Bone Biology
Antiepileptic medication and bone health: Is quantitative ultrasound a reliable monitoring test for AED-associated bone disease?
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: 9342 7109 Email: jdwark@unimelb.edu.au
Aims: To assess quantitative bone ultrasound (QUS) measures compared with dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) in subjects taking anti-epileptic drugs (AEDs) and their non-AED exposed twins or siblings
Background: Epilepsy is the most common serious chronic neurological disease. Most people with active epilepsy take an AED for many years to prevent seizures. Patients taking AEDs have high rates of bone fractures. The reasons for this major adverse effect are likely multifactorial, including an effect of the AEDs resulting in bone fragility. Decreased bone mineral density (BMD) and increased rates of osteoporosis have been demonstrated in people taking long-term AEDs. QUS is a convenient, economical method with potential utility to monitor patients for osteoporosis and fracture risk
Research Plan: Patients aged over 18 years, taking AED for >12 months, who have a same-sex twin (or sibling within 3 years of their age) will be identified, and offered participation. This project forms a sub-study of the AED Twin and Sibling Bone Health Study. The student will also be involved in recruitment of study participants, and conducting study visits.
Skills learnt: Patient interviewing techniques, quantitative ultrasound techniques, blood sample taking, and data management and analysis.
Bone health in children and young people with epilepsy treated with anti-epileptic drugs (AEDs)
Supervisors: Professor John Wark, Dr Peter Simm, Professor George Werther, Dr Sandra Petty
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Epilepsy and the use of anti-epileptic drugs (AEDs) are known to be associated with low bone mass and the risk of bone disease. In most patients, AED therapy once initiated is taken for many years if not for life. Moreover, it is well-established that AED therapy is a major cause of bone fractures in our community. However, there are still limited data concerning bone problems in children and adolescents taking these medications. We propose a novel study to explore their bone health looking at a number of measures, including analysing bone geometry and bone strength, which have not been described previously in this cohort. We will also follow these patients’ growth and development as well as their bone mass accrual and the number of fractures and other injuries that they sustain. These data will give great insight into the effects of epilepsy and its treatment on bone health and lead to improved management of bone health issues in young patients taking AEDs. The findings also will help us to establish a clinical model for the management of bone health in these patients.
Students undertaking this project will gain substantial experience in clinical study design, data collection and management, data analysis and interpretation, as well as translational aspects of biomedical research.
Determinants of osteoporosis, falls and fracture risk: twin studies
Supervisor: Professor John Wark, Dr Rosemary Wong
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Many projects are available within this large, multi-disciplinary program of research into determinants of growth and development, and osteoporosis risk, and involve female twins over a wide age range. Available projects include physiology, biochemistry, nutrition, epidemiology and biostatistics and genetics.
Osteoporotic fractures cluster in families and so may falls. We aim to study genetic and environmental determinants of gait and balance in young twins. The study may help explain why hip fractures run in families. We have identified important relationships between lean body mass, fat mass and bone mineral density (a key predictor of fracture risk) in women. In this project we will explore how regional soft tissue composition predicts bone mass.
We, and others, have demonstrated in randomised, controlled trials that dietary calcium supplementation augments the gain in bone in adolescent girls. In this project, we will evaluate the extent to which the bone gained is retained after supplementation is ceased: this will give insight into the potential benefits of additional dietary calcium in augmenting peak bone mass in young women.
We have a large cohort of female twins studied longitudinally before and during puberty. We now plan follow-up studies after completing growth so that we can evaluate genetic and environmental determinants of bone mass and bone strength.
Bone health in Asian-Australians
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
There are important ethnic differences in osteoporotic fracture risk. To date, osteoporosis risk factors, bone mineral density and fracture rates are almost unstudied in Australians of Asian ethnic background. This project is intended to redress this lack of important information.
Example using well-established research methods we will compare osteoporosis risk factors, bone density and bone ultrasound in Australians of Asian and Caucasian ethnic background also seeking effects of migration on these factors.
Glucocorticoids and bone loss
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Patients treated with glucocorticoids for their anti-inflammatory, immuno-suppressive effects often suffer severe bone loss and fractures. Early recognition of susceptible patients would help in the prevention and treatment of this form of osteoporosis. In this project, the roles of transmission ultrasound and loss of lean body mass in predicting early glucocorticoid-induced bone loss will be evaluated prospectively.
The epidemiological study of bone health in Asian-Australians
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
There are important ethnic differences in osteoporotic fracture risk. To date, osteoporosis risk factors, bone mineral density and fracture rates are almost unstudied in Australians of Asian ethnic background. This project is intended to redress this lack of important information.
Example - using well-established research methods we will compare osteoporosis risk factors, bone density and bone ultrsasound in Australians of Asian and Caucasian ethnic background also seeking effects of migration on these factors.
AED Pharmacogenetic AED bone health
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
A prospective study of patients attending first seizure clinic or private rooms, who are commencing AED treatment for the first time. Patients who attend first seizure clinic or private rooms and are diagnosed with another disorder, or are not commenced on treatment may be enrolled as control subjects.
First visit is within 3 months of starting AED, next visit at two years later. Potential to study at 5 years if funding allows. Currently no balance testing available for this study.
Bone Biopsy will be available as an optional sub study, but is not expected to be required prior to the two year follow up, where subjects who have experienced low-trauma fracture or have low BMD since starting AED therapy will be offered participation. Some of these patients will be enrolled in COMET study (sponsored by UCB), and can be billed for bone tests accordingly.
Konquest bone health study
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
A study commencing at time of first substitution of medications for epilepsy where the original treatment has not controlled the seizures adequately. Patients will have bone measurements (DXA, pQCT, turnover markers) done 3 months after change of meds (Levetiracetam, Carbamazepine or Sodium Valproate) and again at one year.
Predictors of glucocorticoid induced bone loss
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Patients treated with glucocorticoids for their anti-inflammatory, immuno-suppressive effects often suffer severe bone loss and fracture.
Early recognition of susceptible patients would help in the prevention and treatment of this form of osteoporosis. In this project, the roles of transmission ultrasound and loss of lean body mass in predicting early glucocorticoid-induced bone loss will be evaluated prospectively.
Improving the prediction of vertebral fracture risk in osteoporosis
Supervisor: Professor John Wark, Dr Andrew Briggs
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Vertebral fractures account for many of the low-trauma fractures seen in osteoporosis and impact significantly on health-related quality of life. The prediction of vertebral fracture risk therefore is very important for the appropriate diagnosis and treatment of osteoporosis. Dual energy Xray absorptiometry (DXA) is the best available clinical tool to measure bone mass and therefore infer skeletal status. Although DXA can be used to aid in the diagnosis and treatment of osteoporosis, its capacity to provide reliable information about vertebral fracture risk is limited. Individuals with osteoporosis show marked differences in the prevalence of vertebral fractures where areal BMD is comparable. Similarly, individuals with secondary osteoporosis from glucocorticoid therapy are at a significantly higher risk of sustaining a vertebral fracture compared to BMD-matched controls. In both clinical scenarios – primary and secondary osteoporosis – neither patients at risk of sustaining an incident vertebral fracture nor those at risk of entering the vertebral fracture cascade can be readily identified with standard DXA parameters.
Our pilot data suggest that this limitation may be attributable partly to standard-DXA parameters relying solely on a gross measure of vertebral BMD, for example total spine BMD. We have demonstrated that measurement of subregional areal BMD on lateral spine scans can better discriminate between fracture and no-fracture individuals in the context of idiopathic osteoporosis. The aim of the current study is to extend our pilot work to a larger clinical study to provide more robust clinical data. Ultimately, the application of subregional BMD measurement may provide greater diagnostic sensitivity for vertebral fragility in primary and secondary osteoporosis.
Students undertaking this novel project will work with an outstanding research team and gain wide-ranging experience in clinical research including the application of state-of–the-art technology, patient recruitment and data collection techniques, data management and biostatistics, and research translation. They will also help to improve the care of patients with osteoporosis, a common and potentially-debilitating condition.
Is regular table tennis activity associated with increased bone and muscle strength and improved balance in elderly Asian men and women
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Osteoporosis is “a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture” (1). While there are an estimated 1.2 billion people worldwide with osteoporosis, more than 50% of them reside in the Asia-Pacific region with approximately half a million people of Chinese extraction in Australia alone (2). This public health burden will increase significantly over the next 20 years due to ageing of the population (3).
Physical exercise may have beneficial effects on bone mass, muscle strength and balance in the elderly (4-6). Regular weight-bearing exercise for at least one hour per week is associated with increased bone mineral density (BMD) in the normal population (7).
Tai Chi exercise appears to have a beneficial effect on BMD at multiple sites (8, 9). Post-menopausal Chinese women had a greater increase in hip BMD following a combination of calcium supplementation and an exercise programme compared to those receiving calcium supplementation alone (9). Similar findings have been previously reported in non-Chinese women (10). “Keep-Fit” classes involving high-impact exercise two to three times a week maintained muscle strength and increased femoral BMD in men and women aged 50 years and older (11). Significant strength increases after one year of progressive resistance exercises were evident in elderly women and parallelled BMD changes (12). A high-intensity weight-bearing exercise program for patients with rheumatoid arthritis was effective at slowing down hip BMD loss (13). These studies suggest that anti-gravity exercise may be an osteogenic stimulus leading to increased bone mass, thereby reducing fracture risk.
There appear to be no published studies investigating the effects of table tennis activity on BMD or other measures of fracture risk. Table tennis exercise is not excessively strenuous and is therefore suitable for elderly people. Little financial outlay is required as minimal specialised equipment is necessary, unlike gymnasium-based interventions. Moreover, table tennis encourages socialisation. Table tennis is the “national sport” of China and is therefore a culturally-acceptable form of exercise in many communities in the Asia-Pacific region. These factors may favour both uptake of and compliance with table tennis as an exercise intervention compared with more formal gymnasium-based interventions.
Optimising the bone response to dietary calcium: a physiological approach
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
This study aims to identify the type of variable calcium diet that optimises bone mass, density and strengths. This unique approach suggests that a moderate dietary calcium diet followed by a period of high calcium intake is beneficial for bone health. This proof of concept application will utilise the rat as a model to generate data that would directly translate into functional food development for human diary products. This research may lead to the generation of novel functional foods in the form of ‘dairy product packs’. Consumers would drink mild (or eat yogurt) from a :moderated calcium pack’ for 5 days followed by a ‘high calcium pack’ for 5 days. The approach is based on the physiological effect of reduced calcium intake up regulating fractional intestinal calcium absorption. The “primed” intestine will respond to an increased calcium load with enhanced calcium absorption, creating a greater positive calcium balance than would be predicted from the same “steady state” intake. This novel approach will encourage increased dairy intake and be of significant benefit to the Dairy Industry as our strong new evidence from this program of research provides the foundation for the novel marketing strategy.
Low birth weight is associated with adult hypertension, diabetes and obesity as well as reduced bone mass and osteoporosis. We have shown that uteroplacental insufficiency, which restricts nutrients and oxygen supply before birth and lactational nutrition after birth in rats, causes fetal and postnatal growth restriction. These rat pups then develop high blood pressure, increased adiposity and insulin resistance later in life.
The aim of this study is to use cross-fostering techniques in the rat to determine whether restricted nutrition before birth via the placenta, or after birth via lactation, increases the risk of having reduced bone density and growth. Bone changes will be quantified using dual-energy X-ray absorptiometry (DXA) for bone mass, bone mineral density, bone mineral content and soft tissue composition and peripheral quantitative computed tomography (pQCT) for bone strength and lean mass. In addition, the relationship between skeletal development and key bone plasma markers will be assessed. In this project students will undertake state-of-the-art measurements of bone mass and bone strength.
Quitline Cohort Study
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Currently the research group is working on a number of studies investigating the association between smoking and bone health. The aims of the studies are to investigate the effects of smoking cessation on bone health in males and females and to examine the reversibility of smoking-associated loss of bone mineral density (that is, the risk of developing osteoporosis).
Osteoporosis is a common condition where bones are thin and this leads to fractures. It affects mostly women after the menopause, but it also affects men and people with some medical conditions. Because there are now effective treatments for osteoporosis, it is important to make the diagnosis early. Fractures cause pain, disability, deformity and especially after a hip fracture, loss of independence so that you may not be able to live with your family anymore, for example. We can measure how thin or thick your bones are by measuring the density of your bones.
Lifestyles are important determinants of the risk of developing osteoporosis. Cigarette smoking is a key lifestyle risk factor for osteoporosis and is important particularly because it is potentially modifiable. Loss of bone density (bone thinning) has been reported at all medically important sites such as the lower back and hip, the bones where most osteoporotic fractures occur. These losses of bone increase an individual’s risk of developing osteoporosis. These reductions in bone mass have been reported in both men and women across the life span. Smoking is associated with a 30-40% increase in lifetime hip fracture risk. Of all the hip fractures that occur in the community 6-12% of hip fractures may be caused by smoking. That means that for every 100 hip fractures, 6 – 12 of these fractures could have been prevented if people did not smoke. When people stop smoking we want to see if bone density increases, reversing the loss of bone and reducing the risk of having a fracture. By investigating the reversibility of smoking associated bone loss we hope to provide essential information to guide individual patient management aimed at preventing smoking-related fracture and to support public health approaches to quitting smoking and improving bone health.
AED Twin and sibling bone health study
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
A study of twins and siblings, of same gender, siblings aged within 3 years of each other, where one has been taking AED for any indication for more than 12 months. DXA, pQCT, bone turnover markers are done at baseline (time of enrolment) and again two years later. Balance testing is done at first visit. Fat Distribution study is in progress. Patients can be enrolled via ATR, media referral, specialist referral and epilepsy clinics referral.
Bone biopsy is available as an optional sub-study where the AED user has a history of low-trauma fracture or low BMD (ethics approval pending). Mary Sakellarides will be doing a sub study looking at pQCT and US in this group.
The effect of anti-epileptic medication on indices of bone health and risk factors for falls and fracture: a twin/sibling pair study
Supervisor: Professor John Wark, Professor Terence O'Brien, Professor Keith Hill
Location: Department of Medicine (RMH)
Contact details: Professor John Wark T: 9342 7109 Email: jdwark@unimelb.edu.au Professor Terence O'Brien T: 8344 5479 Email: obrientj@unimelb.edu.au
Aims: To utilise the University of Melbourne Twin and Sister Longitudinal Bone Health Study methodology to compare bone mineral density (BMD), biochemical indicators of bone turnover and balance function in subjects taking anti-epileptic drugs (AEDs) with their non-AED exposed twin or sibling.
Background: Epilepsy is the most common serious chronic neurological disease in the community, affecting up to 3% of the population in a lifetime. Most people with active epilepsy are required to take an anti-epileptic drug (AED) for many years, and often lifelong, to prevent the harmful effects of seizures. Patients taking AEDs have high rates of bone fractures. The reasons for this are likely multifactorial, including a direct effect of trauma from the seizures as well as an effect of the AEDs resulting in bone fragility and balance impairments (increasing falls risk). A number of studies have demonstrated decreased bone mineral density (BMD), increased rates of osteoporosis and greater fracture rates in women with epilepsy who have been taking long-term AEDs. However, these studies have been limited by inadequate controls, use of cross sectional design, and lack of adjustment for other BMD determinants. Moreover, the mechanisms by which AEDs might be associated with decreased BMD and increased bone fragility are not well understood.
Research Plan: This study will utilise the University of Melbourne Twin and Sister Longitudinal Bone Health Study methodology to investigate the effects of the long-term use of AEDs for epilepsy on BMD, indices of bone turnover, vitamin D and mineral levels, and measures of balance function. Women who have been using AEDs for >12 months will be identified and compared with their co-twin or matched sister for the above variables.
The study will provide important data on the extent of the effect of AED use on BMD, gait and balance function and potential fracture risk. It has the potential to provide novel insights into the mechanisms underlying the effect of AEDs on BMD, and for the identification of specific types of AEDs that may have greater/less risks.
Smoking - discordant twins: follow-up studies
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
A number of studies address the association between smoking and bone health. The aims of the studies are to investigate the effects of smoking on bone health and to examine the reversibility of smoking-associated loss of bone mineral density (that is, the risk of developing osteoporosis). Osteoporosis is a common condition where bones are thin and this leads to fractures. Lifestyle factors are important determinants of the risk of developing osteoporosis. Cigarette smoking is a key lifestyle risk factor for osteoporosis and is important particularly because it is potentially modifiable. Loss of bone density (bone thinning) has been reported at all clinically-important sites such as the lumbar spine and hip. Smoking is associated with a 30-40% increase in lifetime hip fracture risk. Of all the hip fractures that occur in the community 6-12% may be caused by smoking. That means that for every 100 hip fractures, 6 – 12 of these fractures could have been prevented if people did not smoke.
We want to investigate that extent to which bone loss is ongoing in people who choose to continue smoking. When people stop smoking we want to see whether bone density increases, reversing the loss of bone and reducing the risk of having a fracture. By investigating the reversibility of smoking associated bone loss we hope to provide essential information to guide individual patient management aimed at preventing smoking-related fracture and to support public health approaches to quitting smoking and improving bone health.
In this project students use the powerful twin study design to conduct a follow-up study of twin pairs who are discordant for smoking and who have previously attended our centre for baseline measures of bone mineral measures and a range of hormones and bone turnover markers. Changes in measures of bone health will be assessed and the role of smoking/smoking cessation in determining changes in bone health will be evaluated.
In this novel project students will gain experience in twin study design, implementation of clinical research studies, data collection, management and analysis, and interpretation of twin research data.
Hallux valgus: is it by nature or by nurture? A twin study
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Hallux valgus, also referred to as a “bunion”, is a common condition that may be considered to represent osteoarthritis of the first metatarso-phalangeal joint. Prevalence rates range from 5 to 37%, with the largest study reporting a prevalence of 28%. Hallux valgus has a significant impact on society, being associated with significantly lower score health-related quality of life. Hallux valgus also affects balance and gait patterns, independently increasing the risk of falls in older people. Many people with hallux valgus undergo surgical correction of the deformity.
Despite the considerable burden on society, little is known about risk factors for hallux valgus. Between 58 and 90% of people with hallux valgus report a familial tendency. However, the heritability of the condition has not been established. A classical twin study provides a powerful approach to addressing this important issue and will be performed utilizing an existing cohort of adult female twins involved in longterm studies of bone health.
This novel project will provide students with substantial experience in clinical study design and implementation, an understanding of genetic epidemiology and twin studies, and the analysis and interpretation of twin data.
Lifecourse choices in young women
Supervisor: Professor John Wark,
Location: Department of Medicine (RMH)
Contact details: T: 9342 7109 Email: jdwark@unimelb.edu.au
Behaviours and lifestyle choices of adolescent females have far reaching consequences that impact on health, well-being and productivity in adult life. We aim to perform a longitudinal, community-based study of females aged 16-25 years. Our aim is to provide epidemiological evidence in key national priority areas where lifelong patterns are established during adolescence and young adulthood: obesity and metabolic health, sexual and reproductive health, bone health and mental health. If you are interested in one or more of these health research areas, and are eager to learn how to engage in all aspects of a medical research study, from study design, interviewing and consenting participants, collecting, cleaning and analysing data, and importantly, translating your new knowledge into a scientific communication, then this project is for you!
Suitable projects include:
1. The association between metabolic syndrome and disordered eating in a community sample of young Victorian women. Supervisors: Prof John Wark, Dr Yasmin Jayasinghe, Dr Elya Moore.
2. To investigate the association of bone mineral density and bone strength measures with weight, soft tissue composition, and the metabolic syndrome using peripheral quantitative CT and dual energy Xray absorptiometry. Supervisors: Prof John Wark, Dr Yasmin Jayasinghe, Dr Elya Moore.
Understanding bone loss and the risk of fractures in patients treated for diabetes-related foot complications: a prospective study
Supervisor: Professor John Wark, Dr Paul Wraight, Ms Sue Kantor
Location: Department of Medicine (RMH)
Contact details: Professor John Wark T: 9342 7109 Email: jdwark@unimelb.edu.au Dr Paul Wraight Email: : Paul.Wraight@mh.org.au
Foot disorders are a major cause of morbidity and hospitalization in patients with diabetes, with aetiological factors including vascular insufficiency, neuropathy and predisposition to infection. These patients also appear to be at increased risk of fractures in the affected feet, adding to their morbidity and disability. Therefore, it is proposed that individuals managed for diabetes-related foot complications are more likely to develop significant bone mineral loss causing increased fracture risk during the course of their treatment. Aspects of their therapy (e.g., pressure off-loading) are likely to contribute to this risk. Falls (which predispose to fractures) also are more prevalent in individuals prone to developing foot complications; poor calcium intake, vitamin D deficiency (from reduced outside activities) and other factors also may contribute to bone loss.
This project has three main objectives:
- To determine whether individuals with diabetes-related foot complications are at an increased risk of bone loss, with a corresponding increase in morbidity/fractures.
- If an association is identified between diabetes-related foot complications and bone loss, to identify contributing factors for this bone loss.
- To develop a risk stratification tool in order to identify those individuals who are at highest risk of developing significant bone loss/morbidity/fractures.
This study may lead to improved outcomes in diabetic patients with this important cause of morbidity, poor quality of life and high health care costs. It is proposed to recruit 50 consecutive patients under the care of the RMH Diabetic Foot Unit to assess bone mineral measures during the management of their diabetes-related foot complications. Regional bone mineral density will be measured using dual energy Xray absorptiometry and peripheral quantitative computed tomography in all patients on entry to the study and at 6 months. Patients will be assessed for known and putative risk factors for both local and systemic bone mineral loss including features which may be novel to the management of their foot complication.
Students undertaking this novel project will gain substantial experience in the design and implementation of an original clinical research study, in patient recruitment, and data collection, management, analysis and interpretation.