CLODRONATE - A REVIEW OF ITS PHARMACOLOGICAL PROPERTIES AND THERAPEUTIC EFFICACY IN RESORPTIVE BONE-DISEASE

Clodronate (clodronic acid, dichloromethylene bisphosphonate) is a bis phosphonate which has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption including Paget's disease, hy percalcaemia of malignancy and osteolytic bone metastases. In addition , early reports demonstrating potential efficacy of clodronate in the treatment of osteoporosis suggest a possible role in this debilitating disease. Short term intravenous administration (usually 300 mg/day fo r 5 days) or longer courses of oral clodronate (usually 1600 mg/day fo r 6 months) effectively reduced bone pain and/or improved mobility in most patients with Paget's disease, and these effects persisted for up to 12 months after discontinuing clodronate. When administered intrav enously (300 mg/day for up to 12 days) to patients with malignant hype rcalcaemia, serum calcium levels declined significantly within 2 days of starting treatment and approximately 70 to 95% of patients became n ormocalcaemic. While there is less experience with oral administration , clodronate (800 to 3200 mg/day) achieved normocalcaemia in the major ity of patients, usually within 1 week, and serum calcium levels remai ned significantly reduced from baseline for up to 6 months with contin ued treatment. Clodronate is clearly superior to placebo and, based on a retrospective analysis, appears to produce greater and more sustain ed reductions in serum calcium levels than calcitonin in patients with malignant hypercalcaemia. The few available prospective comparative t rials showed that clodronate is a least as effective as etidronate, bu t comparisons with alendronate and pamidronate produced results of que stionable clinical relevance because of low bisphosphonate dosages use d in these trials. Nevertheless, single intravenous doses of clodronat e 600mg or alendronate 7.5mg (both agents repeated on day 3 if necessa ry) were comparable in efficacy, whereas a single intravenous dose of pamidronate 30mg was more effective than a single intravenous dose of clodronate 600mg. Normocalcaemic patients with osteolytic bone metasta ses due to advanced breast cancer experienced significant reductions i n the number of episodes of hypercalcaemia and terminal hypercalcaemia , incidence of vertebral fractures and overall rate of morbid events, including the need for radiotherapy to treat bone-related pain, follow ing treatment with clodronate 1600 mg/day for 3 years in a large place bo-controlled study. A similar large placebo-controlled trial in patie nts with multiple myeloma demonstrated that clodronate 2400 mg/day ora lly for 2 years significantly reduced progression of osteolytic bone l esions. Follow-up data from clinical trials revealed that the effects on development of fractures and hypercalcaemia persisted for at least 12 months after the drug was discontinued. Preliminary data on the use of clodronate in treating patients with osteoporosis are encouraging and suggest that the drug reduces bone loss and can increase lumbar bo ne density in these patients. However, long term (greater than or equa l to 3 years) clinical trials, which are necessary to adequately asses s the effects of bisphosphonate therapy, have yet to be completed with clodronate. Data from clinical trials indicate that both intravenous and oral administration of clodronate are generally well tolerated, an d indirect comparisons suggest better tolerability of clodronate than pamidronate when these drugs are administered orally.,