Preclinical pharmacology of zoledronic acid

Abstract

The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates with ever-increasing potency. Recent studies have begun to shed light on the unique mechanism of action and pharmacologic properties of these compounds. On the basis of in vitro studies and animal models of osteoclast-mediated bone resorption, zoledronic acid is the most potent bisphosphonate among a large number of compounds tested, including pamidronate and most other commercially available bisphosphonates. Zoledronic acid maintains bone mass in estrogen-deficient animals without adversely affecting bone mineralization. Moreover, the high potency of zoledronic acid translates into dramatic suppression of bone resorption markers at very low doses in patients with bone metastases, and zoledronic acid has shown efficacy across a broad range of tumor types. Preclinical studies have also shown the potential of bisphosphonates to inhibit tumor cell growth and colonization of the bone and to reduce skeletal tumor burden in animal models. A variety of mechanisms have been proposed to explain these observations and continue to be investigated in animal models. Studies are ongoing to determine if the antitumor potential of bisphosphonates can be exploited in the clinical setting.