Bisphosphonates and Cancer-Induced Bone Disease: Beyond Their Antiresorptive Activity

Abstract

Bisphosphonates are primarily known for their ability to inhibit osteoclast-mediated bone resorption. They are an indispensable part of therapy for patients with cancers that cause osteolysis. However, there is now a growing body of evidence from preclinical research showing that bisphosphonates also exhibit antitumor activity, both in vitro and in vivo. They can affect molecular mechanisms of tumor cell adhesion, invasion, and proliferation; reinforce the effects of cytotoxic agents in a synergistic manner; and exhibit antiangiogenic and immunomodulatory effects. These preclinical findings reveal exciting ways of optimizing bisphosphonate therapy in oncology to fully exploit their antitumor potential. (Cancer Res 2005; 65(12): 4971-4)

Protective effect of bisphosphonates on endometrial cancer incidence in data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

“…In numerous in vitro studies, it has been demonstrated that bisphosphonates induce apoptosis, reduce proliferation, and inhibit tumor cell migration and invasion. 25 The antitumor effects reported from in vitro systems led to subsequent investigations using in vivo models in different tumor types. 26 This eventually led to clinical trials of the use of bisphosphonates in combination with standard cytotoxic chemotherapy.…”

Synergistic effect of bisphosphonate and docetaxel on the growth of bone metastasis in an animal model of established metastatic bone disease

“…It was, therefore, thought that inhibitors of bone resorption, such as the bisphosphonates, may not only protect the integrity of bone at metastatic sites but may also have a favourable effect on the local growth of bone metastases. In addition, several in vitro studies have shown that bisphosphonates have direct effects on tumour cells, increase their rate of apoptosis, decrease angiogenesis and prevent their attachment on bone matrices [5,6]. Thus, bisphosphonates, in addition, to their bone protective effect, may also reduce the growth potential of cancer cells in the bone-bone marrow microenvorment.…”

“…Bisphosphonates decrease bone resorption and reduce significantly the rate of skeletal complications in patients with metastatic bone disease [4]. In addition, several in vitro studies reported that bisphosphonates have direct antiproliferative and proapoptotic effects on cancer cells and can inhibit the adhesion of cancer cells to mineralized matrices suggesting that these compounds may also have a favorable action on the growth and invasive behavior of cancer cells [5][6][7][8]. However, in vivo studies in animal models of bone metastasis have produced equivocal results [9][10][11][12][13][14][15][16][17].…”

PLGA-Alendronate Conjugate as a New Biomaterial to Produce Osteotropic Drug Nanocarriers

“…The enhanced efficacy of the drug when loaded in these NPs can be used as an indirect demonstration of the successful delivery of DOX to the bones. The modest activity registered with unloaded PLGA-ALE NPs could be related to the inhibitory effect of ALE conjugated to PLGA on osteoclast activity, that indirectly reduced tumour expansion, and of a direct effect exerted by ALE on tumour cells [48]. Treatment of m i c e w i t h b o t h f r e e o r N P -l o a d e d D O X significantly reduced also the tumour area.…”