Clodronate

Clodronate is a second-generation bisphosphonate of intermediate potency between etidronate and aminobisphosphonates. It is an effective inhibitor of bone resorption, but unlike etidronate does not impair the mineralization of bone. Unlike pamidronate, it can be given both intravenously and orally. There is wide experience in the use of clodronate in the management of patients of hypercalcemia. The most widely used therapeutic regimen is 300 mg intravenously repeated for 5 days or a single infusion of 1500 mg. Efficacy is nearly complete in patients with myelomatosis, less complete in solid tumors with hypercalcemia but without skeletal metastases, and intermediate in patients with solid tumors in the presence of skeletal metastases. Variations in effect appear to be due to differences in renal tubular reabsorption of calcium between the three disorders. Placebo-controlled studies examining the effects of clodronate on bone pain in the absence of hypercalcemia have shown significant decreases in the severity of bone pain. These findings, coupled with the knowledge that suppression of bone resorption persists for the duration of treatment, has led to the long term use of oral doses of clodronate to decrease the incidence of complications of osteolytic bone disease. The long term control of bone resorption with oral clodronate has been demonstrated by double blind histologic studies. The ultimate arbiter of the value of clodronate is whether it decreases the skeletal morbidity associated with osteolysis. Double blind prospective controlled studies suggest that the incidence of bone pain, fracture, and hypercalcemia can be decreased significantly in patients with breast carcinoma. In addition, the use of long term clodronate in patients with myelomatosis significantly decreases the progression of osteolytic bone lesions, the risk of fractures, and the incidence of hypercalcemia. These studies have raised the possibility that bone disease might be prevented in individuals at high risk. Double blind prospective studies in women with recurrent breast carcinoma but no evidence of skeletal metastases showed a small effect of clodronate in decreasing the proportion of women developing metastatic disease. However, there was a large and significant decrease in the number of skeletal metastases associated with a decrease in skeletal morbidity. These observations suggest that clodronate may modify the natural history of the expression of skeletal disease, and thereby significantly improve the quality of life of affected patients.