title: A new synthetic steroid, osaterone acetate (TZP-4238), increases cortical bone mass and strength by enhancing bone formation in ovariectomized rats.
abstract: A new synthetic steroid, 17 alpha-acetoxy-chloro-2-oxa-4,6-pregnadiene-3,20-dione (osaterone acetate, TZP-4238), has a potent antiandrogenic and gestagenic action with virtually no estrogenic and androgenic activity in their classical target organs. In the present study, the effects of TZP-4238 on the structure, strength, and turnover of the rat long bones were examined. Female Wistar rats at 12 weeks of age were ovariectomized (OVX) and treated with TZP-4238 or 17 beta-estradiol (E2) every day for 12 weeks. TZP-4238 significantly increased the diameters and maintained bone mineral density (BMD) of the femur of OVX rats. Although the BMD of the total femur was higher in E2-treated rats than that in TZP-treated rats, E2 did not increase the diameters of the femurs. To examine the effects of TZP-4238 and E2 on the BMD of different regions of the femur, the BMD was further analyzed by dividing it into 20 regions of equal longitudinal length. E2 increased the BMD of the distal and proximal metaphysis, regions rich in trabecular bone, but had no effect on the BMD of the femoral diaphysis compared with OVX control rats. In contrast, 2.5 and 12.5 mg/kg TZP-4238 increased the BMD of the femoral diaphysis, regions rich in cortical bone, but did not affect the BMD at the distal metaphysis. In agreement with the changes in the BMD of different regions of the femur, TZP-4238 but not E2 increased the physical strength of the femoral diaphysis assessed by a three-point bending test. Histomorphometric analyses of the cross-sections of the tibia revealed that TZP-4238 increased but E2 reduced the periosteal bone formation rate compared with OVX rats. In addition, TZP-4238 caused an increase in serum bone alkaline phosphatase with only a mild and transient decrease in urinary deoxypyridinoline excretion, while E2 reduced both of these parameters. These results demonstrate that TZP-4238 increases the dimension, BMD, and physical strength of the rat long bones by enhancing cortical bone formation, while estrogen maintains trabecular BMD by inhibiting bone resorption. Because the physical strength of long bones is affected by cortical bone mass and geometry, the effect of TZP-4238 on cortical bone may have a potential for the treatment of osteoporosis with reduced cortical bone formation.
authors.affiliation: Teikoku Hormone Manufacturing Co., Kanagawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fuse
authors.forename: S
authors.initials: S
authors.lastname: Fukumoto
authors.forename: H
authors.initials: H
authors.lastname: Sone
authors.forename: Y
authors.initials: Y
authors.lastname: Miyata
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Nakayama
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: E
authors.initials: E
authors.lastname: Ogata
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D002715:Chlormadinone Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005269:Femur; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D010710:Phosphates / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia
chemical_list: D000726:Androgen Antagonists; D010710:Phosphates; D002715:Chlormadinone Acetate; D004958:Estradiol; C069297:osaterone acetate; D002118:Calcium