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Introducción: La mayoría de estudios han puesto de manifiesto una disminución de la función y fuerza muscular en pacientes con diabetes mellitus tipo 2 (DM2). Sin embargo, la relación entre la función muscular y la salud ósea en los pacientes con DM2 no está bien definida. Objetivo: El objetivo del estudio fue analizar la relación entre la fuerza muscular y la fragilidad ósea en pacientes con DM2. Material y métodos: Estudio observacional transversal. Se incluyeron un total de 60 pacientes con DM2 (60% varones y 40% mujeres postmenopáusicas) con una edad entre 49-85 años. Se estudiaron variables demográficas, antropométricas, clínicas y bioquímicas. Se determinó la densidad mineral ósea (DMO) en columna lumbar (CL), cuello femoral y cadera total mediante DXA (Hologic QDR 4500), y los valores de TBS (TBS iNsight Software, versión 3.0.2.0, Medimaps, Merignac, France). La fuerza de la mano (kg/cm2) se midió con un dinamómetro hidráulico manual Jamar® (5030j1; jackson, MI). Para evaluar el nivel de movilidad y el riesgo de caídas, se realizó el test Time Up and Go. El análisis estadístico se realizó mediante el programa SPSS (SPSS, inc, v 25.0). Resultados: La edad media de los pacientes fue de 66,3±8,3 años. La HbA1c media fue de 7,7±1,1%, observándose un inadecuado control glucémico (HbA1c >7,5%) en el 73,3% de los pacientes. El 91,7% de las mujeres y el 77,8% de los varones presentaron baja fuerza muscular. El 41,7% de mujeres y el 25% de varones presentaron un riesgo elevado de caídas. Los sujetos con baja fuerza de prensión manual y los que tenían riesgo de caídas elevado presentaron valores significativamente menores de TBS que los que tenían mayor fuerza de la mano (0,99±0,17 vs 1,12±0,15; p=0,03) y bajo riesgo de caídas (0,94±0,13 vs 1,04±0,19; p=0,02). Los pacientes con TBS normal y parcialmente degradado tenían mayor fuerza de agarre manual que los sujetos con TBS degradado (p=0,031). La fuerza de la mano se asoció positivamente con TBS (p

Objetivos: Identificación de biomarcadores que relacionan la osteoporosis con enfermedades pulmonares ocupacionales y ambientales. Material y métodos: Mediante bases de datos de terminología médica unificada se obtuvieron enfermedades relacionadas con enfermedades pulmonares que, junto con la osteoporosis, fueron analizadas en DisGeNET para obtener los genes asociados a cada enfermedad y formar una red de interacción proteína-proteína (PPI) mediante el uso de STRING dentro de Cytoscape. A través de la aplicación de diferentes algoritmos de centralidad utilizando CythoHubba en Cytoscape, se seleccionaron las 5 proteínas de la red con el mayor grado de centralidad. Resultados: 9 enfermedades fueron incluidas en el grupo de enfermedades pulmonares. Se obtuvieron 2.698 genes asociados a enfermedades pulmonares y a osteoporosis. Los genes vinculados con osteoporosis y con al menos dos de las enfermedades pulmonares incluidas dieron lugar a una red PPI con 152 nodos y 1.378 ejes. Las proteínas con mayor grado de centralidad de la red fueron AKT1, ALB, IL6, TP53 y VEGFA. Conclusiones: Existe una elevada relación entre la osteoporosis y las enfermedades pulmonares ambientales estudiadas, a través de genes con una implicación dual. Nosotros proponemos cinco genes importantes que vinculan estas enfermedades y que podrían constituir una base coherente para investigaciones más profundas en este campo.

Objetivos: Identificación de potenciales biomarcadores implicados en procesos de calcificación vascular para avanzar en el diagnóstico y tratamiento de esta patología en sus estadíos subclínicos. Métodos: Se trata de un trabajo experimental en el que se incluyeron 5 pacientes con diabetes mellitus tipo 2 (DM2) con enfermedad arterial periférica e isquemia crítica. Se realizó una extracción proteica e identificación del proteoma mediante cromatografía líquida y espectrometría de masas (LC-MS/MS) de secciones de arteria femoral calcificada. Las proteínas identificadas fueron analizadas a través de gene ontology y comparadas con otras proteínas específicas de patologías vasculares relacionadas mediante la base de datos DisGeNET. Mediante el programa informático Cytoscape se analizó la red de funciones biológicas de las proteínas seleccionadas para su clasificación en base a la patología en la que están implicadas. Resultados: Se identificaron 530 proteínas en las muestras analizadas con funciones mayoritariamente de unión a calcio y catalítica. 37 de ellas fueron comunes en otras patologías vasculares relacionadas. La exploración de las redes biológicas de las 37 proteínas identificadas, dio lugar a la identificación de 2 potenciales marcadores específicos de calcificación vascular en procesos ateroscleróticos, como la proteína mitocondrial de choque térmico de 10 kDa, y la subunidad flavoproteica de la succinato deshidrogenasa. Conclusiones: Existe una importante expresión de proteínas implicadas en procesos de mineralización ósea en tejido vascular calcificado, sugiriendo la existencia de mecanismos moleculares comunes entre la regulación ósea y vascular. El uso de herramientas bioinformáticas sugiere la implicación de la proteína de choque térmico de 10 kDa mitocondrial y la subunidad flavoproteica de la succinato deshidrogenasa como posibles biomarcadores de calcificación vascular en pacientes con DM2, aunque son necesarios estudios adicionales que confirmen esta hipótesis.

Introducción: Estudios previos han relacionado la vía Wnt con la alteración del metabolismo óseo y la patología cardiovascular. Así mismo, el control de la inflamación con terapia biológica tiene un efecto positivo sobre la densidad mineral ósea (DMO) y el riesgo cardiovascular. El objetivo de este estudio fue, por tanto, evaluar el efecto de la terapia biológica en pacientes con artritis reumatoide (AR) que no habían recibido previamente terapia biológica sobre la carga inflamatoria, y su relación con el riesgo cardiovascular y el metabolismo óseo. Pacientes y métodos: Estudio de cohortes prospectivo en pacientes con diagnóstico de AR activa que iniciaban terapia biológica. Los pacientes fueron seleccionados de forma consecutiva no seleccionada. Se recogieron: las concentraciones séricas de proteína Dickkopf-1 (DKK1) y esclerostina, ambas mediante el método ELISA (Biomedica Medizinprodukte GmbH and Co. KG, Viena, Austria); características sociodemográficas y clínicas; marcadores de remodelado óseo; la DMO en columna lumbar y en cadera mediante absorciometría de rayos X de energía dual (DXA); el grosor íntima-media carotídea (c-IMT); y la evaluación de riesgo cardiovascular mediante el modelo Systematic Coronary Risk Evaluation (SCORE). Resultados: El 46,7% de los pacientes presentaron respuesta EULAR al tratamiento a los 12 meses. Sólo en este subgrupo de pacientes encontramos un aumento en las concentraciones de DKK1 tras el inicio de la terapia biológica (basal: 20,55±8,13 pg/ml vs. 12 meses: 31,20±4,88 pg/ml, p=0,03). En cuanto a los marcadores de remodelado óseo, se detectó un aumento en los niveles de osteocalcina (basal: 11,25±3,28 ng/ml vs. 12 meses: 15,78,±4,11 ng/ml, p=0,01). No se encontraron cambios estadísticamente significativos en el c-IMT ni en el SCORE tras 12 meses de tratamiento. Conclusiones: En pacientes con AR tratados con terapia biológica y con respuesta al tratamiento hemos observado un aumento significativo de las concentraciones séricas de DKK1 a los 12 meses de tratamiento, no asociado a cambios en el metabolismo óseo o al riesgo cardiovascular.

Objetivos: La diabetes mellitus tipo 2 (DM2) se asocia a un incremento del riesgo de fracturas y de enfermedades cardiovasculares. Los objetivos de nuestro estudio fueron evaluar los niveles séricos de Dickkopf-1 (DKK1) en una cohorte de pacientes con DM2 y analizar su relación con el metabolismo óseo y la enfermedad ateroesclerótica (EA). Pacientes y métodos: Se estudiaron 126 sujetos: 72 pacientes con DM2 (edad media de 58,2±6 años) y 54 sujetos no diabéticos (edad media de 55,4±7 años). Se midió DKK1 mediante ensayo de inmunoabsorción ligado a enzimas (ELISA, Biomedica Gruppe), se determinó la densidad mineral ósea (DMO) mediante absorciometría dual de rayos X (DXA), se registró la presencia de EA (enfermedad cerebrovascular, enfermedad arterial periférica, cardiopatía isquémica) y se evaluó el grosor de la íntima-media (GIM, ultrasonografía doppler) y la calcificación aórtica (radiología simple). Resultados: No se encontraron diferencias significativas en DKK1 entre diabéticos y no diabéticos. Las concentraciones séricas de DKK1 fueron significativamente mayores en las mujeres de la muestra total (24,3±15,2 vs. 19,6±10,2 pmol/L, p=0,046) y del grupo DM2 (27,5±17,2 vs. 19,8±8,9 pmol/L, p=0,025). Hubo una correlación positiva entre DKK1 y DMO lumbar en la muestra total (r=0,183, p=0,048). Sin embargo, no se encontraron diferencias en función del diagnóstico de osteoporosis o presencia de fracturas vertebrales morfométricas. Los valores de DKK1 fueron significativamente mayores en los pacientes con DM2 y EA (26,4±14,5 pmol/L vs. 19,1±11,6 pmol/L, p=0,026) y también en pacientes con GIM anormal (26,4±15,1 pmol/L vs. 19,8±11,3 pmol/L, p=0,038). En el análisis de la curva ROC para evaluar la utilidad de DKK1 como un marcador de alto riesgo de EA, el área bajo la curva fue de 0,667 (intervalo de confianza -IC- del 95%: 0,538-0,795; p=0,016). Una concentración de 17,3 pmol/L o superior mostró una sensibilidad del 71,4% y una especificidad del 60% para identificar un mayor riesgo de EA. Conclusiones: Los niveles circulantes DKK1 son más altos en los diabéticos con EA y se asocian con un GIM patológico. Por tanto, consideramos que DKK1 puede estar implicado en la enfermedad vascular de los pacientes con DM2.

Objectives: Identify potential biomarkers involved in vascular calcification processes to improve DM2 diagnosis and treatment in its subclinical stages. Methods: This experimental study included 5 patients suffering diabetes mellitus type 2 (DM2) with peripheral arterial disease and critical ischemia. Protein extraction and identification of the proteome were carried out using liquid chromatography and mass spectrometry (LC-MS/MS) of calcified femoral artery sections. The identified proteins were analyzed through gene ontology and compared with other specific proteins of related vascular pathologies through the DisGeNET database. Cytoscape software analyzed the network of biological functions of the proteins selected for classification based on the disease in which they are involved. Results: 530 proteins were identified in the analyzed samples with functions mainly of calcium binding and catalytic. 37 of them were common in other related vascular pathologies. The exploration of the biological networks of the 37 proteins identified, led to the identification of 2 potential specific markers of vascular calcification in atherosclerotic processes, such as 10-kDa thermal shock mitochondrial protein, and the flavoprotein subunit of succinate dehydrogenase. Conclusions: There is significant expression of proteins involved in processes of bone mineralization in calcified vascular tissue, suggesting the existence of common molecular mechanisms between bone regulation and vascular. The use of bioinformatics tools suggests the involvement of the mitochondrial 10 kDa heat shock protein and the subunit of the succinate dehydrogenase as potential biomarkers of vascular calcification in patients with DM2, although additional studies are needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have linked the Wnt pathway in the alteration of bone metabolism and cardiovascular pathology. Also, the control of inflammation with biological therapy has a positive effect on bone mineral density (BMD) and cardiovascular risk. The aim of the study was to evaluate the effect of biological therapy in patients with rheumatoid arthritis, naïve to these therapy, on the inflammatory load and its relation with cardiovascular risk and bone metabolism. Patients and methods: Prospective cohort study performed in patients diagnosed with active rheumatoid arthritis (RA) initiating biological therapy. Patients were selected consecutively not selected. The serum concentrations of Dickkopf-1 protein (DKK1) and sclerostin were collected, both by means of the ELISA method (Biomedica Medizinprodukte GmbH and Co. KG, Vienna, Austria); demographic and clinical variables, markers of bone remodeling, hip and lumbar spine BMDs were measured by dual energy X-ray absorptiometry (DXA), measurement of intima-media thickness (IMT), evaluation cardiovascular risk by Systematic Coronary Risk Evaluation (SCORE). Results: 46.7% of patients presented EULAR response to treatment at 12 months. Only in this subgroup of patients, we found in the subgroup of patients an increase in the concentrations of DKK1 following the initiation of biological therapy (baseline 20.55±8.13 pg/ml vs 12 months 31.20±4.88 pg/ml, p=0.03). Regarding markers of bone remodeling, an increase in osteocalcin levels (baseline: 11.25±3.28 ng/ml vs 12 months 15.78±4.11 ng/ml, p=0.01). There was no change in IMT or SCORE at 12 months of treatment. Conclusions: In patients with RA treated with biological therapy who presented EULAR response we observed a significant increase in serum concentrations of DKK1 at 12 months of treatment not associated with changes in bone metabolism and cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background and objectives: Type 2 diabetes (T2DM) is a risk factor for osteoporotic fractures and cardiovascular disease. The aims of our study were to evaluate serum Dickkopf-1(DKK1) levels in a cohort of T2DM patients and to analyze its relationships with bone metabolism and atheroesclerotic disease (AD). Patients and methods: We studied 126 subjects: T2DM patients (n: 72, mean age 58,2±6 years) and non-diabetic subjects (n: 54, mean age 55,4±7 years). DKK-1 was measured by enzyme-linked immunosorbent assay (ELISA, Biomedica Gruppe). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). The presence of AD (cerebrovascular disease, peripheral arterial disease, ischemic heart disease) was recorded. Intima-media thickness (IMT) was determined by doppler ultra-sonography and aortic calcification by evaluation of lateral view conventional X-rays. Results: We did not find significant differences in DKK1 between groups. Serum DKK1 concentrations were significantly higher in females in total sample (24,3±15,2 vs 19,6±10,2 pmol/L, p=0,046) and in T2DM group (27,5±17,2 vs 19,8±8,9 pmol/L, p=0,025). There was a positive correlation between serum DKK1 and LS BMD in total sample (r=0,183, p=0,048). However, we did not find a significant relationship with osteoporosis diagnosis or morphometric vertebral fractures. Serum DKK1 was significantly higher in T2DM patients with AD (26,4±14,5 pmol/L vs 19,1±11,6 pmol/L, p=0,026) and also in patients with abnormal IMT (26,4±15,1 pmol/L vs 19,8±11,3 pmol/L, p=0,038). In the ROC curve analysis to evaluate the usefulness of DKK-1 as a marker for high risk of AD, the area under the curve was 0,667 (95% confidence interval: 0,538-0,795; p=0,016). A concentration of 17,3 pmol/L or higher showed a sensitivity of 71,4% and a specificity of 60% to identify an increased risk of AD. Conclusions: Circulating DKK1 levels are higher in T2DM with AD and are associated with an abnormal IMT in this cross-sectional study. DKK1 may be involved in vascular disease of T2DM patients. [ABSTRACT FROM AUTHOR]

Background: Typical bone proteins, such as sclerostin and periostin, have been associated with cardiovascular disease (CVD). Simultaneously, several risk scores have been developed to predict CVD in the general population. Therefore, we aimed to evaluate the association of these bone proteins related to CVD, with the main vascular risk scales: Framingham Risk Score (FRS), REGICOR and SCORE2-Diabetes, in patients with type 2 diabetes. We focus in particular on the SCORE2-Diabetes algorithm, which predicts 10-year CVD risk and is specific to the study population., Methods: This was a cross-sectional study including 104 patients with type 2 diabetes (62 ± 6 years, 60% males). Clinical data, biochemical measurements, and serum bioactive sclerostin and periostin levels were collected, and different risk scales were calculated. The association between bioactive sclerostin or periostin with the risk scales was analyzed., Results: A positive correlation was observed between circulating levels of bioactive sclerostin (p < 0.001) and periostin (p < 0.001) with SCORE2-Diabetes values. However, no correlation was found with FRS or REGICOR scales. Both serum bioactive sclerostin and periostin levels were significantly elevated in patients at high-very high risk of CVD (score ≥ 10%) than in the low-moderate risk group (score < 10%) (p < 0.001 for both). Moreover, analyzing these proteins to identify patients with type 2 diabetes at high-very high vascular risk using ROC curves, we observed significant AUC values for bioactive sclerostin (AUC = 0.696; p = 0.001), periostin (AUC = 0.749; p < 0.001), and the model combining both (AUC = 0.795; p < 0.001). For diagnosing high-very high vascular risk, serum bioactive sclerostin levels > 131 pmol/L showed 51.6% sensitivity and 78.6% specificity. Similarly, serum periostin levels > 1144 pmol/L had 64.5% sensitivity and 76.2% specificity., Conclusions: Sclerostin and periostin are associated with vascular risk in the SCORE2-Diabetes algorithm, opening a new line of investigation to identify novel biomarkers of cardiovascular risk in the type 2 diabetes population., (© 2024. The Author(s).)

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.

Introduction: Hypophosphatasia (HPP) is an inborn metabolic error caused by mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP) and leading to decreased alkaline phosphatase (ALP) activity. Although the main characteristic of this disease is bone involvement, it presents a great genetic and clinical variability, which makes it a systemic disease., Methods: Patients were recruited based on biochemical assessments. Diagnosis was made by measuring serum ALP and pyridoxal 5-phosphate levels and finally by Sanger sequencing of the ALPL gene from peripheral blood mononuclear cells. Characterization of the new variants was performed by transfection of the variants into HEK293T cells, where ALP activity and cellular localization were measured by flow cytometry. The dominant negative effect was analyzed by co-transfection of each variant with the wild-type gene, measuring ALP activity and analyzing cellular localization by flow cytometry., Results: Two previously undescribed variants were found in the ALPL gene: leucine 6 to serine missense mutation (c.17T>C, L6S) affecting the signal peptide and threonine 167 deletion (c.498&#95;500delCAC, T167del) affecting the vicinity of the active site. These mutations lead mainly to non-pathognomonic symptoms of HPP. Structural prediction and modeling tools indicated the affected residues as critical residues with important roles in protein structure and function. In vitro results demonstrated low TNSALP activity and a dominant negative effect in both mutations. The results of the characterization of these variants suggest that the pleiotropic role of TNSALP could be involved in the systemic effects observed in these patients highlighting digestive and autoimmune disorders associated with TNSALP dysfunction., Conclusions: The two new mutations have been classified as pathogenic. At the clinical level, this study suggests that both mutations not only lead to pathognomonic symptoms of the disease, but may also play a role at the systemic level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Martínez-Heredia, Muñoz-Torres, Sanabria-de la Torre, Jiménez-Ortas, Andújar-Vera, González-Cejudo, Contreras-Bolívar, González-Salvatierra, Gómez-Vida, García-Fontana and García-Fontana.)

Background: Sclerostin is an inhibitor of the Wnt/b-catenin pathway, which regulates bone formation, and can be expressed in vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease (CVD) and increased serum and tissue expression of sclerostin. However, whether the role of sclerostin is detrimental or protective in the development of CVD is unknown. Therefore, our aims are to determine the level of sclerostin in T2D patients with/without CVD and in controls, both at serum and vascular tissue, and to analyze the role of sclerostin in VSMCs under calcified environments., Methods: Cross-sectional study including 121 controls and 139 T2D patients with/without CVD (48/91). Sclerostin levels in serum were determined by ELISA, and sclerostin expression was analyzed by RT-qPCR and immunohistochemistry in calcified and non-calcified artery of lower limb from T2D patients (n = 7) and controls (n = 3). In vitro experiments were performed in VSMCs (mock and sclerostin overexpression) under calcifying conditions analyzing the sclerostin function by determination of calcium and phosphate concentrations, and quantification of calcium deposits by Alizarin Red. Proliferation and apoptosis were analyzed by MTT assay and flow cytometry, respectively. The regulation of the expression of genes involved in bone metabolism was determined by RT-qPCR., Results: A significant increase in serum sclerostin levels in T2D patients with CVD compared to T2D patients without CVD and controls (p < 0.001) was observed. Moreover, higher circulating sclerostin levels were independently associated with CVD in T2D patients. Increased sclerostin expression was observed in calcified arteries of T2D patients compared to non-calcified arteries of controls (p = 0.003). In vitro experiments using VSMCs under calcified conditions, revealed that sclerostin overexpression reduced intracellular calcium (p = 0.001), calcium deposits (p < 0.001), cell proliferation (p < 0.001) and promoted cell survival (p = 0.015). Furthermore, sclerostin overexpression exhibited up-regulation of ALPL (p = 0.009), RUNX2 (p = 0.001) and COX2 (p = 0.003) and down-regulation of inflammatory genes, such as, IL1β (p = 0.005), IL6 (p = 0.001) and IL8 (p = 0.003)., Conclusions: Sclerostin could play a protective role in the development of atherosclerosis in T2D patients by reducing calcium deposits, decreasing proliferation and inflammation, and promoting cell survival in VSMCs under calcifying conditions. Therefore, considering the bone-vascular axis, treatment with anti-sclerostin for bone disease should be used with caution., (© 2023. The Author(s).)

Osteoglycin, a fundamental proteoglycan within the vascular extracellular matrix, is expressed in vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2D) is associated with cardiovascular disease (CVD) but the role of osteoglycin in the development of CVD is controversial to date. Therefore, our aims are to determine and compare the level of osteoglycin in T2D patients with/without CVD versus control subjects both at serum and vascular tissue and to analyze in vitro role of osteoglycin in VSMCs under calcified conditions. For this, serum osteoglycin levels were determined by enzyme-linked immunosorbent assay (ELISA) in 117 controls and 129 patients with T2D (46 with CVD and 83 without CVD), revealing a significant increase in patients with T2D compared with controls. Osteoglycin level was not an estimator of CVD but correlated with markers of insulin resistance (triglycerides and triglycerides/high-density lipoprotein cholesterol index) in patients with T2D. At the vascular level, osteoglycin expression was assessed by RT-qPCR and immunohistochemistry, and no significant differences were observed between calcified arteries from patients with T2D and noncalcified arteries from controls. In vitro experiments using VSMCs (mock and overexpressing osteoglycin) under calcifying conditions were performed to analyze the osteoglycin function. The overexpression of osteoglycin in VMSCs under calcifying conditions revealed an increase of cell proliferation without effect on apoptosis and an upregulation of the expression of autotaxin ( ATX ) involved in inflammatory processes. In conclusion, osteoglycin could play a role in glycemic homeostasis, being a potential biomarker of insulin resistance in patients with T2D. Furthermore, osteoglycin could indirectly participate in the development of atherosclerosis through its regulatory effect on ATX and by proliferating VSMCs. NEW & NOTEWORTHY This study uncovers an increase of serum osteoglycin levels in patients with type 2 diabetes, which does not appear to be associated with the development of atherosclerosis, but rather with insulin resistance in this population. Overexpression of osteoglycin increased proliferation and upregulated the expression of autotaxin in vascular smooth muscle cells within calcified environments. Osteoglycin could be a biomarker of insulin resistance for type 2 diabetes and could be indirectly involved in the development of atherosclerosis.

Diet is a modifiable factor in bone and muscle health. The Mediterranean diet (MedDiet) is rich in nutrients and contains key bioactive components with probable protective effects on muscle and bone deterioration. Osteoporosis (OP) and sarcopenia are diseases that increase frailty and susceptibility to fracture, morbidity and mortality. Therefore, it is necessary to combat them in the population. In this regard, MedDiet adherence has proven to be beneficial to bone mineral density (BMD), muscle mass, physical function, OP and sarcopenia. Hence, this diet is proposed as a therapeutic tool that could slow the onset of osteoporosis and sarcopenia. However, there is doubt about the interaction between the MedDiet, strength and fracture risk. Perhaps the amount of EVOO (extra virgin olive oil), fruits, vegetables and fish rich in anti-inflammatory and antioxidant nutrients ingested has an influence, though the results remain controversial.

Objectives: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented., Methods: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 - December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5'-phosphate (PLP) and genetic study of ALPL gene., Results: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %)., Conclusions: This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

The pandemic caused by the SARS-CoV-2 virus has triggered great interest in the search for the pathophysiological mechanisms of COVID-19 and its associated hyperinflammatory state. The presence of prognostic factors such as diabetes, cardiovascular disease, hypertension, obesity, and age influence the expression of the disease's clinical severity. Other elements, such as 25-hydroxyvitamin D (25(OH)D3) concentrations, are currently being studied. Various studies, mostly observational, have sought to demonstrate whether there is truly a relationship between 25(OH)D3 levels and the acquisition and/or severity of the disease. The objective of this study was to carry out a review of the current data that associate vitamin D status with the acquisition, evolution, and/or severity of infection by the SARS-CoV-2 virus and to assess whether prevention through vitamin D supplementation can prevent infection and/or improve the evolution once acquired. Vitamin D system has an immunomodulatory function and plays a significant role in various bacterial and viral infections. The immune function of vitamin D is explained in part by the presence of its receptor (VDR) and its activating enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1) in immune cells. The vitamin D, VDR, and Retinoid X Receptor complex allows the transcription of genes with antimicrobial activities, such as cathelicidins and defensins. COVID-19 characteristically presents a marked hyperimmune state, with the release of proinflammatory cytokines such as IL-6, TNF-α, and IL-1β. Thus, there are biological factors linking vitamin D to the cytokine storm, which can herald some of the most severe consequences of COVID-19, such as acute respiratory distress syndrome. Hypovitaminosis D is widespread worldwide, so the prevention of COVID-19 through vitamin D supplementation is being considered as a possible therapeutic strategy easy to implement. However, more-quality studies and well-designed randomized clinical trials are needed to address this relevant question.

The life expectancy of the global population has increased. Aging is a natural physiological process that poses major challenges in an increasingly long-lived and frail population. Several molecular mechanisms are involved in aging. Likewise, the gut microbiota, which is influenced by environmental factors such as diet, plays a crucial role in the modulation of these mechanisms. The Mediterranean diet, as well as the components present in it, offer some proof of this. Achieving healthy aging should be focused on the promotion of healthy lifestyle habits that reduce the development of pathologies that are associated with aging, in order to increase the quality of life of the aging population. In this review we analyze the influence of the Mediterranean diet on the molecular pathways and the microbiota associated with more favorable aging patterns, as well as its possible role as an anti-aging treatment.

Non-alcoholic fatty liver disease (NAFLD) seems to have some molecular links with atherosclerosis (ATH); however, the molecular pathways which connect both pathologies remain unexplored to date. The identification of common factors is of great interest to explore some therapeutic strategies to improve the outcomes for those affected patients. Differentially expressed genes (DEGs) for NAFLD and ATH were extracted from the GSE89632 and GSE100927 datasets, and common up- and downregulated DEGs were identified. Subsequently, a protein-protein interaction (PPI) network based on the common DEGs was performed. Functional modules were identified, and the hub genes were extracted. Then, a Gene Ontology (GO) and pathway analysis of common DEGs was performed. DEGs analysis in NAFLD and ATH showed 21 genes that were regulated similarly in both pathologies. The common DEGs with high centrality scores were ADAMTS1 and CEBPA which appeared to be down- and up-regulated in both disorders, respectively. For the analysis of functional modules, two modules were identified. The first one was oriented to post-translational protein modification, where ADAMTS1 and ADAMTS4 were identified, and the second one mainly related to the immune response, where CSF3 was identified. These factors could be key proteins with an important role in the NAFLD/ATH axis.

Aim: Patients with type 2 diabetes (T2DM) have more risk of bone fractures. However, areal bone mineral density (aBMD) by conventional dual-energy x-ray absorptiometry (DXA) is not useful for identifying this risk. This study aims to evaluate 3D-DXA parameters determining the cortical and trabecular compartments in patients with T2DM compared to non-diabetic subjects and to identify their determinants., Materials and Methods: Case-control study in 111 T2DM patients (65.4 ± 7.6 years old) and 134 non-diabetic controls (64.7 ± 8.6-year-old). DXA, 3D-DXA modelling via 3D-Shaper software and trabecular bone score (TBS) were used to obtain aBMD, cortical and trabecular parameters, and lumbar spine microarchitecture, respectively. In addition, biochemical markers as 25-hydroxyvitamin d, type I procollagen N-terminal propeptide (P1NP), C-terminal telopeptide of type I collagen (CTX), and glycated haemoglobin (HbA1c) were analysed., Results: Mean-adjusted values showed higher aBMD (5.4%-7.7%, ES: 0.33-0.53) and 3D-DXA parameters (4.1%-10.3%, ES: 0.42-0.68) in the T2DM group compared with the control group. However, TBS was lower in the T2DM group compared to the control group (-14.7%, ES: 1.18). In addition, sex (β = 0.272 to 0.316) and body mass index (BMI) (β = 0.236 to 0.455) were the most consistent and positive predictors of aBMD (p ≤ 0.01). BMI and P1NP were negative predictors of TBS (β = -0.530 and -0.254, respectively, p ≤ 0.01), while CTX was a positive one (β = 0.226, p=0.02). Finally, BMI was consistently the strongest positive predictor of 3D-DXA parameters (β = 0.240 to 0.442, p<0.05)., Conclusion: Patients with T2DM present higher bone mass measured both by conventional DXA and 3D-DXA, suggesting that 3D-DXA technology is not capable of identifying alterations in bone structure in this population. Moreover, BMI was the most consistent determinant in all bone outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ubago-Guisado, Moratalla-Aranda, González-Salvatierra, Gil-Cosano, García-Fontana, García-Fontana, Gracia-Marco and Muñoz-Torres.)

Sclerostin is most recognized for its role in controlling bone formation; however, it is also expressed in the heart, aorta, coronary, and peripheral arteries. Human studies have associated high circulating sclerostin levels with the presence of different cardiovascular diseases (CVD), surrogate CVD markers, and a high risk of cardiovascular events in some populations. However, this is still a matter of scientific debate, as the results have been very heterogeneous among studies. In the present review, the association between serum sclerostin levels and CVD and/or cardiovascular mortality was analyzed. For this purpose, a scoping review was performed in which articles measuring serum sclerostin levels and cardiovascular risk in patients were selected. Eleven articles answered the research question; of these articles, 8/11 evaluated the association between sclerostin and CVD, of which 4/8 found a positive association, 2/8 found a negative association, and 2/8 found no association between variables. Five (5/11) of the articles included in the study evaluated cardiovascular mortality, of which 3/5 found a positive association, 1/5 found a negative association, and 1/5 found no association between variables. In conclusion, we did not find sufficient results to be able to demonstrate an association between elevated sclerostin levels and the development of CVD and/or cardiovascular mortality in the general population due to heterogeneity in the results. However, there seems to be a tendency to consider increased sclerostin levels as a risk factor for both the development of cardiovascular events and cardiovascular mortality in specific populations. Further studies in this field will help to solve some of the inconsistencies found during this scoping review and allow for the future use of sclerostin measurement as a strategy in the prevention and diagnosis of CVD and/or cardiovascular mortality.

Recent scientific evidence has shown an increased risk of fractures in patients with obesity, especially in those with a higher visceral adipose tissue content. This contradicts the old paradigm that obese patients were more protected than those with normal weight. Specifically, in older subjects in whom there is a redistribution of fat from subcutaneous adipose tissue to visceral adipose tissue and an infiltration of other tissues such as muscle with the consequent sarcopenia, obesity can accentuate the changes characteristic of this age group that predisposes to a greater risk of falls and fractures. Other factors that determine a greater risk in older subjects with obesity are chronic proinflammatory status, altered adipokine secretion, vitamin D deficiency, insulin resistance and reduced mobility. On the other hand, diagnostic tests may be influenced by obesity and its comorbidities as well as by body composition, and risk scales may underestimate the risk of fractures in these patients. Weight loss with physical activity programs and cessation of high-fat diets may reduce the risk. Finally, more research is needed on the efficacy of anti-osteoporotic treatments in obese patients.

Lifestyle changes are causing an exponential increase in the prevalence of obesity and metabolic syndrome (MetS) worldwide. The most frequent complications of these are the development of diabetes (T2D) and cardiovascular disease (CVD). Accurate tools are needed to classify the cardiovascular risk (CVR) in the MetS population. In recent years, numerous biomarkers of bone metabolism have been associated with CVR. The aim of this study was to determine the levels of undercarboxylated osteocalcin (ucOC) in a cohort of patients with MetS and to analyse its association with MetS parameters and CVR as well as with T2D prevalence. A longitudinal study was conducted in which a MetS population was followed for one year. Weight change, adherence to the Mediterranean diet (MedDiet), ucOC levels, MetS parameters and CVR were analysed and CVR was calculated using different scores. Our results showed a decrease of CVR associated with a better adherence to the MetDiet resulting in higher HDL-C and ucOC levels though the improvement of MetS risk factors. This bone protein appeared as a potential biomarker to classify CVR in the MetS population, especially for MetS patients without prevalent T2D. Furthermore, ucOC serum levels could be good predictors of T2D prevalence.

Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents "mandatory damage" in the development of microvascular complications and only "introductory damage" in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies.

Hypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of ALPL results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of ALPL gene with uncertain significance and no previously described (p.Del Glu23&#95;Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower in vitro ALP activity than the wild-type (WT) genotype ( p -value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn 2+ binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel ALPL gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sanabria-de la Torre, Martínez-Heredia, González-Salvatierra, Andújar-Vera, Iglesias-Baena, Villa-Suárez, Contreras-Bolívar, Corbacho-Soto, Martínez-Navajas, Real, García-Fontana, Muñoz-Torres and García-Fontana.)

Bone fragility is a common complication in subjects with type 2 diabetes mellitus (T2DM). However, traditional techniques for the evaluation of bone fragility, such as dual-energy X-ray absorptiometry (DXA), do not perform well in this population. Moreover, the Fracture Risk Assessment Tool (FRAX) usually underestimates fracture risk in T2DM. Importantly, novel technologies for the assessment of one microarchitecture in patients with T2DM, such as the trabecular bone score (TBS), high-resolution peripheral quantitative computed tomography (HR-pQCT), and microindentation, are emerging. Furthermore, different serum and urine bone biomarkers may also be useful for the evaluation of bone quality in T2DM. Hence, in this article, we summarize the limitations of conventional tools for the evaluation of bone fragility and review the current evidence on novel approaches for the assessment of quality and bone microstructure alterations in patients with T2DM.

The identification of common targets in Alzheimer's disease (AD) and cardiovascular disease (CVD) in recent years makes the study of the CVD/AD axis a research topic of great interest. Besides aging, other links between CVD and AD have been described, suggesting the existence of common molecular mechanisms. Our study aimed to identify common targets in the CVD/AD axis. For this purpose, genomic data from calcified and healthy femoral artery samples were used to identify differentially expressed genes (DEGs), which were used to generate a protein-protein interaction network, where a module related to AD was identified. This module was enriched with the functionally closest proteins and analyzed using different centrality algorithms to determine the main targets in the CVD/AD axis. Validation was performed by proteomic and data mining analyses. The proteins identified with an important role in both pathologies were apolipoprotein E and haptoglobin as DEGs, with a fold change about +2 and -2, in calcified femoral artery vs healthy artery, respectively, and clusterin and alpha-2-macroglobulin as close interactors that matched in our proteomic analysis. However, further studies are needed to elucidate the specific role of these proteins, and to evaluate its function as biomarkers or therapeutic targets.

Aims: To examine the clinical and biochemical determinants of trabecular bone score (TBS) in type 2 diabetes mellitus (T2DM) patients., Methods: Cross-sectional observational study in 137 T2DM patients (49-85 years). Whole-body fat percentage was estimated using the relative fat mass (RFM) equation. Bone mineral density (BMD) and TBS were assessed using dual-energy X-ray absorptiometry and TBS iNsight Software respectively., Results: T2DM patients showed significantly lower TBS values (P < 0.001) despite significantly higher lumbar spine BMD (LS-BMD) (P = 0.025) compared to controls. TBS values ​​were negatively correlated with body mass index (BMI) (P < 0.001), waist circumference (P < 0.001), and HOMA-2IR index (P = 0.004) and positively correlated with sex hormone-binding globulin (SHBG) (P = 0.01) and LS-BMD (P = 0.003). RFM was negatively associated with TBS in both males (P < 0.001) and females (P = 0.005). The multivariate analysis showed that RFM, HOMA2-IR (negative), SHBG, and LS-BMD (positive) were the variables independently associated with TBS. ROC analysis revealed RFM as the variable with the highest predictive value for risk of degraded bone microarchitecture., Conclusions: The adiposity estimated by RFM may negatively affect TBS and this relationship may be influenced by insulin resistance and SHBG. RFM could act as a key estimator of degraded bone microarchitecture risk in the T2DM population., Competing Interests: Conflicts of interests None., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Recent evidence has revealed anti-inflammatory properties of vitamin D as well as extra-skeletal activity. In this context, vitamin D seems to be involved in infections, autoimmune diseases, cardiometabolic diseases, and cancer development. In recent years, the relationship between vitamin D and insulin resistance has been a topic of growing interest. Low 25-hydroxyvitamin D (25(OH)D) levels appear to be associated with most of the insulin resistance disorders described to date. In fact, vitamin D deficiency may be one of the factors accelerating the development of insulin resistance. Vitamin D deficiency is a common problem in the population and may be associated with the pathogenesis of diseases related to insulin resistance, such as obesity, diabetes, metabolic syndrome (MS) and polycystic ovary syndrome (PCOS). An important question is the identification of 25(OH)D levels capable of generating an effect on insulin resistance, glucose metabolism and to decrease the risk of developing insulin resistance related disorders. The benefits of 25(OH)D supplementation/repletion on bone health are well known, and although there is a biological plausibility linking the status of vitamin D and insulin resistance supported by basic and clinical research findings, well-designed randomized clinical trials as well as basic research are necessary to know the molecular pathways involved in this association.

Osteoglycin (OGN) could be a biomarker of mild kidney function impairment in type 2 diabetes (T2D). Our study aimed to determine the association between serum OGN and impaired kidney function risk in T2D patients and to analyze its potential role as an estimator of kidney disturbances in this population. This cross-sectional study included 147 T2D patients (65 ± 8 years, 58.5% males), and 75 healthy controls (63 ± 10 years, 36% males). Circulating OGN levels were determined by ELISA. Linear regression modeling was performed to determine the variables influencing circulating OGN, and an ROC curve was plotted to assess the usefulness of OGN as an estimator of diabetic kidney disease risk. Circulating OGN was significantly increased in T2D patients compared to controls (18.41 (14.45-23.27) ng/mL vs. 8.74 (7.03-12.35) ng/mL; p < 0.001). We found a progressive increase in serum OGN according to the severity of kidney impairment in T2D patients (normal kidney function: 16.14 (12.13-20.48) ng/mL; mildly impaired kidney function: 19.15 (15.78-25.90) ng/mL; moderate impaired kidney function: 21.80 (15.06-29.22) ng/mL; p = 0.006). Circulating OGN was an independent estimator of mildly impaired kidney function risk in T2D patients. We suggest that serum OGN could act as an albuminuria-independent biomarker of incipient kidney dysfunction in T2D patients.

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

Currently, there are not many in-depth studies focusing on the protein analysis of antioxidants involved in the calcification of the femoral artery. In this context, this study aimed to increase the knowledge of the molecular redox mechanisms involved in this process. Samples from calcified femoral artery sections of seven patients diagnosed with type 2 diabetes (T2D) and critical ischemia were analyzed. The isolated proteins were identified using liquid chromatography and mass-mass spectrometry and were used to generate a protein-protein interaction (PPI) network. Subsequently, highly interconnected regions within the PPI network were identified to obtain a representative module linked to oxidative stress. The proteins of this module with a higher degree of centrality (hubs) were selected to validate them by datamining, transcriptomic and proteomic assays. The analysis of modules of the femoral PPI network showed a module with mainly antioxidant function in which superoxide dismutase 2 (SOD2) was reported as the most important hub. SOD2 was validated at transcriptomic and proteomic level and confirmed by datamining. These results indicate that SOD activity is highly linked to the atherosclerotic process. We suggest that SOD2 could be a potential therapeutic target to prevent the calcification of the femoral artery. The maintenance of optimal SOD2 levels and its cofactors could be used as a preventive strategy for vascular calcification and the related cardiovascular complications in T2D patients., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Osteoporosis is a common chronic disease characterized by a decrease in bone mineral density, impaired bone strength, and an increased risk of fragility fractures. Fragility fractures are associated with significant morbidity, mortality and disability and are a major public health problem worldwide. The influence of nutritional factors on the development and progression of this disease can be significant and is not yet well established. Calcium intake and vitamin D status are considered to be essential for bone metabolism homeostasis. However, some recent studies have questioned the usefulness of calcium and vitamin D supplements in decreasing the risk of fractures. The adequate intake of protein, vegetables and other nutrients is also of interest, and recommendations have been established by expert consensus and clinical practice guidelines. It is important to understand the influence of nutrients not only in isolation but also in the context of a dietary pattern, which is a complex mixture of nutrients. In this review, we evaluate the available scientific evidence for the effects of the main dietary patterns on bone health. Although some dietary patterns seem to have beneficial effects, more studies are needed to fully elucidate the true influence of diet on bone fragility.

Undercarboxylated osteocalcin (ucOC) could be a biomarker of glucose disturbances and cardiovascular risk. Our study aimed to determine the association between serum levels of ucOC and cardiovascular risk in metabolic syndrome (MetS) patients and to analyse its potential role as estimator of type 2 diabetes (T2D) risk in this population. This cross-sectional study included 235 patients with MetS, 53.2% women, aged 55-75 years. Circulating ucOC levels were measured by ELISA. Cardiovascular risk was determined as Z-score of the diagnostic criteria for MetS (CV-ZS). Linear regression model was performed to analyse the association between circulating ucOC and CV-ZS. A receiver operating curve (ROC) was performed to analyse the usefulness of ucOC as T2D risk estimator. Patients above the CV-ZS median showed significant lower ucOC levels. We found an inverse association between ucOC levels and CV-ZS in MetS patients without T2D. Patients with ucOC levels below the 25 th percentile showed worse cardiometabolic profile and higher cardiovascular and T2D risk. The area under the curve performed better when ucOC levels were included along with the classic T2D risk factors. The measurement of circulating ucOC could be a useful tool to identify increased cardiovascular and T2D risk in MetS patients without T2D.

Context: Primary hyperparathyroidism (PHPT) has been related to bone loss. Dual-energy x-ray absorptiometry (DXA) cannot distinguish between trabecular and cortical bone compartments but the recently developed three-dimensional (3D)-DXA software might overcome this issue., Objective: To examine the differences in DXA-derived areal bone mineral density (aBMD) and 3D-DXA parameters at the hip site between patients with PHPT and a healthy control group., Design: Cross-sectional pilot study., Setting: Hospital., Patients: 80 adults (59.5 ± 9.1 yrs), 40 with PHPT and 40 age- and sex-matched healthy controls., Measures: aBMD (g/cm2) of the femoral neck, trochanter, shaft, and total hip was assessed using DXA. Cortical surface (sBMD, mg/cm2), cortical volumetric BMD (vBMD, mg/cm3), trabecular vBMD (mg/cm3), integral vBMD (mg/cm3) and cortical thickness (mm) was assessed using 3D-DXA software., Results: Mean-adjusted values showed lower aBMD (7.5%-12.2%, effect size: 0.51-1.01) in the PHPT group compared with the control group (all P < 0.05). 3D-DXA revealed bone impairment (3.7%-8.5%, effect size: 0.47-0.65) in patients with PHPT, mainly in cortical parameters (all P < 0.05). However, differences in trabecular vBMD were not statistically significant (P = 0.055). The 3D mapping showed lower cortical sBMD, cortical vBMD, and cortical thickness at the trochanter and diaphysis in the PHPT group (P < 0.05) compared with the control group. In both groups, the presence of osteopenia or osteoporosis is related to lower cortical bone., Conclusions: aBMD and cortical 3D parameters are impaired in patients with PHPT versus healthy controls. The vBMD of the trabecular compartment seems to be affected, although to a lesser extent., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5'-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.

Background: Patients with primary hyperparathyroidism usually show decreased bone strength that are often not well diagnosed by conventional Dual-energy X-ray absorptiometry (DXA). Trabecular Bone Score (TBS) is a new technique for assessing bone microarchitecture indirectly. This cross-sectional study evaluates the usefulness of TBS in patients with primary hyperparathyroidism in clinical practice., Methodology: Bone mineral density (BMD) by DXA and TBS values by TBS InSight® software were determined in 72 patients with primary hyperparathyroidism to analyze its relationship with fragility fractures. A receiver operating curve was performed to evaluate the usefulness of TBS as predictor of fragility fractures. FRAX index with and without adjustment by TBS was calculated. Additionally, longitudinal data of a subgroup of patients according to the therapeutic management were also evaluated., Results: A total of 51.4% of the patients showed degraded microarchitecture while only 37.5% of them were diagnosed of osteoporosis by DXA. No significant correlation was found between TBS values and BMD parameters. However, TBS values were lower in osteoporotic patients compared to those classified as normal by BMD (1.16 ± 0.12vs 1.26 ± 0.17; p = 0.043) and in patients with fragility fractures compared to nonfractured patients (1.19 ± 0.03vs 1.24 ± 0.02, p < 0.001). The area under the curve for TBS performed better than the combination of femoral, hip and spine-BMD for prevalent fractures (0.714vs 0.679). TBS-adjusted FRAX was higher than nonadjusted model for both major osteoporotic and hip fracture (4.5% vs 3%; 0.9% vs 0.7%; p < 0.001). At follow-up, an improvement in TBS values was observed in treated patients (medical or surgical) vs nontreated close to significance (1.27 ± 0.10vs 1.24 ± 0.11, p = 0.074)., Conclusions: TBS could be a useful tool to identify increased fracture risk in patients with primary hyperparathyroidism underdiagnosed by BMD. Moreover, FRAX adjusted by TBS could be a more robust tool for predicting the risk of osteoporotic fracture to help in therapeutic decisions in this population., (Copyright © 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

The relationship between vitamin D status, calcium intake and the risk of developing type 2 diabetes (T2D) is a topic of growing interest. One of the most interesting non-skeletal functions of vitamin D is its potential role in glucose homeostasis. This possible association is related to the secretion of insulin by pancreatic beta cells, insulin resistance in different tissues and its influence on systemic inflammation. However, despite multiple observational studies and several meta-analyses that have shown a positive association between circulating 25-hydroxyvitamin D concentrations and the risk of T2D, no randomized clinical trials supplementing with different doses of vitamin D have confirmed this hypothesis definitively. An important question is the identification of what 25-hydroxyvitamin D levels are necessary to influence glycemic homeostasis and the risk of developing T2D. These values of vitamin D can be significantly higher than vitamin D levels required for bone health, but the currently available data do not allow us to answer this question adequately. Furthermore, a large number of observational studies show that dairy consumption is linked to a lower risk of T2D, but the components responsible for this relationship are not well established. Therefore, the importance of calcium intake in the risk of developing T2D has not yet been established. Although there is a biological plausibility linking the status of vitamin D and calcium intake with the risk of T2D, well-designed randomized clinical trials are necessary to answer this important question.

Background: Postmenopausal osteoporosis (PMO) is associated with other comorbidities such as impaired glucose homeostasis and cardiovascular disease. Vitamin D insufficiency is highly prevalent and may be a common link between these disorders. However, the relationship between circulating 25-hydroxyvitamin D [25(OH)D] and insulin resistance in women with PMO has not been well evaluated. The aim of this study was to assess the relationship between circulating levels of 25(OH)D and parameters of glucose homeostasis in a cohort of women with PMO to establish a serum concentration threshold of 25(OH)D for improved glycemic parameters., Materials and Methods: This cross-sectional study included 40 women with PMO. We measured 25(OH)D serum levels and glucose homeostasis parameters (glucose and insulin levels, insulin sensitivity, and β-secretion index HOMA2-%S and HOMA2-%B, respectively). Anthropometric, biochemical, and clinical parameters and bone markers were also evaluated., Results: Circulating levels of 25(OH)D were related to glucose parameters (negatively with HOMA2-%B and insulin levels and positively with HOMA2-%S) in women with PMO, resulting in an indicator of insulin sensitivity independent of age, body mass index, percent body fat, and undercarboxylated osteocalcin. Patients with serum 25(OH)D ≥45 ng/mL showed lower HOMA2-%B values and insulinemia and greater HOMA2-%S., Conclusions: Our results support the hypothesis that circulating 25(OH)D levels are related to improved glucose homeostasis in women with PMO. However, this relationship was apparent only in the presence of high circulating levels of 25(OH)D.

Cardiovascular diseases are a health problem throughout the world, especially in people with diabetes. The identification of cardiovascular disease biomarkers can improve risk stratification. Sclerostin is a modulator of the Wnt/β-catenin signalling pathway in different tissues, and it has recently been linked to vascular biology. The current study aimed to evaluate the relationship between circulating sclerostin levels and cardiovascular and non-cardiovascular mortality in individuals with and without type 2 diabetes. We followed up a cohort of 130 participants (mean age 56.8 years; 48.5% females; 75 with type 2 diabetes; 46 with prevalent cardiovascular disease) in which serum sclerostin levels were measured at the baseline. Time to death (both of cardiovascular and non-cardiovascular causes) was assessed to establish the relationship between sclerostin and mortality. We found that serum sclerostin concentrations were significantly higher in patients with prevalent cardiovascular disease (p<0.001), and independently associated with cardiovascular mortality (p = 0.008), showing sclerostin to be a stronger predictor of mortality than other classical risk factors (area under the curve = 0.849 vs 0.823). The survival analysis showed that an increase of 10 pmol/L in the serum sclerostin level resulted in a 31% increase in cardiovascular mortality. However, no significant association was observed between sclerostin levels and non-cardiovascular mortality (p = 0.346). From these results, we conclude that high sclerostin levels are related to mortality due to cardiovascular causes. The clinical implication of these findings is based on the possible use of serum sclerostin as a new biomarker of cardiovascular mortality risk in order to establish preventive strategies., Competing Interests: The authors have declared that no competing interests exist.

Myostatin and irisin are two myokines related to energy metabolism, acting on skeletal muscle and recently suggested on adipose tissue in mice. However, the exact role of these myokines in humans has not been fully established. Our aim was to evaluate the relationship between serum levels of myostatin and irisin in type 2 diabetes mellitus patients and non-diabetic controls and to explore its links with metabolic parameters. Case-control study including 73 type 2 diabetes mellitus patients and 55 non-diabetic subjects as control group. Circulating myostatin and irisin levels were measured by enzyme-linked immunosorbent assays. Type 2 diabetes mellitus patients showed significantly lower myostatin levels (p = 0.001) and higher irisin levels (p = 0.036) than controls. An inverse relationship was observed between myostatin and irisin levels (p = 0.002). Moreover, in type 2 diabetes mellitus patients, after adjusting by confounder factors, myostatin was negatively related to fasting plasma glucose (p = 0.005) and to triglyceride levels (p = 0.028) while irisin showed a positive association with these variables (p = 0.017 and p = 0.006 respectively). A linear regression analysis showed that irisin and fasting plasma glucose levels were independently associated to myostatin levels and that myostatin and triglyceride levels were independently associated to irisin concentrations in type 2 diabetes mellitus patients. Our results suggest that serum levels of myostatin and irisin are related in patients with type 2 diabetes. Triglyceride and glucose levels could modulate myostatin and irisin concentrations as a compensatory mechanism to improve the metabolic state in these patients although further studies are needed to elucidate whether the action of these myokines represents an adaptative response.

Type 2 diabetes mellitus (T2DM) patients have an increased risk of cardiovascular disease (CVD) that represents one of the main causes of mortality in this population. The knowledge of the underlie factors involved in the development of CVD and the discovery of new biomarkers of the disease could help to early identification of high-risk patients. Using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) we analyzed the serum metabolomic profile of 30 subject distributed according three groups: (i) T2DM patients with CVD; (ii) T2DM patients without CVD; (iii) non-diabetic subjects as controls (C) in order to identify potential biomarkers of the CVD related to T2DM. A partial least squares discriminant analysis (PLS-DA) and one-way analysis of variance (ANOVA) were applied to identify differential metabolites between different groups. Four glycerophospholipids were further identified as potential biomarkers of CVD in T2DM patients. Specifically, a reduction in phosphatidylcholine, lysophosphatidylcholine and lysophosphatidylethanolamine (LPE) serum levels were found in T2DM patients compared to controls, presenting the patients with CVD the lowest serum levels of these metabolites. These results show a generalized reduction of circulating phospholipids species in T2DM patients which is more pronounced in those with CVD providing information of the pathways involved in the pathogenesis and progression of CVD associated to T2DM., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: The biological mechanisms associated with an inadequate response to treatment with bisphosphonates are not well known. This study investigates the association between circulating levels of sclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women with postmenopausal osteoporosis., Methods: This case-control study is based on 120 Spanish women with postmenopausal osteoporosis being treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n=66, mean age 68.2±8 years) without incident fractures during 5 years of treatment, or inadequate responders (IRs, n=54, mean age 67±9 years), with incident fractures between 1 and 5 years of treatment. Bone mineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of the distal radius were assessed. Sclerostin concentrations were measured by ELISA and 17β-estradiol levels by radioimmunoassay based on ultrasensitive methods., Results: In the ARs group, sclerostin serum levels were significantly lower (p=0.02) and estradiol concentrations significantly higher (p=0.023) than in the IRs group. A logistic regression analysis was performed, including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D, previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture (OR 14.04, 95% CI 2.38-82.79, p=0.004) and sclerostin levels (OR 1.11, 95% CI 1.02-1.20, p=0.011), both adjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associated with the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameter on bone microstructure., Conclusions: Sclerostin and estradiol levels are associated with the response to bisphosphonate therapy in women with postmenopausal osteoporosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Type 2 diabetes mellitus patients are at significant risk of cardiovascular disease, however, the pathophysiology of these complications is complex and incompletely known in this population. The aim of this study was to compare the serum proteome of patients with type 2 diabetes mellitus presenting or not presenting cardiovascular disease with non-diabetic subjects to find essential proteins related to these cardiovascular complications. This cross-sectional study compares the serum proteome by a combination of protein depletion with 2D-DIGE (2-dimension Difference Gel Electrophoresis) methodology. The proteins differentially expressed were identified by MALDI TOF/TOF (Matrix-assisted laser desorption/ionization and Time-Of-Flight ion detector) or LC-MS/MS (Liquid Chromatography coupled to Mass-Mass Spectrometry). Type 2 diabetes mellitus patients with cardiovascular disease showed higher expression of plasma retinol binding protein and glutathione peroxidase-3 compared to those without cardiovascular disease and non-diabetic controls. These results show that proteins related to the inflammatory and redox state appear to play an important role in the pathogenesis of the cardiovascular disease in the type 2 diabetes mellitus patients.

Objectives: Dickkopf-1 (DKK1) is a potent inhibitor of Wnt signalling, which exerts anabolic effects on bone and also takes part in the regulation of vascular cells. Our aims were to evaluate serum DKK1 in type 2 diabetes (T2DM) patients and to analyze its relationships with cardiovascular disease (CVD). We also evaluated the relationship between DKK1 and bone metabolism., Design: We conducted a cross-sectional study in which we measured serum DKK1 (ELISA, Biomedica) in 126 subjects: 72 patients with T2DM and 54 non-diabetic subjects. We analysed its relationship with clinical CVD, preclinical CVD expressed as carotid intima media thickness (IMT), and bone metabolism., Results: T2DM patients with CVD (P = 0,026) and abnormal carotid IMT (P = 0,038) had higher DKK1 concentrations. DKK1 was related to the presence of CVD in T2DM, independently of the presence of risk factors for atherosclerosis. Therefore, for each increase of 28 pg/ml of serum DKK1 there was a 6,2% increase in the risk of CVD in T2DM patients. The ROC curve analysis to evaluate the usefulness of DKK1 as a marker for high risk of CVD showed an area under the curve of 0,667 (95% CI: 0,538-0,795; P = 0,016). In addition, there was a positive correlation between serum DKK1 and spine bone mineral density in the total sample (r =  0,183; P = 0,048)., Conclusion: In summary, circulating DKK1 levels are higher in T2DM with CVD and are associated with an abnormal carotid IMT in this cross-sectional study. DKK1 may be involved in vascular disease of T2DM patients.

Objective: Wnt/β-catenin signaling is related to the pathogenesis of several diseases. Sclerostin is an inhibitor of Wnt/β-catenin signaling. However, there are few data regarding the sclerostin levels and vascular disease. Our aim was to examine the relationship between serum sclerostin and atherosclerotic disease (AD) in type 2 diabetes mellitus (T2DM)., Research Design and Methods: We performed a cross-sectional study including 78 T2DM patients (45.3% females, mean age 59 ± 5.7 years; 54.7% males, 57.4 ± 6.7 years)., Results: Serum sclerostin concentrations of T2DM patients in the AD group were significantly higher than in the non-AD group (P = 0.006). For each increase of 1 pmol/L in sclerostin level, there was a 4% increase of the risk of AD in T2DM patients. A concentration of ≥ 42.3 pmol/L showed a sensitivity of 69% and a specificity of 54.8% to detect an increased risk of AD. In males, sclerostin levels were higher in those with AD (P = 0.04), abnormal intima-media thickness (IMT) (P = 0.004), carotid plaques (P < 0.001), and aortic calcification (P < 0.001). In females, higher levels of sclerostin were related to abnormal IMT (P = 0.03) and aortic calcifications (P = 0.004). Homocysteine (β = 0.319 [95% CI 0.561-2.586], P = 0.003) and IMT (β = 0.330 [14.237-67.693], P = 0.003) were positively correlated with sclerostin., Conclusions: Circulating sclerostin is increased in T2DM patients with atherosclerotic lesions. Although the sample size of our study was small, these data suggest that sclerostin levels could be a major modulator of Wnt signaling in AD with implications in T2DM patients.