Abbas, A., Schini, M. orcid.org/0000-0003-2204-2095, Ainsworth, G. et al. (7 more authors) (2022) Effect of AZD4017, a selective 11β-HSD1 inhibitor, on bone turnover markers in postmenopausal osteopenia. Journal of Clinical Endocrinology and Metabolism, 107 (7). pp. 2026-2035. ISSN 0021-972X
Abstract
Context
The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age.
Objective
We hypothesized that local 11β-HSD1 might mediate an age-related decrease in bone formation and that selective 11β-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 11β-HSD1 inhibitor) 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 11β-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% CI: −2.69, 4.60). The results from the urinary [THF + alloTHF]/THE ratio (index of 11β-HSD1 activity) and the urinary cortisol/cortisone ratio (index of 11β-HSD2 activity) confirmed a > 90% inhibition of 11β-HSD1 but no change in activity of 11β-HSD2.
Conclusion
This trial demonstrates that AZD4017 selectively inhibits 11β-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 postmenopausal women is not mediated by local intracellular production of cortisol under normal physiological concentrations.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | osteopenia; osteocalcin; 11β-HSD1; glucocorticoids; AZD4017 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 May 2022 12:03 |
Last Modified: | 03 Feb 2023 11:09 |
Status: | Published |
Publisher: | The Endocrine Society |
Refereed: | Yes |
Identification Number: | 10.1210/clinem/dgac100 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:186415 |