Idoxifene, a novel
selective estrogen receptor modulator, was tested for its effects on bone loss, serum
cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat.
Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD). In an intervention study,
idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group.
Idoxifene reduced total serum
cholesterol, which was maximal at 0.5 mg/kg x day.
Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of
estrogen in intact rats. Histologically, myometrial and endometrial
atrophy were observed in both
idoxifene and vehicle-treated Ovx rats. In this report, we also provide molecular-based evidence to support the observations in vivo of a novel
selective estrogen receptor modulator (
SERM) mechanism of action in bone and endometrial cells.
Idoxifene is an agonist through the
estrogen response element (ERE) and exhibits similar postreceptor effects to
estrogen in bone-forming osteoblasts.
Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis. However,
idoxifene differs from
estrogen in a tissue-specific manner. In human endometrial cells, where
estrogen is a potent agonist through the ERE,
idoxifene has negligible agonist activity. Moreover,
idoxifene was able to block
estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study. In the uterus,
idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity. Together with its
cholesterol lowering effect and lack of uterotrophic activity, these data suggest that
idoxifene may be effective in the prevention of
osteoporosis and other postmenopausal diseases without producing unwanted
estrogenic effects on the endometrium.