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The expression of proteins directly or indirectly associated with osteolysis and tumor growth was studied on 163 samples of GCTb. Of these, 33 patients developed lung metastasis during follow\u2010up. The impact of tumor\u2013host interaction on clinical aspects was evaluated with the aim of finding specific markers for new biological therapies, thus improving clinical management of GCTb. Protein expression was evaluated by immunohistochemical analysis on Tissue Microarray. The majority of GCTb samples from patients with metastatic disease were strongly positive to RANKL and its receptor RANK as well as to CAII and MMP\u20102 and to pro\u2010survival proteins NFIB and c\u2010Fos. Kaplan\u2013Meier analysis indicated a significant difference in metastasis free survival curves based on protein staining. Interestingly, the statistical correlation established a strong association between all variables studied with a higher <jats:italic>\u03c4<\/jats:italic> coefficient for RANK\/RANKL, RANK\/NFIB, and RANKL\/NFIB pairs. At multivariate analysis co\u2010overexpression of NFIB, RANK and RANKL significantly increased the risk of metastasis with an odds ratio of 13.59 (95%CI 4.12\u201344.82; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0005). In conclusion, the interconnection between matrix remodeling and tumor cell activity may identify tumor\u2013host endpoints for new biological treatments. \u00a9 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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