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The Oncologist, Vol. 10, No. 5, 315-316, May 2005; doi:10.1634/theoncologist.10-5-315
© 2005 AlphaMed Press

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Letter to the Editor

In Response to Jackson Letter to the Editor Regarding "Safety of Intravenous and Oral Bisphosphonates and Compliance with Dosing Regimens"

PierFranco Conte, Valentina Guarneri

Department of Oncology and Hematology, University Hospital, Modena, Italy

Correspondence: PierFranco Conte, M.D., Department of Oncology and Hematology, University Hospital, Modena, Italy. Telephone: 39-059-4224538; Fax: 39-059-4224429; e-mail: conte.pierfranco{at}unimore.it

Dr. Jackson’s criticism of the statements made in our review article seems to stem from the opinion that the renal safety of zoledronic acid is somehow different from that of other i.v. bisphosphonates, particularly i.v. ibandronate. However, this opinion runs counter to published data from >3,000 patients treated with zoledronic acid in randomized phase III trials, and no prospective data directly compare the renal safety of zoledronic acid and ibandronate. In a large, randomized trial of zoledronic acid versus pamidronate in patients with breast cancer or multiple myeloma, the renal safety profile of zoledronic acid at the recommended dose (4 mg via 15-minute infusion) was not different from that of pamidronate (90 mg via 2-hour infusion) [1, 2]. Kaplan-Meier analysis of serum creatinine increases over 2 years demonstrateda risk ratio of 1.057 (p = .839) [2]. Moreover, several randomized, multicenter, placebo-controlled trials have shown no significant difference in renal tolerability between zoledronic acid (4 mg via 15-minute infusion) and placebo with long-term use [3–5]. Moreover, the incidence of CTC grade 3 or 4 serum creatinine increases in these trials was extremely low.

The merits of published reports cited by Dr. Jackson that presumably demonstrate renal safety issues with zoledronic acid must be evaluated individually [6]. For example, Chang et al. [7] reported 72 cases of renal failure among >430,000 (<0.02%) patients treated with zoledronic acid over 2 years; these patients with advanced cancer had many other risk factors that could have caused renal failure. In two American Society of Clinical Oncology (ASCO) abstracts cited by Dr. Jackson, the frequency of serum creatinine increases (defined on the basis of conservative parameters used in the zoledronic acid phase III trials) was quite variable. In a retrospective study by Johnson et al. [8], the frequency was rather high, but there was no indication of how long patients had been previously treated with pamidronate before switching to zoledronic acid or of other risk factors for renal dysfunction. In a study by Kloth et al. [9] involving 234 evaluable patients, increases in serum creatinine occurred in 4% of patients, primarily those with pre-existing renal impairment or receiving concomitant nephrotoxic agents. Our group recently reported an increase in serum creatinine (all CTC grade 1) in 7.8% of patients treated for up to 10 years with i.v. bisphosphonates including zoledronic acid [10]. These uncontrolled studies must be put into context on the basis of the larger clinical experience with zoledronic acid in well-controlled trials.

Finally, monitoring of renal function is recommended for all i.v. bisphosphonates, based on published ASCO guidelines [11, 12], because all i.v. bisphosphonates have the potential to adversely affect renal function [13]. Use of zoledronic acid is not indicated for patients with serum creatinine >265 µmol/l (>3.0 mg/dl) only because limited clinical data are available on the safety of zoledronic acid in these patients. The statement on page 32 regarding the use of i.v. ibandronate (with the recommended dose adjustment to 2 mg) in patients with severe renal impairment is based on the demonstrated lack of efficacy of 2 mg ibandronate compared with placebo [14].

Therefore, the conclusions drawn and the specific statements made in our review article are accurate and justified on the basis of available clinical data, and will in no way compromise patient safety.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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Dr. Conte has served as a consultant for Novartis.


   REFERENCES
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  1. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377–387.[Medline]
  2. Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735–1744.[CrossRef][Medline]
  3. Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–1468.[Abstract/Free Full Text]
  4. Rosen LS, Gordon D, Tchekmedyian S et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial — the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–3157.[Abstract/Free Full Text]
  5. Kohno N, Aogi K, Minami H et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005. [Epub ahead of print].
  6. Berenson J, Hirschberg R. 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. The Oncologist 2005;10:84–87.[Free Full Text]
  7. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003;349:1676–1679.[Free Full Text]
  8. Johnson KB, Gable P, Kaime EM et al. Significant deterioration in renal function with the new bisphosphonate, zoledronic acid. Proc Am Soc Clin Oncol 2003;22:738.
  9. Kloth DD, McDermott RS, Rogatko A et al. Impact of zoledronic acid (Zol) on renal function in patients (pts) with cancer: is constant monitoring necessary? Proc Am Soc Clin Oncol 2003;22:775.
  10. Guarneri V, Donati S, Nicolini M et al. Renal safety of zoledronic acid in patients with bone metastases from breast cancer (BC) or other tumors treated with IV bisphosphonates (BPS) for up to ten years. Ann Oncol 2004;15:811.
  11. Berenson JR, Hillner BE, Kyle RA et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20:3719–3736.[Abstract/Free Full Text]
  12. Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer [Published erratum in: J Clin Oncol 2004; 22:1351]. J Clin Oncol 2003;21:4042–4057.[Abstract/Free Full Text]
  13. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999;21:389–406.[CrossRef][Medline]
  14. Body JJ, Diel IJ, Lichinitser MR et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399–1405.[Abstract/Free Full Text]
Received March 16, 2005; accepted for publication March 16, 2005.




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