Giant-cell tumor of bone, anti-RANKL therapy

Abstract

Giant-cell tumor of bone (GCTB) is a rare osteolytic tumor of the bone. Although classified as a benign tumor, GCTB is characterized by local aggressiveness and risk of local recurrence. In addition, GTCB can in some cases lead to the development of so-called 'benign' chest metastases. Surgical resection by intralesional curettage with high-speed burring and polymethylmethacrylate cement is the standard treatment for resectable tumors. In cases of metastatic or unresectable disease (when planned surgical procedure is impossible or would result in severe morbidity), medical treatments such as cytotoxic chemotherapy or interferon-α have limited efficacy. Bisphosphonates have been proposed as a therapeutic option to reduce osteoclast activity. In bone, various pathological states may result from an imbalance in the RANK (receptor activator of nuclear factor kappa-B)/RANKL (receptor activator of nuclear factor kappa-B ligand)/OPG (osteoprotegerin) pathway. Involvement of the RANKL pathway in pathogenesis of GCTB was first proposed in 2000. Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL, thereby preventing the activation of the RANK pathway. As it showed the possibility to counteract osteoclast activation in GCTB and prevent the known physiopathological role of RANKL, denosumab has been under evaluation in the clinic as a treatment for GCTB since 2005. Results of a first Phase II trial demonstrate the therapeutic potential of denosumab to inhibit progressive bone destruction and metastatic progression in patients with unsalvageable giant-cell tumor (GCT), and have also provided key insights into the biology of GCT. Denosumab is currently a therapeutic option for patients with unresectable GCTB but its place in the global therapeutic strategy has not yet been defined.

Figure 1. Typical radiographic appearance of giant-cell tumor of bone (CGTB) with expansile, osteolytic and radiolucent lesions.

(a) GCTB of left femur in a 40 years old man. (b) GCTB of right distal femur in a 37 years old man before and after surgical treatment with high speed buring and cement (we see on right picture that cementoplasty is lined with a thin border of osteolysis encircled by osteosclerosis corresponding to the adaptive response of the residual bone).

Figure 2. Typical appearance of giant-cell tumor of bone with multinucleated large giant cells and uniform ovoid mononuclear cells (100×).

Figure 3. RANK/RANKL/OPG (receptor activator of nuclear factor kappa-B)/receptor activator of nuclear factor kappa-B ligand/osteoprotegerin) pathway of osteoclastogenesis.

Stimulation of osteoclast precursor involves multiple cells. Primary stimulator of precursors is osteoblast through expression of RANK ligand (RANKL). Osteoblast can also release osteoprotegerin (OPG), which binds RANK ligand and inactivates it.

Figure 4. Chest metastasis of giant-cell tumor of bone histologically proven before and after 6 months of denosumab treatment.