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Balance in bisphosphonate guidance
- Eugene V McCloskey (2 January 2008)
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Eugene V McCloskey, Senior Clinical Lecturer in Metabolic Bone Disease University of Sheffield S5 7AU
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Dear Sir, Clinical guidance produced by an eminent group(1) is always to be welcomed, but the conclusions drawn seem somewhat biased towards intravenous bisphosphonates, particularly zoledronic acid. While the evidence base is more extensive for zoledronic acid, better evidence for efficacy is not the same as evidence for better efficacy. Furthermore, increased potency as illustrated in Figure 1 of the paper does not automatically confer increased clinical efficacy. In fact, there is an extensive body of evidence in both benign and malignant bone disease that repeatedly demonstrates similar efficacy of bisphosphonates on clinical outcomes, including the Cochrane Review cited by the authors. The apparent lack of objectivity is also compounded by a data synthesis that also appears to be lacking in clarity and accuracy. For example, in Table 2 of the document the relative risks in the final column are drawn over a range of different outcomes, some of which were not primary outcomes; furthermore, the confidence intervals for the clodronate prostate cancer study in Table 3 bear no relation to those reported in the original paper for the primary outcome of this study (RR 0.79, 0.61-1.02, p=0.066).(2) In metastatic breast cancer, use of an IV amino-bisphosphonate is advocated by the group but the comprehensive meta-analysis cited confirmed that the overall risk of developing a SRE is reduced by 17% for IV therapy and 16% for oral therapy.(3) Indeed the only relative risk reduction that appears potentially different across the studies is that for the single placebo-controlled of zoledronate, but as the authors admit the “value of such comparisons is, however, limited by marked heterogeneity in patient populations and study characteristics.” Contrast this result with the published head-to-head comparison of zoledronic acid and pamidronate in an appropriately powered Phase III trial, where equivalence, not superiority, in the primary endpoint and the vast majority of the many secondary endpoints was observed.(4) Adherence is a consideration with any therapy, regardless of how it is administered. The implication that adherence with intravenous therapy is almost universal is not supported by data from the study of pamidronate versus zoledronate (i.e. two active arms with no concern over exposure to a placebo).(4) Less than 40% actually completed the core 13 month study, with only 20% of the original study population continuing treatment exposure out to two years.(4) The importance of good information, the doctor’s attitude and ability to address the patient’s concerns and involve them in decision making are all important contributors to good adherence. There is no compelling argument that intravenous bisphosphonates are better than oral; rather the availability of both routes of administration should be regarded as a positive opportunity to tailor treatment choice to an individual’s needs and circumstances. Guidance from international groups is always welcomed, but the appearance of unbalanced or biased interpretation needs to be avoided Sincerely Eugene McCloskey References 1. Aapro M, Abrahamsson PA, Body JJ et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2007; doi: 10.1093/annonc/mdm442. 2. Dearnaley DP, Sydes MR, Mason MD et al. A double-blind, placebo- controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003;95(17):1300–11. 3. Pavlakis N, Schmidt R, Stockler M. Bisposphonates for breast cancer. Cochrane Database Syst Rev 2005; CD003474. 4. 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(8):1735–44. Conflict of Interest:Research funding and speaker fees from Bayer Schering Pharma, Novartis, P&G, Sanofi Aventis, Roche, Lilly, Pfizer, AstraZeneca, Amgen |
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