The cornerstone of treatment of acute Charcot neuroosteoarthropathy is immediate effective offloading, typically with total contact casting, and reduction in weight bearing. The targets of pharmacological intervention are inhibition of excess osteoclast activation and suppression of an excess proinflammatory cytokine response. Antiresorptive therapy, especially with bisphosphonates, has been used in randomized trials. While evidence of an ideal dosage regime and significant differences in long-term outcome are lacking and should be evaluated in future studies, the trials so far demonstrated improved symptom control, a more rapid decline in foot temperature, and a significant decrease in bone turnover markers, with no demonstration of significant harmful effects. Growing insight into molecular pathways of resorptive bone disease will undoubtedly facilitate novel adjunctive pharmacological therapies.