Bone Selective Protective Effect of a Novel Bone-seeking Estrogen on Trabecular Bone in Ovariectomized Rats

The drawbacks of estrogen restrict the clinical use of hormone replacement therapy, and it would be most helpful to explore new estrogenic substances that could prevent bone loss and be free from any adverse effects. We synthesized a new compound named bone-seeking estrogen (SE(2)) by combining 17β-estradiol (E(2)) with iminodiacetic acid through the Mannich reaction. E(2) and SE(2) were labeled with isotope (3)H, and the tissue distribution tests of E(2)-(3)H and SE(2)-(3)H were analyzed by the radioactivity. The specific nuclear binding of E(2) and SE(2) in osteoblasts was measured. SE(2) exhibited significantly greater affinity for bone but lower affinity for ovary and uterus than did E(2), and SE(2) maintained a high affinity for the estrogen receptor alpha similar to that of E(2). SE(2) administration did not induce uterine hypertrophy. Body weight increase was significantly suppressed by treatment with E(2) but not by SE(2) after ovariectomy (OVX). SE(2) decreased bone turnover as E(2) after OVX detected by serum biochemical markers. Bone histology and micro-CT analysis revealed that SE(2) administration, similar to E(2), could improve bone mass and trabecular architecture after OVX. Biomechanical analyses showed that SE(2) treatment effectively increased mechanical properties after OVX. The results suggested that SE(2) was effective in preventing OVX-induced bone loss and exhibited few side effects on body weight and uterine hypertrophy, which was beneficial in reducing the adverse effects caused by E(2). SE(2) may be a better choice than E(2) for the prevention of postmenopausal osteoporosis.