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30万例骨质疏松症导致的骨折，修复这些骨折的费用超过20亿英镑。在个体层面上，20-30%的髋部骨折患者将在12个月内死亡，这是骨折的直接后果，50%以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的协调变化引起的。这些细胞移除一些骨头，然后用新形成的骨头取而代之。与年龄相关的骨质疏松症是由骨质形成量和吸收量之间的不平衡导致净骨质流失引起的。虽然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，特别是那些纠正与年龄相关的骨转换异常的药物。与年龄相关的骨质流失与糖皮质激素（抗炎类固醇）水平过高引起的骨病有相似之处。然而，血液循环中的糖皮质激素水平不会随着年龄的增长而改变。在一系列研究中，我们发现骨形成细胞本身通过表达11b-羟基类固醇脱氢酶1型（11b-HSD1）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，这似乎导致骨形成量减少，骨被吸收和丢失的量增加。因此，我们认为11b-HSD1及其在骨骼中产生的糖皮质激素是导致与年龄相关的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。我们的假设将在选择性11b-HSD1抑制剂AZD4017或安慰剂用于骨量减少女性的临床试验中得到检验。骨密度低的妇女将被招募到两个专门的骨骼单位。受试者年龄在55岁以上，处于绝经期。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。将取血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。其他血液和尿液测试将确定与安慰剂相比，该药是否有任何负面影响，从而确定该药是否完全安全。这项试验将阐明11bHSD1活性对骨骼年龄相关异常的影响。此外，它将阐明AZD4017是否有潜力逆转与年龄相关的骨病，作为绝经后骨质疏松症的治疗方法。如果AZD4017对骨骼有我们所怀疑的有益作用，那么就有可能在女性身上进行更大规模的更长时间的药物试验，以确定该药物是否能预防骨折并提高整体生活质量。

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.