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Journal of Clinical Oncology, Vol 23, No 34 (December 1), 2005: pp. 8917-8918 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.0519
In Reply:Section of Oncology, Department of Medicine, Haukeland University Hospital, Bergen, Norway The letter by Altundag et al raises an interesting issue—whether bone metabolism may differ in patients with breast cancer compared to healthy controls. As reported in our study,1 patients in the placebo arm experienced a bone loss somewhat higher than expected. Known from the literature,2 the population of Norway together with Sweden has a lifetime risk of hip fracture among postmenopausal women exceeding other European countries. In a recent study, Gjesdal et al3 found postmenopausal women to have a bone density slightly below the reference standard for Lunar densitometry based on American females. This was not of a magnitude explaining a potential discrepancy. Looking at the clinical studies on aromatase inhibitors in the adjuvant setting,4-6 data from subprotocols evaluating bone loss are either on their way or reported as abstracts.7,8 Interestingly, in the MA17 subprotocol,8 which is the only study apart from ours comparing an aromatase inhibitor to placebo, annual bone loss was of the same magnitude in the aromatase inhibitor arm as was recorded in our study. In contrast, the bone loss in the placebo arm was much lower. This could be partially related to a different practice regarding vitamin D and calcium supplementation (administered on a regular basis in the MA17, but not used in our study), as well as the fact that patients in the MA17 study had been exposed to tamoxifen previously, although differences with respect to patient population may not be excluded. Notably, the difference with respect to bone loss between patients treated with an aromatase inhibitor compared to the placebo controls was higher for letrozole8 compared to what we recorded for exemestane,1 pointing to a potential difference between the steroidal compound exemestane compared to nonsteroidal aromatase inhibitors with respect to bone metabolism. We are currently exploring whether hormonal factors or vitamin D deficiency may be related to bone loss among our patients. The potential for heparanase to enhance bone loss in breast cancer patients is an interesting proposal and should definitely be explored further. At this stage, however, it should be recalled that the results of Kelly et al9 were obtained in an experimental system in mice, and we do not know whether they may be extrapolated to humans. Based on what is said above, any study comparing bone loss between women with breast cancer and women who are healthy needs to take into account variables such as population differences, as well as supplementary treatment, meaning such an effect needs to be studied in a controlled setting. Our patients were all suffering from early breast cancer and most of them had small tumors and no lymph node metastases. The study was randomized, double-blind, well balanced between the two arms, and it is difficult to see how tumor-related factors may have influenced the two arms differently. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their 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 description 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) $10,000-99,999 (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. Kanis JA, Johnell O, De Laet C, et al: International variation in hip fracture probabilities: Implications for risk assessment. J Bone Mineral Res 17:1237-1244, 2002[CrossRef][Medline] 3. Gjesdal CG, Aanderud SJ, Haga HJ, et al: Femoral and whole-body bone mineral density in middle-aged and older Norwegian men and women: Suitability of the reference values. Osteoporos Int 15:525-534, 2004[Medline] 4. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline]
5. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003
6. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 7. Coleman R, Banks L, Hall E, et al: Intergroup exemestane study: 1 year results of the bone sub-protocol. Breast Cancer Res Treat 88:S35, 2004 (suppl 1) 8. Perez EA, Josse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women completing >5 years (yrs) of adjuvant tamoxifen: NCIC CTG MA 17b. Breast Cancer Res Treat 88:S36, 2004 (suppl 1, abstr 404)
9. Kelly T, Suva LJ, Huang Y, et al: Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res 65:5778-5784, 2005
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
