While all bisphosphonates have a common basic structure, differences in substituents strongly influence the pharmacologic properties of these compounds. A large number of bisphosphonate analogs were evaluated in an effort to identify a new, high-potency, bisphosphonate that would meet the chemical and biological requirements for a potentially effective and safe antiresorptive treatment. Important parameters that were evaluated included inhibition of bone resorption, lack of effect on bone mineralization, tolerability (particularly renal), molecular mechanism of action, and the ability to prevent bone changes associated with estrogen deficiency. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a bisphosphonate characterized by an imidazole substituent, was selected for further development based on its potent antiresorptive effects in vitro and in vivo, minimal inhibition of bone mineralization, and improved therapeutic ratio (antiresorptive effects v renal tolerability). Zoledronic acid was 2 to 3 orders of magnitude more potent than pamidronate in bone resorption assays, but showed a 3-fold greater renal tolerability than pamidronate. Like other nitrogen-containing bisphosphonates, zoledronic acid inhibits protein prenylation in osteoclasts, confirming a molecular basis for its pharmacologic activity. In long-term animal studies in ovariectomized rats and monkeys, zoledronic acid was able to prevent all the bone changes associated with estrogen deficiency. These studies provided support for further clinical development of this compound in both benign and malignant diseases characterized by excessive bone resorption.