Journal of Clinical Oncology, Vol 19, Issue 14
(July), 2001: 3306-3311
© 2001 American Society for Clinical Oncology
Ovarian Failure After Adjuvant Chemotherapy Is Associated With Rapid Bone Loss in Women With Early-Stage Breast Cancer
By Charles L. Shapiro,
Judith Manola,
Meryl Leboff
From the Division of Adult Oncology and Department of Biostatistical Science, Dana-Farber Cancer Institute; Skeletal Health and Osteoporosis, Brigham and Women’s Hospital, Boston, MA; and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University, Columbus, OH.
Address reprint requests to Charles L. Shapiro, MD, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University, Starling-Loving Hall B421, 320 West 10th Ave, Columbus, OH 43210; email: shapiro-1{at}medctr.osu.edu
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ABSTRACT
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PURPOSE: We sought to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover in a prospective longitudinal study of young women with breast cancer receiving adjuvant chemotherapy.
PATIENTS AND METHODS: Forty-nine premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated within 4 weeks of starting chemotherapy (baseline), and 6 and 12 months after starting chemotherapy with dual-energy absorptiometry and markers of skeletal turnover osteocalcin and bone-specific alkaline phosphatase. Chemotherapy-induced ovarian failure was defined as a negative pregnancy test, greater than 3 months of amenorrhea, and a follicle-stimulating hormone  30 MIU/mL at the 12-month evaluation.
RESULTS: Among the 35 women who were defined as having ovarian failure, highly significant bone loss was observed in the lumbar spine by 6 months and increased further at 12 months. The median percentage decrease of bone mineral density in the spine from 0 to 6 months and 6 to 12 months was -4.0 (range, -10.4 to +1.0; P = .0001) and -3.7 (range, -10.1 to 9.2; P = .0001), respectively. In contrast, there were no significant decreases in bone mineral density in the 14 patients who retained ovarian function. Serum osteocalcin and bone specific alkaline phosphatase, markers of skeletal turnover, increased significantly in the women who developed ovarian failure.
CONCLUSION: Chemotherapy-induced ovarian failure causes rapid and highly significant bone loss in the spine. This may have implications for long-term breast cancer survivors who may be at higher risk for osteopenia, and subsequently osteoporosis. Women with breast cancer who develop chemotherapy-induced ovarian failure should have their bone density monitored and treatments to attenuate bone loss should be evaluated.
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INTRODUCTION
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OVER THE PAST 30 years, mammographic screening and early detection of nonpalpable breast cancers has increased the proportion of breast cancer survivors.1 During the same time interval, the indications for adjuvant treatment have expanded. Guidelines from the recent National Institutes of Health Consensus Development Conference on Adjuvant Treatment and the National Comprehensive Cancer Network recommend adjuvant chemotherapy for invasive breast cancer tumors greater than 1 cm, irrespective of the axillary nodal status.2
One of the most common side effects of adjuvant chemotherapy is primary ovarian failure.3-5 Permanent chemotherapy-induced ovarian failure occurs in 63% to 85% of women treated with cyclophosphamide, methotrexate, and fluorouracil and 50% or more of women treated with anthracycline-containing regimens.6,7 Age is the most important determinate of ovarian failure.8 Patients over 40 years of age, who are closer to their natural menopausal age, develop ovarian failure after a shorter duration of chemotherapy, typically within the first few months.
Breast cancer patients who develop chemotherapy-induced ovarian failure experience decreases in estradiol (E2) and increases in follicle-stimulating hormone (FSH) similar to those observed in postmenopausal women.9 These patients may experience osteopenia, and some of them will be at higher risk for subsequent osteoporosis. We hypothesized that breast cancer patients who develop chemotherapy-induced ovarian failure may experience accelerated bone loss. To test this hypothesis, a prospective evaluation of bone mineral density and biochemical indices of skeletal turnover was performed in premenopausal women with breast cancer before and during the first year of adjuvant chemotherapy.
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PATIENTS AND METHODS
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Eligible women had a histologic diagnosis of invasive stage I or II breast cancer, current menstruation or last menstrual period within 3 months, negative serum pregnancy test, and a physician recommendation for adjuvant chemotherapy. Women with a history of metabolic bone disease, hyperparathyroidism, Paget’s Disease, rheumatoid arthritis, ankylosing spondylitis, and newly diagnosed hyperthyroidism were excluded because these conditions may affect bone metabolism. Likewise, current or recent users (less 2 months) of oral contraceptives, androgens, anabolic steroids, anticonvulsants, lithium, chronic pharmacologic doses of vitamin D (more than 1,000 IU/d), glucocorticoids, bisphosphonates, sodium fluoride, or calcitonin were excluded for the same reasons. Women on thiazide diuretics were eligible if the dose had been stable for more than 3 months. All patients signed informed consent according to institutional guidelines.
The baseline evaluation was scheduled within 4 weeks before the start of adjuvant chemotherapy. The following tests were drawn at baseline (month 0) and repeated at 6, 12, and 24 months: ionized calcium, E2, FSH (radioimmunoassay; Endocrinology Core Laboratory, Massachusetts General Hospital, Boston, MA), markers of bone turnover osteocalcin (radioimmunoassay; K. Grunberg, New Haven, CT), and bone-specific alkaline phosphatase (Alkphase-B; Metra Biosystems, Mountain View, CA). Bone densitometry of the total spine (L2-L4) and proximal femur (femoral neck and trochanter) was measured by dual-energy absorptiometry using the same Quantitative Digital Radiography Machine 2000W (Hologic Inc, Waltham, MA). The reproducibility (coefficient of variation %) of the spine, femoral neck, and trochanter bone density in young women using this machine was 0.68%, 0.99%, and 1.12%, respectively10
At the 12-month evaluation, ovarian failure was defined as follows: negative pregnancy test, 3 or more months of amenorrhea, and an FSH 30 MIU/mL. Women who did not meet these criteria were considered premenopausal. Women were withdrawn from study if they experienced a breast cancer recurrence and received subsequent care at the discretion of the primary oncologists.
The study was originally designed to randomize women who developed ovarian failure to nasal spray calcitonin or nasal spray placebo between months 12 to 24. However, the randomization was terminated in August 1997 after an interim data analysis was presented to a mandated National Cancer Institute external monitoring committee. The monitoring committee consisted of a medical oncologist, an endocrinologist, and lay person all independent and unassociated with the study. The interim analysis revealed an unexpectedly high rate of bone loss between baseline and 12 months in women who developed ovarian failure. Based on these results, the monitoring committee recommended that the placebo-controlled portion of the study be stopped. Only seven women were randomized before this portion of the study was eliminated. We notified women and their physicians of the recommendations of the monitoring committee. After the placebo-controlled portion of the study was eliminated, women were treated at the discretion of their primary physician.
Statistical Analyses
The primary end point was the difference in bone mineral density at 12 months in the patients who did and did not develop ovarian failure. The baseline characteristics of the patients who did and did not develop ovarian failure were compared using the Wilcoxon signed rank to test for differences between the two groups. Signed rank and rank sum tests were used to test for differences over time.
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RESULTS
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Sixty-nine women were registered to the study between June 1994 and December 1998. After registration, one woman was found to have Paget’s Disease and was ineligible, and four women did not complete the baseline study evaluation. Sixty-four women were assessable. Of these, 61 (95%) completed the 6-month evaluation, and 49 (77%) completed the 12-month evaluation. Because of termination of the study as a result of the severity of bone loss at 1 year, only 24 women (38%) completed the 24-month evaluation. The data analysis is based on the 49 women who completed the baseline and 6- and 12-month evaluations. Fifteen (23%) of the 64 women who completed the baseline evaluation did not undergo the 12-month evaluation. Two of these women (3%) were removed from study after they developed breast cancer recurrence, and 13 (20%) did not undergo the required 12-month evaluation. The primary reasons for noncompliance were scheduling difficulties that precluded making an appointment within the required time period (between months 12 to 14) and voluntary patient withdrawal. Thirty-four women (69%) received cyclophosphamide, methotrexate, and fluorouracil, and 15 (31%) received cyclophosphamide and doxorubicin with or without fluorouracil or paclitaxel. Eleven women (22%) received tamoxifen after chemotherapy.
Characteristics of the study population are listed in Table 1. The baseline characteristics of the 15 women who failed to complete the 12-month evaluation did not differ from the 49 women who completed the 12-month evaluation (data not shown). Seven women (14%) were subsequently found to have a FSH greater than 30 MIU/L in the postmenopausal range at the baseline evaluation (Table 2). Data analyses performed with or without these women did not alter the main results, and therefore, all 49 women were included in the analyses.
At the 12-month evaluation, 35 women (71%) were defined as having ovarian failure, and 14 (29%) retained menstrual function. Baseline characteristics for women who did and did not develop ovarian failure are listed in Table 1. The only significant difference between the two groups was median age; women who developed ovarian failure were older (44 years v 38 years, P = .003).
The values for FSH and E2 are described in Figs 1 and 2. As expected, women who developed ovarian failure experienced increases in FSH and decreases in E2. In the women who retained menstrual function, decreased levels of E2 were observed at 6 months, but by 12 months the levels returned to baseline.
The percentage changes in bone mineral density (BMD) among women who did and did not develop ovarian failure are listed in Table 3. In the women who developed ovarian failure, significant decreases in BMD were observed by 6 months and increased through 12 months. In contrast, there were no significant differences in BMD in women who retained menstrual function, with the exception of a -2.0% decrease in the trochanter at 6 months (P = .05). There were no differences in BMD between women who did or did not receive tamoxifen and within the groups that did or did not develop ovarian failure (data not shown).
Significant increases in serum osteocalcin and bone-specific alkaline phosphatase were observed in the women who developed ovarian failure at 6 and 12 months (Table 4). In the group that retained menstrual function, significant increases in these markers were observed at 6 months; however, between 6 and 12 months the markers declined.
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DISCUSSION
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This prospective study shows that women who experience chemotherapy-induced ovarian failure develop rapid and highly significant decreases in BMD in the spine and femur that are detectable within 6 months of starting chemotherapy. In contrast, women who retained menstrual function had nonsignificant decreases in BMD at these sites. These results suggest that chemotherapy-induced ovarian failure is akin to surgical or medical ovarian ablation, with rapid decrease in estrogen levels, rather then natural menopause where the estrogen levels wax and wane and decline over several years.
Retrospective and case-control studies show that chemotherapy-induced ovarian failure is associated with bone loss.6,11 The results of prospective trials are listed in Table 5. The percentage decrease in bone mineral density at 12 months is similar to that observed in our study. In contrast to prior trials, we included a 6-month data evaluation point. Significant decreases in bone mineral density and increases in osteocalcin and bone-specific alkaline phosphatase were detectable after only 6 months in women who developed ovarian failure. This suggests that bone loss begins during adjuvant chemotherapy and has important implications for the design of subsequent intervention trials designed to prevent bone loss.
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Table 5. Percentage Loss of BMD at 1 Year in Chemotherapy-Induced Ovarian Failure Patients Receiving No Treatment or Placebo
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It is interesting to note that statistically significant, though transient, increases in osteocalcin and bone-specific alkaline phosphatase were observed at 6 months in the women who retained menstrual function (Table 4). A possible explanation for this is that these bone markers are sensitive to the transient decrease in serum level of E2 (Fig 1). However, larger studies are required to confirm this hypothesis. Finally, whether there is a direct effect of chemotherapy in addition to decreased serum levels of E2 on markers of skeletal turnover is unknown.
Unfortunately, we do not have reliable data beyond 12 months or an understanding of the effects of nasal spray calcitonin. Only 24 of women (38%) completed the 24-month evaluation point before the data monitoring committee recommended eliminating the randomized nasal spray calcitonin/placebo portion of the trial because of unacceptably high bone loss in those who developed ovarian failure. Subsequently, the women were treated at the discretion of their physicians, and follow-up data was not collected.
Compliance with the required study evaluations was 95% at 6 months but then decreased to 77% at 12 months. The primary reasons for noncompliance were scheduling difficulties that precluded making an appointment within the required time (between months 12 to 14) and voluntary withdrawal. There was no attempt to coordinate regularly scheduled physician follow-up visits with the study evaluations. In retrospect, if these visits were coordinated it may have increased compliance and this should be considered in the design of subsequent studies.
The results in this study suggest that women who develop chemotherapy-induced ovarian failure undergo accelerated and highly significant bone mineral loss most pronounced in the lumbar spine. Although the incidence of vertebral and hip fracture is unknown in breast cancer patients who develop ovarian failure, early menopause is a risk factor for osteoporosis in other settings. Our results support a role for monitoring bone density in women with chemotherapy-induced ovarian failure as well as recommending adequate calcium and vitamin D intake, moderate weight-bearing exercise, and counseling about the relationship between cigarette smoking and alcohol and bone loss.
Interventions to reduce bone loss as well as long-term follow-up studies are a high priority in women who develop chemotherapy-induced ovarian failure. Prospective randomized European trials demonstrate that the oral bisphosphonates clodronate and risedronate mitigate bone loss in women who develop chemotherapy-induced ovarian failure.12-14
Multi-institutional trials of bisphosphonates in the adjuvant setting are planned. The Cancer and Leukemia Cooperative Group B is initiating a randomized trial of intravenous zolendronic acid in early-stage breast cancer to test whether this bisphosphonate can mitigate bone loss in young women. In addition to their established role of preventing complications of skeletal metastases,15 bisphosphonates may also delay or prevent them.16 The Southwest Oncology Group and National Adjuvant Surgical Bowel and Breast Project are starting trials of zolendronic acid and clodronate, respectively, to prevent skeletal metastases in women with node-positive breast cancers. Because the majority of women with early-stage breast cancer will be long-term survivors, trials designed to answer specific questions related to survivorship are necessary.
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ACKNOWLEDGMENTS
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Supported by National Cancer Institute grant nos. R29 CA60050-06.
We thank the contributions of Donna Neuberg, PhD, Rebecca Gelman, PhD, and Jennifer Keating, MD, without whom this work would not be possible.
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Submitted January 19, 2001;
accepted April 11, 2001.
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ABSTRACT
INTRODUCTION
) and 14 patients who retained menstrual function (premenopausal) (
).