A Prospective Study To Identify The Mechanical Causes And Methods For Early Detection Of Knee Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
Knee osteoarthritis is a great cost to society, financially and in quality of life. Anti-inflammatory drugs are commonly used to treat the symptoms, but many people receive joint replacements to stop pain and improve function. We need to prevent osteoarthritis, but the causes for this common disease are largely unknown. Animal studies have shown two particular mechanical factors that cause osteoarthritis, which are seen in the walking and running, or gait, patterns of some people. We call these ....Knee osteoarthritis is a great cost to society, financially and in quality of life. Anti-inflammatory drugs are commonly used to treat the symptoms, but many people receive joint replacements to stop pain and improve function. We need to prevent osteoarthritis, but the causes for this common disease are largely unknown. Animal studies have shown two particular mechanical factors that cause osteoarthritis, which are seen in the walking and running, or gait, patterns of some people. We call these pathological gait patterns as they impose larger-than-normal forces on the knee's articular surfaces. We measure these knee forces with our new computer knee model coupled with data that we measure in a gait analysis laboratory. These forces may cause knee osteoarthritis in humans, but this is still unknown. Currently there is no simple medical test to detect the early onset of knee osteoarthritis. The bones in the knee are one of the first structures to show osteoarthritic changes. Using our new computerised analysis of high definition X-ray of the knee we can identify subtle differences in the knee due to osteoarthritis. This will be compared with changes to joint assessed using MRI. Osteoarthritis develops slowly in normal people, so to study progression of knee osteoarthritis we need a human population that has a higher risk of developing the disease. Partial meniscectomy in the knee is a common surgery performed to improve knee function in those who have suffered a knee meniscus injury. However, partial meniscectomy patients have a high risk of developing knee osteoarthritis. Therefore, using partial meniscectomy patients we are investigating if pathological gait patterns cause knee osteoarthritis, measuring the development of the disease with our new X-ray methods. With the gait analysis methods we can also identify the movements that characterise these pathological gait patterns so we can formulate rehabilitation programmes to help prevent knee osteoarthritis.Read moreRead less
An RCT To Determine The Optimum Frequency Of Botulinum Toxin Injections To The Calf In Children With Cerebral Palsy
Funder
National Health and Medical Research Council
Funding Amount
$286,358.00
Summary
Cerebral Palsy (CP) is the most common cause of disability amongst children across the developed world. There are about 1800 children with CP in Victoria alone. It is caused by damage to the brain in early childhood. Children with CP have difficulty controlling how their muscles work. Muscles are often spastic, which means that they are switched on all the time, and this makes walking and performing other tasks difficult. As the child grows the spastic muscles can become too short and this occur ....Cerebral Palsy (CP) is the most common cause of disability amongst children across the developed world. There are about 1800 children with CP in Victoria alone. It is caused by damage to the brain in early childhood. Children with CP have difficulty controlling how their muscles work. Muscles are often spastic, which means that they are switched on all the time, and this makes walking and performing other tasks difficult. As the child grows the spastic muscles can become too short and this occurs can only be corrected by orthopaedic surgery. The spasticity in particular muscles can be reduced by injecting them with Botulinum Toxin (commonly known as Botox and used cosmetically to remove wrinkles). The effects of a single injection have been closely studied and we know that the effect of the toxin wears off. Children are thus offered repeat injections but there have been no studies to investigate what is the most appropriate interval between injections. The aim of this study is to determine this. In routine clinical practice children tend to get injections approximately once a year. A consideration of what we know about how the toxin acts, however, suggests that injections every 4 months might be expected to be more effective. This study will thus randomly allocate children to receive injections either every twelve months or every four months over a two year period. During the study both groups will be monitored to see if there are differences in how easily they can walk and perform other functions and in their overall quality of life. After the study the children will also be assessed to see whether there is any difference in the length of the spastic muscles. There have been no other studies to investigate the most appropriate interval between injections. This study will thus be the first anywhere and will be the foundation for guidelines for the ongoing use of botulinum toxin in children with cerebral palsy in Australia and throughout the world.Read moreRead less
In Vivo Patellofemoral Joint Measurement Using Kinematic Radiostereometric Analysis (RSA)
Funder
National Health and Medical Research Council
Funding Amount
$141,000.00
Summary
Complications following total knee joint replacement continue to be a major cause for revision surgery and leads to a significant financial burden in terms of health care expenditure. Recent studies suggest that many of these complications are associated with post-surgical pain from the patella knee cap joint, commonly termed anterior knee pain (AKP). Post-surgery AKP may be influenced by the motion of the patella. Recent prospective, randomised trials have compared clinical outcomes between peo ....Complications following total knee joint replacement continue to be a major cause for revision surgery and leads to a significant financial burden in terms of health care expenditure. Recent studies suggest that many of these complications are associated with post-surgical pain from the patella knee cap joint, commonly termed anterior knee pain (AKP). Post-surgery AKP may be influenced by the motion of the patella. Recent prospective, randomised trials have compared clinical outcomes between people with TKA in which the patellar surface is replaced (patellar resurfacing) or retained, but have been unable to accurately account for differences in patellar movement in those people with post-surgery complications. To date, studies of patellar motion after total knee replacement have been limited to two-dimensional analyses. This study addresses the technological limitations of previous trials by utilising accurate techniques for directly measuring skeletal motion using kinematic radiostereometric analysis (RSA). These data will measure patellar kinematics in three-dimensions for the first time. This information will allow optimisation of the design of TKA and the surgical techniques required for their implantation. Furthermore, the results will assist in the identification of surgical indications for patellar resurfacing, and the kinematic factors associated with anterior knee pain following total knee replacement surgery.Read moreRead less
Mesenchymal Progenitor Cells And Intervertebral Disc Repair
Funder
National Health and Medical Research Council
Funding Amount
$754,223.00
Summary
Low back pain affects 80% of the general population and is a major social and economic burden thus there is a clear need for effective treatment. Annual direct and indirect costs for low back pain exceeded $100 billion in the USA in 2006. We will use bone marrow derived multipotent progenitor cells in a regenerative strategy to undertake repair of the intervertebral disc in an ovine mechanical destabilisation model which reproduces early degenerative changes similar to those evident in man.
The Role Of Perlecan In Tensional Connective Tissues
Funder
National Health and Medical Research Council
Funding Amount
$605,037.00
Summary
Musculoskeletal diseases affect tension and weight bearing connective tissues which have notoriously poor repair capabilities. These conditions are difficult to treat clinically and surgical repair in many cases does not provide a return to optimal joint function impinging on the quality of life of afflicted individuals and their carers. Our project aims to better understand the structure and function of these tissues in health and disease with a view to improving repair strategies.
Novel Therapeutic Interventions For The Orthopaedic Complications Of Neurofibromatosis Type 1 (NF1).
Funder
National Health and Medical Research Council
Funding Amount
$628,422.00
Summary
Children with the genetic disease NF1 can develop fractures that fail to unite and this can lead to amputation. We have advanced models of NF1-deficient bone cells and fracture healing that we will use to test new pharmaceutical treatments for NF1.
The Role Of V-ATPase Accessory Subunit Ac45 In Osteoclasts
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus of bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular target for the discovery of novel bone antiresorptive ag ....Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus of bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular target for the discovery of novel bone antiresorptive agents useful for the treatment of lytic bone disorders. The proposed research will give considerable insight into the role of the both V-ATPase accessory subunit Ac45 and V-ATPase complex in osteoclasts. Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone disorders.Read moreRead less
Molecular Determinants Of Bone Remodelling In The Bone Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$317,640.00
Summary
There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, t ....There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and histomorphometric studies will determine whether the understanding derived from tissue culture and animal experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The elucidation of the molecular signalling in the human bone microenvironment is essential for the effective diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data shows that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further investigate mRNA gene expression of a number of cytokines involved in bone cell signalling and their association with the level of microdamage in the bone. Using a animal model of controlled bone microdamage induction we will seek to determine the bone remodelling causal relationship between microdamage and cytokine signalling. Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are not well understood. These studies will provide new insight into the processes that determine trabecular structures. This project will investigate these mechanisms and increase our understanding of bone cell function, essential for diagnosis and design of rational treatment for bone diseases.Read moreRead less
Intrinsic Bone Qualities In Fragility Fracture Patients: Mass, Microarchitecture, Mineralization And Damage Accumulation
Funder
National Health and Medical Research Council
Funding Amount
$447,027.00
Summary
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detec ....Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of bone is of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength and fracture toughness (work to fracture) reduce considerably with age. This proposed study would seek to elucidate the role of bone tissue-level properties in determining bone quality for human subjects: patients with fragility hip fractures on no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies, and normal age- and sex-matched individuals. Our laboratory has extensive experience in the analysis of the structure of human bone tissue. Recently, we have developed novel and unique techniques to assess bone quality, using micro-CT, backscatter SEM imaging, confocal microscopy and immunohistochemistry. This multifaceted study will identify at the bone tissue-level the structural mechanisms (micro-architecture, mineralisation, and microscopic cracking) that are indicative of the efficacy of fragility fracture drugs. Better understanding of the mechanisms by which bones are less likely to fracture will enable better targeting of osteoporosis drug therapy to individuals at risk of fragility fracture.Read moreRead less