Originally published as JCO Early Release 10.1200/JCO.2005.05.4882 on July 5 2006

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Effect of Letrozole Versus Placebo on Bone Mineral Density in Women With Primary Breast Cancer Completing 5 or More Years of Adjuvant Tamoxifen: A Companion Study to NCIC CTG MA.17

Edith A. Perez, Robert G. Josse, Kathleen I. Pritchard, James N. Ingle, Silvana Martino, Brian P. Findlay, Tamara N. Shenkier, Richard G. Tozer, Michael J. Palmer, Lois E. Shepherd, Shifang Liu, Dongsheng Tu, Paul E. Goss

From the St Michael's Hospital; Toronto Sunnybrook Regional Cancer Centre, Toronto; Hotel Dieu Health Sciences Hospital, St Catharines; Juravinski Cancer Centre, Hamilton; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario; British Columbia Cancer Agency, Vancouver Cancer Clinic, Vancouver, British Columbia, Canada; Mayo Clinic, Jacksonville, FL; Mayo Clinic, Rochester, MN; Cancer Institute Medical Group, Santa Monica, CA; and Massachusetts General Hospital, Boston, MA

Address reprint requests to Edith A. Perez, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: perez.edith{at}mayo.edu

	ABSTRACT

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PURPOSE: Aromatase inhibition depletes estrogen levels and may be associated with accelerated bone resorption. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study MA.17B evaluated bone turnover markers and bone mineral density (BMD) in postmenopausal women randomly assigned to MA.17, a placebo-controlled trial of letrozole after standard adjuvant tamoxifen.

PATIENTS AND METHODS: Eligible women had a baseline BMD T score of at least 2.0 in either the hip or L2-4 spine; all received calcium 500 mg and vitamin D 400 U daily. Percentage change in BMD (L2-L4 spine and hip) at 12 and 24 months, rate of osteoporosis, and change in markers of bone formation (serum bone alkaline phosphatase) and resorption (serum C-telopeptide and urine N-telopeptide) at 6, 12, and 24 months were compared.

RESULTS: Two hundred twenty-six patients (122 letrozole, 104 placebo) were enrolled. Baseline characteristics were similar in the two groups, including BMD, median age of 60.7 years (81% < 70 years), and median follow-up of 1.6 years. At 24 months, patients receiving letrozole had a significant decrease in total hip BMD (–3.6% v –0.71%; P = .044) and lumbar spine BMD (–5.35% v –0.70%; P = .008). Letrozole increased urine N-telopeptide at 6, 12, and 24 months (P = .054, < .001, and .016, respectively). No patient went below the threshold for osteoporosis in total hip BMD, whereas at the L2-L4 (posteroanterior view), more women became osteoporotic by BMD while receiving letrozole (4.1% v 0%; P = .064).

CONCLUSION: After 5 years of adjuvant tamoxifen, subsequent letrozole causes a modest increase in bone resorption and reduction in bone mineral density in the spine and hip compared to placebo. Further follow-up is necessary to evaluate the long-term clinical implications of this difference.

	INTRODUCTION

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There is now compelling evidence from randomized phase III clinical trials for the use of aromatase inhibitors as adjuvant treatment of early stage hormone receptor–positive breast cancer in postmenopausal women. There remains debate about whether to use the inhibitors as up-front treatment instead of tamoxifen or in sequence with tamoxifen, and the optimal duration of therapy is also undefined. A concern related to chronic estrogen suppression in postmenopausal women already vulnerable to osteoporosis is the effect of the inhibitors on bone health. Surrogates for these effects are changes in markers of bone metabolism and bone mineral density (BMD), but the ultimate test is the incidence of clinical fractures. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17/JMA.17/BIG 97-01 trial was a double-blind clinical trial in which women were randomly assigned to letrozole or placebo after approximately 5 years of adjuvant therapy with tamoxifen for early breast cancer. It demonstrated a significant overall reduction of 42% in the risk of breast cancer recurrence for women receiving letrozole with good overall tolerability¹ and self-reported quality of life.² MA.17B is a companion study designed to compare the effects on BMD in the L2-L4 (posteroanterior [PA]) region of the spine and hip in women on MA.17 receiving letrozole or placebo.

	PATIENTS AND METHODS

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MA.17B, coordinated by the NCIC CTG, was conducted in centers in Canada and the United States (North Central Cancer Treatment Group; Southwest Oncology Group), as well as one center in Scotland. Participating centers were required to have approved and certified Hologic (Bedford, MA) or Lunar (Madison, WI) instrumentation for BMD assessment. At the sites participating in the bone substudy, all patients randomly assigned to the core MA.17 protocol were approached in an attempt to maintain balance between the two arms of the substudy.

Eligibility
Eligible women were those with a BMD T score at least 2.0 standard deviations below the mean value of peak bone mass in healthy young women. Radiographs were retained on site and were available for central review if requested. Exclusion criteria included malabsorption syndromes, clinically relevant vitamin D deficiency, active hyper- or hypoparathyroidism, Paget's disease, uncontrolled thyroid disease, Cushing's disease, other pituitary diseases, or bone diseases. Medications including anticonvulsants, long-term use of coumadin, corticosteroids in higher than physiological doses, sodium fluoride, anabolic steroids, and bisphosphonates excluded women from the trial. All women participating in this study signed written informed consent.

Patient Population and Test Procedures
Forty-two patients (23 [19%] receiving letrozole and 19 [[18%] receiving placebo) had taken vitamin D before study entry, and 88 (48 [40%] receiving letrozole and 40 [38%] receiving placebo) took calcium before study entry. During the protocol treatment, 117 patients (97%) receiving letrozole and 103 (99%) receiving placebo had received calcium; 118 patients (98%) receiving letrozole and 102 (98%) receiving placebo took vitamin D. Bisphosphonates were allowed after clinically significant bone loss.

A baseline BMD of the L2-L4 (PA view) region of the spine and hip was performed within 4 weeks before or 4 weeks after random assignment to the core MA.17 protocol and were to be repeated at years 1, 2, 3, 4, and 5. If protocol treatment was discontinued for any reason before 5 years, a bone density measurement was obtained unless a measurement had been performed in the prior 6 months or unless the patient had discontinued treatment within the first year after random assignment. Blood and urine for bone biomarkers (serum bone alkaline phosphatase, serum C-telopeptide and urine N-telopeptide) were obtained at baseline, 6 months, and annually for years 1 to 5, and assayed at a central laboratory in Edmonton, Canada. This central laboratory provided the following analytic methods with precision levels for serum bone alkaline phosphatase, serum C-telopeptide, and urine N-telopeptide: bone specific alkaline phosphatase—analytic method, enzyme immunoassay; total precision, 8.5% coefficient of variation (CV) at 13 U/L, 8.0% CV at 66 U/L; carboxyterminal telopeptide of type l collagen—analytic method, radioimmunoassay; total precision, 6.5% CV at 7.7 µg/L, 7.0% CV at 18.6 µg/L; N-telopeptide of type 1 collagen—analytic method, enzyme immunoassay; total precision, 10% CV at 439 nmol/L bone collagen equivalent (BCE), 7% CV at 1,537 nmol/L BCE.

Statistical Design
The primary end points in the original protocol were percentage change in BMD from baseline in the L2-L4 PA region of the spine and hip at 2 years and 5 years from random assignment to the core protocol. Other end points included the proportion of women who developed BMD below the absolute threshold for osteoporosis ( –2.5 below the mean) after baseline assessment; percentage change in bone biomarkers from baseline at 2 years and 5 years from random assignment; and clinical safety of letrozole with respect to osteoporosis in the evaluation of fractures (collected as part of the core protocol). Assuming that the SE for percentage change of BMD from baseline is 10%, then with no drop-outs, 200 patients (100 per treatment arm) guaranteed that a difference in percentage change of BMD of 4% could be detected at the end of 2 years with two-sided type I error .05 and a power of 80%. With a drop-out rate of 50%, a difference in percentage change of BMD of 6% at the end of 5 years between the two treatment arms could be detected.

The first preplanned interim analysis of the core study showed a highly statistically significant increase in disease-free survival for women treated with letrozole, and on the advice of the Data and Safety Monitoring Committee, all the women in the main study and including those participating in MA.17B had their study medication unblinded. Those receiving placebo were offered letrozole treatment starting immediately for 5 years.¹ At the time of unblinding, only a few patients in this study have been followed for more than 24 months because the bone substudy was initiated some time after the core protocol. It was thus decided for the purposes of this report to analyze the changes in hip and spine BMD and bone biomarkers at 6 (for bone markers only), 12, and 24 months.

All analyses were performed by the NCIC CTG central office. For the BMD and biomarker parameters, only those who had baseline observations and follow-up assessments were included in the analyses. Each variable was described as the percentage change from the baseline value at any given time point and compared between treatments using the Wilcoxon test. All comparisons between treatment arms were carried out using a two-sided test at an alpha level of 5% unless otherwise specified. No formal adjustments were made for the multiplicity of inferences for multiple clinical end points.

	RESULTS

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The study was open for accrual from July 2000 until August 2002. A total of 226 patients were randomly assigned into the study: 122 to letrozole and 104 to placebo. The majority of patients (98%) were accrued from Canada and the United States. Six patients (four receiving letrozole and two receiving placebo) were deemed ineligible after random assignment for the following reasons: BMD less than –2.0 (one patient receiving letrozole), use of anticonvulsant medication (one patient in each arm), use of bisphosphonate (one patient receiving placebo), and lack of BMD within the allowed 4-week window (two patients receiving letrozole). All randomly assigned patients were included in an intent-to-treat analysis. Selected baseline patient characteristics are presented in Tables 1 and 2, and are similar to those of the patients in the core study.¹

Tables 6 and 7 summarize the results of exploratory subgroup analyses of BMD parameters and bone biomarkers respectively for women who were osteopenic at the time letrozole/placebo was started (baseline T score < –1.0 at the hip and/or lumber spine) and those with a baseline BMD within the normal range (baseline T score –1.0 at the hip and/or lumber spine). For women with a baseline T score of less than –1.0, those receiving letrozole had a statistically significant decrease in lumbar spine (P = .009) and in total hip BMD (P = .011) at 24 months. Significant increases were also found for those receiving letrozole in urine N-telopeptide at both 12 and 24 months (P = .029 and .045, respectively), in serum alkaline phosphatase at 12 months (P = .018), and in serum C-telopeptide at 24 months (P = .01). For women with a baseline T score of at least –1.0 at baseline, a significant difference was found only in urine N-telopeptide at 12 months (P = .007) and no difference was shown for C-telopeptide or serum alkaline phosphatase.

View this table: [in this window] [in a new window]   Table 7. Analysis of BMD and Bone Biomarkers in Patients With Baseline BMD T Score –1.0 in Total Hip and/or Lumbar Spine

	DISCUSSION

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Those receiving letrozole had a significantly greater decrease in total hip BMD (percentage change in T score, mean –0.71 and –3.60 for placebo and letrozole, respectively; P = .044) and a significant decrease in lumbar spine BMD (percentage change in T score, mean –0.7 and –5.35 for placebo and letrozole, respectively; P = .008) at 24 months. Evaluation of bone turnover biomarkers corroborated the BMD findings. Patients treated with letrozole had an increase at 6 months (P = .054), 12 months (P < .001) and 24 months (P = .016) in urine N-telopeptide, a bone resorption marker. A significant difference between letrozole and placebo in serum alkaline phosphatase was observed at 12 months only (P = .016). No differences were detected with serum C- telopeptide during the 2 years of follow-up. Although no patients during the study had BMD below the absolute threshold for osteoporosis in the total hip, five patients receiving letrozole and none receiving placebo did have T-score measurements below –2.5 in the lumbar spine (4.1% v 0%; P = .064).

Bisphosphonates use was more common in patients receiving placebo (10.6%) compared with letrozole (4.1%)—a puzzling imbalance considering that letrozole, not placebo, patients were more likely to experience decreases in their BMD (Table 3). This factor could have had a positive impact on the BMD of patients on placebo, thereby exaggerating the difference between letrozole and placebo. It is of interest to note that in women who were osteopenic at the time of starting letrozole (T score < –1.0), BMD scores were more likely to show a significant drop than those with BMD within the normal range. It had been postulated that BMD decrease in women already osteopenic may have been less notable, contrary to the findings in our study. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) bone substudy^7,8 demonstrate similar findings that we have observed with letrozole, with a loss of BMD over time in women treated with anastrozole. The proportion of patients who experienced a fracture in the overall ATAC trial⁹ at a median follow-up time of 68 months was significantly higher in the anastrozole group (11%) than in the tamoxifen group (7.7%; P < .0001). In an updated analysis,¹⁰ the proportion of women who experienced a fracture in MA.17 at a median follow-up time of 30 months was higher in the letrozole group (5.3%) than the placebo group (4.6%), but the difference was not statistically significant. One might anticipate a larger bone loss in the placebo arm compared with what was seen in our study. One explanation could be regular treatment with vitamin D and calcium. In MA.17, one expects that women enrolled would generally have superior BMD compared with age-matched controls, with expected bone resorption and a decrease in BMD in all women stopping treatment with tamoxifen. Thus in this substudy, the effects of letrozole on bone metabolism are compared with those of tamoxifen withdrawal. After a median follow-up of 1.6 years, our results indicate that net bone resorption occurred in both arms of the trial, but that letrozole had a modestly greater effect on bone metabolism compatible with increased bone resorption associated with additional estrogen suppression.

Related to another aromatase inhibitor (AI), one clinical model¹¹ and one human volunteer study¹² imply that there is bone formation stimulation by exemestane, and two clinical studies provide additional data on the effects of exemestane on bone metabolism. Lonning et al¹³ compared the effects of exemestane versus placebo in 128 postmenopausal women with early breast cancer. At a median follow-up of 2 years, exemestane led to an annual BMD loss of –2.72% in the femoral neck (hip), compared with –1.48% for placebo (P = .024). Coombes et al¹⁴ reported from the Intergroup Exemestane Study (IES) a trend toward higher incidence of fracture in the exemestane group (3.1%), compared with the tamoxifen group (2.3%; P = .08). In the IES bone substudy¹⁵ after 1 year of therapy, exemestane was associated with significantly greater reductions in lumbar spine (2.9%) and total hip (2.1%) BMD, compared with changes in patients who continued on tamoxifen treatment (0.02% and 0.5%, respectively; P < .0001 for both exemestane v tamoxifen comparisons). Thus, bone studies using both nonsteroidal (anastrozole, letrozole) or steroidal (exemestane) AIs demonstrate fairly similar reductions in bone mineral density compared to baseline, at median follow-up of up to 2 years.

Although issues of bone health need to be taken into consideration when planning endocrine adjuvant therapy, they should be viewed in context of the significant benefits of the AIs. Not only is this class of drugs associated with significant improvements in breast-cancer–free survival as demonstrated with letrozole in MA.17, but the more threatening adverse effects of tamoxifen, such as endometrial cancer and thromboembolic events, are not seen with the same frequency. Of importance is that women receiving letrozole after 5 years of tamoxifen have a better starting BMD than age-matched controls, and thus any fall of BMD on letrozole is in part offset by this. In addition, our data suggest that women with a BMD of –1.0 or greater when starting letrozole after tamoxifen are less vulnerable to enhanced bone resorption, and may not require prophylactic bisphosphonate therapy. The assessment of a woman's individual risk:benefit ratio, prior adjuvant endocrine therapy, breast cancer recurrence risk, and general health will remain pivotal in our clinical decision making. After MA.17 was unblinded, approximately 800 women who had taken placebo remained off therapy, and approximately 1,600 switched to letrozole.

We are therefore continuing to follow three distinct cohorts, those who took letrozole, those who did not, and those who switched at varying time intervals after receiving placebo for up to 5 years. We will thus report on new diagnoses of osteoporosis and clinical fracture risk in all three cohorts in long-term follow-up. Furthermore all women on this bone substudy are being followed with BMD assessments and bone biomarkers, and we will report these results as well.

	Authors’ Disclosures of Potential Conflicts of Interest

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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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Edith A. Perez Genetech (B); Pfizer (B); Sanofi Aventis (B); AstraZeneca (B); Bristol-Myers Squibb (B); Eli Lilly (B) Kathleen I. Pritchard Aventis (A); Roche (A); Pharmacia (A); YM Biosciences (A); Pfizer (A); Biomera (A) Aventis (A); AstraZeneca (A); Pharmacia (A); Pfizer (A) Aventis (N/R); AstraZeneca (N/R) James N. Ingle AstraZeneca (A) Novartis (A) Richard G. Tozer Shering (A); AstraZeneca (A) Paul E. Goss Novartis (A) Novartis (A); Pfizer (A) Novartis Health Canada 2004 (N/R)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Edith A. Perez, Kathleen I. Pritchard, James N. Ingle, Lois E. Shepherd, Dongsheng Tu, Paul E. Goss Administrative support: Silvana Martino, Michael J. Palmer Provision of study materials or patients: Edith A. Perez, Kathleen I. Pritchard, James N. Ingle, Silvana Martino, Brian P. Findlay, Tamara N. Shenkier, Richard G. Tozer, Paul E. Goss Collection and assembly of data: Edith A. Perez, Kathleen I. Pritchard, James N. Ingle, Tamara N. Shenkier, Richard G. Tozer, Michael J. Palmer, Lois E. Shepherd, Dongsheng Tu, Paul E. Goss Data analysis and interpretation: Edith A. Perez, Robert G. Josse, Kathleen I. Pritchard, James N. Ingle, Silvana Martino, Lois E. Shepherd, Shifang Liu, Dongsheng Tu, Paul E. Goss Manuscript writing: Edith A. Perez, Robert G. Josse, Kathleen I. Pritchard, James N. Ingle, Michael J. Palmer, Lois E. Shepherd, Shifang Liu, Dongsheng Tu Final approval of manuscript: Edith A. Perez, Robert G. Josse, Kathleen I. Pritchard, James N. Ingle, Silvana Martino, Tamara N. Shenkier, Richard G. Tozer, Lois E. Shepherd, Shifang Liu, Dongsheng Tu, Paul E. Goss

 

	NOTES

 
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 REFERENCES

 
1. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003[Abstract/Free Full Text]

2. Whelan TJ, Goss PE, Ingle JN, et al: Assessment of quality of life in MA17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23:6931-6940, 2005[Abstract/Free Full Text]

3. Powels TJ: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996[Abstract]

4. Hodgson SF, Watts NB, Bilezikian JP, et al: American Association of Clinical Endocrinologists 2001 medical guidelines for clinical practice for the prevention and management of postmenopausal osteoporosis. Endocr Pract 7:293-312, 2001[Medline]

5. Mincey BA: Osteoporosis in women with breast cancer. Curr Oncol Rep 5:53-57, 2003[Medline]

6. Report of a WHO Study Group: Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 843:1-129, 1994[Medline]

7. Eastell R, Hannon RA, Cuzick J, et al: Effect of anastrozole on bone density and bone turnover: Results of the ‘Arimidex’ (anastrozole), Tamoxifen Alone in combination (ATAC) trial bone sub-protocol. Presented at the 24th Annual Meeting of the American Society for Bone and Mineral Research, San Antonio, TX, September 20-24, 2002 (abstr 17)

8. Howell, A: On Behalf of the ATAC Trialists’ Group 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)

9. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline]

10. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA17. J Natl Cancer Inst 97:1262-1271, 2005[Abstract/Free Full Text]

11. Goss PE, Qi S, Josse RG, et al: The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 34:384-392, 2004[Medline]

12. Subar M, Goss PE, Thomsen T, Banke-Bochita J: Effects of steroidal and non-steroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteer. J Clin Oncol 23:734, 2004 (suppl; abstr 8038)

13. Lonning PE, Geisler J, Krag LE, et al: Effects of exemestane administered for 2 years vs. placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126-5137, 2005[Abstract/Free Full Text]

14. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004[Abstract/Free Full Text]

15. Coleman RE, Banks LM, Hall E, et al: Intergroup exemestane study: 1 year results of the bone sub-protocol. Breast Cancer Res Treat 88:535, 2004 (suppl 1; abstr 901)

Submitted January 13, 2006; accepted May 9, 2006.

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