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      Metastatic bone disease: Pathogenesis and therapeutic options : Up-date on bone metastasis management

      review-article
      a , * , b , b , a
      Journal of Bone Oncology
      Elsevier
      Bone metastases, Osteotropic tumors, Skeletal related events, Bone targeting agents, ActRIIA, activin-A type IIA receptor, BC, breast cancer, BM, bone metastases, BMD, bone mineral density, BMPs, bone morphogenetic proteins, BMSC, bone marrow stromal cells, BPs, bisphosphonates, BTA, bone targeting agents, BTM, bone turnover markers, CCR, chemokine-receptor, CRPC, castration-resistant PC, CXCL-12, C–X–C motif chemokine-ligand-12, CXCR-4, chemokine-receptor-4, DFS, disease-free survival, DKK1, dickkopf1, EBC, early BC, ECM, extracellular matrix, ET-1, endothelin-1, FDA, food and drug administration, FGF, fibroblast growth factor, GAS6, growth-arrest specific-6, GFs, growth factors, GnRH, gonadotropin-releasing hormone, HER-2, human epidermal growth factor receptor 2, HR, hormone receptor, IL, interleukin, LC, lung cancer, MAPK, mitogen-activated protein kinase, MCSF, macrophage colony-stimulating factor, MCSFR, MCSF receptor, MIP-1α, macrophage inflammatory protein-1 alpha, MM, multiple myeloma, MPC, malignant plasma cells, mTOR, mammalian target of rapamycin, N-BPs, nitrogen-containing BPs, NF-κB, nuclear factor-κB, non-N-BPs, non-nitrogen containing BPs, ONJ, osteonecrosis of the jaw, OS, overall survival, PC, prostate cancer, PDGF, platelet-derived growth factor, PFS, progression-free survival, PIs, proteasome inhibitors, PSA, prostate specific antigen, PTH, parathyroid hormone, PTH-rP, PTH related protein, QoL, quality of life, RANK-L, receptor activator of NF-κB ligand, RT, radiation therapy, SREs, skeletal-related events, SSEs, symptomatic skeletal events, TGF-β, transforming growth factor β, TK, tyrosine kinase, TKIs, TK inhibitors, TNF, tumornecrosis factor, v-ATPase, vacuolar-type H+ ATPase, VEGF, vascular endothelial growth factor, VEGFR, VEGF receptor

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Highlights

          • Bone metastases negatively impact on patients’ quality of life (QoL).

          • Skeletal related events have a detrimental effect on both QoL and survival.

          • Both local and systemic treatments are often required to manage bone metastases.

          • Bone turnover modulators reduce the risk of skeletal complications and improve pain.

          • Novel agents may deserve further investigation for the management of bone metastases.

          Abstract

          Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival.

          A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical and clinical studies have showed promising effects of novel agents, whose safety and efficacy need to be confirmed by prospective clinical trials.

          Among BTA, adjuvant bisphosphonates have also been shown to reduce the risk of BM in selected breast cancer patients, but failed to reduce the incidence of BM from lung and prostate cancer. Moreover, adjuvant denosumab did not improve BM free survival in patients with breast cancer, suggesting the need for further investigation to clarify BTA role in early-stage malignancies.

          The aim of this review is to describe BM pathogenesis and current treatment options in different clinical settings, as well as to explore the mechanism of action of novel potential therapeutic agents for which further investigation is needed.

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          Most cited references88

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          WNT signaling in bone homeostasis and disease: from human mutations to treatments.

          Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
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            Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.

            Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis.
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              Bone Metastases: An Overview

              Bone is a frequent site of metastases and typically indicates a short-term prognosis in cancer patients. Once cancer has spread to the bones it can rarely be cured, but often it can still be treated to slow its growth. The majority of skeletal metastases are due to breast and prostate cancer. Bone metastasis is actually much more common than primary bone cancers, especially in adults. The diagnosis is based on signs, symptoms and imaging. New classes of drugs and new interventions are given a better quality of life to these patients and improved the expectancy of life. It is necessary a multidisciplinary approach to treat patients with bone metastasis. In this paper we review the types, clinical approach and treatment of bone metastases.
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                Author and article information

                Contributors
                Journal
                J Bone Oncol
                J Bone Oncol
                Journal of Bone Oncology
                Elsevier
                2212-1366
                2212-1374
                06 November 2018
                April 2019
                06 November 2018
                : 15
                : 004
                Affiliations
                [a ]Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, P.za Giulio Cesare, 11, 70124 Bari, Italy
                [b ]Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Whitham Rd, Sheffield S10 2SJ, England, UK
                Author notes
                [* ]Corresponding author. stella.doronzo@ 123456uniba.it
                Article
                S2212-1374(18)30258-6
                10.1016/j.jbo.2018.10.004
                6429006
                30937279
                70a38b41-aa94-442d-92b9-e34525c4771d
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 29 August 2018
                : 22 October 2018
                : 28 October 2018
                Categories
                Review Article

                bone metastases,osteotropic tumors,skeletal related events,bone targeting agents,actriia, activin-a type iia receptor,bc, breast cancer,bm, bone metastases,bmd, bone mineral density,bmps, bone morphogenetic proteins,bmsc, bone marrow stromal cells,bps, bisphosphonates,bta, bone targeting agents,btm, bone turnover markers,ccr, chemokine-receptor,crpc, castration-resistant pc,cxcl-12, c–x–c motif chemokine-ligand-12,cxcr-4, chemokine-receptor-4,dfs, disease-free survival,dkk1, dickkopf1,ebc, early bc,ecm, extracellular matrix,et-1, endothelin-1,fda, food and drug administration,fgf, fibroblast growth factor,gas6, growth-arrest specific-6,gfs, growth factors,gnrh, gonadotropin-releasing hormone,her-2, human epidermal growth factor receptor 2,hr, hormone receptor,il, interleukin,lc, lung cancer,mapk, mitogen-activated protein kinase,mcsf, macrophage colony-stimulating factor,mcsfr, mcsf receptor,mip-1α, macrophage inflammatory protein-1 alpha,mm, multiple myeloma,mpc, malignant plasma cells,mtor, mammalian target of rapamycin,n-bps, nitrogen-containing bps,nf-κb, nuclear factor-κb,non-n-bps, non-nitrogen containing bps,onj, osteonecrosis of the jaw,os, overall survival,pc, prostate cancer,pdgf, platelet-derived growth factor,pfs, progression-free survival,pis, proteasome inhibitors,psa, prostate specific antigen,pth, parathyroid hormone,pth-rp, pth related protein,qol, quality of life,rank-l, receptor activator of nf-κb ligand,rt, radiation therapy,sres, skeletal-related events,sses, symptomatic skeletal events,tgf-β, transforming growth factor β,tk, tyrosine kinase,tkis, tk inhibitors,tnf, tumornecrosis factor,v-atpase, vacuolar-type h+ atpase,vegf, vascular endothelial growth factor,vegfr, vegf receptor
                bone metastases, osteotropic tumors, skeletal related events, bone targeting agents, actriia, activin-a type iia receptor, bc, breast cancer, bm, bone metastases, bmd, bone mineral density, bmps, bone morphogenetic proteins, bmsc, bone marrow stromal cells, bps, bisphosphonates, bta, bone targeting agents, btm, bone turnover markers, ccr, chemokine-receptor, crpc, castration-resistant pc, cxcl-12, c–x–c motif chemokine-ligand-12, cxcr-4, chemokine-receptor-4, dfs, disease-free survival, dkk1, dickkopf1, ebc, early bc, ecm, extracellular matrix, et-1, endothelin-1, fda, food and drug administration, fgf, fibroblast growth factor, gas6, growth-arrest specific-6, gfs, growth factors, gnrh, gonadotropin-releasing hormone, her-2, human epidermal growth factor receptor 2, hr, hormone receptor, il, interleukin, lc, lung cancer, mapk, mitogen-activated protein kinase, mcsf, macrophage colony-stimulating factor, mcsfr, mcsf receptor, mip-1α, macrophage inflammatory protein-1 alpha, mm, multiple myeloma, mpc, malignant plasma cells, mtor, mammalian target of rapamycin, n-bps, nitrogen-containing bps, nf-κb, nuclear factor-κb, non-n-bps, non-nitrogen containing bps, onj, osteonecrosis of the jaw, os, overall survival, pc, prostate cancer, pdgf, platelet-derived growth factor, pfs, progression-free survival, pis, proteasome inhibitors, psa, prostate specific antigen, pth, parathyroid hormone, pth-rp, pth related protein, qol, quality of life, rank-l, receptor activator of nf-κb ligand, rt, radiation therapy, sres, skeletal-related events, sses, symptomatic skeletal events, tgf-β, transforming growth factor β, tk, tyrosine kinase, tkis, tk inhibitors, tnf, tumornecrosis factor, v-atpase, vacuolar-type h+ atpase, vegf, vascular endothelial growth factor, vegfr, vegf receptor

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