ant Cell Tumor.gif
Fig. 1 AP radiograph of an aggressive, radiographic grade 3 giant cell tumor of the proximal humerus. The lesion has destroyed the cortex, extended into the soft tissues, and left only a small residual portion of the humeral head. Such an aggressive lesion warrants further imaging studies and biopsy. Reprinted from Weber KL, McDonald DJ: Giant Cell Tumor of Bone in Schwartz HS (Ed) Orthopaedic Knowledge Update Musculoskeletal Tumors 2, Rosemont, Ill. American Association of Orthopaedic Surgeons/Musculoskeletal Tumor Society, 2007, pp 133-142

AAOS Now

Published 1/1/2011
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Denis R. Clohisy, MD

New hope for patients with giant-cell tumors

Researchers investigate treatment of giant-cell tumor with denosumab

Giant-cell tumor (GCT) is a rare primary bone tumor that is osteolytic and has low metastatic potential. The rare metastases have a propensity for the lung.

Surgery—usually curettage combined with cementation or allograft supplementation—is considered the primary therapy for GCT of bone. Despite this treatment, local recurrence can occur in 10 percent to 40 percent of patients. The likelihood of local recurrence is thought to depend on the size of the tumor, the location of the lesion, and the surgical treatment. Histologically, GCTs contain large, multinucleated cells (giant-cell), similar to osteoclasts (Fig. 1). This provides the alternative name for the tumor: osteoclastoma.

Advances in understanding the molecular mechanisms driving the formation and survival of osteoclasts have occurred over the past 10 to 15 years. These investigations have led to the discovery of a series of molecules involved in osteoclast formation.

Scientists determined that osteoclasts and their precursor cells express the receptor/activator NFKB (RANK), and that when this receptor is engaged by the RANK ligand (RANK-L), osteoclast formation occurs, osteoclast function increases, and osteoclast survival is prolonged. Identification of the RANK/RANK-L axis for stimulating osteoclastic activity led to the discovery of both naturally occurring and engineered molecules that can block the RANK/RANK-L interaction. As demonstrated in human and animal models, blocking the RANK/RANK-L interaction is a potent means for inducing osteoclast cell death and reducing bone resorption.

Because GCTs of bone are composed of osteoclast-like cells, scientists wondered whether they and their precursors expressed RANK or RANK-L. Research has shown that the osteoclast-like giant-cells and their precursors express RANK, and that some of the mononuclear cells within GCTs express RANK-L. This important observation introduced the notion that inhibiting the RANK/RANK-L axis may be an effective way to eliminate the osteoclast-like giant-cells and their associated mononuclear cells in GCT of bone.

A fully humanized monoclonal antibody (denosumab) has been developed and shown to specifically inhibit RANK-L and, therefore, inhibit osteoclast-mediated bone destruction. Subcutaneous administration of denosumab has been shown to provide rapid and sustained suppression of bone turnover in patients with multiple myeloma and osteolytic bone disease. Researchers sought to determine if inhibition of RANK-L by denosumab might also inhibit bone destruction and reduce tumor burden in patients with GCT.

A recently published study describes the safety and efficacy of denosumab in patients with recurrent or unresectable GCT. This Phase II study epitomizes translational research—hypothesizing that the same molecular mechanisms that drive osteoclast biology may also drive the formation and maintenance of GCTs of bone.

The study involved 35 patients with recurrent or unresectable GCT who were treated with denosumab. Efficacy was based on the endpoints of elimination of at least 90 percent of giant-cells, or no radiographic progression of the primary tumor. Based on the criteria for histology and/or radiographic evaluation, 30 of 35 patients responded to the treatment.

Much work remains to be performed to more thoroughly evaluate RANK-L inhibition as a treatment for GCT. The results of this translational research project, however, will certainly motivate further investigation of the role of RANK-L targeted therapy for the treatment of GCT.

Denis R. Clohisy, MD, is chair of the AAOS Research Development Committee and professor and chair of the department of orthopaedic surgery at the University of Minnesota. He can be reached at clohi001@umn.edu

Bench to Bedside
“Bench to Bedside” is a quarterly column sponsored by the AAOS Research Development Committee (RDC) highlighting new translational research. The RDC—under the auspices of the Council on Research, Quality Assessment, and Technology—serves as the primary liaison to the National Institutes of Health on issues in musculoskeletal research, and oversees research advocacy events, the clinician-scientist development programs, and the Kappa Delta Research Awards.