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Purpose Multiple sclerosis (MS) patients have a high risk of low bone density. The purpose of this study was to examine the molecular mechanisms potentially capable of modulating bone homeostasis in response to interferon-β-1a (IFN-β-1a) treatment and the focus was the bone-modulating system comprised of receptor activator of nuclear factor-κB (RANK), its ligand RANKL and its decoy receptor, osteoprotegerin (OPG). Methods In this open-label pharmacodynamic study, peripheral blood was obtained from relapsing–remitting MS patients just prior to and at multiple time points after intramuscular injection of 30 μg IFN-β-1a. Samples were analysed for RANKL, tumour necrosis factor related apoptosis-inducing ligand (TRAIL), OPG and macrophage inflammatory protein-1 α/β expression. Osteoclast precursor differentiation from peripheral blood cells of MS patients in the presence of exogenously added IFN-β-1a was also assessed. Additionally, the changes in plasma levels of osteocalcin and the C-telopeptides after 1 year of treatment were measured as surrogate markers of bone formation and degradation, respectively. Results IFN-β-1a treatment modulated RANKL and OPG in a selective, time-dependent manner. The levels of OPG protein decreased 25% at the 8-h time point, then increased 43% at the 24-h time point. The levels of free RANKL reached a maximum at the 8-h time point. Increases in the levels of macrophage inflammatory protein-1 β (MIP-1 β), a chemokine that increases osteolysis, were observed. The levels of the bone formation marker, osteocalcin, were lower in MS patients compared to controls and increased after one year of treatment. Ex vivo treatment of peripheral blood lymphocytes with IFN-β resulted in a marked reduction of osteoclast-like cells in the presence of RANKL and macrophage colony stimulating factor. Conclusions IFN-βtreatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients. [ABSTRACT FROM AUTHOR]