title: Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. I.v. effects of osteotropic estradiol on bone mineral density and uterine weight in ovariectomized rats.
abstract: An osteotropic drug delivery system (ODDS) based on the bisphosphonic prodrug was designed for 17beta-estradiol (E2) in order to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The bisphosphonic prodrug of E2, disodium [17beta-(3 '-hydroxy- 1',3',5'-estratrienyloxy) carbonylpropyl carboxamidomethylene] bisphosphonate (E2-BP) was synthesized and its effects on bone mineral density and uterine weight were investigated in ovariectomized (OVX) rats. E2-BP was injected intravenously once a week (4 injections/experiment), and E2 was administrated orally 5 times a week (20 administrations/experiment). Once a week treatment with 0.1 mg/kg E2-BP significantly restored bone mineral reduction by 61.8% without significantly increasing uterine weight. Similarly, once in 4 weeks treatment with 1.0 mg/kg E2-BP (1 injection/experiment) showed almost the same therapeutic effects. On the other hand, 5 times a week oral treatment with 1.0 mg/kg E2 significantly improved bone mineral density by 90.5%, but increased uterine weight up to 98.2% of that of the sham group. In vitro bone resorption analysis revealed that E2-BP exhibits antiresorptive activity not as a bisphosphonate but as a prodrug of E2. These results demonstrated that E2-BP has the potential to improve patient compliance in estrogen therapy by its minimal adverse effects and less frequent medication.
authors.affiliation: Pharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company Ltd., Osaka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Fujisaki
authors.forename: Y
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: F
authors.initials: F
authors.lastname: Shimojo
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Hata
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D007275:Injections, Intravenous; D009929:Organ Size / Q000187:drug effects; D010024:Osteoporosis / Q000517:prevention & control; D010052:Ovariectomy; D011355:Prodrugs / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects*
chemical_list: D004164:Diphosphonates; D011355:Prodrugs; D004958:Estradiol