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Effect of Anastrozole on Bone Mineral Density: 5-Year Results From the Anastrozole, Tamoxifen, Alone or in Combination Trial 18233230

Richard Eastell, Judith E. Adams, Robert E. Coleman, Anthony Howell, Rosemary A. Hannon, Jack Cuzick, John R. Mackey, Matthias W. Beckmann, Glen Clack

From the Academic Unit of Bone Metabolism, University of Sheffield; Cancer Research Centre, Weston Park Hospital, Sheffield; Department of Diagnostic Radiology, University of Manchester; Christie Hospital National Health Service Trust, Manchester; Wolfson Institute of Preventive Medicine, London; AstraZeneca, Cheshire, United Kingdom; Cross Cancer Institute, Edmonton, Alberta, Canada; Universität Erlangen-Nurnberg, Erlangen, Germany

Corresponding author: Richard Eastell, MD, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Herries Rd, Sheffield, S5 7AU United Kingdom; e-mail: r.eastell{at}sheffield.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (median follow-up, 68 months) has shown that adjuvant anastrozole has superior efficacy and better tolerability than tamoxifen. However, anastrozole reduces circulating estrogen, and low estradiol levels are associated with decreased bone mineral density (BMD) and increased fracture risk. It is therefore important to understand the effects of long-term aromatase inhibitor therapy on BMD.

Patients and Methods This prospective substudy of the ATAC trial assessed BMD changes in postmenopausal women with invasive primary breast cancer receiving anastrozole (1 mg/d) or tamoxifen (20 mg/d) as adjuvant therapy for 5 years. Lumbar spine and total hip BMD were assessed at baseline and after 1, 2, and 5 years.

Results One hundred ninety-seven women from the monotherapy arms of the ATAC trial were recruited onto the bone substudy, and 108 were included in the primary analysis. Among anastrozole-treated patients, there was a decrease in median BMD from baseline to 5 years in lumbar spine (–6.08%) and total hip (–7.24%) compared with the tamoxifen group (lumbar spine, +2.77%; total hip, +0.74%). No patients with normal BMD at baseline became osteoporotic at 5 years.

Conclusion Anastrozole is associated with accelerated bone loss over the 5-year treatment period. However, although patients with pre-existing osteopenia are likely to require monitoring and bone-protection strategies, patients with normal BMD would not appear to require monitoring beyond the recommendation for healthy postmenopausal women. The effect of anastrozole on bone should be weighed against its superior efficacy and better tolerability profile versus tamoxifen in the main ATAC trial.

	INTRODUCTION

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Estrogen is known to play a central role in the maintenance of normal bone mineral density (BMD) in women.¹ In postmenopausal women, low estradiol levels are associated with increased bone turnover, low BMD, and an increased risk of fracture.^2-7 In the 10 years following the menopause, there is a reduction in BMD averaging 2% per annum,⁸ and osteoporosis is a major cause of morbidity in postmenopausal women.

Anastrozole (Arimidex; AstraZeneca, Cheshire, United Kingdom), a nonsteroidal aromatase inhibitor (AI), markedly suppresses estrogen levels and is becoming increasingly important as adjuvant hormonal therapy for postmenopausal women with hormone-sensitive early breast cancer. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (ISRCTN 18233230) has shown that adjuvant treatment with anastrozole results in superior efficacy and tolerability compared with tamoxifen. At the completed treatment analysis after a 68-month median follow-up period, treatment with anastrozole produced significant improvements compared with tamoxifen for disease-free survival (hazard ratio [HR], 0.87; 95% CI, 0.78 to 0.97; P = .01) and time to recurrence (HR, 0.79; 95% CI, 0.70 to 0.90; P = .0005).⁹

Due to their mode of action, the AIs as a class have the potential to have a deleterious effect on the skeletal health of postmenopausal women receiving these drugs as adjuvant treatment for early breast cancer. Indeed, in the main ATAC trial (N = 9,366), at 68 months of median follow-up (median duration of treatment, 60 months), the overall incidence of fractures was higher in the anastrozole arm compared with the tamoxifen arm (11.0% v 7.7%; odds ratio = 1.49; 95% CI, 1.25 to 1.77).⁹ Tamoxifen has partial estrogen-agonist activity, which results in a bone-sparing effect, but also increases the risk of endometrial cancer and thromboembolic events. The beneficial effects of tamoxifen on BMD are most apparent at sites of trabecular bone, such as the lumbar spine^10,11; such protective effects are associated with decreased bone resorption and formation.^11,12 However, in total, 80% of the skeleton comprises cortical bone, where the bone-preservation effects of tamoxifen are less obvious.^10,11

Given the concerns about the long-term effects of antiestrogen therapy, the ATAC trial included a prospectively designed subprotocol to assess specifically the effects of long-term treatment with anastrozole and tamoxifen on bone. The 2-year analysis has been reported previously and showed that anastrozole treatment was associated with increased bone turnover and significant BMD loss, whereas tamoxifen therapy (and the combination) was associated with increased BMD.¹³ This is similar to reports of other AIs (letrozole and exemestane).^14,15 To make clinical treatment decisions, it is important to examine the effects of 5 years of AI therapy on BMD in postmenopausal women treated for breast cancer; to determine which women are at risk of becoming osteoporotic during treatment; and to interpret these findings in the context of changes in healthy postmenopausal women. Here, we report the 5-year BMD results from the monotherapy arms (anastrozole alone or tamoxifen alone) of the bone subprotocol of the ATAC trial.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Study Design
The ATAC trial was designed to compare the efficacy and safety of anastrozole and tamoxifen, alone or in combination, in postmenopausal women with localized early breast cancer. Full details of the ATAC trial design and patient inclusion criteria have been reported previously.¹⁶

The bone subprotocol was a randomized, double-blind, multicenter study performed within the ATAC main trial (Fig 1). Following analysis of the main ATAC trial at a median follow-up of 33 months, the combination therapy arm of the study was discontinued, given that there was no apparent efficacy benefit compared with tamoxifen alone.¹⁶ At that time, the primary objectives of the bone subprotocol were restricted to assessing and quantifying the changes in BMD among women receiving anastrozole (1 mg/d) and comparing them with tamoxifen (20 mg/d) alone for the duration of trial therapy. The monotherapy arms continued unchanged, and data from these arms only are presented here. Changes in BMD in the anastrozole and tamoxifen treatment groups are further compared with a small, untreated, nonrandomized control group (Fig 2).

View larger version (45K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram showing the number of patients in each intervention group included in the primary analysis population.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Mean percentage changes in bone mineral density after 1, 2, and 5 years, for patients with data at each time point. Bars represent 95% CI. (A) Lumbar spine change over time; (B) total hip change over time.

Patients
At participating centers, postmenopausal women who were candidates to receive adjuvant endocrine treatment for invasive primary breast cancer (as part of the main ATAC trial), and who were suitable for BMD assessment, were recruited onto the bone subprotocol. Documented, informed consent to participate in the study was obtained before the start of any study procedures. Patients with osteoporosis (T-score < –2.5) were excluded from the primary analysis population; those with osteopenia (T-score between –1 and –2.5) were included at the investigators' discretion. Postmenopausal women with invasive breast cancer, who as part of normal clinical practice were not receiving treatment after primary surgery, were recruited as a reference group for information on BMD changes with time in untreated breast cancer survivors.

Additional exclusion criteria were applied to participants in the bone subprotocol that were not applicable to those in the main ATAC trial. These were use of hormone-replacement therapy or bisphosphonates within the 12 months before randomization or during the study; bone fracture within the 6 months before randomization; use of anticonvulsant or corticosteroid therapy; or a history of chronic renal/hepatic impairment, malabsorption syndrome, or endocrine disorders, including hyperparathyroidism, untreated thyroid disease, Cushing's syndrome, and pituitary disease.

Assessments
The primary assessment was the change in lumbar spine and total hip BMD from baseline, assessed by dual-energy x-ray absorptiometry (DXA), using General Electric Lunar Corp (Madison, WI) and Hologic Inc (Bedford, MA) densitometers. Measurements were made at baseline and after 1, 2, and 5 years of trial therapy, and analyzed locally with quality control checked centrally by Bio-Imaging Technologies Inc (Newtown, PA). For the lumbar spine, DXA measurement was derived by taking an average of the L1, L2, L3, and L4 values. Total hip BMD was calculated from the ratio of the total bone mineral content and bone area from the trochanteric, intertrochanteric, and femoral neck regions of the hip.

Statistical Analysis
To detect a difference in percentage change in BMD of 2.5% between the anastrozole and tamoxifen groups, with 90% power and a two-sided (5%) significance level, it was calculated that a minimum of 67 patients per treatment arm was required. Given that it was expected that approximately 14% of patients in this subprotocol would have disease recurrence by the end of the 2-year follow-up, and that a further 10% would withdraw or have incorrect baseline scans, it was recommended that 86 patients per treatment group be recruited.

This article presents data obtained up to and including the 5-year report. Data for the 1- and 2-year analyses have been reported previously.¹³ All analyses and summaries are based on treatment first received.

Lumbar spine and total hip BMD were considered separately. Analyses focused on percent change from baseline and are based on median changes and their interquartile ranges. Differences between treatment groups were assessed by the Wilcoxon rank sum test. The statistical analysis was done under the supervision of an independent statistician.

To evaluate whether we could identify a baseline value of BMD above which it was unlikely that there would be an osteoporotic BMD at the end of 5 years, we fitted a linear model for minimum T-score at 5 years with an intercept term and a term for a minimum T-score at baseline, and plotted the fitted values to the model along with the corresponding two-sided 80% confidence and prediction intervals.

	RESULTS

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Patients
A total of 308 postmenopausal women from 38 centers in nine countries who were randomly assigned to treatment in the ATAC main trial⁹ were recruited to the bone subprotocol. Of these, 197 women received monotherapy and had a baseline DXA, and 108 (55%) were included in the primary 5-year analysis population (anastrozole, n = 57; tamoxifen, n = 51; Fig 2). An additional 46 postmenopausal women with invasive breast cancer who were not receiving any treatment after primary surgery were recruited as a control group, of whom 30 were eligible for 5-year analysis. Patient demographic and disease characteristics have been published previously¹³; briefly, patient characteristics were well balanced across treatment and untreated control groups. The mean age at entry was 64 years, 60% had a tumor 2 cm in maximum diameter, and 25% had previously undergone a hysterectomy. The monotherapy treatment arms and the nonrandomized, untreated controls were also well matched in terms of bone markers and percentage of patients with osteopenia. At baseline, approximately 45% of the women treated with anastrozole, 48% treated with tamoxifen, and 49% of the untreated control group had osteopenia of the lumbar spine, and 36% of each group had osteopenia of the hip. The BMD mean at baseline for the lumbar spine was 1.071 g/cm² in the anastrozole-treated group, 1.039 in the tamoxifen-treated patients, and 1.055 in the control group, whereas the BMD for the total hip was 0.942 g/cm² in the anastrozole group, 0.911 for the tamoxifen group, and 0.927 for the control population. However, considerably more patients in the anastrozole group were within 1 year of menopause compared with the tamoxifen and the control group.

Overall, 59 patients (35.3%) who received study monotherapy did not complete this substudy (anastrozole, 24 [29.6%] patients; tamoxifen, 35 [40.7%] patients). Of these, eight anastrozole-treated patients and 14 tamoxifen-treated patients had discontinued at the time of the 2-year analysis and were thus subsequently excluded from the 5-year analysis. The most common reasons for discontinuation over the course of the 5-year study were adverse events and investigator discretion. Women who dropped out at 1 year (but not at 2 years) had more rapid bone loss than women who continued for 5 years for anastrozole (P = .006) and tamoxifen (P = .05) for the lumbar spine (but not the total hip).

Effect of Treatment on BMD
Changes from baseline in 5-year BMD are listed in Table 1 and Figure 3. Among women treated with anastrozole, there was a decrease in median BMD from baseline to 5 years for both the lumbar spine (–6.08%) and total hip (–7.24%). The tamoxifen group showed an increase in median BMD over the 5-year period (lumbar spine, +2.77%; total hip, +0.74% [Table 1]). This occurred in the first 2 years and no additional increase was seen in years 2 to 5 (Table 2). The differences between treatment groups were highly significant at both sites (P < .0001). The control group showed changes in median BMD over the 5-year period (lumbar spine, +1.35%; total hip, –2.97%; Fig 3B). These results are in line with those seen at years 1 and 2.¹³

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Ratios of bone mineral density (BMD) at 5 years to baseline for spine and hip (< 1 = reduced BMD; > 1 = increased BMD). The longer horizontal lines indicate geometric mean.

Of those patients continuing in this substudy who had a normal BMD at study entry (T-score > –1.0) and received monotherapy treatment (anastrozole, n = 32; tamoxifen, n = 32), none had become osteoporotic (T-score < –2.5) at 5 years. However, it was noted that more women receiving anastrozole treatment became osteopenic, as compared with tamoxifen-treated women (anastrozole, n = 14; tamoxifen, n = 3). In addition, five women with osteopenia at baseline developed osteoporosis on treatment (anastrozole, n = 4; tamoxifen, n = 1; Table 3). Detailed examination of the shift of T-scores from baseline to year 5 enabled the regression line and 95% CI to be calculated. The T-score used was the minimum of mean lumbar spine T-score or total hip T-score; where either measurement was missing, the classification was made on the basis of the single measurement. No patient with a baseline T-score greater than –1.5 developed a BMD T-score of less than –2.5 on treatment, suggesting that the critical T-score for developing osteoporosis is about –1.5 (Fig 4). Using the linear regression model approach, we found that for a minimum baseline T-score of –1.5 or greater, the lower prediction interval is greater than –2.5.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Shift of T-scores from baseline to year 5. The dotted lines at –1.0 indicate the border between normal bone mineral density (BMD) and osteopenia, and those at –2.5 indicate the BMD level at which osteoporosis is diagnosed. In this analysis, only those patients with a baseline T-score of less than –1.5 developed osteoporosis on treatment (data within blue circle).

Safety
Full safety data for women who received monotherapy have been presented as part of the ATAC main trial report.^9,17

	DISCUSSION

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This study showed that 5 years of anastrozole treatment was associated with bone loss at the spine and hip. The BMD data show that, relative to tamoxifen, significant bone loss occurred throughout the 5 years with adjuvant anastrozole therapy, though there was evidence of a slowing of the rate of bone loss in the lumbar spine in years 2 to 5, compared with baseline to 2 years. This reflects the greater amount of trabecular bone in the spine, which reacts more quickly to antiestrogen therapy. However, it is reassuring that the early change was not sustained in years 2 to 5. It is known that BMD reduction in women accelerates around the menopause, averaging 2% per year over the subsequent 5 to 10 years.⁸ During this period, bone loss follows an exponential decline, with the most pronounced loss being in the immediate postmenopausal period. For this reason, the changes in BMD reported in this subprotocol were evaluated against time since last menstrual period. At 1, 2, and 5 years, we found that the rate of BMD loss at the lumbar spine for the anastrozole group was greater for women in the immediate postmenopausal period (within 4 years of their last menstrual period) than for patients more than 4 years since their menopause (Table 4). The effect of anastrozole was most marked in the first 4 years since menopause; however, there were small numbers of women who were less than 4 years since menopause in both treatment arms.

In large, adjuvant breast cancer trials, the third-generation AIs anastrozole,^9,16,19 letrozole,^20,21 and exemestane²² have all been associated with an increased risk of fractures.²³ Studies on the mechanisms have indicated that letrozole and exemestane are also associated with increased rates of bone loss as compared with tamoxifen²⁴ or placebo,^14,15 and a similar increase in bone turnover markers as compared with anastrozole.²⁵

The current analysis shows that no woman with a normal BMD at baseline had become osteoporotic at 5 years (Table 3), and the data suggest that only those women with a T-score of less than –1.5 are at risk of developing osteoporosis during the treatment period (Fig 4). This suggests that for many patients, if pre-existing osteopenia is excluded, no further monitoring or preventive strategies are necessary beyond those used for all menopausal women. For patients with pre-existing osteopenia or other risk factors (including age, family history, smoking, and concomitant use of drugs such as corticosteroids), regular monitoring of BMD and bone-protection strategies are likely to be required in women treated with AIs. However, AI-associated bone loss in at-risk patients may represent a preventable and treatable condition. Clinical trial evidence indicates that intravenous^26-28 and oral bisphosphonates^29,30 are effective in maintaining BMD in breast cancer patients receiving hormonal therapy.

Given that AIs reduce estrogen levels by approximately 90%, it might be expected that bone loss would be accelerated. However, it is critical to understand the relationship between AIs and fracture risk. BMD measurements are useful in establishing the fracture risk in an individual. Given that the key issue is to identify those women with increased risk of fracture, this is best done by measuring BMD.^23,31

Overall, findings from the ATAC bone subprotocol suggest that adjuvant anastrozole therapy for postmenopausal women with early breast cancer leads to accelerated bone loss. However, they also suggest that the risk of developing treatment-related osteoporosis seems to be confined to those patients already osteopenic at baseline, and other data suggest that bone loss can be managed in this group by DXA scanning and use of bisphosphonates as needed.^27,28 Thus issues related to bone loss seem to be manageable and need not influence the use of AIs in women with breast cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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: Glen Clack, AstraZeneca Leadership: N/A Consultant: Richard Eastell, AstraZeneca, Novartis, Pfizer; Judith E. Adams, AstraZeneca; Robert E. Coleman, AstraZeneca; Anthony Howell, AstraZeneca; Jack Cuzick, AstraZeneca; John R. Mackey, AstraZeneca; Matthias W. Beckmann, AstraZeneca, Novartis, Pfizer Stock: Glen Clack, AstraZeneca Honoraria: Richard Eastell, AstraZeneca, Novartis, Pfizer; Robert E. Coleman, AstraZeneca; Anthony Howell, AstraZeneca, Novartis, Pfizer; Jack Cuzick, AstraZeneca, Novartis, Pfizer; John R. Mackey, AstraZeneca; Matthias W. Beckmann, AstraZeneca, Novartis, Pfizer, Organon, GlaxoSmithKline, Merck, Sharp, & Dohme Research Funds: Richard Eastell, AstraZeneca, Novartis, Pfizer; Robert E. Coleman, AstraZeneca; Rosemary A. Hannon, AstraZeneca; Jack Cuzick, AstraZeneca; Matthias W. Beckmann, AstraZeneca Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Richard Eastell, Judith E. Adams, Anthony Howell, Jack Cuzick, Glen Clack

Administrative support: Glen Clack

Provision of study materials or patients: Judith E. Adams, Robert E. Coleman, John R. Mackey, Matthias W. Beckmann

Collection and assembly of data: Judith E. Adams, Rosemary A. Hannon, Matthias W. Beckmann, Glen Clack

Data analysis and interpretation: Richard Eastell, Robert E. Coleman, Anthony Howell, Rosemary A. Hannon, Jack Cuzick, John R. Mackey, Matthias W. Beckmann, Glen Clack

Manuscript writing: Richard Eastell, Robert E. Coleman, Anthony Howell, Jack Cuzick, John R. Mackey, Glen Clack

Final approval of manuscript: Richard Eastell, Judith E. Adams, Robert E. Coleman, Anthony Howell, Rosemary A. Hannon, Jack Cuzick, John R. Mackey, Matthias W. Beckmann, Glen Clack

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Previous Presentations. These data have been presented in part at several oral and poster presentations, the abstracts, for which have also been published:

Eastell R, Cuzick J, Clack G, et al: Effect of anastrozole on bone density and bone turnover: Results of the ‘Arimidex' (anastrozole), Tamoxifen, Alone or in Combination (ATAC) Study. J Bone Miner Res 17:S165, 2002 (suppl 1)

Eastell R, Adams J: Results of the Arimidex (anastrozole, A), Tamoxifen (T), Alone or in Combination (C) (ATAC) trial: Effects on bone mineral density (BMD) and bone turnover (ATAC Trialists Group). Ann Oncol 13:32, 2002 (suppl 5)

Eastell R: Effect of anastrozole on bone mineral density: 2-year results of the ‘Arimidex' (anastrozole), tamoxifen, alone or in combination (ATAC) trial. J Bone Miner Res 18:S312, 2003 (suppl 2)

Howell A: Effect of anastrozole on bone mineral density: 2-year results of the ‘Arimidex' (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial. Breast Cancer Res Treat 82:S27, 2003 (suppl 1)

Coleman R: Effect of anastrozole on bone mineral density and bone fractures: results from the ‘Arimidex' (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial. Eur J Cancer 2:140, 2004 (suppl 3)

Coleman RE, on behalf of the ATAC Trialists' Group: Effect of anastrozole on bone mineral density: 5-year results from the ‘Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial. J Clin Oncol 24:5s, 2006 (suppl; abstr 511)

Eastell R, Hannon RA, Cuzick J, et al: Effect of anastrozole on bone mineral density: 5-year results of the ‘Arimidex' (anastrozole), tamoxifen, alone or in combination (ATAC) trial. Calcif Tissue Int 78:S25, 2006 (suppl 1)

ATAC Trial Steering Committee Membership.(Members of the Writing Group for this article are marked with an asterisk.) Prof M Baum (Chairman and Principal Investigator for the main ATAC trial), University College London, London, UK; Prof AR Bianco, Universita Degli Studi Di Napoli Federico II, Napoli Italy; Dr A Buzdar, The University of Texas, M.D. Anderson Cancer Centre, Houston, USA; Dr M Coibion, Institut Bordet, Bruxelles, Belgium; *Professor R Coleman, Cancer Research Centre, Weston Park Hospital, Sheffield, UK; Dr M Constenla, Hospital Montecelo, Pontevedra, Spain; *Prof J Cuzick (independent statistician), Cancer Research UK, London, UK; Professor Dr W Distler, Universitätsklinikum, Carl Gustav Carus, Dresden, Germany; Prof M Dowsett, The Royal Marsden Hospital, London, UK; Prof J Forbes, Newcastle Mater Misericordiae Hospital, NSW, Australia; Prof W D George, Beatson Oncology Centre, Western Infirmary, Glasgow, UK; Sr J Gray, Belfast City Hospital, Belfast, UK; Dr JP Guastalla, Centre Leon Berard, Lyon, France; Mrs J Houghton, Dr N Williams, Clinical Trials Group of the Department of Surgery, UCL, London, UK, *Prof A Howell, Christie Hospital, Manchester, UK; Professor Dr JGM Klijn, Dr. Daniel den Hoed Kliniek and University Hospital Rotterdam, Rotterdam, the Netherlands; Dr G Y Locker, Evanston Hospital, Kellogg Cancer Care Center, Evanston IL, USA; *Prof John Mackey, Cross Cancer Institute, Edmonton, Canada; Prof R E Mansel, University of Wales College of Medicine, Cardiff, UK; Dr JM Nabholtz, Breast Cancer Research Institute, Paris, France; Dr T Nagykalnai, Uzsoki U Hospital, Budapest, Hungary; Dr A Nicolucci, GIVIO Coordinating Centre, Consorzio Mario Negri Sud, Centro Di Ricerchi Farmacologichi, E Biomedichi, Chieta, Italy; Dr U Nylen, Radiumhemmet, Karolinska sjukhuset, Stockholm, Sweden; Dr T Sahmoud, Mr R Hellmund, AstraZeneca Pharmaceuticals, Wilmington, USA; Mr R Sainsbury, Royal Free and University College Medical School, London, UK; Dr N Griffiths, Dr G Hoctin-Boes, AstraZeneca Pharmaceuticals, Macclesfield, UK; Dr JS Tobias, The Meyerstein Institute of Clinical Oncology, London, UK.

Principal and main investigators in the ATAC Bone Subprotocol. Prof Apffelstaedt, Tygerberg Hospital, Cape Town, South Africa; Dr WW Bate, Mercy Cancer Centre, Mercy Medical Centre, Mason City, Iowa, USA; *Prof Dr Med MW Beckmann, Universität Erlangen-Nurnberg, Erlangen, Germany; Dr MJ Burnell, Atlantic Health Science Group, Saint John, New Brunswick, Canada; Prof A Buzdar, The University of Texas, M.D. Anderson Cancer Center Breast Oncology Clinic Station, Houston, Texas, USA; Dr PD Byeff, University of Connecticut, John Dempsey Hospital, Farmington, Connecticut, USA; Dr S Cawthorn, Frenchay Healthcare NHS Trust, Frenchay Hospital, Bristol, UK; *Prof R Coleman, Weston Park Hospital, Sheffield, UK; Dr R Coquard, Clinique St Jean, Lyon, France; Dr AC de Boer, Ijsselland Ziekenhuis, Ijssel, Holland; Dr AKR al Debbagh, Trafford General Hospital, Trafford, UK; Dr MA Deutsch, Raleigh Internal Medicine and Wake Hematology/Oncology Clinic, Raleigh, North Carolina, USA; Dr C Dijkhuis, Oosterschelde Ziekenhuis, Goes, Holland; Dr R Fernstad, St Goran's Hospital, Stockholm, Sweden; Dr JP Guestalla, Centre Leon Berard, Lyon, France; Dr D Halkema, Albert Schweitzer Ziekenhuis, Dordrecht, Holland; Mr B Harrison, Northern General Hospital, Sheffield, UK; Dr S Holmberg, SU/Molndal Hospital, Molndal, Sweden; Dr IA Jaiyesimi, Wayne State University School of Medicine, Royal Oak, Michigan, USA; Dr EP Lester, Oncology Care Associates, PLLC, St. Joseph, Michigan, USA; Dr G Locker, Kellogg Cancer Care Center, Evanston, Illinois, USA; Dr PA Lyss, Missouri Baptist Cancer Center, St. Louis, Missouri, USA; *Prof JR Mackey, Cross Cancer Institute, Edmonton, Alberta, Canada; Prof R Mansel, University Hospital of Wales NHS Trust, Cardiff Breast Unit, Cardiff, UK; Dr U Nylén, Karolinska Sjukhuset, Stockholm, Sweden; Dr P Paterson, Royal Cornwall Hospitals NHS Trust, Treliske Hospital, Truro, UK; Dr KB Pendergrass, Kansas City Oncology and Hematology Group, Lenexa, Kansas, USA; Dr JG Posada, Division of Hematology/Oncology Scott and White Memorial Hospital, Temple, TX, USA; Dr O Rixe, Hopital Clinique Claude Bernard, Metz, France; Dr J Robert, CHAUQ - Hospital du St-Sacrement, Quebec City, Quebec, Canada; Prof JFR Robertson, Nottingham City Hospital NHS Trust, Nottingham, UK; Dr S Rotstein, Onkologiska Kliniken, Danderyd, Sweden; Dr A Sami, Saskatoon Cancer Centre, University of Saskatchewan Campus, Saskatoon, Saskatchewan, Canada; Dr JI Spector, Berkshire Hematology Oncology, P.C., Pittsfield, Massachusetts, USA; Dr L Strobbe, Nijmeegs Interconfessioneel, Ziekenhuis Canisius Wilhelmina, Nijmgen, Holland; Dr N Tirumali, Kaiser Permanente/Oncology Research, Portland, Oregon, USA; Dr A Wardley, Christie Hospital NHS Trust, Manchester, UK.

International Project Team. E Foster, SCTN Central Office, Information and Statistics Division, Edinburgh, UK; N Griffiths, A Doe, F Sapunar AstraZeneca Pharmaceuticals, Macclesfield, UK; J Houghton, N Williams, Clinical Trials Group of the Department of Surgery, UCL, London, UK; A Nicolucci, Mario Negri Institute, Chieta, Italy; S Pollard, Northern Yorkshire Clinical Trials Research Unit, Leeds, UK.

Independent Data Monitoring Committee.Dr M Buyse, International Institute for Drug Development (ID squared), Brussels, Belgium; Dr R Margolese, McGill University, The Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec, Canada; Prof J J Body, Institute J Bordet, Bruxelles, Belgium.

Collaborative/Operational Groups.JF Forbes (Group Coordinator), JK Wakeham (Study Coordinator): Australian New Zealand Breast Cancer Trials Group Operations Office; S de Placido (Study Coordinator), C Carlomagno (Study Coordinator): Universita degli Studi Di Napoli Federico II, Italy; A Nicolucci (Group Coordinator), M Belfiglio (Study Coordinator), M Valentini (Study Coordinator): GIVIO Group, Consorzio Mario Negri Sud, Italy; E Foster (Trial Coordinator): Scottish Cancer Therapy Network (SCTN), Information & Statistics Division, Edinburgh, UK; C Lacey (Trial monitor): North West Breast Group, Burnley, Lancashire, UK; S Pollard (Trial Coordinator): Northern & Yorkshire Clinical Trials Research Unit (NCTRU), University of Leeds, Leeds, UK. J Houghton (Senior Lecturer in Clinical Trials), N Williams (Trial Coordinator): Clinical Trials Group of the Department of Surgery, UCL, London, UK.

	ACKNOWLEDGMENTS

 
We thank the patients who are participating in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and all those listed in the Appendix (online only). This study was conducted under the auspices of the ATAC trial steering committee, who were responsible for the study design, interpretation of the data, and preparation of the manuscript. The sponsor, AstraZeneca, provided support for the conduct of the study, data collection, and project management. R. Eastell wrote the manuscript in conjunction with Sally Mitchell PhD, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca; the manuscript was reviewed and changes suggested by the ATAC trial steering committee.

	NOTES

 
Supported in part by AstraZeneca Grants No. RF11494, R/116920-1, RF831144, RF104903, RF105658, RF105659, RF109529, RF104892, and RF110304.

Preliminary data from this study have previously been published in: Eastell R, Hannon RA, Cuzick J, et al: Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) Trial (18233230). J Bone Miner Res 21:1215-1223, 2006.

Presented in part at the 24th Annual Meeting of the American Society for Bone and Mineral Research, September 21-24, 2002, San Antonio, TX; the 27th European Society for Medical Oncology Congress, October 18-22, 2002, Nice, France; the 25th Annual Meeting of the American for Bone and Mineral Research, September 19-23, 2003, San Antonio, TX; the 26th Annual San Antonio Breast Cancer Symposium, December 3-6, 2003, San Antonio, TX; the 4th European Breast Cancer Conference, March 16-20, 2004, Hamburg, Germany; the 42nd American Society for Clinical Oncology Annual Meeting, June 2-6, 2006, Atlanta, GA; and the 33rd European Symposium on Calcified Tissues, May 10-14, 2006, Prague, Czech Republic.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted February 6, 2007; accepted November 12, 2007.

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