PHARMACOLOGY AND CLINICAL USE OF BISPHOSPHONATES IN ONCOLOGY

The bisphosphonates are substances which are chemically characterized by a P-C-P bond. As analogues of pyrophosphate these compounds have a high affinity for bone mineral and only little or no effect on other tissues. Acute and chronic toxicity studies revealed the kidney as the primary target organ for toxicity. Gastrointestinal toxicity has been reported at high oral doses. No significant hematological changes and changes to the immune system have been described. The osteoprotective effect of bisphosphonates has been shown in various animal models with different types of tumor cells. The precise mechanism of action of the bisphosphonates is not clear. They have no direct effect on tumor cells but make bone more resistant against osteolysis and tumor invasion. The intestinal absorption of all bisphosphonates is low and highly variable. The absorbed drug is cleared rapidly from the blood and either excreted in the urine (80%) or incorporated into bone (20%). The retention half-life in bone is long and depends upon the turnover of the skeleton. Bisphosphonates can be used successfully in the treatment of hypercalcemia of malignancy. There are many published reports showing that the usual dose regimen of clodronate, i.v. infusion of 300 mg daily for 5 days, is effective in normalizing hypercalcemia in about 90% of patients. In a recent study, a single intravenous infusion of 1,500 mg was as effective in reducing serum calcium as the same dose given over 5 days without inducing adverse effects. In two pilot studies in multiple myeloma patients the progression of skeletal destruction and the incidence of new osteolytic lesions was reduced by long-term clodronate treatment. This finding was recently confirmed in a placebo-controlled trial in 350 newly diagnosed patients with multiple myeloma. Oral clodronate therapy for 24 months reduced the progression of osteolytic bone lesions. A significant decrease in the incidence of new osteolytic lesions was also found in a prospective study with a median follow-up of 24 months using intermittent parenteral clodronate. This was associated in both studies with a reduction in bone pain, hypercalcemic episodes and pathological fractures. A most interesting finding is the preliminary result of an impressive gain in bone mass within 6 months of clodronate treatment in myeloma patients in contrast to a rapid loss of bone mineral at the same time in the control group. Two further controlled studies are now in progress examining the long-term effects of clodronate in multiple myeloma. A double-blind, placebo-controlled study in 173 patients with bone metastases due to breast cancer demonstrated that antiosteolytic therapy decreased the morbidity from skeletal complications. Treatment with oral clodronate (1,600 mg/day) significantly reduced the number of hypercalcemic episodes and the incidence of vertebral fractures compared to placebo. Improvement in bone pain was demonstrated by reduced radiotherapy requirements for spinal bone pain in the clodronate group. A similar effect had been noted previously in an open study with pamidronate in patients with bone metastases due to advanced breast cancer. An increase in bone mineral density of the lumbar spine was also found in breast cancer patients after clodronate treatment. In patients with bone metastases due to prostate cancer a symptomatic benefit of bisphosphonate therapy has been observed in studies with continuous oral treatment or with intermittent intravenous administration of clodronate. A dosage regimen of 300 mg clodronate daily as intravenous infusion for 1 week followed by oral maintenance of 1,600 mg/day induced definite pain relief in patients with progressive hormone-refractory prostate cancer. Symptomatic improvement was also found with oral administration of clodronate in a placebo-controlled trial including 81 patients with prostatic cancer. The beneficial effect of antiosteolytic agents, particularly clodronate, in tumor-induced hypercalcemia and osteolysis appears to be well established and holds the promise to improve the quality of life of cancer patients by decreasing the incidence of bone pain, hypercalcemia and fractures.