Serum Levels Of Undercarboxylated Osteocalcin Research Articles

Metabolic shifts in ratio of ucOcn to cOcn towards bone resorption contribute to age-dependent bone loss in male mice.

The study of the senile osteoporosis in men still lags significantly behind in women. The changes of protein molecule levels and their relationships with bone loss remain poorly understood. In the present study, we used C57BL/6J male mice at ages from 3 to 24 months to delineate the mechanisms of aging effects on bone loss. We employed the micro-computed tomography, mechanical testing, histomorphometry assays, and detection of serum levels of undercarboxylated osteocalcin (ucOcn) and carboxylated osteocalcin (cOcn) to assess bone mass changes and their relationships with ratios of ucOcn to cOcn in mice from different age groups. The results showed that mouse trabecular bone mass reduced gradually with age while cortical bone loss and mechanical property changes mostly occurred in advanced age. Our findings further demonstrated that the increase in osteoclast activity and the decrease in osteoblast function were significantly corelated with blood levels of ucOcn and cOcn, respectively. The dynamic metabolic changes of ucOcn to cOcn ratio were correlated with age-dependent bone loss in mice. In summary, metabolic shifts in ratio of ucOcn to cOcn towards bone resorption from young adult to elderly mice contribute to the pathogenesis of age-related bone loss. Simultaneously monitoring blood ratios of ucOcn to cOcn may be useful to predict the status of bone mass in vivo.

Study on Undercarboxylated Osteocalcin in Improving Cognitive Function of Rats with Type 2 Diabetes Mellitus by Regulating PI3K-AKT-GSK/3β Signaling Pathwaythrough medical images

ABSTRACT This paper aims to clarify the effect of Undercarboxylated osteocalcin (ucOC) on cognitive function in rats with type 2 diabetes mellitus (T2DM). This research reviewed the cognitive function of 35 diabetic patients, 33 non-diabetic patients and the serum levels of Undercarboxylated osteocalcin (ucOC) in patients. What’s more, we analyzed the correlation between serum ucOC levels and cognitive function. Diabetic rats were treated with high (30 μg·kg−1·d−1) and low (10 μg·kg−1·d−1) doses of ucOC to investigate its effects in regulating ucOC on blood lipid, blood glucose and cognitive function. We systematically detected the phosphorylation levels of cognitive level-related proteins (PI3K, AKT, and GSK/3β) in the hippocampus by Western Blot. Finally, PI3K-Akt pathway involved in regulating cognitive function in diabetic rats by ucOC was verified with AKT pathway inhibitor LY294002. MoCA score and serum ucOC levels were significantly reduced in patients with diabetes mellitus. ucOC could concentration-dose-dependently decrease the blood glucose and lipid levels, and improve glucose metabolism and weaken insulin resistance in diabetic rats (P < 0.001). In addition, escape latency in diabetic rats was significantly higher than that of normal rats in the Morris maze test, and ucOC dose-dependently shortened the escape latency in diabetic rats (all with P < 0.05). After using AKT pathway inhibitor, ucOC failed to shorten the escape latency in diabetic rats. In conclusion, this study explored the relevant mechanisms in inducing cognitive dysfunction of T2DM, suggesting the potential value of ucOC as a drug to improve cognitive dysfunction in patients with T2DM in clinical.

Diversity of Gut Microbiota Affecting Serum Level of Undercarboxylated Osteocalcin in Patients with Crohn's Disease.

Several reports have indicated a possible link between decreasing plasma levels of vitamin K and bone mineral density. It has been suggested that intestinal bacteria contribute to maintenance of vitamin K. Several factors are involved in the reduction of vitamin K in patients with Crohn’s disease (CD). We aimed to assess the relationship between gut microbiota and alternative indicators of vitamin K deficiency in patients with CD. We collected the feces of 26 patients with clinically inactive CD. We extracted 16S rRNA from the intestinal bacteria in the feces and amplified it by polymerase chain reaction. The generated polymerase chain reaction product was analyzed using a 16S metagenomic approach by Illumina Miseq platform. Serum undercarboxylated osteocalcin concentration was used as an alternative indicator of vitamin K deficiency. There was a significant negative correlation between serum undercarboxylated osteocalcin and mean Chao1 index in cases of low activity. The diversity of the gut microbiota was significantly lower, and Ruminococcaceae and Lachnospiraceae were significantly decreased in the vitamin K-deficient group in comparison to the vitamin K-normal group. Taken together, these data suggested the significance of investigating the gut microbiota even in patients with clinically inactive CD for improving patients’ vitamin K status.

Serum levels of undercarboxylated osteocalcin are related to cardiovascular risk factors in patients with type 2 diabetes mellitus and healthy subjects

AIMTo determine a potential relationship between serum undercarboxylated (ucOC) concentration and cardiovascular risk factors in type 2 diabetes (T2D) patients and healthy subjects (HS).METHODSA cross-sectional study was conducted on 140 subjects classified into two groups, 70 with T2D and 70 HS. Medical history and physical examination with anthropometric measurements were obtained from all subjects. Body fat percentage was determined by bioelectrical impendency analysis. Serum ucOC concentration was determined by enzyme immunoassay, while serum levels of insulin and hsCRP were obtained using high sensitivity enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment-IR. Lipid profile [triglycerides, total cholesterol (TC), high-density lipoproteins (HDL-c), low density lipoproteins (LDL-c), very low-density lipoproteins] was determined by spectrophotometry and standard formulas when applicable.RESULTSThe T2D patient group showed significantly higher values of waist circumference, waist-to-hip ratio, systolic blood pressure (SBP), diastolic blood pressure (DBP), current smoking, and alcohol use when compared to the HS group (P < 0.05). We observed a significantly lower serum ucOC concentration in T2D than in HS (1.5 ± 1.4 vs 2.3 ± 1.8, P < 0.05). In the whole study population, ucOC concentration was inversely correlated with body mass index (BMI) (r = -0.236, P < 0.05), fasting plasma glucose (r = -0.283, P < 0.01) and HDL-c (r = -0.255, P < 0.05); and positively correlated with LDL-c/HDL-c ratio (r = 0.306, P < 0.05) and TC/HDL-c ratio (r = 0.284, P < 0.05). In the T2D group, serum ucOC concentration was inversely correlated with BMI (r = -0.310, P < 0.05) and body-fat percentage (r = -0.311, P < 0.05), and positively correlated with DBP (r = 0.450, P < 0.01). In HS group a positive correlation between serum levels of ucOC and SBP (r = 0.277, P < 0.05) was observed.CONCLUSIONSerum ucOC is a potential marker for cardiovascular risk in Mexicans because it is related to adiposity parameters, blood pressure and lipid profile.

Vitamin K deficiency evaluated by serum levels of undercarboxylated osteocalcin in patients with anorexia nervosa with bone loss

Osteoporosis is a chief complication in patients with anorexia nervosa. Serum levels of undercarboxylated osteocalcin reflect serum and bone vitamin K deficiency. We investigated vitamin K status in patients with anorexia nervosa to help establish prevention and treatment recommendations for osteoporosis. Fifty-four female amenorrheic patients with anorexia nervosa (29 restricting-type and 25 binge eating/purging type) (age, 28.0 (26.7-31.1) (mean (95% CI)) years; body mass index, 14.8 (14.1-15.5) kg/m(2), duration of illness; 107.3 (88.5-126.0) months) and 15 age-matched healthy females were included in this study. We measured serum levels of undercarboxylated osteocalcin, biochemical and nutritional markers, and bone metabolic markers. Dietary vitamin K intake was evaluated by a questionnaire. Lumbar bone mineral density and T-scores in patients with anorexia nervosa were 0.756 (0.721-0.790) g/cm(2) and -2.4 (-2.1 to -2.7), respectively, indicating bone loss. Serum levels of undercarboxylated osteocalcin in patients with anorexia nervosa were significantly higher than those of controls. The 17% of restricting type and 40% of binge eating/purging type anorexia nervosa patients, serum levels of undercarboxylated osteocalcin were higher than 4.5 ng/ml and were diagnosed with vitamin K deficiency. Serum levels of undercarboxylated osteocalcin correlated significantly and negatively with vitamin K intake in patients with anorexia nervosa. Patients with anorexia nervosa had vitamin K deficiency. Since a supplement of vitamin K might be effective for maintaining bone quality, we provide recommendations regarding vitamin K intake for prevention and treatment of osteoporosis in patients with AN.

Insulin, osteoblasts, and energy metabolism: why bone counts calories

Recent studies have demonstrated that insulin stimulates bone cells to produce and activate osteocalcin, an endocrine hormone that increases the efficiency of glucose metabolism through its actions on the pancreas and other peripheral tissues. In this issue of the JCI, Wei and colleagues directly explore the contribution of insulin signaling in osteoblasts to the disturbances in whole-body glucose metabolism associated with a high-fat diet. In mice fed a high-fat diet, increased uptake of saturated fatty acids by the osteoblast accelerates the ubiquitination and degradation of the insulin receptor. In this setting, impairments in osteoblast insulin signaling reduce serum levels of undercarboxylated osteocalcin, which in turn exacerbate insulin resistance in muscle and white adipose tissue. These findings underscore the importance of insulin-responsive skeletal cells as components of a newly appreciated endocrine network critical for regulating global energy homeostasis.

Effects of Parathyroid Hormone on Bone Mass, Bone Strength, and Bone Regeneration in Male Rats With Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is associated with increased skeletal fragility and impaired fracture healing. Intermittent PTH therapy increases bone strength; however, its skeletal and metabolic effects in diabetes are unclear. We assessed whether PTH improves skeletal and metabolic function in rats with T2DM. Subcritical femoral defects were created in diabetic fa/fa and nondiabetic +/+ Zucker Diabetic Fatty (ZDF) rats and internally stabilized. Vehicle or 75 μg/kg/d PTH(1-84) was sc administered over 12 weeks. Skeletal effects were evaluated by μCT, biomechanical testing, histomorphometry, and biochemical markers, and defect regeneration was analyzed by μCT. Glucose homeostasis was assessed using glucose tolerance testing and pancreas histology. In diabetic rats, bone mass was significantly lower in the distal femur and vertebrae, respectively, and increased after PTH treatment by up to 23% in nondiabetic and up to 18% in diabetic rats (P < .0001). Diabetic rats showed 23% lower ultimate strength at the spine (P < .0005), which was increased by PTH by 36% in normal and by 16% in diabetic rats (P < .05). PTH increased the bone formation rate by 3-fold in normal and by 2-fold in diabetic rats and improved defect regeneration in normal and diabetic rats (P < .01). PTH did not affect serum levels of undercarboxylated osteocalcin, glucose tolerance, and islet morphology. PTH partially reversed the adverse skeletal effects of T2DM on bone mass, bone strength, and bone defect repair in rats but did not affect energy metabolism. The positive skeletal effects were generally more pronounced in normal compared with diabetic rats.

In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice

Osteocalcin is a hormone produced in bones by osteoblasts and regulating energy metabolism. While osteocalcin exists in two forms, γ-carboxylated and undercarboxylated only the latter appears to function as a hormone in vivo. It has been proposed recently that osteoclasts, the bone-resorbing cells, are responsible of decarboxylating, i.e. activating osteocalcin. To address the role of osteoclasts in the maintenance of energy metabolism we analyzed mutant mouse strains harboring either an increase or a decrease in osteoclasts number. Osteoprotegerin-deficient mice that are characterized by an increase in the number of osteoclasts demonstrate an increase in serum levels of undercarboxylated osteocalcin and are significantly more glucose tolerant than WT animals. Conversely, osteoclasts ablation in mice results in a decrease in serum undercarboxylated osteocalcin levels and in reduced glucose tolerance. These results support the notion that osteoclasts are controlling glucose metabolism at least in part through the regulation of osteocalcin decarboxylation.

Strategy for Prevention of Hip Fractures in Patients with Alzheimer\\\\\\\'s Disease

The incidence of fractures, particularly hip fractures, is known to be high in patients with Alzheimer’s disease. The aim of this review was to clarify the efficacy of interventions against hip fractures in patients with Alzheimer’s disease. The literature was searched using PubMed for randomized controlled trials (RCTs) regarding Alzheimer’s disease and hip fractures. Four RCTs were identified, and the relative risk (RR) and 95% confidence interval (CI) were calculated for the individual RCTs. Sunlight exposure increased the serum level of 25-hydroxyvitamin D, promoted muscle strength, and prevented falls. Menatetrenone (vitamin K2) with vitamin D supplementation decreased the serum level of undercarboxylated osteocalcin. Risedronate with vitamin D supplementation decreased the urinary level of deoxypyridinoline. Sunlight exposure, menatetrenone, and risedronate reduced the incidence of hip fractures, with RR (95% CI) of 0.22 (0.049, 0.999), 0.13 (0.031, 0.554), and 0.28 (0.105, 0.732), respectively. Combined treatment with risedronate and menatetrenone was more effective in preventing hip fractures than single treatment with risedronate, with RR (95% CI) of 0.19 (0.044, 0.858). However, the quality of RCTs was the highest in two risedronate studies which adopted a placebo control group. The present review of the literature implies that sunlight exposure, menatetrenone, and risedronate act on the musculoskeletal system in different manners for preventing hip fractures in patients with Alzheimer’s disease. However, risedronate plus vitamin D supplementation or risedronate plus menatetrenone can be candidates in patients with Alzheimer’s disease.

Serum level of under-carboxylated osteocalcin and bone mineral density in early menopausal Norwegian women

Serum level of under-carboxylated osteocalcin (ucOC) is considered a sensitive measure of vitamin K status, and ucOC levels are associated with bone mineral density (BMD) and fracture risk in elderly persons. The aim of this study was to assess the relationship between ucOC and BMD in early menopausal women. The data reported here come from the enrollment in a double-blinded placebo-controlled randomized trial comprising 334 healthy Norwegian women between 50 and 60 years, 1-5 years after menopause, not using warfarin or medication known to affect bone metabolism. Total hip, femoral neck, lumbar spine, and total body BMD and serum level of ucOC and total osteocalcin were measured, and information of lifestyle was collected through questionnaires. The association between ucOC and BMD at all measurement sites was assessed by multiple regression analyses adjusting for possible confounding variables. The absolute serum level of ucOC was significantly and negatively associated with BMD at all measurements sites, both in univariate analyses (p < 0.01) and in multivariate analyses adjusting for years since menopause, smoking status and weight (p < 0.01). However, serum ucOC, expressed as percentage of the total osteocalcin level, was not associated with BMD at any site. Achievement of adequate vitamin K nutritional intake is important, but ucOC expressed as percentage of total osteocalcin levels as reflection of vitamin K status does not seem to play a central role in determining BMD levels in early menopausal women.

High level of serum undercarboxylated osteocalcin in patients with incident fractures during bisphosphonate treatment

To evaluate the possible interaction of metabolic effects in the mevalonate pathway between amino-bisphosphonates (amino-BP) and vitamin K, the serum level of undercarboxylated osteocalcin (ucOC) was measured in amino-BP users in relationship to incident fracture occurrence. Osteoporotic patients (mean age, 70.7 +/- 9.1 years; n = 231) treated with alendronate or risedronate were followed for 3.4 +/- 2.1 years, and observations regarding the presence or absence of incident fractures in their vertebrae were made based on vertebral X-ray films every year. During the observation period, new fractures were found in a total of 71 patients (incident vertebral fracture, n = 61; the remaining 10 patients had long bone fractures). The baseline data of the patients with incident fractures indicated that incident fractures are more likely to occur in older patients who have a higher number of prevalent vertebral fractures and lower baseline lumbar bone mineral density (LBMD) as compared to patients without incident fractures. There was no significant difference in the changes of LBMD and urinary excretion of NTX after treatment. On the other hand, the serum level of ucOC in patients with incident fractures and with amino-BP treatment was significantly higher (2.75 +/- 0.19 ng/ml) than that in patients without incident fractures and with amino-BP treatment (2.28 +/- 0.13 ng/ml) (P = 0.038). These results indicate that older age, a greater number of prevalent fractures and higher ucOC levels, and lower LBMD are risks for incident fractures despite use of amino-BP. The time-dependent incident fracture rate was higher in accordance with an increase in the number of risk items (P < 0.001 in log-rank and Wilcoxon tests). In conclusion, measurement of undercarboxylated osteocalcin may be useful for assessing fracture risk in patients receiving amino-BP treatment.

RETRACTED ARTICLE: Prevention of hip fractures by exposure to sunlight and pharmacotherapy in patients with Alzheimer’s disease

Hypovitaminosis D and K due to malnutrition or sunlight deprivation, compensatory hyperparathyroidism, increased bone resorption, low bone mineral density (BMD), and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Alzheimer's disease. The purpose of the present study was to clarify the efficacy of interventions against hip fractures in patients with Alzheimer's disease. With respect to randomized controlled trials (RCTs) regarding Alzheimer's disease and hip fractures, the literature was searched with PubMed. Three RCTs were identified, and the relative risk (RR) and 95% confidence interval (CI) were calculated for individual RCTs. Exposure to sunlight with calcium supplementation, menatetrenone (vitamin K2) plus calcium and vitamin D supplementation, and risedronate plus calcium and vitamin D supplementation improved hypovitaminosis D and hyperparathyroidism, contributing to a reduction in bone resorption. Risedronate itself strongly decreased bone resorption. Menatetrenone also decreased the serum level of undercarboxylated osteocalcin. The three interventions increased metacarpal BMD and reduced the incidence of hip fractures. The respective RRs (95% CI) were 0.22 (0.049-0.999), 0.13 (0.031-0.554), and 0.26 (0.100- 0.690). The present study clarified the efficacy of three interventions, including exposure to sunlight, menatetrenone, and risedronate with calcium and/or vitamin D supplementation against hip fractures in patients with Alzheimer's disease.

Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study

The effect of vitamin K(2) (menatetrenone) on bone turnover was investigated in postmenopausal patients with osteoporosis. A 6-month open-label, randomized prospective study was conducted in 109 patients. The control group (n = 53) received calcium aspartate (133.8 mg of elemental calcium daily), while the menatetrenone group (n = 56) received 45 mg of menatetrenone daily for 6 months. Serum and urinary levels of bone turnover markers were monitored. The serum level of undercarboxylated osteocalcin (uc-OC) was significantly lower (P < 0.001) in the menatetrenone group than in the control group (at 1 month), while there was a higher level of osteocalcin containing gamma-carboxylated glutamic acid (Gla-OC) in the menatetrenone group than the control group (P = 0.018). Significant differences of uc-OC and Gla-OC between the two groups were observed from 1 month onward. In addition, a higher level of intact osteocalcin was found in the menatetrenone group compared with the control group after 6 months (P = 0.006). Assessment of bone resorption markers showed that menatetrenone therapy was associated with significantly higher urinary N-telopeptide of type I collagen (NTX) excretion compared with the control group after 6 months, while there was no significant difference of urinary deoxypyridinoline excretion between the two groups. In conclusion, one month of menatetrenone therapy enhanced the secretion and gamma-carboxylation of osteocalcin, while urinary NTX excretion was increased after 6 months of treatment. Further investigations are required to determine whether the effects of menatetrenone on bone turnover are associated with fracture prevention.

Low Serum Levels of Undercarboxylated Osteocalcin in Postmenopausal Osteoporotic Women Receiving an Inhibitor of Bone Resorption

Osteocalcin, a bone-specific protein synthesized by osteoblasts, undergoes vitamin K-dependent gamma-carboxylation. Undercarboxylated osteocalcin (ucOC) represents inadequately carboxylated osteocalcin, and this fraction increases with vitamin K insufficiency. Alendronate is a bisphosphonate that inhibits bone resorption, thereby increasing bone mineral density (BMD), while also reducing bone formation closely coupled with bone resorption. The aim of this cross-sectional study was to evaluate the influence of alendronate on serum levels of ucOC, cross-linked N-telopeptide of type 1 collagen (NTx), a marker of bone resorption, and bone alkaline phosphatase (BAP), a marker of bone formation. Forty-six postmenopausal osteoporotic women were divided into three groups: patients receiving alendronate (5 mg/day or 35 mg/week) for >or= 6 months (n = 29) or < 6 months (n = 7), and patients receiving no medication related to bone metabolism (n = 10). Serum ucOC levels were significantly lower in patients with long-term treatment (p < 0.0001) or short-term treatment (p = 0.0223) than in untreated patients. Serum ucOC levels correlated positively with both BAP (r = 0.695, p < 0.0001) and NTx (r = 0.494, p = 0.0004) in all participants. Since low serum levels of BAP and NTx are associated with decreased levels of bone formation and bone resorption, respectively, these findings suggest that low serum ucOC levels may reflect the suppression of bone turnover. In conclusion, low serum ucOC levels reflect suppressed bone turnover and/or adequate levels of vitamin K in patients receiving an inhibitor of bone resorption.

Effect of vitamin K2 treatment on carboxylation of osteocalcin in early postmenopausal women

Objective. We examined the serum level of undercarboxylated osteocalcin (uc OC), which is a sensitive marker of vitamin K status, and levels of bone turnover markers in early postmenopausal women receiving vitamin K2 treatment with or without vitamin D3.Methods. Thirty-four postmenopausal women with a mean age of 53 years whose bone mineral density (BMD) was less than 0.809 g/cm2 (osteopenia and osteoporosis) were treated with vitamin K2 or with a combination of vitamin K2 and vitamin D3. Seventeen women received daily oral administration of 45 mg vitamin K2 and 17 women received daily oral administration of 45 mg vitamin K2 plus 0.75 µg 1α-hydroxyvitamin D3. Serum levels of uc OC, intact osteocalcin (OC) and bone alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD) levels and BMD at the lumbar spine were measured before and at 1 and 2 years after the start of treatment.Results. Serum uc OC levels in women treated with vitamin K2 alone and with both vitamin K2 and vitamin D3 decreased significantly (p < 0.05). Serum levels of intact OC and BAP in women treated with vitamin K2 did not show significant changes, while those in women who received the combined treatment decreased significantly (p < 0.05). On the other hand, urinary DPD level in women treated with vitamin K2 did not change, while that in women who received the combined treatment tended to decrease (p < 0.1).Conclusion. Serum uc OC levels in early postmenopausal women who received vitamin K2 decreased due to carboxylation of uc OC. Combined treatment with vitamin K2 and vitamin D3 may be effective for sustaining BMD in early postmenopausal women whose bone turnovers are highly activated.

Retracted: Role of Vitamin K2 in the Treatment of Postmenopausal Osteoporosis

Vitamin K2, raloxifene, and bisphosphonates, such as etidronate, alendronate, and risedronate, are widely used in the treatment of postmenopausal osteoporosis in Japan. A meta-analysis study has demonstrated the efficacy of anti-resorptive agents: raloxifene and etidronate have been shown to reduce the incidence of vertebral fractures, and alendronate and risedronate have been shown to reduce the incidence of both vertebral and hip fractures. Furthermore, a report of the World Health Organization (WHO) has provided evidence from a randomized controlled trial suggesting that vitamin K2, which may stimulate bone formation via gamma-carboxylation of osteocalcin and/or steroid and xenobiotic receptors (SXRs), reduces the incidence of vertebral fractures, despite having only modest effects on the bone mineral density (BMD). Based on the weight of the currently available evidence, it is recommended that alendronate and risedronate, rather than vitamin K2, should be chosen initially for the treatment of postmenopausal osteoporosis, because these agents have been shown to be the most efficacious for reducing the incidence of both vertebral and hip fractures among the current range of commercially available agents. However, the more potent anti-fracture efficacy of combined treatment with the anti-resorptive and commercially available anabolic agents may need to be established. Some studies have shown that combined treatment with a bisphosphonate and vitamin K2 may be more effective than treatment with a bisphosphonate alone in preventing vertebral fractures. On the other hand, the results of a preclinical study do suggest the possible efficacy of combined treatment with vitamin K2 and raloxifene in the prevention of vertebral and hip fractures in postmenopausal women, although no clinical studies have reported on the effects of combined treatment with vitamin K2 and raloxifene in postmenopausal women with osteoporosis. Vitamin K deficiency, as indicated by high serum levels of undercarboxylated osteocalcin, has been shown to contribute to the occurrence of hip fractures in elderly women. Thus, we propose that the important role of vitamin K2 used in combination with bisphosphonates or raloxifene should not be underestimated in the prevention of fractures in postmenopausal women with osteoporosis with vitamin K deficiency.