Therapeutic efficacy of pamidronate in combination with chemotherapy to bone metastasis of breast cancer in a rat model.

Bone metastasis is clinically often recognized in breast cancer patients, and in the progression of bone destruction due to bone metastasis, osteoclastic bone resorption is an important step. Therefore, drugs such as bisphosphonates-which have anti-osteoclastic activity-are expected to inhibit the progression of bone metastasis. However, bisphosphonates demonstrate no cytotoxic effects for cancer cells. In the present study we have evaluated the therapeutic efficacy of pamidronate (3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid) combined with mitomycin C (MMC) on bone metastasis of breast cancer using an animal model. The model for bone metastasis was developed by injecting c-SST-2 (spontaneously developed rat mammary adenocarcinoma in a SHR rat) cells into the thoracic aorta of 45-46 day-old female SHR rats. Three weeks after the tumour cell injection, these 48 animals were divided into four groups: control, n = 16; pamidronate, n = 12; MMC, n = 10; pamidronate with MMC, n = 10). In order to evaluate therapeutic effects on bone metastasis in each animal, the whole spine was harvested for histological examination. The bone metabolic markers used were: pyridinoline/creatinine (Pyd/Cr), deoxypyridinoline/creatinine (Dpd/Cr), bone alkaline phosphatase (BAP), and osteocalcin-measured 1 week after therapy. Histological scores of bone destruction in the treatment groups were lower than those of the control, and there were no differences among treatment groups. Although the values of Pyd/Cr and Dpd/Cr in the treatment groups, including pamidronate, were significantly lower than those in the control (P < 0.05), the other markers did not differ. It was suggested that pamidronate inhibited the progression of bone resorption, mainly by osteoclast activation due to bone metastasis, and Pyd/Cr and Dpd/Cr could be useful in part as a marker which reflects therapeutic effect. However, no additional effects were observed when it was combined with MMC.