Inflammatory bone loss in joint replacements: The mechanisms

June 1, 2010

More than 1 million total joint arthroplasties (TJAs) are performed in the United States each year, and much higher demand is projected. Most TJAs are successful, but aseptic loosening of implants remains a problem that limits long-term success. Aseptic osteolysis, an inflammatory reaction, occurs in up to 10% of patients at 10 years postsurgery.

Total joint implants remain one of the miracles of modern medicine, returning mobility and quality of life to millions of persons every year. More than 1 million total joint arthroplasties (TJAs) are performed in the United States each year, and much higher demand is projected with the aging of the baby boomer generation.1,2 Although most TJAs are successful by any outcome measure initially, aseptic loosening of implants remains a problem that limits long-term success. 2,3


mplant performance varies with the type and amount of degradation produced; all implant debris causes a local inflammatory response that eventually results in bone loss and loss of implant fixation.4 This kind of inflammatory reaction-aseptic osteolysis-occurs in up to 10% of patients at 10 years postsurgery, with marked bone loss around the implant, resulting in pain, premature loosening, and revision.5-7 Aseptic osteolysis generally refers to bone loss around an implant that is observable radiographically (Figure 1).

Knowledge of implant debris–induced inflammation and resulting osteolysis has improved over the years, and advances have been made in understanding the inflammatory bone loss at the molecular and cellular levels. Treatment options, ranging from testing preexisting conditions of metal allergy to general management of inflammation to selective blocking of cellular mediators for hindering of implant debris–induced osteolysis promise to help mitigate the problem of bone loss.

In this 2-part article, we offer current insights into inflammatory bone loss in joint replacements. This first part describes the intracellular mechanisms involved in implant debris–induced osteolysis and new avenues for pharmacological treatment. The second part, to appear in an upcoming issue of this journal, will elaborate on the osteoimmunological science.

Innate immune response
by macrophages

Inflammatory osteolysis has been attributed to an innate immune response by macrophages to implant-generated debris (polymer and metal particles) from implant wear and corrosion. Implant loosening resulting from aseptic osteolysis accounts for more than 75% of joint arthroplasty failures and is the limiting factor in long-term implant performance, but there are additional reasons for long-term implant failure (Table 1).8

Properly positioned implants wear predictably. However, the amount of debris-induced bone loss varies from person to person, even if persons have similar rates of implant wear (implant debris). In fact, some persons with severely worn components may demonstrate little inflammation and periprosthetic bone loss while others with modest amounts of wear may demonstrate extensive osteolysis and implant loosening.

Rates of debris-induced immune reactivity with ensuing aseptic inflammation and subsequent early failure may be as high as 4% to 5% at 6 to 7 years postsurgery in some designs of current-generation metal-on-metal total hip arthroplasties (THAs).9-11 Both particulate and soluble ionic debris induce innate immune system activation, primarily via monocyte or macrophage

activation,12-18 that up-regulates the transcription factor nuclear factor κB (NFκB) and releases proinflammatory cytokines interleukin (IL)-1b, tumor necrosis factor a (TNF-α), IL-6, αnd IL-8 (Table 2) (Figure 2).12,16,19,20 However, the way that particles and metal ions initiate these proinflammatory responses and which types of implant debris are most reactive is unclear.

The primary goal of the immune system is to protect against harmful pathogens. However, pathogen protection also causes reactivity to implant debris. Both pathogen protection and unwanted reactivity to implant debris are controlled by the sequential activation of innate and adaptive immune systems. The adaptive immune system generally involves production of a very large repertoire of antigen-specific cells; an innate immune response is less antigen-specific, occurs more quickly, and provides the essential signals for adaptive system activation.

Metal sensitivity
Immune reactivity to implant debris has been attributed primarily to innate immune responses, in particular macrophage-induced inflammation. However, a subset of patients experience exuberant adaptive immune system (lymphocyte)–mediated responses to implant debris, in particular, metals.

This so-called metal hypersensitivity to implant materials may be the result of a preexisting condition or may be acquired by having an implant.21 Metal released from implants may form complexes with native proteins that act as antigens. Metals recognized as sensitizers include beryllium, nickel, cobalt, and chromium; occasional responses to tantalum, titanium, and vanadium have been reported. Nickel is the most common metal sensitizer in humans, followed by cobalt and chromium. The temporal and physical evidence associated with the symptoms of type IV allergic responses (including severe dermatitis, urticaria, and vasculitis) to the implantation of orthopedic devices are severe enough to necessitate revision arthroplasty in what is speculated to be about 1% of patients.

Evaluation for metal sensitivity includes skin testing (so-called patch testing or intradermal testing) and in vitro by lymphocyte transformation testing (LTT). Although general patch testing protocols and commercial kits are available for a variety of commonly antigenic substances,22,23 there is continuing concern about sensitizing patients with patch testing24 and about the questionable use of dermal Langerhans cells as accurate diagnostic proxies of peri-implant antigen-presenting cells.25,26 Metal-LTT, or lymphocyte proliferation testing, involves measuring the proliferative response of lymphocytes obtained from peripheral blood by routine blood draw.

Studies that used both of these testing methods found the incidence of metal sensitivity among patients who have metal-containing total joint replacement (TJR) implants to be about 25% (roughly twice as high as that in the general population) and the average incidence of metal sensitivity among patients who have a “failed” implant (in need of revision surgery) to be about 50% to 60%.27-29 These findings indicate that the adaptive immune system may be involved to a much larger degree in debris-induced inflammation than what previously was attributed to the innate immune system via macrophage reactivity.

Causality between implant outcome and level of immune system reactivity to metals has not been well established in the general population. Thus, prescreening all TJA recipients without a history or specific concern about metal allergy is not yet scientifically supported.

Bone remodeling imbalance
Debris-generated inflammatory responses lead directly or indirectly to an imbalance in the rate of bone remodeling (deposition and resorption); osteoclast (bone resorbing cells) activity eventually becomes more prominent, leading to bone loss and loosening of the implant. How does this occur? Macrophages exposed to implant debris particles (of polymer, ceramic, and metal origin) secrete proinflammatory cytokines that activate osteoclast precursor cells as well as mature osteoclasts, aggravating bone destruction and implant loosening (aseptic loosening), with granulomatous tissue invading the bone-implant interface (see Figure 1).

Although understanding of the intracellular mechanisms involved in implant debris–induced osteolysis remains incomplete, much progress has been made in understanding the osteoimmunological science leading to new avenues for pharmacological treatment. Specific intracellular pathways (including particle-induced activation of NFκB and activation of kinase pathways, such as p38, mitogen-activated protein kinases, extracellular signal-regulated kinases, and c-Jun amino-terminal kinases) have been implicated as mediators of implant debris–induced inflammatory cytokines, such as IL-1, TNF-α, and IL-6 (see Figure 2).30,31

Some new pathways, such as the inflammasome danger-signaling pathway, have been identified as possible “danger sensors” that transduce phagocytosis of seemingly benign sterile implant debris into macrophage production of potent cytokines, such as IL-1β.32 However, the immune cell kinetics of implant debris detection and recognition of broad cellular inflammatory response is still incompletely understood.

There is increasing evidence that elevated metal ion concentrations found locally and systemically have the potential to induce toxic and genotoxic effects on peri-implant cells.9,10,33,34 New types of “alternative” bearings, such as metal-on-metal articulating components, have resulted in new types of biological responses, including lymphocyte-dominated granuloma-like lesions in bone (termed “ALVAL,” for aseptic lymphocyte vasculitis–associated lesion) found around some implants. There is evidence of the involvement of the adaptive immune system in tissue samples retrieved from failed arthroplasties where lymphocytic infiltrates have been found.35,36 This highlights the fact that both innate (macrophage) and adaptive (T lymphocyte) immune system reactivity to implant debris can produce inflammatory cytokines that negatively affect bone remodeling and limit the lifetime of current TJR implants.

Pinpointing a mechanism
is difficult

Pinpointing a specific protein, a cell, or even a cellular mechanism as singularly responsible for the complex process of implant debris–induced inflammatory bone loss is difficult. Earlier studies showed excessive quantities of implant-generated particles and metal ion concentrations in periprosthetic tissue retrieved from failed THAs; as much as 109 particles per gram of tissue and up to 2-mM concentrations of cobalt and chromium ions have been detected.9,37-39 In addition to the high concentrations of soluble and particulate wear debris found in the peri-implant environment, tissue retrieved from patients with aseptic loosening also shows sizable infiltrations of immune and other stromal cells, such as macrophages, fibroblasts, and T lymphocytes in the form of granulomas, necrotic lesions, and fibrous tissue.40-42

The evidence of excessive immune reactivity in the periprosthetic tissue is documented by protein analysis, where concentrations of proinflammatory markers (eg, monokine induced by γ-interferon 1, soluble intercellular adhesion molecule 1, TNF-α, IL-1, IL-6, IL-8, and IL-10) are elevated compared with control samples.43 Elevated immune factors triggered by implant debris play an active role in the inflammatory and osteolytic process. In addition, longitudinal studies performed on cohorts of patients who had undergone TJAs, both with measurable periprosthetic osteolysis and without any observable osteolysis, demonstrated a close relationship between the amount of particulate wear debris found in tissue and the degree of bone resorption measured.2,44 These studies concluded that implant wear debris is the major cause of aseptic loosening of implants.

Understanding of the specific mechanisms by which implant wear triggers an inflammatory response remains incomplete. In addition, knowledge about the direct effects of debris-induced inflammation on other peri-implant cells (fibroblasts, osteoblasts, osteoclasts) and how they all contribute to osteolysis and loosening also remains incomplete. This is the subject of current investigation.

Debris produced from implants is minimized but is unavoidable and results in activation of the innate immune system and, sometimes, the adaptive immune system. The result is local inflammation that over time causes bone loss and implant loosening via aseptic osteolysis.


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