Determining the contribution of the aromatisation of testosterone to estradiol within bone for maintaining skeletal integrity and bone strength.
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Osteoporosis is an extremely common condition affecting over 1 million Australians that causes bones to become fragile and weak. Osteoporosis is highly debilitating, resulting in a high risk of fracture, moderate to severe pain and significant psychological distress. 1 in 5 Australians over the age of 75 have osteoporosis inferring most Australians are likely to be impacted by this disease either directly or indirectly. Whilst there are treatments for osteoporosis currently available that prevent further bone loss with some also stimulating the formation of new bone, they are not without their limitations and side-effects. Additionally, the therapeutic pipeline for osteoporosis is languishing with the most recent available drug taking nearly 20 years to come to market in 2019. Since bone fractures are associated with an increased risk of suffering and death, it is imperative that new improved therapies for osteoporosis are identified.
Sex hormones (ie. estradiol and testosterone) are essential for bone growth during puberty, as well as for maintaining bone strength in adulthood in males and females. The importance of sex hormones for healthy bones in adults is clearly illustrated by the bone loss that occurs at the menopause in women, or with hypogonadism in men, with 1 in 3 women and 1 in 5 men over the age of 50 worldwide suffering an osteoporotic fracture. Estradiol, although at low circulating concentrations in men, is essential for their bone health. Estradiol levels within bone are derived from the circulation by diffusion or can be synthesised locally within bone from the conversion of testosterone to estradiol by the enzyme, aromatase. We hypothesise that it is the local production of estradiol within bone by aromatase that is crucial for maintaining the integrity and strength of the skeleton in both males and females. Our aim is to determine the importance of the local synthesis of estradiol within bone to regulate its structure and strength during both growth and adulthood in males and females. If aromatase is shown to be critical for bone health this offers a significant novel therapeutic target which will facilitate the design of unique drugs that target the local production of estradiol within bone, whilst avoiding side-effects in other tissues. Such a therapy could be used to prevent osteoporotic fractures in both men and women.
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