Effects of a new selective estrogen receptor modulator (MDL 103,323) on cancellous and cortical bone in ovariectomized ewes: A biochemical, histomorphometric, and densitometric study

The aims of this study performed in ewes were: (1) to confirm in this anima l model the effects on bone of ovariectomy (OVX) alone or associated with L entaron (L), a potent peripheral aromatase inhibitor, used to amplify the e ffects of OVX and (2) to evaluate the effects of a new selective estrogen r eceptor modulator (SERM; MDL 103,323) on bone remodeling. Thirty-nine old e wes were divided into five groups: sham(n = 7); OVX (n = 8); OVX + L (n = 8 ); OVX + L + MDL; 0.1 mg/kg per day (n = 8); and OVX + L + MDL 1 mg/kg per day (n = 8). The animals were treated for 6 months. Biochemical markers of bone turnover (urinary excretion of type 1 collagen C-telopeptide [CTX], se rum osteocalcin COG], and bone alkaline phosphatase [BAP]) were measured ea ch month. Bone biopsy specimens were taken at the beginning and after death at the end of the experiment. Bone mineral density (BMD) was measured by d ual-energy X-ray absorptiometry (DXA) on the lumbar spine and femur. OVX in duced a significant increase in biochemical markers. This effect was the hi ghest after 3 months for CTX (+156% vs. sham) and after 4 months for OC and BAP (+74% and +53% vs. sham, respectively). L tended to amplify the effect of OVX on OC and BAP. OVX induced significant increases in the porosity, e roded, and osteoid surfaces in cortical bone but no effect was observed in cancellous bone. MDL treatment reduced the bone turnover as assessed by bon e markers, which returned to sham levels as well as]histomorphometry both i n cortical and in cancellous bone. Cancellous osteoid thickness decreased b y 27% (p < 0.05), mineralizing perimeter by 81% (p < 0.05), and activation frequency by 84% (p < 0.02) versus OVX + L. Femoral and spinal BMD were inc reased by MDL and tended to return to the sham values. The effects of OVX o n bone turnover were different on cortical and cancellous bone. These effec ts on cortical bone were reflected by changes in biochemical markers. MDL m arkedly reduces bone turnover and increases BMD suggesting that this new ag ent may prevent postmenopausal bone loss.