Most patients with multiple myeloma develop a severe osteolytic bone disease. The myeloma cells secrete immunoglobulins and the presence of monoclonal immunoglobulins in the patient’s sera is an important diagnostic criterium. Here, we demonstrate that immunoglobulins isolated from myeloma patients with bone disease promote osteoclast differentiation when added to human pre-osteoclasts in vitro, whereas immunoglobulins from patients without bone disease do not. This effect was primarily mediated by immune complexes or aggregates. The function and aggregation behavior of immunoglobulins are partly determined by differential glycosylation of the Ig-Fc part. Glycosylation analyses revealed that patients with bone disease had significantly less galactose on IgG compared with patients without bone disease and also less sialic acid on IgG compared with healthy persons. Importantly, we also observed a significant reduction of IgG sialylation in serum of patients upon onset of bone disease. In the 5TGM1 mouse myeloma model, we found decreased number of lesions and decreased CTX-1 levels, a marker for osteoclast activity, in mice treated with the sialic acid precursor, N-acetylmannosamine (ManNAc). ManNAc treatment increased IgG-Fc sialylation in the mice. Our data support that de-glycosylated immunoglobulins promote bone loss in multiple myeloma and that altering IgG glycosylation may be a therapeutic strategy to reduce bone loss.Copyright © 2020 American Society of Hematology.