Bone mineral density and circulating biomarkers in the BIG 1-98 trial comparing adjuvant letrozole, tamoxifen and their sequences

Abstract

Purpose To determine the effects of the BIG 1-98 treatments on bone mineral density. BIG 1-98 compared 5-year adjuvant hormone therapy in postmenopausal women allocated to four groups: tamoxifen (T); letrozole (L); 2-years T, 3-years L (TL); 2-years L, 3-years T (LT). Methods Bone mineral density T-score was measured prospectively annually by dual energy X-ray absorption in 424 patients enrolled in a sub-study after three (n=150), four (n=200), and five years (n=74) from randomization, and one year after treatment cessation. Prevalence of osteoporosis and the association of C-telopeptide, osteocalcin and bone alkaline phosphatase with T-scores were assessed. Results At 3 years, T had the highest and TL the lowest T-score. All arms except for LT showed a decline up to 5 years, with TL exhibiting the greatest. At 5 years, there were significant differences on lumbar T-score only between T and TL, whereas for femur T-score differences were significant for T vs. L or TL, and L vs. LT. The 5-year prevalence of spine and femur osteoporosis was highest on TL (14.5%, 7.1%) then L (4.3%, 5.1%), LT (4.2%, 1.4%) and T (4%, 0). C-telopeptide and osteocalcin were significantly associated with T-scores. Conclusions While adjuvant L increases bone mineral density loss compared with T, the sequence LT has an acceptable bone safety profile. C-telopeptide and osteocalcin are useful markers of bone density that may be used to monitor bone health during treatment. The sequence LT may be a valid treatment option in patients with low and intermediate risk of recurrence. Trial registration clinicaltrials.gov NCT00369850

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“…However, this drug is ambivalent concerning its target tissues with agonist estrogen effects on bone, endometrium and also liver. This explains its beneficial effects, such as increased mineral bone density [2], and also its side effects such as thromboembolic events [3], increased endometrial cancer events [4] and hot flushes [5].…”

Assessment and management of bone health in women with early breast cancer receiving endocrine treatment in the DATA study

“…A sub-study of the BIG 1-98 trial, comparing four 5-year regimens of endocrine therapy, looked at the effect of each regimen on BMD. 31 They found that the sequenced treatment of tamoxifen followed by letrozole had the worst effect on BMD and that letrozole followed by tamoxifen appeared to preserve BMD. They hypothesized that the interruption of tamoxifen combined with the rapid fall in oestrogen levels induced by letrozole promotes an accelerated bone turnover and loss of BMD following the switch as was confirmed by bone turnover biomarkers.…”

“…Therefore it can be questioned into which extend our results are influenced by the positive effect of tamoxifen on bone health. A sub‐study of the BIG 1–98 trial, comparing four 5‐year regimens of endocrine therapy, looked at the effect of each regimen on BMD . They found that the sequenced treatment of tamoxifen followed by letrozole had the worst effect on BMD and that letrozole followed by tamoxifen appeared to preserve BMD.…”

“…They hypothesized that the interruption of tamoxifen combined with the rapid fall in oestrogen levels induced by letrozole promotes an accelerated bone turnover and loss of BMD following the switch as was confirmed by bone turnover biomarkers. 31…”

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