Nina L. Petrova

Calcaneal bone mineral density in patients with Charcot neuropathic osteoarthropathy: differences between Type 1 and Type 2 diabetes

Aims  To measure bone density and neuropathy in both feet in Type 1 and Type 2 patients with unilateral Charcot osteoarthropathy and controls.

Emerging drugs for diabetic foot ulcers

Diabetic foot ulceration results from factors extrinsic to the foot such as repeated trauma, ischaemia and infection, as well as intrinsic factors that lead to impairment of wound healing. Intrinsic factors are less well understood, but include deficiency of growth factors, changes in extracellular matrix components with excess proteases, reduced fibroblast activity, cellular abnormalities, deficiencies of angiogenesis, nitric oxide abnormalities and hyperglycaemia. The scientific rationale of therapy is to correct both the external factors that cause diabetic foot ulcers and the internal factors that lead to impairment of wound healing. Current research is leading to new therapies that can be divided into the following classes: growth factors, skin substitutes, extracellular matrix proteins, stem cell therapy, gene therapy, protease inhibitors, angiogenesis stimulants, nitric oxide-releasing agents, adenosine agonists, immunostimulants, vasoactive compounds and granulating agents. These therapies should be considered when existing treatments to correct extrinsic factors have failed to heal ulceration in the diabetic foot.

Neuropathy and the vascular-bone axis in diabetes: lessons from Charcot osteoarthropathy

Emerging evidence from the last two decades has shown that vascular calcification (VC) is a regulated, cell-mediated process orchestrated by vascular smooth muscle cells (VSMCs) and that this process bears many similarities to bone mineralization. While many of the mechanisms driving VSMC calcification have been well established, it remains unclear what factors in specific disease states act to promote vascular calcification and in parallel, bone loss. Diabetes is a condition most commonly associated with VC and bone abnormalities. In this review, we describe how factors associated with the diabetic milieu impact on VSMCs, focusing on the role of oxidative stress, inflammation, impairment of the advanced glycation end product (AGE)/receptor for AGE system and, importantly, diabetic neuropathy. We also explore the link between bone and VC in diabetes with a specific emphasis on the receptor activator of nuclear factor κβ ligand/osteoprotegerin system. Finally, we describe what insights can be gleaned from studying Charcot osteoarthropathy, a rare complication of diabetic neuropathy, in which the occurrence of VC is frequent and where bone lysis is extreme.

Osteoprotegerin gene polymorphism in diabetic Charcot neuroarthropathy

Diabet. Med. 29, 771–775 (2012)

Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute Charcot osteoarthropathy.

To assess markers of inflammation and bone turnover at presentation and at resolution of Charcot osteoarthropathy.

Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy.

We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κβ ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy.

A Prospective Study of Calcaneal Bone Mineral Density in Acute Charcot Osteoarthropathy

OBJECTIVE To measure prospectively bone mineral density (BMD) of the Charcot and non-Charcot foot in 36 diabetic patients presenting with acute Charcot osteoarthropathy. RESEARCH DESIGN AND METHODS Calcaneal BMD was measured with quantitative ultrasound at presentation, at 3 months of casting, and at the time of the clinical resolution. RESULTS BMD of the Charcot foot was significantly reduced compared with BMD of the non-Charcot foot at presentation (P = 0.001), at 3 months of casting (P < 0.001), and at the time of clinical resolution (P < 0.001). Overall, from the time of presentation to the time of resolution there was a significant fall of BMD of the Charcot foot (P < 0.001) but not of the non-Charcot foot (P = 0.439). CONCLUSIONS Although the Charcot foot was treated with casting until clinical resolution, there was a significant fall of BMD only from presentation up until 3 months of casting.

Thermal symmetry of healthy feet: a precursor to a thermal study of diabetic feet prior to skin breakdown

Early identification of areas of inflammation may aid prevention of diabetic foot ulcers. A new bespoke thermal camera system has been developed to thermally image feet at risk. Hotspots (areas at least 2.2 °C hotter than the contralateral site) may indicate areas of inflammation prior to any apparent visual signs. This article describes the thermal pattern and symmetry of 103 healthy pairs of feet. 68% of participants were thermally symmetric at the 33 foot sites measured. 32% of participants had at least one hotspot, but hotspots overall only accounted for 5% of the measurements made. Refinements to the definition of hotspots are proposed when considering feet at risk of ulceration.

A medical thermal imaging device for the prevention of diabetic foot ulceration.

In this paper a description is given of the development, characterisation and first results of a thermal imaging device aimed at significantly reducing the incidence of diabetic foot ulceration (DFU). These devices will be used in three clinical centres and in two preliminary clinical trials. The first will be on healthy volunteers to set a robust baseline for the overall research aims and the second on  >100 patients at high risk of DFU. In the second phase of the project the objective is to demonstrate significant reduction in the incidence of DFU through a comparison of the results of standard care of high risk feet with standard care plus thermal imaging.

Conservative and Pharmacologic Treatments for the Diabetic Charcot Foot

Charcot neuroarthropathy is a disabling complication of diabetic neuropathy. Prolonged immobilization in a total contact cast (TCC) is among the main treatments. Education of health care professionals in the application of TCC together with well-conducted clinical trials are required to overcome its frequent underuse. There are no established pharmacologic therapies to treat this condition; however, there is an overwhelming need for a new therapeutic approach. Novel targeted drug delivery systems are required to prevent the pathologic bone and joint destruction of the Charcot neuroarthropathy and this may lead to an improved outcome in diabetic patients with this condition.