Zoledronic Acid or Methylprednisolone in the Management of Active Charcot's Neuroarthropathy of Foot in Patients With Diabetes Mellitus: A Randomized, Double-blind, Placebo Controlled Trial

Charcot's neuroarthropathy has been identified since 1883, yet we have much to learn about the pathophysiology and evidence based treatment options. Active CNO is characterised by repetitive trauma leading to inflammation in an insensate foot. This includes polypeptide receptor activator of nuclear factor-kB ligand (RANKL) which triggers the synthesis of the nuclear transcription factor nuclear factor-kb (NF-kb), and this in turn stimulates the maturation of osteoclasts from osteoclast precursor cells. At the same time, NF-kb stimulates the production of the glycopeptide osteoprotegerin (OPG) from osteoblasts. This "decoy receptor" acts as an effective antagonist of RANKL . It has been suggested that this results in continual production of proinflammatory cytokines, RANKL, NF-kb, and osteoclasts, which in turn leads to continuing local osteolysis .This has adequately demonstrated by an increase in proinflammatory phenotypes of monocytes in those with active Charcot foot when compared with diabetic control subjects. Also osteoclasts generated in vitro in the presence of macrophage colony-stimulating factor and RANKL from patients with active CN have been shown to be more aggressive and exhibit an increase in their resorptive activity compared with control subjects. Motor neuropathy contributes to altered structure of the foot with resultant abnormal loading. Finally, it is possible that peptides like calcitonin gene-related peptide (CGRP) , which normally antagonizes the synthesis of RANKL, reduced due to neuropathy increase the RANKL expression. Diabetes may predispose to occurrence of CNO through a number of mechanisms. Apart from the presence of neuropathy and possible osteopenia, these include the effects of advanced glycation end products, reactive oxygen species, and oxidized lipids, which may all enhance the expression of RANKL in diabetes.

The average delay in the diagnosis of acute Charcot has been reported to be around 29 weeks. Common misdiagnoses include cellulitis, erysipelas, deep vein thrombosis (DVT), venous insufficiency, gout, pseudogout, acute inflammatory arthritis, fracture, sprain, tumor, septic arthritis, osteomyelitis, Sudeck's atrophy, and rheumatoid arthritis. Delay in prompt diagnosis and initiation of treatment results in progression of the pathology resulting in rigid osseous deformity of the foot increasing the risk of callus formation, ulceration, infection, and lower extremity amputation by 15- to 40-fold .With the propensity for misdiagnosis and high potential for progression to a rigid foot deformity, early recognition and prompt initiation of treatment is paramount.

Radiographs are the primary initial imaging method for evaluation of the foot in suspected CNO. However, they may initially be normal or show subtle fractures and dislocations. Magnetic resonance imaging (MRI) has a higher sensitivity that allows detection of subtle changes in the early stages of active CNO when X-rays could still be normal. MRI primarily images protons in fat and water and can depict anatomy and pathology in both soft tissue and bone in great detail because of its unique capability of differentiating tissues with high detail.

Treatment of CNO is aimed at offloading the foot, treating bone disease, and preventing further foot fractures. Because of the various etiologies of increased local bone resorption and/or secondary osteoporosis in patients with CNO and limited randomized placebo-controlled trials in this area, treatment guidelines are largely based on professional opinion rather than the highest level of clinical evidence. Hence, there remains a dearth of evidence based medical management for Charcot neuroarthropathy. Offloading at the acute active stage of the Charcot foot is the most important management strategy and could arrest the progression to deformity. Ideally, the foot should be immobilized in an irremovable total contact cast (TCC), which is initially replaced at 3 days, then checked each week. Edema reduction is often remarkable in the first few weeks of treatment. The cast should be changed frequently to avoid "pistoning" as the edema subsides.

However, It is important to take into consideration that TCC may actually have unfavorable consequences including unnatural stress patterns, increased instability, loss of muscle tone, proprioception and boe density.Also, they are not designed to affect the underlying physiological mechanisms that cause bone destruction.In this context, treatment by antiresorptive drugs emerges as an attractive option. Bone turnover in patients with active CNO is excessive, hence bisphosphonates, by inhibiting osteoclast mediated resorption, have an important role to play. However, there is little evidence to support their use at present.Both oral and intravenous bisphosphonates have been studied in the treatment of CNO in small randomized, double-blind, controlled trials or in retrospective controlled studies. Whatever the precise pathophysiological mechanism of CNO, bone resorption and osteoclastic hyperactivity is a major feature of the early acute stage of this condition and makes the use of bone-resorption-inhibiting agents such as bisphosphonates(BPs) a logical therapeutic approach. Theoretically, pharmacological treatment of CNO by BPs, which inhibit osteoclastic resorption and may have direct anti-inflammatory properties, might slow or even stop the bony destruction through its ability to cause macrophage apoptosis.