Charcot foot disease: A new approach

Abstract

Charcot neuropathic osteoarthropathy (CNO) is a condition that develops in the presence of neuropathy, most commonly diabetes-related neuropathy. Owing to the neuropathy, microtrauma to the bones occur without the individual feeling them. With continued walking, bone inflammation, resorption, microfractures and structural changes occur in the bones, which result in irreversible deformities. Diagnosing this condition is often difficult and requires advanced imaging techniques, such as scintigraphy or magnetic resonance imaging, as X-ray changes may not be specific. Treatment of CNO includes immobilization, offloading, recalcification (supplementation of vitamin D and calcium) and in the most advanced cases, surgical treatment. This narrative review aims to synthesize the recent research and clinical implications relating to Charcot foot to help healthcare professionals to stay up-to-date in this relevant topic.

Introduction

Charcot neuropathic osteoarthropathy (CNO), commonly referred to as Charcot foot, represents a significant complication of peripheral neuropathy, especially in people with diabetes, that primarily affects the foot and ankle [1]. This condition is characterized by progressive degeneration of weight-bearing joints that can lead to severe deformity, disability and may necessitate amputation if left untreated. Despite being first described over 140 years ago, it remains a frequently overlooked and misdiagnosed condition, and has caused some substantial morbidity among affected individuals [2].

In this narrative review we describe current advances in epidemiology, pathogenesis, diagnosis, different treatment options and future perspectives in the management of Charcot foot.

Clinical Presentation

Bilateral involvement represents a significant epidemiological and clinically important feature of Charcot foot. Current data indicates that 9–39% of patients develop the condition in both feet (both simultaneous and sequential) [3]. When using advanced imaging, such as computerized tomography, bilateral neuroarthropathic changes have been demonstrated in up to 75% of Charcot patients, though many of these changes may be subclinical [4]. National Institute for Health and Care Excellence (NICE) clinical guidelines recognize bilateral CNO in approximately 30% of cases, emphasizing the importance of monitoring both feet in affected patients [5].

Epidemiology

The prevalence of CNO varies considerably across different studies and populations, reflecting both genuine epidemiological differences and variations in diagnostic methodologies. Current estimates suggest that CNO affects between 0.08 to 13% of diabetic patients, with figures tending towards the higher end in specialized foot clinics and high-risk populations [4, 6–8]. This wide range in prevalence statistics highlights the challenges in accurately identifying the condition in routine clinical practice [9]. More specialized imaging techniques reveal much higher rates of the condition. Studies using radiographic assessment have detected changes consistent with CNO in up to 29% of diabetic patients, while magnetic resonance imaging (MRI) can identify the condition in as many as 75% of documented cases [6]. These findings suggest that the true prevalence is substantially higher than clinically recognized cases would indicate.

Important regional variations in prevalence have also been observed. A 17-year study conducted at a specialized diabetic centre in Bangkok, Thailand, found Charcot foot in only 0.5% of the total (n = 40) diabetic patients who attended their foot centre over 16 years, suggesting potentially lower prevalence in some Asian populations compared with Western cohorts [7]. Furthermore, the study noted a higher rate of new CNO event in the contralateral foot (20%) than typically reported in Western literature (approximately 10%).

Demographics and Risk Profile

CNO typically manifests in middle-aged and older adults with longstanding diabetes. Patients most commonly present in their fifties or sixties, with a mean age of approximately 58.7 years according to recent studies [7]. Although earlier reports suggested male predominance, more recent epidemiological data are less conclusive regarding gender distribution [9].

CNO is a complication of peripheral neuropathy due to conditions, such as prolonged diabetes, typically 8–12 years following initial diagnosis. In a Thai cohort, the mean duration of diabetes before Charcot foot diagnosis was 18.0 ± 8.8 years [7]. Similarly, studies have reported that most patients with CNO have had poorly controlled diabetes mellitus for 15–20 years [10]. This extended timeline highlights the importance of vigilant monitoring of people with long-term diabetes for early signs of the condition. Jude et al observed that CNO is predominant in males, occurs in long-standing diabetes, and is often accompanied by microvascular complications (however, significant differences between type 1 and type 2 were seen in the prevalence of retinopathy, neuropathy and nephropathy). Moreover, when compared with people with type 2 diabetes, people with type 1 diabetes and CNO were affected at a younger age, had longer diabetes duration, and had more microvascular complications [11].

While initial clinical understanding assumed comparable Charcot foot incidence rates between type 1 and type 2 diabetes, recent large-scale studies have revealed significant differences in presentation patterns, with type 1 diabetes patients typically developing the condition at younger ages despite longer diabetes duration, whereas type 2 diabetes patients show different demographic and risk factor profiles [11, 12]. Some studies demonstrate a relative preponderance of type 1 diabetes compared with type 2, and people with type 1 diabetes potentially facing higher risk [4]. However, this pattern varies geographically, as evidenced by a Thai study where 95% of Charcot foot patients had type 2 diabetes [7]. This variation likely reflects regional differences in diabetes type, prevalence and potentially genetic or environmental factors influencing Charcot foot development.

Possible risk factors for CNO development include patient-related, diabetes-related and limb-related factors. Suboptimal glycaemic levels that represent a significant risk factor, with affected patients typically showing elevated glycated haemoglobin levels and mostly patients have an average HbA1c level of 8–9%, substantially above recommended targets for diabetes management [7, 11]. This finding underscores the importance of optimal diabetes control in prevention strategies.

Obesity has emerged as a notable risk factor, with at least two-thirds of Charcot patients classified as obese [4]. This association may reflect increased mechanical stress on neuropathic feet or could indicate shared metabolic pathways contributing to both conditions. A Singaporean study revealed that among diabetic patients, 42.1% had sensory neuropathy, while 2% had developed CNO [13].

Diagnostic Challenges and Misdiagnosis

A significant epidemiological concern in Charcot foot is the high rate of misdiagnosis and diagnostic delay, which contributes to poorer outcomes. Diagnosis is missed or delayed in approximately 25% of cases, with delays extending up to 29 weeks in some instances [14]. These delays frequently occur owing to the clinical resemblance of Charcot foot to more common conditions [14, 15].

In acute Charcot foot, misdiagnosis as cellulitis occurs in nearly one-third of patients, while chronic Charcot foot is commonly misdiagnosed as osteomyelitis in approximately 15% of cases. Other frequent misdiagnoses include gout, deep vein thrombosis, soft tissue injury, and rheumatoid arthritis. The difficulty in differentiation between CNO and osteomyelitis represents a particular diagnostic challenge, as both conditions can coexist and require vastly different management approaches [9].

The high frequency of misdiagnosis is largely attributable to limited awareness rather than inherent diagnostic complexity. Increased recognition of the condition's early manifestations—foot warmth, erythema and oedema—could substantially improve early detection rates [15].

Pathogenesis

CNO is a multifactorial and progressive condition, most commonly associated with diabetes mellitus and peripheral neuropathy. Peripheral neuropathy remains the fundamental prerequisite for developing Charcot foot, as the condition does not occur in its absence. Despite more than a century of clinical recognition, its precise pathogenesis remains incompletely elucidated [4]. What is increasingly clear is that CNO results from a convergence of multiple pathological processes, which has aptly been described as an imperfect storm—a critical distortion of the normal reparative response to injury in the context of pre-existing nerve damage [16].

Peripheral neuropathy, both sensory and autonomic, is essential for the development of CNO. The loss of protective sensation leads to unperceived microtrauma, while autonomic dysfunction contributes to increased peripheral blood flow through arteriovenous shunting. This vasodilation promotes increased bone turnover and osteopenia [12, 17]. The repetitive trauma triggers a local inflammatory response, which, in a neuropathic limb, becomes dysregulated and sustained [18, 19]. This exaggerated inflammation is mediated by elevated levels of cytokines, such as tumour necrosis factor- α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), which activate the nuclear factor-kappa B (NF-κB) pathway. Central to this process is the receptor activator of nuclear factor-kappa B ligand (RANKL), which binds to its receptor RANK on osteoclast precursors, promoting their differentiation into active osteoclasts [20]. Normally, this is balanced by osteoprotegerin (OPG), a decoy receptor that inhibits RANKL. In CNO, the RANKL/OPG ratio is markedly increased, leading to unopposed osteoclast activity, local osteolysis and progressive bone resorption (Fig. 1) [18, 21, 22]. Recent findings also highlight the involvement of the Wingless-related integration site (Wnt)/β-catenin signalling pathway, where suppression of Wnt antagonists such as sclerostin and dickkopf-1 (Dkk-1) during the acute phase of Charcot foot may reflect a compensatory anabolic response aimed at promoting bone repair and regeneration [23].

Fig. 1.

Charcot neuropathic osteoarthropathy: molecules affecting bone formation and resorption

Additional metabolic and systemic contributors amplify this process. Chronic hyperglycaemia promotes the accumulation of advanced glycation end-products (AGEs), which not only impair collagen structure in bone but also enhance oxidative stress and RANKL expression [24, 25]. Moreover, vitamin D deficiency, disordered calcium-phosphate metabolism, and vascular medial calcification—frequently seen in people with long-standing diabetes—have all been associated with CNO and may exacerbate bone fragility [26]. There is also increasing recognition of the genetic and epigenetic predisposition to CNA. Polymorphisms in genes regulating the RANK/RANKL/OPG axis, and recent findings in microRNA and methylation profiles, suggest that only a subset of individuals with diabetic neuropathy develop CNO due to specific molecular susceptibilities [27, 28].

The development of CNO is the result of an exaggerated and unregulated inflammatory response to injury in a neuropathic limb, compounded by metabolic derangements and, in some cases, genetic susceptibility. This cascade of events leads to pathological bone resorption, joint disorganization and ultimately, deformity—hallmarks of the Charcot foot.

Diagnosis

Diagnosis of CNO first and foremost requires clinical suspicion of the condition, especially in patients with diabetes and peripheral neuropathy [29]. The key diagnostic approach for active CNO is shown in Fig. 2.

Fig. 2.

The diagnostic algorithm of active CNO (adapted from IWGDF Guidelines [29])

Clinical Examination

Assessed limb is always compared to the other non-CNO limb. We assess the presence of swelling, erythema, increased skin temperature and foot deformities. Pain is often absent due to neuropathy. A temperature difference greater than 2 °C between the feet (measured on the dorsum) is considered clinically relevant for active CNO. Recently, the importance of home monitoring of skin temperature has increased, with patients regularly measuring and recording temperatures in a diary [30].

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can be used to help exclude infection (but lack sensitivity and specificity).

A recently published study from 31 French and Belgian centres (EPiChar study) showed that in the acute phase, oedema and increased foot temperature was present in 75% of patients and the confirmation diagnosis was made mostly by MRI [31].

Radiological Examination

X-rays may reveal osteolysis, bone fragmentation, and joint collapse. Differential diagnosis between changes due to osteomyelitis or CNO is often challenging. MRI is more sensitive for detecting early changes, such as bone marrow oedema, but its limitation lies in the high level of expertise required for accurate interpretation.

Nuclear Medicine Methods

Nuclear medicine methods, particularly two-day three-phase skeletal scintigraphy combined with SPECT/CT (single-photon emission computed tomography), are suitable alternatives when MRI is unavailable. In some cases, a leukoscan using labelled leukocytes may be necessary to definitively distinguish between osteomyelitis and CNO [32].

Early Diagnostic Markers

A recent study evaluated selected markers that could serve as biomarkers for early detection of CNO: interleukin-6, OPG, bone alkaline phosphatase and CRP. The authors concluded that interleukin-6 (IL-6) was strongly associated with the onset of CNO [33]. Cut-off values ≥ 6.6 for IL-6 showed potential to rule out CNO in high-risk patients, with a positive predictive value of 26.1%, a negative predictive value of 97.9%, a sensitivity of 85.7% and a specificity of 73.4%.

Classification

Several classification systems of CNO have been developed over time to describe, diagnose and guide treatment for this disease. The Eichenholtz classification, developed in 1966, remains the most widely used system, although it has undergone significant modifications to incorporate advances in medical imaging and promote earlier disease recognition [34]. Newer classification systems have emerged to address the limitations of traditional approaches, including anatomical classifications, such as Sanders and Frykberg and Brodsky systems, as well as magnetic resonance imaging (MRI)-based classifications that can detect changes before they appear on radiographs [3]. These various classification frameworks reflect the evolution of our understanding of CNO pathophysiology and the critical importance of early diagnosis and intervention to prevent severe deformities and complications.

Original and Modified Eichenholtz Classification

In 1966, orthopaedic surgeon Sidney N. Eichenholtz published a landmark monograph entitled "Charcot Joints" that fundamentally shaped how this condition would be classified for decades [1, 2]. Eichenholtz’s classification was based on clinical, radiographic, and pathologic data from 68 consecutive patients [34, 35]. However, the original Eichenholtz classification was limited as it did not account for early-stage CNO that presented without radiographic changes. Clinical signs of CNO were often present before any radiographic changes could be detected. To address this gap, Shibata et al. in 1990 added a ‘Stage 0’ to the conventional Eichenholtz classification (Table 1). The addition of this prodromal stage has important therapeutic implications because immobilization and off-loading of feet with Stage 0 symptoms may prevent progression of skeletal destruction and deformity [35, 36]. The modified Eichenholtz classification provides a more comprehensive framework for early diagnosis and intervention, potentially preventing severe complications.

Table 1.

Modified Eichenholtz classification (Shibata 1990)

Stage	Pathology/radiological findings	Clinical
0	Normal radiographs, can only be visualized through advanced imaging, such as MRI, which shows bone marrow oedema	Unilateral red, hot, swollen foot and leg
I	Osteopenia, osseous fragmentation, joint subluxation or dislocation on radiographs	Swelling, erythema, warmth and ligamentous laxity
II	Absorption of debris, sclerosis and fusion of larger fragments	Decreased warmth, swelling and erythema
III	Consolidation of deformity, fibrous ankylosis and rounding and smoothing of bone fragments	Absence of warmth, swelling and erythema with potential fixed deformity

Sanders and Frykberg Classification

The Sanders and Frykberg classification identifies five zones of disease distribution according to anatomical location in the foot [3]:

• Zone I: Involves the metatarsophalangeal and interphalangeal joints (forefoot).

• Zone II: Affects the tarsometatarsal joints (Lisfranc's joint)—affected in about 45% of cases (most commonly involved).

• Zone III: Involves the naviculocuneiform, talonavicular and calcaneocuboid joints (Chopart's joint)—affected in about 35% of cases.

• Zone IV: Affects the ankle and subtalar joints.

• Zone V: Involves the calcaneus.

This classification is particularly useful because it can be used without additional clinical information and helps predict patterns of deformity based on anatomical involvement [3].

Brodsky Classification

The Brodsky classification is another widely used anatomical system specifically designed for the foot, based on the most commonly affected regions [35, 37].

Original Brodsky system was later modified by Trepman et al. [38] to include type 4 and type 5 (Table 2).

Table 2.

Modified Eichenholtz classification (Shibata 1990)

Type	Location	Description
1	Midfoot	Involves the tarsometatarsal and naviculocuneiform joints
2	Hindfoot	Affects the subtalar and/or Chopart joint
3A	Ankle	Involves the tibiotalar joint
3B	Calcaneus	Involves a fracture of the calcaneal tuberosity
4	Multiple areas	Multiple areas with sequential or concurrent involvement
5	Forefoot	Forefoot with metatarsophalangeal involvement

The modified Brodsky classification is often used concurrently with the modified Eichenholtz classification to facilitate a comprehensive management of CNO. A recent study by Wukich et al. assessed the intra- and inter-reader reliability of Sanders–Frykberg and modified Brodsky classification systems for CNO. The findings indicated that both classifications demonstrated moderate to substantial reliability among different readers [37]. This suggests that these systems can be consistently applied in clinical settings to classify CNO in people with diabetes [37].

Classification Summary

The ideal classification system should facilitate early diagnosis, accurately predict disease progression, guide appropriate treatment, and ultimately help prevent the devastating consequences of untreated CNO, including severe deformity, ulceration and need for amputation. As our understanding of the pathophysiology of CNO continues to advance and imaging technologies improve, classification systems will likely continue to evolve to better serve these clinical goals. The integration of temporal, anatomical and imaging-based approaches may provide the most comprehensive framework for managing this complex condition.

Treatment

General Approach

Contemporary management of CNO emphasizes early detection and prompt intervention. Recent evidence-based guidelines, including the 2024 surgical management algorithm, stress the necessity of a multidisciplinary team approach in addressing this complex condition. The algorithm synthesizes current best practices based on literature from 2003 to 2023, providing clinicians with a structured decision-making Framework [39].

The Northern Diabetes Foot Care Network guidelines, incorporating NICE guidance, outline a clear pathway for active CNO management [5]. These guidelines recommend immobilization as the primary intervention, with total contact casting (TCC) representing the gold standard treatment. Initial TCC should be removed and recast after seven days owing to significant reduction in swelling, followed by reviews every 1–2 weeks to reassess infrared dermal temperatures for improvement of the foot clinically and to monitor cast fit [40, 41].

The general approach to treating Charcot foot involves an initial phase of strict immobilization and non-weight-bearing, typically using a TCC or specialized boot, to reduce inflammation, prevent further deformity and allow bone healing [29]. Once the acute phase subsides and the foot stabilizes, gradual weight-bearing is introduced with custom orthotic devices or footwear; surgical intervention is reserved for cases with severe deformity, instability or recurrent ulceration that do not respond to conservative management.

Treatment success rates provide some encouragement, with 70% of feet showing resolution of CNO with nonoperative treatment at a mean of 6 ± 5 months in a Canadian study [42]. However, surgical intervention remains necessary in approximately 26% of feet, with lower-limb amputation required in 8% of cases. Among patients who do not require amputation, 61% need custom foot orthoses for long-term management [42].

The ulcer-free rate at 6- and 12-months post-treatment stands at 60% and 58%, respectively, highlighting the ongoing risk of complications even after initial management. This continuing vulnerability emphasizes the importance of lifelong foot care and appropriate accommodative footwear.

Offloading

Modern diagnostic approaches increasingly incorporate temperature assessment (especially self-evaluation at home), with a temperature difference of less than 2 °C between corresponding locations on the two feet for 4–6 consecutive weeks serving as a criterion for inactive disease.

The primary goals of offloading in the Charcot foot is to stop the inflammation-mediated damage of bones, joints and soft tissue structures, to stabilize skeleton and protect the foot from further deformities, to promote the healing process including any associated ulcerations, to prevent complications, such as infection and amputation, and maintain long-term foot structure and function.

Effective offloading achieves these goals by redistributing pressure away from vulnerable areas and immobilizing unstable joints [8]. If implemented correctly and promptly, offloading can significantly alter the natural history of this condition, potentially preventing the characteristic ‘rocker-bottom’ deformity that often develops in untreated cases [1].

There exist a wide range of off-loading modalities recommended for the treatment of Charcot foot, each with specific advantages, disadvantages and limitations. The selection of an appropriate offloading device depends on various factors including disease stage, location of pathological process, presence of ulceration, patient compliance, mobility and weight and resource availability and clinical expertise.

The TCC is widely regarded as the gold standard for offloading in acute Charcot foot (Fig. 3) [43]. These specialized casts are designed to stabilize the skeletal structure of the affected foot, reduce maximal plantar pressures and prevent further progression of bone destruction, swelling and foot deformity development. TCCs are indicated in patients with relatively stable forms of Charcot foot, predominantly of Sanders–Frykberg types I–III [3]. In some cases, however there is more advanced destruction of the foot combined with joints instability and not so rarely with diabetic foot ulcers and osteomyelitis. Empirically, we recommend stabilizing the foot by a combination of a special contact splint with wheelchair [44].

Fig. 3.

Total contact cast (author’s archive)

The TCC redistributes plantar pressures by molding intimately to the foot’s contours to maximize the plantar contact area, evening out weight bearing across the entire sole, transferring roughly 30% of the load from the foot onto the rigid cast walls and markedly reducing peak pressures beneath the metatarsal heads, toes and heel [45]. Its mechanism of action combines immobilization of the foot and ankle—locking the heel and toes to eliminate shear and the propulsive phase of gait—with load-sharing and load-transfer principles, thereby offloading high-pressure zones, protecting vulnerable tissue from microtrauma and promoting ulcer healing [46].

While TCCs represent the standard of care, adherence can be an issue due to factors such as intolerance, bulk, and presence of skin disorders. TCCs are also contraindicated in the presence of unresolved infection and severe ischemia. These can be broadly categorized as removable or irremovable knee high or ankle orthoses. Ankle orthosis, post-operative, preventive or individual shoes are not indicated for treatment of active CNO stages [29].

Principally, irremovable knee-high orthoses should be as effective as TCC [47]. We recommend when possible to use knee high orthoses, preferably making it irremovable [48], rather than ankle orthoses in active CNO. We also prefer customized to prefabricated ones especially in patients complicated by severe deformities, oedema or non-physiological limb configuration (such as fixed ankle varus deformity in the case of CNO).

Studies comparing different off-loading modalities have yielded mixed results [48, 49]. One prospective study that randomized 60 patients comparing TCC, irremovable walking boots and removable walking boots found no significant differences in healing time between the groups [50]. Mean healing time in those three groups did not differ (p = 0.56), and survival analysis also showed no difference between the groups (logrank test p = 0.83). However, another study showed that patients treated with TCCs had higher proportions of healed wounds and faster healing times compared to alternatives (healing sandals and shear-reducing removable boots) [51]. In the intent-to-treat analysis, significantly higher proportion of patients were healed in the TCC group (69.6%) compared to those treated with the shear-reducing foot bed (22.2%, p < 0.05). Although, there was no difference in the rate of healed ulcers in the healing sandals (44.5%) and TCC groups.

Another off-loading device suitable for the treatment of CNO is the Charcot Restraint Orthotic Walker (CROW). It is a rigid, custom-made boot designed specifically for patients with CNO [52] and distributed especially in the USA. It consists of a fully enclosed ankle/foot orthotic with a rocker-bottom sole to facilitate movement. The device has a soft footbed and cushioned liner to provide comfort while maintaining rigid external support. The CROW works by reducing destructive forces in the foot and ankle, protecting the bone while simultaneously reducing pressure on the plantar surface. It is typically prescribed after the acute phase has been managed with TCCs or other irremovable devices and serves as a transition to more conventional footwear.

Patients suffering from unstable CNO of Sanders–Frykberg types I–III, stable Sanders–Frykberg type IV, V or more advanced CNO destruction are empirically treated by Sarmiento orthoses—dynamic or non-dynamic (Fig. 4). Dynamic Sarmiento orthoses completely offload the main weight bearing structures such as the talus, calcaneus, ankle joint or the whole foot. Non-dynamic Sarmiento orthoses, known as the Patellar Tendon Bearing (PTB) castings have also emerged as an effective offloading method, particularly for Charcot foot complicated by diabetic foot ulcers [48]. This technique allows patients to fully weight-bear on the affected limb as tolerated, while still providing effective pressure redistribution. A retrospective study found that patients treated with PTB casts had better outcomes compared to those treated with removable devices, with complete resolution of the condition in a higher percentage of patients [48].

Fig. 4.

Sarmiento orthosis (author’s archive)

After the acute phase has been managed and stability achieved, patients are transitioned to therapeutic footwear and orthoses for long-term management [8]. In general, customised therapeutic footwear is indicated for the long-term management of Charcot foot due to the development of deformities or biomechanical alterations. Custom-made orthopaedic footwear are effective in limb preservation and have been reported to achieve this in nearly 93% cases within 5 years [53]. Patients may then be weaned into supportive footwear with customised foot orthoses [29].

The duration of offloading treatment varies considerably based on disease severity, patient adherence to treatment, quality of recalcification therapy and chosen off-loading method. For acute CNO, TCC treatment typically continues throughout the active phase, with average duration for offloading reported between 2.7 and 7.8 months [54].

Fejfarova et al. showed in a study of removable TCC therapy that patients with diabetic foot ulcers were treated for an average of 6 ± 4.2 months, while those with acute CNO were treated for 5.1 ± 4 months [55]. On the other hand, the large study from the UK observed casting requirement for a median of 9 months till the foot became quiescent. After inflammation subsides, patients are gradually transitioned to less restrictive devices [56].

Healing rates also vary by intervention type. Several studies have specifically reported the time to resolution of acute CNO when managed with TCC [43, 57, 58]. These data confirm that acute Charcot foot managed with TCC typically requires 3–5 months of immobilization for remission, with individual studies reporting durations ranging from 12 weeks up to 7–8 months, depending on patient- and foot-specific factors. In a retrospective study in patients with CNO, the median TCC duration for resolution of acute Charcot foot was 4.3 (IQR 2.7–7.8) months. Post TCC treatment, 48.1% returned to footwear with custom foot orthoses, 25.9% used a life-long Charcot Restraint Orthotic Walker, and 22.2% had soft tissue or bone reconstructive surgery [51]. Non-removable devices generally demonstrate higher healing rates compared to removable alternatives, largely attributed to ensured compliance.

The average management time ranges from 2 to 12 months, with confirmed inactive Charcot diagnosis indicated by complete resolution of clinical signs/symptoms, temperature difference less than 2 °C at corresponding locations for 4–6 consecutive weeks, and weight-bearing x-rays confirming the remodelling phase. Long-term management includes gradual transition to weight-bearing, appropriate footwear with offloading orthoses and potentially custom footwear for moderate or severe deformities. Again, a multi-disciplinary approach to management is essential to optimize best functional outcomes [43, 59].

Pharmacological Treatment

Pharmacological therapy has been investigated as a potential adjunct to the primary management strategy for CNO as presented in Table 3 which describes the pharmacological agents that have been trialled for the treatment of CNO. Given the key role of inflammation and osteoclast-mediated bone resorption in CNO pathophysiology, several agents (Table 3) have been tested with the aim of accelerating remission or preventing deformity [60–62]. However, according to the 2023 guidelines of the International Working Group on the Diabetic Foot (IWGDF), there is currently insufficient evidence to support the routine use of pharmacological treatment in CNO [29].

Table 3.

Drugs trialled to treat Charcot foot

Drug/class	Study/year	N (patients)	Study design	Key findings	Limitations
Pamidronate (Bisphosphonates)	Jude et al., 2001	39	Double-blind RCT	Reduction in bone turnover markers and symptoms; no change in skin temperature	No effect on time to remission; surrogate outcomes only
Alendronate (Bisphosphonates)	Pitocco et al., 2005	20	RCT	Reduced BTMs, improved foot mineralisation, no significant clinical benefit	Small sample size; no functional outcomes; unblinded
Zoledronate (Bisphosphonates)	Pakarinen et al., 2011	35	Double-blind RCT	Zoledronate prolonged immobilisation time; no improvement in remission	Remission criteria varied; relapse rates not reduced
Zoledronate (Bisphosphonates)	Das et al., 2021	36	RCT, 3-arm study	Increased BMC; no difference in remission time versus placebo	Underpowered for long-term outcomes; limited clinical relevance
Calcitonin (intranasal) (Calcium metabolism modifier)	Bem et al., 2006	32	RCT	Reduced BTMs (1CTP, BALP); no effect on temperature or remission	Short follow-up; no placebo; renal impairment in cohort
Denosumab (RANK ligand inhibitor)	Busch-Westbroek et al., 2018	22	Controlled trial with retrospective controls	Shorter remission and fracture healing time versus historical controls	Non-randomised control; unclear CNO diagnostic criteria
Denosumab (RANK ligand inhibitor)	Lasschuit et al., 2024	24	Phase II RCT, open-label	Preserved calcaneal bone quality (Stiffness Index); 92% versus 67% temperature resolution (NS)	Small sample; open-label; temperature resolution not statistically significant
Methylprednisolone (Synthetic glucocorticoid)	Das et al., 2021	11	RCT arm (3-arm study)	Prolonged immobilisation; decreased BMD	Negative impact; not suitable for routine use
Recombinant parathormone (Calcium metabolism modifier)	Petrova et al., 2021	48	Double-blind RCT	Did not reduce time to resolution or enhance fracture healing of CN	Annual recruitment was slower than anticipated. During the second year of the trial, there was unprecedented global shortage of the investigational medicinal product.

Bisphosphonates, such as pamidronate, alendronate and zoledronate, act by inhibiting osteoclast activity and have been studied for their antiresorptive effects [61]. While early reports indicated possible improvements in bone turnover markers and symptom relief, more recent clinical trials and systematic reviews have not demonstrated consistent benefits in reducing time to remission or preventing complications [63]. For example, in a randomised trial, zoledronate was found to increase foot bone mineral content, but without significant impact on long-term outcomes such as fracture or deformity rates [64]. Denosumab, a monoclonal antibody against RANKL, offers a more selective inhibition of osteoclastogenesis. It has shown promise in smaller studies, particularly in individuals with contraindications to bisphosphonates, such as those with impaired renal function. Nevertheless, the IWGDF guidelines advise against its routine use in active CNO, citing a lack of robust evidence and the need for further research [22, 29]. Other pharmacological interventions, including intranasal calcitonin and systemic corticosteroids, have also been explored. Calcitonin has shown limited efficacy, and corticosteroids were associated with reductions in bone mineral content, making them unsuitable for use in this context [60, 64]. Vitamin D and calcium supplementation may be considered in individuals with documented deficiency, but they are not indicated as disease-specific treatment for CNO.

While the concept of pharmacologically targeting bone turnover and inflammation in CNO is promising and ‘makes sense’, current IWGDF guidelines do not endorse such treatment as standard care [29]. Well-designed prospective studies are needed to clarify whether specific subgroups of patients may derive benefit from antiresorptive and/or immunomodulatory interventions.

RCT—randomized controlled trial, CNO—Charcot neuropathic osteoarthropathy, BTM—Bone turnover markers, BDM—Bone density markers, BMC—Bone mineral content, 1CTP—Pyridinoline cross-linked carboxyterminal telopeptide, BALP—Bone alkaline phosphatase, RANK—Receptor activátor of nuclear factor kappa B

Future Directions in the Pharmacological Treatment of Charcot Foot

Emerging pharmacological strategies for CNO focus on modulating bone remodelling pathways and inflammation. One promising target is sclerostin, a Wnt pathway inhibitor produced by osteocytes. Anti-sclerostin antibodies (e.g. romosozumab) enhance osteoblast activity and bone formation, and while currently approved for osteoporosis, their potential in CNO has been explored preclinically [65]. Another avenue includes gene and ribonucleic acid (RNA)-based modulation of the RANKL/OPG pathway to suppress osteoclastogenesis selectively. Immunomodulatory agents targeting IL-1β or TNF-α, key mediators of the inflammatory response in acute CNO, are under investigation in animal models. They show attenuation of bone loss and joint destruction. In parallel, the identification of genetic variants affecting auto-immune regulation (e.g., in RANK, OPG, or Wnt signalling) may enable future stratification of patients for individualized therapy [66, 67]. Although these interventions remain experimental, they represent a rational direction for future targeted therapies in CNO, particularly in individuals unresponsive to standard offloading or with high risk of skeletal complications.

A retrospective case–control study of 200 diabetic foot patients demonstrated that lower haemoglobin levels and elevated C-reactive protein, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio are significantly associated with increased risk of lower-limb amputation [68]. These findings suggest that routine monitoring of haemoglobin, CRP, as well as neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in patients with Charcot foot may help identify those at higher amputation risk and prompt early, targeted interventions to preserve limb integrity.

Surgical Management

While conservative management with TCC remains the first-line treatment, surgical intervention becomes necessary in specific scenarios. The primary indications for surgery in the acute phase is usually severe dislocation or instability threatening skin integrity [69]. Surgical management may also be considered in cases where bony prominences can result in skin breakdown or when conservative management has failed [69]. In the chronic phase of CNO, surgical management may be considered in the following situations: (i) recurrent ulceration at sites of deformity, (ii) gross instability preventing functional ambulation, (iii) severe fixed deformity that preclude use of therapeutic footwear and (iv) after previous failed surgical interventions such as exostectomy [70].

The optimal timing for Charcot foot surgery remains controversial. Classical teaching advises against surgery during the active inflammatory phase (i.e. modified Eichenholtz stages 0–1) and instead recommends for intervention when bone fragments have begun to coalesce (i.e. modified Eichenholtz stage 2) [71].

Recent research comparing outcomes shows higher complication rates (amputation, reoperation and non-union) when surgery is performed during active disease compared with when CNO is inactive [72]. A systematic review found the amputation rate for surgery in the inactive stage was 10.5% versus 12.3% for active/inactive combined cases, while reoperation rates were 31.2% versus 50.0%, respectively [71]. However, some surgeons advocate for early intervention in specific cases to prevent progressive deformity. For instance, when immobilization began within 4.1 weeks of symptom onset, no progression to fracture occurred, whereas delayed treatment (average 6.8 weeks) resulted in disease progression and multiple surgeries in all patients [69].

Surgical Procedures and Techniques

Recent studies have demonstrated successful outcomes with adherence to modern treatment protocols. Pinzur et al. achieved 95.7% limb salvage with a protocol involving radical resection of bone, correction of deformity, external fixation and culture-specific antibiotic therapy [73]. This high success rate underscores the importance of aggressive intervention according to contemporary guidelines.

Exostectomy

This relatively simple procedure involves excision of bony prominences, particularly in a stable Charcot foot with localized bone prominences causing impending ulceration [70]. Studies show success rates of approximately 62% [74], though complications include wound healing problems, recurrent ulceration, and potential instability requiring further intervention.

Reconstructive Arthrodesis

More extensive reconstruction aims to create a stable, plantigrade foot through arthrodesis procedures. This approach is particularly valuable for severely unstable feet or those with recurrent ulceration after failed conservative or simpler surgical treatments [75].

Fixation Methods

Internal Fixation

Modern internal fixation has evolved beyond conventional plates and screws to include locking plate technology that offers fixed-angle constructs for better stability in poor-quality bone [76]. Another approach could be intramedullary beaming techniques using solid bolts or cannulated screws [77]. Custom-designed implants with thread modifications for improved osteointegration emerged recently [78]. These advanced fixation methods are crucial when dealing with the compromised bone quality typical in Charcot patients [79].

External Fixation

External fixators (Fig. 5), particularly circular frames, such as the Ilizarov apparatus, provide solutions for complex cases requiring: (i) management of concurrent soft tissue problems or infection, (ii) gradual correction of severe deformities or (iii) supplementation of internal fixation [80]. This approach is valuable for patients with active infection, ulceration or those who cannot tolerate extensive dissection.

Fig. 5.

External fixation in CNO patients (author’s archive)

Minimally Invasive Techniques

Recent innovations include minimally invasive surgical approaches for Charcot reconstruction that significantly reduce soft tissue complications. Those methods involve percutaneous correction using specialized burrs, small stab incisions for better access to the bone, intramedullary beaming through limited approaches and injectable bone grafts to promote fusion [81]. These techniques require specialized expertise with a learning curve of approximately 20–40 cases for proficiency but show promise in reducing the historically high wound complication rates in these high-risk patients.

Emerging Technologies

Technological advances continue to enhance surgical capabilities for CNO treatment. Three-dimensional (3D)-printed customized titanium implants based on patient-specific computed tomography (CT) data could improve precision treatment [82]. Another useful technique is computer-navigated deformity correction. Gradual correction of a Charcot deformity through the use of computer-assisted hexapod external fixation, has demonstrated safe, accurate and reproducible characteristics that adequately prepare the lower extremity for modified Eichenholtz stage 2 CNO [83].

Combined internal/external fixation methods have been used in several studies and demonstrated the added benefit of this technique at maintaining the structure of the reconstructed foot [84]. The combined technique was also utilized in 18 patients with CNO and resulted in positive outcomes such as a 94% limb salvage rate, 100% fusion rate, enhanced ambulation capacity and improved pain and ulcer-free survival rates at 1 year [85]. These innovations provide surgeons with better tools for addressing the complex deformities encountered in Charcot foot reconstruction.

Postoperative Protocol and Management

Postoperative management is critical for successful outcomes and typically includes an initial non-weight-bearing period in a splint or cast (2–8 weeks) and regular radiographic assessment for healing progression [86]. The transition to protected weight-bearing can be initiated when bony fusion is evident (8–14 weeks). The total recovery period is substantial, with some patients requiring 6–12 months before returning to normal footwear and activities [69]. Serial MRI monitoring every 3 months until resolution of inflammatory changes (average 8.3 months) helps determine appropriate immobilization duration.

Future epidemiological research should focus on standardizing diagnostic criteria, identifying predictive biomarkers and developing risk stratification models to enable earlier intervention in high-risk populations. Additionally, studies examining geographic and ethnic variations in prevalence and presentation would contribute valuable insights into the condition’s underlying pathophysiology and potentially yield targeted prevention strategies. As the global prevalence of diabetes continues to rise, understanding the epidemiology of CNO becomes increasingly vital for effective public health planning and clinical practice.

Clinical Outcomes and Prognosis

Clinical outcomes and prognosis relating to CNO are largely dependent on timely diagnosis and management. Studies that compared early and delayed diagnosis (and management) of CNO reported significant differences in clinical outcomes. Functional outcomes vary considerably among patients. Data from a recent systematic review indicate that only 61% of patients resume normal walking following treatment, while approximately one-quarter become wheelchair-dependent [63]. These mobility limitations significantly impact quality of life and underscore the importance of early intervention.

Mortality rates among patients with Charcot foot remain concerningly high. A Danish study that included 392 patients and reported 5-year mortality of 14% with a mean survival time of 12.7 years [87]. A 5-year mortality of 13% was observed in the Thai cohort, while other studies have reported mortality rates as high as 28.3% within 5 years of diagnosis [6]. These elevated mortality figures likely reflect both the severity of underlying diabetes and the complications associated with reduced mobility and foot complications.

Conclusions

Charcot foot is a serious but often underestimated condition that requires timely and thorough diagnosis and treatment. With a comprehensive approach that includes immobilization, offloading of the affected lower limb and pharmacotherapy, disease stabilization and prevention of serious complications can be achieved. Patient education and regular monitoring are key elements of successful treatment and prevention of recurrent and contralateral episodes. Future research should focus on long-term outcomes of different treatment modalities, early detection strategies and the identification of radiological or biochemical markers to predict disease progression and optimize individualized care. Unmet needs include standardized diagnostic criteria, robust evidence guiding treatment choices and improved methods for monitoring disease evolution and resolution to prevent recurrence and reduce complications.

Declarations

Funding

Supported by the National Institute for Research on Metabolic and Cardiovascular Diseases (Programme EXCELES, Project No. LX22NPO5104), funded by the European Union Next-Generation EU and by the Ministry of Health of the Czech Republic NW24-09-00184.

Conflict of interest

None of the authors (Dubský M, Bém R, Sojáková, Fejfarová V, Hughes M, Jude EB) have any conflicts to report.

Ethics approval

Not applicable.

Consent (participation and publication)

Not applicable.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Code availability

Not applicable.

Author contributions

M.D. wrote the manuscript, R.B. wrote pathogenesis and pharmacotherapy and carried out visualization; D.S. carried out visualization and edited the manuscript; V.F. wrote offloading, edited the manuscript; M.H. edited the manuscript; E. J. edited and supervised the manuscript.