Why do bisphosphonates work in the treatment of CRPS? A translational pharmacological perspective to solve a conundrum.

Bisphosphonates (BPs) have consistently yielded positive results in the treatment of Complex Regional Pain Syndrome (CRPS). However, biochemical and histopathological evidence suggests that osteoclasts, the primary pharmacological target of BPs, is not a key driver in the early pathogenetic steps of CRPS. To critically review and integrate current evidence on pharmacological mechanisms of action of BPs in CRPS and to propose unifying hypotheses explaining their clinical efficacy beyond antiosteoclastic activity. Literature from in vitro studies, animal models, and randomized clinical trials was integrated. Approximately 80 primary and review articles were critically reviewed. BPs efficacy in CRPS is best explained by a bone-driven pharmacological model by which local drug accumulation is achieved in the site of disease. This enables modulation of inflammatory and nociceptive processes on adjacent non-bone cells, including macrophages, neutrophils, keratinocytes, and nociceptive fibers. Inhibition of the mevalonate pathway in these cells may reduce inflammatory cytokines, nerve growth factor (NGF), and reactive oxygen species (ROS), while modulating nociceptive signaling pathways. Additional mechanisms, including modulation of vascular tone and neuropeptide signaling, may further contribute to therapeutic effects. This hypothesis may inform optimal treatment strategies and together improve understanding of CRPS pathophysiology.