Osteolysis

Abstract: Background: Some patients who have a total hip replacement with a second-generation metal-on-metal articulation have persistent or early recurrence of preoperative symptoms. Characteristic histological changes in the periprosthetic tissues suggested the development of an immunological response. Therefore, in order to determine the relevance of these symptoms, we performed a study of the clinical data and periprosthetic tissues associated with endoprostheses with a metal-on metal articulation that had been retrieved at revision. Methods: Periprosthetic tissues as well as the clinical data on the patients were obtained from the first nineteen consecutive revisions performed at the treating hospitals. At the time of the revision, fourteen patients had the metal-on-metal articulation exchanged for either an alumina-ceramic or a metal-on-polyethylene articulation. Five patients received another second-generation metal-on-metal total joint replacement. Five-micrometer sections were prepared from the tissue samples, were stained with routine and immunohistochemical methods, and were examined histologically. Histological specimens from three groups of patients, two of which were treated with non-metal-on-metal implants, served as controls. Results: The majority of patients had persistence of their preoperative pain or early recurrence of the pain after the original total hip replacement, and often a pronounced hip joint effusion had developed after the original replacement. Radiographic follow-up showed the development of radiolucent lines in five hips and of osteolysis in another seven hips. At the revision surgery, both the cup and the stem were found to be well fixed in nine patients. The characteristic histological features were diffuse and perivascular infiltrates of T and B lymphocytes and plasma cells, high endothelial venules, massive fibrin exudation, accumulation of macrophages with droplike inclusions, and infiltrates of eosinophilic granulocytes and necrosis. Only a few metal particles were detected. Immunohistochemical analysis demonstrated that the cellular reaction was still active. The patients who received another second-generation metal-on-metal articulation at the time of the revision had no decrease in symptoms. In the control group of tissues obtained at revisions of endoprostheses without cobalt, chromium, or nickel articulations, there were no similar signs of immune reactions. Conclusions: These histological findings support the possibility of a lymphocyte-dominated immunological response. Although the prevalence of this reaction is low, the persistence or early reappearance of symptoms, including a marked joint effusion and the development of osteolysis, after primary implantation may suggest the possibility of such a reaction.

Abstract: BACKGROUND Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. METHODS This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts. RESULTS Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases. CONCLUSIONS Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear. Cancer 2000;88:2961–78. © 2000 American Cancer Society.

Abstract: Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC(50) values 4.1, 4.2, and 6.9 microM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED(50), 3 microg/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component.