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Letter to the Editor |
a Institute for Myeloma & Bone Cancer Research, West Hollywood, California, USA; b Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
Correspondence: James Berenson, M.D., Institute for Myeloma & Bone Cancer Research, 9201 W. Sunset Boulevard, Suite 300, West Hollywood, California 90069, USA. Telephone: 310-623-1214; Fax: 310-623-1120; e-mail: jberenson{at}myelomasource.org
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 from lung cancer or other solid tumors, decreases in renal function (defined as a rise in serum creatinine by 
0.5 mg/dl with normal baseline creatinine, 1.0 mg/dl with abnormal baseline creatinine, or 2 times baseline) were not statistically different between patients treated with zoledronic acid (4 mg/15 minutes; n = 254) and patients administered placebo (n = 247) in both incidence and time to first episode of increased serum creatinine [4]. No patient treated with 4 mg zoledronic acid experienced a grade 3/4 increase in serum creatinine, whereas two patients (0.9%) treated with placebo did experience such increases. Similarly, in a randomized, controlled trial of zoledronic acid in patients with metastatic prostate cancer, the relative risk for increased serum creatinine between patients treated with 4 mg zoledronic acid and those treated with placebo was 1.07 (95% confidence interval, 0.46–2.47; p = .882), indicating a slightly, nonsignificantly higher risk for decreased renal function compared with placebo [10].
Given the lack of direct safety and efficacy comparisons in prospective, randomized clinical trials of ibandronate with any other i.v. bisphosphonate in the treatment of patients with bone metastases to prevent SREs, safety comparisons with zoledronic acid in these populations can only be inferential and, therefore, not scientifically robust. Published data from randomized, controlled trials of i.v. ibandronate in comparison with placebo are available for patients with breast cancer and bone metastases [6]. However, in that report, the authors do not provide detailed information regarding the renal safety of ibandronate; only a brief statement that increased creatinine levels (defined as 300 mM*) occurred with ibandronate (6 mg/1–2 hours) numerically twice as often as with placebo. The 2-mg dose of ibandronate had a numerically lower incidence of a rise in serum creatinine than placebo, but this dose of ibandronate was ineffective. This lack of efficacy for the 2-mg ibandronate dose was also demonstrated in patients with multiple myeloma [11].
In contrast, in a recently published report of a randomized, double-blind, placebo-controlled, phase III trial of the efficacy of 4 mg zoledronic acid for the prevention of skeletal complications in 227 Japanese women with breast cancer and osteolytic bone metastases, only one (0.9%) patient treated with zoledronic acid experienced an increased serum creatinine level, with the caveat that inclusion criteria for patients in that trial required baseline serum creatinine levels of 
2.0 mg/dl [12]. While understanding the pitfalls of cross-trial comparisons, zoledronic acid (4 mg/15 min) does not appear to be less safe than ibandronate (6 mg/1–2 hours). Moreover, in the pivotal zoledronic acid trials, the threshold that was used to define increased serum creatinine appears to have been more stringent.
Additionally, in their letter, Diel and Bergner cite experimental studies in rats purporting greater nephrotoxicity of zoledronic acid compared with ibandronate [13]. The limitations in the design and conduct of those studies have been discussed in detail elsewhere [14]. Briefly, both ibandronate and zoledronic acid were administered to rats by i.v. bolus injection (whereas zoledronic acid is always administered as an infusion in clinical use) at doses of 1 mg/kg and 1 or 3 mg/kg, respectively. Those doses were derived from subjective renal histology scores in a small pilot rat study and did not take into account the several-fold-higher potency of zoledronic acid. Moreover, the doses selected for zoledronic acid were several times higher than its clinically proven effective dose, whereas ibandronate was tested at only one dose far below such a multiple of its own clinical efficacy. Also, when single 1-mg/kg doses of zoledronic acid and ibandronate were compared, renal pathology was seen only with ibandronate. Therefore, the authors’ conclusion that renal injury depends on the specific renal tissue half-life and dosing interval are not supported by any data in the manuscript.
The arguments by Diel and Bergner that ibandronate shows less toxicity than zoledronic acid are in part based on the incorrect assumption that ibandronate has a shorter tissue half-life, leading to less accumulation of drug in the kidney. The reported ibandronate half-life is clearly an underestimate, owing to the acknowledged short sampling period and the limited sensitivity of bioanalytical methodology [15], whereas the reported terminal half-life of zoledronic acid, which is 146 hours, was derived from prolonged sampling for >1 month post-dose, therefore representing skeletal as well as soft-tissue components of the drug’s disposition [16].
Diel and Bergner also provide case series of decreases in renal function in patients receiving zoledronic acid and point out that these reports are more frequent with zoledronic acid than with other bisphosphonates. Zoledronic acid is the only third-generation bisphosphonate with worldwide regulatory approval for broad indications in patients, including tumor-induced hypercalcemia and advanced malignancies and bone metastases, and is the most commonly prescribed bisphosphonate. The authors of the letter omitted to mention that other third-generation, i.v. bisphosphonates, such as ibandronate, are not FDA approved for the treatment of bone metastases and, presumably, are also not as widely used in the treatment of these patients. Ibandronate, although approved for the treatment of hypercalcemia, is only approved in Europe for the treatment of bone metastases and only for the treatment of bone metastases from breast cancer. Markowitz and associates [17] reported six patients, most of whom had multiple myeloma, who developed renal insufficiency while receiving zoledronic acid, among other therapies. In those cases, toxic acute tubular necrosis was diagnosed, and circumstantial evidence implicated zoledronic acid as a causative or contributing agent. We were not able to include a discussion of that report because it was published after revised submission of our manuscript. In three of those six cases, other associated renal diseases that may have also contributed to the rise in serum creatinine were identified in biopsy specimens. Moreover, the increases in serum creatinine levels were CTC grade 3, and all patients had subsequent recoveries of renal function. In addition, acute renal injury has also been reported with other bisphosphonates [18–22], which justifies our speculation as to a class effect of i.v. bisphosphonates.
Other retrospective, observational series that are presented in the letter by Diel and Bergner describe renal functional deterioration during therapy with zoledronic acid and pamidronate. Those reports are important but need to be placed into critical perspective. The studies lacked valid controls, rendering it impossible to assess the incidence of renal complications associated with bisphosphonate use compared with that intrinsic to the patient population that was evaluated, which is thought to have been rather substantial [23]. Moreover, Diel and Bergner’s interpretation of those reports, which were published only in abstract form, lacks scientific rigor [24–26]. In the report by Stein et al. [26], apparently none of the patients treated with zoledronic acid developed substantial renal insufficiency. With zoledronic acid and prior pamidronate exposure, serum creatinine rose by 0.14 ± 0.2 mg/dl (from 0.7 ± 0.2 to 0.8 ± 0.3), and without prior pamidronate exposure, it rose by 0.11 ± 0.3 (from 0.7 ± 0.2 to 0.8 ± 0.4) after a mean of 5–9 doses [26]. It is unclear what useful conclusion can be derived from these data. Mazj and Lichtman [25] reported a similar incidence of renal function deterioration in patients treated with either zoledronic acid or pamidronate to those reported in controlled clinical trials of zoledronic acid. These retrospective analyses were uncontrolled and were not corrected for associated comorbidities or other concurrent drugs with known nephrotoxicity. Furthermore, the background incidence of renal insufficiency in the study population was not reported, and no effort was made to evaluate causality. Moreover, the statement by Diel and Bergner regarding the study by Johnson et al.—that four patients died due to renal complications—does not correspond to the reference that is provided [24].
Diel and Bergner’s charge of "presenting a case for the renal safety of zoledronic acid by 5-minute infusion" misrepresents the content of our manuscript. Historically, this short infusion interval was used during clinical trials of zoledronic acid, and this fact is correctly discussed in the manuscript. Nevertheless, in several places in the paper, we repeatedly and categorically indicate that 4 mg zoledronic acid should be administered over no less than a 15-minute period, which is consistent with the approved labeling of the drug.
In summary, our manuscript provides a concise and comprehensive review of the efficacy and safety of i.v. bisphosphonates in the prevention of complications of malignancies [1]. Among third-generation bisphosphonates, zoledronic acid has the broadest efficacy, as demonstrated in the largest series of randomized and controlled clinical trials available for any bisphosphonate in oncology. The renal safety of zoledronic acid has also been examined in these studies. Renal toxicity has been observed in zoledronic acid clinical trials as well as in case reports and case series and has also been reported with other bisphosphonates. We agree with Diel and Bergner that renal function monitoring in patients with malignancies who undergo bisphosphonate therapy is strongly advised.
FOOTNOTE
*Perhaps this is a typographical error in the reference manuscript as well as in a subsequently published corrigendum [6] and should read "300 µM" (= 3.4 mg/dl). Either way, this would be a far less stringent definition of increased serum creatinine than that used in the zoledronic acid pivotal trials. The incidence of increased serum creatinine was 2.6% with 6 mg ibandronate versus 1.3% for placebo. Unfortunately, the published corrigendum, which listed the incidence of "clinically relevant" increases in serum creatinine, also failed to provide a definition of the term "clinically relevant," making assessment of renal safety criteria in that trial difficult [6].
REFERENCES
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  P. Conte and V. Guarneri In Response to Jackson Letter to the Editor Regarding "Safety of Intravenous and Oral Bisphosphonates and Compliance with Dosing Regimens" Oncologist, May 1, 2005; 10(5): 315 - 316. [Full Text] [PDF]
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