osteoprotegerin and Diabetic-Foot

Charcot Foot (CF), part of a broader condition known as Charcot Neuro-Osteoarthropathy (CNO), is characterized by neuropathic arthropathy with a progressive alteration of the foot. CNO is one of the most devastating complications in patients with diabetes mellitus and peripheral neuropathy but can also be caused by neurological or infectious diseases. The pathogenesis is multifactorial; many studies have demonstrated the central role of inflammation and the Receptor Activator of NF-κB ligand (RANKL)-Receptor Activator of NF-κB (RANK)-Osteoprotegerin (OPG) pathway in the acute phase of the disease, resulting in the serum overexpression of RANKL. This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. The aim of this narrative review is to analyze this signaling pathway in bone remodeling, and in CF in particular, to highlight its clinical aspects and possible therapeutic implications of targeting drugs at different levels of the pathway. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin. The literature review showed encouraging data on treatment with Denosumab, although in a few studies and in small sample sizes. In contrast, BPs have been re-evaluated in recent years in relation to the high possibility of side effects, while calcitonin has shown little efficacy on CNO.

Topics: Bone Density Conservation Agents; Calcitonin; Denosumab; Diabetes Mellitus; Diabetic Foot; Humans; NF-kappa B; Osteolysis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Charcot neuro-osteoarthropathy (CNO) is one of the more devastating complications affecting diabetic patients with peripheral and/or autonomic neuropathy. The acute phase of the disease is often misdiagnosed, and can rapidly lead to deformity and amputation. The rapid progression towards foot deformation calls for early detection and intervention. Classical neurotraumatic and neurotrophic theories fail to explain all of the features of the condition, although recent advances that have clarified the mechanisms underlying the pathophysiology may make up for this lack. In particular, new data have emerged on the central role of the RANK/RANK-ligand (RANK-L)/osteoprotegerin (OPG) system in the pathogenesis of osteopenia. Also, it is now recognized that the acute phase of CNO can be triggered by any factor leading to local inflammation of the foot, especially in predisposed patients. As the cornerstone of treatment remains any method that avoids weight-bearing on the foot, the primary importance of the RANK/RANK-L/OPG signalling pathway is that it opens up the field to new treatment strategies for the future.

Topics: Alendronate; Arthropathy, Neurogenic; Biomarkers; Bone Density Conservation Agents; Calcitonin; Diabetic Foot; Diagnosis, Differential; Diphosphonates; Early Diagnosis; Foot Deformities, Acquired; Foot Injuries; Humans; Osteoprotegerin; Pamidronate; Randomized Controlled Trials as Topic; RANK Ligand; Weight-Bearing

This study aims to compare the levels of osteoprotegerin (OPG) and 25-hydroxy vitamin D (25(OH)D) in patients with diabetic foot and patients with newly diagnosed type 2 diabetes mellitus (DM) and to investigate the prevalence and severity of 25(OH)D insufficiency in patients with diabetic foot.. This prospective study was conducted on 105 patients including 58 patients with diabetic foot (42 males, 16 females; mean age 63.6 years; range, 31 to 90 years), who applied to our hospital between June 2014 and May 2015, and 47 newly diagnosed type 2 DM patients (27 males, 20 females; mean age 51.4 years; range, 29 to 85 years) (control group). 25(OH)D and osteoprotegerin serum levels in both groups were measured and compared.. Osteoprotegerin levels in diabetic foot group were significantly higher than the control group (p<0.05). The 25(OH)D levels in diabetic foot group were significantly lower than the control group (p<0.05). There were positive correlations between OPG levels and C-reactive protein (CRP) and creatinine levels in patients with diabetic foot.. Elevated levels of OPG in patients with diabetic foot may display the severity of the clinical status due to its positive correlation with CRP and creatinine. We detected severe 25(OH)D deficiency in the majority of diabetic foot patients. Vitamin D supplementation may be required in diabetic foot patients to prevent unfavorable immunologic alterations.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Humans; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Vitamin D

to evaluate the role of clinical characteristics, functional markers of vasodilation, inflammatory response, and atherosclerosis in predicting wound healing in diabetic foot ulcer.. a cohort study (February - October 2010) was conducted from 40 subjects with acute diabetic foot ulcer at clinical ward of Dr. Cipto Mangunkusumo National Central General Hospital, Jakarta, Indonesia. Each subject underwent at least two variable measurements, i.e. during inflammatory phase and proliferation phase. The studied variables were clinical characteristics, complete peripheral blood count (CBC) and differential count, levels of HbA1c, ureum, creatinine, lipid profile, fasting blood glucose (FBG), marker of endothelial dysfunction (asymmetric dimethylarginine/ADMA, endothelin-1/ET-1, and flow-mediated dilation/FMD of brachial artery), and marker of vascular calcification (osteoprotegerin/OPG).. median of time achieving 50% granulation tissue in our study was 21 days. There were nine factors that contribute in the development of 50% granulation tissue, i.e. family history of diabetes mellitus (DM), previous history of wound, wound area, duration of existing wound, captopril and simvastatin medications, levels of ADMA, ET-1, and OPG. There were three out of the nine factors that significantly correlated with wound healing, i.e. wound area, OPG levels, and simvastatin medications.. in acute diabetic foot ulcers, wound area and OPG levels had positive correlation with wound healing, whereas simvastatin medications had negative correlation with wound healing.

Topics: Aged; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Foot; Endothelin-1; Female; Humans; Indonesia; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Tertiary Care Centers; Vascular Calcification; Wound Healing

Chronic kidney disease (CKD) is often observed among patients with type 2 diabetes mellitus (T2DM) and diabetic foot (DF) leading to end stage renal disease. The aim of this pilot study was to determine genetic and environmental factors involved in the etiology of CKD among patients with DF. The following polymorphisms were studied: rs1800469, rs759853, rs1553005, rs1799983, rs1801133, rs3134069, rs2073618, rs8192678, rs6330, rs11466112, rs121917832 in terms of alleles distribution in patients with DF and T2DM, with or without CKD. The study includes 101 patients with T2DM and DF. Studied groups were divided into 39 individuals with CKD (cases) and 62 controls, depending on the presence of kidney failure defined as eGFR < 60ml/min/1.73m(2) and coexistence of microalbuminuria > 30 mg/dl in at least 3 urine samples. Cases and controls were matched according to mean age, gender, mean duration of T2DM, mean duration of insulin therapy, mean duration of DF cholesterol levels and smoking frequencies. The study showed that CKD risk factors were the following variables: creatinine level, body weight, hips circumference, ischemic heart disease, hypertension and diabetic retinopathy. Moreover, the results suggest the protective role of the allele C of rs3134069 polymorphism in CKD development in patients with T2DM and DF in the following allelic variants: [AA] vs. [AC] and [AA] vs. [AC + CC]. The allele C was observed to be less frequent than the allele A in patients with T2DM and DF. None of the other following polymorphisms was observed to be a potential risk factor of CKD in T2DM and DF population: rs6330, rs759853, rs1553005, rs1799983, rs1801133, rs1800469, rs8192678, rs11466112, rs121917832. We concluded that the rs3134069 polymorphism seems to be the most likely protective genetic factor in CKD development in patients with T2DM and DF.

Topics: Aged; Alleles; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Genetic Predisposition to Disease; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Osteoprotegerin; Pilot Projects; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Risk Factors

 Diabetic foot is a severe diabetic complication, which may result in ulcerations that are unresponsive to treatment and in lower limb amputation. Osteoprotegerin is a protein that is involved in the pathogenesis of diabetic foot..  The aim of the study was to evaluate the frequency of alleles in the TNFRSF11B gene rs2073617, rs2073618, and rs3134069 polymorphisms in patients with diabetic foot, diabetes, and healthy controls.. The study comprised 877 patients, including 122 with diabetic foot, 293 with type 2 diabetes without diabetic foot, and 462 healthy controls.. In the rs2073618 polymorphism, the C allele was a risk factor for diabetic foot in patients with diabetes in the allelic variants [CC] vs. [CG + GG] (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.03-2.86; P = 0.035), and in men in the following allelic variants: CC vs. GG (OR, 3.16; 95% CI, 1.27-7.87; P = 0.011), CC vs. CG (OR, 3.33; 95% CI, 1.47-7.54; P = 0.002), and [CC] vs. [CG + GG] (OR, 3.28; 95% CI, 1.48-7.24; P = 0.002). A similar association was observed between men with diabetic foot and those only with diabetes in the following allelic variants: CC vs. GG (OR, 2.30; 95% CI, 0.91-5.85; P = 0.076), CC vs. CG (OR, 2.69; 95% CI, 1.16-6.22; P = 0.018) and [CC] vs. [CG + GG] (OR, 2.56; 95% CI, 1.13-5.77; P = 0.02). For patients with neuropathic diabetic foot, the association was demonstrated in variant CC vs. CG (OR, 2.5; 95% CI, 1.00-6.23; P = 0.044) and only for men in the following allelic variants: [CC] vs. [CG + GG] (OR, 3.17; 95% CI, 1.07-9.38; P = 0.029) and CC vs. CG (OR, 3.49; 95% CI, 1.15-10.58; P = 0.02). The A allele of the rs2073617 polymorphism protected women in variant AA vs. AG against diabetic foot compared with controls (OR, 0.45; 95% CI, 1.00-4.92; P = 0.045). The rs3134069 polymorphism was not observed to be a risk factor for diabetic foot..  The analysis of the TNFRSF11B gene may be used to assess the risk of diabetic foot and neuropathic diabetic foot in patients with type 2 diabetes.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Osteoprotegerin; Polymorphism, Genetic