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Originally published as JCO Early Release 10.1200/JCO.2005.05.3744 on December 11 2006 © 2007 American Society of Clinical Oncology. Zoledronic Acid Inhibits Adjuvant Letrozole–Induced Bone Loss in Postmenopausal Women With Early Breast Cancer
From the Magee-Womens Hospital, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Utah Cancer Specialists, Salt Lake City, UT; Highlands Oncology Group, Springdale, AK; North Florida Regional Medical Center, Gainesville; Cancer Research Network, Plantation; Mayo Clinic, Jacksonville, FL; Fallon Clinic Hematology Oncology, Worcester, MA; and Novartis Oncology, East Hanover, NJ Address reprint requests to Adam Brufsky, MD, PhD, Magee-Womens Hospital, Ste 4628, 300 Halket St, Pittsburgh, PA 15123; e-mail: brufskyam{at}upmc.edu
Purpose: Treatment with aromatase inhibitors decreases bone mineral density (BMD) and may increase the risk of fractures in postmenopausal women with early-stage breast cancer. The addition of zoledronic acid to adjuvant letrozole therapy may protect against bone loss. Patients and Methods: Patients 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 (LS) or total hip (TH) T score decreased to less than –2.0 or when a nontraumatic fracture occurred. The primary end point of this study was to compare the change in LS BMD at month 12 between the groups. Secondary end points included change in TH BMD and changes in serum bone turnover markers at month 12. Results: The upfront and delayed groups each included 301 patients. At month 12, LS BMD was 4.4% higher in the upfront group than in the delayed group (95% CI, 3.7% to 5.0%; P < .0001), and TH BMD was 3.3% higher (95% CI, 2.8% to 3.8%; P < .0001). In the upfront group, mean serum N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 15.1% (P < .0001) and 8.8% (P = .0006), respectively, at month 12, whereas concentrations increased significantly in the delayed group by 19.9% (P = .013) and 24.3% (P < .0001), respectively. Conclusion: With 1 year of follow-up, results of the primary end point of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) indicate that upfront zoledronic acid therapy prevents bone loss in the LS in postmenopausal women receiving adjuvant letrozole for early-stage breast cancer.
The third-generation aromatase inhibitors (AIs; letrozole, anastrozole, and exemestane), administered either alone or sequentially after tamoxifen, are currently the preferred adjuvant treatment of postmenopausal women with hormone receptor–positive breast cancer.1-6 Compared with tamoxifen, the third-generation AIs are not associated with an increased risk for endometrial cancer, thromboembolic events, ischemic cerebrovascular events, deep venous thrombosis, hot flashes, or vaginal bleeding4; however, AIs have been shown to accelerate bone loss and increase fracture risk.2-8 Estrogen plays an essential role in the maintenance of bone mass in adult women.9 In postmenopausal women with breast cancer, the third-generation AIs result in nearly complete suppression of aromatase activity and significant decreases in circulating estrogen concentrations, thereby accelerating the rate of bone loss.10,11 Treatment with AIs is associated with increased concentrations of bone resorption markers and an increased incidence of osteoporosis.6,8,12 Therefore, effective therapy to prevent bone loss associated with AIs is needed. Zoledronic acid, a potent nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, is approved by the US Food and Drug Administration for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors.13 Recent clinical trials have demonstrated that zoledronic acid maintains or increases bone mineral density (BMD) in a variety of hypogonadal states.14-16 We report the results of the primary and secondary end points of the first 12 months of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST), which evaluates the effect of upfront and delayed-start zoledronic acid for prevention of bone loss in postmenopausal women with early-stage breast cancer receiving adjuvant letrozole for 5 years.
Study Patients The study included postmenopausal women from 94 US and Canadian community-based centers who had a history of surgically resectable stage I, II, or IIIA, estrogen receptor–positive and/or progesterone receptor–positive breast cancer; a baseline Eastern Cooperative Oncology Group performance status of  2; and baseline lumbar spine (LS) and total hip (TH) T scores  –2.0. All patients underwent tumor resection, completed chemotherapy and/or radiation therapy within 12 weeks of study entry, and had no evidence of residual disease. Before random assignment, a complete medical history and physical examination were performed; patients were excluded if they had clinical or radiologic evidence of distant metastases, an existing LS or TH fracture, or a history of low-intensity fractures. Patients were also excluded if they had received: letrozole or other adjuvant hormone therapy; endocrine therapy; intravenous (IV) bisphosphonates or prolonged systemic corticosteroids within the previous 12 months; growth hormone, anabolic steroids, or tibolone within the previous 6 months; or teriparatide or systemic sodium fluoride. The use of any other drug known to affect the skeleton was prohibited 2 weeks before and throughout the study. Patients who reported receiving oral bisphosphonates or hormone replacement therapy discontinued use before study entry. Patients with renal dysfunction, other malignancies, and diseases known to influence bone metabolism were excluded.
Study Design The primary end point of this study was the percent change in LS BMD (L1 to L4) at 12 months in patients receiving upfront compared with delayed-start zoledronic acid. The secondary end points were the percent change in TH BMD and changes in serum N-telopeptide (NTx) and bone-specific alkaline phosphatase (BSAP) concentrations at 12 months. Additional secondary end points, including percent change in LS and TH BMD at 2, 3, and 5 years; incidence of any clinical fracture at 3 years; time to disease progression; and rate of decrease in LS and TH BMD from baseline to 5 years, will be reported as these results become available. BMDs of the LS and TH were evaluated at baseline and at 6 and 12 months and will be evaluated at 24, 36, and 48 months and at the final visit using either Hologic (Hologic, Bedford, MA) or Lunar (GE Medical Systems Lunar Corporation, Madison, WI) dual-energy x-ray absorptiometry (DEXA) devices. T scores were calculated using manufacturer-specific T score databases. All DEXA devices were standardized and cross-calibrated using four Bio-Imaging Bona Fide Phantoms (CIRS Tissue Simulation & Phantom Technology, Norfolk, VA). Enrollment eligibility and timing for initiation of zoledronic acid in the delayed group were based on local DEXA readings; however, a central reader (BioImaging Technologies Inc, Newtown, PA) analyzed all DEXA scans for the efficacy analysis. Patients with baseline and month 12 LS BMD measurements (month 6 BMD measurements were carried forward for women with no 12-month measurements) were included in the primary efficacy analysis. The baseline BMD measurements for 48 women were not received by the central reader; baseline BMD measurements were considered missing for these women, and they were excluded from the efficacy analysis. However, these women were included in the safety analysis. Serum NTx concentrations, measured using the Osteomark NTx assay (Wampole Laboratories, Princeton, NJ), and BSAP concentrations, measured using the Metra immunoassay (Quidel Corporation, San Diego, CA), were evaluated in a subset of patients by a central laboratory (Clinical Reference Laboratory Inc, Lenexa, KS) at baseline and every 3 months during the first year; these concentrations will also be measured every 6 months during years 2 to 3, once at 48 months, and at the final visit. Nonfasting blood samples were drawn randomly throughout the day for serum bone marker determinations. Adverse events (AEs) and disease progression were evaluated every 6 months. AEs were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0.18 Serum creatinine levels were measured at baseline, before each infusion, and at the final visit. The institutional review boards of the participating institutions approved the study. Informed consent was obtained from each patient before enrollment. The study was funded by Novartis Oncology (East Hanover, NJ). The study design was based on recommendations from several multidisciplinary medical consultants in the areas of breast oncology and endocrinology. The principal investigator directed the 12-month data review and analysis; all data analyses were performed by PRA International (Reston, VA).
Statistical Analysis
Unless otherwise specified, all statistical tests were performed using a significance level of P = .05 against a two-sided alternative hypothesis. An intent-to-treat population, which was defined as all randomly assigned patients who received at least one dose of study drug (letrozole or zoledronic acid) and underwent at least one postbaseline assessment, was included in the efficacy analysis. The safety analysis included all patients who received at least one dose of zoledronic acid or letrozole. A two-sample t test and Pearson The primary efficacy analysis was performed after all patients had passed the 12-month visit. An analysis of covariance model was used to compare differences between groups; paired t tests were used to compare differences within treatment groups in LS and TH BMD and serum NTx and BSAP concentrations from baseline to month 12. The study was not powered to detect a difference in the incidence of clinical fractures or breast cancer relapse. The frequency of AEs was reported for both groups.
Study Population Between September 28, 2002, and December 5, 2003, 602 patients were randomly assigned to receive either upfront or delayed zoledronic acid (Fig 1). Women in the upfront and delayed groups had similar baseline characteristics (Table 1). Only one patient in the upfront group received prior oral bisphosphonate therapy.
Twenty nine (9.7%) and 42 (14%) patients in the delayed group received zoledronic acid therapy by month 6 and 12, respectively. For these patients, the mean time to initiation of zoledronic acid was 8.8 months (range, 0.03 to 24.15 months). After closer evaluation, only 13 (4.3%) and 25 (8.3%) patients by 6 and 12 months, respectively, were administered zoledronic acid per protocol (ie, T score < –2.0 and/or a clinical fracture). The remaining delayed-group patients did not meet protocol-defined criteria for zoledronic acid therapy.
BMD
At baseline, 433 patients (72%) had normal BMD of the LS and/or TH (217 patients [72.1%] in the upfront group; 216 patients [71.8%] in the delayed group; Table 1). After 12 months, a higher percentage of patients in the delayed group with normal baseline BMD developed mild to moderate osteopenia compared with patients in the upfront group (12.6% v 3.4%, respectively; Table 2). At baseline, 84 patients (27.9%) in the upfront group and 85 patients (28.2%) in the delayed group already had mild to moderate osteopenia of the LS and/or TH, placing them at a higher risk for progressing to severe osteopenia (T score between –2.0 and –2.5) or osteoporosis (T score < –2.5) with letrozole therapy (Table 1). In the delayed group, more patients progressed from mild or moderate to severe osteopenia compared with the upfront group (12 patients [14.8%] v one patient [1.4%], respectively; Table 2). Interestingly, eight patients in the delayed group with osteopenia at baseline improved to a normal BMD of the LS by month 12. Of these eight patients, two patients received zoledronic acid at month 6, and four patients had borderline osteopenia at baseline.
Fractures At month 12, no- or low-trauma fractures occurred in 1% of patients in the upfront group and 0.7% of patients in the delayed group. Traumatic fractures occurred in 2.3% and 2% of patients in the upfront and delayed groups, respectively.
Markers of Bone Turnover
Safety The safety analysis consisted of 300 patients in both groups (Table 3). The occurrence of AEs was similar between the groups with the exception of bone pain, which was higher in the upfront zoledronic acid group compared with the delayed group (11.3% v 4%, respectively), as expected. Neither group experienced grade 3 or 4 renal dysfunction; one patient in the upfront group experienced a grade 1 increase in serum creatinine level. Osteonecrosis of the jaw (ONJ) was not reported in either group. Serious AEs occurred in 16.7% and 18.7% of patients in the upfront and delayed groups, respectively. Seven percent of patients in the upfront group and 9.7% of patients in the delayed group withdrew from the study as a result of AEs; 1.3% and 1% of patients in the upfront and delayed groups, respectively, discontinued therapy because of serious AEs.
Several large, prospective, randomized, controlled trials demonstrate that adjuvant AI therapy alone or sequentially after tamoxifen increases disease-free survival in postmenopausal women with localized endocrine-responsive breast cancer compared with standard tamoxifen therapy.2-6 AIs are associated with accelerated bone loss and an increased fracture risk.2-8,12,16,19,20 This is the first study to evaluate the efficacy and safety of zoledronic acid for the prevention of bone loss in postmenopausal women with early-stage breast cancer receiving adjuvant AI therapy. Our data show that patients who receive upfront zoledronic acid 4 mg IV every 6 months are less likely to develop bone loss at 1 year than women who receive delayed-start zoledronic acid. Women who received upfront zoledronic acid experienced increases in BMD from baseline to month 12 in both the LS (+1.9%) and TH (+1.3%), whereas patients receiving no zoledronic acid (86%) or delayed zoledronic acid (14%) experienced decreases in BMD of the LS (2.4%) and TH (1.98%) from baseline to month 12 (P < .0001 for both). These results are consistent with previously reported rates of bone loss over 12 months in postmenopausal women receiving an AI in the absence of antiresorptive therapy (LS, –2.6% to –3.2%; TH, –1.7% to –2.2%; femoral neck, –2.72%).8,19,21 Our study results indicate that the risk of developing severe osteopenia within the first year of AI therapy may be significant in a small percentage of postmenopausal women. In the delayed group, 12.6% of patients with normal baseline BMD developed mild to moderate osteopenia by month 12, and 14.8% of patients with baseline mild to moderate osteopenia progressed to severe osteopenia. However, in the upfront group, only 3.4% of patients with normal baseline BMD developed osteopenia by month 12, and 1.4% of patients with baseline mild to moderate osteopenia progressed to severe osteopenia. By month 12, 8.3% of patients in the delayed group required zoledronic acid because of either a T score less than –2.0 or the occurrence of a nontraumatic clinical fracture. An additional 5.7% of patients in the delayed group received zoledronic acid but did not meet the protocol-defined criteria for therapy initiation. At study initiation, a few study sites misinterpreted the protocol and started all patients randomly assigned to the delayed group on zoledronic acid at month 6. After re-educating the study sites, the number of administration error protocol violations diminished significantly. In the delayed group, 6-month BMD measurements were carried forward for the 12-month LS and TH analyses in approximately 8% and 13% of patients in the upfront and delayed groups, respectively. The use of 6-month rather than 12-month BMD measurements for these analyses may possibly lead to a smaller percentage of difference in 12-month BMD between the groups. Several studies have shown BMD to be a robust surrogate marker for fracture risk in postmenopausal women.22-25 A meta-analysis of approximately 39,000 men and women participating in 12 osteoporosis trials reported a 1.6- to 2.2-fold increase in fracture risk for each standard deviation decrease in BMD for women.24 Correlation between BMD and fracture risk varies widely and is influenced by many factors other than AI use, such as site of BMD measurement, age, prior fracture history, low body weight, and inactive lifestyle.24-27 The American Society of Clinical Oncology recommends that all women at high risk of osteoporosis, including women receiving AI therapy, receive baseline and annual DEXA scans.27 Only 1% of patients in the upfront and 0.7% of patients in the delayed group developed no- or low-trauma fractures by month 12. A meaningful statistical comparison of 12-month fracture rates was not possible because of the low number of fractures occurring in each group. Although the study was not designed to detect a difference in fracture rate between treatment groups, a statistical analysis of fracture incidence is planned after 36 months of therapy. The changes in bone marker measurements observed in a subset of patients receiving upfront versus delayed zoledronic acid suggest that zoledronic acid's effect on bone remodeling is both rapid and sustained over at least 1 year. In our study, the mean differences in NTx and BSAP concentrations between the upfront and delayed groups were 35% and 33% at month 12; the differences between the treatment and placebo groups in a study of women with postmenopausal osteoporosis were approximately 60% and 50%, respectively.15 The difference in bone marker measurements observed in our study compared with the postmenopausal osteoporosis study may be explained by differences in pretreatment values, assays used to measure BSAP concentrations, body fluids used to measure NTx concentrations (serum v urine), and timing of NTx collection (random v second-morning void).15,28,29 Zoledronic acid was generally well tolerated, with few discontinuations in either group. Bone pain was more common in the upfront than the delayed group but was only mildly to moderately severe.13 Only one patient experienced grade 1 renal impairment, and severe renal dysfunction was not reported. The reported frequency of ONJ in women with breast cancer receiving IV bisphosphonates ranges from 0.6% to 1.2%.30,31 To date, no cases of ONJ have been reported in our study. Currently, the American Society of Clinical Oncology recommends initiation of an IV or oral bisphosphonate only after a patient's T score declines to less than –2.5 (ie, osteoporosis).27 The preliminary results of this ongoing clinical trial suggest that initiation of zoledronic acid 4 mg IV every 6 months in postmenopausal breast cancer patients receiving adjuvant AI therapy may prevent or delay bone loss at 1 year of follow-up. A longer follow-up is needed to determine whether the bone loss observed in the delayed group can be stabilized or restored to baseline values with the administration of zoledronic acid. The 3- and 5-year results of this trial and other ongoing clinical trials are necessary to confirm the optimal timing for bisphosphonate initiation and its impact on fracture rates in early-stage breast cancer patients receiving adjuvant AIs.
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. Employment: John Hohneker, Novartis; Leo Lacerna, Novartis; Stephanie Petrone, Novartis Leadership: N/A Consultant: Adam Brufsky, Novartis Stock: John Hohneker, Novartis; Leo Lacerna, Novartis Honoraria: Adam Brufsky, Novartis; Christopher Seidler, Celgene, Novartis Research Funds: Adam Brufsky, Novartis; Christopher Seidler, Celgene, sanofi aventis; Edith A. Perez, AstraZeneca, Genentech, sanofi aventis
Conception and design: Adam Brufsky, John Hohneker, Leo Lacerna, Stephanie Petrone, Edith A. Perez Financial support: Adam Brufsky, John Hohneker, Leo Lacerna Administrative support: Adam Brufsky, John Hohneker, Leo Lacerna, Stephanie Petrone Provision of study materials or patients: Adam Brufsky, W. Graydon Harker, J. Thaddeus Beck, Robert Carroll, Elizabeth Tan-Chiu, John Hohneker, Leo Lacerna, Edith A. Perez Collection and assembly of data: Adam Brufsky, Robert Carroll, Leo Lacerna, Stephanie Petrone, Edith A. Perez Data analysis and interpretation: Adam Brufsky, Leo Lacerna, Stephanie Petrone, Edith A. Perez Manuscript writing: Adam Brufsky, W. Graydon Harker, Christopher Seidler, Leo Lacerna, Stephanie Petrone, Edith A. Perez Final approval of manuscript: Adam Brufsky, W. Graydon Harker, J. Thaddeus Beck, Elizabeth Tan-Chiu, Christopher Seidler, John Hohneker, Leo Lacerna, Stephanie Petrone, Edith A. Perez
The following Zometa-Femara Adjuvant Synergy Trial (Z-FAST) principle investigators participated in this study: James Abraham, MD, West Virginia University; Fakhiuddin Ahmed, MD, Hematology Oncology Care PC; Haythem Ali, MD, Henry Ford Health System; Bipinkumar Amin, MD, Mid Dakota Clinic; Roberto Arevalo-Araujo, MD, Pasco Pinellas Cancer Center; Luis Baez, MD, Veterans Affairs Medical Center; Charles Bane, MD, Hematology and Oncology of Dayton, Inc; Avi BarLev, MD, Fox Valley Hematology and Oncology; Thaddeus Beck, MD, Highlands Oncology Group; Linda Bosserman, MD, Wilshire Oncology Medical Group, Inc; James Bradof, MD, Palmetto Hematology Oncology, PC; Adam Brufsky, MD, Magee/University of Pittsburgh Cancer Institute Breast Program; Patrick Byrne, MD, Northern Virginia Oncology Group, PC; Richard Caradonna, MD, Community Cancer Centers; Robert Carroll, MD, Robert R. Carroll MD; Thomas Cartwright, MD, Ocala Oncology Center; Michael Castine, MD, Medical Oncology; Patrick Cobb, MD, Hematology-Oncology Centers of the Northern Rockies; Steven Come, MD, Beth Israel Deaconess; Christopher Croot, MD, NMS Hematology and Oncology; Mandeep Dhami, MD, Eastern Connecticut Hematology Oncology Associates; John Eckardt, MD; Arch Medical Services, Inc; Peter Eisenberg, MD, California Cancer Care; Erin Ellis, MD, Swedish Cancer Institute; Patrick Flynn, MD, Metro Minneapolis Community Clinical Oncology Program; Stephen Fox, MD, The Fox Medical Oncology Center, PC; Nashat Gabrail, MD, Nashat y Gabrail, Inc; George Geils, MD, Charleston Hematology/Oncology; Generosa Grana, MD, Cooper Cancer Institute; Jennifer Griggs, MD, University of Rochester Cancer Center; Gary Gross, MD, Blood and Cancer Center of East Texas; Barbara Haley, MD, University of Texas Southwestern Medical Center; Jeffrey Hargis, MD, Kentuckiana Cancer Institute, PLLC; Graydon Harker, MD, Utah Cancer Specialists; Carolyn Hendricks, MD, Oncology Care Associates; Sang Huh, MD, A.P. & S. Oncology/Hematology; David Hyams, MD, Comprehensive Cancer Centers of the Desert; Haresh Jhangiani, MD, Compassionate Cancer Care Medical Group, Inc; C. Michael Jones, MD, C. Michael Jones M.D. Oncology/Hematology; Glen Justice, MD, Pacific Coast Hematology Oncology Medical; Stephen Kahanic, MD, Siouxland Hematology Oncology; Wayne Keiser, MD, Redwood Regional Oncology; Robert Kerr, MD, Southwest Regional Cancer Center; Paula Klein, MD, St Vincent's Comprehensive Cancer Center; Rayna Kneuper-Hall, MD, Medical University of South Carolina/Cannon Park Place; Rosemary Lambert-Falls, MD, South Carolina Oncology Associates, PA; Robert Langdon, MD, Methodist Cancer Center; Julio Lautersztain, MD, Bay Area Oncology; Robert Lemon, MD, Cancer and Blood Institute of the Desert; Richard Levine, MD, Space Coast Medical Associates; James Liebmann, MD, New Mexico Oncology Hematology; Ana Maria Lopez, MD, Arizona Cancer Center; Timothy Lopez, MD, New Mexico Cancer Care; Susan Luedke, MD, St Louis Cancer and Breast Institute; Kirk Lund, MD, Rockwood Clinic; James Maher, MD, Oncology Partners Network; Eleftherios Mamounas, MD, Aultman Hospital; Kelly Marcom, MD, Duke University Medical Center; Raul Mena, MD, East Valley Hematology and Oncology Medical; Carole Miller, MD, St Agnes Cancer Center; Barry Mirtsching, MD, Center for Oncology Research; Halle Moore, MD, Cleveland Clinic Hematology and Oncology; Johannes Nunnink, MD, Vermont Center for Cancer Medicine and Blood Disorders; Brian O'Connor, MD, Frederick Memorial Hospital; Edmund Paloyan, MD, Elmhurst Oncology/Hematology; Steven Papish, MD, Hematology Oncology Associates of Northern New Jersey; Lawrence Pawl, MD, Cook Research Department at Spectrum Health; Kelly Pendergrass, MD, Kansas Cancer Center; Edith Perez, MD, Mayo Clinic Jacksonville; Jorge Perez, MD, Sierra Nevada Oncology Care; Michael Rader, MD, USB Cancer Center at Nyack Hospital; David Rinaldi, MD, Louisiana Oncology Associates; Robert Robles, MD, Bay Area Cancer Research Group; Paula Ryan, MD, PhD, Gillette Center for Women's Cancers; Christopher Seidler, MD, Fallon Clinic; Elizabeth Tan-Chiu, MD, Cancer Research Network; N. Simon Tchekmedyian, MD, Pacific Shores Medical Group; Howard Terebelo, DO, Providence Cancer Institute; John Thropay, MD, Clinical Trials and Research Associates, Inc; Katherine Tkaczuk, MD, University of Maryland; Deborah Toppmeyer, MD, Cancer Institute of New Jersey; Joan Trey, MD, Metro Health Medical Center; Carol VanHaelst, MD, Cascade Cancer Center; Grace Wang, MD, Oncology Hematology Group; John Ward, MD, University of Utah; Tracey Weisberg, MD, Maine Center for Cancer Medicine; Pat Whitworth, MD, Nashville Breast Center; Albert Wood, MD, Cancer Specialists of South Texas, PA; Ron Yanagihara, MD, Ron Yanagihara, MD; and Denise Yardley, MD, Sarah Cannon Cancer Center.
We thank the women who participated in this study, investigators, study coordinators, PRA International, BioImaging Technologies, and CRL Medinet. We thank Richard Theriault, DO, Nicholas Sauter, MD, Eric Winer, MD, Laurence Demers, PhD, Serge Cremers, PharmD, PhD, and Mei Dong, MD, for assistance in the protocol and Syntaxx Communications for manuscript development.
published online ahead of print at www.jco.org on December 11, 2006. Supported by Novartis Oncology, East Hanover, NJ. Presented in part at the 27th Annual San Antonio Breast Cancer Symposium, December 8-11, 2004, San Antonio, TX; and the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Simpson ER, Dowsett M: Aromatase and its inhibitors: Significance for breast cancer therapy. Recent Prog Horm Res 57:317-338, 2002 11. Geisler J, Lønning PE: Endocrine effects of aromatase inhibitors and inactivators in vivo: Review of data and method limitations. J Steroid Biochem Mol Biol 95:75-81, 2005[CrossRef][Medline] 12. Eastell R, Hannon R: Long-term effects of aromatase inhibitors on bone. J Steroid Biochem Mol Biol 95:151-154, 2005[CrossRef][Medline] 13. Novartis Pharmaceuticals Corp: Zometa: Package insert. East Hanover, NJ, Novartis Pharmaceuticals Corp, 2005 14. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169:2008-2012, 2003[CrossRef][Medline] 15. Reid IR, Brown JP, Burckhardt P, et al: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653-661, 2002 16. Gnant M, Jakesz R, Mlineritsch B, et al: Zoledronic acid effectively counteracts cancer treatment induced bone loss (CTIBL) in premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen: Bone density subprotocol results of a randomized multicenter trial (ABCSG-12). Breast Cancer Res Treat 88:S8-S9, 2004 (suppl 1, abstr 6) 17. WHO Study Group: Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Report of a WHO Study Group. World Health Organ Tech Rep Ser 843:1-129, 1994[Medline] 18. National Cancer Institute: Common Toxicity Criteria v2.0. http://ctep.info.nih.gov/reporting/CTC-3.html 19. Coleman RE, Banks LM, Hall E, et al: Intergroup Exemestane Study: 1 year results of the bone sub-protocol. Presented at San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 401) 20. Goss PE, Ingle JN, Martino S, et al: Updated analysis of the NCIC CTG MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. J Clin Oncol 22:87s, 2004 (suppl; abstr 847) 21. Eastell R, Hannon RA, Cuzick J, et al: Effect of anastrozole on bone density and bone turnover: Results of ‘Arimidex’ (anastrozole), Tamoxifen, Alone or in Combination (ATAC) study. Presented at the Annual Meeting of the American Society of Bone and Mineral Research, San Antonio, TX, September 20-24, 2002 22. Kanis JA: Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359:1929-1936, 2002[CrossRef][Medline] 23. Marshall D, Johnell O, Wedel H: Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254-1259, 1996 24. Johnell O, Kanis JA, Oden A, et al: Predictive value of BMD for hip and other fractures. J Bone Miner Res 20:1185-1194, 2005[CrossRef][Medline] 25. Siris ES, Chen Y-T, Abbott TA, et al: Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108-1112, 2004 26. Cummings SR, Nevitt MC, Browner WS, et al: Risk factors for hip fracture in white women. N Engl J Med 332:767-773, 1995 27. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 28. Greenspan SL, Rosen HN, Parker RA: Early changes in serum N-telopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women. J Clin Endocrinol Metab 85:3537-3540, 2000 29. Gertz BJ, Clemens JD, Holland SD, et al: Application of a new serum assay for type I collagen cross-linked N-telopeptides: Assessment of diurnal changes in bone turnover with and without alendronate treatment. Calcif Tissue Int 63:102-106, 1998[CrossRef][Medline] 30. Van Poznak CH, Estilo CL, Sauter NP, et al: Osteonecrosis of the jaw in patients with metastatic breast cancer. Presented at San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 3057) 31. Hoff AO, Toth B, Altundag K, et al: Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy. J Bone Miner Res 20:s55, 2006 (suppl 1, abstr 1218)[CrossRef] Submitted December 16, 2005; accepted May 4, 2006. Related Editorials
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ABSTRACT
INTRODUCTION
2 test were used to compare continuous and discrete variables, respectively. Patients who discontinued the study early were instructed to return for a final assessment of BMD, serum NTx and BSAP concentrations, and AEs 4 weeks after treatment cessation. 
) One patient met protocol-defined criteria but did not receive zoledronic acid (ZA). (
) Twenty-five patients received ZA per protocol. (
) Per study design, 6-month bone mineral density (BMD) data were used if 12-month BMD data were unavailable or invalid (eg, illegible BMD scan).
