A new selective estrogen receptor modulator HMR-3339 fully corrects bone alterations induced by ovariectomy in adult...

The selective estrogen receptor modulator (SERM) raloxifene has been shown to reduce the risk of vertebral fracture, but without significant effect on nonvertebral fractures. However, there is a need for SERMs capable of improving mechanical competence and reducing the risk of fractures at multiple skeletal sites, with minimal side effects. We investigated the effects of a new steroidal SERM, HMR-3339, compared to raloxifene, on bone strength and its determinants (BMD, microarchitecture, dimensions) at various skeletal sites (lumbar spine, tibia, and femur) of adult ovariectomized rats in both prevention and intervention protocols. In a prevention study, HMR-3339 and raloxifene treatments fully prevented alterations of bone strength. In an intervention protocol, where treatment was started 8 weeks after ovariectomy, HMR-3339 fully restored mechanical properties by influencing both areal BMD and outer diameter. This effect was observed at skeletal sites formed of cancellous and cortical bone or of cortical bone only. In contrast, raloxifene positively influenced structures containing mainly cancellous bone. In HMR-3339-treated rats, IGF-I plasma levels were higher than in ovariectomized controls; this was not observed with raloxifene. In conclusion, these results indicate that HMR-3339 increased not only bone mineral mass, but also restored bone mechanical strength at multiple sites in adult osteoporotic rats. In contrast to raloxifene, HMR-3339 also influenced skeletal sites predominantly formed of cortical bone.