title: Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial.
abstract: BACKGROUND
  Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. We assessed effectiveness of oral risedronate for prevention of reduction in bone mineral density (BMD) after 3 years of follow-up in a subset of patients in the IBIS-II trial.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca.
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University London, London, UK. Electronic address: i.sestak@qmul.ac.uk.
authors.forename: Ivana
authors.initials: I
authors.lastname: Sestak
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University London, London, UK.
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University London, London, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.affiliation: Biomedical Engineering Department, King's College London, London, UK.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Blake
authors.affiliation: Imperial College London, London, UK.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Human Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: Fatma
authors.initials: F
authors.lastname: Gossiel
authors.affiliation: Department of Oncology, University of Sheffield, Sheffield, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: University of Newcastle, Calvary Mater Hospital, Australia New Zealand Breast Cancer Trials Group Newcastle, Newcastle, NSW, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Forbes
authors.affiliation: Genesis Breast Cancer Prevention Centre, Manchester, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.affiliation: Department of Human Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
mesh_terms: D000328:Adult; D000368:Aged; D000077384:Anastrozole; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007390:International Agencies; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use*; D010024:Osteoporosis / Q000188:drug therapy* / Q000473:pathology; D017698:Postmenopause / Q000187:drug effects*; D011379:Prognosis; D000068296:Risedronic Acid; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D050071:Bone Density Conservation Agents; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole; D000068296:Risedronic Acid; D012968:Etidronic Acid