Symposium identifies potential treatment Targets
Osteolysis may do more than destroy bone; it may also block bone formation.
This assertion, which could unlock new treatment options for osteolysis, was just one of the many new biological concepts discussed at the 2007 AAOS/National Institutes of Health (NIH) Osteolysis and Implant Wear Research Symposium. (See related story above.)
During the symposium, clinical and research scientists examined recent studies of the cellular mechanisms responsible for the pathogenesis of implant wear-mediated osteolysis. At the end of the scientific meeting, they created a summary statement that outlined key biologic principles. In addition, they included recommended research directions aimed at developing effective pharmacotherapies for osteolysis, improving orthopaedic implant biocompatibility, and reducing implant wear.
“We’ve come a long way”
Timothy Wright, PhD, and Stuart Goodman, MD, PhD, served as co-chairs of the 2007 symposium, as well as of the osteolysis and implant wear research symposiums held in 1995 and 2000. Recently, said Dr. Wright, scientists’ knowledge about the biological response to wear particles has increased dramatically.
“We’ve come a long way in the last 7 years in understanding the biological cascade that results in implant failure,” said Dr. Wright.
Despite all the progress that has been made, however, there is a continued need to unravel the complex interaction of the many factors and cells involved in this process.
Osteolysis: not just a bone-eating disease
Recent research has uncovered the possibility that osteolysis may involve more than the resorption or dissolution of bone tissue. According to Rocky S. Tuan, PhD, chief of the cartilage biology and orthopaedics branch of the National Institutes of Arthritis and Musculoskeletal and Skin Diseases, recent data suggest that biologic effects on bone-forming cells—osteoblasts, osteoprogenitors, and adult mesenchymal stem cells (MSCs)—may also contribute to osteolysis.
“Our research findings suggest the following mechanisms of particle bioreactivity that may contribute to osteolysis: exacerbated inflammation caused by elevated reactive oxygen species production by activated macrophages and osteoclasts; impaired periprosthetic bone formation secondary to disrupted osteogenesis; and compromised bone regeneration resulting from increased cytotoxic response and suppressed osteogenic differentiation of mesenchymal osteoprogenitor cells,” said Dr. Tuan.
This new concept opens up possibilities for the development of therapeutic agents that enhance bone formation. These agents would add to existing therapies—such as bisphosphonates—that inhibit bone destruction.
A possible genetic link
In most diseases of multi-factorial origin, both environmental and genetic factors contribute to disease susceptibility. Osteolysis is likely no exception.
The clinical variation seen in patients’ osteolytic responses to wear debris suggest a possible genetic contribution. Preliminary studies have indicated that certain cytokines (proteins and peptides that are used in organisms as signaling compounds) may promote the disease. If it can be proven that the patient’s susceptibility to cytokines is critical, it may be possible to develop a test to identify patients who are at high risk for developing osteolysis in response to wear particles.
“Changes in gene expression lie at the center of the monocyte/macrophage response to implant wear particles,” said Robert Lane Smith, PhD, a research professor in the department of orthopaedic surgery at the Stanford University School of Medicine. “These changes follow activation of cascades of cell-signaling molecules and remain an area of active research.”
Alternative bearing surfaces
Alternative bearing surfaces such as ceramic biomaterials have lower volumetric wear rates than conventional (metal-on-polyethylene) bearing surfaces and present promising ways to reduce the incidence of osteolysis. Symposium participants urged continued studies, however, on the biologic responses to wear debris caused by alternative bearing surfaces.
According to the summary statement, “It is important to understand the host factors as a response to these alternative bearings 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.”
The emergence of metal-on-metal surfaces has re-emphasized the importance of research on the immunologic response to particles.
“Serum and urine metal concentrations in patients with these implants [metal-on-metal] are substantially higher than those seen in patients with conventional metal-on-polyethylene bearings,” reported Joshua J. Jacobs, MD, past president of the Orthopaedic Research Society and current chair of the AAOS Council on Research, Quality Assessment and Technology.
“These elevated levels may persist for the duration of the implant’s lifetime. This is of particular concern in younger and more active patients whose life expectancy after implantation may exceed 20 or 30 years,” said Dr. Jacobs.
An immune response to metal particles may exist, according to the summary statement, but “clinical testing for implant-associated allergy is not straight-forward, and no gold standard test currently exists for making the diagnosis.”
Biologic markers of wear
According to Thomas W. Bauer, MD, PhD, staff pathologist at the Cleveland Clinic Foundation, potential systemic markers of implant wear include products of the wear process itself (debris and ions), as well as cytokines and other proteins that reflect the cellular response to wear.
The challenge in using biochemical mediators as markers of wear-mediated bone loss is identifying and associating them exclusively with the sequelae of wear.
“Even though materials used in joint replacements are considered biocompatible, in vitro and in vivo studies have demonstrated that wear products of these materials elicit a robust cellular response,” said Arun Shanbhag, PhD, MBA, assistant professor of orthopaedic surgery at the Harvard Medical School and director of the Biomaterials Research Laboratory at Massachusetts General Hospital. “The magnitude of the cellular response depends on various material factors such as type of material, size of the debris, and the dose or debris burden. Additionally, depending on the cellular population studied, the spectrum of biochemical mediators including cytokines and growth factors may be different.”
According to Dr. Shanbhag, there’s still much to be learned regarding the biochemical processes that occur during wear-mediated osteolysis.
“It’s important to comprehensively identify molecules orchestrating peri-implant bone resorption at the bone-implant interface,” said Dr. Shanbhag. “This will better define the inflammatory microenvironment around failed total joint replacements and provide a stronger foundation for identifying biomarkers.”
Aseptic loosening remains the single largest problem facing arthroplasty interface longevity.
Joan E. Bechtold, PhD, director of the Orthopedic Biomechanics Laboratory at the Midwest Orthopaedic Research Foundation, focused on the role of mechanical factors in aseptic loosening. Dr. Bechtold noted that relative motion between an implant and bone leads to the formation of a fibrous membrane.
“We hypothesize,” said Dr. Bechtold, “that a fibrous membrane provides the environment within which other osteolytic stimuli become more potent.”
“Whether implant motion necessarily precedes the formation of a fibrous membrane, or whether there are other conditions under which a fibrous membrane can be engendered, is not known,” continued Dr. Bechtold. “Also unknown is whether an initially secure bony anchorage can deteriorate and leadto the late formation of a fibrous membrane through the newly occurring relative motion between implant and bone.”
Future research directions
According to the symposium participants, further research is required to completely unravel the biological effects and mechanisms of the action of wear particles. Armed with that knowledge, researchers could develop specific pharmacological treatments to block the production of cytokines and inhibit accumulation of inflammatory cells in the interfacial membrane surrounding implants.
“The biologic mechanisms by which orthopaedic biomaterial particles activate monocytes/macrophages remain a primary target for understanding the pathophysiology of periprosthetic inflammation,” said Dr. Smith. “One fundamental question critical to the problem of osteolysis and implant wear is to what extent might a single biological process underlie both the acute and chronic reaction to particulate debris. If such a central pathway were to be identified, interventional strategies could then be formulated to control or modulate the inflammatory response to orthopaedic biomaterial particles.”
The proportion of the total osteolysis risk that may be ascribed to genetic factors also must be quantified. In addition, symposium participants agreed that given the likely involvement of MSCs as an osteoprogenitor cell type capable of new bone formation, future therapeutic developments should also focus on reagents and treatments that will enhance MSC viability, proliferation, and osteogenic activity as a means of optimizing bone quality.
Jennie McKee is a staff writer for AAOS Now. She can be reached at email@example.com