Undercarboxylated Osteocalcin Concentrations Research Articles

Maternal adaptations of pancreatic islets and glucose metabolism after lactation.

Pancreatic islets adapt to metabolic requirements and the hormonal milieu by modifying their size and hormone secretions. Maternal glucose demands and hormonal changes occur after weaning, to rapidly re-establish bone mineralization. Minimal information exists about glucose metabolism and pancreatic islets after lactation. This study investigated islet morphology and glucose homeostasis for 14 days after lactation in C57BL/6NHHsd mice. Compared to the day of weaning, rapid increases in the islets' area and number of beta cells were found from the first day post-lactation, attaining maximum values on the third day post-weaning. These changes were accompanied by modifications in glucose-induced insulin secretion, glucose tolerance and insulin sensitivity. Islet-cell proliferation was already augmented before lactation ceased. Serum undercarboxylated osteocalcin concentrations increased significantly post-lactation; however, it is unlikely that this enhancement participates in earlier cell proliferation augmentation or in decreasing insulin sensitivity. Islet serotonin content was barely expressed, and serum calcium concentrations decreased. By the 14th day post-weaning, islets' area and glucose homeostasis returned to age-matched virgin mice levels. These findings recognize for the first time that increases in islet area and insulin secretion occur during physiological post-weaning conditions. These results open up new opportunities to identify molecules and mechanisms participating in these processes, which will help in developing strategies to combat diabetes.

Vitamin K deficiency, evaluated with higher serum ucOC, was correlated with poor bone status in women

BackgroundAn increase in serum undercarboxylated osteocalcin concentrations suggests vitamin K deficiency. Clinical intervention studies suggested that the vitamin K supplementation might contribute to preventing bone loss in postmenopausal women. Evidence on the relationship between serum undercarboxylated osteocalcin (ucOC) levels and bone parameters of quantitative ultrasound (QUS) is limited. We examined the correlation between serum ucOC concentrations and bone status as measured by QUS among middle-aged and older Japanese men and women.MethodsThe subjects were community-dwelling men (n = 358) and women (n = 503) aged ≥ 40 years in Japan. Heel QUS parameters, including the stiffness index, speed of sound, and broadband ultrasound attenuation, were measured. Serum ucOC concentrations were measured by electrochemiluminescence immunoassay. Grip strength was measured in the dominant hand. Information on alcohol drinking, current smoking, exercise, and menopause in women was collected.ResultsSerum ucOC concentrations were significantly associated with age in both sexes. Serum ucOC concentrations in men were higher at ≥ 80 years than those in the age groups of 40–49, 50–59, and 60–69 years. Serum ucOC concentrations in women were higher in the age groups of 50–59 and 60–69 years than those at 40–49 years. Partial correlation analysis adjusting for covariates (age, body mass index, grip strength, alcohol drinking, current smoking, and exercise in men; age, body mass index, grip strength, alcohol drinking, current smoking, exercise, and menopause in women) showed that serum ucOC concentrations were negatively significantly correlated with all QUS parameters in women. Serum ucOC concentrations were not correlated with them in men.ConclusionsVitamin K deficiency, evaluated with higher serum ucOC, was correlated with poor bone status in women.

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.

Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45mg/day) and risedronate (2.5mg/day or 17.5mg/week) or risedronate (2.5mg/day or 17.5mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95% confidence interval 0.811-1.422, p=0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81±3.93ng/mL to 2.59±1.52ng/mL at 6months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96±4.36ng/mL to 4.05±3.40ng/mL at 6months) (p<0.01). The treatment discontinuation rate was higher in the risedronate and vitamin K2 group than in the risedronate alone group (10.0% vs 6.7%). No unknown adverse drug reactions were reported. In conclusion, concurrent treatment with vitamin K2 and risedronate was not efficacious compared with monotherapy with risedronate in terms of fracture prevention.

Low-Dose Daily Intake of Vitamin K(2) (Menaquinone-7) Improves Osteocalcin γ-Carboxylation: A Double-Blind, Randomized Controlled Trials.

Vitamin K is essential for bone health, but the effects of low-dose vitamin K intake in Japanese subjects remain unclear. We investigated the effective minimum daily menaquinone-7 dose for improving osteocalcin γ-carboxylation. Study 1 was a double-blind, randomized controlled dose-finding trial; 60 postmenopausal women aged 50-69 y were allocated to one of four dosage group and consumed 0, 50, 100, or 200 μg menaquinone-7 daily for 4 wk, respectively, with a controlled diet in accordance with recommended daily intakes for 2010 in Japan. Study 2 was a double-blind, randomized placebo-controlled trial based on the results of Study 1; 120 subjects aged 20-69 y were allocated to the placebo or MK-7 group and consumed 0 or 100 μg menaquinone-7 daily for 12 wk, respectively. In both studies, circulating carboxylated osteocalcin and undercarboxylated osteocalcin were measured. The carboxylated osteocalcin/undercarboxylated osteocalcin ratio decreased significantly from baseline in the 0 μg menaquinone-7 group, in which subjects consumed the recommended daily intake of vitamin K with vitamin K1 and menaquinone-4 (Study 1). Menaquinone-7 increased the carboxylated osteocalcin/undercarboxylated osteocalcin ratio dose dependently, and significant effects were observed in both the 100 and 200 μg groups compared with the 0 μg group. Undercarboxylated osteocalcin concentrations decreased significantly, and the carboxylated osteocalcin/undercarboxylated osteocalcin ratio increased significantly in the 100 μg menaquinone-7 group compared with the placebo group (Study 2). Daily menaquinone-7 intake ≥100 μg was suggested to improve osteocalcin γ-carboxylation.

Strategy for prevention of hip fractures in patients with Parkinson’s disease

Hypovitaminosis D and K due to malnutrition or sunlight deprivation, increased bone resorption due to immobilization, low bone mineral density (BMD) and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Parkinson's disease. The purpose of the present study was to clarify the efficacy of interventions intended to prevent hip fractures in elderly patients with Parkinson's disease. PubMed was used to search the literature for randomized controlled trials (RCTs) regarding Parkinson's disease and hip fractures. The inclusion criteria were 50 or more subjects per group and a study period of 1 year or longer. Five RCTs were identified and the relative risk and 95% confidence interval were calculated for individual RCTs. Sunlight exposure increased serum hydroxyvitamin D [25(OH)D] concentration, improved motor function, decreased bone resorption and increased BMD. Alendronate or risedronate with vitamin D supplementation increased serum 25(OH)D concentration, strongly decreased bone resorption and increased BMD. Menatetrenone (vitamin K(2)) decreased serum undercarboxylated osteocalcin concentration, decreased bone resorption and increased BMD. Sunlight exposure (men and women), menatetrenone (women), alendronate and risedronate with vitamin D supplementation (women) significantly reduced the incidence of hip fractures. The respective RRs (95% confidence intervals) according to the intention-to-treat analysis were 0.27 (0.08, 0.96), 0.13 (0.02, 0.97), 0.29 (0.10, 0.85) and 0.20 (0.06, 0.68). Interventions, including sunlight exposure, menatetrenone and oral bisphosphonates with vitamin D supplementation, have a protective effect against hip fractures elderly patients with Parkinson's disease.

Determinants of undercarboxylated and carboxylated osteocalcin concentrations in type 1 diabetes

To determine whether undercarboxylated osteocalcin (UC-OC) or gamma-carboxyglutamic-carboxylated-type osteocalcin (GLA-OC) concentrations deviate from normal in type 1 diabetes (T1D), serum levels were compared between 115 subjects with T1D and 55 age-matched healthy controls. UC-OC and GLA-OC concentrations were similar between groups; however, in T1D, UC-OC correlated positively with markers of insulin exposure, either endogenously produced or exogenously administered. A study was conducted to determine whether dysregulation of circulating concentrations of UC-OC or GLA-OC occurs in patients with type 1 diabetes, a condition of insulin deficiency without insulin resistance. We measured serum concentrations of UC-OC and GLA-OC in 115 subjects with T1D, ages 14-40 years, and in 55 age-matched healthy control subjects. Relationships between UC-OC and GLA-OC concentrations and patient characteristics (gender and age), indices of glycemic control (hemoglobin A1c (HbA1c), fasting plasma glucose, C-peptide concentration, 3-day average glucose measured by a continuous glucose sensor, total daily insulin dose) and circulating indices of skeletal homeostasis (total calcium, 25-OH vitamin D, parathyroid hormone, insulin-like growth factor 1 (IGF-1), type 1 collagen degradation fragments (CTX), adiponectin, leptin) were examined. Between group differences in the concentrations of UC-OC and GLA-OC were the main outcome measures. Although adiponectin levels were higher in the T1D group, between-group comparisons did not reveal statistically significant differences in concentration of UC-OC, GLA-OC, CTX or leptin between the T1D and control populations. Instead, by multivariate regression modeling, UC-OC was correlated with younger age (p < 0.001), higher CTX (p < 0.001), lower HbA1c (p = 0.013), and higher IGF-1 (p = 0.086). Moreover, within the T1D subgroup, UC-OC was positively correlated with C-peptide/glucose ratio (reflecting endogenous insulin secretion), with IGF-1 (reflecting intra-portal insulin sufficiency), and with total daily insulin dose. In T1D, UC-OC appears to correlate positively with markers of insulin exposure, either endogenously produced or exogenously administered.

Carbohydrate Metabolism and the Skeleton: Picking a Bone with the β-Cell

Novel data show that the bone protein, undercarboxylated osteocalcin, increases islet cell growth and insulin and adiponectin synthesis and enhances glucose metabolism in mice. Human studies, in which undercarboxylated osteocalcin concentrations have been perturbed, show no effect (or a very minor effect) on fasting glucose or insulin concentrations. More extensive and detailed experiments in humans are needed to definitively establish the role of undercarboxylated osteocalcin in human carbohydrate metabolism.

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.

Effect of vitamin K supplementation on bone loss in elderly men and women.

Vitamin K has been implicated in bone health, primarily in observational studies. However, little is known about the role of phylloquinone supplementation on prevention of bone loss in men and women. The objective of this study was to determine the effect of 3-yr phylloquinone supplementation on change in bone mineral density (BMD) of the femoral neck bone in older men and women who were calcium and vitamin D replete. In this 3-yr, double-blind, controlled trial, 452 men and women (60-80 yr) were randomized equally to receive a multivitamin that contained either 500 mug/d or no phylloquinone plus a daily calcium (600 mg elemental calcium) and vitamin D (400 IU) supplement. Measurements of the femoral neck, spine (L2-L4), and total-body BMD, bone turnover, and vitamins K and D status were measured every 6-12 months. Intent-to-treat analysis was used to compare change in measures in 401 participants who completed the trial. There were no differences in changes in BMD measurements at any of the anatomical sites measured between the two groups. The group that received the phylloquinone supplement had significantly higher phylloquinone and significantly lower percent undercarboxylated osteocalcin concentrations compared with the group that did not receive phylloquinone. No other biochemical measures differed between the two groups. Phylloquinone supplementation in a dose attainable in the diet does not confer any additional benefit for bone health at the spine or hip when taken with recommended amounts of calcium and vitamin D.

Change in serum undercarboxylated osteocalcin concentration in bilaterally oophorectomized women

Objective We investigated changes in serum undercarboxylated osteocalcin (ucOC) concentrations, bone turnover markers and spine bone mineral density (BMD) in women who had undergone bilateral oophorectomy during the premenopausal period. Methods The study population comprised 141 bilaterally oophorectomized and 32 premenopausal women for a cross-sectional study. The longitudinal study consisted of 21 bilaterally oophorectomized women. Serum ucOC concentration, serum concentrations of intact osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) as bone formation markers, urine N-telopeptide (NTx) concentration as a bone resorption marker and serum parathyroid hormone (PTH) concentration were measured. Results Serum concentration of ucOC in women at 1 month after bilateral oophorectomy was significantly ( p < 0.05) higher than that in premenopausal women and the high level was sustained after surgical menopause. On the other hand, serum OC concentration at 1 month after surgical menopause was not different from that in premenopausal women. In the longitudinal study, serum ucOC concentration at 1 month after surgical menopause was significantly ( p < 0.05) increased compared to that before bilateral oophorectomy, while serum OC concentrations before and at 1 month after surgical menopause were not significantly different. Conclusion The results of this study showed that serum ucOC concentration rapidly increases in women after bilateral oophorectomy and that change in serum ucOC concentration after surgical menopause is different from change in serum OC concentration.

Effect of calcium fortified milk supplementation with or without vitamin K on biochemical markers of bone turnover in premenopausal women

Objective We compared the effect of supplementation with a fortified skimmed milk product (high calcium skim milk) with or without added phylloquinone (vitamin K 1) on markers of bone formation and resorption in premenopausal women. Methods Eighty-two women 20 to 35 y of age were randomly allocated to three groups. Two groups received two daily servings of high calcium skim milk (1000 mg/d of extra calcium) with or without added phylloquinone (80 μg/d) for 16 wk, and a third control group received no supplementation. Bone density was assessed at baseline and the bone markers, total osteocalcin, type I N-terminal procollagen peptide, and cross-linked C-telopeptide of type I collagen were measured at baseline and at weeks 2, 12, and 16. Serum phylloquinone and undercarboxylated osteocalcin were measured in the control and vitamin K–supplemented groups at weeks 0 and 16. Results Baseline values for age, body mass index, and bone density did not differ across groups. In vitamin K–supplemented women, mean serum phylloquinone concentrations increased from 0.27 to 0.76 μg/L ( P < 0.05) and undercarboxylated osteocalcin concentrations decreased from 9.68 to 4.46 μg/L ( P < 0.05) over 16 wk. Plasma cross-linked C-telopeptide of type I collagen, total osteocalcin, and type I N-terminal procollagen peptide levels decreased significantly in both supplemented groups compared with the control group over 16 wk (cross-linked C-telopeptide of type I collagen >30%, total osteocalcin and type I N-terminal procollagen peptide >15%). Conclusion Fortified milk supplementation in premenopausal women reduced bone turnover significantly. Phylloquinone fortification substantially improved vitamin K status but had no demonstrable additive effect on bone turnover in this short-term study.

Different effects of oral conjugated equine estrogens and transdermal estrogen on undercarboxylated osteocalcin concentration in postmenopausal women

Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status, and triglyceride (TG) has been shown to be the main transporter of vitamin K. In the present study, we examined the difference between ucOC concentrations in postmenopausal women receiving hormone therapy (HT) with oral conjugated equine estrogens (CEE) and transdermal estradiol (TE2). We also examined the associations of ucOC concentration with estradiol concentration and TG. Ninety-two postmenopausal women were recruited for this study. Serum concentrations of ucOC, intact osteocalcin, estradiol, and TG were measured before and after 12 months of HT. Forty-six women received oral administration of 0.625 mg of CEE and 2.5 mg of medroxyprogesterone acetate daily, and 46 women received transdermal administration of 50 mug of 17beta-estradiol twice weekly and 2.5 mg of medroxyprogesterone acetate daily. The ucOC concentration in women during HT with oral CEE was significantly (P < 0.01) lower than that in women during HT with TE2. Serum estradiol concentrations during HT with CEE showed a significant inverse correlation with ucOC concentrations and the ratio of ucOC/OC during HT (P < 0.05 and P < 0.01, respectively). In addition, the serum ucOC concentration in women with an increased percentage of change in TG was significantly (P < 0.01) lower than that in women with a decreased percentage of change in TG during HT with oral CEE. The effect of HT with TE2 on ucOC concentration in women is weaker than the effect of HT with oral CEE. Suppression of ucOC concentration in postmenopausal women during HT with oral CEE might be associated with the effect of vitamin K through increased TG induced by oral CEE.

Undercarboxylated osteocalcin concentration in postmenopausal women receiving hormone therapy daily and on alternate days

Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status. The authors examined the difference in serum ucOC concentrations in postmenopausal women receiving hormone therapy (HT) daily and on alternate days, and assessed the association between ucOC and triglyceride concentrations, which are related to the transport of vitamin K. Seventy-three postmenopausal women were recruited for this study. Thirty-seven women received 0.625 mg of conjugated equine estrogens (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) daily, and 36 women received 0.625 mg of CEE and 2.5 mg of MPA on alternate days. The concentrations of serum ucOC, bone turnover markers, lipid profiles, and hormones were measured before and after 12 months of HT. The ucOC concentration in women taking HT daily was significantly (P < 0.01) lower than that in women taking HT on alternate days. Serum ucOC concentrations during HT showed a significant (P < 0.01) inverse correlation with estradiol concentrations during HT. Serum estradiol concentrations during HT showed a significant (P < 0.01) positive correlation with triglyceride concentrations during HT. Furthermore, ucOC concentrations during HT showed a significant (P < 0.05) inverse correlation with triglyceride concentrations in women receiving HT. The effect of HT on alternate days on ucOC concentration was weaker than the effect of HT daily. In addition, ucOC concentration after 12 months of HT daily might be decreased due to the conversion of ucOC to carboxylated OC by the effect of vitamin K through increased triglyceride levels induced by oral CEE.

Vitamin D, K and bone mineral density

Both vitamin D and vitamin K are essential nutrients for bone health. It is believed that vitamin D deficiency is responsible for rickets in infants and osteomalacia in adults, and chronic vitamin D insufficiency induces hyperparathyroidism and reduces bone mineral density, resulting in an increased risk of osteoporosis. Vitamin K deficiency is thought to cause impaired activation of bone matrix protein osteocalcin, and reduction of osteoblast function, resulting in impaired bone formation. Recently, we reported that a high prevalence of low vitamin D status (low serum 25-hydroxyvitamin D concentration) . low bone mineral density, and a high prevalence of low vitamin K status (high serum undercarboxylated osteocalcin concentration) . high frequency of bone fracture in elderly women in Japan. However, no correlation between low vitamin K status and low bone mineral density was observed in this subjects.

Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population

Biochemical indexes for assessing vitamin K nutritional status were evaluated in 263 healthy subjects (127 males, 136 females) aged 18-85 y. The influences of aging (stratified by decade), menopause, and sex were examined. Total, carboxylated, and undercarboxylated osteocalcin concentrations were affected by sex and aging with increases in the sixth decade in women attributed to menopause. Aging effects in the women and sex differences were eliminated when undercarboxylated osteocalcin was expressed as a percentage of the total. Plasma phylloquinone and undercarboxylated prothrombin (PIVKA-II) concentrations varied little with aging with the exception of lower concentrations of phylloquinone in women in their third decade compared with other ages and higher concentrations of PIVKA-II in younger males compared with younger females. Urinary gamma-carboxyglutamic acid (Gla)-creatinine excretion ratios increased significantly with age in both males (r = 0.68, P < 0.001) and females (r = 0.63, P < 0.001) with values 20% higher in the females on average over the entire age span. The undercarboxylated osteocalcin concentration, shown previously to be responsive to depletion and repletion of phylloquinone, was compared with the other indexes to determine its reliability as an indicator of vitamin K nutritional status. This measure appears promising because it correlated with plasma PIVKA-II concentrations (r = 0.27, P < 0.001) and with plasma phylloquinone concentrations (r = -0.35, P < 0.001), whereas the agreement between plasma phylloquinone and PIVKA-II concentrations was not as strong (r = -0.15, P < 0.05).