Inflammation is the cornerstone of our modern understanding of active Charcot foot (CN) pathogenesis, driving osteolysis via increased expression of receptor activator of nuclear factor kappa-B ligand (RANK-L).1 Peripheral neuropathy is similarly implicated, through compromise of underlying bone integrity, predisposition to injury, and impairment of neurogenic regulation of bone healing.2., 3., 4. In active CN, rapid focal osteopenia leads to asymmetry in bone health compared to the contralateral foot, detectable within weeks of onset using calcaneal quantitative ultrasound (QUS).5 Measurement of bone health, a term used to encompass bone quality or microarchitecture in addition to bone density, is a theoretical advantage of using calcaneal QUS above Dual Energy X-ray Absorptiometry (DEXA).3,6 While necessary to prevent progression of deformity, offloading may further perpetuate osteolysis.7 Even after apparent clinical resolution and cessation of immobilisation, bone density remains compromised and deformity may gradually progress.8,9

The advent of potent antiresorptive therapies provided hope that osteolysis could be mitigated, and outcomes improved. Bisphosphonates improve bone density in the active CN foot as demonstrated using DEXA;10,11 however, they seem to have an equivocal effect on the disease course and may even prolong the immobilisation period.12,13 Denosumab is a human monoclonal antibody targeted to RANK-L, and hence may be more effective in interrupting the pathway between inflammation and osteolysis. Additionally, denosumab is easier to administer and does not require renal dose adjustment. Non-randomised data of denosumab in active CN is promising, with earlier clinical resolution and shorter immobilisation time in comparison to historic cohorts.14,15

The current Charcot Foot Quantitative Ultrasound and Denosumab Study (CRUSADES) is one of three registered randomised controlled trials (RCTs) of denosumab in active CN. Unique to CRUSADES is the inclusion of calcaneal QUS and quality of life measures. CRUSADES aimed to investigate the effect of denosumab in early active CN, on both bone health measured by calcaneal QUS and surrogate measures of disease activity.