BONE SIZE AND BONE TURNOVER: RELATIONSHIP TO FRACTURE RISK OVER TEN YEARS
Funder
National Health and Medical Research Council
Funding Amount
$428,225.00
Summary
The occurrence of fracture in the ageing population is a major public health problem because these fractures are responsible for considerable morbidity and mortality. Of women reaching 90 years of age, one third will fracture their hip and overall, one in every six women will sustain an osteoporotic fracture in her lifetime. The direct cost to the community is unknown but estimated, conservatively, at 175 million dollars annually. Most of this is likely to be the result of hip fractures which oc ....The occurrence of fracture in the ageing population is a major public health problem because these fractures are responsible for considerable morbidity and mortality. Of women reaching 90 years of age, one third will fracture their hip and overall, one in every six women will sustain an osteoporotic fracture in her lifetime. The direct cost to the community is unknown but estimated, conservatively, at 175 million dollars annually. Most of this is likely to be the result of hip fractures which occupy an estimated 400,000 bed-days annually. This bed occupancy is fourth next to mental illness, cardiac disease and cancer. The Geelong Osteoporosis Study is a large population-based epidemiological study currently under way to evaluate the major risk factors for fracture in women . This present study which will be an extension of the study to date, will provide in total, 8-10 years of data concerning the processes that result in increased bone fragility and fracture.Read moreRead less
Investigating The Physiological And Clinical Differences In Weight Loss In Obese Subjects With And Without Diabetes.
Funder
National Health and Medical Research Council
Funding Amount
$101,726.00
Summary
Obesity and type 2 diabetes are linked by the production of inflammatory factors in the body. These factors seem to link weight gain, especially around the abdomen, not only with insulin resistance, the precursor to diabetes, but also independently with the development with heart and kidney disease and reduced fertility. This study will investigate the effect of dieting and weight loss on inflammation and the function of the heart and other organs in obese people with and without diabetes.
Functional Effects Of Polymorphic Variation Of The Aromatase (CYP19) Gene On Enzyme Activity:relationship To Disease
Funder
National Health and Medical Research Council
Funding Amount
$237,708.00
Summary
After menopause, oestrogen synthesis changes from an ovarian to an adipose source by concersion of androgens to estrogens, a process catalyzed by aromatase, the product of the CYP19 gene. We will generate mutants of the CYP19 gene that we have previously found in humans by site-directed mutagenesis and observe the effects of these mutants on aromatase function. This research will help with diagnosis and treatment of breast and other cancers and osteoporosis in humans .
Structural And Biomechanical Basis Of Differences In Bone Fragility In Asian And Caucasian Men And Women
Funder
National Health and Medical Research Council
Funding Amount
$188,500.00
Summary
Lay Summary Fractures occur less commonly in males than females because males have greater periosteal apposition than females during ageing. This increases bone size (reducing load per unit area - stress), and reduces net bone loss, more in males than females so that the increase in bone fragility with advancing age seen in both sexes is less in males than females. Few males than females have a fracture risk index for vertebral fractures (FRI or ratio of load-bone strength) above unity. The purp ....Lay Summary Fractures occur less commonly in males than females because males have greater periosteal apposition than females during ageing. This increases bone size (reducing load per unit area - stress), and reduces net bone loss, more in males than females so that the increase in bone fragility with advancing age seen in both sexes is less in males than females. Few males than females have a fracture risk index for vertebral fractures (FRI or ratio of load-bone strength) above unity. The purpose of this study is to define the structural and biomechanical basis responsible for the racial differences in fracture rates between Asians and Caucasians. Following the same biomechanical principles as published in Caucasian males and females, we hypothesise that racial differences in periosteal expansion during aging may contribute, in part, to the racial differences in bone fragility at the spine and hip. A cross-sectional study will be conducted in 500 healthy Chinese men and 500 Chinese women age ranged 18 to 90 years living in Melbourne, Australia. We have recruited larger numbers of Caucasian men and women in our Centre. BMD and bone size will be measured at the spine, hip and total body by using dual x-ray bone densitometer (DXA). Vertebral body width, depth, height, cross-sectional area (CSA), stress (load per unit CSA) and fracture risk index (load-strength) at the third lumbar vertebrae will be measured by PA and lateral scanning. Femoral neck periosteal-endocortical diameter, cortical thickness, cross-section moment of inertia (CSMI), section modulus buckling index will be measured by using hip structural analysis program. Just as insight into bone fragility in women has been obtained by studies in men, we believe that the results of this study will provide important insights into the pathogenesis of bone fragility in both racial groups.Read moreRead less
Apportioning Deficits In Bone Size And Density In Women With Fractures To Growth Or Ageing By Studies In Their Daughters
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Women fracture their bones because the bones are small and break easily and because the bones are thin or low in denseness (very porous like a honey comb). This study is aimed at identifying why women with fractures have small bones and why the bones are so porous. They may have these problems because they lost a lot of bone as they get older or because growth was abnormal so the size of the bone didn't reach its potential size or because the denseness of the bones didn't develop properly. The s ....Women fracture their bones because the bones are small and break easily and because the bones are thin or low in denseness (very porous like a honey comb). This study is aimed at identifying why women with fractures have small bones and why the bones are so porous. They may have these problems because they lost a lot of bone as they get older or because growth was abnormal so the size of the bone didn't reach its potential size or because the denseness of the bones didn't develop properly. The study will be carried out in women with spine or hip fractures and their daughters. All participants will have bone densitometry, provide a 24 hour urine sample and a fasting blood sample of 20 ml whole blood. Informed consent will be obtained from all participants. The bone density scan is associated with radiation exposure of about 4 mSv, about one tenth of a chest x ray, temporary bruising may follow taking blood. If we can understand the different ways osteoporosis can occur we can then start to devise specific treatments tailored to the individual. Also if we can identify the causes of small bones and bone thinness during growth it may be possible to correct some of these causes before the reduced growth and reduced building of bone occurs. We might also prevent the thinning of bone by identifying and removing causes of bone thinning.Read moreRead less
Is Periosteal Bone Formation Responsible For Sexual Dimorphism In Bone Fragility
Funder
National Health and Medical Research Council
Funding Amount
$316,320.00
Summary
Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures more often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of bone is greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is likely that men and women lose a similar amount of bone, about half what they started with, but during ageing, men lay down more bone on the outside surface of the bone than w ....Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures more often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of bone is greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is likely that men and women lose a similar amount of bone, about half what they started with, but during ageing, men lay down more bone on the outside surface of the bone than women compensating for the similar amount lost on the inside of the bone. We also have evidence to suggest than men and women who get spine fractures do so because the process of laying down bone may fail to occur normally. We will study these processes of bone loss inside the bone and bone gain outside the bone to try to better understand why bones become weak. We will measure the bone size and its density in healthy men and women and patients with fractures to determine how the increasing size of the bone produced by laying down bone on its outside helps to keep it strong and to preserve the bone that would otherwise be lost if it didn't occur or if a disease developed that might reduce the compensatoryRead moreRead less
Therapeutic Regulation Of Hepatic Steatosis And Lipid Transport In The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$522,435.00
Summary
Obesity is an increasing problem in Australia. Elevated fat levels in the liver and blood are associated with obesity and increased risk for heart disease. In this project, we will demostrate new mechanisms of action of Pioglitazone (an insulin-sensitizing agent) and Omacor (fish oils) that will complement the favourable efect of weight loss in the treatment of elevated blood fats and reduction in risk of heart disease in an important groups of subject in the population.
The Mechanisms Of The Anabolic Actions Of Androgens In Bone.
Funder
National Health and Medical Research Council
Funding Amount
$470,960.00
Summary
Androgens (male sex hormones) are one of the few agents that increase bone formation. Androgens act by binding to a specific protein, the androgen receptor (AR). To understand exactly how androgens increase bone formation, we will study mice in which the AR is inactivated only in bone forming cells at specific stages of their development. Understanding the way in which androgens act on bone to increase size and strength will be of great benefit in the design of new treatments for osteoporosis.
Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. ....Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. OCs are formed from white blood cells that are present in the bone marrow and the blood. The recent discovery of a family of new factors that control the formation of OCs has enabled the generation of human OCs in the laboratory so now we can investigate the genes that control the process of conversion of white blood cells to OCs. An important advance in this project involves the use of cord blood that contains stem cells. These very na ve cells will enable us to study the very earliest genes that control differentiation of precursors to OC. We have found a number of genes that are regulated by these new bone-forming factors. In white blood cells the activation of particular genes can regulate OC formation. One example is vitamin D-upregulated gene, VDUP. This gene is of particular interest as it causes inhibition of the mechanism that leads to OC formation in the bone. Obviously, the ability to control a 'switch' that regulates OC formation may enable us to control the progress of bone loss in diseases such as osteoporosis. In this project, we intend to investigate how and why the genes that lead to OC formation are regulated and what influence the various bone cell factors have on the formation of bone-resorbing OCs. These studies will lead to the development of treatments for osteoporosis and other bone diseases.Read moreRead less
Mechanisms Of Hypoglycaemic Damage In Developing Brain- A Protective Role For The Insulin-like Growth Factor System
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
The developing brain in the newborn infant or young child is vulnerable to many damaging influences. It is highly dependent on its essential fuel, glucose. Hypoglycemia, or lack of glucose availability, is therefore among the most damaging insults to the young brain, potentially leading to learning difficulties, developmental delay, cerebral palsy or epilepsy. Babies born premature or very small are at risk, as are those exposed to excessive insulin, such as infants of diabetic mothers. Children ....The developing brain in the newborn infant or young child is vulnerable to many damaging influences. It is highly dependent on its essential fuel, glucose. Hypoglycemia, or lack of glucose availability, is therefore among the most damaging insults to the young brain, potentially leading to learning difficulties, developmental delay, cerebral palsy or epilepsy. Babies born premature or very small are at risk, as are those exposed to excessive insulin, such as infants of diabetic mothers. Children with diabetes are also at risk, when their therapy with insulin may at times be excessive, leading to hypoglycaemia and impaired glucose availability for the brain. This proposal is examining at the cellular level the mechanisms involved in loss of brain cells in the face of glucose starvation in these various conditions. We are using several in vitro models where we can grow segments of developing mouse brain or human nerve cells in a dish, compared to studies with mice subjected to low blood glucose (hypoglycemia). After establishing that our laboratory models are representative of the whole animal, we will explore the cellular mechanisms involved in neuronal death following hypoglycaemia, particularly the interaction between the insulin-like growth factor (IGF) and other cell survival genes. We will also examine the possibility that treatment with IGF will reduce the loss of nerves in the brain after an episode of hypoglycemia. This may offer new and effective early treatment for this damaging brain injury in both newborn babies and children with insulin-dependent diabetes.Read moreRead less