[Update 2017 of the KDIGO guidelines on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). What are the real changes?]

Guidelines for the assessment, diagnosis and therapy of the alterations that characterize the CKD-MBD are an important support in the clinical practice of the nephrologist. Compared to the KDIGO guidelines published in 2009, the 2017 update made changes on some topics on which there was previously no strong evidence both in terms of diagnosis and therapy. The recommendations include the diagnosis of bone anomalies in CKD-MBD and the treatment of mineral metabolism abnormalities with particular regard to hyperphosphataemia, calcium levels, secondary hyperparathyroidism and anti-resorptive therapies. The Italian Study Group on Mineral Metabolism, in reviewing the 2017 recommendations, aimed to assess the weight of the evidence that led to this update. In fact, on some topics there has not been a substantial difference on the degree of evidence compared to the previous guidelines. The Italian Study Group emphasizes the points that may still reserve critical issues, including interpretation, and invites an evaluation that is articulated and personalized for each patient.

Association of Severity of Coronary Lesions with Bone Mineral Density in Postmenopausal Women.

BACKGROUND: Coronary artery disease (CAD) and osteoporosis (OP) are common diseases in postmenopausal women. In both cross-sectional and longitudinal epidemiologic studies, low bone mass has been related to increased frequency of CAD. However, available data on the relationship between bone mineral density (BMD) and severity of coronary lesions is limited. OBJECTIVE: To investigate association between the BMD and severity of coronary lesions assessed by Gensini score in postmenopausal women. METHODS: This study included 122 postmenopausal women who were diagnosed with CAD. These patients were divided into two groups according to the severity of coronary lesions assessed by the Gensini score - patients with mild coronary lesions (Gensini score < 25) and patients with severe coronary lesions (Gensini score ≥ 25). Femoral neck mineral density was measured with dual energy X-ray absorptiometry (DXA). RESULTS: The study included postmenopausal women aged 64.31 ± 4.71 years, 85 of whom (69.7%) exhibited severe coronary lesions. Participants with severe coronary lesions had a significantly higher T score than did those with mild coronary lesions at the femoral neck (p < 0.05). The mean T-score was -0.84 ± 1.01 in mild coronary lesions group, -1.42 ± 1.39 in severe coronary lesions group (p < 0.05). Multivariable logistic regression analysis showed that osteopenia-osteoporosis at the Femoral neck (odds ratio 2.73; 95% confidence interval 1.06 to 6.13) was associated with an increased risk of developing severe coronary lesions. The multiple regression model showed that T-scores (b = -0.407, SE = 0.151, p=0.007) were the independent predictors of Gensini score. CONCLUSION: The relationship between severity of coronary lesions and BMD was significant in postmenopausal women. BMD, a low-cost technique involving minimal radiation exposure, widely used for osteoporosis screening, is a promising marker of severity of coronary lesions.

Association of Severity of Coronary Lesions with Bone Mineral Density in Postmenopausal Women / Associação entre Gravidade das Lesões Coronarianas e Densidade Mineral Óssea em Mulheres Pós-Menopausa

Abstract Background: Coronary artery disease (CAD) and osteoporosis (OP) are common diseases in postmenopausal women. In both cross-sectional and longitudinal epidemiologic studies, low bone mass has been related to increased frequency of CAD. However, available data on the relationship between bone mineral density (BMD) and severity of coronary lesions is limited. Objective: To investigate association between the BMD and severity of coronary lesions assessed by Gensini score in postmenopausal women. Methods: This study included 122 postmenopausal women who were diagnosed with CAD. These patients were divided into two groups according to the severity of coronary lesions assessed by the Gensini score - patients with mild coronary lesions (Gensini score < 25) and patients with severe coronary lesions (Gensini score ≥ 25). Femoral neck mineral density was measured with dual energy X-ray absorptiometry (DXA). Results: The study included postmenopausal women aged 64.31 ± 4.71 years, 85 of whom (69.7%) exhibited severe coronary lesions. Participants with severe coronary lesions had a significantly higher T score than did those with mild coronary lesions at the femoral neck (p < 0.05). The mean T-score was −0.84 ± 1.01 in mild coronary lesions group, −1.42 ± 1.39 in severe coronary lesions group (p < 0.05). Multivariable logistic regression analysis showed that osteopenia-osteoporosis at the Femoral neck (odds ratio 2.73; 95% confidence interval 1.06 to 6.13) was associated with an increased risk of developing severe coronary lesions. The multiple regression model showed that T-scores (b = −0.407, SE = 0.151, p=0.007) were the independent predictors of Gensini score. Conclusion: The relationship between severity of coronary lesions and BMD was significant in postmenopausal women. BMD, a low-cost technique involving minimal radiation exposure, widely used for osteoporosis screening, is a promising marker of severity of coronary lesions.

Resumo Fundamento: A doença arterial coronariana (DAC) e a osteoporose são doenças comuns em mulheres pós-menopausa. Tanto em estudos transversais como em estudos epidemiológicos longitudinais, a massa óssea diminuída foi relacionada à frequência aumentada de DAC. No entanto, dados disponíveis sobre a relação entre densidade mineral óssea (DMO) e gravidade das lesões coronarianas são limitados. Objetivo: Investigar a associação entre DMO e gravidade das lesões coronarianas avaliadas pelo escore de Gensini em mulheres pós-menopausa. Métodos: Este estudo incluiu 122 mulheres pós-menopausa diagnosticadas com DAC. As pacientes foram divididas em dois grupos de acordo com a gravidade das lesões coronarianas avaliada pelo escore de Gensini - pacientes com lesões coronarianas leves (escore de Gensini < 25) e pacientes com lesões coronarianas graves (escore de Gensini ≥ 25). A densidade mineral do colo femoral foi medida por absorção de raios-X de dupla energia (DXA). Resultados: O estudo incluiu mulheres pós-menopausa com idade de 64,31 ± 4,71 anos, 85 delas (69,7%) com lesões coronarianas graves. Pacientes com lesões coronarianas graves apresentaram um escore T mais elevado que aquelas com lesões coronarianas leves no colo femoral (p < 0,05). O escore T médio foi -0,84 ± 1,01 no grupo com lesões leves, e -1,42 ± 1,39 no grupo com lesões graves (p < 0,05). A análise de regressão logística multivariada mostrou que a osteopenia-osteoporose no colo femoral (odds ratio 2,73; intervalo de confiança de 95% 1,06 - 6,13) esteve associada com um risco aumentado de se desenvolver lesões coronarianas graves. O modelo de regressão múltipla mostrou que os escores T (b = -0,407; EP= 0,151; p = 0,007) foram preditores independentes do escore de Gensini. Conclusão: Encontrou-se uma relação significativa entre a gravidade das lesões coronarianas e a DMO em mulheres pós-menopausa. DMO, uma técnica de baixo custo que envolve mínima exposição à radiação, e amplamente utilizada no rastreamento de osteoporose, é um marcador promissor da gravidade de lesões coronarianas graves.

TDF and quantitative ultrasound bone quality in African patients on second line ART, ANRS 12169 2LADY sub-study.

BACKGROUND: Bone demineralization, which leads to osteoporosis and increased fracture risk, is a common metabolic disorder in HIV-infected individuals. In this study, we aimed to assess the change in bone quality using quantitative ultrasound (QUS) over 96 weeks of follow-up after initiation of second-line treatment, and to identify factors associated with change in bone quality. METHODS AND FINDINGS: In a randomized trial (ANRS 12169), TDF and PI-naïve participants failing standard first-line treatment, from Burkina Faso, Cameroon, and Senegal were randomized to receive either TDF/FTC/LPVr, ABC/ddI/LPVr or TDF/FTC/DRVr. Their bone quality was assessed using calcaneal QUS at baseline and every 24 weeks until week 96. Stiffness index (SI) was used to measure bone quality. Out of 228 participants, 168 (74%) were women. At baseline, median age was 37 years (IQR: 33-46 years) and median T-CD4 count was 199 cells/µl (IQR: 113-319 cells/µl). The median duration of first-line antiretroviral treatment (ART) was 52 months (IQR: 36-72 months) and the median baseline SI was 101 (IQR: 87-116). In multivariable analysis, factors associated with baseline SI were sex (ß = -10.8 [-18.1,-3.5] for women), age (ß = -8.7 [-12.4,-5.1] per 10 years), body mass index (BMI) (ß = +0.8 [0.1,1.5] per unit of BMI), and study site (ß = +12.8 [6.5,19.1] for Cameroon). After 96 weeks of second-line therapy, a reduction of 7.1% in mean SI was observed, as compared with baseline. Factors associated with SI during the follow-up were similar to those found at baseline. Exposure to TDF was not associated with a greater loss of bone quality over time. CONCLUSION: Bone quality decreased after second-line ART initiation in African patients independently of TDF exposure. Factors associated with bone quality include age, sex, baseline BMI, study site, and duration of follow-up.

Bone mineral density loss in clinically suspect arthralgia is associated with subclinical inflammation and progression to clinical arthritis.

OBJECTIVE: Peripheral bone mineral density (BMD) may be decreased in early rheumatoid arthritis (RA) but it is unknown whether BMD loss emerges before arthritis is clinically apparent. We aimed to study whether BMD loss occurs in patients with clinically suspect arthralgia (CSA), and whether it is associated with progression to clinical arthritis and magnetic resonance imaging (MRI)-detected subclinical inflammation. METHOD: Patients with CSA had arthralgia for <1 year and were at risk of progressing to RA according to their rheumatologists. At baseline, a 1.5 T MRI was performed of unilateral metacarpophalangeal, wrist, and metatarsophalangeal joints, and scored on synovitis, bone marrow oedema, and tenosynovitis;. summing these features yielded the total MRI inflammation score. Digital X-ray radiogrammetry (DXR) was used to estimate BMD on two sequential conventional hand radiographs (mean interval between radiographs 4.4 months). The change in BMD was studied; BMD loss was defined as a decrease of ≥2.5 mg/cm2/month. Patients were followed for arthritis development for a median of 18.4 months. RESULTS: In CSA patients (n = 108), change in BMD was negatively associated with age (ß = -0.03, p = 0.007). BMD loss in CSA patients was associated with arthritis development [adjusted for age hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.7 to 21.4] and was most frequently estimated in the months before clinical arthritis development. The total MRI inflammation scores were associated with the change in BMD (adjusted for age ß = -0.05, p = 0.047). The total MRI inflammation score and BMD loss were both independently associated with arthritis development (HR = 1.1, 95% CI 1.1 to 1.2, and HR = 4.6, 95% CI 1.2 to 17.2, respectively). CONCLUSION: In CSA patients, severe BMD loss is associated with MRI-detectable subclinical inflammation and with progression to clinical arthritis.

Osteoporosis: A Future Public Health Problem for Israel? Medical and Legal Obligations.

BACKGROUND: Starvation in early life can lead to premature metabolic syndrome and bone demineralization. Osteoporosis in the Jewish population may not yet be a recognized syndrome, but the harsh conditions to which Holocaust survivors were exposed may have increased the incidence of the condition. Immigrants and refugees who came to Israel from East Africa and Yemen - whether decades ago or more recently - may have been at increased risk of under-nutrition during pregnancy, affecting both the mother and consequently the offspring. This malnutrition may be further exacerbated by rapid overfeeding in the adopted developed country. This problem was also recognized at the turn of the 21st century in poor and underdeveloped countries and is becoming a global public health issue. In this review, the risks for premature metabolic syndrome and bone demineralization are enumerated and preventive measures outlined.

Efecto del sistema RANK/RANKL/OPG sobre la desmineralización ósea y la calcificación vascular en la enfermedad renal crónica / Effect of RANK/RANKL/OPG pathway on bone demineralization and vascular calcification in chronic kidney disease

Introducción: En la enfermedad renal crónica (ERC) se producen alteraciones del metabolismo óseo y mineral que favorecen la calcificación de tejidos blandos. Alteraciones del sistema RANK/RANKL/OPG podrían estar favoreciendo la calcificación vascular, importante causa de morbimortalidad en la ERC. Objetivo: Valorar en un modelo experimental in vivo de insuficiencia renal crónica el efecto de la progresión de la misma sobre la calcificación vascular y sobre la pérdida de hueso correlacionando estos cambios con alteraciones en el sistema RANK/RANKL/OPG, utilizando un sistema in vitro para confirmar los hallazgos encontrados. Material y métodos: Se utilizaron dos modelos de calcificación vascular: un modelo in vivo en ratas con insuficiencia renal crónica alimentadas con dieta con diferente contenido en fósforo, y un modelo in vitro en células de músculo liso vascular (CMLV) sometidas a diferentes estímulos calcificantes. Resultados: A las 20 semanas, un 50% de los animales con dieta alta en fósforo presentó calcificaciones aórticas que se acompañó de aumento en la expresión aórtica de RANKL. Por el contrario, la OPG disminuyó como consecuencia probablemente del componente inflamatorio. A las 20 semanas en la tibia aumentó la expresión de RANKL y OPG, mientras que el aumento de OPG ocurrió en fases más tempranas. En CMLV la adición de suero urémico y medio calcificante indujo un incremento del contenido de calcio y de la expresión de RANKL y OPG. La adición de OPG y el silenciamiento de RANK inhibieron este aumento. Conclusiones: Nuestros resultados confirman la participación del eje RANK/RANKL/OPG en el proceso de calcificación vascular (AU)

Introduction: In cases of chronic kidney disease (CKD), bone and mineral metabolism changes occur which favor soft tissue calcification. Alterations in the RANK/RANKL/OPG system could also favor vascular calcification, a major cause of morbidity and mortality in CKD. Objective: In an in vivo experimental model of chronic renal failure progression, we assess the effect of CKD on vascular calcification and bone loss correlating these changes in the RANK/RANKL/OPG pathway. An in vitro system was used to confirm findings. Material and methods: Two models of vascular calcification were used: an in vivo rat model with chronic renal failure fed on a diet with different phosphorus content, and an in vitro model in vascular smooth muscle cells (VSMC) subjected to different calcifying stimuli. Results: At 20 weeks, 50% of animals with a diet high in phosphorus presented aortic calcification accompanied by increased aortic expression of RANKL. In contrast, OPG decreased probably as a consequence of an inflammatory component. At 20 weeks, expression of RANKL and OPG in the tibia increased, while the increase in OPG occurred at earlier stages. In VSMC, the addition of uremic serum and calcification medium increased calcium content and expression of RANKL and OPG. The addition of OPG and silencing of RANK inhibited this increase. Conclusions: Our results confirm RANK/RANKL/OPG system involvement in the vascular calcification process (AU)

Efecto del tratamiento dietoterápico de la obesidad sobre el metabolismo óseo / Effect of dietary treatment of obesity on bone metabolism

La obesidad interfiere con el metabolismo óseo a través de factores mecánicos, hormonales e inflamatorios. El principal tratamiento de dicha enfermedad es la dieta, modificación de la cantidad y tipo de alimento. Este tratamiento nutricional tiene una influencia sobre el metabolismo óseo en dos sentidos: modifica el efecto del sobrepeso y la obesidad sobre el hueso e interviene directamente en el turnover óseo a través de las características de los nutrientes utilizados. Esta revisión analiza la evidencia del efecto sobre el hueso del descenso de peso y del patrón dietético utilizado. Por otra parte, se valorarán las modificaciones que se pueden realizar en la dieta indicada en un paciente obeso para prevenir la pérdida ósea, a corto y largo plazo, y disminuir el riesgo de fractura (AU)

Obesity interferes with bone metabolism through mechanical, hormonal and inflammatory factors. The main treatment of this disease is the diet with modification of the amount and type of food. This nutritional therapy has an influence on bone metabolism in two ways: It modifies the effect of overweight and obesity on bone; and it intervenes in bone turnover through the characteristics of the nutrients used. This review examines the evidence of the effect on bone of weight loss and dietary pattern used. Moreover, we will assess the modifications that can be made in weight-reduction diet to prevent short and long term bone loss and reduce the risk of fracture (AU)

Detección de las calcificaciones cardiovasculares: ¿una herramienta útil para el nefrólogo? / Detection of cardiovascular calcifications: Is it a useful tool for nephrologists?

La enfermedad renal crónica (ERC) ha servido de modelo y fuente de conocimiento sobre los mecanismos, la relevancia clínica y progresión acelerada de los procesos de la calcificación cardiovascular (CV), así como de sus repercusiones en la práctica clínica, aunque se trate de un fenómeno tardío y secundario de osificación sobre el que solo disponemos de evidencias circunstanciales. En esta amplia revisión se describen primero los tipos de calcificación CV que afectan al paciente con ERC y se analiza cómo su presencia está directamente asociada a eventos CV y a un aumento de la mortalidad de estos pacientes. Asimismo, justificamos la valoración de la calcificación CV en la práctica clínica nefrológica habitual, al entender que es un predictor importante de la evolución clínica de estos pacientes, y consideramos que la valoración de las calcificaciones CV es una herramienta que puede y debe ser utilizada por el nefrólogo para la toma individualizada de decisiones terapéuticas en un momento en que se requiere cada vez más de una medicina personalizada (AU)

Chronic kidney disease (CKD) has been used as a model and source of knowledge concerning the mechanisms, clinical relevance and accelerated progression of cardiovascular (CV) calcification, as well as its consequences in clinical practice, despite we know that it is a late secondary ossification phenomenon and only circumstantial evidence is available. In this comprehensive review, we firstly describe the types of CV calcification which affect CKD patients, and we analyse how its presence is directly associated with CV events and increased mortality in these patients. We also justify the use of CV calcification assessment in regular nephrology clinical practice, because CV calcification is an important predictor of clinical outcome in these patients. Consequently, we believe that CV calcification assessment is a tool that could and should be used by nephrologists when making a decision concerning individual patients, consistent with the current trend of an ever-more-personalised therapeutic approach (AU)

Calcificaciones cardiovasculares en la enfermedad renal crónica: Potenciales implicaciones terapéuticas / Cardiovascular calcifications in chronic kidney disease: Potential therapeutic implications

La calcificación cardiovascular (CV) es una condición muy prevalente en todos los estadios de la enfermedad renal crónica (ERC) y se asocia directamente a una mayor morbimortalidad CV y global. En la primera parte de esta revisión hemos mostrado cómo las calcificaciones CV son una característica destacada del complejo CKD-MBD (chronic kidney disease-mineral and bone disorders) así como un predictor superior de la evolución clínica de nuestros pacientes. No obstante, es necesario también demostrar que la calcificación CV es un factor de riesgo modificable y con la posibilidad, como mínimo, de poder disminuir su progresión (o al menos no agravarla) con maniobras iatrogénicas. Aunque estrictamente solo se disponga de evidencias circunstanciales, sabemos que el uso de determinados fármacos puede modificar la progresión de las calcificaciones CV, aunque no se ha demostrado un vínculo directo causal sobre la mejoría de la supervivencia. En este sentido, el uso de quelantes del fósforo no cálcicos ha demostrado reducir la progresión de las calcificaciones CV en comparación con el uso liberal de quelantes cálcicos en varios ensayos clínicos aleatorizados. Por otra parte, aunque solo a nivel experimental, los activadores selectivos del receptor de la vitamina D parecen mostrar un mayor margen terapéutico contra la calcificación CV. Finalmente, los calcimiméticos también parece que podrían atenuar la progresión de la calcificación CV en pacientes en diálisis. Mientras se desarrollan nuevas estrategias terapéuticas (p. ej. vitamina K, SNF472…), proponemos que la valoración de las calcificaciones CV puede ser una herramienta usada por el nefrólogo para la toma individualizada de decisiones terapéuticas (AU)

Cardiovascular (CV) calcification is a highly prevalent condition at all stages of chronic kidney disease (CKD) and is directly associated with increased CV and global morbidity and mortality. In the first part of this review, we have shown that CV calcifications represent an important part of the CKD-MBD complex and are a superior predictor of clinical outcomes in our patients. However, it is also necessary to demonstrate that CV calcification is a modifiable risk factor including the possibility of decreasing (or at least not aggravating) its progression with iatrogenic manoeuvres. Although, strictly speaking, only circumstantial evidence is available, it is known that certain drugs may modify the progression of CV calcifications, even though a direct causal link with improved survival has not been demonstrated. For example, non-calcium-based phosphate binders demonstrated the ability to attenuate the progression of CV calcification compared with the liberal use of calcium-based phosphate binders in several randomised clinical trials. Moreover, although only in experimental conditions, selective activators of the vitamin D receptor seem to have a wider therapeutic margin against CV calcification. Finally, calcimimetics seem to attenuate the progression of CV calcification in dialysis patients. While new therapeutic strategies are being developed (i.e. vitamin K, SNF472, etc.), we suggest that the evaluation of CV calcifications could be a diagnostic tool used by nephrologists to personalise their therapeutic decisions (AU)

Accelerated bone turnover identifies hemiplegic patients at higher risk of demineralization.

Immobilization osteoporosis represents a severe complication in hemiplegic patients (HPs), causing fragility fractures, which may occur during rehabilitation reducing functional recovery and survival. The aim of the study was to investigate determinants of bone loss, independent from length of immobilization, which may be useful in early identification of HPs at higher risk of demineralization. Forty-eight HPs of both sexes underwent anthropometric measurements, evaluation of scores of spasticity and of lower limb motory capacity. Laboratory tests were performed. On serum: calcium; phosphorus; creatinine; ALP; iPTH; 25(OH) vitamin-D; sex hormones; Δ4-androstenedione; DHEA-S; insulin; IGF-1; FT3; FT4; TSH; c-AMP. On urine: c-AMP and calcium/creatinine ratio. Two bone turnover markers were measured: serum osteocalcin (BGP) and urinary deoxypyridinoline (DPD). Bone mineral density was determined at both femoral necks, defining a percentage difference in bone loss between paretic and non-paretic limb, thus controlling for the complex cofactors involved. Only bone turnover markers significantly and directly correlated with the entity of demineralization, controlling for age, sex and length of immobilization in the multivariate analysis (BGP coefficient estimate=0.008; SE=0.003; p=0.020; DPD coefficient estimate=0.005; SE=0.002; p=0.036). BGP and DPD are not dependent on anthropometric and endocrine-metabolic parameters, disability patterns and duration of immobilization, thus represent independent determinants of the degree of demineralization. A cutoff was defined for BGP and DPD above which subjects show significantly greater risk of demineralization. The immobilization event generates more severe bone loss when it occurs in subjects with higher bone turnover. BGP and DPD measurements may be of primary importance for early identification of HPs at risk, with relevant preventive implications.

Serum sclerostin levels, arteriovenous fistula calcification and 2-years all-cause mortality in prevalent hemodialysis patients / Niveles de esclerostina sérica, calcificación de la fístula arteriovenosa y mortalidad por todas las causas a los 2 años en pacientes en hemodiálisis prevalente

Background: Bone and mineral abnormalities, and cardiovascular calcification are associated with increased cardiovascular mortality in patients with chronic kidney disease (CKD). Recent studies have implicated Wnt signaling pathway in the pathogenesis of bone metabolism and vascular calcification. Sclerostin is a soluble inhibitor of Wnt signaling pathway and has been shown to be associated with decreased bone turnover and vascular calcification in CKD patients. Objectives: The aim was to investigate whether the circulating levels of sclerostin are associated with all-cause mortality in prevalent hemodialysis patients. Methods: Data are prospectively collected for 24 months for survival analysis in 350 prevalent hemodialysis patients. At baseline, serum sclerostin levels were measured and arteriovenous fistula calcification was detected by using a 64-detector computerized tomographic scanner. Results: During the follow-up, 84 (24%) patients died. Patients who died had higher serum sclerostin levels. Kaplan-Meier curve revealed that patients with increasing tertiles of serum sclerostin levels at baseline, had a worse survival. In the multivariate Cox regression analysis age, albumin, and presence of arteriovenous fistula calcification, but not sclerostin levels, were found to be independent predictors of survival in maintenance hemodialysis patients. Conclusion: Further clinical studies with longer follow-up are needed to clarify the impact of serum sclerostin levels on morbidity and mortality of maintenance hemodialysis patients. Clinical trial registration number: The study was performed as a post hoc survival analysis of the patients involved in a single-center prospective trial investigating the association between serum sclerostin levels and arteriovenous fistula calcification and patency [Balcý M, et al. Herz 2015;40:289–97] with a Clinicaltrials.gov number: NCT01382966 (AU)

Antecedentes: Algunas anomalías minerales óseas y la calcificación cardiovascular están asociadas con un aumento en la mortalidad cardiovascular en pacientes con enfermedad renal crónica (ERC). Estudios recientes han implicado a la vía de señalización Wnt en la patogenia del metabolismo óseo y la calcificación vascular. La esclerostina es un inhibidor soluble de la vía de señalización Wnt y se ha demostrado que está relacionada con una reducción del recambio óseo y de la calcificación vascular en pacientes con ERC. Objetivo: El objetivo fue investigar si los niveles circulantes de esclerostina están asociados con la mortalidad por todas las causas en pacientes en hemodiálisis prevalente. Métodos: Se recogieron datos de manera prospectiva durante 24 meses para el análisis de supervivencia en 350 pacientes en hemodiálisis prevalente. Al inicio del estudio se midieron los niveles de esclerostina sérica y se detectó calcificación de la fístula arteriovenosa mediante el uso de un escáner tomográfico computarizado de 64 detectores. Resultados: Durante el período de seguimiento, murieron 84 pacientes (24%). Los pacientes que murieron presentaban elevados niveles de esclerostina sérica. La curva de Kaplan-Meier reveló que los pacientes con terciles en aumento de esclerostina sérica al inicio del estudio tenían peores tasas de supervivencia. En el análisis de regresión de Cox multivariado, la edad, los valores de albúmina y la existencia de calcificación de la fístula arteriovenosa, pero no los niveles de esclerostina, demostraron ser los indicadores independientes de supervivencia en pacientes en hemodiálisis de mantenimiento. Conclusión: Se necesitan más estudios clínicos con un seguimiento más extenso para aclarar el impacto de los niveles de esclerostina sérica en la morbimortalidad de los pacientes en hemodiálisis de mantenimiento. Número de registro del ensayo clínico: El estudio se llevó a cabo como un análisis post hoc de supervivencia de los pacientes involucrados en un ensayo prospectivo de un único centro, que investigaba la asociación entre niveles de esclerostina sérica y la calcificación y permeabilidad de la fístula arteriovenosa [Balcý M, et al. Herz 2015;40:289-97], con el númeroNCT01382966 en Clinicaltrials.gov (AU)

Osteocyte-directed bone demineralization along canaliculi.

The mammalian skeleton stores calcium and phosphate ions in bone matrix. Osteocytes in osteocyte lacunae extend numerous dendrites into canaliculi less than a micron in diameter and which are distributed throughout bone matrix. Although osteoclasts are the primary bone-resorbing cells, osteocytes also reportedly dissolve hydroxyapatite at peri-lacunar bone matrix. However, robust three-dimensional evidence for peri-canalicular bone mineral dissolution has been lacking. Here we applied a previously reported Talbot-defocus multiscan tomography method for synchrotron X-ray microscopy and analyzed the degree of bone mineralization in mouse cortical bone around the lacuno-canalicular network, which is connected both to blood vessels and the peri- and endosteum. We detected cylindrical low mineral density regions spreading around canaliculi derived from a subset of osteocytes. Transmission electron microscopy revealed both intact and demineralized bone matrix around the canaliculus. Peri-canalicular low mineral density regions were also observed in osteopetrotic mice lacking osteoclasts, indicating that osteoclasts are dispensable for peri-canalicular demineralization. These data suggest demineralization can occur from within bone through the canalicular system, and that peri-canalicular demineralization occurs not uniformly but directed by individual osteocytes. Blockade of peri-canalicular demineralization may be a therapeutic strategy to increase bone mass and quality.

A pilot study of change in fracture risk in patients with acute respiratory distress syndrome.

INTRODUCTION: Acute skeletal muscle wasting is a major contributor to post critical illness physical impairment. However, the bone response remains uncharacterized. We prospectively investigated the early changes in bone mineral density (BMD) and fracture risk in critical illness. METHODS: Patients were prospectively recruited ≤24 hours following intensive care unit (ICU) admission to a university teaching or a community hospital (August 2009 to April 2011). All were aged >18 years and expected to be intubated for >48 hours, spend >7 days in critical care and survive ICU admission. Forty-six patients were studied (55.3% male), with a mean age of 54.4 years (95% confidence interval (CI): 49.1 to 59.6) and an APACHE II score of 23.9 (95% CI: 22.4 to 25.5). Calcaneal dual X-ray absorptiometry (DXA) assessment of BMD was performed on day 1 and 10. Increase in fracture risk was calculated from the change in T-score. RESULTS: BMD did not change between day 1 and 10 in the cohort overall (0.434 (95% CI: 0.405 to 0.463) versus 0.425 g/cm(2) (95% CI: 0.399 to 0.450), P = 0.58). Multivariable logistical regression revealed admission corrected calcium (odds ratio (OR): 1.980 (95% CI: 1.089 to 3.609), P = 0.026) and admission PaO2-to-FiO2 ratio (OR: 0.916 (95% CI: 0.833 to 0.998), P = 0.044) to be associated with >2% loss of BMD. Patients with acute respiratory distress syndrome had a greater loss in BMD than those without (-2.81% (95% CI: -5.73 to 0.118%), n = 34 versus 2.40% (95% CI: 0.204 to 4.586%), n = 12, P = 0.029). In the 34 patients with acute respiratory distress syndrome, fracture risk increased by 19.4% (95% CI: 13.9 to 25.0%). CONCLUSIONS: Patients with acute respiratory distress syndrome demonstrated early and rapid bone demineralisation with associated increase in fracture risk.

Identifying sex-specific risk factors for low bone mineral density in adolescent runners.

BACKGROUND: Adolescent runners may be at risk for low bone mineral density (BMD) associated with sports participation. Few prior investigations have evaluated bone health in young runners, particularly males. PURPOSE: To characterize sex-specific risk factors for low BMD in adolescent runners. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Training characteristics, fracture history, eating behaviors and attitudes, and menstrual history were measured using online questionnaires. A food frequency questionnaire was used to identify dietary patterns and measure calcium intake. Runners (female: n = 94, male: n = 42) completed dual-energy x-ray absorptiometry (DXA) to measure lumbar spine (LS) and total body less head (TBLH) BMD and body composition values, including android-to-gynoid (A:G) fat mass ratio. The BMD was standardized to Z-scores using age, sex, and race/ethnicity reference values. Questionnaire values were combined with DXA values to determine risk factors associated with differences in BMD Z-scores in LS and TBLH and low bone mass (defined as BMD Z-score ≤-1). RESULTS: In multivariable analyses, risk factors for lower LS BMD Z-scores in girls included lower A:G ratio, being shorter, and the combination of (interaction between) current menstrual irregularity and a history of fracture (all P < .01). Later age of menarche, lower A:G ratio, lower lean mass, and drinking less milk were associated with lower TBLH BMD Z-scores (P < .01). In boys, lower body mass index (BMI) Z-scores and the belief that being thinner improves performance were associated with lower LS and TBLH BMD Z-scores (all P < .05); lower A:G ratio was additionally associated with lower TBLH Z-scores (P < .01). Thirteen girls (14%) and 9 boys (21%) had low bone mass. Girls with a BMI ≤17.5 kg/m(2) or both menstrual irregularity and a history of fracture were significantly more likely to have low bone mass. Boys with a BMI ≤17.5 kg/m(2) and belief that thinness improves performance were significantly more likely to have low bone mass. CONCLUSION: This study identified sex-specific risk factors for impaired bone mass in adolescent runners. These risk factors can be helpful to guide sports medicine professionals in evaluation and management of young runners at risk for impaired bone health.

Comparison of peripheral forearm DXA and clinical risk factor screening using FRAX® to assess the risk of HIV-associated low bone mass: a cross-sectional study.

UNLABELLED: There is growing awareness that HIV infection is associated with low bone mass and fracture. DXA is a relatively scarce resource. Therefore, we evaluated two tools: peripheral DXA (pDXA) at the forearm and Fracture Risk Assessment Tool (FRAX®) to see which performed best at identifying men who should undergo DXA. In this setting, neither pDXA nor FRAX® showed good sensitivity and specificity for DXA. PURPOSE: Infection with human immunodeficiency virus (HIV) is associated with an increased risk of low bone mineral density (BMD) and fractures. European guidance advocates screening using the FRAX® tool at diagnosis, on initiation of antiretroviral therapy and biannually thereafter in order to decide the need for DXA scanning. This cross-sectional study evaluates the performance of FRAX® and compares its sensitivity and specificity with that of another screening tool, peripheral forearm DXA (pDXA). METHODS: HIV-infected men with varying exposure to antiretroviral therapies were recruited. FRAX® scores were calculated for all participants and everybody underwent pDXA scanning. Femoral neck and lumbar spine BMD was acquired on a Hologic QDR machine by an assessor blinded to the results of the FRAX® and pDXA. RESULTS: One hundred and sixty-eight men (median age 45 years) were recruited with a median duration since HIV diagnosis of 74 months. In total, 21 % of subjects had either osteoporosis (aged ≥50 years) or BMD lower than expected for age (aged <50 years), according to axial DXA. Using a pDXA screening threshold of T ≤ -0.9, sensitivity was high (91 %) in defining those with the worst BMD on axial DXA but with poorer specificity (33 %). Alternately, using a threshold of T ≤ -2.7 reduced sensitivity (34 %) with an increase in specificity (91 %). FRAX® with HIV included as a secondary risk factor had poor sensitivity (31 %) and specificity (74 %) for detecting those with the poorest BMD on axial DXA. CONCLUSION: In this setting, neither pDXA scanning nor FRAX® was sensitive and specific for low bone mass on DXA and neither was performance much improved by using both screening tools. Prospective studies with fracture as an outcome are required in HIV.

Strain-induced optical changes in demineralized bone.

Bone "stress-whitens," becoming visibly white during mechanical loading, immediately prior to failure. Stress-whitening is known to make materials tougher by dissipating mechanical energy. A greater understanding of stress-whitening, both an optical and mechanical phenomenon, may help explain age-related increases in fracture risk that occur without changes in bone mineralization. In this work, we directly measure the optical properties of demineralized bone as a function of deformation and immersing fluid (with different hydrogen-bonding potentials, water, and ethanol). The change in refractive index of demineralized bone was linear: with deformation and not applied force. Changes in refractive index were likely due to pushing low-refractive-index fluid out of specimens and secondarily due to changes in the refractive index of the collagenous phase. Results were consistent with stress-whitening of demineralized bone previously observed. In ethanol, the refractive index values were lower and less sensitive to deformation compared with deionized water, corroborating the sensitivity to fluid hydration. Differences in refractive index were consistent with structural changes in the collagenous phase such as densification that may also occur under mechanical loading. Understanding bone quality, particularly stress-whitening investigated here, may lead to new therapeutic targets and noninvasive methods to assess bone quality.

The role of Fibroblast Growth Factor 23 in chronic kidney disease-mineral and bone disorder

Fibroblast Growth Factor 23 (FGF-23) is a bone-derived hormone involved in the regulation of phosphate homeostasis. FGF-23 levels are extremely elevated in Chronic Kidney Disease (CKD) and there is evidence supporting the role of this hormone in the pathogenesis of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Furthermore, recent data associates FGF-23 with the pathogenesis of systemic complications of CKD-MBD. The increasing evidence that the consequences of abnormal mineral metabolism are not restricted to bone disease changed the approach to the pathophysiology and treatment of disturbed bone and mineral metabolism in CKD patients. FGF-23 has been proposed to be the initial adaptive response in early CKD to protect the organism from the adverse effects of phosphate retention. Increased levels of FGF-23 observed in CKD patients are associated with cardiovascular mortality risk and was shown to mediate direct, "off-target" toxicity to the heart. This report aims to review the relevant aspects of the physiology of FGF-23 in bone biology and mineral homeostasis and the role of FGF-23 in the pathophysiology of CKD-BMD and its clinical implications (AU)

El factor de crecimiento fibroblástico 23 (FGF-23) es una hormona derivada del hueso que participa en la regulación de la homeostasis del fósforo. Los niveles de FGF-23 se encuentran extremamente elevados en la enfermedad renal crónica y existe evidencia del papel de esta hormona en la patogénesis de los trastornos óseos y minerales en esta situación. Más aún, datos recientes implican al FGF-23 en la patogénesis de otras complicaciones sistémicas asociadas a las alteraciones óseo-minerales de la enfermedad renal crónica. La evidencia creciente de que las alteraciones del metabolismo mineral no se limitan a la enfermedad ósea ha acentuado el interés por la patofisiología y el tratamiento de las alteraciones del metabolismo mineral en la enfermedad renal crónica. Se ha propuesto que el aumento de FGF-23 es la respuesta inicial en los estadios precoces de la enfermedad renal crónica a la necesidad de proteger al organismo de los efectos adversos de la retención de fósforo. Estos aumentos de FGF-23 se asocian al riesgo creciente de mortalidad cardiovascular en los enfermos renales crónicos y son mediadores directos de toxicidad cardíaca. En esta revisión procuramos presentar aspectos relevantes de la fisiología del FGF-23 en la biología ósea y en la homeostasis mineral, así como en la fisiopatología de la enfermedad renal crónica y sus implicaciones clínicas (AU)

Stress-whitening occurs in demineralized bone.

INTRODUCTION: The incidence of age-related bone fracture is increasing with average population age. Bone scatters more light (stress-whitens) during loading, immediately prior to failure, in a manner visually similar to polymer crazing. We wish to understand the stress-whitening process because of its possible effect on bone toughness. The goals of this investigation were a) to establish that stress-whitening is a property of the demineralized organic matrix of bone rather than only a property of mineralized tissue and that stress whitening within the demineralized bone is dependent upon both b) hydrogen bonding and, c) the orientation of loading. METHODS: Demineralized cortical bone specimens were loaded in tension to failure (0.08 strain/s). The effect of hydrogen bonding on mechanical properties and the stress-whitening process was probed by altering the Hansen's hydrogen bonding parameter (δh) of the immersing solution. RESULTS: Stress-whitening occurred in the demineralized bone. Stress-whitening was negatively correlated with δh (R(2)=0.81, p<0.0001). Stress-whitening was significantly lower (p<0.0001) in specimens loaded orthogonally compared to those loaded parallel to the long (strong) axis. CONCLUSION: The stress-whitening observed was consistent with increased Mie scattering. We suggest that the change in Mie scattering was due to collagen fibril dehydration driven by the externally applied stress. The presence of stress-whitening in demineralized bone suggests that this process may be a property of the collagenous matrix and hence may be present in other collagenous tissues rather than an emergent property of the bone composite.