title: Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study.
abstract: BACKGROUND
  Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer.
  
  
  METHODS
  Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2-3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website .
  
  
  RESULTS
  Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm(3) (2.7%; 95% CI 2.0-3.4; p<0.0001) at the lumbar spine and 0.025 g/cm(3) (1.4%; 0.8-1.9; p<0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; p=0.002) and 0.8% (0.3-1.4; p=0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0.001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13-1.87]; p=0.003).
  
  
  CONCLUSIONS
  These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.
authors.affiliation: Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK. R.E.Coleman@sheffield.ac.uk
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.forename: Linda M
authors.initials: LM
authors.lastname: Banks
authors.forename: Samia I
authors.initials: SI
authors.lastname: Girgis
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Kilburn
authors.forename: Eduard
authors.initials: E
authors.lastname: Vrdoljak
authors.forename: John
authors.initials: J
authors.lastname: Fox
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cawthorn
authors.forename: Ashraf
authors.initials: A
authors.lastname: Patel
authors.forename: Claire F
authors.initials: CF
authors.lastname: Snowdon
authors.forename: Emma
authors.initials: E
authors.lastname: Hall
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bliss
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D000730:Androstadienes / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000453:epidemiology*; D006615:Hip / Q000000981:diagnostic imaging; D006801:Humans; D015994:Incidence; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects; D017698:Postmenopause; D011859:Radiography; D012307:Risk Factors; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D015415:Biomarkers; D013629:Tamoxifen; C056516:exemestane