Institut J. Bordet, Universite Libre de Bruxelles, Brussels, Belgium
Bone metastases constitute a frequent complication of advanced cancer and they are the source of a considerable morbidity including pain and functional disability, fractures, hypercalcemia, and epidural compression. Osteoclast activation is the fundamental process underlying the progression of lytic bone metastases and the development of tumorinduced hypercalcemia (TIH). The clinical introduction of bisphosphonates has dramatically changed the therapeutic approach to this frequent complication of malignancy. Most of the data have been obtained with clodronate and with pamidro-nate (ArediaR) which is a more potent inhibitor of osteoclastic bone resorption. Intravenous pamidronate can indeed normalize serum calcium in 90 to 95 % of hypercalcemic caricer patients. The optimal dose ranges between 60 and 90 mg (or 1.0 to 1.5 mg/kg body-weight). This dose can be given either as a single infusion lasting 6 to 24 hours or can be divided into two or three daily 2-hour infusions. Our results in 160 patients indicate that the fall in serum and urinary calcium after such doses of pamidronate is not significantly influenced by the primary tumor site or the type of cancer hypercalcemia.
Several phase II trials with pamidronate have now been performed in normocalcemic patients with tumor-induced osteolysis (TIO). These studies were not placebo--controlled but they indicate that relief of bone pain could occur in up to 50% of the cases and sclerosis of lytic lesions in about 20%. Objective sclerosis of osteolytic lesions can thus be obtained in patients with advanced cancer and receiving only bisphosphoriate therapy. The optimal therapeutic scheme remains however to be denned. In a biochemical dose-finding study including 47 normocalcemic patients with TIO treated by single pamidronate infusions at doses ranging from 15 to 120 mg, we have demonstrated a prolonged inhibitory effect on bone resorption, estimated by the fasting uCa excretion (up to 2 months), and a significantly greater effect of the 90—120 mg doses compared to the 15—60 mg doses. On the other hand, long term administration of oral pamidronate to patients with breast cancer inhibits bone resorption and could reduce the occurrence of fractures, of hypercalcemic episodes and the development of new bone lesions. Placebo-controlled and doseresponse trials are ongoing to confirm these results and to define the optimal therapeutic schemes. Trials are also underway to prevent bone metastatic infiltration in high-risk patients.
Place of bisphosphonates in the management of cancer hypercalcemia and bone metastases
