• Citer

Individualization of bisphosphonate therapy

par Body, Jean-Jacques
Editeur scientifique Piccart-Gebhart, Martine ;Wood, WC;Hung, MC;Solin, L;Cardoso, F
Référence Breast cancer management and molecular medicine: Towards tailored approaches, Springer, Berlin, Heidelberg, New-York, page (545-564)
Publication Publié, 2006

Partie d'ouvrage collectif

• Détails
• Contenu

Résumé :

According to the literature, 30-90% of patients with advanced cancer will develop skeletal metastases. Carcinomas of the breast (47-85%) and of the prostate (33-85%) are the tumors most commonly associated with bone metastases [31]. The skeleton is in fact the most common site of metastatic disease in breast cancer and the most common site of first distant relapse [21]. These patients have a longer survival after the diagnosis of bone metastases compared to patients with visceral metastases. Their median survival is usually beyond 20 months, and about 10% of them are still alive 5-10 years after the first diagnosis of skeletal dissemination [21]. Osteolytic bone disease is responsible for a considerable morbidity, and markedly decreases quality of life. The clinical consequences of cancer-mediated bone destruction are a source of misery for affected patients. Because of the long clinical course breast cancer may follow, morbidity due to tumor bone disease also makes major demands on resources for health-care provision. The term "skeletal-related events" (SREs) refers to the major complications of tumor bone disease, namely pathological fractures, need for radiotherapy, need for bone surgery, spinal-cord compression, and hypercalcemia. In addition to the complications of bone-marrow invasion, pain and functional disability occur in 45-95% of the cases [12, 31], whereas major complications will be observed in up to one-third of the patients whose first relapse is in bone [4, 21]. Hypercalcemia occurs in 10-15% of the cases and spinalcord compression in about 10%, and when long bones are invaded, fractures will occur in 10-20% of cases [3]. Pathological fractures are a dramatic consequence of tumor bone disease and they occur with a median onset of 11 months from the initial diagnosis of bone involvement [46]. Taken from data in placebo groups of randomized bisphosphonate trials, the mean skeletal morbidity rate (SMR; i.e., the mean number of SREs per year) varies between 2.2 and 4.0 [4, 8, 12, 21, 39, 46]. In a retrospective analysis of 859 patients at a single institution, it was shown that the frequency of SREs is dependent on the presence of other metastatic sites. As shown in Table 27.1, patients with bone metastases only have a much higher rate of SREs than patients with bone and visceral metastases (pleuropulmonary or liver). The frequency of SREs in patients with bone and soft-tissue metastases is intermediate [55]. That study also confirmed that survival from diagnosis of bone metastases was longest for patients with only bone metastases (median survival 24 months) and was least for patients with concomitant bone and liver metastases (median survival 5.5 months) [55]. (Table presented) The osteotropism associated with breast cancer remains incompletely understood. Various properties of cancer cells, such as the production of proteolytic enzymes and specific cell-adhesion molecules, can enhance their metastatic potential. More specifically, deposits into the skeleton can be due to the attraction of tumor cells by chemotactic factors released as a result of the normal remodeling of bone matrix. These factors include fragments of type I collagen and of osteocalcin, and several growth factors [5, 63]. The propensity of breast cancer cells to proliferate in bone is best explained by the "seed and soil" concept [43]. Breast cancer cells (the "seed") appear to secrete factors, such as parathyroid-hormone-related protein (PTHrP), potentiating the development of metastases in the skeleton, which constitutes a fertile "soil" that is rich in cytokines and growth factors, which stimulate the growth of breast cancer cells. Local production of PTHrP and of other osteolytic factors by cancer cells in bone stimulate osteoclastic bone resorption, essentially through the osteoblasts and probably also through the immune cells. Such factors induce osteoclast differentiation from hematopoietic stem cells and could also activate the mature osteoclasts already present in bone. PTHrP also alters the ratio between osteoprotegerin (OPG), the production of which is decreased, and receptor activator for Nf?B (RANK) ligand, the production of which is increased [38]. The net result of this imbalance in these key regulatory factors of osteoclast-mediated bone resorption is an increase in osteoclast proliferation and activity. Increased osteoclast number and activity then cause local foci of osteolysis, an enhanced release of growth factors, and a further stimulation of cancer cell proliferation [43, 64]. Bisphosphonates localize preferentially to sites of active bone remodeling. They act directly on mature osteoclasts, decreasing their bone resorption activity, notably by lowering H+ and Ca++ extrusion and modifying the activity of various enzymes [78]. However, the current view is that bisphosphonates essentially act by inducing osteoclast apoptosis. Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for macrophages and for osteoclasts. On the other hand, nitrogen-containing bisphosphonates, but not clodronate, in terfere with the mevalonate pathway, which is essential for the maintenance of cell membrane integrity. Aminobisphosphonates, such as pamidronate, zoledronate, or ibandronate, are nanomolar inhibitors of farnesyl-pyrophosphate synthase. This leads to an inhibition of posttranslational prenylation of proteins with farnesyl or geranylgeranyl isoprenoid groups. Various cellular proteins have to be anchored to the cell membrane by a prenyl group to become active. Most of these proteins are GTP-binding proteins, including the protein ras, and prenylated proteins are essential for osteoclast function, notably cell activity and attachment [49]. The net result, regardless of the mechanism (clodronate vs aminobisphosphonates), is osteoclast apoptosis, notably through the induction of caspase-3. It has also been found that bisphosphonates can directly inhibit the growth of breast cancer cells by a combination of necrotic and apoptotic processes, and inhibit the stimulatory effects of bonederived growth factors [29, 30]. The relevance of these in vitro observations to the clinical beneficial effects of bisphosphonates remains, however, to be demonstrated. The indications of bisphosphonate therapy, adapted to the individual patient, are reviewed in the following sections, from the correction of cancer hypercalcemia to the prevention of cancer-treatment-induced bone loss. © Springer-Verlag Berlin Heidelberg 2006.