Suppression of Bone Resorption in Ovariectomized Mice Using Estrogen-Immobilized Polyphosphodiesters

Estrogens play a crucial role in bone remodeling. In this study, we synthesized two types of bone-targeted polyphosphodiesters (PPDEs): poly(diethyl sodium phosphate) (PEP center dot Na) and beta-estradiol 17-valerate terminated PEP center dot Na (E 2 V-PEP center dot Na), and determined the inhibitory effect of the terminal estrogen on ovariectomyinduced bone resorption. We first assessed the impact of these polymers on the differentiation of osteoblasts and osteoclasts in vitro. Both PPDEs effectively promoted the differentiation of mouse osteoblastic MC3T3-E1 cells, with E 2 V-PEP center dot Na significantly enhancing the mineralization of these cells. Conversely, the density of osteoclasts formed from bone marrow mononuclear cells (BMNCs) significantly decreased when exposed to E 2 V- PEP center dot Na. Additionally, the formation of resorption pits on calcium phosphate-coated plates was reduced after treating BMNCs with both PPDEs. We then investigated the role of these polymers in treating osteoporosis using ovariectomized (OVX) mice. PEP center dot Na or E 2 V-PEP center dot Na was separately injected into the tail vein of the mice three times at 2 -week intervals, starting 1 day after OVX treatment. Two weeks after the final injection, we observed that E 2 V-PEP center dot Na was distributed in bone tissue in a dose-dependent manner. The injection of E 2 V-PEP center dot Na significantly reduced bone resorption, and all bone parameters of OVX mice treated with E 2 V-PEP center dot Na were superior to those of sham mice. In contrast, PEP center dot Na did not affect bone mineral metabolism. In conclusion, our study is the first to demonstrate that E 2 V-PEP center dot Na can inhibit bone resorption in vivo, offering a promising new polymeric drug for preventing osteoporosis.