Dosing related effects of zoledronic acid on bone markers and creatinine clearance in patients with multiple myeloma and metastatic breast cancer

Abstract

Zoledronic acid (Zol) is frequently used for the treatment of bone disease in patients with multiple myeloma and breast cancer with metastasis to bone. Therefore, there is also an interest in finding the optimal dosing regimen to optimize effects, minimize side effects and reduce costs. In our phase II clinical trial we investigated the effect of Zol treatment on the serum levels of the bone markers collagen type 1 cross-linked C-telopeptide (CTX) and bone specific alkaline phosphatase (bALP) as well as on creatinine clearance (kidney function) in response to dosing and duration of treatment for each individual patient. Methods. We enrolled 30 multiple myeloma (MM) and 30 breast cancer (BC) patients whereof 10 of each had never received bisphosphonate and 20 had received at least six prior Zol treatments. Results. We found that Zol treatment strongly reduced CTX (Spearman's correlation, r_s = −0.59, p = 0.0007) and bALP (Spearman's correlation, r_s = −0.51, p = 0.0042) in MM patients while only CTX (Spearman's correlation, r_s = −0.42, p = 0.024) was significantly affected in BC patients. Multiple linear regression analyses done on the entire cohort showed that the average time between each dose of Zol had the strongest impact on CTX (p < 0.001) and bALP (p = 0.011) levels while the total accumulated number of Zol infusions had a less pronounced effect on CTX levels (p = 0.015). In contrast, multiple linear regression analysis showed that the total number of Zol infusions had a strong negative impact on kidney function (p = 0.014) while the average time between each dose of Zol had no significant impact. Conclusion. Thus, if MM and BC patients are not treated regularly every month with Zol bone turnover is not fully suppressed, while prolonged treatment with zoledronic acid compromises kidney function. We believe that these data significantly contribute to the knowledge needed to find the optimal Zol treatment schedule.

Acknowledgments

We are deeply grateful for the professional, excellent collection and documentation of data according to the GCP guidelines by the project nurses Anne Tørsleff and Annette Rehmeier, and Vibeke Nielsen and Birgit MacDonald for collecting and freezing down most of the urine samples. We wish to thank statistician, René Holst, for statistical advice. We thank Novartis for financial support and interest in the protocol. We would also like to thank the GCP unit of Odense University Hospital for an uncomplicated cooperation. Kent Søe has received partial research funding for the present protocol by Novartis. Torben Plesner has received research funding from Novartis. Erik Jakobsen has been co-investigator on several Novartis trials but has never obtained any financial support. Novartis paid in part the costs of this clinical trial, but had no influence on the study design, interpretation of data or on the decision to submit the manuscript. Novartis merely had the opportunity to comment on the manuscript prior to submission.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Notice of correction

The version of this article published online ahead of print on 28 Oct 2013 contained an error on page 6. Some parts of the figure legend have been left out. The error has been corrected for this version.