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

• Published in: Journal of drug targeting Vol. 5; no. 2; p. 129
• Main Authors: Fujisaki, J, Tokunaga, Y, Takahashi, T, Shimojo, F, Kimura, S, Hata, T
• Format: Journal Article
• Language: English
• Published: England 1998
• Subjects: Animals; Bone Density - drug effects; Diphosphonates - administration & dosage; Disease Models, Animal; Estradiol - administration & dosage; Estradiol - pharmacology; Estrogen Replacement Therapy; Female; Injections, Intravenous; Organ Size - drug effects; Osteoporosis - prevention & control; Ovariectomy; Prodrugs - administration & dosage; Rats; Rats, Wistar; Uterus - drug effects
• ISSN: 1061-186X
• DOI: 10.3109/10611869808995866

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.