Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

Abstract

Purpose: Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB.Experimental Design: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a 90% or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL.Results: Baseline tumor samples were typically composed of densely cellular proliferative RANKLpositive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells.Conclusions: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANKpositive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.

Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts

“…MRI check-up examinations showed that the previous cystic formations had been replaced with solid bone marrow-like tissue, a finding that has also been noted in GCT therapy [3]. Radiculopathy and neurologic symptoms also resolved in both patients.…”

Receptor Activator of Nuclear Transcription Factor Nf-b (Rank), Its Ligand (Rankl) and Natural Inhibitor Osteoprotegerin (Opg) in Blood Serum of Primary Bone Tumor Patients: Association With Clinicopathological Features and Inflammatory Cytokines Levels

“…These observations match the known fact that XGEVA ® (denosumab) -a molecular targeted preparation composed of antiRANKL monoclonal antibodies -was in 2013 recommended by the American Food and Drug Administration for the treatment of inoperable GCBT [16,17]. It was shown that the clinical effect of denosumab observed in a considerable part of the patients was accompanied by more than 90% decrease of the number of tumor-associated giant cells and a decrease of the number of stromal cells [18]. RANK/RANKL interaction inhibitors are also considered as new approaches to the treatment of chordoma [19] and some benign bone lesions [10].…”

Morphologic evaluation of the effect of denosumab on giant cell tumors of bone and a new grading scheme

“…Single case reports indicated alterations in morphology such as benign fibrous histiocytoma-like (BFH) lesions [12]; fibrous cells with partial reactive bone formation; bone regeneration; aggregated inflammatory cells [13]; distinctive pseudosarcomatous spindle cell proliferation with matrix production and paucity of giant cells and mitosis; mimicking osteogenic sarcoma [14]; reactive stromal cells and scattered spindle cells with elongated oval-shaped nuclei without evident atypia and diffusely clustered foamy macrophages [15]; 5-10% necrosis with remaining GCT [16]; extensive necrosis and fibrosis without GCT [17]; lacking giant cells in the metastatic GCT to lung [18]. Branstetter et al evaluated GCTs' pre and posttreatment specimens by immunostaining with RANK, RANKL [19]. They demonstrated the osteoclastic arrest and presented histopathologic and immunohistochemical findings but they did not classify these changes.…”