Denosumab May Reduce the Risk of Fracture in Women with Breast Cancer Receiving Aromatase Inhibitor Therapy

EBM Focus - Volume 10, Issue 32

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Reference: Lancet 2015 August 1;386(9992):433 (level 2 [mid-level] evidence)

Aromatase inhibitor therapy has been shown to reduce the risk of breast cancer recurrence and breast cancer-specific mortality compared to tamoxifen in postmenopausal women with hormone receptor-positive breast cancer (J Clin Oncol 2010 Jan 20;28(3):509). Unlike tamoxifen, however, aromatase inhibitors have been found to progressively decrease bone mineral density and increase the risk of fracture (J Clin Oncol 2008 Nov 20;26(33):5465). Bisphosphonates are often recommended for women receiving aromatase inhibitor therapy with evidence of osteoporosis (Ann Oncol 2011 Dec;22(12):2546), but reports of their efficacy are inconsistent (Oncologist 2013;18(4):353, Gynecol Oncol 2010 Apr;117(1):139). Denosumab has previously been shown to reduce the risk of fractures and skeletal events in postmenopausal women with osteoporosis, but without cancer (N Engl J Med 2009 Aug 20;361(8):756) and in women with breast cancer with bone metastases (Cochrane Database Syst Rev 2012 Feb 15;(2):CD003474). However, the efficacy of denosumab in women with early stage breast cancer is unknown. A recent randomized trial compared denosumab 60 mg vs. placebo 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.

At baseline, 45% of women had low bone mineral density (BMD) with T scores < -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% CI 0.39-0.65). At 36 months, the estimated rate of clinical fractures was 5% with denosumab vs. 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 bone mineral density at 12, 24, and 36 months (p < 0.0001 for all time points). These results were consistent in subgroup analyses by baseline bone mineral density, 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 specific any specific treatment population. Overall, these results suggest that denosumab not only increases bone mineral density, but also reduces the risk of fractures in women with early stage breast cancer receiving treatment with aromatase inhibitors.

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