Effect of AZD4017, a selective 11 beta-HSD1 inhibitor, on bone turnover markers in post-menopausal osteopenia

Context The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. We hypothesized that local 11 beta-HSD1 might mediate an age-related decrease in bone formation and that selective 11 beta-HSD1 inhibition may enhance bone formation. Methods A twin-centre phase II randomized, double-blind, placebo-controlled trial of 90 days' treatment with AZD4017 (a selective 11 beta-HSD1 inhibitor) was conducted. 55 post-menopausal women with osteopenia were recruited. Participants received 400mg twice daily of oral AZD4017 compared to matched placebo over 90 days. The primary outcome measure was the impact on the bone formation marker, osteocalcin. Secondary objectives included correlation with 11 beta-HSD1 activity. Results At 90 days the levels of osteocalcin did not differ between the treatment groups, active [mean 22.3 (SD 8.6) ng/ml, n=22] and placebo [21.7 (SD 9.2) ng/ml, n=24], with an adjusted for baseline treatment effect of 0.95 (95% CI: -2.69, 4.60). The results from the urinary [THF+alloTHF]/THE ratio (index of 11 beta-Fispi activity) and the urinary cortisol/cortisone ratio (index of 11 beta-HSD2 activity), confirmed a >90% inhibition of 11 beta-HSD1 but no change in activity of 1113-HSD2. Conclusion This trial demonstrates that AZD 4017 selectively inhibits 11 beta-HSD1 activity in vivo in a safe and reversible manner. Following treatment for 90 days there is no effect on bone formation, indicating that the relative impairment of bone mineral density in post-menopausal women is not mediated by local intracellular production of cortisol, under normal physiological concentrations.