The Cellular and Molecular Biology of Periprosthetic Osteolysis P. Edward Purdue, PhD; Panagiotis Koulouvaris, MD, PhD; Hollis G. Potter, MD; Bryan J. Nestor MD; and Thomas P. Sculco, MD The generation of prosthetic implant wear after total joint arthroplasty is recognized as the major initiating event in development of periprosthetic osteolysis and aseptic loosen- ing, the leading complication of this otherwise successful sur- gical procedure. We review current concepts of how wear debris causes osteolysis, and report ideas for prevention and treatment. Wear debris primarily targets macrophages and osteoclast precursor cells, although osteoblasts, fibroblasts, and lymphocytes also may be involved. Molecular responses include activation of MAP kinase pathways, transcription factors (including NFB), and suppressors of cytokine sig- naling. This results in up-regulation of proinflammatory sig- naling and inhibition of the protective actions of antiosteo- clastogenic cytokines such as interferon gamma. Strategies to reduce osteolysis by choosing bearing surface materials with reduced wear properties should be balanced by awareness that reducing particle size may increase biologic activity. There are no approved treatments for osteolysis despite the promise of therapeutic agents against proinflammatory mediators (such as tumor necrosis factor) and osteoclasts (bisphosphonates and molecules blocking receptor activator of NFkappaB ligand [RANKL] signaling) shown in animal models. Considerable efforts are underway to develop such therapies, to identify novel targets for therapeutic interven- tion, and to develop effective outcome measures. Periprosthetic osteolysis is the leading complication of a total joint arthroplasty, a surgical procedure so successful that more than 1 million are performed each year. 46 How- ever, periprosthetic osteolysis and subsequent aseptic loos- ening ultimately develop in approximately 20% of pa- tients, 2 and in younger patients failure rates of 13% for the femoral component and 34% for the acetabular component have been reported. 59 Prosthetic wear is thought to play a central role in the initiation and development of osteolysis. Higher wear rates are seen in patients with osteolysis com- pared with control subjects who show no osteolysis. 28,142 An enormous amount of wear particles are associated with the periprosthetic interfacial membrane removed during re- vision surgery. 51,73,105 Particulate debris induced osteolysis in various animal models 76,77,106,111,137,146,152 and inflam- matory responses in cultured macrophages. 9,55,70,76,82,145 These findings suggest wear debris is one of the most important underlying causes of periprosthetic osteolysis. Involvement of other potential contributors to osteolysis and aseptic loosening, such as fluid pressure, 4,5,122 are beyond the scope of this review, and are not discussed. Wear debris may be generated from various prosthesis components (eg, polyethylene, metal, and ceramic) and bone cement. 102 The choice of prosthesis and bearing sur- face profoundly affects the composition, size, and shape of generated particles. Each influences cellular responses, therefore implant design may have a substantial impact on the potential for development of osteolysis. Because oste- olysis is a progressive disease, clinical results with newer implant designs and bearing surfaces have not been fully determined. This is of special interest for younger patients in whom prostheses ideally would function for 50 years or more. We summarize the current knowledge regarding how wear debris participates in the development of osteolysis. We consider the various possible cellular targets of par- ticulate wear debris, and the molecular consequences of these cell-particle interactions. We emphasize two novel features, namely the critical importance of reevaluating the proposed role of proinflammatory cytokine signaling in osteolysis and the unparalleled value of magnetic reso- nance imaging (MRI) in the detection and characterization Received: April 6, 2006 Revised: June 28, 2006 Accepted: August 16, 2006 From the Hospital for Special Surgery, New York, NY. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrange- ments, etc) that might pose a conflict of interest in connection with the submitted article. Correspondence to: P. Edward Purdue, PhD, Hospital for Special Surgery, Osteolysis Research Laboratory, 535 East 70th Street, New York, NY 10021. Phone: 212-606-1437; Fax: 212-249-2373; E-mail: purduee@hss.edu. DOI: 10.1097/01.blo.0000238813.95035.1b CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Number 454, pp. 251–261 © 2006 Lippincott Williams & Wilkins 251 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.