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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skeletal mass is maintained by a balance between cells which resorb bone (osteoclasts) and cells which form bone (osteoblasts). Bone development and growth is an on-going, life-long process. Bone is formed during embryonic life, grows rapidly through childhood, and peaks around 20 years of age (formation exceeds resorption). For humans the skeleton then enters a long period, approximately 40 years, when bone mass remains relatively stable. Skeletal turnover continues but the net effect of resorption and formation on bone mass is zero. For women this ends when they enter menopause and similar bone loss occurs for men, but later in life. These opposite functions are coupled, resorption precedes formation, and osteoblasts, or their precursors, stromal cells, regulate osteoclast formation and activity. Until recently, the molecular nature of this regulation, was poorly understood. However, recent observations have identified members of the TNF family of ligands and receptors as critical regulators of osteoclastogenesis. Osteoprotegerin (OPG) a decoy receptor was first identified. Its ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), was quickly found, and shown to be expressed on stromal cells and osteoblasts. Its cognate receptor, RANK, was found to be expressed in high levels on osteoclast precursors. The interaction between RANKL and RANK was shown to be required for osteoclast formation. These observations have provided a molecular understanding of the coupling between osteoclastic bone resorption and osteoblastic bone formation. Moreover, they provide a framework on which to base a clear understanding of normal (e.g. postmenopausal osteoporosis and age associated bone loss) and pathologic skeletal changes (e.g. osteopetrosis, glucocorticoid-induced osteoporosis, periodontal disease, bone metastases, Paget's disease, hyperparathyroidism, and rheumatoid arthritis).
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PMID:Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. 1131 14

Paget's disease and bone metastases in cancer patients share many common properties. Both are characterized by a localized increase in osteoclast (OCL) formation leading to bone resorption. In both Paget's disease and bone metastases the increased OCL formation and the increased osteoclastogenic nature of the bone microenvironment are mediated by common factors, namely interleukin (IL)-6 and RANK ligand (RANKL). Available data suggest that in the case of Paget's disease there is increased RANKL and IL-6 production, and IL-6 enhances the responsivity of the OCL precursors to RANKL, contributing to the elevated numbers of OCLs. In patients with multiple myeloma, 95% to 100% of whom develop bone lesions, both IL-6 and RANKL levels are increased. Bisphosphonates bind locally to the surfaces of the bone undergoing osteoclastic resorption to inhibit this process. Paget's disease has in the past and will continue in the future to provide a model to test the efficacy of bisphosphonates in inhibiting bone resorption. Paget's disease provides an ideal model in which to investigate the efficacy of the new third-generation bisphosphonates in the treatment of bone metastases as well as nonmalignant bone disease.
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PMID:Studies in Paget's disease and their relevance to oncology. 1154 71

Metastasis of prostate cancer to bone is a common complication of progressive prostate cancer. Skeletal metastases are often associated with severe pain and thus demand therapeutic interventions. Although often characterized as osteoblastic, prostate cancer skeletal metastases usually have an underlying osteoclastic component. Advances in osteoclast biology and pathophysiology have led toward defining putative therapeutic targets to attack tumor-induced osteolysis. Several factors have been found to be important in tumor-induced promotion of osteoclast activity. One key factor is the protein receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclastogenesis. RANKL is produced by prostate cancer bone metastases, enabling these metastases to induce osteolysis through osteoclast activation. Another factor, osteoprotegerin, is a soluble decoy receptor for RANKL and inhibits RANKL-induced osteoclastogenesis. Osteoprotegerin has been shown in murine models to inhibit tumor-induced osteolysis. In addition to RANKL, parathyroid hormone-related protein and interleukin-6 are produced by prostate cancer cells and can promote osteoclastogenesis. Finally, matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of the nonmineralized bone matrix. MMP inhibitors have been shown to diminish tumor establishment in bone in murine models. Thus, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The importance of osteoclasts in the establishment and progression of skeletal metastases has led to clinical evaluation of therapeutic agents to target them for slowing metastatic progression. Bisphosphonates are a class of compounds that decrease osteoclast life span by promoting their apoptosis. The bisphosphonate pamidronate has proven clinical efficacy for relieving bone pain associated with breast cancer metastases and has a promising outlook for prostate cancer metastases. Another bisphosphonate, zoledronic acid, appears to directly target prostate cancer cells in addition to diminishing osteoclast activity at the metastatic site. In addition to bisphosphonates, other novel therapies based on studies that delineate mechanisms of skeletal metastases establishment and progression will be developed in the near future.
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PMID:The role of osteoclastic activity in prostate cancer skeletal metastases. 1253 87

Standard management of breast cancer metastatic to bone includes systemic chemotherapy and, if applicable, hormone therapy, as well as radiotherapy for control of pain or prevention of pathologic fractures. In addition, orthopedic surgical procedures are used to prevent or correct pathologic fractures in weight-bearing areas of the osseous skeleton. Inhibitors of osteoclast function, including bisphosphonates and gallium nitrate, have been shown in clinical trials to decrease bone-related complications. Consequently, bisphosphonates have become an integral part of the management of bone metastases from breast cancer. Improved understanding of the biology of osteoclastogenesis led to the identification of osteoprotegerin as a critical modulator of osteoclast activity. The clinical evaluation of several osteoprotegerin preparations has shown therapeutic effects as measured by significant reductions in biochemical markers of bone resorption. Monoclonal antibodies to RANK ligand and parathyroid hormone-related protein, as well as Src kinase inhibitors, are also currently under clinical evaluation.
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PMID:Novel approaches to the management of bone metastases. 1461 37

Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-beta. Secreted factors transmit the interactions between tumor and bone. They provide novel targets for therapeutic interactions to break the vicious cycle of bone metastases. Clinically approved bisphosphonate anti-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.
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PMID:Tumor-bone cellular interactions in skeletal metastases. 1561 99

Enhanced osteoclastogenesis and osteoclastic activity through receptor activator of nuclear factor-kappa B (RANK) ligand - RANK system together with cytokines released from bone matrix during bone resorption play important roles in the development of bone metastases. Bisphosphonates with potent inhibitory activity on bone resorption have been shown to reduce the number of skeletal events and have some analgesic effect in patients with bone metastases from breast cancer or multiple myeloma. However, bisphosphonates do not affect survival of these patients and better drugs for prevention and treatment of bone metastases are necessary.
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PMID:[Treatment of bone metastases]. 1577 17

The most common skeletal complication of breast cancer is osteolytic bone metastasis. Bone metastases are present in 80% of patients with advanced disease and cause significant morbidity. They are most often osteolytic, but can be osteoblastic or mixed. Tumor cells, osteoblasts, osteoclasts and bone matrix are the four components of a vicious cycle necessary for the initiation and development of bone metastases. Tumor cell gene expression is modified by interaction with bone-derived factors. For example, parathyroid hormone related protein (PTHrP), a tumor cell factor, is upregulated by bone-derived transforming growth factor beta (TGFbeta). Tumor cell factors, in turn, act upon bone cells to cause dysregulated bone destruction and formation. PTHrP increases osteoblast expression of RANK (receptor activator of NFkappaB) ligand which, in turn, activates osteoclasts. PTHrP-independent osteolytic factors, such as interleukin [IL]-11 and IL-8, also contribute to the vicious cycle. Other tumor-bone interactions, such as stimulation of tumor-homing through the CXCR4 chemokine receptor by its bone-derived ligand stromal-derived factor-1 (SDF-1), may be responsible for the site-specific predilection of breast cancer for bone. These factors and their roles in fueling the vicious cycle may identify novel targets for therapies to prevent metastasis.
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PMID:Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. 1602 23

Amgen, as part of its program targeting the RANK/RANKL/ osteoprotegerin pathway, is developing denosumab, a fully human monoclonal antibody, delivered subcutaneously, targeting the receptor activator of nuclear factor-kappaB ligand, for the potential treatment of diseases associated with bone loss, such as osteoporosis and bone metastases. The antibody is currently undergoing phase III clinical trials.
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PMID:Technology evaluation: denosumab, Amgen. 1637 Mar 84

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.
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PMID:Regulation of cancer cell migration and bone metastasis by RANKL. 1731 31

Receptor activator of NF-kappaB ligand (RANKL), its receptor RANK, and osteoprotegerin (OPG), the physiological inhibitor of RANKL, were discovered using a genomics-based approach. Bone loss is dependent on RANKL, the primary mediator of osteoclast formation, function, and survival. The study of the RANK/RANKL/OPG axis in animal models has firmly established the central importance of this pathway in bone mass regulation and provided the initial rationale for the design of a mechanism-based targeted approach to inhibit RANKL in pathologic bone loss settings, including cancer-induced bone disease. Denosumab (AMG 162), a fully human monoclonal antibody that can bind and inhibit human RANKL in a way that mimics the natural bone-protecting actions of OPG, is currently in development. A phase 1 clinical trial in patients with multiple myeloma or breast carcinoma with bone metastases showed that a single subcutaneous injection of denosumab caused rapid and sustained suppression of bone turnover markers and was well tolerated. Larger trials are underway to investigate the effect of denosumab for the treatment of cancer-induced bone disease and other bone loss disorders.
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PMID:[Monoclonal antibody targeting RANKL as a therapy for cancer-induced bone diseases]. 1658 14


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