Innovative measures of frailty in patients with bone impairment

Frailty is a condition characterised by a declining function across several homeostatic systems leading to increased vulnerability to stressors and the risk of adverse health outcomes. Today frailty is an emerging global health burden with major implications for clinical practice and public health. Both in literature and in clinical practice standard measurements of frailty have not been unanimously agreed upon yet. Many reviews highlighted the need for standard instruments to diagnose frailty, as these would allow the heterogeneity of frailty to reduce worldwide. Scientists are asked to expand the knowledge of pathophysiology and of the natural course of frailty, identifying precise biomarkers and evaluating changes in organs. The overall aim of my PhD was to find out the biological changes that may lead to frailty and vulnerability, thus understanding the relation between the changes in different organs and in tissues. This thesis includes three research projects: the first one focused on the effective identification of biomarkers involved in the bone-vascular axis, which might significantly improve the prediction of atherosclerotic cardiovascular disease; the second research project investigated the prevalence of vertebral fractures in a population with a very high cardiovascular risk and it evaluated a possible relationship with frailty and daily calcium intake; the third one focused on elderly people affected by COVID pneumonia, investigating the behaviour of skeletal muscle mass, thoracic aortic calcifications and bone mineral density through measures obtained from CT scans of the chest. 1st Research project: this study was based on much pre-clinical and clinical evidence suggesting an interplay between atherosclerosis and osteoporosis, both chronic diseases involved in ageing and frailty. Bone turnover biomarkers were studied for a possible role in the bone-vascular axis, thus they were also considered as novel markers of vascular health. The aim was to evaluate the association between serum concentrations of soluble bone biomarkers (Osteopontin, Osteoprotegerin, Klotho and Sclerostin) and atherosclerotic disease severity assessed through coronary angiography, gold standard for the diagnosis of coronary artery disease and carotid doppler ultrasound. We proceeded by testing the associations of these candidate bone biomarkers with traditional cardiovascular risk factors. The results of this phase demonstrated that elevated serum levels of OPG are independently associated with advanced atherosclerosis, confirming a link between bone metabolism and vascular disease. 2nd Research project: the second part of the project looked at the presence of vertebral fractures on spine radiographs, which are often neglected in clinical practice. In addition, this study highlighted elderly people's nutritional aspects, in particular the intake of calcium as calcium is one of the elements involved both in the development of osteoporosis and in the increase of atherosclerosis. The aim was to investigate the prevalence of vertebral fractures in a population with very high cardiovascular risk, and to evaluate a possible connection to frailty and the daily intake of calcium from food. The results of this investigation demonstrated how unrecognised vertebral fractures and a low daily calcium intake are associated with a higher frailty score, confirming the link between bone health and vascular diseases. 3rd Research project: this study was influenced by the recent COVID pandemic, which had the most dramatic impact on frail older people. Thoracic CT, currently used to evaluate lung extension and the severity of pneumonia, could be used to investigate other aspects, not only as a marker of frailty in elderly people, but also as a predictor of poor prognosis in COVID pneumonia. The hypothesis was that the complex pathophysiology of frailty in elderly people involves common pathways to muscle mass, macro vascular calcifications and bone density. The results of this research demonstrated how vascular calcification is inversely related to bone mineral density and muscle mass density, while bone and muscle density are directly correlated. Finally descending thoracic aorta calcium score has a good diagnostic power to identify an increased risk of death in older adults with SARS CoV 2 pneumonia.