OSTEOTROPIC DRUG-DELIVERY SYSTEM (ODDS) BASED ON BISPHOSPHONIC PRODRUG - IV - EFFECTS OF OSTEOTROPIC ESTRADIOL ON BONE-MINERAL DENSITY AND UTERINE WEIGHT IN OVARIECTOMIZED RATS

An osteotropic drug delivery system (ODDS) based on the bisphosphonic prodrug was designed for 17 beta-estradiol (E-2) in order to improve p atient compliance in estrogen replacement therapy of postmenopausal os teoporosis, The bisphosphonic prodrug of E-2, disodium [17 beta-(3'-hy droxy-1',3',5'-estratrienyloxy) carbonylpropyl carboxamidomethylene] b isphosphonate (E-2-BP) was synthesized and its effects on bone mineral density and uterine weight were investigated in ovariectomized (OVX) rats. E-2-BP was injected intravenously once a week (4 injections/expe riment), and E-2 was administrated orally 5 times a week (20 administr ations/experiment). Once a week treatment with 0.1 mg/kg E-2-BP signif icantly restored bone mineral reduction by 61.8% without significantly increasing uterine weight, Similarly, once in 4 weeks treatment with 1.0 mg/kg E-2-BP (1 injection/experiment) showed almost the same thera peutic effects, On the other hand, 5 times a week oral treatment with 1.0 mg/kg E-2 significantly improved bone mineral density by 90.5%, bu t increased uterine weight up to 98.2% of that of the sham group. In v itro bone resorption analysis revealed that E-2-BP exhibits antiresorp tive activity not as a bisphosphonate but as a prodrug of E-2. These r esults demonstrated that E-2-BP has the potential to improve patient c ompliance in estrogen therapy by its minimal adverse effects and less frequent medication.