Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone

Abstract

Denosumab and Zoledronic acid (ZOL) are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action but both have been shown to delay the onset of skeletal-related events in patients with giant cell tumor of bone (GCT). However, the anti-tumor mechanisms of denosumab on the neoplastic GCT stromal cells remain unknown. In this study, we focused on the direct effects of denosumab on the neoplastic GCT stromal cells and compared with ZOL. The microscopic view demonstrated a reduced cell growth in ZOL-treated but not in denosumab-treated GCT stromal cells. ZOL was found to exhibit a dose-dependent inhibition in cell growth in all GCT stromal cell lines tested and cause apoptosis in two out of three cell lines. In contrast, denosumab only exerted a minimal inhibitory effect in one cell line and did not induce any apoptosis. ZOL significantly inhibited the mRNA expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in two GCT stromal cell lines whereas their protein levels remained unchanged. On the contrary, denosumab did not regulate RANKL and OPG expression at both mRNA and protein levels. Moreover, the protein expression of Macrophage Colony-Stimulating Factor (M-CSF), Alkaline Phosphatase (ALP), and Collagen α1 Type I were not regulated by denosumab and ZOL either. Our findings provide new insights in the anti-tumor effect of denosumab on GCT stromal cells and raise a concern that tumor recurrence may occur after the withdrawal of the drug.

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

“…Recently, denosumab has been approved by the FDA for the treatment of unresectable GCTB (18). However, it has been speculated that recurrence may occur in GCTB patients when these drugs are withdrawn (20). One of the reasons is that both bisphosphonates and denosumab mainly target osteoclasts, but not proliferative NSCs (20).…”

“…However, it has been speculated that recurrence may occur in GCTB patients when these drugs are withdrawn (20). One of the reasons is that both bisphosphonates and denosumab mainly target osteoclasts, but not proliferative NSCs (20). On the other side, stress fracture is associated with the long-term use of antiresorptive medications, such as denosumab and bisphosphonate (34,35).…”

“…However, both bisphosphonates and denosumab mainly target osteoclasts by inducing osteoclast apoptosis and suppressing osteoclast differentiation (19). The obvious limitation of these drugs for GCTB is that these drugs show very mild inhibitory effect on the proliferative NSCs (20). It has been speculated that GCTB may recur when these drugs are withdrawn (20), suggesting that NSCs are a vital target for curing GCTB.…”

“…The obvious limitation of these drugs for GCTB is that these drugs show very mild inhibitory effect on the proliferative NSCs (20). It has been speculated that GCTB may recur when these drugs are withdrawn (20), suggesting that NSCs are a vital target for curing GCTB. Therefore, suppression of both osteoclast formation and NSC growth could be a promising strategy for curing GCTB.…”

Denosumab Therapy in Giant Cell Bone Tumor: Review of Literature

“…Zoledronik asit, neoplastik stromal hücreler tarafından RANKL'nin mRNA ekspresyonunu inhibe ederken, denosumab bu etkiye sahip değildir. Lau ve arkadaşlarının denosumabın dev hücreli tümör stromal hücre dizileri üzerinde sadece minimal inhibitör etkiye neden olduğunu ve herhangi bir apopitoza neden olmadığını savunmaktadır (54). Bu denosumabın kesilmesinden sonra tekrarlamanın meydana gelebileceği hipotezini güçlendirmektedir.…”