Undercarboxylated Osteocalcin Research Articles

6683 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)

Abstract Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None. Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022. Presentation: 6/1/2024

9275 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)

Abstract Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None. Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022. Presentation: 6/1/2024

Correlations between Bone Turnover Marker Concentrations and Maxillary and Mandibular Cancellous Hounsfield Units: A Crosssectional Study.

Purpose: This study aimed to investigate the associations between the concentrations of bone turnover markers and maxillary and mandibular cancellous Hounsfield units to determine whether bone turnover marker assessments are effective for preoperative examinations for implant treatment. Materials and Methods: The study included 94 patients (37 males and 57 females) with a mean age of 62.0±11.9 years. Spearman's rank correlation and multivariate linear regression coefficients were used to determine the associations between the bone turnover markers and maxillary and mandibular cancellous Hounsfield units. Results: Multivariate bias correction showed that the concentrations of bone-specific alkaline phosphatase, procollagen type I N-terminal propeptide, and deoxypyridinoline were negatively associated with the maxillary Hounsfield units. The concentration of undercarboxylated osteocalcin tended to be negatively associated with the maxillary Hounsfield units but not significantly. The concentrations of deoxypyridinoline and tartrateresistant acid phosphatase 5b were significantly negatively associated, and the concentrations of bone-specific alkaline phosphatase and procollagen type I N-terminal propeptide only tended to be negatively associated with the mandibular Hounsfield units. Conclusion: Several bone formation and resorption markers were negatively correlated with the maxillary and mandibular Hounsfield units. BTM measurement is effective for preoperative examination for implant treatment.

No Impairment in Bone Turnover or Executive Functions in Well-Treated Preschoolers with Phenylketonuria-A Pilot Study.

Patients with phenylketonuria (PKU) present signs of impaired executive functioning and bone health in adolescence and adulthood, depending in part on the success of therapy in childhood. Therefore, nine children with well-treated PKU (4-7 years old, 22.2% ♀, seven with a full set of data, two included into partial analysis) and 18 age-, gender- and season-matched controls were analyzed for differences in executive functioning and bone parameters in plasma. Plasma was analyzed with commercially available kits. Cognitive performance in tonic alertness, visuo-spatial working memory, inhibitory control and task switching was assessed by a task battery presented on a touch screen. Regarding cognition, only the performance in incongruent conditions in inhibitory control was significantly better in children with PKU than in controls. No further differences in cognitive tests were detected. Furthermore, no significant difference in the bone turnover markers osteocalcin, undercarboxylated osteocalcin and CTX were detected between children with PKU and controls, while children with PKU had a significantly higher vitamin D concentration (69.44 ± 12.83 nmol/L vs. 41.87 ± 15.99 nmol/L, p < 0.001) and trended towards lower parathyroid hormone concentrations than controls (48.27 ± 15.16 pg/mL vs. 70.61 ± 30.53 pg/mL, p = 0.066). In this small group of well-treated preschoolers with PKU, no impairments in cognitive performance and bone turnover were observed, while vitamin D supplementation of amino acid supplements seems to be sufficient to achieve good vitamin D status.

Dairy consumption, bone turnover biomarkers, and osteo sono assessment index in Japanese adults: A cross-sectional analysis of data from the Iwaki Health Promotion Project

PurposeDairy foods are nutritional sources of calcium, phosphorus, protein, and other nutrients that improve bone health. However, the effects of dairy consumption on bone biomarkers in the Japanese population remain unclear. This study explored the association between dairy consumption and bone biomarkers in Japanese adults. MethodsThis cross-sectional study was conducted as part of the Iwaki Health Promotion Project in Aomori, Japan. In total, 1063 adults were included in the analysis. Bone turnover marker levels were measured in local citizens during their annual medical checkups. The calcaneus osteo sono assessment index (OSI) was calculated using a quantitative ultrasound technique. The dietary intake of foods and nutrients was estimated using a food frequency questionnaire. Linear regression models were established using dairy consumption and bone biomarkers with adjustments. Statistic significance was considered by P < 0.05. ResultsIn multivariate models, the tartrate-resistant acid phosphatase 5b and parathyroid hormone concentrations were inversely associated with dietary dairy consumption after adjusting for age and sex. The undercarboxylated osteocalcin, a procollagen type I N-terminal peptide to bone alkaline phosphatase ratio, and OSI were the directly associated with dairy consumption in multivariate models with adjustment. ConclusionsDairy consumption is partially associated with bone turnover biomarkers and OSI in adult Japanese participants. Habitual consumption of dairy foods may contribute to the nutritional supplementation for maintaining bone health, including turnover and structure. Clinical trial registry number and website where it was obtainedThe Japanese Clinical Trials Registry (UMIN000040459), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000046175.

Association between uncarboxylated osteocalcin, blood glucose, and BMI among Saudi diabetic patients: an evaluation study.

Uncarboxylated osteocalcin is an important osteocalcin enzyme found in the bloodstream and is a crucial protein for maintaining calcium binding in bones, controlling blood sugar levels, and balancing body minerals. Due to the lack of data, the current study intends to investigate the relationship between uncarboxylated osteocalcin levels and DM-II in Saudi patients. For 138 patients, case-control research was conducted in 2021-2023, with 69 type II diabetes mellitus patients and 69 matching healthy control participants. An enzyme immunoassay kit was used to quantify the levels of uncarboxylated osteocalcin in fasting blood samples, and an automated analyzer evaluated Hb1Ac, fasting blood glucose, enzymes, electrolytes, lipid, and kidney profiles. Data processing and analysis were carried out using GraphPad Prism statistical software. According to our study, patients with type II diabetes mellitus had considerably lower levels of uncarboxylated osteocalcin than healthy controls. According to the correlation analysis, uncarboxylated osteocalcin and fasting blood sugar had a negative relationship. In the overweight BMI group, uncarboxylated osteocalcin was considerably higher in control subjects. We concluded that, in Saudi type II diabetes mellitus patients, the compromised glucose level is associated with diminished serum uncarboxylated osteocalcin. This study has limitations, such as a small sample size and only measuring the uncarboxylated form of plasma osteocalcin. Future research is needed to understand how anti-diabetic drugs affect undercarboxylated osteocalcin's effect on metabolic control and provide more efficient techniques and resources in diabetes and osteoporosis prevention and care.

Association of serum osteocalcin with bone microarchitecture and muscle mass in Beijing community-dwelling postmenopausal women.

Osteoporosis is a systemic skeletal disease with increasing bone fragility and prone to fracture. Osteocalcin (OC), as the most abundant non collagen in bone matrix, has been extensively used in clinic as a biochemical marker of osteogenesis. Two forms of OC were stated on circulation, including carboxylated osteocalcin (cOC) and undercarboxylated osteocalcin (ucOC). OC was not only involved in bone mineralization, but also in the regulation of muscle function. This study explored the relationship between serum OC, cOC, ucOC levels and bone mineral density (BMD), bone microarchitecture, muscle mass and physical activity in Chinese postmenopausal women. 216 community-dwelling postmenopausal women were randomized enrolled. All subjects completed biochemical measurements, including serum β-isomer of C-terminal telopeptides of type I collagen (β-CTX), N-terminal propeptide of type 1 procollagen (P1NP), alkaline phosphatase (ALP), OC, cOC and ucOC. They completed X-ray absorptiometry (DXA) scan to measure BMD, appendicular lean mass (ALM) and trabecular bone score (TBS). They completed high resolution peripheral quantitative CT (HR-pQCT) to assess peripheral bone microarchitectures. Serum OC, cOC and ucOC were elevated in osteoporosis postmenopausal women. In bone geometry, serum ucOC was positively related with total bone area (Tt.Ar) and trabecular area(Tb.Ar). In bone volumetric density, serum OC and ucOC were negatively associated with total volume bone mineral density (Tt.vBMD) and trabecular volume bone mineral density (Tb.vBMD). In bone microarchitecture, serum OC and ucOC were negatively correlative with Tb.N and Tb.BV/TV, and were positively correlated with Tb.Sp. Serum OC and ucOC were positively associated with Tb.1/N.SD. Serum OC was negatively related with Tb.Th. Serum ucOC was positively associated with ALM. The high level of serum OC was the risk factor of osteoporosis. ALM was the protective factor for osteoporosis. All forms of serum OC were negatively associated with BMD. Serum OC and ucOC mainly influenced microstructure of trabecular bone in peripheral skeletons. Serum ucOC participated in modulating both bone microstructure and muscle mass.

Associations of Serum Irisin and Fibroblast Growth Factor-21 Levels With Bone Mineral Characteristics in Eumenorrheic Adolescent Athletes With Different Training Activity Patterns.

To describe serum irisin and fibroblast growth factor-21 (FGF-21) concentrations in healthy female adolescents with different training activity patterns and their associations with bone mineral properties and metabolic markers. A total of 62 adolescent girls aged 14-18years were recruited: 22 rhythmic gymnasts, 20 swimmers, and 20 untrained controls. Bone mineral characteristics by dual-energy X-ray absorptiometry, daily energy intake by dietary recall, serum irisin, FGF-21, undercarboxylated osteocalcin, and C-terminal telopeptide of type I collagen were measured in all girls. Whole body and lumbar spine areal bone mineral density and lumbar spine bone mineral content were higher in the rhythmic gymnasts group compared with swimmers and untrained controls groups (P < .05). Serum irisin, FGF-21, undercarboxylated osteocalcin, and C-terminal telopeptide of type I collagen levels were not significantly different between the groups. In the rhythmic gymnasts group, serum FGF-21 concentration was positively correlated with lumbar spine areal bone mineral density independently of confounding factors (r = .51; P = .027). Serum irisin and FGF-21 levels were not different between adolescent eumenorrheic girls with different training activity patterns. FGF-21 was positively associated with lumbar spine areal bone mineral density, which predominantly consists of trabecular bone in adolescent rhythmic gymnasts.

Plasma undercarboxylated osteocalcin dynamics with glycemic stress reflects insulin sensitivity and beta-cell function in humans with and without T2DM

This study aimed to better understand the relationship between bone-related biomarkers and nutrient stress in the context of metabolic health. We investigated plasma osteocalcin (OC) during an oral glucose challenge and experimental hyperinsulinemia in Type 2 diabetes (T2DM) and lean healthy controls (LHC). Older individuals with obesity and T2DM (n = 9) and young LHCs (n = 9) underwent a 75g oral glucose tolerance test (OGTT) and a 40 mU/m2/min hyperinsulinemic-euglycemic clamp. Plasma undercarboxylated OC (ucOC) and total OC were measured at baseline, 60mins, and 120mins of the OGTT and clamp via ELISA. In addition, plasma alkaline phosphatase (ALP), leptin, adiponectin, Vitamin D and insulin were measured and indices of insulin sensitivity and β-cell function were derived. The T2DM group had lower (p<0.05) ucOC and ucOC:total OC ratio than LHC during both the OGTT and clamp. Further, baseline ucOC was positively correlated to indices of β-cell function and negatively correlated to indices of insulin resistance when both groups were combined (all p<0.05). Suppression of OC observed in T2DM may be related to glucose intolerance and insulin resistance. Similarly, our data suggest that the observed phenotypic differences between groups are likely a product of long-term glucose dysregulation rather than acute flux in glucose or insulin.

PIVKA‑II is associated with liver function, bone metabolism, and muscle function in patients with liver disease.

Protein induced by vitamin K (VK) absence-II (PIVKA-II) is a sensitive marker for diagnosing hepatoma but is occasionally detected in patients without hepatoma Here, the clinical significance of serum PIVKA-II levels in patients who were not administered warfarin and did not have hepatoma or liver disease were evaluated. As VK is related to muscle and bone metabolism, PIVKA-II and clinical factors related to bone and muscle were compared. A total of 441 patients with various liver diseases were evaluated. Of these, 236 patients were female. Clinical factors and anthropometric measurements were obtained for each participant during outpatient visits. Among the clinical factors, type I procollagen N-propeptide (P1NP), a low titer of undercarboxylated osteocalcin (ucOC), and 25(OH) vitamin D (VD) were used as bone metabolic markers, and SARC-F and grip strength were used as muscle-related markers. Serum PIVKA-II levels above the upper limit were associated with Child B/C (Child-Pugh score), high titers of total P1NP, and low titers of ucOC in females, and alcohol-related liver disease and low VD in males. The titer of PIVKA-II were associated with immunoglobulin (Ig) A and prothrombin time (PT)-international normalized ratio (INR) in females, and fibrosis-4-4, IgG, total bilirubin, PT-INR, and SARC-F in males. Elevated PIVKA-II levels were associated with abnormal bone physiology in females, weak muscles in males, and severe liver disease in both sexes. Assessing PIVKA-II may assist in evaluating the clinical and bone-muscle metabolic stages in liver disease. Nutrition and supplementation with fat-soluble vitamins, including VK and VD may thus serve as a potential method to alleviate or prevent bone-muscle pathophysiology in patients with liver disease.

The Effect of Vitamin K2 Supplementation on PIVKA-II Levels in Patients with Severe Motor and Intellectual Disabilities Undergoing Long-Term Tube Feeding.

Nutritional support is essential for patients with severe motor and intellectual disabilities (SMID) to ensure the smooth provision of medical care. These patients often require long-term tube feeding with enteral formulas, potentially leading to deficiencies in vitamins and trace elements. Additionally, frequent antibiotic use for infections often disrupts gut microbiota, inhibiting vitamin K2 production by intestinal bacteria. We assessed the serum protein induced by vitamin K absence or antagonists-II (PIVKA-II) and undercarboxylated osteocalcin (ucOC) levels to assess the vitamin K status in 20 patients with SMID (median age: 44.1 years, 11 men and 9 women) undergoing long-term tube feeding for durations ranging from 3 to 31 years. Thirteen (65%) and nine (45%) patients had elevated PIVKA-II (<40 mAU/mL) and serum ucOC levels (reference value < 4.50 ng/mL), respectively. Dietary vitamin K1 intake did not differ between patients with and without elevated PIVKA-II levels. Vitamin K2 supplementation for 3 months decreased serum PIVKA-II levels near those within the reference range. Approximately half of the patients with SMID on tube feeding had subclinical vitamin K deficiency. Further studies are needed to ascertain if long-term vitamin K2 supplementation effectively prevents vitamin K deficiency-induced hypercoagulation, osteoporosis, and vascular calcification in patients with SMID.

Evaluation of bone mineral density and bone turnover in children on anticoagulation.

Childhood and adolescence are critical periods of bone mineral acquisition. Children on anticoagulation (AC) might have an increased risk for reduced bone mineral density (BMD). Risk factors for impaired bone accumulation include chronic diseases, immobility, and medication. Vitamin K (VK) deficiency reflected by undercarboxylated osteocalcin levels (ucOC) has been identified as a predictor of osteoporosis and fractures. Data on bone health in children under AC are sparse. To evaluate BMD in children on AC and characterize the risk factors of low BMD, including VK and Vitamin D (VD) status. Single-center cross-sectional study of clinical, biochemical, and densitometric parameters. Assessment of VK surrogate parameters included ucOC and matrix gla protein (MGP). A total of 39 children (4-18 years; 12 females) receiving AC were included, 31 (79%) on VK antagonists and 8 (21%) on direct oral anticoagulants. Overall, BMD was decreased for both the lumbar spine (LS; -0.7SDS) and total body less head (TBLH; -1.32SDS) compared with pediatric reference data. Significant associations were found between early pubertal development and TBLH-BMD, and between BMI and LS-BMD. VK surrogate parameters were highly related to patients' age and pubertal development. Neither serum parameters nor AC-related factors predicted BMD. VD was detected in 10/39 patients with lower values during puberty. Our data indicate BMD reduction in pediatric patients on AC. Although AC-related factors did not predict reduced BMD, low BMI and pubertal stages represented important risk factors. Awareness of risk factors for low BMD and high prevalence of VD deficiency during puberty could contribute to the improvement of bone health in this vulnerable patient group.

Abstract B034: A scoping review of carcinogenic potential in prostate cancer from 40+ years of functional vitamin D and K deficiency

Abstract Introduction: Carcinogenesis is a form of accelerated genetic “Darwinian” evolution. Many cells start genetic change. Tobacco tar, an example of extensively researched carcinogen, demonstrates that it takes chronic exposure over 40+ years, accumulating mutations before death with multiple genetic events. Terminal acceleration often includes loss of major histocompatibility (MHC) antigens. Other co-carcinogens, genetic inheritance and chronic inflammation accelerates this process. Experiments, showing that malignant change induced in vitro is much faster than in vivo, suggest that other factors impact on the pace of malignant evolution. Two such factors (DNA repair and immune surveillance) are the best established. As considerable research is targeting DNA repair gene damage, this abstract focuses on latent immunity (less dependent on MHC system than T cell immunity) and its under-performance in carcinogenesis due to Vitamin D and K deficiency. Literature Review terms: Vitamin D(VD), Vitamin K(VK), Cancer, Carcinogenesis, Latent Immunity. Results: Three pieces of evidence that functional long-term VD and VK deficiency could have oncogenic potential were identified. The first was discovery that patients with chronic inflammation had hypermethylation of the VD receptor resulting in failure of the liver to convert stored VD into its active forms. Cancer patients with higher extent of methylation of VD receptor had worse clinical outcomes. Such deficiency is associated with reduced innate immunity due to macrophage dysfunction and this deficiency could increase microbiome dysbiosis. This suggestion is supported by studies linking PCa with 40+ years of persistent infection with the sun-sensitive microaerophilic bacterium Cutibacterium acnes and VD deficiency is linked with increased cancer but limited benefits in VD trials. The second observation is the demonstration that VK2 (Menaquinone) not VK1 (Phylloquinone) deficiency increased risk of PCa. These authors also showed that undercarboxylated osteocalcin, a biomarker of VK2 deficiency, was also linked with risk of PCa. The third observation was evidence from in-vitro breast cancer cell-line studies that Calcitriol plus K2 was synergistic in cytotoxicity assays. Measuring these effects, through the study of the biological age using methylation-based measures PhenoAge and GrimAge because of their relationship between biological aging and cancer, could be useful to monitor in future trials. Conclusions: Combined VD and VK studies have been found safe and beneficial in bone health. This limited review justifies further exploration of this combination in cancer patients. Using serial epigenetic clock scores is justified, given that these clocks are known to improve from diet and exercise interventions. Functional deficiency of VD and VK could be acting as co-carcinogens through enhanced inflammatory process, a precursor in many cancers including those without known carcinogen involvement such as PCa and also involved in accelerating tumour growth after primary treatment. Citation Format: Tim R.D. Oliver, Belinda Nedjai. A scoping review of carcinogenic potential in prostate cancer from 40+ years of functional vitamin D and K deficiency [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B034.

Associations of estrogen therapy and non-estrogen anti-resorptive therapy with diabetes mellitus risk: A classical and Bayesian meta-analysis.

Anti-resorptive therapy (AT) increases insulin resistance and decrease insulin secretion through reduced undercarboxylated osteocalcin in mice. However, there are inconsistent findings regarding the impact of AT use on the risk of diabetes mellitus in humans. We examined the association between AT and incident diabetes mellitus using classical and Bayesian meta-analysis. We searched Pubmed, Medline, Embase, Web of Science, Cochrane, and Google Scholar for studies listed from database inception to 25 February 2022. Randomized controlled trials (RCTs) and cohort studies reporting associations of estrogen therapy (ET) and non-estrogen anti-resorptive therapy (NEAT) with incident diabetes mellitus were included. Two reviewers independently extracted research data such as ET and NEAT, diabetes mellitus, risk ratios (RRs), and 95% confidence intervals (CIs) for incident diabetes mellitus associated with ET and NEAT from individual studies. This meta-analysis included data from nineteen original studies, consisting of fourteen ET and five NEAT studies. ET was associated with reduced risk of diabetes mellitus in the classical meta-analysis (RR: 0.90; 95% CI: 0.81-0.99). Slightly stronger results were found in the meta-analysis of RCTs (RR: 0.83; 95% CI: 0.77-0.89). The probability that RR<1.0 was 95% in the overall analysis and 99% in RCTs under weakly informative prior. Although NEAT was associated with reduced risk of diabetes mellitus overall (RR: 0.80; 95% CI: 0.67-0.97), this was not found in the RCT meta-analysis (RR: 0.90; 95% CI: 0.75-1.10). Under weakly informative prior, the probabilities that NEAT reduces diabetes mellitus by >0% were 99%, and 73% in the overall and RCT meta-analysis, respectively. In conclusion, meta-analysis provided consistent evidence against the hypothesis that AT increases diabetes risk. ET may reduce the risk of diabetes mellitus. Whether NEAT reduces the risk of diabetes mellitus is uncertain and requires additional evidence from RCTs.

Reference Range of Vitamin K Evaluating Indicators in Chinese Childbearing Women.

Vitamin K is an essential fat-soluble vitamin for the human body and its functions, such as promoting blood coagulation, bone health and preventing atherosclerosis, have attracted increasing attention. However, there is no recognized indicator and corresponding reference range for evaluating vitamin K status of different populations at present. The aim of this study is to establish a reference range for vitamin K evaluating indicators in healthy women of childbearing age in China. The population sample in this study was from the Chinese Adult Chronic Disease and Nutrition Surveillance (CACDNS) 2015-2017. A total of 631 healthy women of childbearing age (18-49 years) were included using a series of strict inclusion and exclusion criteria. The concentrations of VK1, MK-4 and MK-7 in serum were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The other commonly-reported indicators evaluating vitamin K nutritional status, including undercarboxylated osteocalcin (ucOC), osteocalcin (OC), matrix Gla protein (MGP), desphosphorylated undercaboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), were measured by enzyme-linked immunosorbent assay (ELISA). The reference range was obtained by calculating the 2.5% to 97.5% interval of the vitamin K evaluating indicators in the reference population. The reference ranges of VK1, MK-4 and MK-7 in serum were 0.21-3.07 ng/mL, 0.02-0.24 ng/mL and 0.12-3.54 ng/mL, respectively. The reference ranges of ucOC, %ucOC, dp-ucMGP and PIVKA-II were 1.09-2.51 ng/mL, 5.80-22.78%, 2.69-5.88 ng/mL and 3.98-8.40 ng/mL, respectively. The cut-off values that can be used to evaluate subclinical vitamin K deficiency were as follows: VK1 < 0.21 ng/mL, MK-7 < 0.12 ng/mL, ucOC > 2.51 ng/mL, %ucOC > 22.78%, dp-ucMGP > 5.88 ng/mL and PIVKA-II > 8.40 ng/mL. The reference range of VK1, MK-4, MK-7 and vitamin K-related indicators for healthy women of childbearing age established in this study could be used to assess the nutritional and health status of this population.

Undercarboxylated osteocalcin and ibandronate combination ameliorates hindlimb immobilization-induced muscle wasting.

Immobilization leads to muscle wasting and insulin resistance, particularly during ageing. It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect muscle wasting independent of ucOC. We hypothesize that the combination of ucOC and ibandronate (IBN) treatments has superior protective effects against immobilization-induced muscle wasting and insulin resistance than either treatment alone. C57BL/6J mice were hindlimb-immobilized for two weeks, with injections of vehicle, ucOC (90ng/g daily) and/or IBN (2μg/g weekly). Insulin/oral glucose tolerance tests (ITT/OGTT) were performed. Immediately after immobilization, muscles (extensor digitorum longus (EDL), soleus, tibialis anterior, gastrocnemius and quadriceps) were isolated and measured for muscle mass. Insulin-stimulated glucose uptake (EDL and soleus) was examined. Phosphorylation/expression of proteins in anabolic/catabolic pathways were examined in quadriceps. Primary human myotubes derived from older adult muscle biopsies were treated with ucOC and/or IBN, then signalling proteins were analysed. Combined treatment, but not individual treatments, significantly increased the muscle weight/body weight ratio in immobilized soleus (31.7%; P=0.013) and quadriceps (20.0%; P=0.0008) muscles, concomitant with elevated p-Akt (S473)/Akt ratio (P=0.0047). Combined treatment also enhanced whole-body glucose tolerance (16.6%; P=0.0011). In human myotubes, combined treatment stimulated greater activation of ERK1/2 (P=0.0067 and 0.0072) and mTOR (P=0.036), and led to a lesser expression of Fbx32 (P=0.049) and MuRF1 (P=0.048) than individual treatments. These findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing. KEY POINTS: It has been suggested that undercarboxylated osteocalcin (ucOC) improves muscle mass and glucose metabolism. Bisphosphonates, an anti-osteoporosis treatment, might protect against muscle wasting independent of ucOC. The combination treatment of ucOC and ibandronate was shown to exert a greater therapeutic effect against immobilization-induced muscle wasting, and led to greater activation of anabolic pathway and less expression of catabolic signalling proteins in myotubes derived from older adults, compared with individual treatments. The combination treatment was found to improve whole-body glucose tolerance. Our findings suggest a potential therapeutic role for the ucOC and bisphosphonates combination in protecting against muscle wasting induced by immobilization and ageing.

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.

First Comparative Evaluation of Short-Chain Fatty Acids and Vitamin-K-Dependent Proteins Levels in Mother-Newborn Pairs at Birth.

The interplay between vitamin K (vitK) (as carboxylation cofactor, partially produced by the gut microbiota) and short-chain fatty acids (SCFAs), the end-product of fiber fermentation in the gut, has never been assessed in mother-newborn pairs, although newborns are considered vitK deficient and with sterile gut. We collected venous blood from 45 healthy mothers with uncomplicated term pregnancies and umbilical cord blood from their newborns at birth. The concentrations of total SCFAs and hepatic/extra-hepatic vitK-dependent proteins (VKDPs), as proxies of vitK status were assayed: undercarboxylated and total matrix Gla protein (ucMGP and tMGP), undercarboxylated osteocalcin (ucOC), undercarboxylated Gla-rich protein (ucGRP), and protein induced by vitK absence II (PIVKA-II). We found significantly higher ucOC (18.6-fold), ucMGP (9.2-fold), and PIVKA-II (5.6-fold) levels in newborns, while tMGP (5.1-fold) and SCFAs (2.4-fold) were higher in mothers, and ucGRP was insignificantly modified. In mother-newborn pairs, only ucGRP (r = 0.746, p < 0.01) and SCFAs (r = 0.428, p = 0.01) levels were correlated. Conclusions: We report for the first time the presence of SCFAs in humans at birth, probably transferred through the placenta to the fetus. The increased circulating undercarboxylated VKDPSs in newborns revealed a higher vitamin K deficiency at the extrahepatic level compared to liver VKDPs.

Mini Nutritional Assessment Short-Form as screening tool for osteoporosis in patients with chronic obstructive pulmonary disease.

Osteoporosis is a common complication of chronic obstructive pulmonary dis-ease (COPD). It is impractical to measure bone mineral density (BMD) in all patients with COPD. This study aimed to investigate the relationship between Mini Nutritional Assessment Short-Form (MNA-SF), a simple nutritional status questionnaire, and osteoporosis, and to determine whether it can be used as a reliable screening tool for osteoporosis in patients with COPD. Thirty-seven patients with stable COPD were enrolled in this prospective cohort study. Patients with MNA-SF scores >11 were defined as well-nourished, and those with scores of ≤11 being at risk for malnutrition. Body composition, BMD, and undercarboxylated osteocalcin (ucOC), a bone metabolism marker, were measured using bioelectrical impedance, dual energy X-ray, and electrochemiluminescence immunoassay, respectively. Seventeen (45.9%) were classified as at risk for malnutrition, and 13 (35.1%) had osteoporosis. Patients at risk for malnutrition had significantly more osteoporosis and higher ucOC values than well-nourished patients (p=0.007, p=0.030, respectively). Patients with osteoporosis also had significantly lower body mass index (BMI) and fat-free mass index than those without osteoporosis (p= 0.007 and p=0.005, respectively), although FEV1 % pred was not significantly different. MNA-SF (cutoff value; 11) had better sensitivity to identify the presence of osteoporosis than BMI (cutoff value; 18.5 kg/m2) (sensitivity, 0.769; specificity, 0.708; sensitivity, 0.462; specificity, 0.875, respectively). MNA-SF was associated with osteoporosis and bone metabolism markers in patients with COPD. MNA-SF may be a useful screening tool for osteoporo-sis in patients with COPD.

Functional tooth number in the posterior region associated serum ucOC levels

PurposeThe purpose of this study was to investigate serum undercarboxylated osteocalcin (ucOC) levels in partially edentulous patients scheduled to receive implant treatment and determine the association between ucOC levels, vegetable intake, vitamin K, dietary fiber intake, and functional tooth number in the posterior region (p-FTN).MethodsA total of 46 patients (20 male and 26 female, 61.9 ± 12.7 years old) were included. The association among serum ucOC levels, vegetable intake, vitamin K and dietary fiber intake was assessed using Spearman’s rank correlation coefficient and binary logistic regression analysis.ResultsIn total, 35% of patients (16/46 subjects) showed an abnormally high ucOC level (≧ 4.5 ng/mL). p-FTN showed a weak positive correlation with vegetable intake, vitamin K and dietary fiber intake (r = 0.28, 0.21, and 0.14, respectively) and a significant negative correlation with ucOC levels (r = − 0.51). Multivariate analysis demonstrated that p-FTN as well as vitamin K intake showed a significant negative association with serum ucOC levels.ConclusionsMore than one-third of patients showed abnormally high ucOC levels. p-FTN showed a negative association with serum ucOC levels, which indicated the possibility that oral status affected bone quality.