Advances in the biology and treatment of myeloma bone disease.

Potential antitumor effects of bisphosphonates are discussed, and trial results of zoledronic acid, a bisphosphonate that recently received FDA approval for the treatment of hypercalcemia of malignancy (HCM), are described. Substitution at two sites on the central carbon in the phosphate-carbon-phosphate backbone has resulted in bisphosphonates increasingly more potent than the first such drug, etidronate disodium. Besides having an antihypercalcemic effect, the nitrogen-containing bisphosphonates pamidronate disodium and zoledronic acid have been shown to have an antitumor effect. Possible mechanisms include inducing apoptosis in tumor cells, inhibiting angiogenesis, and reducing adherence of cancer cells to the bone matrix. Zoledronic acid 4 mg is superior to pamidronate disodium 90 mg in achieving a normal serum calcium concentration, without increased toxicity. Zoledronic acid has a higher response rate, faster onset, and longer duration of action, and is more convenient to administer. Doses of > or = 1.5 mg given every four weeks for three months resulted in sustained reductions in urinary markers of bone resorption. Clinical trial results suggest that zoledronic acid 4 mg is at least as effective as pamidronate disodium 90 mg in preventing skeletal complications of osteolytic disease. Zoledronic acid is superior to pamidronate disodium in treating HCM and more convenient to administer. More research to evaluate its safety and effectiveness at higher doses is needed before its full antitumor potential is realized.