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However, its role in metastasis progression remains incompletely understood. Herein, we examined whether the overexpression of human RANKL in transgenic mice (TgRANKL) affects their susceptibility to breast cancer bone metastasis compared to their wild-type (WT) littermates. Bone metastasis was induced by injecting EO771 mouse mammary adenocarcinoma cells into the caudal artery of syngeneic WT and TgRANKL mice. RANKL overexpression led to an earlier onset and increased burden of bone metastasis in EO771-bearing TgRANKL mice compared to WT mice. It also exacerbated the bone destruction caused by metastasis-associated osteolysis. The prophylactic inhibition of RANKL activity with denosumab, a monoclonal antibody targeting human RANKL, prevented osteolysis and significantly reduced the incidence and progression of bone metastases in TgRANKL mice. However, the therapeutic denosumab treatment had no effect on metastasis incidence or tumor burden, although it alleviated osteolysis. The treatment with zoledronic acid, an anti-resorptive agent inhibiting osteoclast activity, yielded results similar to those of denosumab. These findings emphasize the significance of initiating early treatment with anti-resorptive agents such as denosumab or zoledronic acid to reduce the risk of bone metastasis in patients at high risk.<\/jats:p>","DOI":"10.3390\/ijms26114990","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T10:24:45Z","timestamp":1747909485000},"page":"4990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["RANKL Drives Bone Metastasis in Mammary Cancer: Protective Effects of Anti-Resorptive Treatments"],"prefix":"10.3390","volume":"26","author":[{"given":"Evi","family":"Gkikopoulou","sequence":"first","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"},{"name":"Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos-Chrysovalantis","family":"Syrigos","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"},{"name":"Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Mantogiannakou","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysa-Eleni","family":"Petraki","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"},{"name":"Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Stathopoulou","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"},{"name":"Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Dragolia","sequence":"additional","affiliation":[{"name":"Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2390-3136","authenticated-orcid":false,"given":"Vagelis","family":"Rinotas","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1271-1187","authenticated-orcid":false,"given":"Vasileios","family":"Ntafis","sequence":"additional","affiliation":[{"name":"Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Rauner","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III and Center for Healthy Aging, University Medical Center, Technical University of Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0004-5121","authenticated-orcid":false,"given":"Eleni","family":"Douni","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 16672 Vari, Greece"},{"name":"Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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