In recent years, significant insights regarding the biology and therapy of giant cell tumor of bone (GCTB) have been published. Crucial for diagnostics was the discovery of the highly characteristic mutation in the H3F3A gene, which leads to a G34W amino acid exchange in histone H3. In addition, the treatment of inoperable GCTB with the anti-RANKL antibody denosumab has become established in therapy. Reports of malignant transformation of GCTB in association with denosumab therapy have been published, however the concrete influence of denosumab is not clearly clarified. The Arbeitsgemeinschaft Knochentumoren (AGKT e. V.) has initiated a multi-institutional study to establish a clinically well-defined cohort of GCTB with the aim of a) a detailed description of morphological changes caused by denosumab; b) identification of possible risk factors regarding a potential malignant transformation into sarcoma for establishment of a histological risk stratification; c) comparison of these data to recurrent GCTB for identification of potential risk factors of recurrency in GCTB. For this purpose, 26 GCTB before and after denosumab therapy and 14 recurrent GCTB compared to the primary tumor without denosumab were included in this study in pairs. Techniques used are a detailed histological assessment of morphological changes during denosumab therapy and in recurrent GCTB including a broad panel of markers for immunohistochemical analysis. This clinically well-defined cohort will serve as a basis for a database and tissue bank for further molecular pathologic analysis.