Antitumor effects of bisphosphonates.

Bisphosphonates are widely used to treat skeletal complications of malignancy. These drugs accumulate in bone where they inhibit osteoclastic bone resorption and reduce the local release of factors that stimulate tumor growth. The mechanism of action of bisphosphonates is dependent on chemical structure: Nonnitrogen-containing compounds (e.g., etidronate, clodronate) are metabolized into cytotoxic analogues of ATP, whereas the more potent nitrogen-containing compounds (N-BPs; e.g., pamidronate, ibandronate, zoledronic acid) inhibit protein prenylation, thus affecting cell function and survival. Because protein prenylation is required by all cells, not just osteoclasts, the possibility arises that N-BPs could also affect the viability of tumor cells. Several groups have investigated the in vitro effects of bisphosphonates, either alone or in combination with other antineoplastic agents, on the viability and metastatic properties of many tumor cell types. Similarly, the effect of bisphosphonate treatment on osteolysis and tumor burden has been studied in a variety of animal tumor models. In vitro, submicromolar concentrations of N-BPs inhibited tumor cell adhesion and reduced invasion through extracellular matrix. At higher concentrations, antiproliferative and proapoptotic effects have been reported. In animal models of bone metastases, bisphosphonate treatment markedly reduced osteolytic lesions. There is also evidence of a reduction in tumor burden in bone and occasionally in other organs. Survival may be prolonged, but bisphosphonates do not appear to inhibit the growth of primary soft tissue tumors or orthotopic xenografts. The cell culture data clearly demonstrated that N-BPs exert antitumor properties and interact synergistically with other antineoplastic agents. As bisphosphonates accumulate in bone, they can also exert cytostatic effects on tumor cells in bone metastases, either directly or indirectly via osteoclast inhibition and alterations in the bone microenvironment. Further in vivo research is now required to optimize the dosing regimen of N-BPs to exploit fully their antitumor potential.