Effect of AZD4017, a Selective 11β-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal Osteopenia.
Effect of AZD4017, a Selective 11β-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal Osteopenia.
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AZD4017（一种选择性11β-HSD1抑制剂）对绝经后骨质减少症的骨转换标记的影响。
DOI：
10.1210/clinem/dgac100
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发表时间：
2022-06-16
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影响因子：
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循环糖皮质激素过量和骨质疏松症之间的因果关系是公认的。增加局部皮质醇产生的酶11 β-羟基类固醇脱氢酶1型（11 β-HSD1）在人成骨细胞中表达，其活性随年龄增加而增加。我们假设局部11 β-HSD1可能介导年龄相关的骨形成减少，选择性11 β-HSD1抑制可能增强骨形成。在55名绝经后骨质减少女性中开展了一项为期90天的AZD 4017（一种选择性11 β-HSD1抑制剂）治疗的双中心、II期、随机、双盲、安慰剂对照试验。受试者在90天内接受400 mg口服AZD 4017，每日两次，与匹配的安慰剂相比。主要结果测量是对骨形成标志物骨钙素的影响。次要目的包括与11 β-HSD1活性的相关性。在90天时，治疗组之间的骨钙素水平没有差异：活性药物组（平均22.3 [SD 8.6] ng/mL，n = 22）和安慰剂组（21.7 [SD 9.2] ng/mL，n = 24），基线校正的治疗效应为0.95（95% CI：-2.69，4.60）。 尿[THF + alloTHF]/THE比值（11 β-HSD1活性指数）和尿皮质醇/可的松比值（11 β-HSD2活性指数）的结果证实11 β-HSD1抑制> 90%，但11 β-HSD2活性无变化。 该试验证明，AZD 4017在体内以安全和可逆的方式选择性抑制11 β-HSD1活性。治疗90天后，对骨形成没有影响，表明绝经后妇女骨密度的相对损害不是由正常生理浓度下皮质醇的局部细胞内产生介导的。
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. 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. 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. 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. 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.
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影响因子：
7.3
作者：
Hardy, Rowan S.;Doig, Craig L.;Hussain, Zahrah;O'Leary, Mary;Morgan, Stuart A.;Pearson, Mark J.;Naylor, Amy;Jones, Simon W.;Filer, Andrew;Stewart, Paul M.;Buckley, Christopher D.;Lavery, Gareth G.;Cooper, Mark S.;Raza, Karim
通讯作者：
Raza, Karim
影响因子：
5.4
作者：
Han Y;Zhang L;Xing Y;Zhang L;Chen X;Tang P;Chen Z
通讯作者：
Chen Z
影响因子：
4.3
作者：
MORRISON, D;CAPEWELL, S;RIADFAHMY, D
通讯作者：
RIADFAHMY, D
影响因子：
5.8
作者：
Nieman, Lynnette K.;Biller, Beverly M. K.;Tabarin, Antoine
通讯作者：
Tabarin, Antoine
影响因子：
16.2
作者：
Rosenstock, Julio;Banarer, Salomon;Huber, Reid
通讯作者：
Huber, Reid