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

年龄相关性骨质疏松症是影响约30%绝经后妇女的主要健康问题。在英国，每年有超过30万例继发于骨质疏松的骨折，修复这些骨折的费用超过20亿GB。在个人层面上，20-30%的髋部骨折患者将在12个月内死于骨折的直接后果，50%以前独立的人随后无法独立生活。骨质疏松症是由骨骼内细胞活动的协调性改变引起的。这些细胞移除一些骨骼，然后用新形成的骨骼取代它。与年龄相关的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。尽管有一些药物可以帮助降低骨质疏松症患者骨折的风险，但目前的药物并没有直接解决细胞活动不平衡的根本原因。因此，需要更多的药物来降低骨折风险，特别是那些纠正与年龄相关的骨转换异常的药物。与年龄相关的骨丢失与糖皮质激素(抗炎类固醇)水平过高引起的骨病相似。然而，循环中的糖皮质激素水平并不会随着年龄的增长而变化。在一系列研究中，我们已经证明，骨形成细胞本身通过表达11b-羟基类固醇脱氢酶1(11b-HSD1)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急剧增加，这似乎会导致骨形成量减少，而被吸收和丢失的骨量增加。因此，我们认为11b-HSD1及其在骨骼中产生的糖皮质激素是与年龄相关的骨丢失的主要原因。此外，我们建议关闭这种酶的药物将对骨骼产生戏剧性的影响，有效地逆转随年龄增长而出现的变化。我们的假设将在选择性11b-HSD1抑制剂AZD4017或安慰剂在骨量减少的女性中的临床试验中得到验证。骨密度低的女性将被招募到两个骨科专科。受试者将超过55岁，并处于绝经后。他们都将给予知情同意，然后随机接受AZD4017或匹配的安慰剂治疗3个月。将抽取血液来测量该药物对骨形成和吸收标志物的影响。扫描将测量治疗对骨骼密度的影响。其他血液和尿液测试将确定该药物与安慰剂相比是否有任何负面影响，因此将确定该药物是否完全安全。这项试验将阐明11bHSD1活性在骨骼中与年龄相关的异常中的作用。此外，它还将阐明AZD4017是否具有逆转年龄相关性骨病作为治疗绝经后骨质疏松症的潜力。如果AZD4017对骨骼有我们怀疑的有益效果，那么就有可能在更长一段时间内对该药物进行更大规模的女性试验，以确定该药物是否能防止骨折并改善整体生活质量。

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.