J Am Acad Orthop Surg, Vol 16, No suppl_1, July 2008, S68-S71.
© 2008 the American Academy of Orthopaedic Surgeons
Are there biological markers of wear?
Thomas W. Bauer, MD, PhD and
Arun S. Shanbhag, PhD, MBA
Dr. Bauer is Staff Pathologist, Department of Pathology, and holds joint appointments with the Department of Orthopedic Surgery and the Spine Center, The Cleveland Clinic, Cleveland, OH. Dr. Shanbhag is Assistant Professor of Orthopaedic Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA.
*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. Bauer or a member of his immediate family has received research or institutional support from Stryker Orthopaedics, Stryker Spine, Spinal Kinetics, DePuy Spine, and Applied Spine Technologies and is a consultant to Stryker Orthopaedics. Neither Dr. Shanbhag nor a member of his immediate family has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article.
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Abstract
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Potential systemic markers of implant wear include products of the wear process (particles and ions) and mediators of the inflammatory reaction that can be induced by wear. Ions from polymers used in arthroplasty are not specific, but high metal ion levels may help identify patients with unexpectedly high wear of metal-on-metal implants. The kinetics of ion production, transport, and excretion are complex, however, so it is currently difficult to interpret the significance of mild elevations in metal ions. Indices of bone turnover (eg, collagen fragments) and mediators involved in the inflammatory reaction to particles (eg, osteoprotegerin, RANKL, interleukins) may be associated with osteolysis, but systemic disorders (eg, osteoarthritis) and the use of medications that influence bone remodeling limit the predictive value of these analytes with respect to the consequences of implant wear. Using genomic and proteomic methods to measure multiple analytes offers promise, but the challenge is to identify markers specifically associated with wear that are not elevated by other conditions that often coexist in this patient population.
In identifying diagnostic markers that relate to implant wear, both the products of the wear process and mediators that reflect the biologic consequences of wear must be considered. Products of wear include particles, metal ions, and other byproducts. Particles are in highest concentration locally. Because some particles migrate to distant organs, quantifying particles is an inefficient measure of implant wear. Metal ions derive directly from wear and from corrosion of implant surfaces and wear particles.
Many studies have documented elevated levels of metal ions in patients with failed implants. It has also been suggested that patients with joint arthroplasty components containing titanium who have levels of serum titanium that exceed 8 ppm may have either mechanical failure of the device (aseptic loosening or a delaminated metal-backed patellar component in a total knee arthroplasty) or accelerated wear associated with a polyethylene counterface. One might anticipate that in a patient with a metal-on-metal total hip arthroplasty (THA), the serum concentration of metal ions would correlate with activity. However, after continuously monitoring activity over a 2-week period in patients with metal-on-metal THAs, Heisel et al1 reported no significant correlation between serum metal ion levels and physical activity. They suggested that the serum ion levels could be used to monitor wear without regard to activity, but also noted that corrosion of particles derived from run-in wear could dominate serum ion levels in the long term.
While correlating wear with serum ions in patients with metal-on-metal THAs awaits more sensitive measures of implant wear, several studies have provided hints that such correlations may exist in some patients. For example, Brodner et al2 reported a significant correlation between serum cobalt and chromium levels and the inclination of the acetabular component in metal-on-metal hip arthroplasty, a factor sometimes thought to be associated with increased wear. Elevated cobalt and chromium ions were also reported in patients with metal-on-metal total intervertebral disk implants.3 However, the kinetics of particle and metal ion production, corrosion, transport, and excretion are complicated, and, for the most part, correlation between metal ion levels and wear awaits robust retrieval studies in which wear of metal-on-metal implants has been quantified. Current methods of wear measurement in vivo are not sensitive enough to show a correlation between serum ion levels and implant wear in most patients. Standardization of ion detection methods among laboratories is needed, as high serum ion levels may have value in identifying patients with unexpectedly high wear of metal-on-metal bearings.
Besides measuring the products of wear, one could also target measuring the consequences of wear, including measuring markers of bone turnover and of the underlying inflammatory process. Several cross-sectional studies4-8 have attempted to correlate wear with serum and urine markers, which are often used to follow the response of patients with Paget’s disease or osteoporosis who are being treated with bisphosphonates. Studies with larger control groups have identified high false-positive results, lowering the perception of test specificity,9 although Savarino et al7 reported 33% sensitivity and 100% specificity of serum cross-linked N-terminal telopeptide of type I collagen (NTx) with respect to osteolysis. A few studies reported changes in collagen fragments over time in patients with unstable or well-fixed implants. Schneider et al10 showed that, like serum C-reactive protein and erythrocyte sedimentation rate, serum NTx values are abnormal for several months after arthroplasty, but these values appear to normalize after about 6 months. In general, serum and urine collagen fragments are significantly different between patients with osteolysis and implant loosening compared to patients with stable implants. However, relatively low sensitivity and specificity limit the practical application of these tests in any given patient, largely because other clinical factors, such as osteoarthritis or drugs, also influence bone metabolism and, consequently, these markers.
Although markers of bone turnover have thus far shown limited predictive value, several studies have quantified mediators associated with the inflammatory process. In vitro and in vivo studies have clearly demonstrated that wear debris and byproducts of materials used in joint arthroplasties elicit a robust cellular response and release a variety of biologic mediators. The magnitude of the cellular response depends on material factors such as composition, size of the debris particles, and the dose or debris burden.11-15 Furthermore, depending on the cellular population studied, the spectrum of biochemical mediators, including cytokines and growth factors released, may be different. Thus, an opportunity exists to use these biologic mediators released by cells as markers of the consequences of wear. Granchi et al16 measured serum osteoprotegerin (OPG) and receptor activator of nuclear factor 
B ligand (RANKL) in four groups of patients: (1) healthy patients without implants, (2) patients with osteoarthritis but no implants, (3) patients with clinically stable hip arthroplasties, and (4) patients with loose hip implants. The results showed significantly increased OPG in patients with osteoarthritis (but no arthroplasty) and in patients with loose implants. RANKL was higher in patients without osteolysis compared to patients with loose implants. The authors used a receiver operating characteristic curve to calculate optimum cutoff values. Although their control groups were relatively small, they found that serum OPG >2,300 pg/mL had a sensitivity of 92% and specificity of 75% with respect to osteolysis.
In vitro models using target cells are useful in dissecting the mechanisms leading to a wear-induced bone resorptive process, but they introduce various artifacts and thus are less useful in helping pinpoint specific mediators as clinical markers of wear. Evaluating tissues from patients with clinical osteolysis represents another option for detecting and identifying biochemical markers of wear.17 For measuring protein levels, the enzyme-linked immunosorbent assay (ELISA) is the easiest and most convenient technique to detect mediators in protein extracts from clinical tissues. Although ELISAs are also reliable, investigators are limited to studying only one mediator at a time, and relatively large samples (~400 mL) are currently required for assessment. These requirements restrict the assortment of mediators that can be investigated from small patient samples. In situ hybridization and immunohistochemistry have also been used to identify mediators in tissues.18,19 These techniques also limit the number of markers that can be assessed in clinical tissues.
The emerging field of proteomics has spawned a variety of new technologies to quantify large numbers of protein markers simultaneously in small biologic samples. Similar in concept to the gene array, the protein chip is a solid-phase ligand-binding assay that uses Fab' fragments of monoclonal antibodies tethered in a spatially optimized manner onto the surface of microscopically etched silica posts (Figure 1).
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Figure 1 A, Protein chip manufactured by Zyomyx (Hayward, CA) that can quantify 30 different mediators in each sample. B, Each chip can be used to analyze six samples in separate chambers arranged as lanes. C, Each sample chamber contains 200 etched silica posts with specific monoclonal antibodies tethered in a predetermined configuration. The 200 spot features account for five replicate samples for each analyte and positive and negative controls.
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Shanbhag et al20 have used such high-throughput protein chips to identify inflammatory markers in osteolytic tissues from around failed metal-on-polyethylene total joint arthroplasties. They identified several markers associated with osteolysis, including interleukin (IL)-8 and -6, which recruit osteoclast precursors and facilitate the maturation of osteoclasts. Additionally, various T-cell chemotactic factors such as IP-10 (interferon 
-inducible protein of 10 kDa) and MIG (monokine induced by interferon ) were significantly elevated in the osteolytic tissues. These mediators point to the role of an immune response, but other activators of cytotoxic T-cells, antibody-producing B-cells, eosinophils, and factors related to a delayed-type hypersensitive response were not detected in the periprosthetic granulomas. Interestingly, all the mediators present in osteolytic tissues were also present in capsular tissues from patients with end-stage degenerative joint disease. This finding is not surprising considering that degenerative joint diseases are also associated with localized bone resorption and are likely mediated by the same inflammatory markers as the wear debris process. Thus, the challenge in using biochemical mediators as markers of wear-mediated bone loss is identifying and associating the markers exclusively with the sequelae of wear.
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Future Directions for Research
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Although indices of bone remodeling and inflammation are abnormal in patients with implant wear and osteolysis, these markers are also abnormal in patients being treated with various drugs and those with clinical conditions such as osteoarthritis. The challenge is to identify markers specific for implant wear, loosening, and osteolysis, independent of other disorders. The need exists, therefore, for standardized protocols in the retrieval and processing of material samples used for biomarker development; methods for identifying biomarkers associated exclusively with a wear-mediated process; availability of clinically relevant markers for validating markers in model systems; and techniques to distinguish these biomarkers from non–wear-related bone-resorptive pathologies. From the large numbers of mediators associated with the bone resorptive process, investigators will likely be able to identify a smaller subset of markers that are exclusively associated with wear-induced osteolysis. Such techniques may also identify markers for other processes that may be associated with implant loosening, such as subclinical infection or possible immune reactions to materials used in joint arthroplasties.
A complete understanding of the biochemical processes that occur in wear-mediated osteolysis has not been achieved. Technologies such as whole genome screening will be instrumental in comprehensively defining the inflammatory microenvironment around failed total joint arthroplasties and providing a stronger foundation for identifying biomarkers. Toward this goal, genomic and proteomic studies show great promise.
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References
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- Brodner W, Gr ü bl A, Jankovsky R, Meisinger V, Lehr S, Gottsauner-Wolf F: Cup inclination and serum concentration of cobalt and chromium after metal-on-metal total hip arthroplasty. J Arthroplasty 2004;19(8 suppl 3): 66-70.
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Abstract
Future Directions for Research
