Rapid Bone Loss Following Adjuvant Breast Cancer Chemotherapy

Abstract & Commentary

Synopsis: The effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover were evaluated in a prospective study of 49 premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy. Thirty-five women developed ovarian failure and had significant decreases in bone mineral density from baseline observed by 6 months and increased further by 12 months. Fourteen women retained menstrual function and had no significant change from baseline in bone mineral density except for a -2.0% decrease in the trochanter at 6 months. This rapid bone loss following chemotherapy-induced ovarian failure supports monitoring bone density in these high-risk women and considering interventions for those who demonstrate bone loss.

Source: Shapiro C, et al. J Clin Oncol. 2001;19(14): 3306-3311.

Many premenopausal women with operable breast cancer receive adjuvant chemotherapy as an approach to prolong disease-free and overall survival. In addition to the acute toxicities of adjuvant chemotherapy, many of these women experience chemotherapy-related amenorrhea and premature menopause as a sequela of this treatment.1 Problems associated with premature menopause include vasomotor symptoms, psychosocial changes, genitourinary changes, concerns about cardiovascular disease, and concerns about osteoporosis.1 The current study investigates the concern about loss of bone mineral density in premenopausal women following adjuvant chemotherapy for breast cancer. Since osteoporosis can cause significant morbidity and predispose to hip and other fractures, it is essential to identify individuals at risk for this disease and to identify prevention strategies for these high-risk individuals.

This study by Shapiro and colleagues is a prospective longitudinal study of 49 premenopausal women with stage I/II breast cancer receiving adjuvant chemotherapy. Eligible women needed to be premenopausal as defined by current menstruation or last menstrual period within 3 months, and women with medical conditions known to affect bone metabolism were excluded. Bone measurements obtained in this study included ionized calcium, markers of bone turnover osteocalcin, bone-specific alkaline phosphatase, and bone densitometry of the total spine and proximal femur. Measures of ovarian function included levels of estradiol and follicle-stimulating hormone. Study measurements were obtained at a baseline time within 4 weeks before starting chemotherapy and at 6 and 12 months. At the 12-month evaluation period, 71% of the women (35 women, median age of 44 years [range, 33-52]) were defined as having ovarian failure, and 29% of the women (14 women, median age of 38 years [range, 32-44]) retained menstrual function. Significant decreases in bone mineral density were observed by 6 months and increased further by 12 months in the women with ovarian failure. These significant decreases were measured as percentage change over time and occurred from baseline to 6 months (total spine: median of -4.0; range, -10.4-1.0; femoral neck: median of -2.6; range, -10.3-5.4; trochanter: median of -3.0; range, -12.6-1.5) and continued to decrease from 6 to 12 months (total spine: median of -3.7; range, -10.1-9.2; femoral neck: median of -2.0; range, -7.7-2.5; trochanter: median of -1.1; range, -7.9-3.3). The women who retained ovarian function following chemotherapy had no significant changes in bone mineral density from baseline to 6 months or from 6 to 12 months with the exception of a change in the trochanter from baseline to 6 months (median of -2.0; range, -9.8 to 2.2). Markers of bone turnover (osteocalcin and bone-specific alkaline phosphatase) increased in women with ovarian failure at 6 and 12 months, while these markers increased at 6 months, but declined between 6 and 12 months, in women who retained ovarian function. Shapiro et al conclude that significant bone loss begins during adjuvant chemotherapy and suggest monitoring bone density in women with chemotherapy-induced ovarian failure. Clinical trials to evaluate treatments to attenuate bone loss are suggested for these individuals.

Comment by Mark R. Albertini, MD

The occurrence of significant bone loss with early menopause due to breast cancer chemotherapy has been previously described.2,3 Women older than 40 years of age are at particularly high risk, and significant decreases in bone density have been reported at 1 and 2 years following adjuvant chemotherapy.2 The current study confirms these earlier reports and demonstrates that this rapid bone loss occurs and can be demonstrated as early as 6 months following chemotherapy. Several earlier studies have suggested a role for the bisphosphonates as a treatment strategy to reduce skeletal complications in these women at high-risk for rapid bone loss.2,3 These treatments have been generally quite well tolerated and represent promising options for these individuals.2,3 In addition, the oral bisphosphonate Clodronate has also demonstrated an ability to reduce the number and incidence of new metastases (both bone and visceral) in women at high risk for skeletal metastases.4 Thus, the bisphosphonates represent a promising intervention option for premenopausal women with loss of ovarian function following chemotherapy. Additional clinical studies will hopefully clarify the benefits that can be achieved by intervention strategies for these patients.

The current study confirms the problem of bone loss in premenopausal early stage breast cancer patients receiving chemotherapy and demonstrates the rapid onset of the sequela of ovarian failure following chemotherapy. The finding of bone loss as early as 6 months following chemotherapy has implications for clinical studies to evaluate bone loss as well as for monitoring of patients for this treatment-associated toxicity. The assessment of bone density represents an important monitoring parameter for premenopausal women experiencing ovarian failure following chemotherapy. Women with demonstrated loss of bone mineral density should be considered for potential intervention strategies. The bisphosphonates were not evaluated in the current study, but several earlier studies have identified them as a promising option for these patients.2,3 Additional clinical studies are needed, and emphasis for routine monitoring of these patients is appropriate.

References

1. Bines J, et al. J Clin Oncol. 1996;14(5):1718-1729.

2. Saarto T, et al. J Clin Oncol. 1997;15(4):1341-1347.

3. Delmas P, et al. J Clin Oncol. 1997;15(3):955-962.

4. Diel I, et al. N Engl J Med. 1998;339:357-363.

Dr. Albertini is Associate Professor, Department of Medicine, University of Wisconsin Medical School, Madison, Wis.