Level 2 (mid-level) evidence
Bisphosphonates are often recommended for postmenopausal women receiving aromatase inhibitor therapy for hormone-receptor-positive breast cancer with evidence of osteoporosis. Denosumab has previously been shown to reduce the risk of fractures and skeletal events in women with breast cancer with bone metastases (Cochrane Database Syst Rev. 2012;:CD003474). However, the efficacy of denosumab in women with early-stage breast cancer is unknown. A recent randomized trial compared 60 mg of denosumab to placebo administered subcutaneously once every 6 months in 3,425 postmenopausal women (median age, 64 years) with early-stage hormone-receptor-positive breast cancer receiving adjuvant aromatase inhibitor therapy. In addition, elemental calcium and vitamin D supplements were recommended for all women (Lancet. 2015;386:433-443).
At baseline, 45% of women had low bone mineral density (BMD) with T scores less than -1.0. During the median 38 months of treatment, women were treated with a median of 7 doses of their respective study drug. Compared to placebo, denosumab was associated with prolonged time to first clinical fracture (hazard ratio for fracture, 0.5; 95% confidence interval [CI], 0.39-0.65). At 36 months, the estimated rate of clinical fractures was 5% with denosumab, compared to 9.6% with placebo (p<0.05; NNT, 22). The difference in clinical fracture rates was even more substantial at 84 months, with a rate of 11.1% in the denosumab group vs. 26.2% in the placebo group (p<0.05; NNT, 7). Denosumab was also associated with increased BMD at 12, 24, and 36 months (p<0.0001 for all time points). These results were consistent in subgroup analyses by baseline BMD, age, tumor stage, grade, and histology.
Although 24% of women prematurely discontinued treatment, there were no significant differences in adverse events, serious adverse events, or withdrawals due to adverse events. Denosumab was effective regardless of baseline total lumbar spine BMD (low or normal), suggesting it may be helpful for preventing as well as treating bone loss related to aromatase inhibitor treatment. In further subgroup analyses, the benefit of denosumab was not limited to any specific treatment population.
Overall, these results suggest that denosumab not only increases BMD, but also reduces the risk of fractures in women with early-stage breast cancer receiving treatment with aromatase inhibitors.
Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester.
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