Lasofoxifene (CP-336,156) protects against the age-related changes in bonemass, bone strength, and total serum cholesterol in intact aged male rats

The purpose of this study was to evaluate if long-term (6 months) treatment with lasofoxifene (LAS), a new selective estrogen receptor modulator (SERM ), can protect against age-related changes in bone mass and bone strength i n intact aged male rats. Sprague-Dawley male rats at 15 months of age were treated (daily oral gavage) with either vehicle (n = 12) or LAS at 0.01 mg/ kg per day (n = 12) or 0.1 mg/kg per day (n = 11) for 6 months. A group of 15 rats was necropsied at 15 months of age and served as basal controls. No significant change was found in body weight between basal and vehicle cont rols. However, an age-related increase in fat body mass (+42%) and decrease in lean body mass (-8.5 %) was observed in controls. Compared with vehicle controls, LAS at both doses significantly decreased body weight and fat bo dy mass but did not affect lean body mass. No significant difference was fo und in prostate wet weight among all groups. Total serum cholesterol was si gnificantly decreased in all LAS-treated rats compared with both the basal and the vehicle controls. Both doses of LAS treatment completely prevented the age-related increase in serum osteocalcin. Peripheral quantitative comp uterized tomography (pQCT) analysis at the distal femoral metaphysis indica ted that the age-related decrease in total density, trabecular density, and cortical thickness was completely prevented by treatment,vith LAS at 0.01 mg/kg per day or 0.1 mg/kg per day. Histomorphometric analysis of proximal tibial cancellous bone showed an age-related decrease in trabecular bone vo lume (TBV; -46%), trabecular number (Tb.N), wall thickness (W.Th), mineral apposition rate, and bone formation rate-tissue area referent. Moreover, an age-related increase in trabecular separation (Tb.Sp) and eroded surface w as observed. LAS at 0.01 mg/kg per day or 0.1 mg/kg per day completely prev ented these age-related changes in bone mass, bone structure, and bone turn over. Similarly, the age-related decrease in TBV and trabecular thickness ( Tb.Th) and the age-related increase in osteoclast number (Oc.N) and osteocl ast surface (Oc.S) in the third lumbar vertebral cancellous bone were compl etely prevented by treatment with LAS at both doses. Further, LAS at both d oses completely prevented the age-related decrease in ultimate strength (-4 7%) and stiffness (-37%) of the fifth lumbar vertebral body. These results show that treatment with LAS for 6 months in male rats completely prevents the age-related decreases in bone mass and bone strength by inhibiting the increased bone resorption and bone turnover associated with aging. Further, LAS reduced total serum cholesterol and did not affect the prostate weight in these rats. Our data support the potential use of a SERM for protecting against the age-related changes in bone and serum cholesterol in elderly m en.