Preclinical overview of the bisphosphonate ibandronate in tumor-related bone diseases

F. Bauss Ph.D.

Roche Diagnostics GmbH, Pharma Research, D-82372 Penzberg, Germany and Institute of Pharmacology and Toxicology, Heidelberg University, D-68169 Mannheim, Germany

AIMS: Ibandronate is a highly potent nitrogen-containing bisphosphonate, a class of drug that selectively binds to bone mineral and inhibits osteoclast function. This presentation reviews the use of preclinical models of tumor metastasis to bone to investigate the antiresorptive and antitumor properties of ibandronate. METHODS: Human breast cancer cells, MDA-MB-231 or MCF-7/Neu were inoculated intra-cardially or intra-arterially to nude mice or nude rats. Walker 256 breast cancer cells were injected into bone marrow or subcutaneously into immune-competent rats. Tumor cell attachment and spreading onto bone slices was also investigated. RESULTS: In nude mice (MDA-MB-231), ibandronate not only prevented the development of new bone metastases but also suppressed the progression of already established metastasis. Anti-tumor effects were also demonstrated in nude rats. In the intra-osseous Walker model, a dramatic destruction of trabecular integrity and cortical bone was totally inhibited by ibandronate. Ibandronate also inhibited hypercalciuria and accelerated bone resorption in the subcutaneous model. These effects were directly correlated with changes in osteoclast number and urinary markers of bone resorption. In all models, all beneficial effects were most prominent when treatment was initiated as early as possible, as shown in the reduction of osteosclerotic metastases in the MCF-7 mouse model. The anti-metastatic properties can most probably be explained by a reduced osteoclast-mediated release of tumor growth factors from bone matrix. In-vitro, ibandronate pretreatment of bone slices inhibited tumor cell attachment and spreading. When added with tumor cells to untreated bone slices, ibandronate showed additive effects with cytotoxic agents such as taxoids. CONCLUSION: Ibandronate has a high therapeutic potential in bone disease associated with pathologically increased bone resorption such as metastatic bone disease.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.