Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment

doi:10.1016/S0959-8049(01)00317-3

European Journal of Cancer

Volume 37, Issue 18, December 2001, Pages 2373-2378

https://doi.org/10.1016/S0959-8049(01)00317-3 Get rights and content

Abstract

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and −1.3% in the menstruating group and −7.5 and −10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and −0.3%, and −3.5 and −5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine −3.0% compared with controls −7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: −1.7% versus −2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine −5.8% versus −9.7% (P=0.008) and femoral neck −3.5% versus −5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Introduction

Adjuvant chemotherapy significantly improves survival of premenopausal breast cancer patients [1]. In a majority of these patients, however, adjuvant chemotherapy causes ovarian failure and rapid bone loss which may increase the risk of osteoporosis later in life 2, 3, 4, 5, 6.

Biphosphonates have successfully been used in the treatment of osteoporosis. Biphosphonates prevent bone loss in patients with established osteoporosis 7, 8, 9, 10, 11, 12. Moreover, etidronate, risedronate and alendronate have been proven to reduce the risk of vertebral fractures in postmenopausal osteoporosis 10, 13, 14, 15, 16. In breast cancer patients with bone metastases, biphosphonates reduce the risk of skeletal complications such as pain, pathological fractures and hypercalcaemia [17, 18, 19, 20, 21, 22, 23]. However, the role of adjuvant biphosphonate treatment in early stage breast cancer is still controversial 24, 25, 26.

We have previously reported that the 2-year-adjuvant clodronate treatment significantly reduced the bone loss in premenopausal early stage breast cancer patients who were treated with adjuvant chemotherapy [6]. In this paper we report (1) the long-term results of the impact of chemotherapy-induced ovarian failure on bone mineral density (BMD), (2) the effect of 3-year clodronate treatment and (3) the effect of its cessation on the bone mineral density at 5-years follow-up.

Section snippets

Patients

The study population consisted of 148 premenopausal newly diagnosed breast cancer patients without haematogenic metastases who were included in a trial of adjuvant clodronate. Eligible for the trial were patients with operable breast cancer and histologically-proven axillary metastases, T1-3 N1-2 M0, treated between May 1992 and July 1993 at the Helsinki University Hospital, Department of Oncology. Exclusion criteria were the following: (1) Karnofsky performance index below 70%; (2) other

Results

During 1 year follow-up, 27 patients of 73 had developed permanent amenorrhoea, at 3 years this was 40 patients, and at 5 years 51 patients. 5 years after chemotherapy, 74% of the patients were permanently amenorrhoea. 3 patients had had a hysterectomy at entry and all of them had FSH of postmenopausal levels at 5 years. One patient had a hysterectomy during follow-up and her FSH level reached postmenopausal levels prior to the operation.

Effect of menstrual changes on BMD

Changes in BMD correlated significantly with menstrual function after chemotherapy at 5 years (in lumbar spine P=0.0001; in femoral neck P=0.001). Changes in BMD of the lumbar spine and femoral neck were −1.3 and −0.3% in the menstruating group, −10.4 and −5.8% in the amenorrhoea groupic respectively (Table 4). At 5 years, the amenorrhoeic patients were further divided into those who experienced amenorrhoea early, that is, during the first year after chemotherapy and those who developed

Effect of clodronate treatment on BMD

Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine −3.0% compared with controls −7.4% (P=0.003). In the femoral neck, no significant differences were found between the study groups: −1.7% versus −2.8% (P=0.86). At 5 years, 2 years after termination of treatment, the differences between the clodronate and control groups were still statistically significant in the lumbar spine, but not in the femoral neck (P=0.008 and P=0.91, respectively) (Table 5 and Fig. 1

Discussion

As we have previously reported [6], adjuvant chemotherapy for breast cancer exposes premenopausal patients to early menopause and rapid bone loss especially in the lumbar spine. However, the bone loss rate is greatest during the first few years, getting slower thereafter.

In this present study, 74% of the women experienced menopause during the 5-year follow-up. In accordance with previous studies, women most prone to the onset of menopause after chemotherapy were those in their 40s, while women

Acknowledgements

We want to express our gratitude to Professor Seppo Sarna, PhD from Department of Public Health (Biostatistics) University of Helsinki, for the advice and valuable contribution to the statistical analyses. This study was supported by Leiras Pharmaceutical Company.

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Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment

Abstract

Introduction

Section snippets

Patients

Results

Effect of menstrual changes on BMD

Effect of clodronate treatment on BMD

Discussion

Acknowledgements

Bone

Am. J. Med.

Bone

Lancet

Lancet

Bone Miner.

Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women

Lancet

Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer

J. Clin. Oncol.

Relative contributions of aging and estrogen deficiency to postmenopausal bone loss

N. Engl. J. Med.

Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy

Ann. Intern. Med.

Influence of early age at menopause on vertebral bone mass

J. Bone Miner. Res.

Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronatea randomized study in premenopausal breast cancer patients

J. Clin. Oncol.

Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis

N. Engl. J. Med.

Intermittent cyclical etidronate treatment of postmenopausal osteoporosis

N. Engl. J. Med.

Cyclic clodronate is effective in preventing postmenopausal bone lossa comparative study with transcutaneous hormone replacement therapy

J. Bone Miner. Res.