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Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25-hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism.