head metal-on-metal prostheses, *J Bone Joint Surg* 

inhibits osteoblastic differentiation ofbone cells by ERK and NF-kB, *Biochem Biophys* 

S.Q. (2005). Reactive oxygen species stimulates receptor activator of NF-kappaB

between oxidative stress and bone mineral density, *Biochem Biophys Res Commun*

extend longevity of hip arthroplasty.

**9. Conclusion** 

total hip arthroplasty.

*Am* Vol.90(Suppl. 3):142-8.

*Res Commun* Vol.314:197–207.

Vol.288(No.1):275-9.

movement, *J Bone Joint Surg Br* Vol.78:641–646.

polyethylene, *Bone Joint Surg Br* Vol.84:915-919.

**10. References** 


Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty 315

Khoschsorur, G.A., Winklhofer-Roob, B.M., Rabl, H., Auer, T., Peng, Z. & Schaur, R. J.

Kido, A., Pap, G., Nagler, D.K., Ziomek, E., Ménard, R., Neumann, H.W. & Roessner A.

Kim, W.K., Meliton, V., Bourquard, N., Hahn, T.J. & Parhami, F. (2010). Hedgehog signaling

Kinov, P., Leithner, A., Radl, R., Bodo, K., Khoschsorur, G. A., Schauenstein, K. & R.

Kinov, P., Tivchev, P., Doukova, P. & Leithner, A. (2006). Effect of risedronate on bone

Kurtz, S.M. (2004). *The UHMWPE handbook: ultra-high molecular weight polyethylene in total* 

Kurtz, S.M., Austin, M.S., Azzam, K., Sharkey, P.F., MacDonald, D.W., Medel, F.J. &

Lam, J., Takeshita, S., Barker, J.E., Kanagawa, O., Ross, F.P. & Teitelbaum, S.L. (2000). TNF-

Lee, M.C., Yoshino, F., Shoji, H., Takahashi, S., Todoki, K., Shimada, S. & Kuse-Barouch, K.

Li, M., Zhao, L., Liu, J., Liu, A.L., Zeng, W.S., Luo, S.Q. & Bai, X.C. (2009). Hydrogen

Lim, C.S. & Vaziri, N.D. (2004). Iron and oxidative stress in renal insufficiency, *Am J Nephrol*

Limbach, L.K., Wick, P., Manser, P., Grass, R.N., Bruinink, A. & Stark, W.J. (2007). Exposure

Lin, F. & Girotti, A.W. (1993). Photodynamic action of merocyanine 540 on leukemia cells:

permissive levels of RANK ligand, *J Clin Invest* Vol.106(No.12):1481-8. Lean, J.M., Jagger, C.J., Kirstein, B., Fuller, K. & Chambers, T.J. (2005). Hydrogen peroxide is

inhibited by oxidative stress, *J Cell Biochem* Vol.111(No.5):1199-209.

*Chromatographia* Vol.52:181–184.

*Orthop Relat Res* Vol.425:230–236.

*Orthop Res* Vol.24:55-62.

*Orthop Belg* Vol.72(No.1):44-50.

*joint replacement*, Elsevier, Boston.

*Arthroplasty* Vol.25(No.4):614-23.

*Anat Rec (Hoboken)* Vol.292(No.8):1107-13.

Vol.146:728–735.

Vol.84:178-82.

Vol.24:569–575.

Vol.41(No.11):4158-63.

Vol.300(No.2):714-23.

(2000). Evaluation of a sensitive HPLC method for the determination of malondialdehyde, and application of the method different biological materials,

(2004). Protease expression in interface tissues around loose arthroplasties. *Clin* 

and osteogenic differentiation in multipotent bone marrow stromal cells are

Windhager. (2006). Role of free radicals in aseptic loosening of hip arthroplasty, *J* 

metabolism after total hip arthroplasty: a prospective randomised study, *Acta* 

Hozack, W.J. (2010). Mechanical properties, oxidation, and clinical performance of retrieved highly cross-linked crossfire liners after intermediate-term implantation, *J* 

alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to

essential for estrogendeficiency bone loss and osteoclast formation, *Endocrinology*

(2005). Characterization by electron spin resonance spectroscopy of reactive oxygen species generated by titanium dioxide and hydrogen peroxide, *J Dent Res*

peroxide induces G2 cell cycle arrest and inhibits cell proliferation in osteoblasts,

of engineered nanoparticles to human lung epithelial cells: influence of chemical composition and catalytic activity on oxidative stress, *Environ Sci Technol*

iron-stimulated lipid peroxidation and cell killing, *Arch Biochem Biophys*


Engh, C.A., Massin, P. & Suthers, K.E. (1989). Roentgenographic assessment of the biologic

Fiorito, S., Goze, C., Adrey, J., Magrini, L., Goalard, C. & Bernier, P. (2001). Increase in free

Firkins, P.J., Tipper, J.L., Saadatzadeh, M.R., Ingham, E., Stone, M.H., Farrar, R. & Fisher, J.

Fleury, C., Petit, A., Mwale, F., Antoniou, J., Zukor, D.J., Tabrizian, M. & Huk, O.L. (2006).

Goldring, S.R., Jasty, M., Roueke, C.M., Bringhurst, F.R. & Harris, W.H. (1986). Formation of

Hallab, N., Merritt, K. & Jacobs, J.J. (2001). Metal sensitivity in patients with orthopaedic

Hallab, N.J., Anderson, S., Stafford, T., Glant, T. & Jacobs, J.J. (2005). Lymphocyte responses in patients with total hip arthroplasty, *J Orthop Res* Vol.23(No.2):384-91. Hamel, P., Abed, E., Brissette, L. & Moreau, R. (2008). Characterization of oxidized low-

Harris, W.H., Schiller, A.L., Scholler, J.M., Friberg, R.A. & Scott, R. (1976). Extensive

Harris, W.H. & Penenberg, B.L. (1987). Further follow-up on socket fixation using a metal-

Horowitzm S.M., Algan, S.A. & Purdon, M.A. (1996). Pharmacologic inhibition of particulate-induced bone resorption, *J Biomed Mater Res* Vol.31:91–96. Jones, L.C. & Hungerford, D.S. (1987). Cement disease, *Clin Orthop Relat Res* Vol.225:192–

Kamikawa, K., Harada, Y., Nagata, K. & Moriya, H. (2001). Differential effects of oxidised

Keegan, G.M., Learmonth, I.D. & Case, C.P. (2007). Orthopaedic metals and their potential

Hogg, N. (1998). Free Radicals in Disease, *Semin Reprod Endocrin* Vol.16:241-248.

implants, *J Bone Joint Surg Am* Vol.83(No.3):428-36.

*Cell Physiol* Vol.294(No.4):C1021-33.

vitro, *J Bone Joint Surg Br* Vol.83:593-7.

strategies, *J Bone Joint Surg Br* Vol.89(No.5):567-73.

products, *J Biomed Mater Res* Vol.57:35–40.

Vol.11(No.2):143–157.

Vol.91(No.2):274-81.

Vol.29(No.7):836–842.

*Surg Am* 58:612–618.

Vol.69:1140–1143.

206.

128.

fixation of porous-surfaced femoral components, *Clin Orthop Relat Res* Vol.257:107–

radicals on UHMWPE hip prostheses components due to inflamed synovial cell

(2001). Quantitative analysis of wear and wear debris from metal-on-metal hip prostheses tested in a physiological hip joint simulator, *Biomed Mater Eng*

Effect of cobalt and chromium ions on human MG-63 osteoblasts in vitro: morphology, cytotoxicity, and oxidative stress, *Biomaterials* Vol.27:3351-3360. Friedl, G., Radl, R., Stihsen, C., Rehak, P., Aigner, R. & Windhager, R. (2009). The effect of a

single infusion of zoledronic acid on early implant migration in total hip arthroplasty. A randomized, double-blind, controlled trial, *J Bone Joint Surg Am*

a synovial-like membrane at the bone-cement interface. Its role in bone resorption and implant loosening after total hip replacement, *Arthritis Rheum*

density lipoprotein-induced hormesis-like effects in osteoblastic cells, *Am J Physiol* 

localized bone resorption in the femur following total hip replacement, *J Bone Joint* 

backed acetabular component for total hip replacement, *J Bone Joint Surg Am*

and non-oxidised polyethylene particles on human monocyte/macrophages in

toxicity in the arthroplasty patient: A review of current knowledge and future


Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty 317

Paprosky, W.G. & Burnett, R.S. (2002). Assessment and classification of bone stock deficiency in revision total hip arthroplasty, *Am J Orthop* Vol.31:459–464. Park, S.K., Kim, J., Seomun, Y., Choi, J., Kim, D.H., Han, I.O., Lee, E.H., Chung, S.K. & Joo,

Park, Y.S., Moon, Y.W., Lim, S.J., Yang, J.M., Ahn, G. & Choi, Y.L. (2005). Early osteolysis

Petit, A., Mwale, F., Tkaczyk, C., Antoniou, J., Zukor, D.J. & Huk O.L. (2005). Induction of

Purdue, P.E., Koulouvaris, P., Nestor, B.J. & Sculco, T.P. (2006). The central role of wear

Rached, M.T., Kode, A., Xu, L., Yoshikawa, Y., Paik, J.H., Depinho, R.A. & Kousteni, S.

Reddy, G.K. & Enwemeka, C.S. (1996). A simplified method for the analysis of

Riedle, B. & Kerjaschki, D. (1997). Reactive oxygen species cause direct damage of

Sabokbar, A., Fujikawa, Y., Neale, S., Murray, D.W. & Athanasou, N.A. (1997). Human

Schaich, K.M. (1992). Metals and lipid oxidation. Contemporary issues, *Lipids* 

Schmalzried, T.P., Jasty, M. & Harris, W.H. (1992). Periprosthetic bone loss in total hip

Shanbhag, A.S., Hasselman, C.T. & Rubash, H.E. (1997). Inhibition of wear debris mediated

Sieber, H.P., Rieker, C.B. & Köttig, P. (1999). Analysis of 118 second-generation metal-on-

Tietze, F. (1969). Enzymic method for quantitative determination of nanogram amounts of

Tkaczyk, C., Petit, A., Antoniou, J., Zukor, D.J., Tabrizian, M. & Huk, O.L. (2010).

Tsaryk, R. (2009). Effects of metal-induced oxidative stress on endothelial cells in vitro,

metal retrieved hip implants, *J Bone Joint Surg Br* Vol.81:46-50.

disease, *Biomed Pharmacother* Vol.57(No.3-4):145-55.

arthroplasty derived macrophages differentiate into osteoclastic bone resorbing

arthroplasty. Polyethylene wear debris and the concept of the effective joint space, *J* 

osteolysis in a canine total hip arthroplasty model, *Clin Orthop Relat Res* Vol.344:33-

total and oxidized glutathione: applications to mammalian blood and other tissues,

Significance of Elevated Blood Metal Ion Levels in Patients with Metal-on-Metal Prostheses: An Evaluation of Oxidative Stress Markers, *Open Orthop J* Vol.4:221-7. Townsend, D.M., Tew, K.D. & Tapiero, H. (2003). The importance of glutathione in human

hydroxyproline in biological tissues, *Clin Biochem* Vol.29:225–229.

Sawyer, D.T. (1990). Iron induced activation of HOOH*, J Exp Pathol* Vol.31:116–131.

Engelbreth-Holm-Swarm matrix, *Am J Pathol* Vol.151:215–231. Ring PA. (1967). Total hip replacement, *Proc R Soc Med* Vol.60(No.3):281-4.

debris in periprosthetic osteolysis, *HSS J* Vol.2(No.2):102-13.

factor, *Biochem Biophys Res Comm* Vol.284:966–971.

Vol.87:1515-1521.

Vol.11(No.2):147-60.

Vol.27(No.3):209-18.

43.

*Biomaterials* Vol.26:4416-4422.

cells. *Ann Rheum Dis* Vol.56:414-420.

*Bone Joint Surg Am* Vol.74:849–863.

*Anal Biochem* Vol.27:502–522.

*Dissertation*, Mainz.

C.K. (2001). Hydrogen peroxide is a novel inducer of connective tissue growth

following second-generation metal-on-metal hip replacement, *J Bone Joint Surg Am*

protein oxidation by cobalt and chromium ions in human U937 macrophages,

(2010). FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. *Cell Metab*


Liu, H., Sun, J.C., Zhao, Z.T., Zhang, J.M., Xu, H. & Li, G.S. (2010). Fluoride-induced

Livermore, J., Ilstrup, D. & Morrey, B. (1990). Effect of femoral head size on wear of the polyethylene acetabular component, *J Bone Joint Surg Am* Vol.72:518–528. Lubec, G. (1996). The hydroxyl radical: from chemistry to human disease, *J Investig Med*

Marmunti, M., Gavazza, M. & Catala, A. (2004). Nonenzymatic and enzymatic lipid

Mazière, C., Savitsky, V., Galmiche, A., Gomila, C., Massy, Z. & Mazière, J.C. (2010).

McKay, G.C., Macnair, R., MacDonald, C. & Grant, M.H. (1996). Interactions of orthopaedic metals with an immortalized rat osteoblast cell line, *Biomaterials* Vol.17:1339-1344. McKee, G.K. & Watson-Farrar, J. (1966). Replacement of arthritic hips by the McKee-Farrar

McKellop, H., Shen, F.-W., Lu, B., Campbell, P. & Salovey, R. (1999). Development of an

Millett, P.J., Allen, M.J. & Bostrom, M.P. (2002). Effects of alendronate on particle-induced

Minotti, G. & Aust, S.D. (1992). Redox cycling of iron and lipid peroxidation, *Lipids*

Mirra, J.M., Amstutz, H.C., Matos, M. & Gold, R. (1976). The pathology of the joint tissues

Mlakar, S.J., Osredkar, J., Prezelj, J. & Marc, J. (2010). The antioxidant enzyme GPX1 gene

Mody, N., Parhami, F., Sarafian, T.A. & Demer, L.L. (2001). Oxidative stress modulates

Muratoglu, O.K., Bragdon, C.R., O'Connor, D.O., Jasty, M. & Harris, W.H. (2001). A novel

Muratoglu, O.K. & Kurtz, S.M. (2002). Alternate bearing surfaces in hip replacement, *in*

Ollivere, B., Darrah, C., Barker, T., Nolan, J. & Porteous, M.J. (2009). Early clinical failure of

Ozgocmen, S., Kaya, H., Fadillioglu, E., Aydogan, R. & Yilmaz, Z. (2007). Role of antioxidant

*Res* doi: 10.1007/s12011-010-8881-0 [Epub ahead of print]

Vol.44(No.6):324-46.

Vol.27(No.3):219-26.

Vol.31:509–519.

New York, pp. 1-46.

*Cell Biochem* Vol.295(No.1-2):45-52.

*Biophys Acta* Vol.1802(No.11):1013-9.

prosthesis, *J Bone Joint Surg Br* Vol.48(No.2):245–259.

osteolysis in a rat model, *J Bone Joint Surg Am* Vol.84:236-49.

mechanical properties, *J Arthrop* Vol.16(No.2):149–160.

softtissue necrosis, *J Bone Joint Surg Br* Vol.91:1025-1030.

replacements, *J Orthop Res* Vol.17(No.2):157–167.

markers, *Dis Markers* Vol.29(No.2):71-80.

Vol.265:1–9.

oxidative stress in three-dimensional culture of os732 cells and rats, *Biol Trace Elem* 

peroxidation of microsomes and nuclei obtained from rat liver, *Mol Cell Biochem*

Oxidized low density lipoprotein inhibits phosphate signaling and phosphateinduced mineralization in osteoblasts. Involvement of oxidative stress, *Biochim* 

extremely wear resistant ultra-high molecular weight polyethylene for total hip

and its clinical relevance in prosthesis failure. *Clin Orthop Relat Res* Vol.117:221–240.

polymorphisms are associated with low BMD and increased bone turnover

osteoblastic differentiation of vascular and bone cells, *Free Radic Biol Med*

method of crosslinking UHMWPE to improve wear, reduce oxidation and retain

Sinha, R.K. (ed.), *Hip replacement. Current trends and controversies,* Marcel Dekker,

the Birmingham metal-onmetal hip resurfacing is associated with metallosis and

systems, lipid peroxidation, and nitric oxide in postmenopausal osteoporosis, *Mol* 


**16** 

Jiri Gallo et al.\*

*Czech Republic* 

**Aseptic Loosening of Total Hip** 

 **Failure of Tissue Homeostasis** 

**Arthroplasty as a Result of Local** 

*Department of Orthopaedics, Palacky University, Teaching Hospital Olomouc,* 

Total hip arthoplasty (THA) is the most effective and safest method for treating severe degenerative, post-traumatic and other diseases of the hip joint. It is estimated that more than 1,000,000 THAs are performed each year globally. The incidence of primary THA increased in the period 1990 to 2002 in the USA from 47/100,000 to 69/100,000 (Kurtz et al. 2007). A similar study in Denmark reported an increased rate of THAs from 101/100,000 to 131/100,000 during the period 1996 to 2002 (Pedersen et al. 2005). More importantly,

It is believed that THA can reliably relieve pain and improve function in the majority of patients for a period of 15 to 20 years or more postoperatively. On this basis, with the extension of THAs to a younger and generally more active population, the expected time of service of THAs would be insufficient and the number of revision surgeries would therefore increase during this time. The Kaplan-Meier ten-year revision-free survival estimates for younger patients range from 72% (95%CI: 67-76) in Finland to 86% (95%CI: 84,5-88,2) in Sweden (Corbett et al. 2010). Hence, 14% to 28% of such patients on average did not achieve

The main reason for late failure of THA is *aseptic loosening accompanied by osteolysis* followed by infection and instability of the THA that compromise more the early postoperative

 Yrjö T. Konttinen1, Stuart B. Goodman2, Jacob P. Thyssen3, Emmanuel Gibon4, Jukka Pajarinen1, Yuya Takakubo5, Peter Schalock6, Zygmunt Mackiewicz7, Eemeli Jämsen1, Martin Petrek8,

*1Department of Medicine and Department of Anatomy, Helsinki University Central Hospital, ORTON* 

*6Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, USA 7Department of Histology and Embryology, Medical University in Bialystok, Poland* 

*Orthopaedic Hospital of the Invalid Foundation, COXA Hospital for Joint Replacement, Finland 2Department of Orthopaedic Surgery, Stanford University, USA 3Department of Dermato-Allergology Copenhagen University Hospital Gentofte, Denmark 4Department of Orthopaedic Surgery, Bichat Teaching Hospital, Paris School of Medicine, France 5Department of Orthopaedics, Yamagata University, Japan* 

*8Department of Immunology, Palacky University Olomouc, Czech Republic 9Valdoltra Orthopaedic Hospital, Ankaran, Slovenia 10College of Health Care, University of Primorska, Izola, Slovenia* 

modelled future projections expect further increase in the need for THAs.

**1. Introduction** *(Gallo)*

 \*

a 10-year THA functioning without revision.

Rihard Trebse9, Andrei Coer10 and Michiaki Takagi5

