Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230).
Aromatase inhibitors reduce estrogen levels in postmenopausal women with breast cancer. Residual estrogen is an important determinant of bone turnover. Adjuvant anastrozole was associated with significant BMD loss and increased bone remodeling, whereas tamoxifen reduced bone marker levels.


BACKGROUND
In the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial after a median follow-up of 68 months, a significant improvement in disease-free survival was observed with anastrozole treatment (hazard ratio [HR], 0.87; 95% CI, 0.78-0.97; p = 0.01). Anastrozole was also associated with tolerability benefits compared with tamoxifen, but with higher fracture rates. The HR of anastrozole compared with tamoxifen after 60 months of treatment was 1.49 (95% CI, 1.25-1.77).


METHODS
This prospectively designed subprotocol (n = 308) of ATAC assessed changes in BMD and bone turnover markers in postmenopausal women with invasive primary breast cancer receiving anastrozole 1 mg/day, tamoxifen 20 mg/day, or combination treatment with both agents for 5 years. Patients with osteoporosis were excluded (osteopenia permitted at the investigators discretion). Lumbar spine and total hip BMD was assessed at baseline and after 1 and 2 years; bone turnover markers (serum C-telopeptide, urinary N-telopeptide [NTX], free deoxypyridinoline, serum procollagen type-1 N-propeptide, bone alkaline phosphatase [ALP]) were assessed at baseline and after 3, 6, and 12 months. Results were expressed as median percentage change.


RESULTS
After 2 years of anastrozole treatment, BMD was lost at lumbar spine (median 4.1% loss) and total hip (median 3.9% loss) sites; increases of 2.2% and 1.2%, respectively, were observed with tamoxifen. After 1 year of anastrozole treatment, increased bone remodeling was observed (NTX, +15%; 95% CI, 3-25%; bone ALP, +20%; 95% CI, 14-25%); decreased bone remodeling was observed with tamoxifen (NTX, -52%; 95% CI, -62% to -33%; bone ALP, -16%; 95% CI, -24% to -11%).


CONCLUSIONS
Anastrozole is associated with significant BMD loss and a small increase in bone turnover, whereas tamoxifen (and the combination) is associated with increased BMD and decreased remodeling. These data may explain the increased fracture risk observed with anastrozole treatment in the ATAC trial. The impact of anastrozole on bone should be weighed against its overall superior efficacy and tolerability as observed in the main ATAC trial.
Eastell
Richard
R
Bone Metabolism Group, Division of Clinical Sciences (North), University of Sheffield, UK. r.eastell@sheffield.ac.uk
Hannon
Rosemary A
RA
Cuzick
Jack
J
Dowsett
Mitch
M
Clack
Glen
G
Adams
Judith E
JE
D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced; D006615:Hip / Q000000981:diagnostic imaging; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects*; D017698:Postmenopause; D011859:Radiography; D012306:Risk; D013629:Tamoxifen / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects*
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D015415:Biomarkers; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole