Integration of denosumab therapy in the management of giant cell tumors of bone

Abstract

A review of the literature indicated denosumab is gaining favorability in the oncology community, particularly with increasing frequency in GCTB. Will denosumab be the breakthrough GCTB treatment? Here, we provide a pertinent case example, a review of the literature regarding the history and basic science behind the use of denosumab for GCTB, highlight the newest insights into the dosing and duration of treatment, and note advancements in the field.

Keywords: Denosumab; Giant cell tumor of the bone (GCTB); RANKL.

Fig. 1

(A) Coronal CT scans of the chest showing initial 2.6 × 3.1 cm mass at the level of the left pulmonary hilum. (B) Interval 4 month follow-up CT scan of the chest showing significant interval change in decreasing hilum tumor burden.

Fig. 2

Physiologic Signaling Pathway of the Basic Metabolic Unit (BMU) and precursors. Osteoblasts and Osteocytes are derived from Mesenchymal Stem Cells (MSC). Osteoblasts mineralize bone by forming Hydroxyapatite while Osteocytes support mature bone with nutrients and waste removal. Osteocytes are formed by differentiated Osteoblasts. Osteoclasts are of myeloid origin from the monocyte/macrophage lineage. Osteoclasts work to resorb bone by demineralizing the hydroxyapatite from the osteoid. The major cell responsible for osteological regulation of metabolism is the osteocyte by its regulation of osteoblasts through sclerostin; and the control of osteoclasts through RANKL/OPG expression.

Fig. 3

Parathyroid Hormone (PTH), Parathyroid related Hormone (PTHrP), and Teriparatide actions on BMU physiology.

Fig. 4

RANKL acts on RANK and promotes osteoclastogenesis and osteoclast survival. RANKL expression and signaling is one of the most important mechanisms for activating osteoclasts and causing subsequent bone remodeling through hydroxyapatite and collagen resorptive events.

Fig. 5

The effects of Bisphosphonates, Denosumab, and PTH agonists on BMU physiology. PTHrP and Teriparatide acts in the same manner as PTH in inducing RANKL expression and sclerostin inhibition. Denosumab is a human monoclonal antibody against RANKL that inhibits osteoclastogenesis. Nitrogen containing bisphosphonates (N-BPs) primarily inhibit the mevalonate pathway in osteoclast precursors and mature osteoclasts. Non-Nitrogen containing bisphosphonates (NN-BPs) inhibit cellular metabolism of osteoclasts and their precursors by producing non-hydrolysable ATP.

Fig. 6

Nitrogen Containing Bisphosphonates (N-BP) mechanism of action on osteoclasts.

Fig. 7

Human monoclonal antibody against RANKL (Denosumab) mechanism of action. RANKL has been shown to take different forms. Recent studies have shown that the transmembrane form of RANKL on osteocytes is the most physiologically active from which promotes upregulation of osteoclast activity. The soluble form of RANKL (sRANKL) has been shown to be released from the membrane by metalloproteinases and are not as physiologically activating. Denosumab inhibits RANKL by binding RANKL and preventing RANKL binding to RANK on osteoclasts, downregulating osteoclastogenesis. Interestingly, studies show Denosumab action against osteoclastogenesis only, and not osteoclast survival.