Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats

Abstract

Purpose: This study was conducted to examine the bone and body composition effects of S-4, an aryl-propionamide derived Selective Androgen Receptor Modulator (SARM) in an ovariectomy induced model of accelerated bone loss.

Methods: One hundred twenty female Sprague-Dawley rats aged to twenty-three weeks were randomly assigned to twelve treatment groups. Drug treatment was initiated immediately following ovariectomy and continued for one hundred twenty days. Whole body bone mineral density (BMD), body composition, and lumbar vertebrae BMD were measured by dual energy x-ray absorptiometry. More stringent regional pQCT and biomechanical strength testing was performed on excised femurs.

Results: We found that S-4 treatment maintained whole body and trabecular BMD, cortical content, and increased bone strength while decreasing body fat in these animals.

Conclusions: The data presented herein show the protective skeletal effects of S-4. Our previous reports have shown the tissue selectivity and muscle anabolic activity of S-4. Together these data suggest that S-4 could reduce the incidence of fracture via two different mechanisms (i.e., via direct effects in bone and reducing the incidence of falls through increased muscle strength). This approach to fracture reduction would be advantageous over current therapies in these patients which are primarily antiresorptive in nature.

Fig. 1

Bone mineral density as measured by DEXA in excised bones. Lumbar vertebrae (L5–L6). Data presented as mean ± S.E.M. ^adenotes P < 0.05 versus OVX controls.^bdenotes P < 0.05 versus intact controls.

Fig. 2

pQCT analysis of the mid-shaft and distal femur. (A) Cortical thickness at the femoral mid-shaft. (B) Periosteal circumference at the femoral mid-shaft. (C) Cortical content at the femoral mid-shaft. (D) Cortical bone density at the femoral mid-shaft. (E) Trabecular density of the distal femur. Data presented as mean ± S.E.M. ^adenotes P < 0.05 versus OVX controls. ^bdenotes P < 0.05 versus intact controls.

Fig. 3

Femoral maximum load determined by 3-point bending. Data presented as mean ± S.E.M. ^adenotes P < 0.05 versus OVX controls. ^bdenotes P < 0.05 versus intact controls.

Fig. 4

Primary bone marrow osteoprogenitor cell cultures. (a) Percent ALP+ve CFU-F. (b) Trap+ve multinucleated osteoclasts. Data presented as mean ± S.E.M.