Academic Directorate of Specialised Medicine: Metabolic Bone
If you are interested in getting actively involved in what we do, we have a Lay Advisory Patient Panel for bone research that meets monthly to provide a lay perspective and to influence research conducted in bone disorders. For more information please click here
|Prof Richard Eastell
|Research Lead, Director BRU MSK|
|Prof Eugene McCloskey||Professor in Adult Bone Disease & Academic Lead|
|Dr Nicola Peel||Clinical Lead, Consultant Physician|
|Dr Jennie Walsh||Theme lead, Consultant Physician|
|Josh Wright||Clinical Director|
|Prof Eugene McCloskey||
Professor in Adult Bone Disease
|Dr Lang Yang||Lecturer, Theme Lead|
|Deputy Operations Director|
|Julie Senior||Deputy Group Finance Manager|
|Mark Palmer||Directorate Accountant|
|Directorate Research Coordinator|
Metabollic Bone Research
(Research Lead on Specialised Medicine Executive – Prof Eugene McCloskey)
The Metabolic Bone Centre (Clinical Lead Dr Nicola Peel) is one of only a few NHS units in the UK dedicated specifically to research in this field and provides one of the largest out-patients services that complements international-level research carried out within the Academic Unit of Bone Metabolism (Director Prof Richard Eastell).
Basic science is undertaken in conjunction with colleagues in the Mellanby Centre for Bone Research within the Department of Human Metabolism in the University of Sheffield as well as other collaborators within the Universities of Liverpool and Newcastle as part of CIMA. There is also a burgeoning and productive collaboration with Insigneo within the University.
The primary research focus is osteoporosis for which Sheffield has been recognised as one of the world-leading centres. According to Thomson Reuter's Science Watch, Sheffield is ranked fourth among academic centres in the world for citations in osteoporosis, and first in the UK and Europe (http://sciencewatch.com/ana/st/osteo2/institution/). Studies have evaluated the epidemiology, pathogenesis, diagnosis and treatment of the disease. This has involved developing and establishing assays for bone turnover markers and studying their clinical utility as well as new approaches to the definition of vertebral fracture. More recent techniques include tools such as high-resolution quantitative computed tomography, ultrasound and finite element modelling of bone strength. Sheffield was the leader in the definition of osteoporosis in 1994 and has more recently led a further paradigm shift in the management of osteoporosis through the development of the FRAX tool (www.shef.ac.uk/FRAX). The Centre has also contributed to many of the studies that have established the wide range of effective therapies for osteoporosis that are now available. Orthopaedic research into areas such as genetics of osteoarthritis, joint prosthesis loosening and interventions are led by Prof Mark Wilkinson.
Within Metabolic Bone Disease, there are excellent links to allied clinical services, diagnostic radiology, clinical chemistry and other support services within the Trust. It also has strong academic links and collaborations with academic centres in Birmingham, Manchester, Oxford, Cambridge, Edinburgh, Liverpool, Newcastle, London, Nottingham and Bristol. Research in the musculoskeletal diseases is further supported through the NIHR Yorkshire and Humber Network of which Prof McCloskey is also a co-lead for the specialty.
The directorate hosts a PPI group, the Bone Research Patient Panel, which helps inform our research goals. All areas of research and priorities are discussed with our PPI panel with their feedback informing our directions and decisions; the Bone Research Patient Panel also ensures close alignment with the Trust’s PROUD agenda ensuring that patients lie at the heart of our research. Metabolic Bone Disease also contributes to the success of the Specialised Medicine Academic Directorate in the training of basic and clinical researchers.
Research nursing support is through two FT band 6 research nurses experienced in Metabolic Bone Disease research who cater for the needs of our potential patient groups. These posts are funded via a combination of RCF, Senior Investigator Awards and commercial study income. We can also access other nursing support through the CRF nursing staff. Consultant time is heavily reliant on academic as well as NHS clinical staff.
Programme 1 - Developing novel bone anabolic agents. Lead investigator: Richard Eastell
It is important to develop new treatments for osteoporosis, and anabolic therapies hold the greatest potential for benefit. We have been developing a number of techniques that make us well-placed to study the early anabolic effects of drugs on bone. These include the use of bone formation markers, bone histomorphometry and QCT of the spine and hip. The latter allows us to identify bone mineral density and structural changes within six months of starting therapy. High resolution CT is also being used to study the effects of anabolic drugs on the peripheral skeleton (forearm and lower leg). We are now working with our industrial partners to develop strategies for making an early assessment of the efficacy of novel anabolic therapies. This will help to speed up drug development in this area.
Programme 2 – Developing novel bone turnover markers. Lead investigator: Richard Eastell
The Unit has a long history of research into the use of biochemical bone turnover markers (BTMs) to monitor response to therapy. The development of new osteoporosis treatments involving novel mechanisms of action has led to a demand for methods to evaluate the efficacy of these treatments. We are currently assessing the use of BTMs for monitoring the response to new therapeutic agents under development as well as carrying out further in-depth studies of licensed treatments. We have routinely used BTMs within the clinical service to monitor treatment response for over 10 years. Their use in this setting has evolved over this time and the current protocol is being assessed as part of a service evaluation.
We are working with key molecules from recently described pathways, such as DKK1, a component of the Wnt signalling pathway, as well as seeking to develop improved assay techniques for existing markers such as urinary NTX. We are also developing an assay platform for measuring multiple markers which may be a useful advancement in fracture prediction studies.
Programme 3 – Attainment of peak bone mass. Lead investigator: Jennie Walsh
We are currently studying changes in bone structure in adolescents to help us understand the influences on the attainment of peak bone mass. This is of specific importance in cases of childhood disease that may lead to pituitary failure, anti-inflammatory therapy with steroids, radiotherapy and chemotherapy, so that we may understand how to maximise bone development.
We are using our state-of-the-art high-resolution peripheral CT scanner (the XtremeCT machine) to study changes in the structural elements during the attainment of peak bone mass and the hormones that regulate them.
Body mass index (BMI) has an impact on bone turnover rates, and metabolically-active fat mass (android) is a major determinant of high BMI. Under this programme we are investigating whether there are further endocrine influences on bone in young adults, using the XTremeCT to compare bone microarchitecture in lean and obese patients.
Programme 4 - Interactions between physical and pharmacological interventions. Lead investigator: Eugene McCloskey
Weight-bearing exercise can strengthen bone, but is not appropriate for the frail and elderly or patients with osteoporosis. There is some evidence that low-level mechanical stimulation of bone by means of vibration therapy has beneficial effects. The patient stands on a vibrating footplate and the vibrations pass through the body. However, little is known about the extent to which these vibrations travel, the best frequency or length of therapy in different patients or the interaction between vibration therapy and pharmaceutical treatments. We are evaluating these issues, with the aim of assessing the impact of low level mechanical vibration, alone and in combination with other treatments, on bone turnover, bone density (both cancellous and cortical bone), bone geometry and muscle mass. Mechanical stimulation provides an anabolic effect on bone, so we are developing clinical, imaging and biochemical tools to test whether the combination of a low level mechanical stimulus and pharmacological therapies (e.g. parathyroid hormone (PTH) or oestrogen) improve skeletal responsiveness—resulting in enhanced anti-fracture efficacy and/or reductions in treatment costs and adverse effects.
The XTremeCT will be invaluable in measuring the response in the targeted bone, potentially allowing us to more efficiently target specific areas with combined vibration/pharmacological treatments.
Programme 5 - Biomechanical determinants of spine and hip fracture. Lead investigator: Lang Yang
Fragility fractures of the hip and spine are associated with increased morbidity and mortality and significant treatment costs to the NHS. We have developed a more accurate definition of osteoporotic versus traumatic vertebral fracture, and we are now evaluating the risk factors for these fractures. We want to be able to more accurately identify patients at increased risk of fracture, so that we can treat them accordingly and improve their bone strength.
Low bone mineral density (BMD) is known to be a strong predictor of future fracture risk; however, there is no BMD threshold for fracture and many patients with low bone density do not sustain fractures. Clearly, other factors influence bone strength and these may include bone size, geometry, structure and microarchitecture. Dual-energy x-ray absorptiometry (DXA) is the current standard for the assessment of BMD, but these other properties are not captured by conventional DXA.
To address this problem, we are developing bio-engineering models of the hip and evaluating these in relation to fracture risk. To do this we construct 3D models of the hip, and perform finite element analyses to build structural engineering models (SEMs). We can then carry out bio-mechanical analyses on these models to examine the relationship between the other factors, along with things such as muscle force and loading.
In addition to this, we are applying these models to observe the different effects of osteoporosis treatments in different regions of the hip.