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Tamoxifen Treatment After Adjuvant Chemotherapy Has Opposite Effects on Bone Mineral Density in Premenopausal Patients Depending on Menstrual Status

From the Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

Address reprint requests to Leena Vehmanen, MD, Department of Oncology, Helsinki University Central Hospital, PO Box 180, FIN-00290 HUCH, Helsinki, Finland; e-mail: leena.vehmanen{at}kolumbus.fi

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Adjuvant chemotherapy followed by tamoxifen is a standard treatment option for women with intermediate or high-risk hormone receptor–positive breast cancer. Premenopausal women treated with chemotherapy often develop early menopause and thus, enter a period of accelerated bone loss. We conducted a prospective study of the effect of sequential adjuvant therapy with chemotherapy followed by tamoxifen on bone mineral density (BMD) in premenopausal patients.

PATIENTS AND METHODS: One hundred eleven premenopausal women with early breast cancer were treated with adjuvant chemotherapy. Patients with hormone receptor–positive tumors went on to tamoxifen 6 months after the beginning of the chemotherapy (tamoxifen group), while those with hormone receptor–negative tumors received no further therapy (control group). The effect of tamoxifen and menstrual status on BMD was studied.

RESULTS: Tamoxifen treatment and menopausal status correlated significantly with the changes in lumbar spine BMD (P < .0001). A significant bone loss was noted in those tamoxifen-treated patients who continued to menstruate after chemotherapy. At 3 years of follow-up, menstruating patients on tamoxifen had lost –4.6% of their baseline BMD values, while a modest gain of +0.6% was noted in the control group. In contrast, bone loss was reduced among tamoxifen-treated women as compared with controls in patients who developed chemotherapy-induced early menopause. In amenorrheic patients, the lumbar spine BMD values decreased –6.8% in tamoxifen users and –9.5% in the controls, respectively.

CONCLUSION: We conclude that tamoxifen usage was associated with bone loss in patients who continued to menstruate after adjuvant chemotherapy. On the contrary, tamoxifen decreased bone loss in those women who developed chemotherapy-induced amenorrhea.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Epidemiologic studies show that the risk of breast cancer is greater in postmenopausal women with higher bone mineral density (BMD).¹ However, standard treatments for breast cancer, such as adjuvant chemotherapy, can increase bone loss, and hence, may increase the risk of osteoporosis.¹ In a majority of premenopausal breast cancer patients, adjuvant chemotherapy causes early menopause and a rapid bone loss.^2,3

The incidence of adjuvant chemotherapy-induced amenorrhea varies from 26% to 89% depending on the drugs used.⁴ Generally, the higher the cumulative dose of cyclophosphamide, the higher the observed incidence of menopause.⁵ Two-thirds of premenopausal women experience amenorrhea with the adjuvant regimen of cyclophosphamide, methotrexate, and fluorouracil (CMF),⁶ while rates of amenorrhea associated with anthracycline therapy show variation among studies.^6-8 Women most prone to develop ovarian failure and early menopause are those in their 40s, while younger women have better preservation of menstruation after adjuvant chemotherapy.^6,9

Changes in BMD are strongly associated with menstrual function after chemotherapy. Only women who develop chemotherapy-induced ovarian failure undergo accelerated bone mineral loss, while those who continue to menstruate have only minimal changes in BMD.^2,3 The decrease in BMD during the first year after adjuvant chemotherapy-induced amenorrhea averages –7% in the lumbar spine.^2,3 A similar rapid bone loss has also been demonstrated after surgical ovarian ablation.¹⁰

Adjuvant chemotherapy followed by tamoxifen is standard treatment for women with intermediate or high-risk hormone receptor–positive breast cancer. However, the effects of tamoxifen on BMD have been extensively studied only in postmenopausal women. The data accumulated to date confirm that tamoxifen significantly decreases bone loss in the lumbar spine and to a somewhat lesser degree at the femoral neck in postmenopausal women.^11-15 The positive effect of tamoxifen on BMD has been shown to last over a treatment period of 5 years, but a rapid bone loss ensues after cessation of the treatment.¹⁶

While tamoxifen prevents bone loss in postmenopausal women, effects may be opposite for premenopausal women. Powles et al¹⁷ measured BMD in women participating in a placebo-controlled tamoxifen chemoprevention study. In a subpopulation of 33 women who remained premenopausal through the observation period of 3 years, a loss of –1.4% per year in the lumbar spine BMD was noted as compared with a modest gain of +0.24% for women on placebo. Similar findings were observed in the ZIPP (Zoladex in Premenopausal Patients) trial comparing different endocrine approaches in early breast cancer. After 2 years of tamoxifen treatment a significant decline of –1.5% in total-body bone density was seen in premenopausal patients.¹⁸

To our knowledge, the consequences of sequential chemotherapy and tamoxifen treatment on BMD in premenopausal women have not been studied before. In the present study, we report the effects of this chemoendocrine therapy on BMD in premenopausal women with early breast cancer.

	PATIENTS AND METHODS

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Patients
The study population consists of 159 premenopausal women with newly diagnosed T1-3 N0-2 M0 breast cancer, treated between January 1998 and May 2001 at Helsinki University Hospital, Department of Oncology (Helsinki, Finland). Exclusion criteria were the following: (1) Karnofsky performance index < 70; (2) serum creatinine greater than 150 umol/L; (3) peptic ulcer; (4) hysterectomy or bilateral oophorectomy; (5) osteoporosis; (6) untreated hypothyreosis; (7) bisphosphonate, calcitonin or peroral steroid therapy; (8) pregnancy or lactation; (9) other malignancies; and (10) age older than 55 years. Premenopausal status was defined as ongoing menstruation during the last 6 months.

All patients underwent surgery with total mastectomy or breast-conserving resection and axillary evacuation. Postoperative radiotherapy involved a dose of 50 Gy in 25 fractions. Following mastectomy, radiation therapy was delivered to the chest wall, if indicated. After breast-conserving surgery, radiotherapy on the basis of computed tomography planning was delivered with two tangential fields to encompass the residual breast. In addition, ipsilateral lymph node regions of the axilla and supraclavicular fossa were irradiated in node-positive patients.

All patients received adjuvant chemotherapy. As the standard chemotherapy regimen at the Helsinki University Hospital was changed during the study, patients received either six cycles of cyclophosphamide 600 mg/m², methotrexate 40 mg/m², and fluorouracil 600 mg/m² and one cycle of cyclophosphamide during the radiotherapy or six cycles of cyclophosphamide 600 mg/m², epirubicin 60 mg/m², and fluorouracil 600 mg/m² (CEF), both given intravenously with 3 weeks' intervals. High-risk patients with either eight positive lymph nodes or five positive lymph nodes and other risk factors were given nine cycles of CEF. The prophylactic antiemetic regimen consisted typically of a serotonin (HT3) receptor antagonist (tropisetron or granisetron), metoclopramide, and dexamethasone.

Six months after the beginning of the chemotherapy, 5-year adjuvant tamoxifen treatment was started in hormone receptor–positive patients. In addition, a subpopulation of 48 patients was randomly allocated to receive intravenous bisphosphonate (clodronate) treatment before each chemotherapy infusion or no further therapy. The effects of this clodronate therapy on BMD have been reported elsewhere.¹⁹ The 23 patients randomly assigned to clodronate were excluded from the current analyses on the effect of tamoxifen on BMD. As those 25 patients randomly assigned not to receive clodronate were treated and followed in a similar way as the rest of the study population, they were included in the current analyses.

Of the 159 patients at entry, data from 48 patients were excluded mainly because of clodronate treatment (23 patients) or because of distant metastases before 3 years of follow-up (17 patients). Concurrent bisphosphonate use was not allowed during the study period of 3 years. In addition, four patients discontinued follow-up, two patients discontinued tamoxifen treatment because of side effects, one patient developed hypothyreosis, and one patient had medication possibly affecting bone metabolism (antiepileptics). Overall, 111 metastasis-free patients were eligible for analyses at 3 years of follow-up.

Of the 111 patients included in the analyses, 49 patients received six cycles of CEF, 55 patients received six cycles of CMF and one cycle of cyclophosphamide, and seven high-risk patients were given nine cycles of CEF. Eighty-eight patients had hormone receptor–positive tumors and were still on tamoxifen treatment at 3 years of follow-up (tamoxifen group). Twenty-three patients had hormone receptor–negative tumors and therefore, received no hormonal treatment after chemotherapy (control group). Tumors containing more than 10% of estrogen- and/or progesterone-receptor positive cells were classified as hormone receptor positive.

Methods
Informed consent was obtained from all participants. The Local Ethical Committee at the Department of Oncology, Helsinki University Central Hospital, approved the study. Staging investigations included clinical examination, thoracal x-ray, liver ultrasound, and bone scintigraphy. Basic laboratory tests included a complete blood count and sedimentation rate, liver enzymes (transaminases, alkaline phosphatase, 5-nucleotidase), serum creatinine, albumin, calcium, and potassium. These basic laboratory tests and the serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol were measured before the initiation of the chemotherapy and 3, 6, 9, 12, and 36 months thereafter.

Patients were interviewed regarding general health, medications, and menopausal status at entry and at 6, 12, and 36 months. Simultaneously, BMD (grams per square centimeter) was assessed by dual-energy x-ray absorptiometry using a Hologic QDR densitometer (Hologic Inc, Waltham, MA). BMD was measured at the lumbar vertebrae (LI-LIV) and at the femoral neck, femoral trochanter and Ward's triangle, intertrochanteric, and total femoral area in the right femoral area.

At 36 months (3 years) of follow-up, the patients were divided into those who continued to menstruate and those with amenorrhea. Amenorrhea was defined as absent menstruation for at least 6 months.

Nine patients either had a levonorgestrel-releasing intrauterine system (LNG IUS) as a contraceptive device at entry or had it inserted during the follow-up. The low-dose of LNG released rarely suppresses ovulation, even in those women who experience an absence of bleeding because of the device.²⁰ Seven patients with LNG IUS (six in the tamoxifen group and one in the control group) developed amenorrhea with postmenopausal FSH values and menopausal symptoms during follow-up and were included in the amenorrhea group. Two young women of the control group (age 30 and 35 years) with LNG IUS, on the other hand, did not menstruate but had FSH at premenopausal level at 3 years of follow-up (5.1 and 7.6 U/L, respectively) and no menopausal symptoms and were included in the menstruating group.

Statistical Methods
BMD values are presented as percentages of the baseline value. The changes in BMD were compared among the four subgroups (Fig 1; tamoxifen group: amenorrhea/menstruating and control group: amenorrhea/menstruating). Two-way analysis of variance of repeated measurements was performed with tamoxifen usage and menopausal status as grouping (between subjects) variables and age and duration of chemotherapy (number of chemotherapy cycles) as covariates. Other comparisons were made using the Mann-Whitney U test. We calculated 95% CIs for the main outcomes.

View larger version (18K): [in this window] [in a new window]   Fig 1. Subgroups of the patients according to tamoxifen use (tamoxifen/no hormonal therapy) and menstrual status (amenorrhea/menstruating).

	RESULTS

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As hormone receptor–negative tumors are far less common than hormone receptor–positive tumors, the number of control patients (no hormonal therapy) relative to those treated with tamoxifen was small. However, the tamoxifen and control groups were well-balanced, according to the baseline characteristics (Table 1).

Tamoxifen treatment caused a significant decrease from baseline values in lumbar spine BMD in premenopausal patients who continued to menstruate 3 years after adjuvant chemotherapy. At the 3-year follow-up, the mean bone loss at lumbar spine was –4.6% in the tamoxifen group, while a modest gain of +0.6% was noted in the control group (Fig 2; Table 2). At the femoral neck, tamoxifen-treated women lost –1.8% and women in the control group lost –1.4% of their baseline BMD values during the 3-year observation period (Fig 3; Table 2).

View larger version (14K): [in this window] [in a new window]   Fig 2. Percent changes in lumbar spine bone mineral density (BMD) according to tamoxifen use and menstrual status. Symbols: White box = chemotherapy only, menstruating. Black box = chemotherapy + tamoxifen, menstruating. Black circle = chemotherapy + tamoxifen, amenorrhea. White circle = chemotherapy only, amenorrhea.

View larger version (14K): [in this window] [in a new window]   Fig 3. Percent changes in femoral neck bone mineral density (BMD) according to tamoxifen use and menstrual status. Symbols: White box = chemotherapy only, menstruating. Black box = chemotherapy + tamoxifen, menstruating. Black circle = chemotherapy + tamoxifen, amenorrhea. White circle = chemotherapy only, amenorrhea.

Thus, tamoxifen was associated with bone loss in patients who continued to menstruate after adjuvant chemotherapy. On the contrary, a decrease in bone loss was seen in those women who developed chemotherapy-induced amenorrhea. The interaction between tamoxifen therapy and menstrual status on lumbar spine BMD changes seen during the 3-year follow-up was highly significant (P < .0001). A similar trend toward an interaction was noted between tamoxifen therapy and menstrual status on BMD changes at the femoral neck (P = .074). The interaction terms were adjusted for age and duration of chemotherapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
This prospective descriptive cohort study was planned to assess the effects of tamoxifen after adjuvant chemotherapy on BMD. The impact of menstrual status on the BMD effects was specifically studied. As is generally true for breast cancer patients, most of the women included had hormone receptor–positive tumors (tamoxifen group), while the number of patients with hormone receptor–negative tumors (control group) was small. In line with previous studies, most women developed chemotherapy-induced amenorrhea.^2,3,21 The small size of some of the subgroups clearly presents a problem in interpreting the results of our study.

The correct definition of menstrual status is challenging. In the present study, premenopausal status was defined as ongoing menstruation during the last 6 months. This definition may include patients who are perimenopausal. Another potential source of error may be an interference of tamoxifen on our classification of menstrual status. Tamoxifen has estrogenic effects in hypothalamus-pituitary-axis as it decreases the levels of FSH.²² The FSH levels were significantly lower among tamoxifen-users than nonusers also in the present study. Menstrual irregularities are common among tamoxifen-users.²³ Our definition of amenorrhea as absent menstruation for at least 6 months may overestimate the incidence of permanent ovarian failure. The effects of tamoxifen on menstrual cycle and FSH levels constitute a difficulty in judging between true amenorrhea and a transient effect of tamoxifen. Some patients deemed amenorrheic during tamoxifen treatment might regain menstruation when the treatment is stopped. This may potentially lead to an overestimation of the beneficial effect of tamoxifen on BMD in amenorrheic women.

The chemotherapy regimen was not identical for patients included in the current study. More women in the tamoxifen group received CEF than those in the control group; the difference, however, was not statistically significant. This does not rule out a different effect of different chemotherapy regimens (CMF v CEF) on rates of amenorrhea. Cumulative cyclophosphamide dose seems to predict the development of chemotherapy-induced amenorrhea. Most patients received six to seven cycles, while few patients received nine cycles of chemotherapy, with a prescribed cyclophosphamide dose of 600 mg/m² per cycle. The duration of chemotherapy did not affect the main results.

Because of obvious ethical reasons, this was not a randomized study as tamoxifen was given to all patients with estrogen/progesterone-positive tumors. Thus, the effect of tamoxifen on BMD could potentially be confounded by hormone receptor status of the patients. To our knowledge, however, there is no biologic reason why bone metabolism would differ according to hormone-receptor status. Moreover, the baseline BMD levels were similar in hormone receptor–positive (tamoxifen group) and negative (control group) patients (Table 1). Before tamoxifen was started, the BMD changes seemed to reflect only the menopausal status of the patients (Fig 2). Therefore, it seems likely that the opposite effects of tamoxifen on BMD, depending on menstrual status, reflect a true effect of tamoxifen and not that of hormone-receptor status.

Tamoxifen is a selective estrogen receptor modulator possessing variable pharmacologic attributes of an estrogen antagonist or agonist dependent on the target tissue.²⁴ The main effect of tamoxifen on breast tissue is estrogen antagonistic, whereas, many of its other effects such as those on the uterus, lipid metabolism, vasculature, blood-clotting mechanisms, and bone resorption are considered to be estrogen-agonistic.^11,24,25 In postmenopausal women with low endogenous estrogen levels, tamoxifen treatment results in a decrease in bone resorption. However, in the presence of premenopausal levels of estrogen, tamoxifen seems to act as an estrogen-antagonist and causes bone loss.¹⁷ An estrogen-antagonist effect during premenopause was also suggested in a few preclinical studies, where tamoxifen reduced bone mass in rats with intact ovaries.^26,27

While no bone loss occurred in women who preserved menstruation after chemotherapy in the current study, a significant bone loss was observed in menstruating patients given chemoendocrine therapy with tamoxifen. This is in accordance with results of the tamoxifen prevention trial and the ZIPP trial, which also reported bone loss in premenopausal women receiving tamoxifen.^17,18 In our study, the bone loss was clearly seen in the lumbar spine (–4.6% within 3 years), while it was less marked at the femoral neck. This could, at least partly, be explained by the fact that lumbar spine consists largely of cancellous bone where bone turnover is fast. Cortical bone, on the other hand, located at the femur, is metabolically slower than cancellous bone and is, therefore, less affected by alterations in bone turnover.²⁸ Findings of the tamoxifen-prevention study and some preclinical evidence suggest that in premenopause, tamoxifen causes bone loss especially in the cancellous bone.^17,27

Tamoxifen treatment significantly reduced lumbar spine bone loss by 28% in patients with chemotherapy-induced amenorrhea at 3 years of follow-up, but it did not totally prevent the bone loss. As stated before, bone loss in patients who develop amenorrhea after chemotherapy is extremely rapid and comparable with that seen after surgical oophorectomy.^2,3,10 Though tamoxifen is effective in preventing bone loss later in postmenopause,^11-16 it cannot counteract the sudden and rapid bone turnover seen during the chemotherapy-induced perimenopausal transition period.

Our findings indicate that tamoxifen treatment is associated with significant bone loss in patients remaining premenopausal after adjuvant chemotherapy for breast cancer. On the other hand, tamoxifen offers some protection against bone loss in patients with chemotherapy-induced early menopause. Whether the detrimental effects on BMD after adjuvant therapy result in an increase in fracture risk warrants further follow-up. Probably most long-term survivors of breast cancer who have received adjuvant therapy are at increased risk of osteoporosis, and bone health intervention should be considered as part of their follow-up.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Leena Vehmanen, Inkeri Elomaa, Tiina Saarto Collection and assembly of data: Leena Vehmanen, Tiina Saarto Data analysis and interpretation: Leena Vehmanen, Carl Blomqvist, Tiina Saarto Manuscript writing: Leena Vehmanen, Inkeri Elomaa, Carl Blomqvist, Tiina Saarto Final approval of manuscript: Leena Vehmanen, Inkeri Elomaa, Carl Blomqvist, Tiina Saarto

 

	NOTES

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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3. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306-3311, 2001[Abstract/Free Full Text]

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15. Grey AB, Stapleton JP, Evans MC, et al: The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med 99:636-641, 1995[CrossRef][Medline]

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18. Sverrisdottir A, Fornander T, Jacobsson H, et al: Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. J Clin Oncol 22:3694-3699, 2004[Abstract/Free Full Text]

19. Vehmanen L, Saarto T, Risteli J, et al: Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure. Breast Cancer Res Treat 87:181-188, 2004[CrossRef][Medline]

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21. Vehmanen L, Saarto T, Elomaa I, et al: Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Eur J Cancer 37:2373-2378, 2001[CrossRef][Medline]

22. Ellmen J, Hakulinen P, Partanen A, et al: Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res Treat 82:103-111, 2003[CrossRef][Medline]

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Submitted April 15, 2005; accepted November 2, 2005.

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