Joint destruction from various pathologies, most notably rheumatoid arthritis (RA) and osteoarthritis, leads many individuals to elect total joint replacement. Worldwide, more than 1.3 million total joint arthroplasties are performed each year [
1]. This number can be expected to increase dramatically in the 21st century. While total joint replacement is remarkably effective in relieving pain and improving function and mobility, it it not without complications. Up to 20% of patients so treated will show evidence of osteolysis within 10 years [
2,
3,
4]. This osteolysis usually leads to implant failure and need for revision arthroplasty, which has a poorer clinical result and a shorter duration of survival than primary total joint replacement [
5,
6]. Because of such failures, many younger people who would otherwise be excellent candidates for surgery are told to wait, because they might need two or three revisions in their lifetime. Therefore, a clinical intervention to prevent prosthetic implant loosening is greatly needed.
Prosthesis failure results from multiple factors, including those relating to materials, biomechanics, and host responses. The quest for more durable and wear-resistant materials, as well as for better implant designs, and the study of the forces involved in implant integration and prosthesis failure continue to be areas of active investigation. Several groups, however, have focused on the host response to debris produced by wearing of the joint, postulating that wear-debris-induced osteolysis in the main cause of failure of prosthetic implants [
7]. In this model, wear debris generated from the prosthesis is phagocytosed by macrophages and initiates an inflammatory response that leads to the recruitment of activated osteoclasts and to osteolysis at the bone-implant interface. Several lines of evidence support this model. First, as many as 10
9 particles per gram of tissue can be recovered from the inflamed membrane attached to the failed prosthesis after revision surgery [
8]. Second, ingestion of wear-debris particles induces cytokine production by mononuclear phagocytes
in vitro [
9]. Third, high concentrations of cytokines, including TNF-α, that are produced by macrophages are found in the fluid and tissue surrounding loose implants [
10,
11,
12]. Fourth, conditioned medium from monocytes stimulated by wear debris can stimulate increased bone resorption
in vitro [
13]. Fifth, animal models of wear-debris-induced osteolysis have demonstrated the importance of cytokines in this process [
14,
15].
This wear-debris-induced osteolysis, which is associated with aseptic loosening, is very different from the phenomenon of stress shielding. In stress shielding, an implant takes on a portion of the mechanical load transmitted to the skeleton and shields bone from this stress [
16,
17,
18]. Since bone metabolism is dependent upon mechanical load, bone density decreases in the affected area. Stress shielding is different in several ways from the inflammatory bone loss that occurs in response to particulate debris. First, stress shielding occurs in the absence of inflammation [
18]. Second, it occurs around implants (such as rods, plates and screws) that do not release particles [
19]. Third, it is not influenced by polyethylene or the bearing surface, but is reduced by using implants that have a lower modulus of elasticity so that bone takes on more of the mechanical load [
16,
17]. Fourth, like disuse osteopenia or osteoporosis, stress shielding increases the general porosity of bone, whereas aseptic loosening is associated with localized endosteal bone erosions [
20]. Fifth, and most importantly, stress shielding has not been associated with mechanical loosening of the implant [
17,
18,
21,
22].
The first clinical manifestation of prosthesis failure is pain with associated radiographic evidence of osteolysis (Fig. ). If the volume of osteolysis is small (up to 2 mm in diameter), osteolysis often does not progress and the implant remains fixed. However, when the lesion is greater than 2 mm, osteolysis usually continues rapidly, leading to implant failure. In these lesions, bone is resorbed by osteoclasts and is replaced by a fibro-inflammatory membrane containing lymphocytes, macrophages, and fibroblasts (Fig. ) [
7]. Although the histopathology and initiating mechanisms differ from those for RA, the tissue reaction in peri-implant osteolysis resembles the pannus of RA in its tendency to produce localized cytokine-mediated bone loss. Thus, a central aim in developing a therapeutic intervention for aseptic loosening is to identify a drug that will eliminate or dramatically reduce inflammation in the periprosthetic synovium-like membrane.
TNF-α has been identified as a drug target in aseptic loosening for many of the same reasons it has been a focus in RA. First, since addition of anti-TNF-α antibodies inhibits the production of other pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and GM-CSF (granulocyte-macrophage colony-stimulating factor) by synovial tissue, it has been proposed that this factor is at the apex of the pro- inflammatory cytokine cascade in the synovium [
23,
24,
25]. Another reason is that TNF-α can induce joint inflammation and proliferation of joint cells [
26]. Also, it can stimulate bone resorption by inducing osteoclastogenesis and activating mature osteoclasts [
27]. A fourth reason is that TNF receptor I knockout mice have virtually no osteolytic response to polymethylmethacrylate [
15] or titanium [
14]. And finally, in animal models, the TNF-α antagonist etanercept has been used to prevent wear-debris-induced osteolysis [
28,
29].
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