Data on the risk of bone fracture in premenopausal women with breast cancer being treated with endocrine therapy are lacking, and the evidence of efficacy in preventing fractures is relatively poor. The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) randomized, open-label, phase III study was designed to compare tamoxifen plus goserelin versus anastrozole plus goserelin, both with or without zoledronic acid for 3 years in premenopausal women with endocrine-responsive breast cancer.1 The study revealed that during the entire treatment course the rate of bone loss in premenopausal women treated with endocrine therapy is higher than in postmenopausal women who receive aromatase inhibitors.
There are currently no approved therapies for the treatment or prevention of bone loss induced by cancer therapy. The ABCSG-12 bone substudy confirms that hormone deprivation therapies can directly affect bone mass in a particular subset of premenopausal women. The primary end point of the substudy of ABCSG-12 was the effect of zoledronic acid on bone mineral density (BMD) in 404 premenopausal women with endocrine-responsive breast cancer who were treated with adjuvant endocrine therapy. In this prospective, phase III, open-label trial, patients were randomly assigned to receive endocrine therapy alone with tamoxifen (20 mg per day orally) or anastrozole (1 mg per day orally) both with goserelin (3.6 mg subcutaneously every 28 days) (n = 199) or endocrine therapy plus upfront zoledronic acid (4 mg intravenously every 6 months) (n = 205) for 3 years. The authors reported the changes in BMD during the 3 years of treatment and a period of 2 years after completing adjuvant treatment.1 Premenopausal women enrolled in the study had received surgery for stage I/II estrogen-receptor-positive or progesterone-receptor-positive (or both) breast cancer.
There are ... no approved therapies for the treatment or prevention of bone loss induced by cancer therapy
The women treated with hormonal therapy during the study experienced very rapid loss of BMD at the lumbar spine (reduced by 11.3%), and at the hip (reduced by 7.3%). Bone loss was completely prevented in patients treated with upfront zoledronic acid (this result was not reported in the study1). Interestingly, during the 2-year follow-up period after the cessation of therapy, BMD only partially recovered in the group treated with endocrine therapy alone, remaining significantly lower than baseline levels—particularly in the goserelin plus anastrozole group—at both skeletal sites (BMD decreased 7.8% versus baseline, P = 0.003). By contrast, patients treated with zoledronic acid significantly increased bone mass versus baseline values, mainly at the spine, in the same 2-year period (BMD increased by 4.0% versus baseline, P = 0.022). The yearly rate of bone loss both at trabecular and cortical sites in the control group of patients was twofold higher than that reported in postmenopausal women treated with aromatase inhibitors alone in another study,2 and is comparable to the rate of loss found in premenopausal women after adjuvant chemotherapy.2 Moreover, the yearly rate of bone loss of approximately 3% at the spine in the subgroup of patients taking goserelin plus tamoxifen is consistently higher than that seen in postmenopausal patients with cancer treated with aromatase inhibitors, which suggests that tamoxifen could not exert a strong bone-sparing effect.3
More-interesting data from the study are the changes in BMD during the 2-year, post-treatment follow-up period. The imbalance induced by hormonal depletion and the regain of ovarian function (in 75% of the study population) both contributed to the partial recovery of BMD in the group who received hormone therapy alone. However, BMD still remained significantly lower than baseline values in this group, particularly in the subgroups treated with goserelin plus anastrozole (decrease by 7.8%, P = 0.003), and a greater proportion of patients developed osteoporosis than in the zoledronic acid group. We could postulate that patients who had premature menopause without regain of ovarian function could have a smaller recovery of BMD or a progression of bone loss. However, the BMD regain comparison, between patients who regain ovarian function versus patients who do not regain ovarian function after cessation of hormonal therapy, is lacking in the study and would be useful to investigate.
Taken together these data raise some practical issues about the management of cancer-treatment-induced bone loss, and indicate the necessity of monitoring BMD after cessation of adjuvant hormonal therapy if bisphosphonate was not used, and the need to begin bisphosphonate therapy in time. Surprisingly, patients treated with hormonal therapy and zoledronic acid significantly gained bone mass during the 2-year post-treatment period at the rate of about 2% per year above the baseline levels. The long-term pharmacological effect of zoledronic acid on bone turnover after hormonal withdrawal is well documented,4 and zoledronic acid is used for intermittent therapy in postmenopausal osteoporosis. BMD is one of the most important determinants of bone strength but it represents only a surrogate end point for the risk of fracture. A high rate of bone loss, as documented in the study population, is sustained through a high bone turnover that impairs bone quality, particularly bone microarchitecture. In fact, the rate of bone loss predicts the risk of fragility fractures independently of bone mass. Finally, as impaired bone microarchitecture can not be completely restored, even if baseline BMD is regained, this effect can not completely account for bone strength integrity.5 Gnant et al. did not measure bone turnover markers and, more importantly, the incidence of fragility fractures was not explored. Consequently, the real risk of fragility fracture is uncertain in this group of patients, and this limits the definition of efficacy and cost-effectiveness of zoledronic acid in this setting.
In conclusion, the results of the ABCSG-12 bone substudy demonstrate a significant benefit in preservation of bone mass derived from the concomitant administration of zoledronic acid with endocrine therapies in premenopausal patients with breast cancer, which correlates with the data in postmenopausal patients.6 These encouraging results should be further confirmed in clinical trials with fragility fracture prevention as a primary end point.
Practice point
- In premenopausal women with breast cancer treated with endocrine therapy, the administration of zoledronic acid (4 mg every 6 months) for 3 years is able to prevent loss of bone mineral density for a period of 2 years after completion of adjuvant treatment
- These results need to be confirmed in clinical trials with fragility fracture prevention as a primary end point, before the use of zoledronic acid for prevention of fractures can be recommended in this population of patients
