Whether inflammatory cytokines affect the skeletal response to glucocorticoid (GC) treatment is unclear. Our objectives were to (1) identify the cytokine(s) elevated during exacerbations of inflammatory bowel disease (IBD); (2) determine whether the cytokine(s) identified in this way is related to systemic GC sensitivity; and (3) examine whether cytokines and/or measures of GC sensitivity are related to changes in bone formation or resorption following GC therapy. We designed a combined cross-sectional and prospective study, including patients with active (n = 31) and inactive (n = 34) IBD as well as controls (n = 29). We assessed circulating concentrations of cytokines, PINP and βCTX, as well as GC sensitivity in peripheral blood mononuclear cells. IL-6 was the only cytokine increased in active IBD, 2.35 (2.63) versus 1.64 (1.21) versus 1.31 (2.79) pg/μl active IBD, inactive IBD, and controls, respectively (median [interquartile range]) (P = 0.03, ANOVA). IL-6 was positively related to magnitude of GC sensitivity (beta = 0.02, 95% CI 0.008–0.04, P = 0.005). Following treatment with GC in active IBD, PINP decreased (P < 0.001), whereas βCTX showed no significant change (P = 0.2). Subsequently, multiple regression analyses revealed that plasma IL-6 concentrations were inversely related to the extent of PINP suppression following GC (beta = 3.3, 95% CI 0.2–6.4, P = 0.04, adjusted for baseline PINP and duration of GC treatment), while no association was observed with GC sensitivity. In conclusion, IL-6 is elevated in active IBD and may protect against GC-induced suppression of bone formation via a mechanism which appears to be independent of systemic GC sensitivity.