Bone mineral density in breast cancer patients treated with adjuvant letrozole, tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07)

Abstract

Background: The risk of osteoporosis and fracture influences the selection of adjuvant endocrine therapy. We analyzed bone mineral density (BMD) in Swiss patients of the Breast International Group (BIG) 1-98 trial [treatment arms: A, tamoxifen (T) for 5 years; B, letrozole (L) for 5 years; C, 2 years of T followed by 3 years of L; D, 2 years of L followed by 3 years of T].Patients and methods: Dual-energy X-ray absorptiometry (DXA) results were retrospectively collected. Patients without DXA served as control group. Repeated measures models using covariance structures allowing for different times between DXA were used to estimate changes in BMD. Prospectively defined covariates were considered as fixed effects in the multivariable models.Results: Two hundred and sixty-one of 546 patients had one or more DXA with 577 lumbar and 550 hip measurements.Weight, height, prior hormone replacement therapy, and hysterectomy were positively correlated with BMD; the correlation was negative for letrozole arms (B/C/D versus A), known osteoporosis, time on trial, age, chemotherapy, and smoking. Treatment did not influence the occurrence of osteoporosis (T score < 22.5 standard deviation).Conclusions: All aromatase inhibitor regimens reduced BMD. The sequential schedules were as detrimental for bone density as L monotherapy.

Differential profile of letrozole and exemestane on bone turnover markers in vinylcyclohexene diepoxide treated ovotoxic female mice

“…Letrozole pretreatment for 1 month in ovotoxic mice resulted in further reduction in ALP and HxP and enhanced TRAP activity in both femoral epiphysis and lumbar vertebrae indicating significantly enhanced bone turnover. This is in agreement with clinical and preclinical studies showing bone loss with letrozole. While ALP is a bone formation marker and represent osteoblastic activity , both TRAP and HxP are considered markers of bone resorption .…”

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

“…Our results are consistent with a retrospective study on BMD changes involving all Swiss participants in the BIG 1-98 study, 121 of whom were also enrolled in the current study, where LT approached T changes on BMD after 5 years [12]. Whereas tamoxifen is known to counteract BMD loss and to decrease bone fracture rate in postmenopausal women [13], the sequence of T followed by L had the worse effect on BMD.…”

Guidelines for the diagnosis, prevention and management of osteoporosis

“…There is a substantial difference in the rate of bone turnover, and thereby in the rate of bone loss, among different patient populations (men, premenopausal and postmenopausal women at diagnosis) and with different types of antihormonal therapy (chemotherapy-induced menopause, GnRH with or without tamoxifen, or aromatase inhibitors from oils, androgen deprivation therapy). Patient categories at the highest risk of osteoporosis are (in descending order): premenopausal women with chemotherapy-induced menopause treated with GnRH agonists, men on androgen deprivation, women switched from tamoxifen to aromatase inhibitors, women on aromatase inhibitors, especially if aged <70 years (52,54,55). Given the high prevalence of risk factors for fractures, irrespective of hormone therapy, and the high prevalence of vertebral fracture at cancer diagnosis, all subjects with breast or prostate cancer should be assessed for fragility fractures (including morphometric vertebral fractures) (56,57).…”