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The Oncologist, Vol. 13, No. 5, 503-514, May 2008; doi:10.1634/theoncologist.2007-0206
© 2008 AlphaMed Press

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Breast Cancer

Integrated Analysis of Zoledronic Acid for Prevention of Aromatase Inhibitor–Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole

Adam Brufskya, Nigel Bundredb, Robert Colemanc, Rosemary Lambert-Fallsd, Raul Menae, Peyman Hadjif, Lixian Jing, Nora Schenkg, Solveig Ericsong, Edith A. Perez Z-FAST and ZO-FAST Study Groupsh

aMagee-Womens Hospital, Pittsburgh, Pennsylvania, USA; bUniversity Hospital of South Manchester NHS Foundation Trust, Academic Department of Surgery, Education and Research Center, Wythenshawe, Manchester, United Kingdom; cAcademic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom; dSouth Carolina Oncology Associates, Columbia, South Carolina, USA; eEast Valley Hematology & Oncology Medical Group, Burbank, California, USA; fPhilipps-Universität Marburg, University Hospital of Giessen and Marburg, GmbH, Marburg, Department of Gynecology, Marburg, Germany; gNovartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; hMayo Clinic Jacksonville, Jacksonville, Florida, USA

Key Words. Breast neoplasm • Zoledronic acid • Aromatase inhibitor • Osteoporosis

Correspondence: Adam Brufsky, M.D., Ph.D., Magee-Womens Hospital, Suite 4628, 300 Halket Street, Pittsburgh, Pennsylvania 15123, USA. Telephone: 412-641-6500; Fax: 412-641-2296; e-mail: brufskyam{at}upmc.edu

Received October 26, 2007; accepted for publication April 8, 2008.

Disclosure: Study drugs (zoledronic acid and letrozole) were provided by Novartis Pharmaceuticals Corporation. A.B. has acted as a consultant for and has a financial interest in Novartis. N.B. has acted as a consultant for Novartis, AstraZeneca, and Pfizer. R.C. has acted as a consultant for, has a financial interest in, and has received research support from Novartis. S.E. owns stock in Novartis. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Author Contributions
 Acknowledgments
 References
 
After reading this article, the reader should be able to:

  1. Monitor for and treat to prevent bone loss in postmenopausal breast cancer patients receiving an aromatase inhibitor.
  2. Describe the methodology of the Z-FAST and ZO-FAST clinical trials.
  3. Discuss the effectiveness and tolerability of zoledronic acid when administrated to prevent bone loss associated with aromatase inhibitors.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Author Contributions
 Acknowledgments
 References
 
Background. The interim (12-month) results of two similarly designed, ongoing studies (the Zometa®-Femara® Adjuvant Synergy Trials [Z-FAST and ZO-FAST]) suggest that zoledronic acid (4 mg intravenously every 6 months) when initiated with adjuvant letrozole increases bone mineral density (BMD) of the lumbar spine (LS) in postmenopausal women with early-stage breast cancer compared with patients who receive zoledronic acid only when bone loss became clinically significant or a fragility fracture occurred.

Methods. An integrated analysis was performed to maximize the value of the large pool of data from the two studies in answering clinically relevant questions. The primary objective was to compare the change in LS BMD at month 12. Secondary objectives included comparing (a) the change in total hip (TH) BMD, (b) changes in bone turnover marker concentrations, (c) time to disease recurrence, and (d) safety at month 12.

Findings. The integrated analysis included 1,667 patients. At month 12, LS BMD was 5.2% higher in the upfront group than in the delayed group; TH BMD was 3.5% higher. N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 21.3% and 12.8% in the upfront group and increased by 21.7% and 24.9% in the delayed group, respectively (p < .0001 for intergroup comparisons). Fewer patients receiving upfront zoledronic acid experienced disease recurrence than patients in the delayed group—seven patients (0.84%) versus 17 patients (1.9%) (p = .0401). Fracture rates were similar. No confirmed osteonecrosis of the jaw was reported.

Conclusions. The results of this analysis strengthen the statistical validity of the preliminary results of the Z-FAST and ZO-FAST studies, showing that upfront zoledronic acid prevents aromatase inhibitor–associated bone loss more effectively than delayed-start zoledronic acid in postmenopausal women with early-stage breast cancer receiving letrozole. Additionally, disease recurrence appears to be lower with upfront zoledronic acid, but further follow-up is needed to confirm these interim results.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 Author Contributions
 Acknowledgments
 References
 
The results of several large clinical trials comparing tamoxifen with the third-generation aromatase inhibitors (AIs) administered either alone or sequentially after 2–3 years of tamoxifen, in postmenopausal women with early-stage, hormone receptor–positive breast cancer, show that treatment with AIs results in a longer disease-free survival interval and produces fewer endometrial and thromboembolic adverse events (AEs) than tamoxifen [1–4]. Consequently, more women are receiving AIs as first-line adjuvant hormonal therapy or following tamoxifen therapy. However, because AIs nearly completely ablate the production of estrogen, a hormone that is essential for maintaining bone health, AI therapy places postmenopausal women with early-stage breast cancer at a greater risk for bone loss and fracture, by significantly increasing the rate of bone turnover [2–9]. Annual bone loss rates associated with AIs are higher than those observed in healthy postmenopausal women (2.2%–2.6% versus approximately 0.5%) [7, 10–13]. Similarly, higher fracture rates of one and a half to two times those observed in healthy postmenopausal women and postmenopausal breast cancer patients receiving tamoxifen have been reported [1, 13, 14]. Therefore, clinicians prescribing AIs must consider and assess the risk for skeletal complications and include bone loss prevention strategies as appropriate [15].

Zoledronic acid, a potent nitrogen-containing bisphosphonate, has been shown to maintain or increase bone mineral density (BMD) in premenopausal women with early-stage breast cancer receiving adjuvant hormone therapies as well as healthy postmenopausal women with low BMD; whether zoledronic acid is as effective in postmenopausal women with breast cancer receiving adjuvant AI therapy is under investigation [12, 16–18]. The interim results of two similarly designed, ongoing, randomized, multicenter studies—the Zometa®-Femara® Adjuvant Synergy Trials (Novartis Pharmaceuticals Corporation, East Hanover, NJ) Z-FAST (12 months, 24 months, and 36 months) and ZO-FAST (12 months, 24 months)—comparing the effects of zoledronic acid initiated concurrently with letrozole (i.e., upfront administration) or when bone loss becomes clinically significant or a fragility fracture has occurred (i.e., delayed administration) indicate that upfront administration of zoledronic acid is more effective in preserving BMD of the lumbar spine (LS) and total hip (TH) than delayed administration [12, 18–21]. To strengthen the statistical validity of these results, a combined analysis of the Z-FAST and ZO-FAST studies was performed; the results are reported herein.


   MATERIALS AND METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 Author Contributions
 Acknowledgments
 References
 
Study Population
Postmenopausal women from 94 North American (Z-FAST) and 132 international (ZO-FAST) community- and academic-based centers who had a history of surgically resectable stage I, II, or IIIa estrogen and/or progesterone receptor–positive breast cancer as well as baseline LS and TH T scores of –2.0 or greater were considered eligible. Eligible patients had completed initial therapy (i.e., tumor resection, adjuvant chemotherapy, and/or radiation therapy) within 4 weeks (ZO-FAST) or 12 weeks (Z-FAST) of study entry and had no evidence of residual disease. Patients with clinical or radiologic evidence of distant metastases, existing LS or TH fracture, or a history of nontraumatic fractures were excluded. Patients were also excluded if they had received letrozole or another adjuvant hormone therapy, i.v. bisphosphonates, endocrine therapy, or prolonged systemic corticosteroids within 12 months; anabolic steroids, growth hormone, or tibolone within 6 months; prior parathyroid hormone treatment for >1 week; > 3 months of systemic sodium fluoride in the past 2 years; or other investigational drugs. The use of other drugs known to affect the skeleton was prohibited 2 weeks before and throughout the study. Patients who reported receiving an oral bisphosphonate or hormone replacement therapy were required to discontinue use 3 weeks before study entry. Patients with diseases known to influence bone metabolism or with renal dysfunction (serum creatinine [SCr] level ≥3 mg/dl), other malignancies within the past 5 years, or nonmalignant systemic diseases (HIV and/or uncontrolled infections, type 2 diabetes mellitus, or thyroid dysfunction, and/or cardiovascular, renal, hepatic, and lung diseases, or thromboembolism that would prevent follow-up) were also excluded. Informed consent was obtained from each patient before enrollment, and the protocols were conducted in accordance with the review boards of the participating institutions.

Study Design
In these ongoing, phase IIIB, open-label studies, patients were randomized to receive upfront or delayed-start zoledronic acid, 4 mg i.v., as a 15-minute infusion every 6 months up to a maximum of 5 years. Patients in the upfront group received zoledronic acid within 14 days of randomization, whereas patients in the delayed group received zoledronic acid only if (a) any postbaseline LS or TH T score decreased to less than –2.0 or (b) a nontraumatic fracture occurred. All patients received oral letrozole (2.5 mg/day) for a maximum of 5 years or until disease recurrence occurred. All patients were instructed to take an oral calcium supplement (500–1,200 mg/day) and a multivitamin tablet containing vitamin D (400–800 IU/day). Patients were stratified according to baseline adjuvant chemotherapy (yes versus no) and baseline BMD—normal baseline BMD (T score more than –1.0) versus low baseline BMD (mild–moderate osteopenia; T score of –1.0 or lower and –2.0 or greater).

The primary endpoint of this analysis was the percentage change in LS (L1 – L4) BMD from baseline to month 12 between patients receiving upfront zoledronic acid and those receiving delayed-start zoledronic acid. Secondary endpoints were (a) the percentage change in TH BMD, (b) changes in serum concentrations of bone turnover markers (N-telopeptide [NTX] and bone-specific alkaline phosphatase [BSAP]), (c) time to disease recurrence, and (d) safety. The proportion of patients experiencing a cumulative reduction in BMD of at least 8% from baseline to month 12 was also recorded.

BMD was measured using dual-energy x-ray absorptiometry (DEXA) devices. Each DEXA device was crosscalibrated at baseline using four Bio-Imaging Bona Fide Phantoms® (Bio-Imaging Technologies, Inc., Newtown, PA); the stability of the DEXA devices was monitored quarterly. T scores, defined as the difference in the number of standard deviations (SDs) between an individual's BMD and the mean BMD for a group of young, healthy females, were calculated using manufacturer-specific T score databases [22]. Eligibility and timing for zoledronic acid initiation in the delayed group were based on local DEXA scan readings; however, all DEXA scans included in the efficacy analysis were analyzed by a central reader (BioImaging Technologies, Inc.). Month-6 BMD measurements were used as 12-month measurements for women with no 12-month measurements.

In a subset of patients, random, nonfasting blood samples were analyzed by a central laboratory (Z-FAST, Clinical Reference Laboratory, Inc., Lenexa, KS; ZO-FAST, CRL.Medinet B.V., Breda, The Netherlands) to determine serum NTX and BSAP concentrations at baseline and at 3, 6, 9, and 12 months. The Osteomark NTX assay (Osteomark, Inverness Medical Innovations Inc., Princeton, NJ) and the Metra assay (Metra Biosystems Inc., Mountainview, CA) were used to measure NTX and BSAP concentrations, respectively.

Patients were assessed for AEs and disease recurrence every 6 months. AEs were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0 (Z-FAST) and 3.0 (ZO-FAST) [23]. SCr levels were measured at baseline, before each infusion, and at the final visit.

Statistical Analysis
The 12-month data from the Z-FAST and ZO-FAST studies were combined for this integrated analysis. By combining the data from the large sample sizes of each of these studies, the statistical capabilities of the analyses were maximized. The efficacy analyses included the intention-to-treat (ITT) population, comprising all randomized patients from the two studies. All patients who received at least one dose of study drug (either letrozole or zoledronic acid) were included in the safety analyses.

All statistical tests were performed against a two-sided, alternative hypothesis using a significance level of 0.05 and a 95% confidence interval (CI). SAS® Version 8.2 (SAS Institute, Inc., Cary, NC) was used to summarize and analyze data. Adjustments for multiple tests were not performed. 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; an analysis of covariance model compared the differences between the two groups, including covariates for treatment, baseline BMD, years since menopause, prior chemotherapy, and region. Descriptive statistics, including sample size, SD, median, and range, are reported for continuous variables; discrete variables are summarized using frequencies and percentages.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 Author Contributions
 Acknowledgments
 References
 
Study Patients
Accrual occurred between September 2002 and December 2003 (Z-FAST), and between April 2003 and November 2004 (ZO-FAST). All 1,667 patients enrolled in the Z-FAST and ZO-FAST studies were included in the integrated efficacy analysis (Fig. 1). Patients were randomized to receive upfront (833 patients) or delayed (834 patients) zoledronic acid. Baseline characteristics were similar between the two groups (Table 1Go); 30% of patients in both the upfront and delayed groups had mild–moderate osteopenia (T score of –1 or lower and –2 or greater) at baseline.


Figure 1
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  		Figure 1. Enrollment and outcomes for an integrated analysis of two separate studies (Z-FAST and ZO-FAST) with similar study designs. The individual studies have been published [12, 18]. aZ-FAST/ZO-FAST: 602/1,065 patients. bITT population (Z-FAST/ZO-FAST: 301/532 patients). cITT population (Z-FAST/ZO-FAST: 301/533 patients). dSafety population.

Abbreviations: ITT, intention-to-treat; Z-FAST/ZO-FAST, Zometa®-Femara® Adjuvant Synergy Trials.

 


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  		Table 1. Patient demographics

 


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  		Table 1. (Continued)

 
Efficacy Results

BMD
At months 6 and 12, patients receiving upfront zoledronic acid experienced an increase in LS and TH BMD from baseline (12 months, p < .0001); however, the delayed group patients experienced a decrease in LS and TH BMD from baseline (12 months, p < .0001) (Fig. 2; please see online supplemental data for mean baseline and 12-month BMD values). Between the two groups, significant least squares mean differences in percentage change in LS and TH BMD from baseline to month 12 were also observed (LS: 5.2%; 95% CI, 4.8–5.6; TH: 3.5%; 95% CI, 3.2–3.8; p < .0001 for both). Patients with low baseline BMD (i.e., mild–moderate osteopenia) receiving upfront zoledronic acid were found to have greater BMD increases than patients with normal baseline BMD of both the LS (2.6% versus 1.8%) and TH (1.8% versus 1%) (Fig. 3). Patients in the delayed group with normal baseline BMD experienced greater decreases in LS (–3.4% versus –2.5%) and TH (–2.3% versus –1.9%) BMD than patients with low baseline BMD (Fig. 3). Six-month BMD measurements were carried forward for the 12-month LS and TH BMD analyses in approximately 7% and 8% of patients in the upfront and delayed groups, respectively. The use of 6-month BMD measurements for these analyses may possibly lead to a smaller percentage difference in 12-month BMD between the two groups. At month 12, the mean changes from baseline in LS and TH T scores were 0.183 and 0.087 in upfront patients and –0.303 and –0.179 in delayed patients, respectively.


Figure 2
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  		Figure 2. Mean (SEM) percentage change in BMD of the lumbar spine and total hip from baseline to months 6 and 12 in women with early-stage breast cancer receiving upfront or delayed zoledronic acid. p-value corresponds to comparisons between the upfront and delayed groups.

Abbreviations: BMD, bone mineral density; SEM, standard error of the mean.

 


Figure 3
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  		Figure 3. Mean (SEM) percentage change in BMD of the lumbar spine and total hip from baseline to month 12 in women with early-stage breast cancer administered upfront or delayed zoledronic acid and stratified according to baseline BMD.

Abbreviations: BMD, bone mineral density; SEM, standard error of the mean.

 
Based on LS T scores, patients receiving upfront zoledronic acid were less likely to experience a shift to a lower T-score category (e.g., normal BMD to mild–moderate osteopenia) than patients in the delayed group, regardless of their baseline T score. For example, more patients in the delayed group with normal baseline BMD developed mild–moderate osteopenia by month 12 than patients in the upfront group with normal baseline BMD (17% versus 1.8%; p < .0001); likewise, 17% of patients in the delayed group with baseline mild–moderate osteopenia progressed to severe osteopenia/osteoporosis (T score less than –2.0) compared with only 1% of patients receiving upfront zoledronic acid (p < .0001).

Ninety-two patients (11%) in the delayed group initiated zoledronic acid by month 12 (mean time to initiation, 8.8 months; SD, 4.3 months) because of either an LS or TH T score lower than –2.0 and/or a nontraumatic fracture. An additional 30 delayed patients (3.6%) initiated zoledronic acid by month 12, but did not meet the protocol-defined criteria for zoledronic acid initiation. The protocol was inadvertently misinterpreted by a few study sites, and several patients randomized to the delayed group received zoledronic acid at month 6 instead of in accordance with protocol-defined criteria. The number of administration-error protocol violations diminished significantly after these study sites were re-educated about the protocol.

The proportion of patients with a cumulative decrease in LS BMD of at least 8% from baseline to month 12 was lower in patients receiving upfront zoledronic acid than in patients randomized to the delayed group (0.1% versus 9.7%) (Fig. 4). Additionally, patients in the delayed group with normal baseline BMD were significantly more likely to have BMD decreases of at least 8% than patients with low baseline BMD (Fig. 4).


Figure 4
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  		Figure 4. Percentage of women with early-stage breast cancer administered upfront or delayed zoledronic acid and stratified according to baseline BMD whose 12-month lumbar spine BMD decreased at least 8% from baseline. p-value corresponds to comparisons between the upfront and delayed groups.

Abbreviation: BMD, bone mineral density.

 

Markers of Bone Turnover
The NTX reagent vendor was changed during the study; therefore, the NTX data from the ZO-FAST study were excluded from this analysis. Serum NTX and BSAP concentrations were measured in a subset of 231 (Z-FAST only) and 633 (Z-FAST and ZO-FAST) patients, respectively. The decreases in NTX and BSAP concentrations from baseline to month 12 in patients receiving upfront zoledronic acid were significant (NTX, –21.3%; BSAP, –12.8%; p < .0001 for both) (Fig. 5); in contrast, delayed group patients were found to have increases in NTX (Z-FAST patients only) and BSAP concentrations from baseline (NTX: 21.7%; p = .0011; BSAP: 24.9%; p < .0001) (Fig. 5). Between the two groups, the differences in percentage change for both NTX (Z-FAST patients only: range, 33.3%–49%; p < .0001) and BSAP (range, 30.3%–48.9%; p < .0001) concentrations were statistically significant at all time points.


Figure 5
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  		Figure 5. Mean (SEM) percentage change in (A) NTX and (B) BSAP concentrations from baseline in women with early-stage breast cancer administered upfront or delayed zoledronic acid. *p < .0001; p-value corresponds to comparisons between the upfront and delayed groups.

Abbreviations: BSAP, bone-specific alkaline phosphatase; NTX, N-telopeptide; SEM, standard error of the mean.

 

Fractures
At month 12, 18 upfront patients (2.2%) and 17 delayed patients (2.1%) suffered a fracture. Because of the low number of fractures occurring, a meaningful statistical comparison of 12-month fracture rates was not possible.

Disease Recurrence
Fewer patients receiving upfront zoledronic acid experienced disease recurrence or death than patients in the delayed group—nine (1.1%) versus 20 (2.3%) patients, respectively (p = .0396). Disease recurrence, alone, was also less common in upfront patients—seven (0.84%) versus 17 (1.9%) patients, respectively (p = .0401). Both differences were statistically significant. No local disease recurrences occurred in upfront patients; five (0.6%) delayed patients, however, experienced local recurrence. Distant disease recurrences were also more common in delayed patients—upfront, seven patients (0.84%); delayed, 12 patients (1.3%). Death was reported in four upfront patients (0.48%) and five delayed patients (0.6%). Two patients in each group expired following disease recurrence.

Safety
In general, zoledronic acid was well tolerated (Table 2). AE-related study discontinuations were similar between the two groups—49 (5.9%) upfront patients and 54 (6.5%) delayed patients. Grade 3 or 4 bone pain was reported by 1.2% of upfront and 0.6% of delayed patients. AEs believed to be related to the study drug (letrozole or zoledronic acid) occurred in 528 (63.8%) and 418 (50.7%) upfront and delayed patients, respectively (see online supplemental data for a listing of study drug–related AEs occurring in at least 5% of upfront or delayed patients).


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  		Table 2. Adverse events in at least 5% of upfront or delayed patients

 
One upfront patient developed grade 2 renal impairment believed to be related to the study drug; zoledronic acid was permanently discontinued in that patient. One delayed patient developed grade 3 renal impairment and another delayed patient developed grade 4 acute renal failure; however, neither patient received zoledronic acid before experiencing renal dysfunction. Renal impairment–related dose adjustments or temporary interruptions of study drug because of renal AEs were not reported for either group, although the Z-FAST protocol did not allow dose adjustments.

Serious AEs were observed in 66 (8%) upfront patients and 53 (6.4%) delayed patients, leading to study drug discontinuation in only 1.5% and 1%, respectively. Two patients in the upfront group and three patients in the delayed group died (upfront group: cerebral hemorrhage, unexplained death; delayed group: sudden cardiac death, subdural hygroma, suicide). No confirmed cases of osteonecrosis of the jaw (ONJ) were reported in either group.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 Author Contributions
 Acknowledgments
 References
 
Although zoledronic acid is not indicated in the studied population at this point in time, we evaluated the effects of zoledronic acid in postmenopausal breast cancer patients receiving adjuvant AI therapy in an effort to identify effective strategies for preventing bone loss–related morbidity. To our knowledge, the Z-FAST and ZO-FAST trials are the first studies to evaluate i.v. bisphosphonates for the prevention of bone loss in these patients [12, 18–21]. The results of these studies show that early-stage breast cancer patients who receive upfront zoledronic acid (4 mg i.v. every 6 months) have significantly less bone loss during the first 12 months of AI therapy than patients who receive delayed-start zoledronic acid (p < .0001, both BMD sites, both studies) [12, 18]. The integrated analysis of the Z-FAST and ZO-FAST studies confirms these results—upfront patients experienced significant increases in LS (+2%) and TH (+1.2%) BMD; in contrast, LS (–3.1%) and TH (–2.2%) BMD decreased in patients in the delayed treatment arm who received zoledronic acid (15.3%) or did not receive zoledronic acid (84.7%) (p < .0001, both BMD sites). Our study results also concur with the recent findings of the Austrian Breast and Colorectal Cancer Study Group-12 study that evaluated zoledronic acid in premenopausal breast cancer patients receiving anastrozole or tamoxifen plus goserelin as adjuvant endocrine therapy. In that study, AI–associated bone loss was prevented by the administration of zoledronic acid (4 mg i.v. every 6 months) in premenopausal women with early-stage breast cancer [16].

Because of the naturally occurring decline in circulating estrogens associated with menopause, postmenopausal breast cancer patients are at risk for bone loss even before receiving AI therapy [8]. Indeed, approximately 30% of patients enrolled in the Z-FAST and ZO-FAST trials had mild–moderate osteopenia at baseline [12, 18]. The results of this integrated analysis show that zoledronic acid not only prevents but also reverses bone loss in the majority of patients receiving upfront zoledronic acid; approximately 70% of patients receiving upfront zoledronic acid who had a BMD change at month 12 were found to have an increase in BMD. At least 25% of patients receiving upfront zoledronic acid who had baseline mild–moderate osteopenia achieved normal T scores (i.e., a T score greater than –1.0) by month 12 compared with only 7% of patients in the delayed group (p < .0001). In contrast, significantly more delayed patients had progressive BMD loss by month 12; approximately 17% of patients with normal BMD or mild–moderate osteopenia at baseline developed mild–moderate or severe osteopenia/osteoporosis by month 12 (p < .0001). Furthermore, significantly more delayed patients with low baseline BMD lost at least 8% of their BMD compared with upfront patients with low baseline BMD, indicating that considerable bone loss continues to occur in breast cancer patients with low baseline BMD receiving adjuvant letrozole without bisphosphonate therapy. Interestingly, delayed-group patients with normal baseline BMD were more likely to have a decrease in BMD of at least 8% by month 12 than were patients with low baseline BMD. Rapid bone loss such as this is often accompanied by structural damage that may further place the patient at risk for fractures, suggesting that women with normal BMD may also be at high risk for developing bone loss and fracture with AI therapy [24].

By month 12, 14.6% of delayed patients were initiated on zoledronic acid; 3.6% of these patients, however, inadvertently received study drug at month 6 without meeting the protocol-defined criteria for therapy initiation. Because zoledronic acid not only prevented further bone loss but also increased BMD, inclusion of all delayed patients who received zoledronic acid (i.e., the ITT population) in the efficacy analyses would most likely have skewed the results in favor of the delayed group. Nevertheless, a statistically significant difference in the percentage change in BMD from baseline to month 12 between groups was observed.

The positive effect of zoledronic acid on BMD is further supported by the rapid and sustained decrease in concentrations of serum NTX and BSAP, suggesting that zoledronic acid has a rapid and sustained effect on bone remodeling throughout the first 12 months of adjuvant letrozole therapy.

Fractures are the most relevant clinical consequence of bone loss [25]. During the first 12 months of the Z-FAST and ZO-FAST studies, clinical fractures occurred in 2.2% of upfront and 2.1% of delayed patients. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial investigators, however, observed a difference in fracture rate between patients receiving anastrozole and those receiving tamoxifen after only 6 months of therapy [26]. Furthermore, gradients of fracture risk independent of age have been reported; for every one SD decrease in T score, the fracture risk increases one and a half to threefold depending on the anatomical site of BMD measurement [25]. Neither the Z-FAST nor the ZO-FAST trial was powered or designed to reliably detect a difference in fracture rates between treatment groups. When data are available, the cumulative fracture rate after 36 months of adjuvant letrozole and bisphosphonate therapy will be analyzed using descriptive statistics.

Compared with delayed patients, patients receiving upfront zoledronic acid had a lower 12-month rate of disease recurrence. Although this difference is statistically significant, the clinical significance of this observation after 12 months of follow-up is uncertain. Longer follow-up is needed to determine the clinical robustness of this finding.

Zoledronic acid was generally well tolerated. Only bone pain and pyrexia were more common in the upfront than the delayed group; however, only 9.1% and 10.5% of bone pain and pyrexia cases in upfront group patients were believed to be study drug related. Only one upfront patient experienced grade 2 renal impairment believed to be related to zoledronic acid; severe renal dysfunction was not reported. To date, no confirmed cases of ONJ have been reported in the Z-FAST trial, and only one case of delayed dental healing has been reported in the ZO-FAST trial [18, 21]. The incidence of ONJ in cancer patients treated with bisphosphonates is unknown, but it is most commonly observed in patients who have undergone dental procedures and/or received chemotherapy and/or corticosteroid therapy [27]. Prospective, randomized, controlled studies of longer duration and larger sample size in breast cancer patients receiving infrequent (i.e., every 6 months) bisphosphonate therapy are needed to provide reliable data regarding the incidence of ONJ in this patient population.

Although our analysis suggests that zoledronic acid may be appropriate for postmenopausal breast cancer patients initiating adjuvant AIs, several questions regarding this strategy remain unanswered. The current American Society of Clinical Oncology guidelines recommend initiation of an i.v. or oral bisphosphonate only after a patient's T score declines to lower than –2.5 (i.e., osteoporosis), but the preliminary results of our study suggest that patients in whom zoledronic acid was initiated concurrently with letrozole experienced significantly greater BMD increases and were significantly less likely to progress to a lower T score over 12 months than patients who did not receive zoledronic acid or received it only when bone loss occurred [28].

Whether patients with normal baseline BMD should receive a bisphosphonate when initiating AI therapy is unknown. No patients in our study with a normal baseline BMD developed severe osteopenia/osteoporosis by 12 months; similar results were observed in the bone substudies of the Intergroup Exemestane Study and the ATAC trial, in which no patients with normal baseline BMD developed osteoporosis at 2 years and 5 years, respectively [14, 29]. Nonetheless, 17% of delayed patients with normal baseline BMD developed mild–moderate osteopenia, and >10% of delayed patients with normal baseline BMD experienced LS BMD decreases of at least 8%. At the 2007 San Antonio Breast Cancer Symposium, Hadji and colleagues [30] identified a list of clinical risk factors that clinicians could use to identify breast cancer patients receiving AI therapy who are at a higher risk for experiencing fracture and would likely benefit from upfront zoledronic acid. These clinical risk factors have been validated in healthy postmenopausal women and include T score lower than –1.5, age >65 years, body mass index <20 kg/m2, a family history of hip fracture, a personal history of fragility facture after age 50 years, tobacco use, and corticosteroid use for >6 months.

Also unclear is the optimal duration of adjuvant AI therapy, and hence, bisphosphonate therapy. Several clinical trials, including the Z-FAST and ZO-FAST trials, are evaluating the long-term BMD effects of adjuvant AIs and the ability of zoledronic acid to impede these effects [7]. Finally, the hypothetical concern of greater bone fragility caused by bisphosphonate-related increases in BMD, through oversuppression of bone turnover, remains an unproven theoretical risk [31–34]. The absolute median levels of bone turnover markers in our patients receiving zoledronic acid are still within the normal premenopausal reference ranges and do not suggest oversuppression of bone, but rather appropriate suppression. A longer follow-up and further studies are required to answer this question.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
Author Contributions
 Acknowledgments
 References
 
AI-associated bone loss can be prevented in postmenopausal women with early-stage breast cancer receiving concurrent zoledronic acid (4 mg i.v. every 6 months). Additionally, disease recurrence in patients receiving upfront zoledronic acid appears to be lower than in those who receive delayed zoledronic acid. The long-term effects of zoledronic acid on BMD and disease recurrence, however, are unknown; the final results of these trials are eagerly awaited.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Author Contributions
Acknowledgments
 References
 
Conception/design: Adam Brufsky, Robert Coleman

Administrative support: Lixian Jin

Provision of study materials or patients: Adam Brufsky, Nigel Bundred, Robert Coleman, Rosemary Lambert-Falls, Raul Mena, Peyman Hadji, Edith A. Perez

Collection/assembly of data: Adam Brufsky, Nigel Bundred, Robert Coleman, Peyman Hadji, Lixian Jin, Solveig Ericson, Edith A. Perez

Data analysis and interpretation: Adam Brufsky, Nigel Bundred, Robert Coleman, Peyman Hadji, Lixian Jin, Nora Schenk, Solveig Ericson, Edith A. Perez

Manuscript writing: Adam Brufsky, Nigel Bundred, Robert Coleman, Rosemary Lambert-Falls, Raul Mena, Peyman Hadji, Lixian Jin, Nora Schenk, Solveig Ericson, Edith A. Perez

Final approval of manuscript: Adam Brufsky, Nigel Bundred, Robert Coleman, Rosemary Lambert-Falls, Raul Mena, Peyman Hadji, Lixian Jin, Nora Schenk, Solveig Ericson, Edith A. Perez


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Author Contributions
 Acknowledgments
References
 
We are indebted to PRA International and Ghulam Warsi, Ph.D., for their statistical contributions; Mei Dong, M.D., for clinical trial management, data review, and manuscript contributions; Eliza Argonza-Aviles, R.N., M.S.H.S., for oversight of clinical trial management, data review, and manuscript contributions; and Stephanie Butler, Lisa Holle, and Alison Shore (Syntaxx Communications, Inc.) for assistance with manuscript development with the support of Novartis Pharmaceuticals Corporation. The manuscript was written and approved independently of Novartis by the senior authors and co-authors.

Study results, in part, were previously presented at the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 14–17, 2006.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 Author Contributions
 Acknowledgments
 References
 

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