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Minimizing Bone Loss Related to Therapy with Aromatase Inhibitors

Denosumab seemed protective against AI-induced bone loss in women with early-stage breast cancer.

Integration of aromatase inhibitors (AIs) into adjuvant therapy improves disease-free survival for postmenopausal women with early-stage breast cancer. However, AIs are associated with loss of bone-mineral density (BMD) that escalates with duration of therapy. Such BMD loss is mediated by osteoclasts, which depend on the receptor activator of nuclear factor-B ligand (RANKL) for their formation, function, and survival. RANKL stimulates osteoclast-mediated bone resorption by binding to its receptor, RANK, on preosteoclasts and osteoclasts. Previous reports have shown that denosumab — a humanized monoclonal antibody that inhibits bone resorption by binding to RANKL with high affinity and specificity — can augment bone mass in postmenopausal women with low BMD for up to 2 years (J Bone Miner Res 2007 Dec; 22:1832 and JW Womens Health Apr 4 2006).

To assess the ability of denosumab to protect against AI-induced bone loss in postmenopausal women with early-stage breast cancer, investigators conducted an industry-sponsored, randomized trial involving 252 patients receiving adjuvant AI therapy for nonmetastatic, hormone-receptor–positive disease. At enrollment, eligible patients had evidence of low bone mass (T-score, –1.0 to –2.5) but not osteoporosis (T-score, <–2.5). Patients received supplemental calcium and vitamin D and were randomized to placebo or subcutaneous denosumab (60 mg on day 1 and every 6 months thereafter for 18 months); randomization was stratified by duration of prior AI therapy (6 months vs. >6 months). The primary endpoint was percentage change in lumbar-spine BMD at 12 months. Secondary efficacy endpoints included change in lumbar-spine BMD at 6 months and in femoral-neck and total-hip BMD at 6 and 12 months. Patients were matched with respect to age, race (>90% white), type of AI therapy (anastrozole, letrozole, or exemestane), duration of AI therapy, previous exposure to adjuvant chemotherapy (~60%) or tamoxifen, and baseline BMD.

At 12 months, lumbar-spine BMD had increased by 4.8% in the denosumab group and decreased by 0.7% in the placebo group, for an overall difference in BMD of 5.5%; at 24 months, this intergroup difference in BMD was 7.6% (P<0.0001 at both time points). Increases in BMD also were observed in the total hip, total body, femoral neck, and the one-third radius (predominantly cortical bone); these occurred as early as 1 month postrandomization and were not influenced by type or duration of AI therapy. Exploratory analysis showed that bone-turnover markers C-telopeptide 1 (sCTx) and procollagen type 1 N-terminal peptide (P1NP) decreased by a wider margin in the denosumab group than in the placebo group by as early as 1 month (median reduction from baseline, 91% vs. 9%, respectively); this effect was sustained for the duration of the trial. Denosumab was well tolerated, and the rate of adverse effects was similar between treatment groups. No difference in fracture rate was detected between the two groups, but the study was not powered to evaluate this endpoint.

Comment: As a novel agent that seems to increase BMD, denosumab potentially could offset bone loss and its consequences in women receiving AI therapy. Whether denosumab can diminish the risk for fracture associated with long-term AI use will require larger confirmatory trials. Denosumab seems to be well tolerated without causing hypocalcemia or tumor necrosis of the jaw (TNJ). However, the association between use of another drug type (bisphosphonate) and TNJ did not become apparent until after approval, thus highlighting the requirement for clinicians to be vigilant for unexpected or rare side effects of any new compound.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology September 30, 2008

Citation(s):

Ellis GK et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008 Aug 25; [e-pub ahead of print]. (http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.16.3832)