Investigating the Use of Denosumab in the Treatment of Acute Charcot Neuroarthropathy.

Charcot neuroarthropathy is a devastating condition, most commonly affecting poorly controlled diabetic patients with peripheral neuropathy. Pharmacological options for the condition are currently limited. The purpose of this study was to investigate the potential of Prolia® (denosumab) as a safe and feasible option in the treatment of acute Charcot neuroarthropathy. A total of 7 consecutive subjects were enrolled and followed for 1 year. Subjects received a single one-time injection of denosumab 60 mg. Subjects also received standard of care treatment, which included total contact casting, restricted weightbearing status, and biweekly office visits until normalization of the skin temperature gradient. Overall, the pharmaceutical treatment was generally well-tolerated. One subject developed a diabetic foot infection with cellulitis of the contralateral lower extremity, which occurred following the 6-month follow-up visit and which resolved with oral antibiotics One subject identified transient muscle pain in the same upper extremity which received the injection. Subjects were found to exit the acute phase of the condition at an average of 52.00 ± 17.89 days after their injection, which was defined by normalization of skin temperature to within 2°C of the contralateral foot. Treatment of acute Charcot neuroarthropathy with denosumab was well-tolerated in this open-label, pilot study. The clinical outcomes suggest that the medication may be efficacious, though a larger sample size would be needed to confirm these preliminary results. An adequately-powered, randomized, controlled study may be an appropriate follow-up.

Charcot neuroarthropathy after simultaneous pancreas-kidney transplantation: risk factors, prevalence, and outcome.

We retrospectively analyzed outcome and risk factors of developing Charcot foot (CF) in 100 patients with type 1 diabetes mellitus who underwent a simultaneous pancreas-kidney (SPK) transplantation. Patients who developed CF after SPK transplantation had significantly higher mortality (56% vs. 18%) and more frequently graft failure (44% vs. 13%). Recipients with CF also experienced acute rejections more frequently (78% vs. 41%). They furthermore had higher pre-transplant values of HbA1c , received cyclosporine and azathioprine more often, and had significantly higher cumulative corticosteroid use. Patients transplanted in an earlier era (1992-1998) received cyclosporine and azathioprine more often and had a significantly higher cumulative corticosteroid use with the higher prevalence of CF. Conversely, patients with diabetes transplanted more recently (1999-2012) received lower doses of corticosteroids as part of their tacrolimus-based immunosuppressive therapy, resulting in fewer CF attacks. In conclusion, development of CF after SPK is associated with poor patient and graft outcome. Poor pre-transplant diabetic control and the use of high-dose corticosteroids are risk factors for the development of CF. We recommend reduction in or even total avoidance of corticosteroids after SPK transplantation. Given the importance of the diagnosis of CF on outcome, a systematic examination of SPK patients' feet is recommended.

Effect of immobilization, off-loading and zoledronic acid on bone mineral density in patients with acute Charcot neuroarthropathy: a prospective randomized trial.

BACKGROUND: Bisphosphonates are commonly used as an adjuvant in the management of acute Charcot neuroarthropathy (CNA), although the clinical efficacy of the treatment is controversial. The aim of the present study is to investigate the effect of immobilization and zoledronic acid on bone mineral density (BMD) changes during the treatment of acute CNA. METHODS: Thirty-five patients with acute midfoot CNA were randomly assigned to treatment with either zolendronic acid or placebo. BMD of the lumbar spine and both hips was measured at baseline and after six months of treatment. RESULTS: Comparison between BMD at presentation and at 6 months demonstrated a significant fall in BMD in the placebo group at the CNA-affected femoral neck (-3.2%, p=0.016) and in the CNA-free hip (-1.2%, p=0.026). Conversely, a significant rise in BMD was observed in the zolendronic acid group at all measured areas of the CNA-free hip. DISCUSSION AND CONCLUSIONS: Immobilization and off-loading does not lead to marked disuse osteoporosis in patients with acute CNA after 6 months of treatment. Treatment with zoledronic acid led to a statistically significant increase in hip BMD compared to placebo.

A Surgeon's guide to advances in the pharmacological management of acute Charcot neuroarthropathy.

Acute Charcot neuroarthropathy is a devastating condition and, its incidence is increasing. Currently, treatment consists of immobilisation and off-loading of the involved extremity. Outcomes are frequently poor and novel treatments are being sought urgently. This review aims to outline advances in the pharmacological treatment of this, condition. PubMed and the Cochrane Database of systematic reviews were searched. Relevant papers were cross referenced. Eleven original studies were identified. The limited data available suggest pamidronate, alendronate and calcitonin provide some clinical and biochemical improvements while zoledronic acid is deleterious and, increases off-loading times. However, the data is not robust enough to convincingly demonstrate clinically meaningful effects. The studies were predominantly low quality and heterogeneous. They differed markedly in study type, pharmacological agent used, dosing regimen, disease, aetiology/stage/location, concurrent off-loading regimen, outcomes and, follow-up. Few were rigorous in controlling for associated confounding variables and none investigated long term outcomes. The routine use of pharmacological treatment modalities for this condition is not recommended in the United States by the Food and Drug Administration or in the United Kingdom by the National Institute for Health and Clinical Excellence. Given the evidence available this is justified and further higher quality research is required.

Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature.

AIM/HYPOTHESIS: We undertook a systematic review of the literature concerning the efficacy and safety of bisphosphonates in acute Charcot neuropathic osteoarthropathy. METHODS: MEDLINE, PubMed, the Cochrane Database of Systematic Reviews, and abstracts presented during the meetings of the American Diabetes Association and the European Association of Diabetes were searched for relevant publications from the period January 1990 to September 2011. RESULTS: A total of ten studies on the treatment of acute Charcot osteoarthropathy with bisphosphonates were identified and included in the analysis. Only four clinical trials were published, three of which were randomised. Bisphosphonates appeared to induce significant reductions in skin temperature and bone turnover markers compared with placebo, without serious adverse events. Nevertheless, bisphosphonates did not shorten the immobilisation time. Moreover, no data were available regarding their long-term effects. CONCLUSIONS/INTERPRETATIONS: Bisphosphonates have been shown to be effective for reducing bone turnover markers and skin temperature in some studies. Nevertheless, the long-term efficacy, specifically that regarding the occurrence of deformities and ulcerations, remains to be demonstrated as no follow-up studies have been published. Moreover, some studies have suggested that bisphosphonates may lengthen the resolution phase of the disease. In our opinion, the data are too weak to support the use of bisphosphonates as a routine treatment for acute Charcot neuroarthropathy.

Audit of acute Charcot's disease in the UK: the CDUK study.

AIMS/HYPOTHESIS: We studied factors associated with the development and resolution of acute Charcot foot using a web-based observational study. METHODS: Clinicians managing cases of acute Charcot foot in the UK and Ireland between June 2005 and February 2007 were invited to register anonymised details on a secure website. RESULTS: A total of 288 cases (age 57.0 ± 11.3 years [mean ± SD]; 71.2% male) were registered from 76 centres. Of these, 36% of patients recalled an episode of relevant trauma in the preceding 6 months, while 12% had had surgery to the affected foot. In 101 (35%) cases, ulceration was present at registration and 20% of these had osteomyelitis. Non-removable off-loading devices were used at presentation in 35.4% of cases, with removable off-loading used in 50%. Data on resolution were available for 219 patients. The median time to resolution was 9 months in patients whose initial management included the use of non-removable off-loading, compared with 12 months in the remainder (p = 0.001). Bisphosphonates were administered intravenously in 25.4% and orally in 19.4% of cases. The median time to resolution in patients who received bisphosphonates was 12 months and was longer than in those who did not (10 months, p = 0.005). CONCLUSIONS/INTERPRETATION: The median time to resolution was longer than in earlier series. Although limited by being observational and non-randomised, these data suggest that the use of non-removable off-loading at presentation may shorten the time to resolution. They provide no evidence to indicate that the use of bisphosphonates is beneficial.

Knee Reconstruction Using 3D-Printed Porous Tantalum Augment in the Treatment of Charcot Joint.

BACKGROUND: Charcot joint disease is a rare neurogenic lesion of the joint characterized by progressive joint destruction with dislocation or subluxation. However, whether a joint replacement should be performed for severe joint damage is controversial. CASE PRESENTATION: This paper reports a case of severe Charcot joint disease with a large bone defect that was treated with arthroplasty assisted by a customized 3D-printed porous tantalum. The patient was admitted to the hospital with a 9-year history of bilateral knee pain that had aggravated in the past 2 months. Radiography showed osteogeny and sclerosis in both knees, free bone fragments, heterotopic ossification, new bone, and osteophyte formation, irregular margins, apparent narrowing of joint space, and severe joint damage (Anderson Orthopedic Research Institute classification type III). Based on the present illness, history, imaging, and laboratory examination, Charcot joint disease was confirmed. Conservative treatment has been reported in the literature. There are limited reports on the surgical treatment of severe Charcot joint disease. We followed up with the patient for a year after the operation, and the imaging and clinical evaluation results were good. Postoperative X-ray examinations showed good alignment of force lines, good joint space, and no evidence of loosening. The patient was mobile and did not need crutches. CONCLUSIONS: Through accurate surgical evaluation and preparation of 3D-printed porous tantalum implants, severe AORI classification type III Charcot joint disease can effectively restore the range of motion of the knee joint, the lower limb alignment, and finally achieve good functional results of walking without crutches.

Inappropriate antibiotic administration in the setting of Charcot arthropathy: A case series and literature review.

AIMS: Differentiating Charcot neuropathic osteoarthropathy (CN) from infection is challenging. The diagnosis of CN is often missed or delayed, resulting in inappropriate and delayed treatment. We hypothesized that the misdiagnosis of CN results in inappropriate antibiotic prescriptions and explore the sequelae of unnecessary antibiotic use. METHODS: A retrospective review of patient electronic medical records from January 2010 to December 2017 was conducted for those diagnosed with CN after being referred to an orthopaedic foot and ankle specialist. RESULTS: Our review showed 58 of 103 (56%) patients received antibiotics on the date, or within the next 7 days, of referral to foot and ankle orthopaedic specialist. The antibiotic of choice given on referral were as follows: Sulfamethoxazole/Trimethoprim 18 of 58 (31%), doxycycline 13 of 58 (22%), clindamycin 13 of 58 (22%), cephalexin 9 of 58 (16%), minocycline 5 of 58 (9%). CONCLUSION: Missed diagnoses for CN are common and result in complications stemming from inappropriate treatment, delays in appropriate therapy, and may accelerate antibiotic resistance. Misdiagnosis of CN contributes to the inappropriate use of prescription antibiotics.

Efficacy of medical treatment for Charcot neuroarthropathy: a systematic review and meta-analysis of randomized controlled trials.

No pharmacotherapeutic agents are yet recommended for active CN though many anti-resorptive agents have been studied. We conducted a systematic review and meta-analysis of the randomized placebo-controlled trials (RCTs) evaluating the time to remission of active CN with anti-resorptive or antiinflammatory drugs. RCTs published in PubMed, EMBASE, SCOPUS and Cochrane Library from January 1994 to December 2019 were accessed. We reviewed studies and extracted information on study design, participants' characteristics, time to remission, bone turnover markers, bone mineral content (BMC) and temperature difference between feet. Five RCTs out of 588 total identified records were included. Standardized mean differences (SMD) between groups with 95% CI are summarized. Pharmacotherapy nonsignificantly increased time to remission [SMD 0.52 weeks (- 0.71, 1.75), p = 0.402; I2 = 88.6%] as compared to TCC alone. The pooled median time to remission with the intervention was 18.5 weeks (11.2, 28.1) compared to 16.8 weeks (8.7, 27.7) with TCC. A nonsignificant increase in BMC [SMD 3.39% (- 0.78, 7.56), p = 0.109; I2 = 96.7%], a decrease in foot temperature [SMD - 0.42 °C (- 0.78, - 0.07), p = 0.020; I2 = 0%] and alkaline phosphatase [SMD = -2.51% (- 3.24, - 1.77), p < 0.001; I2 = 0%] was observed with intervention. Limited evidence from available studies does not support the role of anti-resorptive or anti-inflammatory drugs for earlier remission when added to offloading with total contact cast for active CN of the foot.

Long-term foot outcomes following differential abatement of inflammation and osteoclastogenesis for active Charcot neuroarthropathy in diabetes mellitus.

AIMS: Inflammatory osteolysis is sine-qua-non of active Charcot neuroarthropathy (CN) causing decreased foot bone mineral density (BMD) and fractures. We aimed to explore the effect of anti-inflammatory or anti-resorptive agents for effect on foot bone mineral content (BMC) and consequent long-term outcomes of foot deformities, fractures and amputation. METHODS: Forty-three patients with active CN (temperature difference >2°C from normal foot) were evaluated. Patients were off-loaded with total contact cast and randomized to receive either methylprednisolone (1gm) (group A), zoledronate (5mg) (group B) or placebo (100ml normal saline) (group C) once monthly infusion for three consecutive months. Change in foot BMC was assessed at 6 months or at remission and followed subsequently up to 4 years for the incidence of new-onset fracture, deformities, or CN recurrence. RESULTS: Thirty-six participants (24 male, 12 female) were randomized (11 in group A, 12 group B, 13 group C). The mean age was 57.7± 9.9 years, duration of diabetes 12.3± 5.8 years and symptom duration 6.5± 2.8 weeks. BMC increased by 36% with zoledronate (p = 0.02) but reduced by 13% with methylprednisolone (p = 0.03) and 9% (p = 0.09) with placebo at remission. There were no incident foot fractures, however, two patients sustained ulcers, and 3 had new-onset or worsening deformities and none required amputation during 3.36 ± 0.89 years of follow-up. CONCLUSION: Bisphosphonate for active CN is associated with an increase in foot bone mineral content as compared to decrease with steroids or total contact cast but long-term outcomes of foot deformities, ulceration and amputation are similar. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03289338.

The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: a retrospective case series.

Prophylactic infusion of factor concentrates is a safe, effective intervention for preventing arthropathy in patients with haemophilia; on-demand treatment is insufficient to prevent the orthopaedic complications and subsequent haemophilic arthropathy that stem from recurrent joint haemorrhages. The usefulness of prophylaxis in haemophilia patients without inhibitors suggests that patients with haemophilia and inhibitors could derive similar benefits. In patients with haemophilia and high-titre (>5 BU mL(-1)) inhibitors, bleeding episodes are treated with bypassing agents such as activated prothrombin complex concentrates (APCCs) and recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark). It is possible to administer bypassing therapy regularly to prevent haemorrhages, with the goal of limiting arthropathy and serious life- and limb-threatening bleeding. The data evaluating the efficacy and safety of this approach in patients with inhibitors are limited, consisting of results from one prospective trial and retrospective case reports. This report describes our experience with the prophylactic use of the APCC Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA; Baxter AG, Vienna, Austria). Data from patients at one treatment centre were retrospectively evaluated. Case records of six patients with haemophilia A or B and high-titre inhibitors were identified. When APCC was administered regularly, most patients exhibited a reduction in the numbers of haemorrhages, an improvement in orthopaedic status, and an improvement in quality of life. Prophylaxis with APCC can reduce haemorrhages and halt further joint deterioration in patients with haemophilia and inhibitors.

Combined Intramedullary Nail Coated With Antibiotic-Containing Cement and Ring Fixation for Limb Salvage in the Severely Deformed, Infected, Neuroarthropathic Ankle.

BACKGROUND:: The severely deformed, infected, and unstable neuroarthropathic ankle is challenging to treat. We evaluated our preliminary experience and results of combined internal and external ring fixation for a complex neuropathic population. METHODS:: We retrospectively reviewed medical records and radiographs for 8 patients with unilateral severely deformed ankle neuroarthropathy associated with infection and ulceration. Treatment included single-stage reconstruction arthrodesis with an interlocked intramedullary nail coated with antibiotic-containing cement combined with ring fixation. Taylor Spatial Frame™ technology was used when the deformity was not amenable to acute correction (5 patients). Protected postoperative weightbearing was permitted. Their mean age averaged 55.6 (range, 42-66) years with an average body mass index of 38.4 (range, 28.7-49.6) kg/m2. RESULTS:: Seven patients achieved limb preservation. Average time for fusion healing was 15.2 (range, 12.2-22.2) weeks, frame time was 17.7 (range, 12.2-23.0) weeks, and follow-up was 34.1 (range, 24.1-68.8) months. All presenting wounds and infection successfully resolved. Reinker and Carpenter scale was excellent for 2 patients, good for 2 patients, and fair for 3 patients. Foot and Ankle Ability Measure averaged 59.0% (range, 39.3%-87.5%). One patient developed a recalcitrant calcaneal ulcer with osteomyelitis that required a transtibial amputation 17 months after successful ankle arthrodesis. CONCLUSIONS:: Combined use of interlocked intramedullary nail and ring external fixation for neuroarthropathic ankle arthrodesis achieved a functional and clinically stable salvaged lower limb for most patients. LEVEL OF EVIDENCE:: Level IV, retrospective case series.

Acute Charcot arthropathy successfully treated with pamidronate: long-term follow-up.

Charcot arthropathy is a relatively rare complication of diabetic neuropathy that may lead to significant discomfort, deformity, and disability, including severe function loss and limb amputation. Initial diagnosis of Charcot arthropathy is often delayed for several weeks, and it is compounded by the lack of specific clinical and laboratory diagnostic parameters. Increasing understanding of the underlying pathogenic events provide strong support for an important role for osteoclastic activity and pro-inflammatory cytokines. This has led to the successful use of bisphosphonates in patients with acute presentation. Herein we report 3 patients with active (acute) Charcot arthropathy secondary to diabetic neuropathy that exhibited an excellent long-term clinical response to intravenous pamidronate therapy.

Medical treatment of Charcot neuroosteoarthropathy.

The cornerstone of treatment of acute Charcot neuroosteoarthropathy is immediate effective offloading, typically with total contact casting, and reduction in weight bearing. The targets of pharmacological intervention are inhibition of excess osteoclast activation and suppression of an excess proinflammatory cytokine response. Antiresorptive therapy, especially with bisphosphonates, has been used in randomized trials. While evidence of an ideal dosage regime and significant differences in long-term outcome are lacking and should be evaluated in future studies, the trials so far demonstrated improved symptom control, a more rapid decline in foot temperature, and a significant decrease in bone turnover markers, with no demonstration of significant harmful effects. Growing insight into molecular pathways of resorptive bone disease will undoubtedly facilitate novel adjunctive pharmacological therapies.

A review of bone metabolism and developments in medical treatment of the diabetic Charcot foot.

Charcot foot is a rare but severe, and possibly limb-threatening, complication to neuropathy and diabetes mellitus. The current treatment consists of long-term off-loading, and has a large negative impact on the patient's life. Much research has gone into understanding the condition and its biochemical mechanisms, however, the underlying pathogenesis of a Charcot foot is not yet fully understood. In the recent decades several key advances in our understanding of the Charcot foot have been made, both in regards to the changes in bone metabolism and structure an acute Charcot foot can cause, and to the molecular pathways involved in this. This review summerizes the available research into the bone metabolism around a Charcot foot, with an emphasis on the biochemical profile. The existing data regarding attempts at medical treatment is also reviewed, including novel trials targetting specific inflammatory pathways upregulated in the acute diabetic Charcot foot.

[Neuropathic arthropathy of the shoulder]. / Artropatía neuropática de hombro.

Neuropathic arthropathies is a destructive and deforming joint process related to a disruption of propioceptive and nocioceptive innervation. Growth factors, neurological and vascular factors might be involved. Diabetes, alcoholic neuropathy or syringomyelia appear as the most common causes. We report the case of a 61-year-old woman affected by syringomyelia, with a neuropathic arthropathy of the shoulder. Differential diagnosis includes neurological diseases, septic arthritis, tumours and other destructive arthropathies such as aseptic nechrosis, chronic osteomyelitis, synovial chondromatosis, metabolic diseases (gout, chondrocalcinosis) or repetitive haemarthrosis in haemophilia.

[Arthritis as a consequence of diabetes mellitus or haemochromatosis]. / Artritis ten gevolge van diabetes mellitus of hemochromatose.

Four patients with arthritis appeared to have this as a consequence of an internal disorder: a 60-year-old woman and a 20-year-old man with diabetes mellitus and arthritis of an ankle had Charcot arthropathy, whilst a 53-year-old woman and a 60-year-old man with polyarthritis had previously undiagnosed haemochromatosis. Patients were then adequately treated. Charcot arthropathy and haemochromatosis are not uncommon. Early diagnosis is important with respect to preventive and therapeutic measures. In patients with Charcot arthropathy immobilisation allows healing of the fractures. Bisphosphonates may be given in order to decrease bone resorption. In patients with haemochromatosis therapeutic bleeding may limit further damage to the joints and to the internal organs.

Etanercept: new preparation. Useful after methotrexate failure in inflammatory rheumatism.

There is no reference second-line treatment for patients with rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthropathy or ankylosing spondylitis after failure or intolerance of a slow-acting antirheumatic drug such as methotrexate. Etanercept, a immunosuppressant targeting TNF-alpha (like infliximab), is now approved in France for use in these situations, with the exception of spondylitis. In the second-line treatment of adults with rheumatoid arthritis, the clinical evaluation dossier on etanercept contains data from dose-finding studies and two placebo-controlled trials involving patients in whom several single-agent treatments had failed. At a dose of 25 mg subcutaneously twice a week, etanercept worked partially in about half the patients. Without direct comparisons, the place of etanercept relative to other slow-acting antirheumatic drugs is difficult to establish. From indirect comparisons, etanercept seems a slightly better treatment option than infliximab. In the first-line treatment of rheumatoid arthritis, one trial showed that etanercept worked faster than methotrexate, but there was no significant difference between the two treatments after two years. Little is known about the efficacy of etanercept in patients with juvenile chronic arthritis who do not respond adequately to methotrexate. There are no comparative trials. One double-blind placebo-controlled trial showed that etanercept, when it worked, remained active for at least 7 months. In one trial, etanercept was more effective than placebo in patients with psoriatic arthropathy and ankylosing spondylitis who continued to receive their usual treatment, which included a slow-acting antirheumatic drug in about 50% of cases. More than 50% of patients treated with etanercept have a cutaneous reaction to the injection. These reactions are usually mild or moderate. Active pharmacovigilance is needed, given its mechanism of action, and previous notifications of a wide variety of adverse effects (even though it is sometimes difficult to establish a foolproof link between etanercept and the adverse effect). Long-term studies of large numbers of patients are needed to determine the precise risk of side effects including haematological, infectious, neurological, oncological and immunological effects. In practice, methotrexate remains the first-line treatment for inflammatory arthritis. Etanercept can be a useful second-line treatment, especially in juvenile chronic arthritis.