The Oncologist, Vol. 10, No. 5, 311-312, May 2005; doi:10.1634/theoncologist.10-5-311
© 2005 AlphaMed Press
Response to Letters to the Editor from Lugassy and Balla Regarding "Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid"
James Berenson
Institute for Myeloma and Bone Cancer Research, West Hollywood, California, USA
Correspondence: James R. Berenson, M.D., Institute for Myeloma and Bone Cancer Research, 9201 W. Sunset Blvd., Suite 300, Los Angeles, California 90069, USA. Telephone: 310-623-1214; Fax: 310-623-1120; e-mail: jberenson{at}myelomasource.org
I appreciate the interest of Prof. Lugassy [1] and Dr. Balla [2] in the potential complications from intravenously administered bisphosphonate therapy. Regarding the impairment of renal function from intravenously administered bisphosphonates, this has been known since the early reports with clodronate. It is important to recognize that the presence of a rise in creatinine in cancer patients receiving these agents does not necessarily implicate the bisphosphonate since these patients have a myriad of other possible causes for their deterioration in renal function including progression of the cancer itself. In large placebo-controlled as well as pamidronate-controlled trials involving patients with all types of cancers, it is clear that this risk is extremely low as long as zoledronic acid is infused over 15 minutes every 3–4 weeks. In addition, among the patients in these studies (baseline creatinine <3 mg/dl), there was no clear cut higher risk of renal deterioration among patients enrolled with higher baseline serum creatinine levels. Although Dr. Balla suggests that the risk of renal impairment is likely to be higher with the more frequent dosing of zoledronic acid used in cancer patients compared to those patients with osteoporosis not associated with cancer, it is important to recognize that these less intense infrequent dosing schedules have not been shown to be effective in reducing the risk of skeletal complications in the setting of the profound bone loss that occurs in cancer patients with metastatic bone disease. Monitoring of renal function with monthly serum creatinine has become a necessary part of the treatment ritual for these patients, and has been shown to help reduce the risk of any significant permanent renal damage from these agents.
There have also been several very recent reports of a potential association of these agents with the development of an otherwise rare complication of the jaw known as osteonecrosis of the jaw (ONJ). These reports involve a series of anecdotal reports documenting jaw abnormalities among cancer patients receiving either zoledronic acid or pamidronate. After the acceptance of our paper, a recent web-based survey was reported in abstract form at the December, 2004 American Society of Hematology meeting, and showed a high incidence of jaw problems among myeloma and breast cancer patients answering the survey who received these drugs [3]. Because of the anonymous nature of the web-based survey which was entered through a site that asked patients with these cancers if they had jaw problems, the patient’s cancer diagnosis, exact nature of the jaw problem, or any other responses could not be confirmed. Although the anecdotal reports also are interesting and suggest a possible link, this has not been firmly established by any of the reports published to date. Recently, I have observed ONJ confirmed by an expert oral surgeon regarding this condition in six myeloma patients receiving pamidronate or zoledronic acid. It is also important to be aware that this condition can vary greatly in severity. Many patients including my own improve with better oral hygiene and intermittent antibiotic therapy, and continue long-term intravenous bisphosphonate treatment without significant sequelae from their jaw problem. With the recent recognition that aggressive surgery may worsen this condition, it is hoped that the clinical manifestations of this problem will be greatly reduced for most patients. As a result of this potential complication, an ODAC panel was convened to address this problem on March 4, 2005. It is clear that prospective studies are necessary to define the condition, and determine exactly the risk of this problem among cancer patients receiving these bisphosphonates and potential other risk factors that may be able to be reduced in this patient population. It will also be important to better define the clinical consequences of ONJ. Only through these types of well designed studies will we be able to provide patients with the necessary information to make informed decisions regarding the relative benefits of reducing the devastating consequences of metastatic bone disease with intravenously administered zoledronic acid or pamidronate versus the potential clinical effects of ONJ. In the meantime, one has to carefully weigh the major reduction in bony complications consistently demonstrated in large randomized clinical trials that results from use of these agents by cancer patients compared to the unknown risk and its consequence from ONJ and the rare occurrence of clinically significant irreversible renal failure from these agents when patients are properly monitored and treated.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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Dr. Berenson has received research grants, served as a consultant and served on speakers’ bureaus for Novartis, Celgene, Cell Therapeutics, Millenium, and Chugai. He has received research grants from Amgen, Xcyte, and Pfizer. He has been a consultant for Amgen, Ariad, OrthoBiotech, and Seattle Genetics.
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REFERENCES
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- Lugassy G. "Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid": Not So Safe. Letter to the Editor. The Oncologist 2005;10:309–310.[Free Full Text]
- Balla J. The issue of renal safety of zoledronic acid from a nephrologist’s point of view. Letter to the Editor. The Oncologist 2005;10:306–308.[Free Full Text]
- Durie B, Katz M, McCoy J et al. Osteonecrosis of the Jaws in Myeloma: Time Dependent Correlation with Aredia® and Zometa® Use. Blood 2004;104:756a.
Received March 26, 2005;
accepted for publication March 26, 2005.
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