Adverse events and bone health during anastrozole therapy in postmenopausal Japanese breast cancer patients
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- Sagara, Y., Kosha, S., Baba, S. et al. Breast Cancer (2010) 17: 212. doi:10.1007/s12282-009-0135-7
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Although anastrozole (ANA), an aromatase inhibitor (AI), has been widely used for breast cancer patients; adverse events during ANA therapy in Japanese patients have not been reported.
The study included 656 postmenopausal breast cancer patients receiving ANA as postoperative adjuvant therapy in our hospital. Adverse events during ANA therapy, such as musculoskeletal effects and cerebro- and cardiovascular accidents, were investigated over a 5-year period. The percentage changes in lumbar (L2-4) spine bone mineral density (BMD) were determined in 71 patients receiving ANA alone and 26 patients receiving bisphosphonate in combination with ANA for 7–24 months.
The follow-up period ranged from 6 to 60 months (median 23 months). Joint pain, the most common adverse event, was observed in 3.6% (24/656) of the patients. Cerebral infarctions occurred in 0.3% (2/656) of the patients, and no cardiovascular accidents occurred. Bone fractures occurred in nine patients receiving ANA alone. The mean age and BMD of the nine patients were 67.6 years and 71.8% (compared to the young adult mean BMD), respectively. Accumulated and annual fracture rates were 1.3 and 0.8%, respectively. A decrease in BMD was observed in 62.0% (44/71) of the ANA group compared to 26.9% (7/26) of the combination bisphosphonate group (P < 0.01).
Incidence of adverse events during AI therapy in this Japanese postmenopausal population appears to be lower than that of the ATAC trial. The incidence of bone fractures during AI therapy is lower in Japan, and the addition of bisphosphonates enhances bone health. We should perform a prospective trial in the future to investigate the precise risk of bone fractures in Japanese patients.
KeywordsBreast cancerAromatase inhibitorAnastrozoleBone mineral densityFracture
Postmenopausal osteoporosis is an important public health problem in developed countries. Thus, prevention of bone mineral loss and bone fracture is a high priority. Bone mineral density (BMD) is affected by many factors. Low estradiol levels are associated with decreased BMD and increased bone fracture risk . Aromatase inhibitors (AIs), such as anastrozole (ANA), have been used as a postoperative adjuvant therapy in the treatment of early and advanced breast cancer in postmenopausal women. The beneficial effect of AIs on breast cancer is based on reducing the circulating estrogen level in the peripheral blood . Thus, it is well established that AIs carry a potential risk of bone mineral loss. In fact, there are several reports concerning the impact of AIs on BMD in Western populations [1–7]. However, treatment modalities for AI-induced bone mineral loss and adverse events during ANA therapy have not been reported in Japan.
The present study investigated the impact of ANA therapy on bone health and other adverse events in postmenopausal breast cancer patients in Japan.
Materials and methods
Informed consent was obtained from each patient, and the study was conducted in accordance with the Declaration of Helsinki. The study enrolled 656 postmenopausal breast cancer patients receiving ANA as a postoperative adjuvant therapy for a period of 5 years. All of the patients had been diagnosed with breast cancer and underwent surgical resection between February 2001 and June 2006 at Sagara Hospital in Kagoshima City, Japan. Only patients with an estrogen receptor (ER) positive tumor status were enrolled. ANA was orally administered (1 mg daily). All of the patients had undergone natural menopause. Post-menopausal status was defined as absence of menstruation for at least 12 months prior to the investigation or circulating estradiol levels <20 pg/ml and follicle-stimulating hormone >25 mIU/ml. Exclusion criteria were ovarian tumors, a history of malignancy, postmenopausal hormone replacement therapy (either previously or currently), and use of tamoxifen.
The interval of postoperative follow-up was every 3 months, and mammography, breast ultrasonography, and dual-energy X-ray absorptiometry (DEXA) were performed annually. Patients’ characteristics, including age, years since menopause, height, weight, body mass index, and stage of breast cancer, as well as adjuvant chemotherapy were recorded. Over a 5-year period, adverse events data, including joint pain (stiffness), bone fractures, and cerebro- and cardio-vascular accidents during ANA therapy, were collected retrospectively. During a 7–24 month observation period, the percentage change in lumbar spine BMD was determined in 71 patients receiving ANA and in 26 patients receiving ANA in combination with a bisphosphonate. BMD was measured at lumbar spine L2-4 by DXA (Discovery; Hologic, Marlborough, MA). The quality control was performed every day by using a bone mineral density phantom. The precision of BMD measurements showed coefficients of variation <1.0% each. All recordings were made by the same investigator, who was masked to the purpose of the study.
Inter-group comparisons were made by a chi-square test or Student’s t test, as appropriate. P < 0.05 was considered significant.
Mean ± SD
No. of patients
63.4 ± 9.2
151.8 ± 6.0
Years since menopause (years)
12.2 ± 9.0
Body weight (kg)
55.2 ± 9.2
Body mass index
24.0 ± 3.8
Stage of breast cancer and chemotherapy regimen
No. of patients
Anthracycline followed taxan
Did not receive chemotherapy
Adverse events during anastrozole administration
Number of patients
Discontinuation of ANA for adverse events
Joint pain (stiffness)
Serious adverse events
Detail of nine patients with bone fracture
Cause of fracture
Treatment duration until fracture (months)
Bone mineral density (young adult mean)
Baseline characteristics of the two groups
Combination bisphosphonate group
61.2 ± 8.0
63.9 ± 6.9
152.1 ± 4.9
150.6 ± 5.5
Years since menopause (years)
14.0 ± 8.9
13.8 ± 11.2
Body weight (kg)
54.4 ± 8.4
50.2 ± 10.2
Body mass index
23.5 ± 3.5
22.2 ± 3.1
Baseline BMD (%)
84.3 ± 11.1
66.9 ± 8.1
Median follow-up period (months)
28.5 ± 13.9
21.5 ± 14.4
Anti-cancer chemotherapy induces bone mineral loss through its direct action on bone or chemotherapy-induced amenorrhea (i.e., hypoestrogenism) . AI is not a cytotoxic agent, but it acts on hormone-sensitive breast cancer through an anti-estrogenic effect [9, 10]. ANA is superior to tamoxifen in terms of disease-free survival, time to recurrence, and the incidence of contralateral breast cancer [11–14]; however, it is well established that AIs are associated with reduction in BMD. In our study, BMD loss was observed in 62.0% of patients in the ANA alone group, while only 26.9% of patients had a BMD loss in the combination bisphosphonate group. The findings of AI-induced BMD loss and its prevention by bisphosphonates agree with previous reports [6, 15–20]. In postmenopausal women, there is an established concept that circulating estrogens, most of which are minimal and unmeasurable by conventional RIA methods, are derived from aromatization in peripheral adipose tissue . ANA completely blocks the pathway from androgen to estrogen. Thus, in postmenopausal women (i.e., a hypoestrogenic state), estrogen reduction by AI can decrease BMD even when the level remains below the threshold of detection.
In our study, the annual fracture rate was 0.8%, which appears to be lower than the results of recent reports [22–24]. Possible reasons for this discrepancy may include the differences in race, baseline characteristics, age distribution, and the number of enrolled subjects. There are several clinical trials showing that fracture risk in Asians is lower than that of Caucasians [25, 26]. After adjusting for BMD, weight, and other covariates, white and Hispanic women had the highest risk of fracture, followed by Native Americans, African Americans, and Asian Americans . The length of the follow-up period is also important. Our observation period was shorter than the ATAC trial (mean observation period, 17 months vs. 100 months) . Thus, further long-term follow-up is necessary to validate the effect of ANA on bone health in Japanese women. Buzdar et al. [12, 15] reported that the fracture rate with ANA stabilized after 2 years, and any increase in fracture risk with ANA was modest. However, in the present study, nine bone fractures were observed in the ANA group, but were not observed in the combination bisphophonate group. This finding suggests that the addition of bisphosphonates enhances bone health in breast cancer patients receiving ANA. In addition, it is important to protect bones from traumatic falls, as suggested in our study.
Some patients receiving ANA alone showed an increase in BMD during the follow-up period. These factors, including regular physical exercise, calcium, and vitamin D intake, may partially contribute to an increase in BMD.
Thus, for postmenopausal women receiving adjuvant ANA therapy, it is recommended that serial BMD measurements using DXA should be repeated regularly. Patients will require appropriate assessment of fracture risk with the use of an anti-osteoporotic therapy, including bisphosphonates, if necessary. In addition, regular physical exercise aimed at maintaining BMD and prevention of falling are advised as well as added calcium (1,500 mg) and vitamin D (800 U) daily to reduce bone mineral loss [27, 28].
The low incidence of cerebro- and cardiovascular events found in our study is consistent with previous reports showing that anastrozole is associated with reduced risk of thromboembolic and cerebrovascular events compared with tamoxifen . The overall rate of cardiovascular events in patients treated with AIs was within the range reported in an age-matched, non-breast cancer population . AI is associated with a significantly lower incidence of venous thromboembolic events, vaginal bleeding, and vasomotor symptoms than tamoxifen . We must also consider the ethnic differences in the baseline risk of these events. There is a significant difference of body mass index (BMI) between our study (mean BMI 24.0) and the ATAC trial (mean BMI 27.4). BMI is associated with increased cerebro- and cardiovascular risks. Data from the Nurses’ Health Study found that both an increased BMI (27 kg/m2) and weight gain after age 18 years were associated with an increased risk of ischemic stroke .
In the ANA group, similar to previous reports [29, 31, 32], arthralgia was the most common reason for withdrawal. Joint pain (stiffness) is a profound hypoestrogenic effect of ANA. However, it appears that the incidence of ANA discontinuation in the present study was not higher compared with a previous report [22, 24].
Based on these findings, we conclude that postmenopausal breast cancer patients receiving ANA therapy are at an increased risk of osteoporosis and bone fractures, though the risk appears to be lower in Japanese patients. We should perform a prospective trial in the future to precisely define the risk of bone fractures in Japanese breast cancer patients.
Conflict of interest statement
None of the authors have a potential conflict of interest relevant to this article.