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

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.

Age-related osteoporosis is a major health problem affecting ~30% of post-menopausal women. It is caused by an imbalance between bone formation and bone resorption leading to net bone loss. Current medications do not directly address the underlying cause of the imbalance and there is 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 that due to glucocorticoid excess. We have shown that osteoblasts generate glucocorticoids through expression of the 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) enzyme. The expression/activity of 11b-HSD1 in osteoblasts increases dramatically with age and 11b-HSD1 activity reduces bone formation markers and increase bone resorption. We thus hypothesise that 11b-HSD1 is a mediator of age-related bone remodelling imbalance. Furthermore we propose that therapeutic inhibition of 11b-HSD1 activity 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 osteopaenia will be recruited at two specialist bone units. Subjects will be >55 and post-menopausal and consenting subjects will be randomised to either 400mg BD of AZD4017 or placebo for 3 months. Serum will be taken for biochemical markers of bone turnover; novel markers of glucocorticoids action on bone; HPA axis function, and measures of drug safety. Urine will be taken for measures of 11bHSD1 activity. Bone density will be measured by DXA and pQCT. Subjects will be seen regularly during treatment and 90 days after. This trial will clarify the contribution that 11bHSD1 activity makes to age-related abnormalities in bone remodelling. Furthermore it will clarify whether AZD4017 has the potential to reverse age-related bone disease as a treatment for post-menopausal osteoporosis.

Beneficiaries of this research and how they will benefit:

Individuals with osteoporosis:
This research programme has the potential to reduce morbidity and mortality in patients with osteoporosis and/or high fracture risk. Age-related osteoporosis is a major public health problem affecting ~30% of post-menopausal women. There are over 300,000 fragility fractures per year in the UK secondary to osteoporosis. On a global basis there are 9 million osteoporosis related fractures annually (data from 2000) of which 1.6 million are hip fractures. The number of hip fractures is expected to rise to 6.3 million by 2050. 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. Several classes of anti-osteoporosis medications have been developed over the last 3 decades. However, these all have significant limitations including uncertainty over their long-term safety and effectiveness (as highlighted recently by the FDA) and the general issue that they do not correct the underlying age-related abnormality in bone remodeling. This work addresses the hypothesis that age-related abnormalities of bone remodeling are due to an age-related increase in 11b-HSD1 activity within bone. If this proves to be the case there is an excellent prospect for AZD4017 to become an effective and widely used drug for osteoporosis, reducing the risk and burden of fractures. If the interim analysis supports a beneficial effect on bone a phase III study of 3 years duration will be considered. As such there is a prospect that this research will lead to an effective treatment within approximately 5 years of this work being funded.

Healthcare and social care service providers including the NHS:
In addition to the personal cost of osteoporotic fracture there is also a substantial economic cost associated with their treatment with the estimated annual direct cost of treating these fractures being over £2 billion. Direct costs of fracture treatment in Europe and the USA are estimated to be 36 billion Euros and $20 billion respectively. The social care cost of osteoporotic fracture has been estimated to be around twice the direct cost. As such osteoporosis is associated with a considerable economic cost that is predicted to rise sharply as the average age of the population increases. AZD4017 has the prospect to reduce this economic burden through prevention of osteoporotic fracture.

Industrial collaborators:
The global market for osteoporosis medications is estimated to be around $6.8 billion (estimates for 2009) and is predicted to continue to rise. Several previous osteoporosis medications have been billion dollar medications but their continuing role in the treatment of osteoporosis is becoming less certain. If the hypothesis being explored in this study (that AZD4017 can reverse the adverse features of skeletal ageing) is supported then this medication would have the potential to become a major treatment for age-related bone loss and fracture risk. No other treatment has been developed that appears to specifically correct the underlying pathophysiology associated with skeletal ageing.