Effect of 17beta-hydroxysteroid dehydrogenase type 2 inhibitor on bone strength in ovariectomized cynomolgus monkeys.
In both sexes, a reduction in sex steroid production with aging impairs the musculoskeletal system. The goal of our study was to test the ability of WH-9062, a novel non-steroidal small molecule inhibitor of the 17beta-Hydroxysteroid Dehydrogenase type 2 enzyme, to maintain or improve bone strength without raising serum levels of testosterone or estradiol. Mature, female cynomolgus monkeys with sealed growth plates were allocated into six groups: Sham controls, OVX controls, OVX+Premarin (15 mg/kg/d), and three groups of OVX monkeys receiving WH-9062 at 1, 5 and 25 mg/kg/day. All treatments were administered by daily oral dosing for 23 weeks. Changes in lipid profile caused by OVX were corrected with WH-9062 and included lowering total of cholesterol and non-HDL cholesterol, and maintenance of initial plasma levels of HDL cholesterol. Only the highest dose of WH-9062 lowered bone resorption relative to OVX controls. Elevated bone specific alkaline phosphatase, osteocalcin, BMC and dynamic bone histomorphometry data resulted in desirable bone balance and bone strength. The obtained results support our theory that inhibition of 17beta-HSD type 2 resulted in high local estrogen and/or testosterone levels leading to maintenance of bone formation and bone strength. Collectively, our data demonstrated that the treatment paradigm that utilizes tissue selectivity and receptor bioavailability in conversion of inactive hormones to active forms could be achieved and could result in desirable effects on target tissues such as bone and muscles.
Bagi
C M
CM
PGRD, Pfizer, Inc., Groton, CT 06340, USA. cedo.bagi@pfizer.com
Wood
J
J
Wilkie
D
D
Dixon
B
B
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D008252:Macaca fascicularis; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D013718:Tensile Strength / Q000187:drug effects*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
C540795:5-(15-hydroxy(5-(3-pyridyl)(2-thienyl))methyl)-1-methyl-4-phenylpyrrolidin-2-one; D004791:Enzyme Inhibitors; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D011760:Pyrrolidinones; D013876:Thiophenes; D015675:Osteocalcin; D015067:17-Hydroxysteroid Dehydrogenases; D000469:Alkaline Phosphatase