MICA: Phase II study of the impact of AZD4017 a selective 11beta-HSD1 inhibitor on biochemical markers of bone turnover in post-menopausal osteopaenia

MICA：选择性 11β-HSD1 抑制剂 AZD4017 对绝经后骨质疏松症骨转换生化标志物影响的 II 期研究

• 批准号: MR/K015176/1
• 负责人: Paul Stewart
• 金额: $ 39.86万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK015176%2F1
• 关键词: MICA; Phase; II; study; impact

Age-related osteoporosis is a major health problem affecting ~30% of post-menopausal women. There are over 300,000 bone fractures per year in the UK secondary to osteoporosis and the cost of repairing these fractures is over £2 billion. On an individual level 20-30% of people who sustain a hip fracture will die within 12 months as a direct consequence of the fracture and 50% of previously independent individuals cannot live independently subsequently. Osteoporosis is caused by changes in the coordination of the activity of cells within bone. These cells remove some bone and then replace it with newly formed bone. Age-related osteoporosis is caused by an imbalance between the amount of bone formed and the amount resorbed leading to net bone loss. Although some medications are available to help reduce the risk of fracture in people with osteoporosis, current medications do not directly address the underlying cause of the imbalance in cellular activity. There is thus a need for additional medications to reduce fracture risk, particularly those that correct the age-related abnormality in bone turnover. Age-related bone loss shares similarities with the bone disease caused by excess levels of glucocorticoids (anti-inflammatory steroids). However, the level of glucocorticoids in the circulation does not change as we get older. In a series of research studies we have shown that the bone forming cells themselves generate glucocorticoids through expression of an enzyme caused 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). The ability of this enzyme to produce glucocorticoids in bone forming cells increases dramatically with age and this appears to lead to a reduced amount of bone formation and an increased amount of bone to be resorbed and lost. We thus believe that 11b-HSD1, and the glucocorticoids that it generates within bone, is a major cause of age-related bone loss. Furthermore we propose that drugs that switch off this enzyme will have a dramatic effect on bone, effectively reversing changes seen with age.Our hypothesis will be examined in a clinical trial of a selective 11b-HSD1 inhibitor, AZD4017, or placebo in women with reduced bone mass. Women with low bone density will be recruited at two specialist bone units. Subjects will be over 55 years of age and be post-menopausal. They will all give informed consent and then be randomised to treatment with either AZD4017 or a matched placebo for 3 months. Blood will be taken to measure the effect of the drug on markers of bone formation and resorption. Scans will measure the impact of the treatment on the density of the bones. Other blood and urine tests will determine whether there are any negative effects of the drug compared to placebo and so will determine whether this drug is entirely safe. This trial will clarify the contribution that 11bHSD1 activity makes to age-related abnormalities in bone. Furthermore it will clarify whether AZD4017 has the potential to reverse age-related bone disease as a treatment for post-menopausal osteoporosis. If AZD4017 has the beneficial effects on bone that we suspect it will have, then it will be possible to move to a much larger trial of the drug in women for a longer period of time to determine whether the drug prevents fractures and improves quality of life overall.

绝经相关的骨质疏松症是影响约30%绝经后妇女的主要健康问题。英国每年有超过30万例继发于骨质疏松症的骨折，修复这些骨折的费用超过20亿英镑。在个人层面上，20-30%的髋部骨折患者将在12个月内死亡，50%的先前独立的个体随后无法独立生活。骨质疏松症是由骨内细胞活动协调的变化引起的。这些细胞去除一些骨，然后用新形成的骨代替它。骨质疏松症是由骨形成量和骨吸收量之间的不平衡引起的，导致净骨丢失。虽然有些药物可以帮助降低骨质疏松症患者骨折的风险，但目前的药物并不能直接解决细胞活动不平衡的根本原因。因此，需要额外的药物来降低骨折风险，特别是那些纠正骨转换中与年龄相关的异常的药物。骨质疏松相关的骨丢失与糖皮质激素（抗炎类固醇）过量引起的骨病有相似之处。然而，循环中的糖皮质激素水平不会随着年龄的增长而改变。在一系列的研究中，我们已经表明，骨形成细胞本身通过表达引起11b-羟基类固醇脱氢酶1型（11b-HSD 1）的酶来产生糖皮质激素。这种酶在骨形成细胞中产生糖皮质激素的能力随着年龄的增长而显著增加，这似乎导致骨形成量减少和骨吸收和丢失量增加。因此，我们认为11b-HSD 1及其在骨内产生的糖皮质激素是年龄相关性骨质流失的主要原因。此外，我们提出，关闭这种酶的药物将对骨骼产生巨大的影响，有效地逆转随着年龄的增长而发生的变化。我们的假设将在一项选择性11b-HSD 1抑制剂AZD 4017或安慰剂在骨量减少的女性中的临床试验中进行检验。骨密度低的妇女将在两个专门的骨单位招募。受试者年龄超过55岁且已绝经。他们都将提供知情同意书，然后随机接受AZD 4017或匹配的安慰剂治疗3个月。将采集血液以测量药物对骨形成和骨吸收标志物的影响。扫描将测量治疗对骨骼密度的影响。其他血液和尿液检查将确定与安慰剂相比药物是否有任何负面影响，从而确定这种药物是否完全安全。这项试验将阐明11bHSD 1活性对骨骼年龄相关异常的贡献。此外，本研究还将阐明AZD 4017作为绝经后骨质疏松症的治疗药物是否具有逆转年龄相关性骨病的潜力。如果AZD 4017对骨骼有我们怀疑的有益作用，那么就有可能在女性中进行更长时间的更大规模的药物试验，以确定该药物是否能预防骨折并改善整体生活质量。

项目成果

Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer.

米托坦治疗的肾上腺皮质癌患者的速释氢化可的松与改良释放氢化可的松。

• DOI: 10.1111/cen.13302
• 发表时间: 2017
• 期刊: Clinical endocrinology
• 影响因子: 3.2
• 作者: Weigel M

The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy.

• DOI: 10.1186/s12902-020-00633-1
• 发表时间: 2020-10-10
• 期刊: BMC endocrine disorders
• 影响因子: 2.7
• 作者: Dineen R;Behan LA;Kelleher G;Hannon MJ;Brady JJ;Rogers B;Keevil BG;Tormey W;Smith D;Thompson CJ;McKenna MJ;Arlt W;Stewart PM;Agha A;Sherlock M
• 通讯作者: Sherlock M

High throughput LC-MS/MS method for the simultaneous analysis of multiple vitamin D analytes in serum.

• DOI: 10.1016/j.jchromb.2016.01.049
• 发表时间: 2016-03-01
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Jenkinson C;Taylor AE;Hassan-Smith ZK;Adams JS;Stewart PM;Hewison M;Keevil BG
• 通讯作者: Keevil BG