Comparison of Fc-osteoprotegerin and zoledronic acid activities suggests that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms

Abstract

Zoledronic acid (ZA) has been shown to inhibit prostate tumor growth in vitro and have beneficial effects in patients with advanced prostate cancer (CaP). The aim of this study was to determine whether ZA exhibits direct anti-tumor effects on CaP cells in vivo. To distinguish the effects of inhibition of osteolysis and direct antitumor activity of ZA in vivo, we compared the results of treatment with ZA and osteoprotegerin (Fc-OPG), which inhibits osteolysis, but without significant direct anti-tumor effects. In vitro Fc-OPG had no significant effects on C4-2 proliferation, whereas ZA decreased proliferation. However, both agents decreased tumor growth in bone. Moreover, both increased bone volume and prevented the overall decreases in BMD associated with growth of C4-2 cells in bone. Our study provides novel and significant observations that the in vivo effects of ZA are consistent with indirect effects mediated by osteoclasts.

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…We investigated the effects of combination therapy on the bone in the presence of CaP cells, employing multiple modalities, including BMD, BHM, and µCT analyses. C4-2 tumor growth caused decreases in BMD (69.4 ± 2.0% of contralateral tibiae, P < 0.0001) that were similar to our published results [26]. Although TAX and RAD001 decreased serum PSA levels and tumor volume, they did not prevent changes in BMD (Fig.…”

“…After exclusion of animals with tumor in the muscle at the end of the study, each group had 7-9 animals (total 66 animals). Dosing regimens were determined based on the results of the preliminary individual studies with RAD001 and TAX and our previously published results with ZOL [25,26]. We sought to use low doses to elicit better-defined differences between groups and also to minimize adverse side effects of the treatments in a manner consistent with clinical practice.…”

“…Histomorphometrical analysis-Five micrometer sections of methacrylate-embedded tibiae stained with Goldner's stain as described [25,26,36] were used for this analysis (n = 4-5 per group). Tumor volume (TuV, mm 2 ), tissue volume (TV, mm 2 ), and bone volume (BV, mm 2 ) were measured in a blinded fashion on longitudinal sections of the tibiae using Bioquant Analysis Software (Bioquant Image Analysis Corporation, Nashville, TN).…”

“…However, this survival advantage was modest (1.9-2.4 months), and the drug is also associated with significant adverse side effects [23,24]. ZOL is a bisphosphonate which exerts beneficial effects in CaP patients with bone metastases, reducing both pain and skeletal related events [25][26][27][28][29][30]. Our previously published results suggested that the most likely mode of action of ZOL in retarding the growth of bone metastases is indirect, involving diminished availability of growth factors otherwise released through osteolysis, although we cannot rule out the possibility that ZOL directly inhibits the growth of CaP cells as well [26].…”

“…ZOL is a bisphosphonate which exerts beneficial effects in CaP patients with bone metastases, reducing both pain and skeletal related events [25][26][27][28][29][30]. Our previously published results suggested that the most likely mode of action of ZOL in retarding the growth of bone metastases is indirect, involving diminished availability of growth factors otherwise released through osteolysis, although we cannot rule out the possibility that ZOL directly inhibits the growth of CaP cells as well [26]. Based on these facts we hypothesize that the combination of RAD001, TAX, and ZOL-all acting on different pathways-will result in more pronounced inhibition of CaP tumor growth in the bone environment than any single treatment alone.…”