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.