Association between undercarboxylated osteocalcin, bone mineral density, and metabolic parameters in postmenopausal women

ABSTRACT Objective: Osteocalcin has been associated with several effects on energy and glucose metabolism. However, the physiological role of undercarboxylated osteocalcin (U-osc; the hormonally active isoform of osteocalcin) is still controversial. To correlate the serum levels of U-osc with bone mineral density (BMD) values and metabolic parameters in postmenopausal women. Subjects and methods: Cross-sectional study including 105 postmenopausal women (age 56.5 ± 6.1 years, body mass index [BMI] 28.2 ± 4.9 kg/m2) grouped based on the presence of three or less, four, or five criteria of metabolic syndrome according to the International Diabetes Federation (IDF). The subjects underwent dualenergy x-ray absorptiometry (DXA) for the assessment of body composition and BMD and blood tests for the measurement of U-osc and bone-specific alkaline phosphatase (BSAP) levels. Results: The mean U-osc level was 3.1 ± 3.4 ng/mL (median 2.3 ng/mL, range 0.0-18.4 ng/mL) and the mean BSAP level was 12.9 ± 4.0 ng/mL (median 12.1 ng/mL, range 73-24.4 ng/mL). There were no associations between U-osc and BSAP levels with serum metabolic parameters. Lower fasting glucose levels were observed in participants with increased values of U-osc/femoral BMD ratio (3.61 ± 4 ng/mL versus 10.2 ± 1.6 ng/mL, p = 0.036). When the participants were stratified into tertiles according to the U-osc/ femoral BMD and U-osc/lumbar BMD ratios, lower fasting glucose levels correlated with increased ratios (p = 0.029 and p = 0.042, respectively). Conclusion: Based on the ratio of U-osc to BMD, our study demonstrated an association between U-osc and glucose metabolism. However, no association was observed between U-osc and metabolic parameters.The U-osc/BMD ratio is an innovative way to correct the U-osc value for bone mass.

Prevalencia de deficiencia de vitamina K y factores asociados en pacientes con fibrosis quística sin aporte suplementario / Prevalence of vitamin K deficiency and associated factors in non-supplemented cystic fibrosis patients

Introducción. La deficiencia de vitamina K es prevalente en pacientes con fibrosis quística (FQ) aun con aporte suplementario. Se desconocen factores de riesgo fiables para determinar su ocurrencia. Nuestro objetivo fue evaluar la prevalencia de deficiencia de vitamina K y factores asociados en los pacientes con FQ que no recibían aporte suplementario. Métodos. Se determinaron protrombina inducida por ausencia de vitamina K (PIVKA-II) y osteocalcina infracarboxilada (OCic). Se evaluó el estado clínico y su relación con la deficiencia de vitamina K. El análisis estadístico incluyó prueba de Mann-Whitney, ANOVA o Kruskal-Wallis, prueba χ² o prueba de Fisher-Freeman-Halton y regresión logística múltiple lineal y escalonada hacia adelante. Resultados. Se incluyeron 79 pacientes con FQ de entre 0,4-25,3 años. Se observaron valores anómalos de PIVKA-II y OCic en 56 (70,9%) y 45 (57,0%) pacientes. Los pacientes con PIVKA-II elevada eran significativamente mayores (p = 0,0184) y tenían puntajes Z de peso corporal (p= 0,0297) inferiores a los pacientes que tenían concentraciones normales. No se hallaron diferencias entre los pacientes con OCic normal o patológica. Se notificaron valores anómalos de PIVKA-II y OCic más frecuentemente en pacientes con dos mutaciones graves en el gen CFTR y con un estado nutricional malo/deficiente. Los análisis de regresión múltiple lineal y de regresión múltiple escalonada hacia adelante no revelaron factores predictivos sólidos para determinar la deficiencia de vitamina K. Conclusión. La deficiencia de vitamina K es altamente prevalente durante la evolución natural de la fibrosis quística. No se hallaron determinantes clínicos fiables para precisar su ocurrencia.

Introduction. Vitamin K deficiency is highly prevalent in cystic fibrosis (CF) patients despite supplementation. Moreover, no reliable risk factors for its occurrence are known. The aim was to assess the prevalence of vitamin K deficiency and associated factors in non-supplemented CF patients. Methods. Prothrombin concentration induced by vitamin K absence (PIVKA-II) and the undercarboxylated osteocalcin percentage (u-OC) were determined. In all patients clinical status was assessed and its relation to vitamin K deficiency determined. The following tests were used for statistical analysis: Mann-Whitney test, ANOVA test or the Kruskal Wallis test, the chi-squared test or the Fisher-Freeman-Halton test, and multiple linear and multiple forward stepwise logistic regression analysis. Results. The study group comprised 79 CF patients aged 0.4-25.3 years. PIVKA-II and u-OC were abnormal in 56 (70.9%) and 45 (57.0%) patients. Patients with elevated PIVKA-II were significantly older (p= 0.0184) and had lower Z-score values for body weight (p= 0.0297) than those with normal concentrations. Patients with normal or pathological u-OC percentage did not differ. Abnormal PIVKA-II and u-OC were reported more frequently in subjects with two severe CFTR mutations and with worse/poor nutritional status. Multiple linear and forward stepwise regression analyses did not reveal strong predictive factors of vitamin K deficiency. Conclusion. Vitamin K deficiency is highly prevalent in the natural course of cystic fibrosis. There are no reliable clinical determinants of its occurrence.

El esqueleto como órgano endocrino: funciones metabólicas de la osteocalcina / The skeleton as an endocrine organ: metabolic functions of osteocalcin

El esqueleto es uno de los sistemas más grandes de un vertebrado y, como tal, es razonable especular que no puede funcionar aislado del resto del organismo. De hecho, sabemos que existen sistemas complejos de regulación cruzada entre el esqueleto y muchos otros órganos. Hoy poseemos herramientas que nos permiten realizar supresión genética en células o tejidos específicos. Esto nos ha permitido comprender cómo los órganos se comunican entre sí y ha revitalizado el concepto de fisiología del organismo como un todo. Efectivamente, los últimos años han sido testigos del descubrimiento de funciones inesperadas que ejerce el esqueleto y que afectan al organismo en su totalidad. Una de tales funciones reconocidas recientemente es el control del metabolismo energético, a través de la secreción de osteocalcina. La osteocalcina es una hormona producida por los osteoblastos que regula la secreción de insulina, la sensibilidad a esta hormona y el metabolismo energético. Los hallazgos iniciales suscitaron varias preguntas fundamentales sobre la naturaleza de la acción de la insulina sobre el hueso. Pero esto solo fue la punta del iceberg. Efectivamente, más adelante se descubrió, mediante el análisis de ratones que carecen del receptor de insulina (Ins R) solamente en osteoblastos, que la acción de la insulina sobre estas células favorecía la homeostasis de la glucosa en todo el cuerpo. Es importante destacar que esta función de la insulina en los osteoblastos opera mediante la regulación negativa de la carboxilación y la biodisponibilidad de la osteocalcina. Más aún, se observó que las vías de señalización de la insulina en los osteoblastos regulan positivamente no solo la formación sino también la resorción del hueso. Curiosamente, parece que las vías de señalización de la insulina en osteoblastos pueden inducir la activación de la osteocalcina mediante la estimulación de la actividad de los osteoclastos. De hecho, el bajo pH generado durante la resorción ósea es suficiente para desencadenar la descarboxilación (y subsiguiente activación) de la osteocalcina. En breve discutiremos dos nuevas proposiciones: 1) los osteoblastos son un blanco utilizado por la insulina para controlar la homeostasis de la glucosa en todo el organismo y 2) la resorción ósea desempeña un papel fundamental en la regulación de la activación de la osteocalcina. (AU)

The skeleton is one of the biggest systems in a vertebrate animal and, as such, it is reasonable to speculate that it cannot function isolated from the rest of the organism. In fact, we know that complex systems exist for the cross-regulation between the skeleton and several other organs. Today, we have the tools that allow us to perform genetic suppression in specific cells or tissues. This has allow us understand the mechanisms by which the organs communicate with each other and has revitalized the concept of organismal physiology as a whole. Studies conducted in recent years have uncovered unexpected functions performed by the skeleton. One of these is the control of global energy metabolism, through the secretion of osteocalcin, a protein produced by osteoblasts that acts as a hormone regulating insulin secretion, insulin sensitivity and energy expenditure. The evidence comes from the analysis of mice lacking insulin receptor (InsR) exclusively in osteoblasts. These mice have a global metabolic phenotype demonstrating that the action of insulin in osteoblasts promotes the homeostasis of glucose throughout the body. This action of insulin in osteoblasts is mediated by the negative regulation of the carboxylation (and bioavailability) of osteocalcin. The decarboxylation (and activation) of osteocalcin, in turn, occurs in the osteoclastic resorption pit. Briefly: the osteoblast is a target used by insulin to control the homeostasis of glucose throughout the body and bone resorption is the mechanism that regulates the activation of osteocalcin. (AU)

Significance of undercarboxylated osteocalcin in the diagnosis of Kawasaki disease with coronary artery lesions / 中华实用儿科临床杂志

Objective To investigate the changes and diagnostic significance in plasma undercarboxylated osteocalcin in children with Kawasaki disease (KD),especially with coronary artery lesions (CALs).Methods The data of 36 KD children were collected,who were inpatients at Department of Cardiovascular and Rheumatology,Shanxi Province Children's Hospital from January 2015 to December 2015,including 20 boys and 16 girls,aged (2.3 ± 1.1)years old.According to the course of the disease,KD children were divided into an acute stage group and a subacute stage group.Based on the echocardiography findings,KD children were subdivided into CALs group and no coronary artery lesions (NCALs) group.Twenty-five healthy children from the physical examination during the same period were selected as the healthy control group,13 boys and 12 girls,aged (2.6-± 1.0) years old.Plasma undercarboxylated osteocalcin level was measured by double antibody sandwich enzyme-linked immunosorbent method.Sigrnaplot 12.5software was used to analyze the data statistically,and the receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic effect of plasma undercarboxylated osteocalcin in KD with CALs.Results The levels of plasma undercarboxylated osteocalcin in the healthy control group,the acute stage group and the subacute stage group were (16.4 ± 1.6) μg/L,(14.2 ± 1.6) μg/L,(14.3-± 1.7) μg/L,respectively.Compared with the healthy control group,the plasma undercarboxylated osteocalcin level in the acute stage and the subacute stage were significantly lower,the differences were statistically significant (q =6.088,5.687,all P ＜ 0.01).But there was no difference of plasma undercarboxylated osteocalcin level between the acute stage group and the subacute stage group (q =0.466,P ＞ 0.05).The levels of plasma undercarboxylated osteocalcin in acute stage group with CALs and acute stage group with NCALs were (12.9 ± 1.2) μg/L,(15.0 ± 1.4) μg/L.Compared with healthy control group,the plasma undercarboxylated osteocalcin levels of children with CALs and with NCALs were obviously decreased,the differences were statistically significant (q =8.711,3.891,all P ＜ 0.01).There was a statistical difference in plasma undercarboxylated osteocalcin level between the acute stage with CALs and the acute stage with NCALs (q =5.171,P ＜ 0.01).The plasma undercarboxylated osteocalcin levels of KD children with CALs in the subacute stage was (13.0-± 1.3) μg/L.Compared with acute stage,there was no statistical difference (t =0.257,P ＞ 0.05).There was a sensitivity of 79％,specificity of 82％,positive predictive value of 88％ and negative predictive value of 70％ for the 15.7 μg/L undercarboxylated osteocalcin for diagnosing KD.There was a sensitivity of 83％,specificity of 88％,positive predictive value of 83％ and negative predictive value of 88％ for the 13.7 μg/L undercarboxylated osteocalcin for diagnosing KD with CALs.Conclusions Osteocalcin is related to the pathogenesis and development of KD.Plasma undercarboxylated osteocalcin contributes to the diagnosis of KD with CALs.

Osteocalcin, energy and glucose metabolism / Osteocalcina, metabolismo energético e da glicose

Osteocalcin is a bone matrix protein that has been associated with several hormonal actions on energy and glucose metabolism. Animal and experimental models have shown that osteocalcin is released into the bloodstream and exerts biological effects on pancreatic beta cells and adipose tissue. Undercarboxylated osteocalcin is the hormonally active isoform and stimulates insulin secretion and enhances insulin sensitivity in adipose tissue and muscle. Insulin and leptin, in turn, act on bone tissue, modulating the osteocalcin secretion, in a traditional feedback mechanism that places the skeleton as a true endocrine organ. Further studies are required to elucidate the role of osteocalcin in the regulation of glucose and energy metabolism in humans and its potential therapeutic implications in diabetes, obesity and metabolic syndrome.

A osteocalcina é uma proteína da matriz óssea que tem sido implicada com várias ações hormonais relacionadas à homeostase de glicose e ao metabolismo energético. Modelos animais e experimentais têm demonstrado que a osteocalcina é liberada do osso para a circulação sanguínea e age nas células betapancreáticas e no tecido adiposo. A osteocalcina decarboxilada é a isoforma hormonalmente ativa e estimula a secreção e sensibilidade à insulina no tecido adiposo e muscular. A insulina e a leptina, por sua vez, atuam no tecido ósseo modulando a secreção da osteocalcina, formando uma alça de retroalimentação tradicional em que o esqueleto torna-se um órgão endócrino. Novos estudos ainda são necessários para elucidar o papel da osteocalcina na regulação glicêmica e no metabolismo energético em humanos, com potenciais implicações terapêuticas no tratamento de diabetes, obesidade e síndrome metabólica.

Diagnostic Utility of Osteocalcin, Undercarboxylated Osteocalcin, and Alkaline Phosphatase for Osteoporosis in Premenopausal and Postmenopausal Women

BACKGROUND: We aimed to investigate the diagnostic utility of osteocalcin (OC), undercarboxylated osteocalcin (ucOC), and alkaline phosphatase (ALP) in pre- and postmenopausal women for femoral neck, L1-4, and L2-4 bone mineral density (BMD) values by taking into consideration their age, body mass index (BMI), and menopausal status. METHODS: Premenopausal (N=40) and postmenopausal cases (N=42) were classified as 25-34 or 35-45 yr of age and within the first 5 yr or 5 yr or more after the onset of menopause, respectively. RESULTS: Among the groups, statistical differences were found for age, BMI, OC, ucOC, ALP, femoral neck BMD, L1-4 BMD, and L2-4 BMD. The highest serum OC, ucOC, and ALP levels were observed in cases within the first 5 yr after the onset of menopause, probably due to a more rapid bone turnover rate. The best predictors for the femoral neck osteoporosis were ALP, OC, and calcium (areas under the ROC curve [AUC]=0.882, 0.829, and 0.761, respectively), and those for L1-4 and L2-4 osteoporosis were OC, ALP, and ucOC (AUC=0.949, 0.873, and 0.845; and 0.866, 0.819, and 0.814, respectively). Multiple logistic regression analysis revealed that the most discriminative parameter for osteoporosis was OC. CONCLUSIONS: These results indicate that serum OC levels, with or without ucOC and ALP, may be useful to monitor follow-up changes that currently cannot be assessed with BMD and to diagnose femoral neck, L1-4 spine, and L2-4 spine osteoporosis.

Vitamin K Supplement Along with Vitamin D and Calcium Reduced Serum Concentration of Undercarboxylated Osteocalcin While Increasing Bone Mineral Density in Korean Postmenopausal Women over Sixty-Years-Old

There are inconsistent findings on the effects of vitamin K on bone mineral density (BMD) and undercarboxylated osteocalcin (UcOC). The present intervention study evaluated the effect in subjects over 60-yr-old. The vitamin K group (vitamin K + vitamin D + calcium supplement; 15 mg of vitamin K2 [menatetrenone] three times daily, 400 IU of vitamin D once a day, and 315 mg of calcium twice daily) and the control group (vitamin D + calcium supplement) were randomly assigned. During the six months of treatment, seventy eight women participated (38 in the vitamin K group and 40 in the control group) and 45 women completed the study. The baseline characteristics of study participants did not differ between the vitamin K and the control groups. In a per protocol analysis after 6 months, L3 bone mineral density has increased statistically significantly in the vitamin K group compared to the control group (0.01 +/- 0.03 g/cm2 vs -0.008 +/- 0.04 g/cm2, P = 0.049). UcOC concentration was also significantly decreased in the vitamin K group (-1.6 +/- 1.6 ng/dL vs -0.4 +/- 1.1 ng/dL, P = 0.008). In conclusion, addition of vitamin K to vitamin D and calcium supplements in the postmenopausal Korean women increase the L3 BMD and reduce the UcOC concentration.

Relationship between vitamin K status, bone mineral density, and hs-CRP in young Korean women

Vitamin K intake has been reported as an essential factor for bone formation. The current study was conducted under the hypothesis that insufficient vitamin K intake would affect inflammatory markers and bone mineral density in young adult women. The study was a cross-sectional design that included 75 women in their 20s. Physical assessments, bone mineral density measurements, 24-hr dietary recalls, and biochemical assessments for high sensitivity C-reactive protein (hs-CRP) and percentages of undercarboxylated osteocalcin (%ucOC) were performed. An analysis of vitamin K nutritional status was performed comparing first, second, and third tertiles of intake based on %ucOC in plasma. Vitamin K intake levels in the first, second, and third tertiles were 94.88 +/- 51.48 microg, 73.85 +/- 45.15 microg, and 62.58 +/- 39.92 microg, respectively (P < 0.05). The T-scores of the first and third tertiles were 1.06 and -0.03, respectively, indicating that bone mineral density was significantly lower in the group with lower vitamin K intake (P < 0.05). There was a tendency for different serum hs-CRP concentrations between the first (0.04 +/- 0.02) and third tertiles (0.11 +/- 0.18), however this was not statistically significant. Regression analysis was performed to identify the correlations between vitamin K nutritional status, inflammatory markers, and bone mineral density after adjusting for age and BMI. Serum hs-CRP concentrations were positively correlated with vitamin K deficiency status (P < 0.05). And bone mineral density, which was represented by speed, was negatively correlated with vitamin K deficiency status (P < 0.05). In conclusion, status of vitamin K affects inflammatory status and bone formation. Therefore, sufficient intake of vitamin K is required to secure peak bone mass in young adult women.

Correlation of Undercarboxylated Osteocalcin (ucOC) Concentration and Bone Density with Age in Healthy Korean Women

Uncarboxylated osteocalcin (ucOC) is important in evaluating vitamin K status and it is inversely associated with bone mineral density (BMD). We studied the correlationship between ucOC and BMD in healthy Korean women. This study recruited 337 healthy women between ages 20-70 were recruited. Serum ucOC, calcium, alkaline phosphatase, body mass index (BMI), and BMD were measured and compared. Mean BMI was lowest (20.3+/-1.9 kg/m2) in the 20 yr old group and highest (24.8+/-2.6 kg/m2) in the 60 yr old group. Women age 20-70 yr old had ucOC inversely related to BMD independent of other factors that may influence BMD. Serum ucOC concentration and BMD of lumbar spine showed a significant inverse relationship. Serum mean alkaline phosphatase was lowest (122+/-30 IU/L) in the age 30 group and highest (190.3+/-55.8 IU/L) in the age 60 group. Serum ucOC was inversely associated with BMI, and positively associated with alkaline phosphatase. Uncarboxylated osteocalcin (ucOC) was inversely associated with spinal BMD in healthy Korean women. Serum mean ucOC was highest in the age 20 group, followed by age 50 group, which may indicate vitamin K insufficiency could be related to high bone turnover in these groups. These results suggest that vitamin K supplement may be considered to help both bone growth and bone loss during these periods.