Introduction: Third-generation aromatase inhibitors have demonstrated superior efficacy and safety over the selective estrogen receptor modulator tamoxifen in the adjuvant treatment of estrogen receptor-positive early breast cancer in postmenopausal women. Previous findings suggest that aromatase inhibitors may increase the risk for osteoporosis and bone fracture. Tamoxifen, on the other hand, has demonstrated bone-sparing effects. This prospective randomized controlled trial is a substudy of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and was designed to examine the effects of these agents on bone mineral density (BMD) after 5 years of treatment.
Methods: The substudy involved 71 postmenopausal women with localized early breast cancer, 50 of whom had evaluable data and were included in the analysis. The patients had received anastrozole (1 mg/day) and/or tamoxifen (20 mg/day) for 5 years and remained cancer free with no signs of osteoporosis on lumbar or total hip scans. The participants were then followed off-treatment for 2 years.
Results: In the anastrozole group, median BMP at the lumbar spine and total hip increased at years 6 and 7 (+2.35% and +4.07%; P=0.04 and P=0.0004, respectively) as well as the median total hip BMD. In contrast, these measures decreased in the tamoxifen group (-0.79% and -0.3%; P=0.01 and P=0.09, respectively). None of the patients in either group became osteoporotic after treatment.
Conclusion: While greater bone loss was found with anastrozole compared with tamoxifen during 5 years of active treatment, the anastrozole groups showed evidence of partial recovery in bone mineral density at the lumbar spine and no further loss of bone mineral density at the hip in the anastrozole group.
Eastell R, Adams J, Clack G, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol. 2011;22(4):857-862.
Commentary by Azeez Farooki MD
Dr. Azeez Farooki is an academic endocrinologist practicing in New York City. His expertise includes general endocrinology with a sub-focus in osteoporosis / metabolic bone diseases.
This study provides valuable clinical insight into what happens to bone mineral density (BMD) when adjuvant aromatase inhibitors given for breast cancer are discontinued after 5 years of continuous use. We know that all three aromatase inhibitors increase bone turnover and decrease bone mineral density via depletion of estrogen.
When aromatase inhibitors are stopped, the small amount of estrogen that is produced in postmenopausal women from peripheral aromatization returns; with it comes an increase in BMD, which is particularly robust (approaching the baseline BMD prior to starting the aromatase inhibitor) at the trabecular bone-rich lumbar spine site. Given the favorable changes in BMD and bone turnover off of aromatase inhibitors, one would think fracture risk is very likely to drop. As reported by the same investigators, this is probably the case. However, the "quality" of the BMD that has returned is an open question and whether the aromatase inhibitors have caused significant irreparable microarchitectural deterioration in the trabecular and/or cortical bone compartments are open questions. As hip fracture risk increases markedly with age, data such as this study in the breast cancer survivor population is very welcome.
My take home from this study is that a given patient's fracture risk will decrease once they stop taking an aromatase inhibitor; that residual risk may or may not then be enough to still warrant anti-fracture therapy.