Background. Charcot neuropathic osteoarthropathy is a rare, destructive process affecting the bones and joints of feet in patients with diabetic peripheral neuropathy. The aetiology of Charcot remains unknown, although it has been suggested that it is triggered by the occurrence of inflammation in the foot of a susceptible individual, and that the inflammation results in increased osteoclastic activity. Hypothesis. The increased bone turnover in acute Charcot is associated with increased concentrations of pro-inflammatory cytokines, related signalling peptides and bone turnover markers. Methods. 17 patients newly presenting with acute Charcot in diabetes and 16 non-diabetic patients without neuropathy undergoing elective forefoot surgery provided informed consented to participate. Samples of bone were taken by needle biopsy, and were stained with H&E to determine bone architecture and bone remodelling. Serum ALP, CTX, OPG and sRANKL TNF, IL1-beta, IL6 and CRP were measured by immunoassay. Blood was taken from the dorsal foot vein of both the affected and the unaffected foot, as well as an antecubital vein. Results. Classic histopathology features of fracture and bone remodelling were evident in Charcot bone biopsies. Systemic circulating concentrations in the Charcot group antecubital vein for both IL6 and OPG were significantly greater than in controls (p<0.05). There were no significant differences between the dorsal vein concentrations of any analyte when the affected and unaffected feet were compared. However, in patients with an acute Charcot foot the concentration of OPG, ALP and CTX was higher in sera from the dorsal vein of affected foot when compared to controls (p<0.05), this difference was highly significant for IL6 (p<0.001). Conclusion. The elevation in CTX observed in the affected foot in patients with an acute Charcot foot reflects the bone breakdown and remodelling which is present. The higher circulating concentration of IL-6 in the Charcot patient group, reflects the inflammation which is present and which is thought to be central to the development of the condition. Although OPG values were significantly greater in Charcot than control group, circulating concentrations of OPG are known to be higher in diabetes