Abstract
Aromatase inhibitor-associated bone loss has not been proved in the Japanese or Asian women. The aim of this study was to evaluate an upfront or delayed strategy of bone protection therapy with zoledronic acid administered at 4 mg every 6 months in postmenopausal Japanese women with early breast cancer to compare with results of the Z-FAST and ZO-FAST studies in western countries. Postmenopausal women with hormone receptor positive early breast cancer receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months). The delayed group received zoledronic acid when lumbar spine (L2–L4) bone mineral density (BMD) decreased to less than young adult mean −2.0SD or when a nontraumatic fracture occurred. The primary endpoint of this study was to compare the percent change in L1–L4 BMD at 12 months between the groups. Secondary endpoints included percent changes in L2–L4 and total hip (TH) BMD. The upfront and delayed groups included 94 and 95 patients, respectively. At 12 months, L1–L4, L2–L4, and TH BMD significantly decreased by 2.0, 2.4, and 2.4%, respectively, in the delayed group. L1–L4 BMD was 4.9% higher in the upfront group than in the delayed group (95% CI 3.9–5.8%; p < 0.001). L2–L4 BMD was 5.6% higher (95% CI 4.5–6.6%; p < 0.001), and TH BMD was 4.4% higher (95% CI 3.3–5.4%; p < 0.001). At 12 months, upfront zoledronic acid therapy prevented bone loss in postmenopausal Japanese women who were receiving adjuvant letrozole, confirming the Z-/ZO-FAST study results in western populations.
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References
Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 11(12):1135–1141. doi:10.1016/S1470-2045(10)70257-6
Colleoni M, Giobbie-Hurder A, Regan MM, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Lang I, Smith I, Chirgwin J, Pienkowski T, Wardley A, Price KN, Gelber RD, Coates AS, Goldhirsch A (2011) Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1–98 study. J Clin Oncol 29(9):1117–1124. doi:10.1200/JCO.2010.31.6455
Bertelli G, Hall E, Ireland E, Snowdon CF, Jassem J, Drosik K, Karnicka-Mlodkowska H, Coombes RC, Bliss JM (2010) Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)—a randomised controlled trial of exemestane versus continued tamoxifen after 2–3 years tamoxifen. Ann Oncol 21(3):498–505. doi:10.1093/annonc/mdp358
Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M (2008) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9(1):45–53. doi:10.1016/S1470-2045(07)70385-6
Coleman RE, Banks LM, Girgis SI, Kilburn LS, Vrdoljak E, Fox J, Cawthorn SJ, Patel A, Snowdon CF, Hall E, Bliss JM, Coombes RC (2007) Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol 8(2):119–127. doi:10.1016/S1470-2045(07)70003-7
Rabaglio M, Sun Z, Price KN, Castiglione-Gertsch M, Hawle H, Thurlimann B, Mouridsen H, Campone M, Forbes JF, Paridaens RJ, Colleoni M, Pienkowski T, Nogaret JM, Lang I, Smith I, Gelber RD, Goldhirsch A, Coates AS (2009) Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1–98 trial. Ann Oncol 20(9):1489–1498. doi:10.1093/annonc/mdp033
Eastell R, Adams J, Clack G, Howell A, Cuzick J, Mackey J, Beckmann MW, Coleman RE (2011) Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol 22(4):857–862. doi:10.1093/annonc/mdq541
Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, Nevitt MC, Suryawanshi S, Cummings SR (2000) Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 85(11):4118–4124
Felsenberg D, Miller P, Armbrecht G, Wilson K, Schimmer RC, Papapoulos SE (2005) Oral ibandronate significantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis. Bone 37(5):651–654. doi:10.1016/j.bone.2005.05.004
Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11(1):83–91
Lester JE, Dodwell D, Purohit OP, Gutcher SA, Ellis SP, Thorpe R, Horsman JM, Brown JE, Hannon RA, Coleman RE (2008) Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 14(19):6336–6342. doi:10.1158/1078-0432.CCR-07-5101
Hines SL, Mincey BA, Sloan JA, Thomas SP, Chottiner E, Loprinzi CL, Carlson MD, Atherton PJ, Salim M, Perez EA (2009) Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. J Clin Oncol 27(7):1047–1053. doi:10.1200/JCO.2008.19.1783
Bock O, Felsenberg D (2008) Bisphosphonates in the management of postmenopausal osteoporosis–optimizing efficacy in clinical practice. Clin Interv Aging 3(2):279–297
Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ (2002) Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346(9):653–661. doi:10.1056/NEJMoa011807346/9/653
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356(18):1809–1822. doi:10.1056/NEJMoa067312
Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, Hohneker J, Lacerna L, Petrone S, Perez EA (2007) Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25(7):829–836. doi:10.1200/JCO.2005.05.3744
Bundred NJ, Campbell ID, Davidson N, DeBoer RH, Eidtmann H, Monnier A, Neven P, von Minckwitz G, Miller JC, Schenk NL, Coleman RE (2008) Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer 112(5):1001–1010. doi:10.1002/cncr.23259
Yoneda K, Tanji Y, Okishiro M, Taguchi T, Tamaki Y, Noguchi S (2006) Influence of adjuvant anastrozole on bone mineral density in Japanese postmenopausal breast cancer patients: is there a racial difference? Ann Oncol 17(7):1175–1176. doi:10.1093/annonc/mdj128
Aihara T, Suemasu K, Takei H, Hozumi Y, Takehara M, Saito T, Ohsumi S, Masuda N, Ohashi Y (2010) Effects of exemestane, anastrozole and tamoxifen on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: results of N-SAS BC 04, the TEAM Japan substudy. Oncology 79(5–6):376–381. doi:10.1159/000323489
Aihara T, Takatsuka Y, Ohsumi S, Aogi K, Hozumi Y, Imoto S, Mukai H, Iwata H, Watanabe T, Shimizu C, Nakagami K, Tamura M, Ito T, Masuda N, Ogino N, Hisamatsu K, Mitsuyama S, Abe H, Tanaka S, Yamaguchi T, Ohashi Y (2010) Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study. Breast Cancer Res Treat 121(2):379–387. doi:10.1007/s10549-010-0888-x
Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE (2002) Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20(3):751–757
Dixon JM, Renshaw L, Young O, Murray J, Macaskill EJ, McHugh M, Folkerd E, Cameron DA, A’Hern RP, Dowsett M (2008) Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol 26(10):1671–1676. doi:10.1200/JCO.2007.13.9279
Monnier A (2010) FACE: the barefaced facts of AI potency. Cancer Manag Res 2:267–276. doi:10.2147/CMR.S13511
McCloskey EV, Hannon RA, Lakner G, Fraser WD, Clack G, Miyamoto A, Finkelman RD, Eastell R (2007) Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women. Eur J Cancer 43(17):2523–2531. doi:10.1016/j.ejca.2007.08.029
McCaig FM, Renshaw L, Williams L, Young O, Murray J, Macaskill EJ, McHugh M, Hannon R, Dixon JM (2010) A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 119(3):643–651. doi:10.1007/s10549-009-0646-0
Okishiro M, Taguchi T, Kim SJ, Tanji Y, Shimazu K, Tamaki Y, Noguchi S (2009) Incidence of joint symptoms and bone fractures in Japanese postmenopausal breast cancer patients treated with adjuvant anastrozole. J Cancer Res Clin Oncol 135(6):823–827. doi:10.1007/s00432-008-0518-8
Van Poznak C, Hannon RA, Mackey JR, Campone M, Apffelstaedt JP, Clack G, Barlow D, Makris A, Eastell R (2010) Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol 28(6):967–975. doi:10.1200/JCO.2009.24.5902
Llombart A, Frassoldati A, Paija O, Sleeboom HP, Jerusalem G, Mebis J, Deleu I, Miller J, Schenk N, Neven P (2011) Immediate administration of zoledronic acid reduces aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer: 12-month analysis of the E-ZO-FAST Trial. Clin Breast Cancer. doi:10.1016/j.clbc.2011.08.002
World Health Organization Technical Report (1994) Assessment of fracture risk and its applications to screening for postmenopausal osteoporosis. Report of a WHO Study Group
Orimo H, Hayashi Y, Fukunaga M, Sone T, Fujiwara S, Shiraki M, Kushida K, Miyamoto S, Soen S, Nishimura J, Oh-Hashi Y, Hosoi T, Gorai I, Tanaka H, Igai T, Kishimoto H (2001) Diagnostic criteria for primary osteoporosis: year 2000 revision. J Bone Miner Metab 19(6):331–337
Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757. doi:10.1056/NEJMoa052258
Conte P, Frassoldati A (2007) Aromatase inhibitors in the adjuvant treatment of postmenopausal women with early breast cancer: putting safety issues into perspective. Breast J 13(1):28–35. doi:10.1111/j.1524-4741.2006.00359.x
Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Hadji P, Jin L, Schenk N, Ericson S, Perez EA (2008) Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 13(5):503–514. doi:10.1634/theoncologist.2007-0206
Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, Gil M, Houston SJ, Grieve RJ, Barrett-Lee PJ, Ritchie D, Pugh J, Gaunt C, Rea U, Peterson J, Davies C, Hiley V, Gregory W, Bell R (2011) Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365(15):1396–1405. doi:10.1056/NEJMoa1105195
Acknowledgments
We thank all the participating investigators, Dr. M. Hosoda (Hokkaido University Hospital), Dr. Y. Koibuchi, Dr. R. Nagaoka, Dr. N. Rokutanda, Dr. H. Tokiniwa (Gunma University Hospital), Dr. H. Bando (Tsukuba University Hospital), Dr. M. Satoh, Dr. H. Ohsawa (Jichi Medical University Hospital), Dr. A. Ohsaki (Saitama Medical University), Dr. K. Yamada, Dr. H. Kaise (Tokyo Medical University), Dr. Y. Itoh, Dr. N. Tokudome, Dr. E. Makita, Dr. K. Tada, Dr. S. Nishimura, Dr. K. Iijima, Dr. Y. Miyagi, Dr. H. Morizono, Dr. K. Kimura (Cancer Institute Hospital of JFCR), Dr. T. Kuwayama, Dr. M. Mori (St. Luke’s International Hospital), Dr. M. Saitoh, Dr. E. Tokuda (Juntendo University Hospital), Dr. H. Isaka, Dr. K. Imi (Kyorin University Hospital), Dr. H. Jinno (Keio University Hospital), Dr. Y. Tamaki, Dr. S.J. Kim, Dr. T. Nakayama, Dr. K. Shimazu (Osaka University Hospital), Dr. Y. Hashimoto (Kinki University Hospital), Dr. K. Nakashima (Kawasaki Medical University), Dr. S. Murakami, Dr. N. Masumoto, Dr. J. Emi (Hiroshima University Hospital), Dr. H. Iwase, Dr. Y. Yamamoto (Kumamoto University Hospital) for their contribution, and Miss M. Yamazaki and Miss C. Suitsu (Cancer Institute Hospital of JFCR) for data management.
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ST and SN are consultants, and have received remuneration and research support from Novartis.
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Takahashi, S., Iwase, T., Kohno, N. et al. Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 12-month results. Breast Cancer Res Treat 133, 685–693 (2012). https://doi.org/10.1007/s10549-012-1973-0
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DOI: https://doi.org/10.1007/s10549-012-1973-0