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 parients.
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: Richard Eastell
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.
Programme 6 - Bone and Joint arthroplasty
Lead investigator: Mark Wilkinson
This programme aims to study the causes of conditions leading to joint arthroplasty (such as osteoarthritis (OA) and hip dysplasia), the effect of joint prostheses on local bone and systemic health, and the reasons for and treatments to avoid prosthesis failure.
To meet these objectives we are conducting a detailed radiographic phenotyping of hip and knee osteoarthritis subjects to examine the genetic basis for hip shape and OA, bone remodelling and OA and between OA sites using data from an ongoing genome wide association study (GWAS) in osteoarthritis (arcOGEN study). We are also examing the effect of genetic variation on the risk of prosthesis failure after hip replacement using a 2-stage GWAS design. This study is a collaboration with the musculskeletal BRU in Oxford, and with other European partners. We are studying the potential adverse effects of metal ion release from hip resurfacing implants on bone cells. This work seeks to examine whether this implant bearing type has an adverse effect on the local bone microenvironment and is a collaboration with the Mellanby Centre for Bone Research at the University of Sheffield.
Four intercalated BMedSci Medical Students have recently completed 1-year research programmes within the BRU, all receiving 1st class honours. One studied the effect of implant design on periprosthetic bone loss after hip replacement and found that cemented femoral prosthesis geometry has little effect on early bone loss after hip replacement. Another examined the effect of metal ions at clinically relevant concentrations on bone cells in-vitro that provided the pilot work for a current PhD student’s work. A third student studied the potential role of variation within genes that modulate the TLR and RANK signalling pathway and the risk of osteolysis after hip replacement. The fourth student studied the potential adverse general health effects of metal-on-metal hip resurfacing prostheses in a case-matched cross-sectional study.
