Juvenile idiopathic arthritis (JIA) is a disease associated with loss of bone mass, deterioration in bone mass quality and an increased risk of fractures. The objective of this study was to evaluate factors that predict bone mineral density (BMD) alterations in young adult patients with active JIA before and during therapy with tumour necrosis factor α (TNFα) inhibitors. Thirty-one patients (twelve males and nineteen females; mean age =25.1 ± 6.1 years) with active JIA (mean Disease Activity Score in 28 joints (DAS28) =6.36 ± 0.64; mean high-sensitivity C-reactive protein (hsCRP) =18.36 ± 16.95 mg/L) were investigated. The control group consisted of 84 healthy individuals matched by sex and age. BMD, bone turnover markers and serum concentrations of soluble receptor activator of nuclear factor κB ligand, osteoprotegerin, dickkopf Wnt signalling pathway inhibitor 1 (Dkk1) and sclerostin were evaluated. Baseline BMD values in the lumbar spine, proximal femur, femoral neck and distal radius were significantly lower in patients with JIA compared to healthy control participants. Baseline sclerostin serum concentrations were significantly higher in patients with JIA compared to control participants. After 2 years of treatment with TNFα inhibitors, BMD was significantly increased in the lumbar spine. This increase correlated with a drop in DAS28 score. A statistically significant correlation between hsCRP and Dkk1 was found at baseline, as well as during the 2-year follow-up period. A significant reduction in serum sclerostin after 1 year of therapy was predictive of a drop in DAS28 score observed with a 1-year delay after reduction of serum sclerostin. A significant correlation between the sclerostin serum concentration and the number of tender and swollen joints, but not BMD, supports the hypothesis that chondrocytes and cells of the subchondral bone may contribute to circulating sclerostin in JIA.