Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.
Clodronate (clodronic acid, dichloromethylene bisphosphonate) is a bisphosphonate which has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption including Paget's disease, hypercalcaemia 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 for 5 days) or longer courses of oral clodronate (usually 1600 mg/day for 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 intravenously (300 mg/day for up to 12 days) to patients with malignant hypercalcaemia, serum calcium levels declined significantly within 2 days of starting treatment and approximately 70 to 95% of patients became normocalcaemic. While there is less experience with oral administration, clodronate (800 to 3200 mg/day) achieved normocalcaemia in the majority of patients, usually within 1 week, and serum calcium levels remained significantly reduced from baseline for up to 6 months with continued treatment. Clodronate is clearly superior to placebo and, based on a retrospective analysis, appears to produce greater and more sustained reductions in serum calcium levels than calcitonin in patients with malignant hypercalcaemia. The few available prospective comparative trials showed that clodronate is at least as effective as etidronate, but comparisons with alendronate and pamidronate produced results of questionable clinical relevance because of low bisphosphonate dosages used in these trials. Nevertheless, single intravenous doses of clodronate 600 mg or alendronate 7.5 mg (both agents repeated on day 3 if necessary) were comparable in efficacy, whereas a single intravenous dose of pamidronate 30 mg was more effective than a single intravenous dose of clodronate 600 mg. Normocalcaemic patients with osteolytic bone metastases due to advanced breast cancer experienced significant reductions in 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, following treatment with clodronate 1600 mg/day for 3 years in a large placebo-controlled study. A similar large placebo-controlled trial in patients with multiple myeloma demonstrated that clodronate 2400 mg/day orally for 2 years significantly reduced progression of osteolytic bone lesions. 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Plosker
G L
GL
Adis International Limited, Auckland, New Zealand.
Goa
K L
KL
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D002114:Calcinosis / Q000517:prevention & control; D002986:Clinical Trials as Topic; D004002:Clodronic Acid / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D006909:Hydroxyproline / Q000652:urine; D006934:Hypercalcemia / Q000188:drug therapy / Q000209:etiology; D007262:Infusions, Intravenous; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000150:complications; D010001:Osteitis Deformans / Q000188:drug therapy; D010024:Osteoporosis / Q000188:drug therapy; D014018:Tissue Distribution
D004002:Clodronic Acid; D006909:Hydroxyproline