Plasma Osteocalcin Research Articles

Impaired bone matrix glycoprotein pattern is associated with increased cardio-metabolic risk profile in patients with type 2 diabetes mellitus

Osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC) are matrix glycoproteins which mediate bone mineralization; moreover, their effects on glucose/insulin homeostasis have recently been demonstrated. Higher circulating OPN and OPG levels have been associated with the presence of insulin resistance, atherosclerosis and coronary heart disease. No data are available on contextual changes of these markers in type 2 diabetes mellitus (T2DM). Therefore, aims of this study were to evaluate serum OPN, OPG and OC levels in T2DM patients and their clinical correlates. We recruited 83 consecutive T2DM patients referring to our diabetes outpatient clinics at Sapienza, University of Rome, and 71 non-diabetic sex and age-comparable subjects as a control group. Study population underwent metabolic characterization and carotid ultrasound for intima-media thickness measurement. Plasma OPN, OPG and OC were measured by MILLIPLEX Multiplex Assays Luminex. T2DM patients had significantly higher circulating OPN and OPG levels than controls (14.3 ± 13.6 vs 10.6 ± 13.7ng/ml p < 0.001, 0.70 ± 0.60 vs 0.54 ± 4.1ng/ml, p = 0.02) while OC levels were similar in the two cohorts (6.35 ± 5.8 vs 7.80 ± 7.0ng/ml, p = n.s). OPN and OPG positively correlated with greater systolic blood pressure (SBP) values, HOMA-IR and HOMA-β, and with the presence of dyslipidemia and carotid atherosclerosis. The association between greater OPN and OPG levels and SBP was independent from possible confounders (both p = 0.01). Circulating OPN and OPG levels are increased in T2DM patients and identify a particularly unfavourable metabolic profile, mostly expressed by higher SBP. Bone peptides may represent novel markers of vascular stress and accelerated atherosclerosis in diabetes, constituting a possible tool for cardiovascular risk stratification in diabetes.

Association of Bone Turnover Levels with MTHFR Gene Polymorphisms among Pregnant Women in Wuhan, China.

Pregnancy is a critical stimulator of bone mineral resorption. We used to find the MTHFR gene polymorphisms are related with blood lead levels among pregnant women. Pregnancy-stimulated bone turnover may be associated with MTHFR gene polymorphisms too. In this article, we aimed to determine the relationship between MTHFR gene polymorphisms and bone turnover rates among the pregnant women. The participants including pregnant and non-pregnant women were selected and recruited during their routine prenatal or physical examination from July to October in 2012. A total of 1000 participants, including 250 pregnant women in the first, second, and third trimesters and 250 non-pregnant women, were enrolled in the study. Finally, after excluding 27 participants unable to provide blood samples, 973 eligible participants (i.e., 234,249, and 248 pregnant women in the first, second, and third trimesters, respectively, and 242 non-pregnant women) were included in the research. The MTHFR gene 1298CC homozygote carriers were more susceptible to yield higher plasma homocysteine levels than the 1298AA/AC carriers, with standardized coefficients of 0.086 (P<0.05) and 0.104 (P<0.01) of all the participants and the pregnant women, respectively. The MTHFR gene 1793AA homozygote carriers more likely showed higher plasma osteocalcin levels (standardized β=0.091,P<0.01) than the 1793GG/GA carriers among all the subjects. Plasma homocysteine levels were positively correlated with blood lead levels among the participants and the pregnant women with standardized coefficients of 0.320 (P<0.01) and 0.179 (P<0.01), respectively. Plasma osteocalcin levels were positively associated with blood lead levels among pregnant and non-pregnant women with standardized coefficients of 0.084 (P<0.05) and 0.125 (P<0.01), respectively. In conclusion, homocysteine and osteocalcin contents in plasma are associated with the MTHFR gene A1298C polymorphism and blood lead levels among pregnant women. The MTHFR gene A1298C polymorphism-related homocysteine is a possible risk factor for increased blood lead levels among Chinese women.

Osteogenic impact of football training in 55- to 70-year-old women and men with prediabetes.

The effects of football training on bone health were examined in 55- to 70-year-old sedentary women and men with prediabetes. Patients (n=50) with prediabetes (age; 61±9years, BMI 29.7±0.6kg/m2 , body fat content; 37±1%, VO2max ; 22.7±0.8mL/min/kg and mean arterial pressure; 104±3mmHg) were randomized into a football training group (FTG; n=27, 14 women) and a control group (CON; n=23, 11 women). At baseline, 73% and 24% were diagnosed with femur osteopenia and osteoporosis, respectively. FTG performed football training twice weekly 30-60-minute sessions in 16weeks, and both FTG and CON received professional dietary advice. Pre- and post-intervention whole-body and regional bone mineral content (BMC) and density (BMD) were determined with DXA-scans, and venous blood samples were drawn and analyzed for plasma bone turnover markers. Change scores were greater (P<0.05) in FTG compared to CON in leg BMD (0.023±0.005 vs -0.004±0.001g/cm2 ) and in leg BMC (32±8 vs -4±6g). Between-group changes in favor of FTG (P<0.05) also occurred in the femur neck BMD (3.2%) and femur shaft BMD (2.5%). Whole-body BMC and BMD were unchanged in both groups during the intervention. In FTG, resting plasma osteocalcin, P1NP, and CTX-1 rose (P<0.05) by 23±8, 52±9 and 38±7%, with greater change scores (P<0.05) than in CON. Finally, P1NP (formation)/CTX-1 (resorption) ratio increased (P<0.05) in FTG (127±15 vs 150±11) from pre- to post-intervention, with no change in CON (124±12 and 123±12). In conclusion, football training provides a powerful osteogenic stimulus and improves bone health in 55- to 70-year-old women and men diagnosed with prediabetes.

Association between bone metabolism regulators and arterial stiffness in type 2 diabetes patients

Background and AimOsteopontin (OPN), osteonectin (ON) and osteocalcin (OC) play an important role in the development of vascular calcifications, but it is unclear whether these bone metabolism regulators contribute to the development of arterial stiffness in type 2 diabetes patients. We therefore aim to determine the relationship between plasma concentrations of OPN, ON, OC and arterial stiffness in type 2 diabetes patients. MethodsCross-sectional study of 1003 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART)-cohort. Generalized linear models were used to evaluate the relation between plasma levels of OPN, ON and OC and arterial stiffness as measured by pulse pressure (PP), ankle-brachial index (ABI) (≥0.9), carotid artery distension and an arterial stiffness summary score. Analyses were adjusted for age, sex, kidney function, diabetes duration and diastolic blood pressure.Higher OPN plasma levels were significantly related to a lower ABI (β-0.013; 95%CI −0.024 to −0.002) and a higher arterial stiffness summary score (OR1.24; 95%CI 1.03–1.49). OPN levels were not related to PP (β 0.59; 95%CI −0.63–1.81) or absolute carotid artery distention (β −7.03; 95%CI −20.00–5.93). ON and OC plasma levels were not related to any of the arterial stiffness measures. ConclusionOnly elevated plasma levels of OPN are associated with increased arterial stiffness in patients with type 2 diabetes as measured by the ankle-brachial index and arterial stiffness summary score. These findings indicate that OPN may be involved in the pathophysiology of arterial stiffness and call for further clinical investigation.

Altered Ethanol Consumption in Osteocalcin Null Mutant Mice.

Osteocalcin (OC) is an abundant extracellular calcium-binding protein synthesized by osteoblasts. Although most OC is bound to hydroxyapatite mineral during bone formation, a consistent amount is released directly to circulation. Plasma OC (pOC) levels are highly sensitive to stressful stimuli that alter stress-responsive hormones, such as glucocorticoids (cortisol or corticosterone) and the catecholamines norepinephrine and epinephrine. To gain a better understanding of the apparent relationship of OC to the effects of ethanol (EtOH) and the stress responses, we compared mice that have OC (WT [OC+/+] and HET [OC+/-]) with OC null mutants (KO [OC-/-]), which have no OC in either plasma or in bone. One experiment included chronic unpredictable stress, a second was conducted in the absence of any known stressors other than EtOH, while a third imposed a more severe acute immobilization stress in addition to EtOH consumption. The data obtained confirmed significant differences in EtOH consumption in mice that previously experienced various stressful stimuli. We also determined that adrenal tyrosine-hydroxylase expression was inversely proportional to EtOH consumption and tended to be lower in KO than in WT. Data suggest that OC possesses the ability to modulate the adrenal gene expression of the catecholamine synthetic pathway. This modulation may be responsible for differences in EtOH consumption under stress.

Relationship between plasma osteocalcin, glycaemic control and components of metabolic syndrome in adult Nigerians with type 2 diabetes mellitus

AimsTo determine the levels of plasma osteocalcin (OC) in Nigerians with type 2 diabetes mellitus (DM) and compare these to levels in non-diabetic controls (NDM). To assess the relationship of OC to glycaemic control and parameters of metabolic syndrome (MetS) and compare its levels in Nigerians with and without MetS. MethodsThe waist circumference (WC), body mass index (BMI) and blood pressure of 200 study participants were taken. Plasma osteocalcin, fasting glucose (FPG), glycated haemoglobin (HbA1c), high density lipoprotein cholesterol (HDL-c) and triglyceride (TG) levels were determined. Metabolic syndrome was defined by the International Diabetes Federation criteria. Statistical significance was set at 0.05. ResultsOsteocalcin levels were lower in the DM group (p=0.002) and inversely related to FPG (r=−0.198, p=0.003), HbA1c (r=−0.313, p<0.001), BMI (r=−0.331, p<0.001), WC (r=−0.339, p<0.001) and TG (r=−0.145, p=0.040), but directly related to HDL-c levels (r=0.166, p=0.019). Osteocalcin was higher in participants without MetS (Median 8.75ng/mL IQR[5.48-12.68]ng/mL) than in those with MetS (Median 4.74ng/Ml, IQR[2.80–9.12]ng/mL), p<0.001. ConclusionsPlasma osteocalcin levels are inversely associated with good glycaemic control and components of MetS and are lower in individuals with DM and in those with MetS. These findings support a vital role of the bone, in the regulation of glucose and energy metabolism, in Nigerians. Further extensive studies are required to explore the potentials of OC in the management of DM and MetS.

Uniparental disomy causes deficiencies of vitamin K‐dependent proteins

Background Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in the γ-glutamyl carboxylase gene (GGCX) or the vitamin K epoxide reductase gene (VKORC1), with great heterogeneity in terms of both clinical presentation and response to treatment. Objective To characterize the molecular basis of VKCFD in a Spanish family. Methods and Results Sequencing of candidate genes, comparative genomic hybridization and massive sequencing identified a new mechanism causing VKCFD in the proband. Uniparental disomy (UPD) of chromosome 2 caused homozygosity of a mutation (c.44-1G>A) resulting in aberrant GGCX splicing. This change contributed to absent expression of the mRNA coding for the full-length protein, and to four-fold overexpression of the smaller mRNA isoform lacking exon 2 (Δ2GGCX). Δ2GGCX might be responsible for two unexpected clinical observations in the patient: (i) increased plasma osteocalcin levels following vitamin K1 supplementation; and (ii) a mild non-bleeding phenotype. Conclusions Our study identifies a new autosomal disease, VKCFD1, caused by UPD. These data suggest that the Δ2GGCX isoform may retain enzymatic activity, and strongly encourage the evaluation of both hepatic and non-hepatic vitamin K-dependent proteins to assess differing responses to vitamin K supplementation in VKCFD patients.

Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.

Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases.

Effects of a moderately high-protein diet and interval aerobic training combined with strength-endurance exercise on markers of bone metabolism, microarchitecture and turnover in obese Zucker rats

BackgroundWeight loss is a public health concern in obesity-related diseases such as metabolic syndrome, and the protein level of the diets seem to be crucial for the development and maintenance of bone. The nature of exercise and whether exercise in combination with moderately high-protein dietary interventions could protect against potential bone mass deficits remains unclear. ObjectivesTo investigate the effects of a moderately high-protein diet and interval aerobic training combined with strength-endurance exercise (IASE) protocol on bone status, and to assess potential interaction effects (i.e. diet*IASE). MethodsMale Zucker fatty rats were randomized distributed into 4 groups (n=8): normoprotein+sedentary; normoprotein+exercise; moderately high-protein+sedentary, and moderately high-protein+exercise. Training groups conducted an IASE program, 5days/week for 2months. Markers of bone metabolism were measured in plasma. Parameters of bone mass and 3D outcomes for trabecular and cortical bone microarchitecture were assessed by micro-computed tomography. ResultsFemur length, plasma osteocalcin, sclerostin, osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, insulin, leptin, PTH, uric acid and urinary phosphorus levels were lower in the moderately high-protein compared to the normoprotein groups (all, p<0.05), whereas plasma alkaline phosphatase, aspartate aminotransferase, alanine transaminase, and urinary uric acid concentrations, and cortical total volume (TV) and bone volume (BV) were higher in the moderately high-protein (all, p<0.01). Final body weight and alkaline phosphatase levels were lower in the exercise compared to the sedentary (both, p<0.05), whereas femur length and weight, aminoterminal propeptides of type I procollagen and C-terminal telopeptides of type I collagen concentrations, and cortical TV and BV were higher in the exercise compared to the sedentary groups (all, p<0.05). ConclusionThe combination of interventions may be effective to enhance trabecular bone microarchitecture and BMD, and has a partial impact on cortical bone in obese rats. Nevertheless, they do not induce any alteration on the bone turnover markers.

Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.

BackgroundGlucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7–14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose–response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.MethodsIn this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5–60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8.ResultsDaily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects.ConclusionsThis characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.Trial registration numberNCT02767089 (retrospectively registered: 21 April 2016).

The Osteogenic Response was higher in Postmenopausal than in Premenopausal Women Following The Same Exercise Intervention

Bone loading exercise is an important osteogenic stimulus, and multimodal exercise regimens associated with high bone strains are suggested to improve bone mass. However, it is discussed whether it is possible to induce improvements in bone mass after peak bone mass, especially after menopause. PURPOSE: To investigate the osteogenic impact of high-intensity, multimodal training in postmenopausal women (I-POM) compared to premenopausal women (I-PREM) and two matched control groups (C-POM and C-PREM). METHODS: The supervised intervention lasted 19 weeks, 3 x 30 min weekly. The varied training was of high musculoskeletal intensity aimed to elicit large and powerful forces on the skeleton. 49 healthy, sedentary women participated: I-POM (N=21; 57.1±4.8 yrs; 64.5±8.1 kg), C-POM (N=12; 57.9±3.9 yrs; 63.9±10.6 kg), I-PREM (N=9; 43.6±4.7 yrs; 76.5±15.5 kg), and C-PREM (N=7; 42.9±5.9 yrs; 66.0±12.3 kg). DXA-derived bone mineral density (BMD, g/cm2) in right (R) and left (L) proximal femur (PF) and lumbar spine (LS), plasma Osteocalcin (OC, μg/l), procollagen type 1 amino-terminal propeptide (P1NP, μg/l) and C-terminal telopeptide of type 1 collagen (CTX-1, μg/l) were measured at baseline and post-intervention. OC, P1NP and CTX-1 were also measured after 3 and 12 weeks. RESULTS: Post-intervention BMD was increased more (0.001<P<0.05) in I-POM than in C-POM in PF (total R 0.8±1.6% vs. -1.0±1.1%; total L 0.7±1.6% vs. -0.5±1.1%; shaft R 0.8±2.1% vs. -0.8±1.6%; shaft L 1.1±1.9% vs. -0.3±1.0%; trochanter R 1.2±2.4% vs -1.1±2.0%; trochanter L 0.8±3.4% vs. -0.3±1.9%) and in LS (L1-L4 0.9±2.3% vs. -1.1±2.8%; L2 1.3±3.1% vs. -1.3±3.2%). Plasma OC was increased more (0.0005<P<0.005) in I-POM than in C-POM after 3 weeks (11.7±20.5% vs. -9.3±19.4%), 12 weeks (23.7±17.6% vs. -11.5±29.0%) and post-intervention (18.0±25.9% vs. -14.8±28.6%), but plasma P1NP and CTX-1 did not differ between the groups. The change scores in BMD, plasma OC, P1NP and CTX-1 did not differ between I-PREM and C-PREM. CONCLUSION: The osteogenic effect of 19 weeks training was higher in postmenopausal than in premenopausal women following the same multimodal high-intensity exercise intervention. It was possible to improve bone mass after menopause and counteract the age-related reduction in BMD.

High plasma osteocalcin is associated with low blood haemoglobin in elderly men: the MrOS Sweden Study.

It has been suggested that osteoblasts are involved in the regulation of haematopoietic stem cells. Whether osteocalcin, which is derived from osteoblasts and is metabolically active, influences blood haemoglobin (Hb) levels is not known. To determine whether plasma osteocalcin is a determinant of Hb in elderly men. A total of 993 men (mean age 75.3±3.2years) participated in the population-based MrOS (osteoporotic fractures in men) study. Plasma osteocalcin concentration was evaluated in relation to Hb and adjustments were made for potential confounders (i.e. age, body mass index, erythropoietin, total oestradiol, fasting insulin, adiponectin, ferritin and cystatin C). Hb correlated (age adjusted) negatively with osteocalcin in the total study group (r=-0.12, P<0.001) as well as in the subgroup of nondiabetic men (r=-0.16, P<0.001). In nondiabetic men with higher osteocalcin levels, it was more likely that Hb would be in the lowest quartile (odds ratio per SD decrease in osteocalcin 1.32, 95% confidence interval 1.13-1.53). Quartiles of Hb were negatively associated (age adjusted) with osteocalcin (P<0.001). Anaemic men (47/812) (Hb<130gL(-1) ) had significantly higher mean osteocalcin levels than nonanaemic men (33.9 vs. 27.1μgL(-1) , P<0.001). In multiple stepwise linear regression analyses (adjusted for age, body mass index, total oestradiol, adiponectin, erythropoietin, fasting insulin, cystatin C, leptin, ferritin and holotranscobalamin), osteocalcin was an independent predictor of Hb concentration in nondiabetic men (P<0.05). These data add further support to the evidence indicating that the bone-specific protein osteocalcin has several endocrine functions targeting the pancreas, testes, adipocytes, brain. An additional novel finding is that osteocalcin may also have a paracrine function as a regulator of haematopoiesis.

Decreased Cathepsin K Plasma Level may Reflect an Association of Osteopoenia/Osteoporosis with Coronary Atherosclerosis and Coronary Artery Calcification in Male Patients with Stable Angina

The aim of this study was to evaluate the plasma levels of bone turnover markers (BTMs) in male patients with stable angina depending on the bone mineral density (BMD), coronary atherosclerosis (CA) and coronary artery calcification (CAC). We recruited 112 males with verified stable angina. All the patients underwent coronary angiography, multislice spiral computed tomography, and dual-energy X-ray absorptiometry. Plasma levels of BTMs were measured by enzyme-linked immunosorbent assay. Osteopoenia and osteoporosis were reported in 90 (80.4%) and 34 (30.4%) patients, respectively. Multivessel coronary artery disease, severe CA and CAC, decreased cathepsin K plasma level, and increased osteocalcin plasma level were significantly more prevalent in patients with osteopoenia/osteoporosis compared to the subjects with normal BMD. Patients with severe CA and CAC had significantly reduced cathepsin K plasma levels. We revealed a significant association of osteopoenia/osteoporosis with severe CA and CAC in males with stable angina. Cathepsin K and osteocalcin plasma levels may be suggested as the significant markers of osteopoenia/osteoporosis. In addition, cathepsin K plasma level can be also a valuable marker of severe CA and CAC.

Bone histomorphometry and indicators of bone and mineral metabolism in wait-listed dialysis patients

The aim of this study was to evaluate the associations between bone histomorphometry and bone volume measured by dual-energy X-ray absorptiometry (DXA) in wait-listed dialysis patients. Further, the circulating markers of mineral metabolism and bone turnover were compared. Bone biopsies were performed on 61 wait-listed dialysis patients. Plasma samples were obtained for indicators of mineral metabolism and bone turnover. Bone mineral density (BMD) was determined by DXA and bone histomorphometry was performed. Bone histomorphometry could be determined in 52 patients (72% men, 54% on hemodialysis and median dialysis vintage 18 months). Adynamic bone disease was present in 21% of patients and 4% had osteomalacia. High turnover bone disease (mixed uremic osteodystrophy and osteitis fibrosa) was observed in 48% of patients (17% and 31%, respectively). 10% of patients had normal bone histomorphometry while 17% had mild osteitis fibrosa. Mineralization defect was found in 33% of patients. There was a strong correlation between femoral neck (FN) T-score and histologically measured cancellous bone volume (p = 0.004), FN T-score having a good negative predictive value for low cancellous bone volume. Plasma osteocalcin levels were significantly higher in the high-turnover group and lower in the mineralization defect group (p = 0.014 and p = 0.02, respectively). Our study confirms the high frequency of abnormal bone histology in wait-listed dialysis patients. Low bone turnover was less common than previously reported. Noninvasive markers had a limited value for assessing bone histology, whereas femoral BMD reflected bone volume well.

Osteocalcin as a potential risk biomarker for cardiovascular and metabolic diseases.

Clear evidence supports a role for circulating and locally-produced osteocalcin (OC) in the pathophysiology of cardiovascular (CV) lesions and CV risk, also in combination with metabolic changes, including type 2 diabetes mellitus (T2DM). Reduced plasma OC levels are associated with greater incidence of pathological CV changes, like arterial and valvular calcification, coronary and carotid atherosclerosis and increased carotid intima-media thickness. The actual relationship between OC levels and incidence of major CV events is, however, still unclear. Moreover, reduced circulating OC levels have been mostly associated with insulin resistance, metabolic syndrome or T2DM, indicating relevant OC actions on pancreatic β-cells and insulin secretion and activity. Based on these observations, this review article will attempt to summarize the current evidence on the potential usefulness of circulating OC as a biomarker for CV and metabolic risk, also evaluating the currently open issues in this area of research.

The influence of bexarotene, a selective agonist of the retinoid receptor X (RXR), and tazarotene, a selective agonist of the retinoid acid receptor (RAR), on bone metabolism in rats

PurposeThe purpose of this study was to investigate the influence of selective agonists of the retinoid receptor X (RXR) and the retinoid acid receptor (RAR) on bone metabolism in rats. MethodsThirty six male Wistar rats were divided into three groups: receiving bexarotene, or tazarotene, or to control group. Serum biochemical markers of bone turnover (osteocalcin – OC, tartrate resistant acid phosphatase 5 – TRACP5b and osteoprotegerin – OPG) and mechanical properties of bones were analyzed. ResultsThere was a significant decrease in the femur index value in groups receiving tazarotene and bexarotene on Day 14 (8% and 20% respectively, p=0.0039). On Day 28, 14 days after discontinuation of tazarotene and bexarotene, the difference in femur indexes was still significant (4% for T1–6 and B1–6, p=0.0270). In the bexarotene group an increase in mean plasma osteocalcin level and mean plasma TRACP5b level was detected. In the tazarotene group the mean osteocalcin level remained unchanged and the mean plasma TRACP5b level decreased. An increased yield stress was detected in groups receiving retinoids comparing to controls after 14 days of tazarotene and bexarotene administration. ConclusionAlthough bexarotene and tazarotene administration caused decrease in the femur index, mechanisms responsible for that effect seem to be different. Our results suggest that bexaroten increases bone turnover. On the contrary, tazaroten seems to have inhibitory effect on bone turnover. A counter influence of selective RAR and RXR agonists on the bone turnover might be the reason for inconsistency in results from published research concerning the influence of retinoids on bone metabolism.

Effects of soccer vs swim training on bone formation in sedentary middle-aged women.

The present study examined the effects of 15 weeks of soccer training and two different swimming training protocols on bone turnover in sedentary middle-aged women. Eighty-three premenopausal mildly hypertensive women [age: 45 ± 6 (± SD) years, height: 165 ± 6 cm, weight: 80.0 ± 14.1 kg, body fat: 42.6 ± 5.7 %, systolic blood pressure/diastolic blood pressure: 138 ± 6/85 ± 3 mmHg] were randomized into soccer training (SOC, n = 21), high-intensity intermittent swimming (HS, n = 21), moderate-intensity swimming (MS, n = 21) intervention groups, and a control group (C, n = 20). The training groups completed three sessions per week for 15 weeks. DXA scans were performed and resting blood samples were drawn pre- and post-intervention. In SOC, plasma osteocalcin, procollagen type I N propeptide and C-terminal telopeptide increased (P < 0.05) by 37 ± 15, 52 ± 23 and 42 ± 18 %, respectively, with no changes in MS, HS and C. The intervention-induced increase in SOC was larger (P < 0.05) than in MS, HS and C. In SOC, leg BMC increased (P < 0.05) by 3.1 ± 4.5 %, with a larger increase in SOC than in C. Femoral shaft and trochanter bone mineral density (BMD) increased (P < 0.05) by 1.7 ± 1.9 and 2.4 ± 2.9 %, respectively, in SOC, with a greater (P < 0.05) change in SOC than in MS and C, whereas total body and total leg BMD did not change in any of the groups. In conclusion, 15 weeks of soccer training with sedentary middle-aged women caused marked increases in bone turnover markers, with concomitant increases in leg bone mass. No changes in bone formation and resorption markers were seen after prolonged submaximal or high-intensity intermittent swimming training. Thus, soccer training appears to provide a powerful osteogenic stimulus in middle-aged women.

Soy protein is beneficial but high-fat diet and voluntary running are detrimental to bone structure in mice

Physical activity and soy protein isolate (SPI) augmentation have been reported to be beneficial for bone health. We hypothesized that combining voluntary running and SPI intake would alleviate detrimental changes in bone induced by a high-fat diet. A 2 × 2 × 2 experiment was designed with diets containing 16% or 45% of energy as corn oil and 20% SPI or casein fed to sedentary or running male C57BL/6 mice for 14 weeks. Distal femurs were assessed for microstructural changes. The high-fat diet significantly decreased trabecular number (Tb.N) and bone mineral density (BMD) and increased trabecular separation (Tb.Sp). Soy protein instead of casein, regardless of fat content, in the diet significantly increased bone volume fraction, Tb.N, connectivity density, and BMD and decreased Tb.Sp. Voluntary running, regardless of fat content, significantly decreased bone volume fraction, Tb.N, connectivity density, and BMD and increased Tb.Sp. The high-fat diet significantly decreased osteocalcin and increased tartrate-resistant acid phosphatase 5b (TRAP 5b) concentrations in plasma. Plasma concentrations of osteocalcin were increased by both SPI and running. Running alleviated the increase in TRAP 5b induced by the high-fat diet. These findings demonstrate that a high-fat diet is deleterious, and SPI is beneficial to trabecular bone properties. The deleterious effect of voluntary running on trabecular structural characteristics indicates that there may be a maximal threshold of running beyond which beneficial effects cease and detrimental effects occur. Increases in plasma osteocalcin and decreases in plasma TRAP 5b in running mice suggest that a compensatory response occurs to counteract the detrimental effects of excessive running.

The role of enteric hormone GLP-2 in the response of bone markers to a mixed meal in postmenopausal women with type 2 diabetes mellitus.

BackgroundType 2 diabetes mellitus (T2D) is a complex disease associated with several chronic complications, including bone fragility and high fracture risk due to mechanisms not yet fully understood. The influence of the gastrointestinal tract and its hormones on bone remodeling has been demonstrated in healthy individuals. Glucagon-like peptide 2 (GLP-2), an enteric hormone secreted in response to nutrient intake, has been implicated as a mediator of nutrient effects on bone remodeling. This study aimed to analyze the dynamics of bone resorption marker C-terminal telopeptide of type I collagen (CTX), bone formation marker osteocalcin, and GLP-2 in response to a mixed meal in diabetic postmenopausal women.MethodsForty-three postmenopausal women with osteopenia or osteoporosis (20 controls – group CO – and 23 diabetic – group T2D) were subjected to a standard mixed meal tolerance test, with determination of serum CTX, plasma osteocalcin and serum GLP-2 concentrations at baseline and 30, 60, 120 and 180 minutes after the meal.ResultsT2D women had higher body mass index as well as higher femoral neck and total hip bone mineral density. At baseline, luteinizing hormone, follicle-stimulating hormone, osteocalcin and CTX levels were lower in group T2D. In response to the mixed meal, CTX and osteocalcin levels decreased and GLP-2 levels increased in both groups. The expected CTX suppression in response to the mixed meal was lower in group T2D.ConclusionsBone turnover markers were significantly reduced in T2D women at baseline. Confirming the role of nutrient intake as a stimulating factor, GLP-2 increased in response to the mixed meal in both groups. Importantly, CTX variation in response to the mixed meal was reduced in T2D women, suggesting abnormal response of bone remodeling to nutrient intake in T2D.

Do premenopausal hypothyroid women on levothyroxine therapy need bone status monitoring?

BACKGROUNDSuppressive doses of levothyroxine therapy are reported to reduce bone mineral density (BMD) in women. Data on bone changes in premenopausal hypothyroid women with replacement therapy are limited. Hence, this study was undertaken to evaluate bone changes in this group using bone markers and BMD.MATERIALS AND METHODSA hospital-based case–control study including 75 premenopausal women aged 30–45 years was conducted. The subjects were categorized based on their thyroid function and history into three groups of 25 euthyroid, 25 newly diagnosed hypothyroid, and 25 hypothyroid women on 100–200 μg of levothyroxine for a minimum of 5 years. The bone changes were evaluated and compared among the groups biochemically by estimating their plasma osteocalcin and serum calcium and phosphorus and radiologically by measuring their BMD by quantitative ultrasonography. Statistical analysis was conducted by using analysis of variance, Tukey’s test, and Pearson’s correlation using IBM SPSS Statistics 20.RESULTSLevels of plasma osteocalcin, serum calcium, and serum phosphorus in patients on long-term levothyroxine therapy were significantly higher than those in newly diagnosed hypothyroid women and in the euthyroid group. BMD showed definite features of osteopenia (T-score: −2.26 ± 0.5) among the women in the treatment group, while it was well within the normal range in the newly diagnosed and euthyroid women. A significant correlation was found between the osteocalcin levels and T-score.CONCLUSIONHypothyroid women on long-term levothyroxine therapy showed signs of increased bone turnover and increased resorptive changes, though not frank osteoporosis. Hence, it may be important to evaluate the bone status of patients on levothyroxine for >5 years.