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Paget´s disease of bone (PDB) is characterized by increased bone resorption followed by an excessive compensatory bone formation, with an abnormal bone structure with altered mechanical properties. Pagetic bone also has a higher vascularization and marrow fibrosis. Despite of pagetic bone being a highly vascularized tissue, there are no studies on the plasma levels of angiogenic mediators in the different states of the disease; moreover, the effect of PDB treatment on plasma levels of these angiogenic mediators is not very well known. The aim of this study was to analyse plasma levels of cytokines implicated in the increased bone turnover (OPG, RANKL, sclerostin) and hypervascularization (VEGF, PGF, ENG) observed in PDB and their evolution and response to zoledronic acid treatment in 70 PDB patients, 29 with an active disease measured by plasma alkaline phosphatase (ALP). Plasma ALP concentration was higher in active PDB than in inactive PDB patients, whereas there were no differences in OPG, RANKL, sclerostin, VEGF, PGF and ENG plasma levels between active and inactive PDB patients. ALP decreased at 3 and 12 months after zoledronic acid treatment. RANKL levels were reduced and sclerostin levels were increased after 12 months of treatment. PGF levels were lower 12 months after zoledronic acid treatment, whereas there were no differences in plasma VEGF and ENG after zoledronic acid treatment. Summarizing, zoledronic acid treatment is associated to decreases in plasma levels of ALP, RANKL, sclerostin and P1GF in active PDB patients. This treatment may reduce bone turnover and might reduce the pathological vascularisation typical of pagetic bone., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.