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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9434-9435 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3018
In Reply:Haukeland University Hospital, Bergen, Norway The letter by Cheung et al raises several issues. First, they discuss different techniques of bone mineral assessment. We agree with the authors that this is an important topic; however, it would be beyond the scope of a correspondence to discuss such an extensive issue in detail. Here, the important issue is whether the choice of method may have influenced the results and thus the conclusion of our study.1 The presentation of the figures by Cheung et al related to percentage change in bone mineral density (BMD) may be confusing. Even in case the standard deviation of individual measurements may be as high as 5% to 10%, corresponding standard errors of the mean will be 0.5% and 1%, respectively, in a population of 100 individuals. In our paper, we reported alterations in T-core as well as the percentage of bone loss, including confidence intervals for all parameters, as well as P values. Based on estimates in the literature,2 we discussed the potential impact on fracture risk, and concluded that this was likely to be small. The study was double-blinded, and the two groups were well balanced. Further, each patient had repeated BMD assessment performed in the same laboratory with use ofthe same technique. Thus, we do not see how their arguments may seriously question our findings. Second, Cheung et al discuss the conflicts between our data and what has previously been reported by Goss et al3 regarding effects of exemestane on bone metabolism in a rat model. Administering exemestane as 20 to100 mg/kg body weight weekly by the intramuscular route, an anabolic effect on bone metabolism was recorded. While the difference could be species related, it may also be related to the dose administered. Thus, in a previous study4 we found exemestane to express androgen-agonistic effects on sex hormone binding globulin. This effect was dose dependent over the range of 5 to 200 mg/daily explored. While it is tempting to speculate exemestane administered at high doses may have anabolic effects on bone metabolism in humans, long-term administration of exemestane at doses greater than 100 mg daily causes hirsuitism4 and is not a valid treatment option. We definitely share the opinion of Cheung et al that there may be a difference between steroidal and nonsteroidal aromatase inhibitors regarding side effects on bone tissue as well as clinical efficacy,5 and the subject is discussed in detail elsewhere.6 While their data on bone biomarkers7 suggesting a potential difference between steroidal and nonsteroidal inhibitors are interesting, in contrast to our report their results are only available as abstracts. Finally, we agree with Cheung et al that we need more data to assess potential differences between aromatase inhibitors regarding their effects on bone metabolism. The data from the different studies are complementary. While there are several studies in the pipeline that either compare aromatase inhibitors to tamoxifen or compare a steroidal and nonsteroidal compound regarding the effect on bone metabolism, our study is the only one comparing the effect of an aromatase inhibitor versus placebo on bone mineral density in patients not exposed to tamoxifen. In contrast to studies comparing the effect of an aromatase inhibitor to either tamoxifen or an inhibitor of another class, our study allows assessment of the neat effect of an aromatase inhibitor on bone metabolism. We concur that the MA 27 trial conducted by Goss et al is important to addressing the potential differences between exemestane and anastrozole. Their study however does not include a placebo arm. Thus, in strict terms, the argument by Cheung et al that this study addresses the effect of exemestane on bone loss is incorrect. Reading the text of our original report,1 it seems there are little differences between our own interpretation of the data and the interpretations made by Cheung et al. It seems we both agree that exemestane has minor effects on bone metabolism, and we find it difficult to spot any major disagreement on this issue. More data may strengthen the conclusion, but it seems unlikely they should change the scenario significantly revealing exemestane to have either a bone protective effect or causing detrimental effects on bone loss. In our opinion, the question is not whether the jury is still out. The question is whether there is any major disagreement to solve and a topic calling for a verdict. Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
REFERENCES
1. Lønning PE, Geisler J, Krag LE, et al: Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126-5137, 2005 2. Cummings SR, Bates D, Black DM: Clinical use of bone densitometry - Scientific review. JAMA 288:1889-1897, 2002 3. Goss PE, Qi S, Cheung AM, et al: Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res 10:5717-5723, 2004 4. Johannessen DC, Engan T, Salle Ed, et al: Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: A phase I study. Clin Cancer Res 3:1101-1108, 1997[Abstract] 5. Lønning PE, Bajetta E, Murray R, et al: Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 18:2234-2244, 2000 6. Geisler J, Lønning PE: Aromatase inhibitors as adjuvant treatment of breast cancer. Crit Rev Oncol Hematol, in press 7. Subar M, Goss P, Thomsen T, et al: Effects of steroidal and nonsteroidal aromatase inhibitors (Als) on markers of bone turnover and lipid metabolism in healthy volunteers. Am Soc Clin Oncol 23:734, 2004 Related Correspondence
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
