Summary <p>Contrary to popular belief, a recent study did not show increased osteoclastic activity in acute complex regional pain syndrome. Conversely, osteoblastic activity seems to be enhanced. The real meaning of diagnostic tools needs to be reassessed. Therefore, bisphosphonates act through mechanisms of action different from their anti-osteoclastic effect.</p> Introduction <p>Bone tissue involvement is a widely acknowledged event in the course of complex regional pain syndrome (CRPS), and it is invariably depicted as “high turnover osteoporosis.” This statement needs to be revised in light of a recent biochemical study on bone turnover markers and regulators in patients with early CRPS.</p> Methods <p>The real meaning of the findings arising from biochemical, radiological, and histopathological studies and the possible mechanism of action of parenteral bisphosphonates have been reviewed according to the bone metabolism derangement specific to this disease.</p> Results <p>Consistent with the results of the recent biochemical study, no reliable data emerge from diagnostic studies sustaining an increased osteoclastic activity. Conversely, osteoblastic activity seems to be enhanced for an increased Wnt signaling due to lower levels of Sclerostin and Dickkopf-1. These results may provide a different and alternative interpretation of previous diagnostic and therapeutic studies.</p> Conclusions <p>For the emerging role of bone in CRPS pathogenesis, these remarks could be useful for improving knowledge of the pathophysiology of the disease.</p>