EFFECTS OF DROLOXIFENE ON PREVENTION OF CANCELLOUS BONE LOSS AND BONETURNOVER IN THE AXIAL SKELETON OF AGED, OVARIECTOMIZED RATS

The purpose of this study was to determine the efficacy of droloxifene (DRO), an estrogen antagonist/agonist, in preventing ovariectomy (OVX )-induced lumbar vertebral cancellous bone loss and bone turnover in a ged female rats. Fifty-three Sprague-Dawley female rats were OVX or sh am-operated at 19 months of age, and divided into 6 groups: (I) sham-o perated controls; (II) OVX vehicle controls; (III) OVX rats treated wi th E(2) at 30 mu g/kg/day; (IV)-(VI) OVX rats treated with DRO at eith er 2.5, 5, or 10 mg/kg p.o. daily. The treatment period was 8 weeks. S tatic and dynamic cancellous bone histomorphometric parameters were de termined on 4 and 10 mu m thick, undecalcified, double-fluorescent lab eled sections of the fourth lumbar vertebral body. Changes in body wei ght, uterine weight, and total serum cholesterol were also determined. OVX for 8 weeks in 19-month-old female rats resulted in reduced trabe cular bone volume (-18%) and trabecular width (-10%) and increased lab eling perimeter (+52%), bone formation rate/bone surface referent (+60 %), bone formation rate/bone volume referent (+77%), osteoclast number (+41%), and osteoclast perimeter (+41%). E(2) treatment at 30 mu g/kg /day for 8 weeks prevented OVX-induced cancellous bone loss and decrea sed bone resorption, bone formation, and bone turnover to the values o f sham controls. DRO at 2.5-10 mg/kg/day completely prevented bone los s and bone turnover associated with estrogen deficiency. Osteoclast nu mber and perimeter were significantly decreased in DRO-treated-OVX rat s compared to both sham and OVX controls. Trabecular bone volume, trab ecular width, labeling perimeter, bone formation rate/bone surface ref erent, and bone formation rate/bone volume referent showed no differen ces in DRO-treated OVX rats compared to those of E(2)-treated OVX rats and sham controls. These histomorphometric results indicated that DRO is an estrogen agonist on cancellous bone of lumbar vertebral bodies of aged, OVX rats. Further, E(2) treatment prevented the OVX-induced i ncrease in body weight gain and nonsignificantly reduced total serum c holesterol compared to OVX controls. Body weight gain and total serum cholesterol did not differ between OVX rats treated with E(2) and sham controls. In OVX rats treated with DRO, body weight decreased signifi cantly in a dose-response manner, and total serum cholesterol was sign ificantly reduced by 65% to 70% compared to both sham and OVX controls . In addition, treatment with E(2) increased uterine weight to the val ue of sham controls in OVX rats. However, DRO had no effect on uterine weight at either 2.5 or 10 mg/kg/day, while it only slightly but sign ificantly increased uterine weight over OVX controls at 5 mg/kg/day. W e conclude that DRO was efficacious in the prevention of lumbar verteb ral cancellous bone loss and in the decline of total serum cholesterol but had no effect on uterine weight in the aged, OVX female rats. Our data suggest that DRO is a potentially useful agent for the preventio n of vertebral bone loss leading to spinal fractures in postmenopausal women.