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

Abstract

The third generation aromatase inhibitors are currently the drugs of choice for treatment of early and advanced breast cancer in postmenopausal women. One of the significant limiting factor during therapy is their negative impact on bone health. In the present study, we compared the effects of a non-steroidal (letrozole) and a steroidal aromatase inhibitor (exemestane) on bone mineral density and markers of bone turnover including alkaline phosphatase (ALP), tartrateresistant acid phosphatase (TRAP), hydroxyproline (HxP), receptor activator of nuclear factor kappa-B ligand (RANKL), sclerostin and dickkopf-1 (DKK-1) in vinlycyclohexene di epoxide (VCD)-induced ovotoxic female mice. VCD administration for 15 days mimicked a postmenopausal state with reduced serum estradiol levels. Ovotoxicity was accompanied by reduced ALP, HxP and enhanced TRAP, sclerostin and DKK-1 activity in femoral epiphysis and lumbar vertebrae of mice. While letrozole (1mg/kg) administration for one month enhanced bone turnover in ovotoxic mice, exemestane (3.25 mg/kg) was devoid of such effects in both normal and ovotoxic mice. The latter, however, reduced ALP in femoral epiphysis of ovotoxic mice.Letrozole depleted estradiol levels in ovotoxic mice and enhanced RANKL activity while exemestane neither affected estradiol nor RANKL in both normal and ovotoxic mice, and enhanced sclerostin and DKK-1 in femoral epiphysis only. The study indicates that the two aromatase inhibitors possesses differential profile in terms of their effects on bone and that exemestane could be a better option for the treatment of breast cancer in postmenopausal women at least in terms of its effects on bone.