Homocysteine (HCY) is a sulfur-containing amino acid involved in two metabolic pathways, catalized by cystathionine-B-synthase and methionine synthase, depending on vitamin (vit) B6, B12, and folate levels and enzymatic activity of methylenetetrahydrofolate. High HCY levels (HHCY) are associated with cardiovascular (CV) and bone diseases, in particular osteoporosis (OP)/hip fracture. As regards the mechanisms involved in the link between HHCY, CV diseases (CVD), and OP, it has been proposed the role of lysyl-oxydase inhibition that might interfere with collagen crosslink formation. Some studies suggested the dysregulation of the osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK) ligand/RANK axis, others the involvement of oxidative stress. These mechanisms may act both on bone and CV system, but whether the common denominator is HCY itself or HCY is merely a marker, remains to be clearly established. Folate, vit B6, and B12 supplementation is associated with HCY reduction, but is unable to certainly reduce the incidence of OP/fracture and CVD, probably because, in the majority of patients, HCY is only moderately increased.