GENETIC PREDICTION OF FRACTURE IN A RISK-STRATIFIED POPULATION
Funder
National Health and Medical Research Council
Funding Amount
$363,000.00
Summary
Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14-year) Dubbo Osteoporosis Epidemiology Study, more than half of indivi ....Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14-year) Dubbo Osteoporosis Epidemiology Study, more than half of individuals with osteoporosis (e.g., low BMD) did not sustain a fracture, while approximately 60% of fracture cases had BMD above the high risk levels. Thus, BMD alone is not a good discriminant of fracture versus non-fracture cases. It is widely known that the liability to fracture is determined in part by genes. Previous studies, including from our group, have suggested a number of candidate genes that are associated with fracture risk. The fundamental issue that this study is concerned is that how and whether genetic markers could be used to facilitate case finding. It is proposed that common variations of certain genes are associated with fracture risk independent of BMD. That is, they can identify individuals at relatively high and low fracture risk after stratification for BMD. Hence, some markers may identify those individuals likely (and unlikely) to fracture even with low (osteoporotic) BMD. Similarly, some, possibly the same, markers may identify individuals at high risk of fracture despite relatively good (ie non-osteoporotic) BMD. It is further proposed that no single gene will achieve this outcome, but rather a small set of such gene polymorphisms will provide clinically useful risk information. This effect is entirely analogous to the use of clinical risk indicators (eg, age, weight, sex, family history, etc) to assess the risk of future fracture.Read moreRead less
Myeloma Plasma Cell Dormancy - 'Eradicating The Sleeping Giant'
Funder
National Health and Medical Research Council
Funding Amount
$834,428.00
Summary
Multiple myeloma is a fatal cancer that develops in the skeleton. Current therapies are initially effective, but patients develop resistance and the disease returns. This makes the search for drugs to overcome resistance a priority. Myeloma cells can hide in bone in a dormant state where they are insensitive to chemotherapy. We have identified new drug targets in dormant cells. We are investigating whether these new targets can be used eradicate myeloma cells and cure the disease.
Osteoporosis is a major and increasing public health problem. Fracture, the ultimate consequence of osteoporosis is associated with significant morbidity, mortality and economic costs. The Dubbo Osteoporosis Epidemiology Study, starting in 1989, with over 2000 women and men, is one of the longest running epidemiological studies in osteoporosis worldwide. It has been at the forefront of epidemiological advances in osteoporosis. It has identified osteoporotic fracture risks including low bone dens ....Osteoporosis is a major and increasing public health problem. Fracture, the ultimate consequence of osteoporosis is associated with significant morbidity, mortality and economic costs. The Dubbo Osteoporosis Epidemiology Study, starting in 1989, with over 2000 women and men, is one of the longest running epidemiological studies in osteoporosis worldwide. It has been at the forefront of epidemiological advances in osteoporosis. It has identified osteoporotic fracture risks including low bone density and bone loss, muscle weakness and postural instability, as well as the extent of the problem in men, and the significant costs, ill-heath and mortality associated with fracture. Despite the clarification of risk factors over the past decade, there are significant gaps in knowledge about osteoporosis, particularly in the accurate prediction of fracture risk and in identification of factors related to fracture-associated mortality and survival post fracture. Although bone density is one of the best predictors of fracture risk, it incompletely discriminates between those who will fracture from those who will not. Although a number of clinical risk factors, and other measures of bone strength, such as quantitative ultrasound and geometry, have been shown to be independent predictors of fracture risk, it is not clear that these measures can be integrated with BMD to improve fracture prediction. The aim of the current study, is to develop and validate models using bone density, other measures of bone strength and clinical parameters that will more accurately predict fracture risk and mortality following fracture in older men and women. The more precise identification of those at high risk of fracture and at risk for poor outcomes following fracture will provide a rational basis for the development of more cost effective interventions for prevention of fracture and its associated morbidity and mortality.Read moreRead less
This study aims to elucidate central pathways which can be manipulated to drive the storage of excess energy away from fat and instead directing it into the production of bone mass. Having identified leptin-responsive NPY neurons as important in the control of energy partitioning, we will focus on manipulating these neurons in the hypothalamus using innovative technology to alter body composition. This research has the potential to result in novel treatments for obesity and osteoporosis.
Role Of IGF Binding Protein-3 (IGFBP-3) And IGFBP-5 As Modulators Of Nuclear Hormone Signalling
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain ....The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain cells perform specialised functions. In test-tube experiments, IGFBP-3 and IGFBP-5 interact directly with the receptors that regulate the effects of these hormones. If the same thing happens inside the cell, IGFBP-3 and IGFBP-5 could change the way these receptors respond to signals from outside the cell. We will investigate what effect these IGFBPs have in living cells and in whole animals and how this may relate to human disease. If we are able to understand how IGFBP-3 and IGFBP-5 affect the way cells respond to vitamin A and D, then we may be able to develop new ways to treat certain human diseases.Read moreRead less
How Do Bone-active Drugs Increase Patient Survival?
Funder
National Health and Medical Research Council
Funding Amount
$613,952.00
Summary
Bisphosphonates are a class of drugs used to prevent bone destruction in diseases such as osteoporosis. Evidence is emerging that these drugs also act on cells outside the skeleton to have additional beneficial effects, for example prolonging patient survival. This project will identify the cells affected and the mechanisms involved. With this knowledge, these drugs could be used more effectively and in different ways for the prevention or treatment of cancer and chronic human illnesses.
Bone Marrow Macrophages: “Resident Evil” In The Establishment And Progression Of Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$570,585.00
Summary
Multiple myeloma (MM) is a cancer that develops within the bone marrow (BM). To date, which cells of the BM stroma are required for the support of MM growth remains unknown. Our preliminary data suggest BM resident macrophages, expressing CD169 and CX3CR1, are essential for MM growth. Using innovative and elegant animal models of MM, we will define the role of these macrophages in MM growth and determine if macrophage-targeted therapies can delay MM growth in the relapsed disease setting.
Whole Body Vibration For Osteoporosis: Shaking Up Our Treatment Options
Funder
National Health and Medical Research Council
Funding Amount
$961,017.00
Summary
Our aim is to examine the ability of vibration alone and in combination with osteoporosis drugs to reduce hip fracture in postmenopausal women. In Australia, 1 in 2 women >60yrs, will sustain an osteoporotic fracture. Only drugs notably decrease fracture; however none are entirely effective and some patients don’t respond. Whole body vibration has emerged as a potentially effective therapy. A combination of vibration and drugs may enhance the effects of both and revolutionise treatment.