<p>The crosstalk between osteoporosis and atherosclerosis has gained substantial attention due to the shared risk factors and pathophysiological mechanisms underlying both conditions. Osteoporosis, marked by the diminished bone mineral density (BMD), augmented risk for fractures and atherosclerosis, and accumulation of plaques within the arterial walls, are together prevalent in the aging populations. This review highlights the intricate crosstalk between these two conditions, focusing on the role of inflammatory biomarkers, genetic predispositions, and metabolic alterations. We have analyzed reported studies on common pathways such as the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (NF-κB) (RANK)/receptor activator of NF-κB ligand (RANKL) (OPG/RANK/RANKL) signaling pathway and systemic inflammation in the human subjects and animal and cell culture models, which contribute to both bone resorption and vascular calcification. Additionally, we have explored impact of chronic diseases such as the chronic kidney disease (CKD) on exacerbation of both osteoporosis and atherosclerosis through changes in mineral metabolism. Therapeutic interventions targeting these shared mechanisms including the actions of bisphosphonates, romosozumab, denosumab, and anti-inflammatory agents are discussed for their efficacies to mitigate simultaneously the bone loss and vascular calcification. This comprehensive overview on current understanding of the relationship between osteoporosis and atherosclerosis discloses the unmet need for a targeted research approach that precisely addresses the interdependent nature of these conditions towards improving the outcomes in patients encountering both diseases.</p>