The double-blind IBIS-II trial recruited 3864 healthy, postmenopausal women at increased risk of
breast cancer and randomly allocated them oral
anastrozole (1 mg/day) or matched placebo. 1410 (36%) postmenopausal women were then enrolled in a bone substudy and stratified at baseline according to their lowest baseline T score at spine or femoral neck (stratum I: T score at least -1·0; stratum II: T score at least -2·5 but less than -1·0; stratum III: T score less than -2·5 but greater than -4·0). Women in stratum I were monitored only; women in stratum III were all given
risedronate (35 mg/week). Women in stratum II were randomly assigned (1:1) to
risedronate (35 mg/week) or matched placebo by use of a block randomisation schedule via a web-based programme. The primary outcome of this per-protocol analysis (done with all women with a baseline and 3 year DXA assessment) was the effect of
risedronate versus placebo for osteopenic women in stratum II randomly allocated to
anastrozole (1 mg/day). Secondary outcomes included effect of
anastrozole (1 mg/day) on BMD in women not receiving
risedronate (strata I and II) and in osteoporotic women who were all treated with
risedronate (stratum III). The trial is ongoing, but no longer recruiting. This trial is registered, number ISRCTN31488319.
FINDINGS: Between Feb 2, 2003, and Sept 30, 2010, 150 (58%) of 260 women in stratum II who had been randomly allocated to
anastrozole and either
risedronate or placebo had baseline and 3 year assessments. At the lumbar spine, 3 year mean BMD change for the 77 women receiving
anastrozole/
risedronate was 1·1% (95% CI 0·2 to 2·1) versus -2·6% (-4·0 to -1·3) for the 73 women receiving
anastrozole/placebo (p<0·0001). For the total hip, 3 year mean BMD change for women receiving
anastrozole/
risedronate was -0·7% (-1·6 to 0·2) versus -3·5% (-4·6 to -2·3) for women receiving
anastrozole/placebo (p=0·0001). 652 (65%) of 1008 women in strata I and II who were not randomly allocated to
risedronate had both baseline and 3 year assessments. Women not receiving
risedronate in stratum I and II who received
anastrozole (310 women) had a significant BMD decrease after 3 years of follow-up compared with women who received placebo (342 women) at the lumbar spine (-4·0% [-4·5 to -3·4] vs -1·2% [-1·7 to -0·7], p<0·0001) and total hip (-4·0% [-4·4 to -3·6] vs -1·8% [-2·1 to -1·4], p<0·0001). 106 (79%) of 149 women in stratum III had a baseline and a 3 year assessment. The 46 women allocated to
anastrozole had a modest BMD increase of 1·2% (-0·1 to 2·6) at the spine compared with a 3·9% (2·6 to 5·2) increase for the 60 women allocated to placebo (p=0·006). For the total hip, a small 0·3% (-0·9 to 1·5) increase was noted for women allocated
anastrozole compared with a 1·5% (0·5 to 2·5) increase for women allocated placebo, but the difference was not significant (p=0·12). The most common adverse event reported was
arthralgia (stratum I: 94 placebo and 114
anastrozole; stratum II: 39 placebo/placebo, 25 placebo/
risedronate, 34
anastrozole/placebo, and 34
anastrozole/
risedronate; stratum III: 21 placebo/
risedronate, 17
anastrozole/
risedronate). Other adverse events included hot flushes,
alopecia,
abdominal pain, and
back pain.
INTERPRETATION:
Risedronate counterbalances the effect of
anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with
anastrozole treatment to provide an improved risk-benefit profile.
FUNDING:
Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca.