Effect of AZD4017, a Selective 11ß-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal Osteopenia.
J Clin Endocrinol Metab
; 107(7): 2026-2035, 2022 06 16.
Article
en En
| MEDLINE
| ID: mdl-35275196
ABSTRACT
CONTEXT The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. OBJECTIVE:
We hypothesized that local 11ß-HSD1 might mediate an age-related decrease in bone formation and that selective 11ß-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 11ß-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 11ß-HSD1 activity.RESULTS:
At 90 days, osteocalcin levels did not differ between treatment groups active (mean 22.3 [SD 8.6] ng/mL, nâ =â 22) and placebo (21.7 [SD 9.2] ng/mL, nâ =â 24), with a baseline-adjusted treatment effect of 0.95 (95% CI -2.69, 4.60). The results from the urinary [THFâ +â alloTHF]/THE ratio (index of 11ß-HSD1 activity) and the urinary cortisol/cortisone ratio (index of 11ß-HSD2 activity) confirmed a > 90% inhibition of 11ß-HSD1 but no change in activity of 11ß-HSD2.CONCLUSION:
This trial demonstrates that AZD4017 selectively inhibits 11ß-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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Enfermedades Óseas Metabólicas
/
Niacinamida
/
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1
Tipo de estudio:
Clinical_trials
Límite:
Female
/
Humans
Idioma:
En
Revista:
J Clin Endocrinol Metab
Año:
2022
Tipo del documento:
Article
País de afiliación:
Reino Unido