The growth and differentiation of bone cells is controlled by various factors which can be modulated by heparan sulphates. Here, we investigated the effects of an oversulphated exopolysaccharide (OS-EPS) on bone. We compared the effect of this compound with that of a native exopolysaccharide (EPS). Long-term administration of OS-EPS causes cancellous bone loss in mice due, in part, to an increase in the number of osteoclasts lining the trabecular bone surface. No significant difference in cancellous bone volume was found between EPS-treated mice and age-matched control mice, underlying the importance of sulphation in trabecular bone loss. However, the mechanism sustaining this osteoporosis was unclear. To clarify OS-EPS activities, we investigated the effect of OS-EPS on osteogenesis. Our results demonstrated that OS-EPS inhibited osteoclastogenesis in two cell models. Using the surface plasmon resonance technique we revealed that OS-EPS can form a hetero-molecular complex OS-EPS/RANKL/RANK and that RANK had a higher affinity for RANKL pre-incubated with OS-EPS than for RANKL alone, which would be in favour of an increase in bone resorption. However, in vitro, OS-EPS inhibited the early steps of osteoclast precursor adhesion and therefore inhibited the cell fusion step. In addition, we showed that OS-EPS reduced proliferation and accelerated osteoblastic differentiation, leading to strong inhibition of mineralized nodule formation, which would be in favour of an increase in bone resorption. Taken together, these data show different levels of bone resorption regulation by exopolysaccharides, most of them leading to proresorptive effects.