There is compelling evidence that the most important factor in late periprosthetic bone resorption is an inflammatory reaction to debris. Based on results from several laboratories, it seems likely that opsonized particles activate the macrophage nuclear factor-kappa B signal transduction system via membrane receptors, leading to release of tumor necrosis factor-alpha and other cytokines and growth factors. Tumor necrosis factor stimulates osteoblasts to release cytokines that recruit inflammatory cells and osteoclast precursors to the site and promote the differentiation of early osteoclasts. Tumor necrosis factor influences fibroblasts to release tissue metalloproteinases, and induces c-src in osteoclast precursors, the expression of which is necessary for additional bone resorption. Phagocytosis of debris by osteoblasts may reduce collagen synthesis, whereas phagocytosis by fibroblasts may induce chemokines that amplify inflammation. Bone has been partially protected from particle-induced resorption in animals with defective or inhibited tumor necrosis factor or nuclear factor-kappa B signaling. Many aspects of this inflammatory reaction require clarification, including identifying the factors that influence variability among patients, and testing the importance of costimulatory molecules such as bacterial endotoxin, but the fundamental importance of particles in most cases of aseptic loosening seems certain.
