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