Droloxifene inhibits cortical bone turnover associated with estrogen deficiency in rats

Droloxifene (DRO), an estrogen antagonist/agonist, has been shown to possess estrogen-like effects in inhibiting bone turnover leading to cancellous bone loss in ovariectomized (OVX) rats. The purpose of this study was to determine the effects of DRO on cortical bone turnover in OVX rats. Sprague-Dawley female rats at 5 months of age were sham-operated (sham, N=8) and orally treated with vehicle, or OVX (n=56) and orally treated with either vehicle, DRO at 0.1, 1, 5, or 10 mg/kg/day, or 17α-ethynyl estradiol (EE) at 3 or 30 μg/kg/day for 4 weeks. Static and dynamic cortical bone histomorphometry was performed on double fluorescent labeled, undecalcified cross sections of tibial diaphyses (proximal to the tibiofibular junction). There were no significant differences in tibial diaphyseal cross sectional area, marrow cavity area, and cortical bone area between groups after 4 weeks of administration. Periosteal mineralizing surface, mineral apposition rate, and bone formation rate-surface referent and endocortical eroded surface increased significantly, while endocortical mineral apposition rate and bone formation rate-surface referent increased nonsignificantly in OVX controls compared to sham controls. Treatment with DRO at doses of 0.1 to 10 mg/kg/day dose-dependently attenuated the OVX-induced higher bone formation indices in both the periosteal and endocortical surfaces and higher bone resorption index in the endocortical surface. At the highest dose (10 mg/kg/day), DRO completely inhibited the increases in bone formation and resorption indices in OVX rats. Similarly, EE at 30 μg/kg/day inhibited the increase in periosteal and endocorrical bone formation and endocortical bone resorption associated with estrogen deficiency in rats, while 3 μg/kg/day, EE decreased only periosteal mineral apposition rate in OVX rats. Our results indicated that DRO prevented OVX-induced higher bone turnover on endocortical surfaces and higher bone formation in periosteal surfaces of tibial diaphyses in an identical manner to EE. Therefore, we concluded that DRO is an estrogen agonist on cortical bone in ovariectomized rats.