Zoledronic Acid

Abstract

Zoledronic acid (Zometa®¹) is an effective inhibitor of osteoclast-mediated bone resorption. Zoledronic acid demonstrated efficacy in the reduction of skeletal-related events (SREs) in patients with multiple myeloma or bone metastases secondary to breast cancer, prostate cancer or other solid tumours, or hypercalcaemia of malignancy. Zoledronic acid was effective in patients with multiple myeloma or metastatic breast cancer with osteolytic or mixed bone lesions. The proportion of patients who experienced an SRE was similar during 12 months of treatment with zoledronic acid 4mg or pamidronic acid 90mg, but significantly fewer patients receiving zoledronic acid required radiotherapy to bone. Furthermore, in patients with breast cancer and osteolytic lesions, median time to a first SRE was more than 4 months longer with zoledronic acid than with pamidronic acid. In the multiple event analysis in a 12-month extension study (total study duration was 25 months) in patients with breast cancer, zoledronic acid was superior to pamidronic acid, with an 18% reduction in the risk of experiencing an SRE. Both drugs were associated with a slight reduction in pain. Zoledronic acid 4mg, compared with placebo, significantly reduced the proportion of patients with prostate cancer bone metastases experiencing an SRE, particularly pathological fractures after 15 months’ treatment. The drug also significantly delayed the onset of skeletal complications compared with placebo in patients with prostate cancer and other solid tumours including non-small cell lung cancer. When administered as a single 15-minute intravenous infusion, zoledronic acid 4mg was significantly more effective than pamidronic acid administered as a 2-hour infusion in the treatment of severe hypercalcaemia of malignancy, as assessed by complete responses measuring normalised serum calcium concentrations at day 10 after a single dose. Furthermore, zoledronic acid normalised serum calcium concentrations significantly faster than pamidronic acid, and the duration of response and median time to relapse were approximately twice as long in zoledronic acid recipients than in pamidronic acid recipients. Zoledronic acid is well tolerated and has a similar tolerability profile to pamidronic acid. The most commonly reported adverse events included flu-like symptoms (fever, arthralgias, myalgias and bone pain), fatigue, gastrointestinal reactions, anaemia, weakness, dyspnoea and oedema. Conclusion: In conjunction with antitumour therapy, zoledronic acid should be considered for routine use to reduce skeletal complications in patients with advanced malignancies involving bone. In patients with hypercalcaemia of malignancy, zoledronic acid is expected to become the treatment of choice. Zoledronic acid is an effective inhibitor of osteoclast activity and binds to calcified matrices, such as the hydroxyapatite phase of mineralised bone, preventing the attachment of more mature osteoclastic precursors to the bone surface. In vitro and in vivo studies suggest that zoledronic acid is a more effective inhibitor of osteoclast-mediated bone resorption than pamidronic acid. Furthermore, zoledronic acid and pamidronic acid decreased the proliferation of immortalised human fetal osteoblasts in cell culture, and promoted their differentiation and mineralisation. Clinical trials have also demonstrated that zoledronic acid has a clinically significant impact on mixed and osteoblastic metastases in patients with breast or prostate cancer, respectively. When administered intravenously as a single dose or every 4 weeks for up to 10 months to patients with multiple myeloma or bone metastases secondary to breast, prostate or non-small cell lung cancer (NSCLC), zoledronic acid reduced concentrations of all the measured markers of bone resorption (N-telopeptide, pyridinoline, deoxypyridinoline, hydroxyproline and calcium). The N-telopeptide/creatinine ratio was reduced to a similar extent with zoledronic acid 4mg and pamidronic acid 90mg after 10 months’ treatment. Zoledronic acid was also more effective than pamidronic acid (and all other bisphosphonates tested) at inhibiting calcitriol-induced hypercalcaemia in thyroparathyroidectomised rats. Most patients with hypercalcaemia of malignancy achieved normocalcaemia in a small dose-ranging study which found the most effective zoledronic acid doses to be at the high end of the range tested (1.2 and 2.4mg). Furthermore, zoledronic acid displayed in vitro antitumour activity, inhibiting the growth of multiple myeloma cells, breast cancer cells and prostate cancer cells via apoptosis, cell necrosis and/or cytostasis. Furthermore, zoledronic acid displayed in vitro antitumour activity, inhibiting the growth of multiple myeloma cells, breast cancer cells and prostate cancer cells via apoptosis, cell necrosis and/or cytostasis. The mean plasma concentration of zoledronic acid in patients with bone metastases was 264μg/L at the end of a 15-minute infusion of a 4mg dose. Plasma concentrations of the drug exhibited a rapid triphasic decline; 24 hours post-infusion, plasma concentrations of zoledronic acid were <1% of that immediately at the end of the infusion. Plasma half-lives for the first two phases of elimination were 0.24 and 1.87 hours, respectively. The terminal elimination phase was long, with low concentrations of zoledronic acid persisting in the plasma between days 2 and 28; the terminal elimination half-life was 146 hours. Zoledronic acid is not metabolised. Approximately 39% of an intravenous dose of 2–16mg was recovered in the urine within 24 hours. The remainder of the dose is thought to be bound to bone and slowly released back into the systemic circulation. Renal clearance of zoledronic acid during the first 24 hours after administration was 3.7 L/h. Results from three large randomised, double-blind, multicentre trials have...