Prevention of Aromatase Inhibitor-Induced Bone Loss Using Risedronate:The SABRE Trial

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J Clin Oncol. 2010 Jan 11; Epub ahead of print, C Van Poznak, RA Hannon, JR Mackey, M Campone, JP Apffelstaedt, G Clack, D Barlow, A Makris, R Eastell

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In this phase III/IV study of aromatase inhibitor−induced bone loss, treatment with a bisphosphonate increased BMD in women at high risk for fractures.

STUDY IN CONTEXT

Aromatase inhibitors, which include anastrozole, exemestane, and letrozole, are used as standard adjuvant therapy for postmenopausal women with hormone-receptor (HR)–positive early breast cancer. Because these agents reduce circulating estrogen, their use raises concerns about accelerated bone loss and increased risk of fracture. Bone loss associated with estrogen deficiency can be managed with bisphosphonates (e.g. risedronate sodium). In this phase III/IV study—designated as SABRE (Study of Anastrozole with the Bisphosphonate Residronate)—Van Poznak et al investigated the effects of adjuvant therapy with anastrozole, with or without risedronate, , on bone mineral density (BMD) in postmenopausal women with HR+ early breast cancer. The study enrolled 234 patients, who were stratified to 3 treatment groups according to their risk of fracture (based on baseline T-scores). The higher-risk (n = 38) and lower-risk groups (n = 42) were enrolled in open-label, noncomparative study arms. Patients in the higher-risk group were given anastrozole (1 mg/d) plus risedronate 35 mg/wk (A + R). Patients in the lower-risk group received anastrozole alone (A). Patients in the moderate-risk group (n = 154) were randomized to treatment with either A+ R (n = 77) or anastrozole (1 mg/d) plus placebo (A + P; n = 77). All treatment was given for 2 years, in combination with calcium and vitamin D.

At 12 months, patients in the higher-risk group exhibited significant increases in percent change from baseline lumbar spine BMD (+3.4%; P < .001). In the moderate-risk group, the percent change from baseline lumbar spine BMD was significantly greater in the A + R than in the A + P group (1.2% vs –1.2%; P< .0001). In the lower-risk group, the percent change from baseline for lumbar spine BMD was not significant (0.6%; P = .3511).

At 24 months, both lumbar spine and total hip BMD increased significantly from baseline in women in the higher-risk group (3.0%; P = .0006 and 2.0%; P = .0104, respectively). In the moderate-risk group, the percent change from baseline BMD for both lumbar spine and total hip was significantly improved in the A + R compared with the A + P group (2.2% vs −1.8% for lumbar spine and 1.8% vs −1.1% for hip; P < .0001 for both). For women in the lower-risk group, the percent change from baseline BMD showed a significant decrease for the lumbar spine (–2.1%; P = .0109) and a numerical decrease for total hip (–0.4%; P = .5988). Results were confirmed in an ANOVA model.

Three bone markers were tested in this study: serum C-telopeptide of type I collagen (sCTX), procollagen type 1 N-propeptide (P1NP), and bone isoforms of alkaline phosphatase (bALP). At 6 and 12 months, significant reductions in all 3 bone markers were observed in higher-risk patients. Moderate-risk patients in the A + R group exhibited significantly reduced sCTX, P1NP, and bALP levels when compared with the A + P group. Patients in the lower-risk group showed no significant changes in bone marker levels at 6 months. However, at 12 months, significant increases in sCTX and bALP levels were observed.

Treatment was well tolerated in all groups. Toxicity was comparable among treatments. Safety profiles for anastrozole and risedronate were comparable to those reported in previous clinical trials.

This study, which stratified patients based on risk of fracture, showed that not all patients given aromatase inhibitors require prophylactic bisphosphonate therapy. However, for maintaining bone health in postmenopausal women receiving these drugs as adjuvant therapy, concomitant bisphosphonate therapy was effective.

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