Pharmacological treatment for Charcot neuroarthropathy: a systematic review

BACKGROUND: Charcot neuroarthropathy (CN) is a debilitating joint disorder that predominantly affects patients with neuropathy, particularly those with diabetic peripheral neuropathy (DPN). CN causes painless, rapid joint destruction and often leads to foot deformity, ulceration, osteomyelitis, and, in severe cases, amputation. Its pathogenesis involves repetitive microtrauma due to loss of protective sensation, triggering an inflammatory cascade that activates osteoclasts (OCs) disproportionately relative to osteoblasts (OBs) via the RANKL-RANK-OPG pathway, resulting in progressive bone loss and joint destruction. This systematic review and meta-analysis evaluated the efficacy of anti-resorptive agents in promoting bone remodeling and alleviating clinical symptoms in patients with active or stable CN. METHODS: Following Cochrane Collaboration guidelines, we searched MEDLINE, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) comparing anti-resorptive agents, such as bisphosphonates, denosumab, calcitonin, and parathyroid hormone analogues, with placebo or no treatment in patients with Charcot neuroarthropathy. Two independent reviewers performed data extraction and risk-of-bias assessment using the Cochrane RoB 2 tool. Primary outcomes were bone mineral density (BMD), bone turnover markers (BTMs), time to remission, change in foot temperature, and adverse events. Statistical analyses were conducted using Stata 18, with random-effects models used to pool results. RESULTS: We identified 936 records and nine reports describing seven RCTs met the inclusion criteria. The meta-analysis showed no significant difference in BMD between anti-resorptive agents and control groups. However, anti-resorptive therapy significantly reduced bone resorption markers. Clinical outcomes, including foot temperature change and time to remission, did not differ significantly between groups. Adverse events were similar between the intervention and control groups. CONCLUSIONS: Although anti-resorptive agents reduce bone resorption markers in patients with Charcot neuroarthropathy, current evidence does not support their efficacy in improving BMD or providing clinically meaningful symptom relief beyond standard offloading. High-quality clinical trials and mechanistic studies are needed to define the role of these agents in CN management.