In Response to Diel I, Bergner R. Letter to the Editor of The Oncologist Re: Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid (2005)

The Oncologist 2005;10:84-87 www.TheOncologist.com Diel and Bergner take objection to some of the statements that were made in our manuscript [1]. In their letter, these two authors propose that we did not appropriately address renal safety concerns, especially with zoledronic acid (Zometa®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com) in comparison with ibandronate (Bondronat®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com). While we share their concern of the nephrotoxicity of i.v. bisphosphonates, we respectfully disagree with several imprecise remarks made by Diel and Bergner. In the manuscript, we reviewed in detail the renal safety findings from prospective, randomized, controlled clinical trials, which is the accepted gold standard for the determination of clinical efficacy and safety of medicinal drugs. Those trials, which included more than 3,000 patients, have demonstrated the superior efficacy of zoledronic acid in the treatment of hypercalcemia of malignancy (HCM), exceeding that of pamidronate (Aredia®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis. com), and in the prevention of skeletal-related events (SREs) in patients with multiple myeloma or documented bone metastases from solid tumors [2–5]. Zoledronic acid is approved for the treatment of all these conditions and, hence, has the broadest U.S. Food and Drug Administration (FDA) approval among all i.v. bisphosphonates. In contrast, i.v. ibandronate is not FDA approved, and data on the efficacy and safety of this bisphosphonate in patients with bone metastases are available only from one published prospective, randomized clinical trial, which enrolled 466 patients [6]. Moreover, clinical trial data providing a direct comparison of the efficacy and/or safety of i.v. ibandronate with those of pamidronate show only equivalent efficacy of ibandronate (4 mg) to pamidronate (60 mg) in the treatment of HCM [7]. In contrast, 4 mg zoledronic acid has been examined in two randomized, prospective trials in direct comparison with 90 mg pamidronate [2, 3]. In patients with HCM, the efficacy of zoledronic acid surpasses that of pamidronate in normalizing serum calcium [2]. In patients with breast cancer and documented bone metastases, 4 mg zoledronic acid was significantly more effective than 90 mg pamidronate in reducing the overall risk of developing an SRE [8, 9]. Neither ibandronate nor any other i.v. bisphosphonate has, to date, been shown to have greater or, in the least, similar overall efficacy. Safety comparisons between two bisphosphonates are only meaningful when balanced for efficacy. As reviewed in our manuscript (page 322), 4 mg zoledronic acid was associated with slightly lower incidences of National Cancer Institute Common Toxicity Criteria (CTC) grade 4 (0% versus 1%) and grade 3 (2% versus 3%) serum creatinine levels in comparison with pamidronate in a pooled analysis of patients with HCM [2]. In patients with skeletal lesions from breast cancer or multiple myeloma, the incidence of stringently defined increases in serum creatinine levels with 4 mg zoledronic acid via a 15-minute infusion (8.9%) is similar to that of 90 mg pamidronate via a 2-hour infusion (8.2%) [3]. These data were also described in detail in the manuscript (page 324). In a large, randomized, placebo-controlled trial of patients with bone metastases The Oncologist Letter to the Editor