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in-brief |
Dr. Goodman is Robert L. and Mary Ellenburg Professor of Surgery, and Professor, Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA. Dr. Goldberg is Professor, Case Western Reserve University, Cleveland, OH. Dr. O’Keefe is Professor of Orthopaedic Surgery, Chairman of the Department of Orthopaedics and Rehabilitation, and Director of the Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY.
*The Implant Wear Symposium 2007 Biologic Work Group included Thomas W. Bauer, MD, PhD, Joan Bechtold, PhD, Mathias Bostrom, MD, Patricia A. Campbell, PhD, Victor Goldberg, MD, Stuart B. Goodman, MD, PhD, Ed M. Greenfield, PhD, Joshua J. Jacobs, MD, Yrjö Konttinen, MD, PhD, Regis O’Keefe, MD, PhD, Francis Young-In Lee, MD, Edward M. Schwarz, PhD, Arun S. Shanbhag, PhD, MBA, Robert Lane Smith, PhD, Rocky S. Tuan, PhD, and J. Mark Wilkinson, PhD, FRCS(Tr&Orth).
Dr. Goodman or a member of his immediate family has received research or institutional support from Zimmer, and is an employee or consultant for NIAMS, Biomimedica, Zimmer, and NIH. Dr. Goldberg or a member of his immediate family has received research or institutional support from Ferring Pharmaceuticals and Sanofi-Aventis, has received royalties from Zimmer and Wright Medical Technology, Inc., and is a consultant for Zimmer and Wright Medical Technology. Dr. O’Keefe or a member of his immediate family has received research or institutional support from DePuy, has received royalties from Laget, Inc, is a consultant for Laget, Inc, and has stock or stock options and other financial or material support from Osteobiologics, Inc.
, prostaglandin E2, nitric oxide, and oxygen metabolites. The cellular response has been clearly documented as a monocyte-macrophage lineage that ultimately results in osteoclastic bone resorption. Since the previous implant wear symposium in 2000, a significant number of new studies have pointed to additional cell involvement. These cells include vascular endothelial cells, which appear to respond to the loosening implants. In the past, emphasis was placed on cells that are involved in bone loss. However, other recent data suggest that additional cells involved in bone accretion are also equally responsive to wear debris. These include osteoblasts, osteoprogenitors, and mesenchymal stem cells that are precursors of osteoblasts. Also, fibroblasts have been implicated in the response to particles and the production of an interstitial fibrous collagenous matrix surrounding the loosening implant.
In addition to proinflammatory cytokines, a class of chemoattractive cytokines known as chemokines, which are produced by the myriad of cells involved in this inflammatory process, have been implicated in the recruitment of osteoclast precursors. However, the downstream effect of both chemokines and cytokines in ultimately forming osteoclasts is the activation of the receptor activator of nuclear factor-
B ligand (RANKL)-RANK sequence of events. Significant work has been undertaken identifying the signal transduction cascade that responds to particles that ultimately leads to osteoclast differentiation. These studies have also implicated the redundancy of the inflammatory pathways in response to wear debris.
Recent work has pointed to the role of genetic contribution to osteolysis. The studies, although preliminary, have implicated several cytokines, such as TNF- and IL-1 gene clusters, as potential promoters of osteolysis. Specific polymorphisms have been identified, and preliminary data suggest that patients who have an enhanced osteolytic response to wear particles demonstrate a single nucleotide polymorphism in the TNF- promoter gene.
Further research is required to completely unravel the biologic effects and mechanisms of action of wear particles to develop a specific pharmacologic treatment that can block the production of cytokines and inhibit accumulation of inflammatory cells in the interfacial membrane surrounding implants. Additionally, genetic variations as they relate to the host response to wear particles will perhaps allow us to identify the total osteolytic risk in response to wear particles.
During the past decade, alternative bearing surfaces that reduce surface wear have been introduced. These surfaces include highly cross-linked ultra-high–molecular-weight polyethylene, ceramic-on-ceramic, and metal-on-metal bearing surfaces. All of these have shown promise to reduce volumetric wear and the long-term complications of osteolysis. However, any wear debris that is generated by these newer bearing surfaces does result in host biologic responses. It is important to appreciate the host factor’s response to these alternative bearings in order to understand the issues of osteolysis. For example, recent reports have suggested that highly cross-linked polyethylene debris tends to be smaller and more bioreactive than conventional polyethylene debris. Submicron-sized ceramic particles are also of concern.
The emergence of metal-on-metal surfaces has led to renewed emphasis on research into the immunologic response to particles. Metal particles, ions such as chromium, and their byproducts, interact with phagocytic cells and not only cause the release of osteolytic cytokines but also result in activation of the B and T lymphocytes and plasma cells. A complex relationship exists between these wear products and the cells of the innate and adaptive immune system. Metal allergy clearly is seen; however, its importance remains unclear. Although there appears to be an immune response to metal particles, clinical testing for implant-associated allergy is not straightforward, and currently there is no gold standard test for the diagnosis.
Recently, a unique histologic response—a prominent perivascular lymphocyte infiltration in the periprosthetic tissues from patients with metal-on-metal implants—has been reported, suggesting a type 4 delayed-type hypersensitivity response. This response has been termed ALVAL (aseptic lymphocytic vasculitis–associated lesion). This issue is not completely understood. It appears, therefore, that hard-on-hard bearing couples, although they have a lower volumetric wear rate and represent a promising solution to reduction in osteolysis, other issues require study. For example, host factors, including differing reactivity to wear products, remain poorly defined, and the toxicologic significance of elevated metal ions has not been established. Additional studies in the area of the immunologic response to these particles are required.
It has become clearer that there are other biologic and mechanical factors that could contribute to osteolysis. For example, a class of immunostimulatory molecules known as pathogen-associated molecular patterns (PAMPs) has been identified. Lipopolysaccharides, the classic endotoxin, increase the biologic activity of orthopaedic wear particles in vitro and in animal models, yet the crucial question of whether these PAMPs contribute to aseptic loosening in patients remains unanswered. Additional studies are required to understand the role of PAMPs clinically in the development of osteolysis and implant loosening. A promising approach might well be to evaluate the role of these PAMPs and aseptic loosening clinically by using polymorphisms in the genes encoding the PAMP receptors associated with an increased risk of aseptic loosening.
Recent data point to the importance of implant stability in the generation of wear debris and osteolysis. Motion between the implant and bone leads to the formation of a fibrous membrane; environments that are stable facilitate bone growth and implant integration. Implant instability and increased fluid pressure have been shown to enhance the pumping of particles along the fibrous membrane and can directly erode bone. The sequence of events that lead to implant stability versus instability is still not well delineated. Further studies that define the factors associated with secure bony integration and prevention of bone-implant deterioration are necessary.
Osteolysis is a complex response of the host to wear particles. Several experimental approaches, including in vitro and in vivo and the use of clinical tissue retrieval, can be effective in investigating the biologic effects of particles. No single in vitro or in vivo model reproduces the complex clinical circumstances of implant loosening and osteolysis. Investigators must clearly define the important parameters in their use of specific models and employ approaches that isolate specific aspects of the complex sequence of events. New experimental models should be developed that more closely reproduce the clinical environment of significant osteolysis.
If therapeutic interventions are to be developed for patients with osteolysis, biologic markers of wear must be developed. Specific biomarkers currently reflect bone turnover; however, no single specific biomarker is available that can provide the data necessary to quantitatively assess therapeutic approaches to osteolysis. Additionally, indices of inflammation and the products of wear can be shown to be abnormal in patients with implant wear and osteolysis. However, the challenge is to identify specific markers for implant wear, loosening, and osteolysis, independent of underlying clinical disorders. Perhaps in the future, genomic technologies will be instrumental in comprehensively defining the inflammatory microenvironment around failed total joint arthroplasties and provide a stronger foundation for identifying biomarkers. The emerging fields of proteomics and genomics show promise in this direction.
Because of the enhanced understanding of the biologic responses of the host to wear particles, several potential effective biologic therapies have emerged to prevent continued bone loss. In diseases such as osteoporosis and rheumatoid arthritis, these therapeutic interventions appear to be effective. However, several issues exist with regard to drug development and testing as they relate to periprosthetic osteolysis treatment. These issues are the absence of quantitative outcomes to measure the progression of osteolysis in patients and, most importantly, the cost-effectiveness of any treatment in a process in which the vast majority of patients do not develop significant periprosthetic osteolysis. Possible therapeutic agents include those that enhance bone formation as well as those that inhibit bone destruction. These include the bisphosphonates and the TNF- antagonists. However, no study has definitively indicated the success of these biologic therapies. The recent implication of the RANKL-RANK pathway has resulted in the development of a specific RANKL antagonist known as denosumab. Although this drug has been used in in vitro models and early phase I clinical studies, a multicenter clinical trial using quantitative imaging techniques is required to clearly demonstrate its efficacy.
The biologic sequence of events of the host response to wear debris has been extensively studied. Much has been accomplished in the past decade, delineating the inflammatory pathways and cellular constituents; however, there is continued need to unravel the complex interaction of the many factors and cells involved in this process.
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