Antitumor Effects of Clinical Dosing Regimens of Bisphosphonates in Experimental Breast Cancer Bone Metastasis

Abstract

Daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in a mouse model.

Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo

“…We and others have shown previously that inhibiting bone resorption is also associated with antitumor effects in these experimental models. (43)(44)(45)(46) However, osteoblastic bone formation was not typically examined in these previous studies. This report is one of the first to provide evidence that stimulating osteoblast differentiation and bone formation is also associated with antitumor effects and the reduction of metastases.…”

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

“…This difference can to some extent be justified by the higher level of overall bone turnover in young mice, compared with adult humans. Treatment of established B02 breast tumors in bone with a single injection of 100 μg/kg zoledronic acid has been shown to have no effect on tumor volume, tumor cell apoptosis, or proliferation (23,32). However, an accumulative dose of 100 μg/kg, where mice were given zoledronic acid daily or weekly, significantly reduced intraosseous tumor burden (23).…”

“…Treatment of established B02 breast tumors in bone with a single injection of 100 μg/kg zoledronic acid has been shown to have no effect on tumor volume, tumor cell apoptosis, or proliferation (23,32). However, an accumulative dose of 100 μg/kg, where mice were given zoledronic acid daily or weekly, significantly reduced intraosseous tumor burden (23). Thus, it seems that multiple doses of zoledronic acid are required to induce anticancer effects in vivo.…”

“…Antitumor effects of bisphosphonates have also been reported in in vivo model systems that mimic tumorinduced bone disease from a variety of cancer types including breast (18,19), prostate (20), leukemia (21), and multiple myeloma (22). These studies also used high doses and frequent administration of zoledronic acid (from 120 μg/kg 2× per week to 120 μg/kg daily), whereas a clinically relevant dose of zoledronic acid (100 μg/kg 1× per month) was reported not to exert anticancer effects in a model of breast cancer bone metastases (23).…”

Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis

“…Furthermore, data from preclinical studies demonstrate that bisphosphonates may have antitumor activity by preventing tumor cell adhesion to bone [11][12][13], by inducing tumor cell apoptosis [14], by antagonising of growth factors [15], and by antiangiogenic effects [16]. In addition, a recent clinical trial evidenced that use of zoledronic acid in adjuvant treatment of early breast cancer setting may prolong disease free survival when compared with non use [17].…”