JBJS | The Basic Science of Periprosthetic Osteolysis*

The Journal of Bone & Joint Surgery, Volume 82, Issue 10

Articles | October 01, 2000

The Basic Science of Periprosthetic Osteolysis*

Michael J. Archibeck, M.D.; Joshua J. Jacobs, M.D.; Kenneth A. Roebuck, Ph.D.; Tibor T. Glant, M.D., Ph.D.

An Instructional Course Lecture, American Academy of Orthopaedic Surgeons
*Printed with permission of the American Academy of Orthopaedic Surgeons. This article, as well as other lectures presented at the Academy's Annual Meeting, will be available in March 2001 in Instructional Course Lectures, Volume 50. The complete volume can be ordered online at www.aaos.org, or by calling 800-626-6726 (8 a.m.-5 p.m., Central time).
One or more of the authors has received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. In addition, benefits have been or will be directed to a research fund, foundation, educational institution, or other nonprofit organization with which one or more of the authors is associated. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants AR 39310 and AR 45835, Crown Family Chair of Orthopaedic Surgery, and Zimmer, Incorporated.
Department of Orthopaedic Surgery (M. J. A., J. J. J., and T. T. G.), Department of Immunology (K. A. R.), and Department of Biochemistry (T. T. G.), Rush-Presbyterian-St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, Illinois 60612. E-mail address for J. J. Jacobs: jacobs@ortho4.pro.rpslmc.edu.

The Journal of Bone & Joint Surgery. 2000; 82:1478-1478

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Introduction

Total joint replacement has been very successful and cost-effective in restoring function and mobility to millions of patients worldwide since its advent more than thirty years ago. With improvements in prophylaxis against infection, the fatigue strength of the components, and skeletal fixation, wear and its sequelae have become the primary limitation to joint replacement longevity¹. Initially termed "cement disease,"² osteolysis is believed to be a biological response not only to polymethylmethacrylate but also to a variety of particles that may originate at several locations around a joint replacement. These include the articulating surfaces, modular component interfaces, fixation surfaces, and devices used for adjuvant fixation³.

Recent research has been directed at understanding the biological cascade of events that is initiated by particulate debris and results in periprosthetic bone loss. Clinically, periprosthetic osteolysis can lead to aseptic loosening of components, massive bone loss that renders revision surgery substantially more complex, and periprosthetic pathological fracture (Fig. 1). We present the current understanding of osteolysis with regard to the sources of wear, the morphology of wear particles, and the biological response to wear particles according to findings reported in cell-culture, tissue-explant, and animal studies.

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Fig. 1:: Radiograph demonstrating extensive osteolysis in the proximal part of the femur in a patient with a cemented total hip replacement.

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Fig. 2-A:: Photomicrograph of chromium orthophosphate hydrate-rich corrosion products around the rim of the bore of a cobalt-chromium-alloy femoral head that was coupled with a titanium-alloy stem (× 7). (Figs. 2-A and 2-B reprinted from: Urban, R. M.; Jacobs, J. J.; Gilbert, J. L.; and Galante, J. O.: Migration of corrosion products from modular hip prostheses. Particle microanalysis and histopathological findings. J. Bone and Joint Surg., 76-A: 1347, Sept. 1994.)

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Fig. 2-B:: Photomicrograph of chromium orthophosphate hydrate-rich corrosion products circumscribing the neck of a cobalt-chromium-alloy femoral component, just distal to the head-neck junction (× 5).

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Fig. 3-A:: Figs. 3-A and 3-B: Photomicrographs of polyethylene particles isolated from tissues, showing spheroids (Fig. 3-A) and clusters of finer particles with bridging fibrils (Fig. 3-B). (Reprinted, with permission, from: Shanbhag, A. S.; Jacobs, J. J.; Glant, T. T.; Gilbert, J. L.; Black, J.; and Galante, J. O.: Composition and morphology of wear debris in failed uncemented total hip replacement. J. Bone and Joint Surg., 76-B(1): 63, 1994.)

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Fig. 3-B:: Figs. 3-A and 3-B: Photomicrographs of polyethylene particles isolated from tissues, showing spheroids (Fig. 3-A) and clusters of finer particles with bridging fibrils (Fig. 3-B). (Reprinted, with permission, from: Shanbhag, A. S.; Jacobs, J. J.; Glant, T. T.; Gilbert, J. L.; Black, J.; and Galante, J. O.: Composition and morphology of wear debris in failed uncemented total hip replacement. J. Bone and Joint Surg., 76-B(1): 63, 1994.)

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Fig. 4:: Autoradiograph of Northern blot analysis, showing the expression of mRNAs for procollagen a1(I) and a2(III) in human MG-63 osteoblast-like cells incubated for forty-eight hours with various particles at a concentration of 0.05 percent. The lowest panel shows the responses of corresponding RNAs. (Reprinted from: Yao, J.; Cs-Szabñª??.; Jacobs, J. J.; Kuettner, K. E.; and Glant, T. T.: Suppression of osteoblast function by titanium particles. J. Bone and Joint Surg., 79-A: 109, Jan. 1997.)
A: The cells were untreated (lane 1) or treated with small (one to three-micrometer) titanium particles (lane 2), large (twenty-one to eighty-five-micrometer) titanium particles (lane 3), small (1.14 ± 0.007-micrometer) polystyrene particles (lane 4), large (21.1 ± 4.09-micrometer) polystyrene particles (lane 5), or small (0.7 to 1.3-micrometer) silver particles (lane 6).
B: The cells were incubated for forty-eight hours without titanium particles (lane 7), with small (one to three-micrometer) titanium particles (lane 8), or with particle-free medium in which small titanium particles had been preincubated alone without cells (lane 9).

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Fig. 5-A:: Photomicrographs of periprosthetic interfacial tissue removed from patients with failed cementless (Fig. 5-A) and cemented (Fig. 5-B) total hip replacements. Numerous submicrometer birefringent particles that are most likely polyethylene (Fig. 5-A) and dark metal particles (Fig. 5-B) are seen within the cells (original magnification, × 50). (Reprinted, with permission, from: Glant, T. T.; Jacobs, J. J.; Mikecz, K.; Yao, J.; Chubinskaja, S.; Williams, J. M.; Urban, R. L.; Shanbhag, A. S.; Lee, S.; and Sumner, D. R.: Particulate-induced prostaglandin- and cytokine-mediated bone resorption in an experimental system and in failed joint replacements. Am. J. Ther., 3: 33, 1996.)

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Fig. 5-B:: Photomicrographs of periprosthetic interfacial tissue removed from patients with failed cementless (Fig. 5-A) and cemented (Fig. 5-B) total hip replacements. Numerous submicrometer birefringent particles that are most likely polyethylene (Fig. 5-A) and dark metal particles (Fig. 5-B) are seen within the cells (original magnification, × 50). (Reprinted, with permission, from: Glant, T. T.; Jacobs, J. J.; Mikecz, K.; Yao, J.; Chubinskaja, S.; Williams, J. M.; Urban, R. L.; Shanbhag, A. S.; Lee, S.; and Sumner, D. R.: Particulate-induced prostaglandin- and cytokine-mediated bone resorption in an experimental system and in failed joint replacements. Am. J. Ther., 3: 33, 1996.)

Sources of Periprosthetic Wear Debris

The generation of particulate debris after total joint arthroplasty can occur as a result of two processes: wear and corrosion. Wear has been defined as the removal of material from the prosthesis in the form of debris⁴. The fundamental mechanisms of wear include adhesion, abrasion, and fatigue⁵. The mechanical conditions under which the prosthesis is functioning when wear occurs have been classified as modes of wear⁴. Mode 1 refers to the generation of wear debris that occurs with motion between the two bearing surfaces as intended by the designers. Mode 2 refers to a primary bearing surface rubbing against a secondary surface in a manner not intended by the designers (for example, a femoral head articulating with an acetabular shell following wear-through of the polyethylene). Mode 3 refers to two primary bearing surfaces with interposed third-body particles (such as bone, cement, metal, and so on). Mode 4 refers to two nonbearing surfaces rubbing together (such as back-sided wear of an acetabular liner, fretting of the Morse taper, stem-cement fretting, and so on)³. While several modes of wear often occur simultaneously, mode 1 accounts for the majority of wear in well functioning hip or knee replacements⁵.

Corrosion is an electrochemical process in which metal ions are released from an implant surface. Corrosion products can be generated from any metal surface, but they most commonly originate from metal-on-metal modular interfaces, such as the head-neck junction in both mixed-metal or similar-metal femoral stems in total hip replacements⁶ (Fig. 2-A and Fig. 2-B). The particles are metal-salt precipitates of these ions that form in the surrounding aqueous environment. Fine particulate debris of chromium phosphate corrosion products is often observed in the periprosthetic tissues of specimens retrieved at revision⁶. Chromium phosphate corrosion products from the modular junction have been found in sites remote from the hip joint as well⁶.

The most common particle in the periprosthetic tissues is polyethylene, which is predominantly generated by means of mode-1 wear. The remaining particles in the periprosthetic tissues include polymethylmethacrylate, cobalt-alloy, and titanium-alloy particles. In much smaller volumes, silicates and stainless-steel particles are also seen; these most likely represent contaminants from surgical tools, supplemental fixation wires, or remnants from surface processing. Wear debris can gain access to all periprosthetic regions that are accessible to joint fluid^7,8. This so-called effective joint space⁸ is dependent on many variables, including component design and implantation techniques. The concentration of wear particles within periprosthetic tissues can extend into billions per gram of tissue^8-13.

Morphology of Wear Particles

It has recently been recognized that most wear particles are less than one micrometer in size. As light-microscopy resolution is limited by the wavelength of visible light (0.4 to 0.7 micrometer), submicrometer particles cannot be well visualized with these techniques. As such, the volume of particulate polyethylene debris was greatly underestimated in many early studies of periprosthetic tissues. Numerous research groups recently established techniques for the isolation, separation, and characterization of particles within periprosthetic tissues^11-14. These techniques typically involve digestion of periprosthetic tissue with proteolytic enzymes and a strong acid or alkali. Particles can be separated with use of density-gradient centrifugation and characterized with an automated particle analyzer. With these techniques, the mean size of polyethylene particles has been found to be approximately 0.5 micrometer, with more than 90 percent of the particles less than one micrometer in size^11,12.

Studies of wear debris from periprosthetic tissues characterized by scanning electron microscopy have demonstrated that 70 to 90 percent of the recovered particles are submicrometer polyethylene particles, with a mean size of about 0.5 micrometer^10,11,13,14. These particles vary in shape, with spheroid forms being the most common (Fig. 3-A). Fibrillar and globular shapes are also present (Fig. 3-B). The morphological characteristics of polyethylene particles after total hip arthroplasty are different from those after total knee arthroplasty. Submicrometer particles are more prevalent in tissues around total hip replacements than in those around total knee replacements^10,15,16. In hip replacements, microabrasion and microadhesion produce polyethylene particles that are primarily less than one micrometer in length⁴. In total knee replacements, decreased conformity and differing motion patterns result in higher contact stresses and more prevalent fatigue-type wear, leading to much larger polyethylene wear particles^17,18.

Biological Response to Particulate Debris

Background

In 1977, Willert and Semlitsch were among the first to hypothesize that aseptic loosening of joint replacements was caused by the local macrophage response to wear debris¹⁹. Goldring et al. subsequently described the synovial-like character of the bone-implant interface in patients with a loose total hip replacement and demonstrated that the cells within the membrane had the capacity to produce large amounts of the so-called bone-resorbing factors PGE2 (prostaglandin E2) and collagenase²⁰. While these initial reports concerned cemented implants, similar processes have been identified in association with cementless implants^8,21,22. Since then, a plethora of studies have documented the release of a variety of mediators of bone resorption from periprosthetic tissues in tissue culture. More recently, molecular biological tools have been utilized to study tissue samples retrieved from patients with osteolysis. Techniques including immunohistochemistry, in situ hybridization, and quantitative polymerase chain reaction have provided powerful tools to elucidate the basic biology of loosening²³.

Size, Composition, and Concentration of Particles

A number of investigators have examined the effects of particle size, composition, and dose on cell response. With regard to size, Horowitz et al. demonstrated that polymethylmethacrylate particles that are phagocytosable (less than approximately seven micrometers in size) stimulate macrophage activation and release of TNF-a (tumor necrosis factor-a), while larger particles do not²¹. Gelb et al., using an air-pouch model in rats, found that small (less than twenty-micrometer), irregularly shaped polymethylmethacrylate particles produced a greater inflammatory reaction than did larger (fifty to 350-micrometer) particles as expressed by the release of TNF-a, neutral metalloprotease, and PGE2²⁴. Catelas et al., using a macrophage cell-culture line and particles of ceramic and polyethylene, found that cytotoxicity increased with the size and concentration of particles of greater than two micrometers²⁵. Smaller particles (0.6 micrometer) caused limited cell mortality only at higher concentrations. Goodman et al. examined the histological effects of different sizes of polyethylene particles implanted into rabbit tibiae and found that the larger particles (mean, sixty-seven micrometers) produced more fibrous encapsulation than did smaller particles²⁶.

The composition of the particles also has been shown to affect cellular responses. Haynes et al. studied the in vitro response of human monocytes to particles of cobalt-chromium-molybdenum, stainless steel, and titanium-aluminum-vanadium of a similar size²⁷. Stainless-steel and cobalt-chromium-molybdenum particles were toxic, while titanium-aluminum-vanadium particles did not affect cell viability. With regard to the release of proinflammatory cytokines, titanium-aluminum-vanadium particles were the strongest stimulators of IL-6 (interleukin-6) and PGE2 release, while all particles induced the release of TNF-a and IL-1b²⁷. Catelas et al. found no difference in cell mortality and release of TNF-a when Al2O3 and ZrO2 particles were compared²⁵. They found release of TNF-a in response to polyethylene to be greater than that in response to ceramics. Shanbhag et al. found that polyethylene particles were less toxic to cells than were polymethylmethacrylate particles²⁸. Two of us (T. T. G. and J. J. J.) and colleagues studied the effect of titanium and polymethylmethacrylate particles on macrophage IL-1 and PGE2 secretion and bone-resorbing activity²⁹. In the initial study, titanium particles were found to be the most stimulatory. This effect was most marked when there were about ten to fifteen particles per cell and only when the particles were of phagocytosable size (one to three micrometers). In a subsequent study, different macrophage populations (peritoneal macrophages and transformed macrophage cell-lines P388D and IC-21) were found to respond differently to these particles³⁰. The peritoneal macrophages responded to titanium particles with significantly enhanced bone-resorbing activity (p < 0.01), while polymethylmethacrylate elicited this effect to a greater extent in the P388D and IC-21 cell lines³⁰. In a rabbit model, Kubo et al. found that the material composition was more strongly correlated (regression analysis, p < 0.09) with histiocyte reaction than were particle size and total surface area³¹. They found the reaction to be greatest around particles of polyethylene (eleven micrometers), cobalt-chromium (0.03 and 3.9 micrometers), stainless steel (3.9 micrometers), and titanium alloy (0.03 micrometer). Less response was identified around larger polyethylene particles (ninety-nine micrometers), larger titanium-alloy particles (3.9 micrometers), and alumina ceramics (3.9 micrometers)³¹. Cobalt-chromium, titanium, and polyethylene particles have been used to challenge peripheral blood monocytes as well^28,32. Metallic particles were more stimulatory for PGE2, IL-1a, IL-1b, TNF-a, and IL-6 than were polyethylene particles.

The concentration of particulate debris to which a macrophage is exposed has been shown to alter its response as well. Catelas et al. demonstrated increasing phagocytosis with increasing concentrations of particles of up to two micrometers in size²⁵. Phagocytosis of larger particles (up to 4.5 micrometers) reached a plateau independent of size and concentration that suggested a saturation of phagocytosis possibly dependent on the volume of particles ingested²⁵. In a more recent study, Catelas et al. found macrophage apoptotic cell death to be both size and concentration-dependent, reaching a plateau at a concentration of more than 150 particles per macrophage for both ceramic and polyethylene particles³³. Shanbhag et al. used the concept of surface-area ratio to standardize the particle challenge in a study of macrophage response to titania and polystyrene particles³⁴. With use of weight percent, volume percent, or number of particles, a nonuniform challenge may result if particles of varying densities and sizes are compared. They found that the macrophage response to particulate debris was dependent on particle size, composition, and dose as given by surface-area ratio³⁴.

Thus, the bioreactivity of particles has been shown to depend on their size, composition, and concentration. Most studies have suggested that particles of phagocytosable sizes are the most stimulatory and that higher doses elicit more response (often up to a saturation level). At this time, it is not possible to generalize about the role of composition, as all particle types (metal, polymer, and ceramic) can elicit a cell response, which varies with the cell type and the specific response measured (such as cell toxicity, proinflammatory cytokine release, and so on). It is clear that particle production can lead to bone resorption, but currently it is not possible to determine which particle types will have the least clinical effect.

Cell and Organ-Culture Studies

Macrophages and/or other cell lines cultured with particles in vitro have added to our understanding of the events that lead to bone resorption in response to particulate debris. Cell-culture studies have demonstrated that particulate wear debris from prosthetic materials or bone cement (less than twelve to fifteen micrometers in size) are phagocytosed by macrophages and these activated cells release various mediators. Of the numerous cellular mediators released, IL-1, IL-6, TNF-a, and PGE2 are believed to be among the most important components capable of inducing cell proliferation, promoting osteoclast formation, and stimulating osteoclasts to resorb the adjacent bone^2,29,35-37. Other factors involved in bone resorption include the enzymes responsible for the catabolism of the organic component of bone. These include the matrix metalloproteinases collagenase and stromelysin³⁸. While cytokines secreted by the macrophage may directly lead to the stimulation of osteoclastic bone resorption, the intermediary role of other cells, such as osteoblasts and fibroblasts, has recently been identified^21,23.

An earlier study identified the toxic effects of many of these particles on cultured macrophages³⁹. Cobalt-chromium-alloy particles were found to lead to altered phagocytic activity and cell death³⁹. Shanbhag et al. demonstrated that cell death increased with increasing dosages of particles^28,34.

Although toxic to macrophages, these same particles have the ability to activate macrophage production of proinflammatory cytokines at lower doses. Two of us (T. T. G. and J. J. J.) and colleagues demonstrated the release of PGE2 and IL-1 from cultured macrophages in response to polymethylmethacrylate and titanium particles^29,30. Horowitz identified TNF-a as a primary mediator released by particle-activated macrophages⁴⁰. TNF-a stimulates osteoblasts to produce granulocyte-macrophage colony-stimulating factor and IL-6, both of which stimulate recruitment of additional macrophages, osteoclasts, and other inflammatory cells into the area. TNF-a was also found to stimulate the release of PGE2 by osteoblasts, which, in turn, activates osteoclastic bone resorbtion⁴⁰. Nakashima et al. found increased monocyte/macrophage expression of C-C chemokines, which primarily function as chemoattractants, in response to polymethylmethacrylate and titanium-alloy particles⁴¹. Pollice et al. used an in vitro rat osteoclast precursor model to investigate the role of activated macrophages in bone resorption⁴². They found that bone resorption was mediated, in part, by factors secreted by osteoblasts responding to activated macrophages.

Fibroblasts have been studied in cell culture as well. Maloney et al. exposed cultured bovine synovial fibroblasts to particulate metallic debris⁴³. The effects of the metallic particles on the synthesis and secretion of proteolytic enzymes and on cell proliferation and viability were examined. At high concentrations of particles, all particles were toxic and caused a decrease in proteolytic and collagenolytic activity. Titanium elevated the level of lysosomal enzyme hexosaminidase except at high concentrations. Scanning electron microscopy demonstrated that the morphological response was typical of active fibroblasts⁴³. In a study by Yao et al., synovial fibroblasts and fibroblasts that had been isolated from interfacial membranes of patients with a failed total hip replacement were challenged with titanium particles³⁸. Both types of fibroblasts responded with elevated expressions of collagenase, stromelysin, and, to a much lesser extent, the tissue inhibitor of metalloproteinases (TIMP)³⁸. Manlapaz et al. demonstrated that introduction of titanium-alloy particles resulted in direct activation of fibroblasts and release of proinflammatory mediators (IL-6 and PGE2) and fibroblast growth factor⁴⁴. In addition, collagenase activity increased.

Ongoing work in the area of cellular signal transduction pathways has begun to elucidate the basic molecular mechanisms by which particles induce cellular (osteoblast, osteoclast, macrophage, and fibroblast) response. A recent study showed upregulation of TNF-a and IL-6 expression in macrophages in the absence of phagocytosis, suggesting that cell membrane-particle interactions are sufficient to initiate macrophage activation^45,46. The nuclear transcription factors nuclear factor-kappa B (NF-kB) and nuclear factor-interleukin-6 (NF-IL-6) are key upstream intermediaries in this process⁴⁵. Other work has shown that the initial response of osteoblasts to particulate metallic debris includes phosphorylation of protein tyrosine kinase pathways and activation of NF-kB⁴⁶.

Normal bone maintenance relies on the balance of bone formation and bone resorption. While the above-mentioned investigations have, for the most part, focused on the bone-resorption limb of this cascade, more recent studies have examined the effect of particles on bone formation. Yao et al. found that both titanium and polystyrene particles smaller than three micrometers suppressed the expression of the genes that code for collagen type-I and type-III precursor molecules. The suppression of these genes was related to the size but not to the composition of the particles. The biosynthesis of both type-I and type-III collagen also was decreased in an osteoblastic cell-line that had been treated with titanium particles (Fig. 4)⁴⁷. Studies, from other laboratories, performed with use of a bone-chamber model have shown diminished bone ingrowth in the presence of particulate degradation products⁴⁸. The amount of bone ingrowth was greatest in the control specimens, moderately decreased in the presence of high-density-polyethylene particles, and greatly decreased in the presence of cobalt-chromium particles⁴⁸.

Tissue-Explant Studies

The histopathological features of the periprosthetic membrane have been studied extensively. Common findings in cases of aseptic loosening or osteolysis include a fibrous stroma, abundant macrophages, foreign-body giant cells, and wear debris (Fig. 5-A and Fig. 5-B)^20,36. As mentioned previously, the majority of particles are submicrometer in size and require electron microscopy for visualization and quantitation. Larger nonphagocytosable particles (more than thirty micrometers) generate a foreign-body reaction with surrounding giant cells. The quantity of macrophages and the presence of radiographic osteolysis have been associated with the amount of particulate debris⁸. Analysis of these membranes has demonstrated the presence of many biochemical mediators of inflammation, cellular recruitment, and bone resorption.

PGE2 was one of the first mediators to be identified in tissues surrounding loose implants. Many studies of this membrane have identified high levels of PGE2 capable of causing bone resorption²⁰. Goodman et al. demonstrated that the levels of PGE2 in the membranes of loose implants were significantly elevated compared with the levels in the membranes of implants that were not loose (p < 0.05)³⁶. Cila et al. found that the degree of prosthetic loosening was associated with significantly higher levels of periprosthetic PGE2 activity (p < 0.01)⁴⁹. Dorr et al. found no difference in the levels of IL-1, PGE2, and collagenase when periprosthetic membranes from failed titanium-alloy and cobalt-chromium-alloy components were compared³⁵. Kim et al. analyzed membranes from failed hip prostheses inserted without cement and found a histological appearance similar to that described for membranes from failed cemented implants²². They found biochemical mediators, including collagenase, IL-1, and PGE2, in these membranes as well. Chiba et al. studied interfacial tissues from failed cementless total hip replacements with and without femoral osteolysis and found a greater activity of IL-1, TNF-a, and IL-6 in hips with osteolysis than in those without osteolysis⁵⁰. Goodman et al., using immunohistochemistry and in situ hybridization techniques on periprosthetic membranes, demonstrated increased quantities of macrophages, T-lymphocyte subgroups, and IL-1 and IL-6 expression in osteolytic lesions around cemented implants⁵¹. In the vicinity of cementless implants, osteolysis was associated with elevated levels of T-lymphocyte subgroups and TNF-a, suggesting different biological mechanisms of loosening for cemented and cementless implants. Jiranek et al. used in situ hybridization techniques to identify the cellular components of the periprosthetic membrane²³. Those authors demonstrated that the membrane consists predominantly of macrophages, fibroblasts, and, less commonly, T-lymphocytes (less than 10 percent). Nucleic acid probes used in that same study demonstrated IL-1b mRNA to be expressed primarily in macrophages. IL-1b protein was identified on both macrophages and fibroblasts, suggesting that the protein was bound by both cell types but was secreted predominantly by macrophages. Platelet-derived growth-factor transcripts were found in both macrophages and fibroblasts²³.

Other species identified in periprosthetic tissues from loose implants include matrix metalloproteinases (MMPs) that act to degrade the extracellular matrix. In a study of the membranes from failed cementless total hip replacements, Vidovszky et al. compared tissue from osteolytic regions with that from nonosteolytic regions and found that the expression of collagenase, gelatinase, and stromelysin (MMP-1, MMP-2, and MMP-11) was elevated in the membranes from the osteolytic regions⁵². Takagi et al. demonstrated elevated production of MMP-2 and induction of MMP-9 in tissue extracts from both the interface tissues between bone and implants and the pseudocapsular tissues around loose implants⁵³. Ishiguro et al. found elevated expression of MMPs and tissue inhibitors of metalloproteinase from tissues around loose cemented total hip replacements⁵⁴. Other substances recently identified in tissue-explant studies include mesenchymal collagenase⁵⁵, elastase⁵⁶, cathepsin G⁵⁷, nitrous oxide synthase mRNA⁵⁸, and C-C chemokines (chemoattractants)⁴¹.

Analysis of synovial fluid from patients with a loose hip prosthesis has demonstrated the presence of similar chemical mediators. Sabokbar and Rushton found elevation in the levels of PGE2, IL-6, IL-8, and multiple adhesion molecules in the synovial fluid around loose implants compared with the levels in the synovial fluid around controls⁵⁹. Kim et al. found elevation in the levels of IL-6, soluble IL-6 receptor (sIL-6R), and tartrate-resistant acid phosphatase (TRAP) in joint fluid from failed total hip replacements⁶⁰. They also demonstrated that, compared with controls, this joint fluid was able to significantly stimulate osteoclastic bone resorption on dentin slices (p < 0.05).

Bone-resorbing cytokines and other factors have also been studied in the serum of patients with aseptic loosening of a total hip replacement. Granchi et al. found an elevation in the level of serum granulocyte-macrophage colony-stimulating factor, while the levels of IL-6 and TNF-a were not significantly elevated⁶¹. Serum IL-1b levels were found to be higher in patients who had a titanium-aluminum-vanadium cemented prosthesis.

Animal Studies

The use of animal models has allowed researchers to perform well controlled studies, with standardized models, to elucidate the complex biological response of both bone and soft tissues to particles. When implanted in bulk form, medical polymers and metals are surrounded by an incomplete fibrous-tissue layer⁶². When implanted in particle form, these same materials induce an inflammatory reaction, including the infiltration of macrophages, foreign-body giant cells, and fibrous tissue similar to that seen around loose implants^26,62.

Animal models of osteolysis have been developed as well. Howie et al. demonstrated osteolysis after injection of polyethylene particles around an acrylic plug placed in the femora of rats⁶³. Spector et al. developed a canine model of aseptic loosening by loosely implanting a femoral component into a bed of preinserted cement particles⁶⁴. They isolated and cultured periprosthetic cells from these animals and found an elevated secretion of IL-1 and PGE2. The secretion of these mediators paralleled the radiographic appearance of loosening. The PGE2 response was partially suppressed by in vitro administration of naproxen⁶⁴. Goodman et al. used New Zealand rabbits to demonstrate the process of aseptic loosening of a poorly cemented tibial hemiprosthesis⁶⁵. Subsequent tissue-culture supernatants from this model demonstrated elevated PGE2 levels in association with loose implants. Gelb et al. used a subcutaneous air-pouch rat model to quantitatively demonstrate the in vivo effects of the size, morphology, and surface area of polymethylmethacrylate particles on the acute inflammatory response²⁴. Kubo et al. evaluated the response to a variety of particles (ultra-high molecular weight polyethylene, cobalt-chromium, alumina ceramics, stainless steel, and titanium-aluminum-vanadium) of differing sizes by inserting a polymethylmethacrylate plug with a groove for particle placement into rabbit femora³¹. They found a marked histiocytic response around particles of ultra-high molecular weight polyethylene (eleven micrometers), stainless steel (3.9 micrometers), and cobalt-chromium (3.9 micrometers). A less intense histiocytic response was found surrounding particles of alumina ceramics and titanium (3.9 micrometers for each)³¹.

Turner et al. reported on aseptic loosening of cemented total hip prostheses in a canine model⁶⁶. They found thick fibrous and granulomatous membranes at the failed cement-bone interface with sheets of histiocytes and occasional foreign-body giant cells. They identified granulomatous cortical erosions with evidence of particulate debris. Dowd et al. also used an in vivo canine hip-arthroplasty model to study the effects of motion and particles⁶⁷. The prosthesis was designed with a reservoir for particles. In addition, a midshaft ball-joint allowed motion between the proximal and distal portions of the prosthesis. The histological and biochemical characteristics of the experimentally induced membranes were similar to those of tissues retrieved at revision surgery⁶⁷. This model has been implemented in other investigations⁶⁸. Merkel et al. recently used a murine model to investigate the in vivo response to particles⁶⁹. The model involved subperiosteal exposure of the cranium with placement of particles directly on the surface of the bone. With use of this model, they investigated genetically engineered mice that were deficient in TNF-a receptors and found that these mice were protected from the particle-induced bone resorption seen in wild mice⁶⁹.

Pharmacological Intervention in Particulate-Induced Bone Resorption

The goal in gaining a better understanding of the mechanism of osteolysis is to reduce wear-related complications after joint arthroplasty. Investigators are approaching this goal with efforts both to reduce particle generation and to inhibit the biological response to particulate debris. Currently, intensive research and development activities are directed toward reducing the production of particulate debris by polyethylene bearing materials and so-called hard-on-hard bearings. As these activities are beyond the scope of this review, we present a summary of the preliminary in vitro and animal studies directed at the pharmacological modification of the adverse host response to particulate debris.

Horowitz et al., in a rat calvaria/macrophage co-culture model, studied the effects of indomethacin, anti-TNF-a antibody, and disodium pamidronate on bone resorption induced by macrophages exposed to bone-cement particles⁷⁰. They found that indomethacin inhibited the production of PGE2 but not the release of TNF-a or calcium. Anti-TNF antibodies neutralized the presence of TNF to undetectable levels but did not affect release of PGE2 or calcium. In contrast, the addition of disodium pamidronate was effective in inhibiting the release of calcium, indicating decreased bone resorption⁷⁰. Haynes et al. treated macrophages with drugs that prevent a decrease in pH within phagosomes⁷¹. This treatment significantly reduced the toxicity of cobalt-chromium particles (p < 0.05) and reduced the levels of PGE2 and IL-6 release induced by titanium particles (p < 0.005). Two of us (T. T. G. and J. J. J.) and colleagues demonstrated a partial inhibitory effect of indomethacin and misoprostol on the bone resorption activity of cultured cells from the interfacial membranes of failed total hip replacements⁷². Shanbhag et al. used a canine total-hip replacement model to study the efficacy of an oral bisphosphonate for inhibition of wear-debris-mediated bone resorption⁶⁸. They demonstrated a reduction in the frequency of radiographic periprosthetic radiolucencies, while the levels of PGE2 and IL-1 remained elevated in cultures of tissue from the sites of these implants. Blaine et al. found that cAMP agonists inhibited the release of TNF-a by titanium-stimulated peripheral monocytes, while cAMP antagonists enhanced the production of TNF-a³². Dobai et al. demonstrated suppressed collagen gene expression and diminished collagen synthesis induced by particulate debris in bone-marrow-derived osteoblasts⁷³. It was found that these effects were reversed by pretreatment of the osteoblasts with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Clearly, human trials are needed before any of these potential pharmacological treatments are recommended for clinical use.

Other Possible Factors in the Etiology of Osteolysis

Recently, the role of elevated intra-articular pressure in the development of osteolysis has been studied⁷⁴. Computer simulations and direct measurements have demonstrated fluid pressures in the hip or knee to be elevated to as high as 700 millimeters of mercury with activity. Van der Vis et al. found that a pressure of 200 millimeters of mercury applied for two weeks in a rabbit bone-chamber model caused massive bone resorption under the pressurized area⁷⁵. The histological findings were similar to those in areas of periprosthetic osteolysis, with large quantities of macrophages. With fluctuating pressures (between fifty and 150 millimeters of mercury), bone resorption was also present but to a lesser degree⁷⁶. Histologically, bone resorption was preceded by osteocyte death. Van der Vis et al., using a similar rabbit model, found that compression of a fibrous membrane interposed between bone and a prosthesis can lead to resorption of the underlying bone primarily because of osteocyte death and subsequent resorption of dead bone tissue⁷⁷. They thought that this finding might explain the observation that early migration of a hip or knee prosthesis is predictive of clinical loosening of the prosthesis.

Aspenberg and Herbertsson used a rat model to determine the role of motion in periprosthetic bone resorption⁷⁸. A titanium plug was inserted through a plate into a milled depression in the cortex. After use of motion of the flat titanium surface and/or application of particles to the milled depression, they concluded that mechanical stimuli were of primary importance in prosthetic loosening and that particles may modulate the later stages of the process.

The role of hypersensitivity in periprosthetic osteolysis has yet to be established. Evans was one of the first to suggest that metal sensitivity may contribute to aseptic loosening⁷⁹. He found that nine of fourteen patients with loose metal-on-metal implants demonstrated cutaneous sensitivity to one or more of the components of the alloys. In subsequent studies, however, metal hypersensitivity was not found to be associated with loosening^80,81. Gil-Albarova et al. investigated lymphocyte-mediated immune response to polymethylmethacrylate in patients with a failed cemented total hip replacement⁸². Patch tests of reactivity to polymethylmethacrylate were positive in 50 percent (thirteen) of twenty-six patients. However, they found no difference in patch-test reactivity between patients who had a granulomatous loosening pattern and those who had a nongranulomatous loosening pattern. Wooley et al. studied in vitro cellular immune responses to particulate cobalt-chromium alloy and polymethylmethacrylate in patients before and after total joint replacement⁸³. They found an elevated proliferative cellular response to polymethylmethacrylate and metallic particles in patients examined before revision surgery and in those evaluated after a primary joint replacement. These immune responses were more marked in patients with aseptic loosening and were diminished following revision for loosening. They concluded that specific cellular responses to polymethylmethacrylate and/or cobalt-chromium-alloy particles may be associated with loose or painful prostheses.

Santavirta et al. cultured peripheral blood mononuclear cells with polymethylmethacrylate particles and found induction of inflammatory mononuclear cell migration and adhesion leading to a nonspecific lymphocyte reaction⁸⁴. They concluded that polymethylmethacrylate is essentially immunologically inert. In a subsequent study, they used a human lymphocyte culture protocol to identify the biocompatibility of ultra-high molecular weight polyethylene particles⁸⁵. Polyethylene did not cause an increase in lymphocyte DNA synthesis and did not stimulate the expression of major histocompatibility complex class-II antigen or IL-2 receptor CD25. Santavirta et al. concluded that ultra-high molecular weight polyethylene, while inducing a foreign-body reaction, was relatively immunologically inert. Jiranek et al. examined the response induced by injections of particulate polymethylmethacrylate into four strains of mice, one of which was immunocompetent and three of which had different levels of lymphocyte dysfunction⁸⁶. The granulomas were similar among the strains, with a paucity or absence of lymphoid cells. They concluded that, in mice, there is a lymphocyte-independent pathway of macrophage activation in response to particles⁸⁶. Overall, findings reported in the literature conflict with regard to the role of specific immune responses in association with aseptic loosening and osteolysis. Clearly, additional work in this area is needed.

Overview

Despite improvements in the techniques, materials, and fixation of total joint replacements, wear and its sequelae continue to be the main factors limiting the longevity and clinical success of arthroplasty. Since Charnley first recognized aseptic loosening in the early 1960s⁸⁷, we have gained a tremendous amount of information on the basic science of osteolysis. Tissue-explant, animal, and cell-culture studies have allowed us to develop an appreciation of the complexity of cellular interactions and chemical mediators involved in these processes. Cellular participants have been shown to include the macrophage, osteoblast, fibroblast, and osteoclast. The plethora of chemical mediators that are responsible for the cellular interactions and effects on bone primarily include PGE2, TNF-a, IL-1, and IL-6. Recent and ongoing work in the field of signaling pathways will continue to advance our understanding of the mechanisms of periprosthetic bone loss. While initial animal studies are promising for the development of possible pharmacological agents for the treatment and prevention of osteolysis, well controlled human trials are required.

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