Periodic Reporting for period 2 - FIDELIO (Training network for research into bone Fragility In Diabetes in Europe – towards a personaLised medIcine apprOach)
Reporting period: 2021-10-01 to 2024-03-31
Compared to non-diabetic people, patients with diabetes have a higher risk of fragility fractures. Fragility fractures are those that occur where healthy bone would not normally break, for example when falling from a standing position. Common fragility fractures include those of the hip and vertebrae (in the spine).
Lower bone mineral density (as with osteoporosis) is a major factor in the risk of fragility fracture. However, it appears that bone structure and quality are also affected in people with diabetes, so contributing to a higher fracture risk.
FIDELIO (Training network for research into Fractures In Diabetes in Europe – towards a personalised medicine approach) was funded by the European Union during 2019-2024. FIDELIO aimed to:
-understand more about the effects of diabetes on bone health
-assess how these changes may result in a higher risk of fragility fracture
-and determine how we can use this new knowledge to help better diagnose and treat people with diabetes
As an Innovative Training Network, FIDELIO has involved bone and diabetes scientific researchers, medical doctors and companies to train 14 PhD students (Early Stage Researchers, ESRs). Each student had their own individual research project investigating an aspect of bone health in diabetes.
Overall, FIDELIO has contributed significantly to our understanding of how diabetes affects bone structure, its impact on bone cells, and fracture risk. The differing impacts of T1D and T2D on bone fragility and fracture risk have been clarified, and broader insights gained into the mechanisms of diabetes. New computational tools have been developed which will be useful in future research and clinical care.
The genetic basis of fracture risk in diabetes was investigated using data from population cohort and large genomic studies. Genetic sub-groups of T2D were classified, with disease duration identified as a major factor in fracture risk. This research provides new insights into the links between T2D and other metabolic conditions.
The potential role of the human gut microorganism population (microbiome) was also investigated in population cohort studies. Differences in microbiome profiles were found between healthy and less healthy people. Preliminary findings relating to musculoskeletal health are currently being validated.
Analysis of microRNAs in blood samples may be useful to predict fracture risk. In FIDELIO, microRNA analysis was performed in animal models and in patients, comparing to measurements of bone strength and quality. So far, none were confirmed to specifically indicate diabetic bone disease, but some microRNAs are of interest to study further in relation to diabetes or bone health in general.
A clinical study of T2D patients has examined the effects of a high fibre diet on bone. So far, this found a positive effect of the diet on metabolic health, but not on bone parameters. However, a study of the same diet in a T2D mouse model has observed interesting effects on bone that will be investigated further.
Bone samples were analysed for chemical changes due to high sugar levels in diabetes, and how these affect bone strength and quality. In T1D samples, effects on osteocytes, the most abundant bone cell, and damage to bone microstructure were observed. A computational model was developed that calculates bone strength, fracture properties and localised bone loading from patient scans. Scans from studies of diabetes patients has been analysed for their differences in bone microstructure. Bone formation and remodelling has been observed over repeated scans. Also an image processing tool has been developed correct for any motion of patients during scans. These tools are available for use by researchers and for eventual clinical applications.
Mouse models of diabetes have been characterised. The TallyHO model commonly used for T2D was found not to develop diabetic bone disease, while a study of the protein Dkk-1 in a T1D model suggest it has a role in regulating bone and fat metabolism. The role of mitochondrial dysfunction has been investigated with a focus on the Polg gene, in cells and an animal model, and in metabolic analysis of cells from patients. The effects of diabetes and exercise on osteocyte cells and bone properties have been studied in cells and in a T2D mouse model.
The FIDELIO training programme of residential courses, online training and secondments was implemented, with some modification due to the COVID-19 pandemic. ESRs received interdisciplinary scientific training including courses on imaging, animal models and bone biomechanics, while transferable skills training including scientific writing, video production and a professional development programme.
FIDELIO results are being disseminated in open access journal publications, available to the research and medical community for further research, development of new clinical guidelines and tools to improve patient care.
Videos about FIDELIO and each ESR project are available on YouTube, and lay summaries of publications are also available on the project website.
Many results of FIDELIO are already published and are available to researchers and clinicians. Further research is required to confirm findings in larger groups of patients, potentially leading to new protocols to identify patients at higher risk of fracture.
The project evaluated several potential markers of fracture risk, including miRNAs and bone turnover markers that can be measured in blood samples. So far, no specific marker has been associated with a higher risk of fracture in clinical samples, but several findings relating to diabetes or bone health in general, are of interest for further study. Similarly, studies of dietary intervention (high fibre diet) have not so far identified a benefit for bone health, but indicate it improves diabetes. Further research is required to develop preventative or therapeutic strategies, for example drug therapies targeting the impact of diabetes on bone osteocyte cells.
FIDELIO has also developed several new computational methods for processing of bone scans that can be used in future research, clinical studies or patient care. These include tools for estimation of localised bone loading and fracture properties, correction of subject motion and combining scans taken at different times. Diabetes animal models have been characterised, and the results will assist selection and use of models in future studies.