Zoledronic acid (Zometa (R)), a third-generation amino-bisphosphonate, has been approved in the US, the EU and many other countries worldwide for the prevention of skeletal-related events in patients with bone metastases of malignancy. In several well designed trials, zoledronic acid 4 mg administered as a 15-minute infusion every 3-4 weeks was effective in reducing the occurrence of skeletal complications in patients with bone metastases secondary to multiple myeloma, breast cancer or prostate cancer. Zoledronic acid was as effective as pamidronic acid in reducing the occurrence of skeletal complications in patients with multiple myeloma or breast cancer. In patients with solid tumours other than breast or prostate cancer, zoledronic acid did not show significant clinical benefit over placebo in terms of the primary endpoint; however, some benefit of therapy in terms of secondary endpoints was observed with zoledronic acid relative to placebo. Its efficacy in a broad range of tumours and short infusion time (15 minutes) are an advantage over other available bisphosphonates. Modelled pharmacoeconomic analyses in patients with breast cancer suggested that zoledronic acid therapy is cost effective relative to no therapy with regard to the cost per quality-adjusted life-year (QALY) gained; however, results were mixed when zoledronic acid was compared with other commonly used bisphosphonates. Zoledronic acid is generally well tolerated; the risk of osteonecrosis of the jaw may be minimized by adhering to recommendations regarding dental therapy. Additional efficacy and economic data are required to definitively position zoledronic acid with respect to other bisphosphonates. Nevertheless, available clinical data indicate that zoledronic acid is an effective treatment option for the management of bone metastases of malignancy. Pharmacological Properties Zoledronic acid accumulates rapidly in bone tissue, binding with high affinity to hydroxyapatite of bone. During bone resorption, it is released from bone surfaces and internalized by osteoclasts, where it mediates its antiresorptive activity by inhibiting the mevalonate pathway, which may be critical in inducing the pharmacodynamic effects of the drug (e.g. inhibition of bone resorption and induction of apoptosis in osteoclasts). Plasma concentrations of zoledronic acid increase rapidly to peak at the end of the infusion period, with a rapid decline to <10% of peak at 4 hours and <1% at 24 hours after the infusion. A large part of the dose is bound to bone tissue and released slowly into the systemic circulation, accounting for the low, prolonged serum concentration of the drug. Zoledronic acid is not metabolized and is excreted unchanged via the kidneys, with approximate to 39% (mean) of the dose being recovered in urine over the first 24 hours after infusion and the majority of the remainder being taken up by bone. Therapeutic Efficacy Intravenous zoledronic acid was effective in preventing skeletal complications in several randomized phase III clinical trials in patients with bone metastases secondary to multiple myeloma, breast cancer or prostate cancer. In a 12-month, placebo-controlled trial in Japanese women with breast cancer, zoledronic acid 4 mg therapy was associated with fewer skeletal complications than with placebo. The adjusted skeletal-related event (SRE) rate ratio between the two treatment groups was 0.61 (primary endpoint). Similarly, 12 months' zoledronic acid therapy was also effective in a noncomparative trial in breast cancer patients with newly diagnosed (<= 6 weeks) bone metastases. Zoledronic acid 4 mg was as effective as pamidronic acid 90 mg in a randomized, double-blind trial in patients with multiple myeloma or breast cancer. There was no significant between-group difference in terms of the overall number of patients experiencing at least one SIZE in zoledronic acid and pamidronic acid recipients at 13 and 25 months (44% vs 46% and 47% vs 51%; primary endpoint). Furthermore, there were no significant between-group differences in terms of secondary endpoints, including health-related quality-of-life measures. Zoledronic acid 4 mg was effective in terms of reducing the number of patients experiencing at least one SIZE (primary endpoint) in a trial in patients with hormone-refractory prostate cancer. Fewer (p < 0.05) zoledronic acid 4 mg than placebo recipients experienced at least one SIZE after 15 or 24 months' therapy (33% vs 44% and 38% vs 49%). At 24 months, the median time to first SIZE was 488 days with zoledronic acid compared with 321 days with placebo. In a phase III trial in patients with solid tumours other than breast or prostate cancer, at 9 and 21 months, the proportion of patients experiencing at least one SIZE was similar in zoledronic acid 4 mg and placebo recipients (primary endpoint). However, zoledronic acid therapy significantly (p < 0.05) reduced the risk of experiencing an SIZE and extended the median time to SIZE at 21 months. Pharmacoeconomic Cost-utility analyses in patients with breast cancer suggested that zoledronic acid Analyses therapy is cost effective relative to no therapy with regard to cost per QALY gained. When compared with other bisphosphonates in patients with breast cancer, zoledronic acid therapy was cost effective relative to comparators in analyses from healthcare payer perspectives in several countries, but was dominated by ibandronic acid in analyses of subgroups of breast cancer patients receiving chemotherapy or hormonal therapy. In patients with prostate cancer, the cost per QALY gained with zoledronic acid versus placebo therapy in a 15-month cost-utility analysis exceeded that of the commonly accepted willingness-to-pay threshold of $US50000. Tolerability Zoledronic acid 4 mg was generally well tolerated in patients with bone metastases of malignancy, with adverse events being generally mild to moderate in severity. In pooled data from clinical trials, the most common suspected drug-related adverse events in zoledronic acid recipients were bone pain (9.1%), pyrexia (7.2%) and nausea (5.8%). The tolerability profile of zoledronic acid was generally similar to that of pamidronic acid. The overall incidence of suspected drug-related adverse events was 35.2%, 35.0% and 20.2% in zoledronic acid, pamidronic acid and placebo recipients, respectively. Few (<3%) patients in any treatment group had grade 3 or 4 hypocalcaemia, hypomagnesaemia, hypermagnesaemia or decrease in the levels of serum creatinine. Furthermore, the tolerability profile of the drug during extended (<= 24 months) therapy was generally similar to that observed during <= 15 months' therapy. There have been reports of osteonecrosis of the jaw in cancer patients receiving zoledronic acid therapy in several post-marketing studies, where the majority of cases were associated with dental procedures.
