Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With S
http://www.100md.com
▲還散笫雖悝◎
the Section of Oncology, Department of Medicine, Haukeland University Hospital
Laboratory for Clinical Biochemistry, Haukeland University Hospital
Center for Clinical Trials, Bergen
Department of Surgery, Rogaland Central Hospital, Stavanger
Department of Oncology, The Norwegian Radiumhospital
Department of Surgery, Ullevaal University Hospital, Oslo
Department of Oncology, University Hospital of North Norway, Troms?
Department of Surgery, St Olavs Hospital, Trondheim, Norway
Pharmacia Italia SpA, Pfizer Group, Clinical Development, Milan, Italy
ABSTRACT
PURPOSE: To evaluate potential detrimental effects of exemestane on bone and lipid metabolism.
PATIENTS AND METHODS: Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting. Primary objective was to evaluate the effect of exemestane on bone mineral density. Secondary objectives were effects on bone biomarkers, plasma lipids, coagulation factors, and homocysteine. Planned size was 128 patients.
RESULTS: One hundred forty-seven patients were enrolled. All patients completed their 24-month visit except for those discontinuing treatment at an earlier stage. The mean annual rate of bone mineral density loss was 2.17% v 1.84% in the lumbar spine (P = .568) and 2.72% v 1.48% in the femoral neck (P = .024) in the exemestane and placebo arm, respectively. The mean change in T-score after 2 years was 每0.21 for exemestane and 每0.11 on placebo in the hip, and 每0.30 and 每0.21, respectively, in the lumbar spine. Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers. Except for a modest reduction in high-density lipoprotein cholesterol (P < .001) and apolipoprotein A1 (P = .004), exemestane had no major effect on lipid profile, homocysteine levels, or coagulation parameters.
CONCLUSION: Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.
INTRODUCTION
Endocrine therapy plays a key role in the treatment of hormone receptor每positive breast cancer. While treatment of advanced breast cancer is palliative, adjuvant therapy with ovarian ablation or tamoxifen improves relapse-free as well as overall survival in pre- as well as in postmenopausal women with estrogen receptor每positive breast cancers.1,2
While aromatase inhibition has been known for more than two decades as a treatment option for postmenopausal breast cancer,3 implementation of the novel third-generation nonsteroidal inhibitors (anastrozole and letrozole) and the third-generation steroidal inactivator exemestane represents a therapeutic breakthrough. These compounds induce more than 98% inhibition of total-body aromatization in postmenopausal women,4,5 causing only minimal side effects. Based on the superiority of the novel third-generation aromatase inhibitors and inactivators in metastatic disease compared with conventional treatment,6-8 these drugs are currently explored as adjuvant therapy of postmenopausal women with exciting results.9-11
Possible detrimental effects on blood lipids and, in particular, accelerated bone loss due to long-term estrogen deprivation12-14 may represent major concerns to the use of aromatase inhibitors and inactivators in early breast cancer. Thus, the toxicity of these compounds is a major issue in clinical development.
Here, we report the results of a double-blind randomized study comparing 2 years of exemestane versus placebo in women with early breast cancer who are not subject to regular adjuvant therapy due to their low-risk profile. The major end point was the effect on bone mineral density (BMD); secondary end points were effects on biochemical parameters of bone resorption and formation as well as plasma lipids and homocysteine levels.
PATIENTS AND METHODS
Study Design
The study was designed and conducted by the Norwegian Breast Cancer Group in collaboration with Pfizer Inc. Postmenopausal women with low-risk, surgically treated early breast cancer (n = 129) or ductal carcinoma-in-situ (n = 18) were randomly assigned (double-blind) to either exemestane 25 mg daily or placebo by mouth for 2 years and subsequently followed up for 1 year for the study main end point (BMD) and up to 5 years for disease-free survival. All bone biomarkers were recorded at baseline and after 6, 12, 18, and 24 months of treatment and after 3 and 6 months of follow-up. Lipids were measured at baseline and after 3, 6, 12, and 24 months of treatment and after 3, 6, and 12 months of follow-up, while coagulation parameters were recorded after 3, 12, and 24 months of treatment and after 12 months of follow-up. BMD was recorded at baseline and after 6, 12, and 24 months of therapy and finally after 12 months of follow-up. The study was carried out at six Norwegian centers and enrolled patients from January 1999 to October 2001. At that time, postmenopausal patients with low-risk breast cancer as defined in the inclusion criteria (Table 1) were not offered routine adjuvant systemic treatment according to the Norwegian National Guidelines.
The protocol was approved by the regional ethical committees, and each patient gave written informed consent before being enrolled. Random assignment was performed by center; patients were randomly assigned to treatment by blocks of four. A data monitoring board, including an oncologist and a lipid and a bone expert not involved in the study oversaw the safety of patients as well as the quality of the bone density data produced.
Assessment of BMD and Bone Biomarkers
BMD was measured on the lumbar spine (L1 to L4) and on the femoral neck with Hologic densitometry (Hologic Inc, Walthem, MA,) in 130 patients and Lunar densitometry (Lunar Corp, Madison, WI) in 17 patients. Absolute mineral density, as well as T-scores (which represent standard deviations [SDs] from the mean value in normal young adults), were recorded. Patients were categorized having normal bone density or osteopenia or osteoporosis according to the WHO definition, applied to either the spine or the femoral neck.15 Bone metabolism markers were determined by Synarc SAS (Lyon, France). Lipid profile, coagulation profile and other safety parameters were determined centrally by the Haukeland University Laboratory of Clinical Chemistry on fresh samples delivered by courier. Serum sex steroids (estradiol, estrone, estrone sulfate, androstenedione and testosterone) were measured by a coupled GC/MS/MS bioanalytic method (Taylor Technology Inc, Princeton, NJ). Relapses and adverse events, together with drug compliance, were monitored at each visit.
Statistical Analysis
The trial was powered to detect a difference in annual BMD loss versus the placebo arm 1.1%, which was considered to be of potential clinical relevance. In postmenopausal women, the expected rate of BMD loss per year is estimated to be 1%, with a SD of 2.5%.16 Assuming an annual loss of 2.1% in the exemestane arm, 64 assessable patients per treatment arm were required to detect such a difference given a 1-tailed level of .05 and .80 power. The reason for adopting a 1-sided test was that exemestane was expected to have a detrimental effect on the bone. Statistical methods for primary and secondary end points were prespecified in the statistical section of the study protocol. The primary analysis was conducted on BMD-assessable patients, defined as patients having at least two BMD determinations〞one at baseline and one at 12 or 24 months. The mean rate of BMD loss per year was calculated by fitting a linear regression model of the BMD percent changes over time in each individual patient. The annual rate of bone loss in the two treatment arms was compared using a t test. Bone markers, lipids, coagulation parameters, homocysteine, and sex-steroids were analyzed by repeated-measures analysis of variance as percent changes from baseline obtained after 6 (3 months for the coagulation parameters), 12, and 24 months on treatment. The treatment, time, and treatment-time interaction effects were tested. Due to the exploratory analysis of these secondary end points, no adjustment for multiple testing was considered. Values were log-transformed before the analysis if specified in the protocol. Patients receiving lipid-lowering drugs or lipid-lowering dietary supplements were considered not assessable for the analysis of lipids, and patients receiving anticoagulant drugs were not assessable for the analysis of coagulation profile. General safety analysis included all treated patients.
RESULTS
Study Population
A total of 147 patients were randomly assigned, 73 to exemestane and 74 to placebo. The two treatment groups were well balanced for demographic, BMD, and bone metabolism markers in serum and urine (Table 2). A total of 128 patients (62 on exemestane and 66 on placebo) were included in the primary analysis of bone mineral densitometry (Fig 1). Nonassessability was due to inadequate assessment of BMD (only baseline and/or month-6 data were available for patients who discontinued treatment prematurely) in 10 and eight patients on exemestane or on placebo, respectively, and to prolonged treatment with corticosteroids for a pulmonary condition in one exemestane patient. In the subset of BMD-assessable patients, there was a higher number of patients with femoral neck osteoporosis in the exemestane arm than in the placebo arm, resulting in a lower bone mineral densitometry value at baseline for this evaluation field.
Effects on Bone
The effect of 2 years of exemestane treatment on BMD values is described in Figure 2. Exemestane induced a nonsignificant increase in the mean annual rate of BMD loss on the spine (2.17% v 1.84% on placebo, P = .568; difference, 0.33%; 90% CI of the difference, 每0.62% to 1.27%) and a slightly significant increase on the femoral neck (2.72% v 1.48% on placebo, P = .024; difference, 1.24%; 90% CI of the difference, 0.34% to 2.14%). Of note, the mean annual rate of BMD loss observed on placebo in the spine and in the femoral neck was 84% and 48% higher than expected, respectively. After 24 months of treatment, the mean change from baseline in the T-score was modestly reduced; the mean changes were 每0.30 (95% CI, 每0.41 to 每0.19) and 每0.21 (95% CI, 每0.31 to 每0.11) in the lumbar spine and 每0.21 (95% CI, 每0.31 to 每0.12) and 每0.11 (95% CI, 每0.20 to 每0.03) in the femoral neck on exemestane and placebo, respectively. There was a significant increase in the biomarkers of bone resorption C-telopeptide (CTX) and N-telopeptide (NTX), but also markers of bone formation (ie, bone alkaline phosphatase [BAP], pro每collagen type I amino-terminal propeptide [PINP], and osteocalcin; Table 3 and Figs 3 and 4).
Table 4 gives correlations between alterations in bone biomarkers and BMD during treatment in the two arms. BAP was the only biomarker with a highly significant correlation with both spine and hip joint BMD in each of the treatment groups.
No patient with normal BMD at baseline according to WHO definition developed osteoporosis on exemestane, while six (21%) of 28 patients with lumbar osteopenia at baseline and three (11%) of 27 patients with femoral neck osteopenia became osteoporotic; the corresponding frequencies on placebo are five (18%) of 27 and five (14%) of 36 (Table 5). A total of nine patients suffered fractures (of any cause) on study〞four on exemestane and five on placebo (Table 6) .
Effects on Lipids and Coagulation Parameters
The lipid profiles on exemestane and placebo were very similar, with the most marked effect of exemestane being a 6% to 9% mean reduction in plasma high-density lipoprotein (HDL) 每cholesterol versus a 1% to 2% increase on placebo (P < .001) accompanied by a 5% to 6% v 0% to 2% reduction in apolipoprotein A1 on exemestane versus placebo (P = .004). No significant difference between the two arms was seen for the other lipid parameters or the coagulation factors. A marginal increase of homocysteine on exemestane was observed (Table 3 and Figs 5 and 6).
Effects on Sex Steroids
Exemestane reduced the mean serum estradiol levels at 12 and 24 months by 83% from pretreatment levels, and both estrone and estrone sulfate by 92% to 93%, respectively (Table 3 and Fig 7). No relevant changes in adrostenedione and testosterone levels were observed.
Safety and Tolerability
Drug-related side effects are summarized in Table 7. Notably, while 30.1% of patients experienced hot flushes on exemestane treatment, the corresponding figure for the placebo arm was 24.7%.
Treatment Exposure
The frequency of patients exposed to drug till the end of the 2-year treatment was 79.5% on exemestane and 87.8% on placebo. The reasons for discontinuing therapy included patient refusal, adverse events, relapses, and the occurrence of new non每breast cancer malignancies (Fig 1).
DISCUSSION
The results of three phase III studies evaluating anastrozole,9 letrozole,10 and exemestane11 in the adjuvant setting all revealed the benefits of third-generation aromatase inhibitors and inactivators given as monotherapy or as sequential treatment for early postmenopausal breast cancer. It is noteworthy that each of these studies reported an increased fracture rate in the aromatase inhibitor/inactivator arm, though the difference was of statistical significance only in the ATAC (Arimidex and Tamoxifen Alone or in Combination) study comparing anastrozole monotherapy to tamoxifen.9 This may be due to a higher number of events recorded in both arms of that study. The differences regarding design of these studies, as well as the limited number of events, do not allow any conclusions to be made at this stage.
While a few studies have reported the effects of short-term treatment with aromatase inhibitors on plasma lipids and bone biomarkers in healthy males and in women with breast cancer,17,18 no long-term results or data on BMD are available. Even for biomarkers like BAP, short-term (12-week) data may not predict long-term effects.19
This is the first study reporting bone and lipid parameters during long-term treatment with an aromatase inactivator. There are two main reasons for using a placebo-controlled double-blind protocol. Subprotocols have been designed to measure bone density and plasma lipids in studies comparing aromatase inhibitors or inactivators to tamoxifen. However, tamoxifen itself may influence all these parameters20,21 and also reduce the risk of fractures in postmenopausal women,22 making it difficult to assess the effects of estrogen deprivation per se. Second, while bone mineral loss is a continuous process in postmenopausal women,23 the substantial variation between results reported in different studies16,23 underlines the need for a control group. This argument is further underlined by the finding of a bone loss higher than expected upfront in the placebo group. It is noteworthy that the women in our study did not receive calcium or vitamin D supplement, which may have contributed. It should also be noted that the Scandinavian countries represent the geographic area with the highest incidence of hip fractures in the world.24 It is less likely that this bone loss is due to their breast cancer or therapy. While an increased risk of osteoporosis and vertebral fractures has been recorded in breast cancer patients,25 this is related to systemic treatment, in particular when affecting ovarian function.26
In our study, we found modestly increased bone loss from the femoral neck and a nonsignificant increase in bone loss from the vertebrae in patients treated with exemestane; none of our patients with a normal BMD at baseline became osteoporotic on treatment. Our findings suggest a minor increased risk of bone fractures during treatment with exemestane. While our results contrast those of Goss et al,27 who found exemestane to have an anabolic effect on bone metabolism in ovariectomized rats, the difference could be related to species, but also to the high doses of exemestane used in their experiments.
The finding that not only bone resorption but also bone formation was increased in patients treated with exemestane is interesting. One possibility is that enhanced bone degradation could lead to enhanced synthesis per se.28 However, while increased bone turnover has been suggested to be a risk factor for fracture, the results from prospective studies have revealed elevated markers of bone resorption, but not markers of bone formation, to be associated with fracture risk.29 Two small studies reported short-term treatment with anastrozole to increase biomarkers of bone resorption but not bone formation (BAP and osteocalcin) in healthy males18 and postmenopausal women with advanced breast cancer with no evidence of skeletal metastases.30 Estrogens are known to reduce biomarkers of bone resorption,31,32 while the addition of androgens stabilized formation without influencing resorption.31 Exemestane differs from the nonsteroidal aromatase inhibitors in as much as its main metabolite, 17-hydro-exemestane, expresses androgen agonistic activity.33 Thus, the observation that BAP increases during treatment with exemestane could be due to this androgenic effect. While this could indicate a difference between exemestane and the nonsteroidal aromatase inhibitors on bone metabolism, there is a need to assess long-term effects of the nonsteroidal compounds anastrozole and letrozole on bone metabolism.
A second concern with the use of aromatase inhibitors is a potential detrimental effect on cardiovascular risk factors. While estrogens are known to have a beneficial effect on blood lipids,34 the beneficial effects on cardiovascular morbidity, at least for short-term periods, have been challenged in recent studies,35-37 in particular by the recent report on use of estrogens without progestins in the large Womens Health Initiative Study.38 This could be due to the complex effects of estrogens on other factors, including blood clotting. Data on the effects of nonsteroidal aromatase inhibitors on cardiovascular risk factors are limited to small, noncontrolled, short-term studies,17,39 revealing inconsistent results. We found exemestane to cause a 9% drop in plasma HDL-cholesterol after 2 years of therapy. While epidemiologic evidence and results from several prospective studies on lipid-lowering agents have found HDL-cholesterol to be a cardioprotective factor,40,41 the relevance of plasma HDL-cholesterol levels and alterations on therapy are modified by changes in other lipid parameters. Several prospective studies evaluating the effects of different estrogen replacement regimens with or without progestins in healthy postmenopausal women as well as patients with a diagnosis of cardiovascular disease consistently reported no effect on cardiovascular morbidity despite a 6% to 10% mean increase in HDL-cholesterol and a drop in low-density lipoprotein (LDL) 每cholesterol.35,37,42,43 Except for a small drop in apolipoprotein A1, we observed no significant effects of exemestane on plasma triglycerides, total cholesterol, LDL-cholesterol, or the HDL- and LDL-associated lipoprotein A and apolipoprotein B. Neither did we observe any change in the coagulation factors.
Elevated plasma homocysteine has been shown to be associated with a moderately increased risk of coronary disease and stroke,44 and estrogens are known to suppress plasma homocysteine levels.45 The finding that treatment with exemestane elevated plasma homocysteine levels marginally contrasts the substantial increase observed in patients with metastatic breast cancer treated with the first-generation nonsteroidal aromatase inhibitor aminoglutethimide.46
In conclusion, treatment with exemestane versus placebo for 2 years moderately increased bone loss from the femoral neck and caused a modest drop in plasma HDL-cholesterol. Current knowledge suggests a drop in T-score in the range of 0.10 (difference between placebo and exemestane arms throughout the 2-year study period) may increase life-time risk of a hip fracture for a 60- or 70-year-old woman with a T-score of 0 from approximately 10% to 11% and with a T-score of 每1.0 from 17% to 18%, corresponding to an increase in risk of less than 15%.47 Considering risk for all fractures, the increase may be as low as 5% to 6%.47 The US Preventive Services Task Force (USPSTF) recommends that all women should undergo bone density measurement at the age of 65 years.48 Our data suggest that all women commencing adjuvant therapy with exemestane should undergo bone density measurement before commencing therapy, with subsequent follow-up and treatment according to general guidelines for healthy women. The effect on HDL-cholesterol suggests long-term follow-up of cardiovascular morbidity and mortality in all studies assessing aromatase inhibitors and inactivators in early breast cancer; no particular precautions are needed for individual patients receiving exemestane.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have 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.
Acknowledgment
We are indebted to all the women who participated in this trial. We appreciate the contribution of G?ril Knutsen, Enrico Di Salle, Barbara Duncan and Peter Buchan at Pfizer Inc, and Randi Eikeland, Clinical Cancer Research Office, Haukeland University Hospital. Considering the bone density measurements, we acknowledge the contribution from Arne H?iseth (Ullevaal), ?yvin Skarra (Laboratory for osteoposoris, Oslo), Johan B. Svartberg (Troms?), Ingfrid Fjosavik (Stavanger) and Unni Syvertsen (Trondheim). The following research nurses participated in the data collection and patient contact: Brita G. Kolstad (Bergen), Grethe Lauvvang (The Norwegian Radium Hospital), Ellen J. Felker (Stavanger), Britt-Ann W. Eilertsen (Troms?) and Nina V. Hansen (Trondheim). The following participated in sample handling and logistics at the laboratories in Bergen. Dagfinn Ekse, Hildegunn Helle, Linn-Marie J?rgensen, Nhat K. Duong and Tone Minde.
NOTES
Supported by Pfizer Inc; P.E.L. and J.G. both received speakers honorarium from Pfizer Inc as well as AstraZeneca and Novartis (the major companies involved in development of aromatase inhibitors), and research support from the same companies.
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Prestwood KM, Kenny AM, Kleppinger A, et al: Ultralow-dose micronized 17 beta-estradiol and bone density and bone metabolism in older women: A randomized controlled trial. JAMA 290:1042-1048, 2003
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Laboratory for Clinical Biochemistry, Haukeland University Hospital
Center for Clinical Trials, Bergen
Department of Surgery, Rogaland Central Hospital, Stavanger
Department of Oncology, The Norwegian Radiumhospital
Department of Surgery, Ullevaal University Hospital, Oslo
Department of Oncology, University Hospital of North Norway, Troms?
Department of Surgery, St Olavs Hospital, Trondheim, Norway
Pharmacia Italia SpA, Pfizer Group, Clinical Development, Milan, Italy
ABSTRACT
PURPOSE: To evaluate potential detrimental effects of exemestane on bone and lipid metabolism.
PATIENTS AND METHODS: Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting. Primary objective was to evaluate the effect of exemestane on bone mineral density. Secondary objectives were effects on bone biomarkers, plasma lipids, coagulation factors, and homocysteine. Planned size was 128 patients.
RESULTS: One hundred forty-seven patients were enrolled. All patients completed their 24-month visit except for those discontinuing treatment at an earlier stage. The mean annual rate of bone mineral density loss was 2.17% v 1.84% in the lumbar spine (P = .568) and 2.72% v 1.48% in the femoral neck (P = .024) in the exemestane and placebo arm, respectively. The mean change in T-score after 2 years was 每0.21 for exemestane and 每0.11 on placebo in the hip, and 每0.30 and 每0.21, respectively, in the lumbar spine. Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers. Except for a modest reduction in high-density lipoprotein cholesterol (P < .001) and apolipoprotein A1 (P = .004), exemestane had no major effect on lipid profile, homocysteine levels, or coagulation parameters.
CONCLUSION: Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.
INTRODUCTION
Endocrine therapy plays a key role in the treatment of hormone receptor每positive breast cancer. While treatment of advanced breast cancer is palliative, adjuvant therapy with ovarian ablation or tamoxifen improves relapse-free as well as overall survival in pre- as well as in postmenopausal women with estrogen receptor每positive breast cancers.1,2
While aromatase inhibition has been known for more than two decades as a treatment option for postmenopausal breast cancer,3 implementation of the novel third-generation nonsteroidal inhibitors (anastrozole and letrozole) and the third-generation steroidal inactivator exemestane represents a therapeutic breakthrough. These compounds induce more than 98% inhibition of total-body aromatization in postmenopausal women,4,5 causing only minimal side effects. Based on the superiority of the novel third-generation aromatase inhibitors and inactivators in metastatic disease compared with conventional treatment,6-8 these drugs are currently explored as adjuvant therapy of postmenopausal women with exciting results.9-11
Possible detrimental effects on blood lipids and, in particular, accelerated bone loss due to long-term estrogen deprivation12-14 may represent major concerns to the use of aromatase inhibitors and inactivators in early breast cancer. Thus, the toxicity of these compounds is a major issue in clinical development.
Here, we report the results of a double-blind randomized study comparing 2 years of exemestane versus placebo in women with early breast cancer who are not subject to regular adjuvant therapy due to their low-risk profile. The major end point was the effect on bone mineral density (BMD); secondary end points were effects on biochemical parameters of bone resorption and formation as well as plasma lipids and homocysteine levels.
PATIENTS AND METHODS
Study Design
The study was designed and conducted by the Norwegian Breast Cancer Group in collaboration with Pfizer Inc. Postmenopausal women with low-risk, surgically treated early breast cancer (n = 129) or ductal carcinoma-in-situ (n = 18) were randomly assigned (double-blind) to either exemestane 25 mg daily or placebo by mouth for 2 years and subsequently followed up for 1 year for the study main end point (BMD) and up to 5 years for disease-free survival. All bone biomarkers were recorded at baseline and after 6, 12, 18, and 24 months of treatment and after 3 and 6 months of follow-up. Lipids were measured at baseline and after 3, 6, 12, and 24 months of treatment and after 3, 6, and 12 months of follow-up, while coagulation parameters were recorded after 3, 12, and 24 months of treatment and after 12 months of follow-up. BMD was recorded at baseline and after 6, 12, and 24 months of therapy and finally after 12 months of follow-up. The study was carried out at six Norwegian centers and enrolled patients from January 1999 to October 2001. At that time, postmenopausal patients with low-risk breast cancer as defined in the inclusion criteria (Table 1) were not offered routine adjuvant systemic treatment according to the Norwegian National Guidelines.
The protocol was approved by the regional ethical committees, and each patient gave written informed consent before being enrolled. Random assignment was performed by center; patients were randomly assigned to treatment by blocks of four. A data monitoring board, including an oncologist and a lipid and a bone expert not involved in the study oversaw the safety of patients as well as the quality of the bone density data produced.
Assessment of BMD and Bone Biomarkers
BMD was measured on the lumbar spine (L1 to L4) and on the femoral neck with Hologic densitometry (Hologic Inc, Walthem, MA,) in 130 patients and Lunar densitometry (Lunar Corp, Madison, WI) in 17 patients. Absolute mineral density, as well as T-scores (which represent standard deviations [SDs] from the mean value in normal young adults), were recorded. Patients were categorized having normal bone density or osteopenia or osteoporosis according to the WHO definition, applied to either the spine or the femoral neck.15 Bone metabolism markers were determined by Synarc SAS (Lyon, France). Lipid profile, coagulation profile and other safety parameters were determined centrally by the Haukeland University Laboratory of Clinical Chemistry on fresh samples delivered by courier. Serum sex steroids (estradiol, estrone, estrone sulfate, androstenedione and testosterone) were measured by a coupled GC/MS/MS bioanalytic method (Taylor Technology Inc, Princeton, NJ). Relapses and adverse events, together with drug compliance, were monitored at each visit.
Statistical Analysis
The trial was powered to detect a difference in annual BMD loss versus the placebo arm 1.1%, which was considered to be of potential clinical relevance. In postmenopausal women, the expected rate of BMD loss per year is estimated to be 1%, with a SD of 2.5%.16 Assuming an annual loss of 2.1% in the exemestane arm, 64 assessable patients per treatment arm were required to detect such a difference given a 1-tailed level of .05 and .80 power. The reason for adopting a 1-sided test was that exemestane was expected to have a detrimental effect on the bone. Statistical methods for primary and secondary end points were prespecified in the statistical section of the study protocol. The primary analysis was conducted on BMD-assessable patients, defined as patients having at least two BMD determinations〞one at baseline and one at 12 or 24 months. The mean rate of BMD loss per year was calculated by fitting a linear regression model of the BMD percent changes over time in each individual patient. The annual rate of bone loss in the two treatment arms was compared using a t test. Bone markers, lipids, coagulation parameters, homocysteine, and sex-steroids were analyzed by repeated-measures analysis of variance as percent changes from baseline obtained after 6 (3 months for the coagulation parameters), 12, and 24 months on treatment. The treatment, time, and treatment-time interaction effects were tested. Due to the exploratory analysis of these secondary end points, no adjustment for multiple testing was considered. Values were log-transformed before the analysis if specified in the protocol. Patients receiving lipid-lowering drugs or lipid-lowering dietary supplements were considered not assessable for the analysis of lipids, and patients receiving anticoagulant drugs were not assessable for the analysis of coagulation profile. General safety analysis included all treated patients.
RESULTS
Study Population
A total of 147 patients were randomly assigned, 73 to exemestane and 74 to placebo. The two treatment groups were well balanced for demographic, BMD, and bone metabolism markers in serum and urine (Table 2). A total of 128 patients (62 on exemestane and 66 on placebo) were included in the primary analysis of bone mineral densitometry (Fig 1). Nonassessability was due to inadequate assessment of BMD (only baseline and/or month-6 data were available for patients who discontinued treatment prematurely) in 10 and eight patients on exemestane or on placebo, respectively, and to prolonged treatment with corticosteroids for a pulmonary condition in one exemestane patient. In the subset of BMD-assessable patients, there was a higher number of patients with femoral neck osteoporosis in the exemestane arm than in the placebo arm, resulting in a lower bone mineral densitometry value at baseline for this evaluation field.
Effects on Bone
The effect of 2 years of exemestane treatment on BMD values is described in Figure 2. Exemestane induced a nonsignificant increase in the mean annual rate of BMD loss on the spine (2.17% v 1.84% on placebo, P = .568; difference, 0.33%; 90% CI of the difference, 每0.62% to 1.27%) and a slightly significant increase on the femoral neck (2.72% v 1.48% on placebo, P = .024; difference, 1.24%; 90% CI of the difference, 0.34% to 2.14%). Of note, the mean annual rate of BMD loss observed on placebo in the spine and in the femoral neck was 84% and 48% higher than expected, respectively. After 24 months of treatment, the mean change from baseline in the T-score was modestly reduced; the mean changes were 每0.30 (95% CI, 每0.41 to 每0.19) and 每0.21 (95% CI, 每0.31 to 每0.11) in the lumbar spine and 每0.21 (95% CI, 每0.31 to 每0.12) and 每0.11 (95% CI, 每0.20 to 每0.03) in the femoral neck on exemestane and placebo, respectively. There was a significant increase in the biomarkers of bone resorption C-telopeptide (CTX) and N-telopeptide (NTX), but also markers of bone formation (ie, bone alkaline phosphatase [BAP], pro每collagen type I amino-terminal propeptide [PINP], and osteocalcin; Table 3 and Figs 3 and 4).
Table 4 gives correlations between alterations in bone biomarkers and BMD during treatment in the two arms. BAP was the only biomarker with a highly significant correlation with both spine and hip joint BMD in each of the treatment groups.
No patient with normal BMD at baseline according to WHO definition developed osteoporosis on exemestane, while six (21%) of 28 patients with lumbar osteopenia at baseline and three (11%) of 27 patients with femoral neck osteopenia became osteoporotic; the corresponding frequencies on placebo are five (18%) of 27 and five (14%) of 36 (Table 5). A total of nine patients suffered fractures (of any cause) on study〞four on exemestane and five on placebo (Table 6) .
Effects on Lipids and Coagulation Parameters
The lipid profiles on exemestane and placebo were very similar, with the most marked effect of exemestane being a 6% to 9% mean reduction in plasma high-density lipoprotein (HDL) 每cholesterol versus a 1% to 2% increase on placebo (P < .001) accompanied by a 5% to 6% v 0% to 2% reduction in apolipoprotein A1 on exemestane versus placebo (P = .004). No significant difference between the two arms was seen for the other lipid parameters or the coagulation factors. A marginal increase of homocysteine on exemestane was observed (Table 3 and Figs 5 and 6).
Effects on Sex Steroids
Exemestane reduced the mean serum estradiol levels at 12 and 24 months by 83% from pretreatment levels, and both estrone and estrone sulfate by 92% to 93%, respectively (Table 3 and Fig 7). No relevant changes in adrostenedione and testosterone levels were observed.
Safety and Tolerability
Drug-related side effects are summarized in Table 7. Notably, while 30.1% of patients experienced hot flushes on exemestane treatment, the corresponding figure for the placebo arm was 24.7%.
Treatment Exposure
The frequency of patients exposed to drug till the end of the 2-year treatment was 79.5% on exemestane and 87.8% on placebo. The reasons for discontinuing therapy included patient refusal, adverse events, relapses, and the occurrence of new non每breast cancer malignancies (Fig 1).
DISCUSSION
The results of three phase III studies evaluating anastrozole,9 letrozole,10 and exemestane11 in the adjuvant setting all revealed the benefits of third-generation aromatase inhibitors and inactivators given as monotherapy or as sequential treatment for early postmenopausal breast cancer. It is noteworthy that each of these studies reported an increased fracture rate in the aromatase inhibitor/inactivator arm, though the difference was of statistical significance only in the ATAC (Arimidex and Tamoxifen Alone or in Combination) study comparing anastrozole monotherapy to tamoxifen.9 This may be due to a higher number of events recorded in both arms of that study. The differences regarding design of these studies, as well as the limited number of events, do not allow any conclusions to be made at this stage.
While a few studies have reported the effects of short-term treatment with aromatase inhibitors on plasma lipids and bone biomarkers in healthy males and in women with breast cancer,17,18 no long-term results or data on BMD are available. Even for biomarkers like BAP, short-term (12-week) data may not predict long-term effects.19
This is the first study reporting bone and lipid parameters during long-term treatment with an aromatase inactivator. There are two main reasons for using a placebo-controlled double-blind protocol. Subprotocols have been designed to measure bone density and plasma lipids in studies comparing aromatase inhibitors or inactivators to tamoxifen. However, tamoxifen itself may influence all these parameters20,21 and also reduce the risk of fractures in postmenopausal women,22 making it difficult to assess the effects of estrogen deprivation per se. Second, while bone mineral loss is a continuous process in postmenopausal women,23 the substantial variation between results reported in different studies16,23 underlines the need for a control group. This argument is further underlined by the finding of a bone loss higher than expected upfront in the placebo group. It is noteworthy that the women in our study did not receive calcium or vitamin D supplement, which may have contributed. It should also be noted that the Scandinavian countries represent the geographic area with the highest incidence of hip fractures in the world.24 It is less likely that this bone loss is due to their breast cancer or therapy. While an increased risk of osteoporosis and vertebral fractures has been recorded in breast cancer patients,25 this is related to systemic treatment, in particular when affecting ovarian function.26
In our study, we found modestly increased bone loss from the femoral neck and a nonsignificant increase in bone loss from the vertebrae in patients treated with exemestane; none of our patients with a normal BMD at baseline became osteoporotic on treatment. Our findings suggest a minor increased risk of bone fractures during treatment with exemestane. While our results contrast those of Goss et al,27 who found exemestane to have an anabolic effect on bone metabolism in ovariectomized rats, the difference could be related to species, but also to the high doses of exemestane used in their experiments.
The finding that not only bone resorption but also bone formation was increased in patients treated with exemestane is interesting. One possibility is that enhanced bone degradation could lead to enhanced synthesis per se.28 However, while increased bone turnover has been suggested to be a risk factor for fracture, the results from prospective studies have revealed elevated markers of bone resorption, but not markers of bone formation, to be associated with fracture risk.29 Two small studies reported short-term treatment with anastrozole to increase biomarkers of bone resorption but not bone formation (BAP and osteocalcin) in healthy males18 and postmenopausal women with advanced breast cancer with no evidence of skeletal metastases.30 Estrogens are known to reduce biomarkers of bone resorption,31,32 while the addition of androgens stabilized formation without influencing resorption.31 Exemestane differs from the nonsteroidal aromatase inhibitors in as much as its main metabolite, 17-hydro-exemestane, expresses androgen agonistic activity.33 Thus, the observation that BAP increases during treatment with exemestane could be due to this androgenic effect. While this could indicate a difference between exemestane and the nonsteroidal aromatase inhibitors on bone metabolism, there is a need to assess long-term effects of the nonsteroidal compounds anastrozole and letrozole on bone metabolism.
A second concern with the use of aromatase inhibitors is a potential detrimental effect on cardiovascular risk factors. While estrogens are known to have a beneficial effect on blood lipids,34 the beneficial effects on cardiovascular morbidity, at least for short-term periods, have been challenged in recent studies,35-37 in particular by the recent report on use of estrogens without progestins in the large Womens Health Initiative Study.38 This could be due to the complex effects of estrogens on other factors, including blood clotting. Data on the effects of nonsteroidal aromatase inhibitors on cardiovascular risk factors are limited to small, noncontrolled, short-term studies,17,39 revealing inconsistent results. We found exemestane to cause a 9% drop in plasma HDL-cholesterol after 2 years of therapy. While epidemiologic evidence and results from several prospective studies on lipid-lowering agents have found HDL-cholesterol to be a cardioprotective factor,40,41 the relevance of plasma HDL-cholesterol levels and alterations on therapy are modified by changes in other lipid parameters. Several prospective studies evaluating the effects of different estrogen replacement regimens with or without progestins in healthy postmenopausal women as well as patients with a diagnosis of cardiovascular disease consistently reported no effect on cardiovascular morbidity despite a 6% to 10% mean increase in HDL-cholesterol and a drop in low-density lipoprotein (LDL) 每cholesterol.35,37,42,43 Except for a small drop in apolipoprotein A1, we observed no significant effects of exemestane on plasma triglycerides, total cholesterol, LDL-cholesterol, or the HDL- and LDL-associated lipoprotein A and apolipoprotein B. Neither did we observe any change in the coagulation factors.
Elevated plasma homocysteine has been shown to be associated with a moderately increased risk of coronary disease and stroke,44 and estrogens are known to suppress plasma homocysteine levels.45 The finding that treatment with exemestane elevated plasma homocysteine levels marginally contrasts the substantial increase observed in patients with metastatic breast cancer treated with the first-generation nonsteroidal aromatase inhibitor aminoglutethimide.46
In conclusion, treatment with exemestane versus placebo for 2 years moderately increased bone loss from the femoral neck and caused a modest drop in plasma HDL-cholesterol. Current knowledge suggests a drop in T-score in the range of 0.10 (difference between placebo and exemestane arms throughout the 2-year study period) may increase life-time risk of a hip fracture for a 60- or 70-year-old woman with a T-score of 0 from approximately 10% to 11% and with a T-score of 每1.0 from 17% to 18%, corresponding to an increase in risk of less than 15%.47 Considering risk for all fractures, the increase may be as low as 5% to 6%.47 The US Preventive Services Task Force (USPSTF) recommends that all women should undergo bone density measurement at the age of 65 years.48 Our data suggest that all women commencing adjuvant therapy with exemestane should undergo bone density measurement before commencing therapy, with subsequent follow-up and treatment according to general guidelines for healthy women. The effect on HDL-cholesterol suggests long-term follow-up of cardiovascular morbidity and mortality in all studies assessing aromatase inhibitors and inactivators in early breast cancer; no particular precautions are needed for individual patients receiving exemestane.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have 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.
Acknowledgment
We are indebted to all the women who participated in this trial. We appreciate the contribution of G?ril Knutsen, Enrico Di Salle, Barbara Duncan and Peter Buchan at Pfizer Inc, and Randi Eikeland, Clinical Cancer Research Office, Haukeland University Hospital. Considering the bone density measurements, we acknowledge the contribution from Arne H?iseth (Ullevaal), ?yvin Skarra (Laboratory for osteoposoris, Oslo), Johan B. Svartberg (Troms?), Ingfrid Fjosavik (Stavanger) and Unni Syvertsen (Trondheim). The following research nurses participated in the data collection and patient contact: Brita G. Kolstad (Bergen), Grethe Lauvvang (The Norwegian Radium Hospital), Ellen J. Felker (Stavanger), Britt-Ann W. Eilertsen (Troms?) and Nina V. Hansen (Trondheim). The following participated in sample handling and logistics at the laboratories in Bergen. Dagfinn Ekse, Hildegunn Helle, Linn-Marie J?rgensen, Nhat K. Duong and Tone Minde.
NOTES
Supported by Pfizer Inc; P.E.L. and J.G. both received speakers honorarium from Pfizer Inc as well as AstraZeneca and Novartis (the major companies involved in development of aromatase inhibitors), and research support from the same companies.
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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