Prevention of bone loss with risedronate in breast cancer survivors: a randomized, controlled clinical trial

Abstract

In postmenopausal women with low bone mass and hormone-receptor-positive breast cancer on an aromatase inhibitor, risedronate maintained skeletal health assessed by bone density and turnover markers. Women with the greatest decreases in bone turnover markers at 12 months had the greatest increases in bone density at 24 months.

Introduction: Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone-receptor-positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if (1) oral bisphosphonate therapy can prevent bone loss in women on an AI and (2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD).

Methods: We conducted a 2-year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an AI (anastrozole, letrozole, or exemestane) for hormone-receptor-positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo, and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)], and safety.

Results: Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 ± 0.7 percentage points at the spine and 3.2 ± 0.5 percentage points at the hip (both p < 0.05). The adjusted difference between the active treatment and placebo groups were 0.09 ± 0.04 nmol/LBCE for CTX and 23.3 ± 4.8 μg/mL for P1NP (both p < 0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD (p < 0.05). The oral therapy was safe and well tolerated.

Conclusion: In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health.

Keywords: Antiresorptives; Biochemical markers of bone turnover; Clinical trials; DXA.

Figure 1

Enrollment and Study Design Flow Chart- CONSORT Diagram

Figure 2

Mean ± SE percent change in bone mineral density in spine (A), total hip (B), femoral neck (C), total body (D) and the absolute change in biochemical markers of bone turnover including CTX [(E), nmol/L BCE] and P1NP [(F), µg/mL] from baseline to 24 months (unadjusted). * p<0.05, ** p<0.01 change from baseline using paired t-test. #p<0.05, ##p<0.01 for comparison between risedronate (solid line) and placebo (dashed line) groups using linear mixed models.

Figure 3

Percent change in spine bone mineral density (BMD) after 24 months of risedronate grouped by percentage decrease in bone turnover markers (in tertiles) at 12 months. Results as mean ± SEM. For CTX (overall ANOVA pairwise comparison p<0.05), group a) lowest tertile (<13%), b) middle tertile (13 – <43%) and c) highest tertile (>43% decrease). For P1NP (overall ANOVA pairwise comparison p<0.01), group d) lowest tertile (<37%), e) middle tertile (37–50%), and f) highest tertile (>50% decrease). Significance between tertiles: a vs. c (p<0.01), b vs. c (p<0.05), d vs. e (p<0.05), d vs. f (p<0.01), and e vs. f (p=0.07).