Effect of AZD4017, a Selective 11[beta]-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal 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), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. Obj...

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Published in:The journal of clinical endocrinology and metabolism 2022-07, Vol.107 (7), p.2026
Main Authors: Abbas, Afroze, Schini, Marian, Ainsworth, Gemma, Brown, Sarah R, Oughton, Jamie, Crowley, Rachel K, Cooper, Mark S, Fairclough, Rebecca J, Eastell, Richard, Stewart, Paul M
Format: Article
Language:English
Subjects:
Bones
Corticosteroids
Creatine kinase
Denosumab
Density
Osteoporosis
Patient compliance
Physiological aspects
Postmenopausal women
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Summary:Context: The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11 [beta]-hydroxysteroid dehydrogenase type 1 (11 [beta]-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. Objective: 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 dual-center, phase II, randomized, double-blind, placebo-controlled trial of 90 days' treatment with AZD4017 (a selective 11 [beta]-HSD1 nhibitor) was conducted in 55 postmenopausal women with osteopenia. Participants received 400 mg oral AZD4017 twice daily vs 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, osteocalcin levels did not differ between 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 a baseline-adjusted treatment effect of 0.95 (95% Cl: -2.69, 4.60). The results from the urinary [THF + alloTHF]/THE ratio (index of 11[beta]-HSD1 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 11[beta]-HSD2. Conclusion: This trial demonstrates that AZD4017 selectively inhibits 11[beta]-HSD1 activity in vivo in a safe and reversible manner. Following 90 days of treatment, there is no effect on bone formation, indicating that the relative impairment of bone mineral density in postmenopausa women is not mediated by local intracellular production of cortisol under normal physiological concentrations. Key Words: osteopenia, osteocalcin, 11[beta]-HSD1, glucocorticoids, AZD4017 Abbreviations: 11[beta]-HSD, 11[beta]-hydroxysteroid dehydrogenase; 25(OH)D, 25-hydroxyvitamin D; alloTHF, allotetrahydrocortisol; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BAP, bone alkaline phosphate; BMD, bone mineral density; CK, creatine kinase; CTX, C-terminal cross-linked telopeptide; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; MR, mineralocorticoid receptor; PINP, procollagen I intact N-terminal propeptide; RANKL, receptor activator of nuclear factor-KB ligand; RR, relative rate; THE, tetrahydrocortisone; THF, tetrahydrocortisol; ULN, u
ISSN:0021-972X
DOI:10.1210/clinem/dgac100