{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T19:57:10Z","timestamp":1784231830552,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2013,10,14]],"date-time":"2013-10-14T00:00:00Z","timestamp":1381708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited in bone marrow capillaries), and molecular characteristics of the cancer cells that allow them to adapt to the bone marrow microenvironment. The goals of treating osseous metastases are manifold. Proper treatment can lead to significant improvements in pain control and function, and maintain skeletal integrity. The treatment plan requires a multidisciplinary approach. Widespread metastatic disease necessitates systemic therapy, while a localized problem is best managed with surgery, external beam radiotherapy, or both. Patients with bone metastasis can have prolonged survival, and proper management can have a significant impact on their quality of life. We will review the factors in this article that are promising molecular bone-targeted therapies or will be likely targets for future therapeutic intervention to restore bone remodeling and suppress tumor growth.<\/jats:p>","DOI":"10.3390\/jcm2040176","type":"journal-article","created":{"date-parts":[[2013,10,14]],"date-time":"2013-10-14T11:11:20Z","timestamp":1381749080000},"page":"176-187","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bone Targeted Therapies for Bone Metastasis in Breast Cancer"],"prefix":"10.3390","volume":"2","author":[{"given":"Wajeeha","family":"Razaq","sequence":"first","affiliation":[{"name":"Stephenson Cancer Center, The University of Oklahoma, Norman, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1158\/1078-0432.CCR-07-2223","article-title":"The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance","volume":"14","author":"Meads","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/leu.2008.48","article-title":"The bone marrow niche: Habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites","volume":"22","author":"Shiozawa","year":"2008","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s10549-006-9279-8","article-title":"Transcriptome analysis reveals an osteoblast-like phenotype for human osteotropic breast cancer cells","volume":"101","author":"Bellahcene","year":"2007","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrc867","article-title":"Metastasis to bone: Causes, consequences and therapeutic opportunities","volume":"2","author":"Mundy","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s10585-007-9112-8","article-title":"Bone metastasis: Pathogenesis and therapeutic implications","volume":"24","author":"Teti","year":"2007","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1196\/annals.1443.016","article-title":"RANK\/RANKL: Regulators of immune responses and bone physiology","volume":"1143","author":"Leibbrandt","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/jcp.22272","article-title":"Activin A and bone metastasis","volume":"225","author":"Leto","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.canlet.2007.07.007","article-title":"Bisphosphonates in cancer therapy","volume":"257","author":"Stresing","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"279","DOI":"10.6004\/jnccn.2010.0020","article-title":"Does adjuvant bisphosphonate in early breast cancer modify the natural course of the disease? A meta-analysis of randomized controlled trials","volume":"8","author":"Mauri","year":"2010","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1200\/JCO.2008.19.2146","article-title":"Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates","volume":"27","author":"Fizazi","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Stopeck, A., Boer, R., Fujiwara, Y., Lichinitser, M., Tonkin, K., Yardley, D., Fan, M., Jiang, Q., Jun, S., Dansey, R., and Braun, A. (2009). A comparison of denosumab versus zoledronic acid for the prevention of skeletal-related events in breast cancer patients with bone metastases. Cancer Res., 69.","DOI":"10.1158\/0008-5472.SABCS-09-22"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1056\/NEJMe068003","article-title":"The long and the short of bone therapy","volume":"354","author":"Whyte","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1097\/SPC.0b013e32830baea9","article-title":"Cathepsin K inhibitors as treatment of bone metastasis","volume":"2","author":"Bonnelye","year":"2008","journal-title":"Curr. Opin. Support. Palliat. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.bone.2007.09.044","article-title":"Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts","volume":"42","author":"Fuller","year":"2008","journal-title":"Bone"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1021\/jm050915u","article-title":"Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors","volume":"49","author":"Yamashita","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_16","first-page":"1085","article-title":"Effect of 1 year treatment with the cathepsin-K inhibitor, balicatib, on bone mineral density (BMD) in postmenopausal women with osteopenia\/osteoporosis","volume":"21","author":"Adami","year":"2006","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jaad.2008.03.009","article-title":"Drug-induced morphea: Report of a case induced by balicatib and review of the literature","volume":"59","author":"Peroni","year":"2008","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1124\/jpet.106.102004","article-title":"Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: Implications for therapy","volume":"318","author":"Rucci","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s10585-007-9065-y","article-title":"Src kinase promotes adhesion-independent activation of FAK and enhances cellular migration in tamoxifen-resistant breast cancer cells","volume":"24","author":"Hiscox","year":"2007","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s10549-005-9120-9","article-title":"Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells","volume":"97","author":"Hiscox","year":"2006","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/(SICI)1096-9896(199612)180:4<383::AID-PATH686>3.0.CO;2-N","article-title":"c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis","volume":"180","author":"Verbeek","year":"1996","journal-title":"J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.2174\/1381612023393323","article-title":"Targeting protein kinases for bone disease: Discovery and development of Src inhibitors","volume":"8","author":"Metcalf","year":"2002","journal-title":"Curr. Pharm. Des."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1083\/jcb.151.2.311","article-title":"Decreased c-Src expression enhances osteoblast differentiation and bone formation","volume":"151","author":"Marzia","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/0092-8674(91)90499-O","article-title":"Targeted disruption of the c-Src proto-oncogene leads to osteopetrosis in mice","volume":"64","author":"Soriano","year":"1991","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ccr.2009.05.017","article-title":"Latent bone metastasis in breast cancer tied to Src-dependent survival signals","volume":"16","author":"Zhang","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1006\/bbrc.1994.1363","article-title":"Evidence that c-Src is involved in the process of osteoclastic bone resorption","volume":"199","author":"Hall","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6658","DOI":"10.1021\/jm049486a","article-title":"Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src\/Abl kinase inhibitor with potent antitumor activity in preclinical assays","volume":"47","author":"Lombardo","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Finn, R.S., Finn, R.S., Bengala, C., Ibrahim, N., Strauss, L.C., Fairchild, J., Sy, O., Roche, H., Sparano, J., and Goldstein, L.J. (2009). Phase II trial of dasatinib in triple-negative breast cancer: Results of study CA180059. Cancer Res., 69.","DOI":"10.1158\/0008-5472.SABCS-3118"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4876","DOI":"10.1158\/1078-0432.CCR-10-0748","article-title":"Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors","volume":"16","author":"Baselga","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1158\/0008-5472.CAN-06-2027","article-title":"A Src\/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo","volume":"67","author":"Jallal","year":"2007","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1083\/jcb.200611083","article-title":"Syk, c-Src, the avb3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption","volume":"176","author":"Zou","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2174\/156800909789760348","article-title":"Integrins in bone metastasis formation and potential therapeutic implications","volume":"9","year":"2009","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2748","article-title":"Integrins in cancer: Biological implications and therapeutic opportunities","volume":"10","author":"Desgrosellier","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/35065016","article-title":"Involvement of chemokine receptors in breast cancer metastasis","volume":"410","author":"Homey","year":"2001","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/annonc\/mdn740","article-title":"Chemokine receptors in advanced breast cancer: Differential expression in metastatic disease sites with diagnostic and therapeutic implications","volume":"20","author":"Cabioglu","year":"2009","journal-title":"Ann. Oncol."},{"key":"ref_36","first-page":"761","article-title":"Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone","volume":"21","author":"Richert","year":"2009","journal-title":"Oncol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7975","DOI":"10.1158\/1078-0432.CCR-07-4846","article-title":"Translating an antagonist of chemokine receptor CXCR4: From bench to bedside","volume":"14","author":"Wong","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hotte, S.J., Hirte, H.W., and Iacobucci, A. (2008, January 21\u201324). Final Results of a Phase I\/II Study of CTCE-9908, a Novel Anticancer Agent that Inhibits CXCR4, in Patients with Advanced Solid Cancers. Proceedings of the 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Geneva, Switzerland.","DOI":"10.1016\/S1359-6349(08)72339-5"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1159\/000315736","article-title":"FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation","volume":"78","author":"Brave","year":"2010","journal-title":"Oncology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.2174\/138161210791034049","article-title":"TGFb pathway as a therapeutic target in bone metastases","volume":"16","author":"Guise","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4619","DOI":"10.1200\/jco.2009.27.15_suppl.4619","article-title":"Interim results of the phase I\/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinom","volume":"27","author":"Oettle","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1200\/jco.2009.27.15_suppl.2037","article-title":"Randomized, active-controlled phase IIb study with trabedersen (AP 12009) in recurrent or refractory high-grade glioma patients: Basis for phase III endpoints","volume":"27","author":"Bogdahn","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cell.2008.01.046","article-title":"TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4","volume":"133","author":"Padua","year":"2008","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/nrrheum.2009.175","article-title":"Promising bone-related therapeutic targets for rheumatoid arthritis","volume":"5","author":"Choi","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1056\/NEJMoa030847","article-title":"The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma","volume":"349","author":"Tian","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1182\/blood-2006-09-047712","article-title":"Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo","volume":"109","author":"Yaccoby","year":"2007","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1182\/blood-2008-11-191577","article-title":"Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma","volume":"114","author":"Fulciniti","year":"2009","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1002\/ijc.23625","article-title":"Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastases","volume":"123","author":"Bu","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10585-006-9010-5","article-title":"Activin A circulating levels in patients with bone metastasis from breast or prostate cancer","volume":"23","author":"Leto","year":"2006","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrc990","article-title":"The endothelin axis: Emerging role in cancer","volume":"3","author":"Nelson","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1158\/0008-5472.CAN-03-1069","article-title":"A role for endothelin-2 and its receptors in breast tumor cell invasion","volume":"64","author":"Grimshaw","year":"2004","journal-title":"Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1628::AID-CNCR13>3.0.CO;2-1","article-title":"Radiation for bone metastases: Conventional techniques and the role of systemic radiopharmaceuticals","volume":"80","author":"Janjan","year":"1997","journal-title":"Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/0277-5379(91)90257-E","article-title":"A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone","volume":"27","author":"Lewington","year":"1991","journal-title":"Eur. J. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/S0959-8049(97)00155-X","article-title":"A dose-controlled study of 153Sm-Ethylenediaminetetramethylenephosphate (EDTMP) in the treatment of patients with painful bone metastases","volume":"33","author":"Resche","year":"1997","journal-title":"Eur. J. Cancer"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/2\/4\/176\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:49:51Z","timestamp":1760219391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/2\/4\/176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,14]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["jcm2040176"],"URL":"https:\/\/doi.org\/10.3390\/jcm2040176","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,10,14]]}}}