Serum Osteocalcin Levels Research Articles

Plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects that prevents menopausal-related osteoporosis in mice

Osteoporosis is caused by enhanced bone resorption and relatively reduced bone formation. There is an unmet need to develop new agents with both antiresorptive and anabolic effects to treat osteoporosis, although drugs with either effect alone are available. A small molecular compound, plumbagin, was reported to inhibit receptor activator of nuclear factor kappa-B ligand–induced osteoclast (OC) differentiation by inhibiting IκBα phosphorylation–mediated canonical NF-κB activation. However, the key transcriptional factor RelA/p65 in canonical NF-κB pathway functions to promote OC precursor survival but not terminal OC differentiation. Here, we found that plumbagin inhibited the activity of NF-κB inducing kinase, the key molecule that controls noncanonical NF-κB signaling, in an ATP/ADP-based kinase assay. Consistent with this, plumbagin inhibited processing of NF-κB2 p100 to p52 in the progenitor cells of both OCs and osteoblasts (OBs). Interestingly, plumbagin not only inhibited OC but also stimulated OB differentiation in vitro. Importantly, plumbagin prevented trabecular bone loss in ovariectomized mice. This was associated with decreased OC surfaces on trabecular surface and increased parameters of OBs, including OB surface on trabecular surface, bone formation rate, and level of serum osteocalcin, compared to vehicle-treated mice. In summary, we conclude that plumbagin is a NF-κB-inducing kinase inhibitor with dual anabolic and antiresorptive effects on bone and could represent a new class of agent for the prevention and treatment of osteoporosis.

Evaluation of Bone Mineral Density, Serum Osteocalcin, and Osteopontin Levels in Postmenopausal Women with Type 2 Diabetes Mellitus, with/without Osteoporosis.

Objective Osteoporosis (OP) is a worldwide ailment; we aim to establish new biomarkers in diagnosis by determining the levels of serum osteocalcin and osteopontin along with bone mineral density (BMD) and lumbar T-score, in postmenopausal women with type 2 diabetes mellitus (T2DM) with or without OP. Methods This observational study included 160 postmenopausal women who were an attendee at outpatient clinics in Al-Hussein Hospital, Thi-Qar province; subdivided into 3 groups based on their T-score testing: Group I (n = 40) comprised postmenopausal women without T2DM as controls, Group II (n = 60) comprised postmenopausal women with T2DM but without OP, and Group III (n = 60) comprised postmenopausal women with T2DM with OP. The dual-energy X-ray absorptiometry was used to measure the BMD (total body, lumbar spine, and femoral) and T-score for lumbar spine and femoral. Glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), osteocalcin, and osteopontin levels were assessed in all three groups. Results Compared with controls, Group III demonstrated significantly lower BMD (total body, lumbar spine, and femoral), T-score for lumbar spine and femoral, serum osteocalcin, and osteopontin levels than Group II and Group I (P < 0.001). FBG and HbA1c levels were significantly higher in Group III than in Groups I and II (P < 0.001). A negative correlation was proved between HbA1c levels with BMD, osteocalcin levels, and osteopontin levels in the three groups. Conclusions Iraqi postmenopausal women with T2DM had a significantly lower bone mineral density, serum osteocalcin, and osteopontin levels. These results may serve as adjuvants in screening for OP, particularly among diabetic patients.

Traditional Japanese apricot (Prunus mume) induces osteocalcin in osteoblasts.

The fruit of Prunus mume (ume, also known as Japanese apricot) has been used as a functional food in Japan since ancient times. We previously reported that ume stimulates the differentiation of preosteoblastic cells. Osteocalcin (OCN) is secreted by osteoblasts, and there is known association with glucolipid metabolism and cognitive function. This study sought to clarify the relationship between ume extracts and OCN production both in vitro and in vivo. Alkaline phosphatase activity and OCN level in the ethyl acetate extracts of ume-treated extracts were significantly increased in preosteoblast MC3T3-E1 cells compared with the control group. In human study, serum OCN level was significantly higher in the high ume intake group than in the low intake group in community-dwelling participants over 60 years old. These results suggest that ume has the potential to upregulated OCN production both in vitro and in vivo.

The Association of Serum Osteocalcin Levels with Metabolic Parameters and Inflammation in Postmenopausal Women with Metabolic Syndrome.

Introduction: Although adipose tissue largely plays a role in the etiopathogenesis of metabolic syndrome (MS), which is an inflammatory process, the skeleton may also contribute to this process through osteocalcin (OC), which is a bone-derived protein. In this study, we aimed to evaluate OC levels in postmenopausal women with MS and to investigate the association of OC levels with the metabolic and inflammatory parameters. Methods: Thirty-five postmenopausal women diagnosed with MS were recruited for the study. Sixteen postmenopausal women without any of the MS criteria formed the control group. Body weight, height, and waist and hip circumference of all of the subjects were measured and body mass indices (BMIs) were calculated. Levels of serum glucose, insulin, C-peptide, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, albumin, creatinine, calcium, phosphorus, total alkaline phosphatase, parathormone, and as inflammatory parameters, erythrocyte sedimentation rate, fibrinogen, and high-sensitive C-reactive protein (hsCRP) were studied from fasting venous blood samples of all the subjects. Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. Serum total OC levels were studied from all of the subjects. Bone mineral densities were also measured. Results: Serum OC levels of the group with MS median (5.37 ng/mL) were lower than the OC levels of the group without MS (P < 0.01). Serum OC levels significantly and negatively correlated with fasting blood glucose (r = -0.310, P < 0.05), insulin (r = -0.343, P < 0.05), and HOMA-IR (r = -0.384, P < 0.01) values. Serum OC levels showed a significant and negative correlation with body weight (r = -0.293, P < 0.05), BMI (r = -0.333, P < 0.05), and waist-to-hip ratio (r = -0.384, P < 0.05). The inflammatory markers in the patient group were significantly higher than the control group. We found a negative association between serum OC levels and hsCRP levels in all cases (r = -0.283, P < 0.05). Conclusion: In the presence of MS, OC levels are significantly low and display a close association with glucose metabolism and adipose tissue. In addition, OC may play a regulatory role in subclinical systematic inflammatory response.

Propionic acid beneficially modifies osteoporosis biomarkers in patients with multiple sclerosis.

Background:The impact of the gut and its microbiota are increasingly appreciated in health and disease. Short-chain fatty acids (SCFAs) are among the main metabolites synthesized from bacterial fermentation. Recently, we showed the anti-inflammatory and potentially neuroprotective effect of propionic acid (PA) in multiple sclerosis (MS). Osteoporosis is one of the most common co-morbidities for MS patients with limited therapeutic options available. Osteoporosis is closely linked to an imbalance of cells of the immune system and an immune-mediated impact on bone structure via the gut has been shown. Interestingly, intake of SCFA leads to bone mass increase and concomitant reduction of inflammation-induced bone loss in mice.Objective:To determine the impact of PA supplementation on markers of bone metabolism in MS patients.Methods:We investigated the influence of 14 days supplementation with PA on bone metabolism in 20 MS patients. To this end, β-CrossLaps and osteocalcin, established markers of bone metabolism, were measured in serum before and after PA intake and correlated with phenotypic and functional immunodata.Results:Supplementation with PA induced a significant increase in serum levels of osteocalcin, a surrogate marker for bone formation. Levels of β-CrossLaps, a marker for bone resorption, were significantly decreased after therapy. Regulatory T-cell (Treg) numbers and suppressive capacity positively correlated with serum levels of osteocalcin while Th17 cell numbers showed an inverse correlation. Our findings are in line with animal studies showing that SCFA induced increased bone formation and reduced bone resorption.Conclusion:In addition to its immune regulatory, disease-modifying effect on MS disease course, supplementation with PA beneficially influences serum levels of β-CrossLaps and osteocalcin and may thus also protect against osteoporosis, a common co-morbidity in MS.

Effects of Morinda officinalis Polysaccharides on the Proliferation and Viability of Osteoblasts in Rats with Osteoporosis

We aimed to evaluate the effects of Morinda officinalis polysaccharides on the proliferation and viability of osteoblasts in rats with osteoporosis. 24 non-parous Sprague-Dawley rats were assigned into normal, model, low-dose and high-dose Morinda officinalis polysaccharide groups. The model of osteoporosis was established by ovariectomy. After successful modeling, 50 mg/kg and 75 mg/kg Morinda officinalis polysaccharides were subcutaneously injected in low-dose and high-dose Morinda officinalis polysaccharide groups, respectively. After 3 w of intervention, osteoblasts were prepared using the skull and their proliferation index and alkaline phosphatase activity were measured. The histopathological changes in femoral tissues were observed. The bone mineral density and levels of serum osteocalcin, calcium and phosphorus, as well as the protein levels of receptor activator of nuclear factor kappa-B, receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were determined. The proliferation index and alkaline phosphatase activity were highest in high-dose Morinda officinalis polysaccharide group (p<0.05). Bone tissues had decreased cell spaces and gradually reduced spaces between the medullary cavities in Morinda officinalis polysaccharide groups. Model group had the highest bone mineral density and levels of serum osteocalcin, calcium and phosphorus (p<0.05). The protein expression levels of receptor activator of nuclear factor kappa-B ligand and receptor activator of nuclear factor kappa-B showed a decreasing trend, while that of osteoprotegerin displayed a rising trend sequentially in model, low-dose, high-dose Morinda officinalis polysaccharide and normal groups (p<0.05). Morinda officinalis polysaccharides promotes the proliferation of osteoblasts, enhances their viability and maintains the balance between bone resorption and formation in rats with osteoporosis probably by modulating the protein expression of the receptor activator of nuclear factor kappa-B ligand/receptor activator of nuclear factor kappa-B/osteoprotegerin pathway.

Protective effect of aqueous extracts from Taxillus chinensis (DC.) Danser on ovariectomy-induced osteoporosis in rats

As one of classic Chinese kidney-tonifying herbal medicines, Taxillus chinensis (DC.) Danser is widely applied in Chinese folk medicine as herbal tea for nutraceutical purposes including nourishing kidney, strengthening muscle and bone to against weakness, etc. In the present study, we investigated the protective effect of aqueous extracts from Taxillus chinensis (AETCs) on the ovariectomy (OVX)-induced osteoporosis in rats. Results showed that AETC treatment at the dose of 12.0 g raw materials/kg for 12 weeks significantly enhanced the bone mineral densities of femur and tibia, improved the trabecular microarchitecture compared with OVX controls. The serum levels of osteogenic markers alkaline phosphatase and osteocalcin were increased, and the levels of bone resorption biomarkers tartrate-resistant acid phosphatase 5b and telopeptides of collagen type I were suppressed by AETCs. Moreover, 12.0 g raw materials/kg AETC treatment significantly reduced the OVX-induced up-regulation of cyclooxygenase (COX)-2 mRNA and protein expression in bone tissues. Data suggested that AETCs showed anti-osteoporotic effect in OVX rats, possibly via promoting bone formation and inhibiting bone absorption. The down-regulation of inflammatory COX-2 might be involved in the protection of AETCs against OVX –induced osteoporosis.

AACE2021-A-1050: Relationship of Serum Level of Bone Formation Biomarker Osteocalcin and CIMT and Metabolic Parameters in Post-Menopausal Females and Type 2 Diabetes

To determine the association between serum levels of OCN and metabolic parameters and carotid intima media thickness (CIMT) in a group of post-menopausal females with type 2 diabetes (T2DM). This cross-sectional study comprised 75 postmenopausal women with T2DM (group 1; 25 patients with normal bone mineral density (BMD), group 2; 25 patients with osteopenia and group 3; 25 patients with osteoporosis) and 40 age matched non-diabetic postmenopausal females. All subjects included in this study were subjected to the following: thorough clinical evaluation, laboratory investigations including fasting blood glucose (FBG), glycated hemoglobin (HbA1c) and lipid profile. Bone mineral density (BMD) was measured by DEXA scan. CIMT was assessed with B-mode ultrasonography. Serum OCN was measured using ELISA. Person’s correlation analysis was used to evaluate the relation of OCN to different parameters of the studied population. Multivariate logistic regression model was used to quantitatively analyze the interactions. Although there was no significant difference between patients with T2DM and control subjects in BMD, serum OCN was significantly lower in patients with T2DM compared to control (63.73±27.20 vs 136.16±21.96 pg/mL, P<.001). Also, there was significant reduction in OCN level in diabetic patients with osteoporosis as compared to those with osteopenia and normal BMD. In diabetic patients there was significant negative correlation between serum OCN and CIMT (r= -0.332; P=0.003) (fig.1), FBG (r= -0.732; P< 0.001), serum insulin(r= -0.302; P=0.007), HbA1c (r= -0.672; P< 0.001) (fig.2), HOMAIR (r= -0.672; P< 0.001). Multiple linear regression analysis showed that serum insulin (β= -0.183, P=0.033), FBG (β= -0.604, P< 0.001) and LDL (β= -0.195, P= 0.02) were still negatively correlated with the serum OCN. Serum OCN concentration is reduced in postmenopausal women with T2DM and it is lower in patients with osteoporosis than those with normal BMD. Low serum OCN level is a significant and independent factor associated with worse glycemic profile and higher insulin resistance conferring thus a larger risk of developing atherosclerosis in this group of patients.

Efficacy of nanomicelle curcumin, Nigella sativa oil, and their combination on bone turnover markers and their safety in postmenopausal women with primary osteoporosis and osteopenia: A triple-blind randomized controlled trial.

Literature supports the potential effects of nanomicelle curcumin and Nigella sativa on the amelioration of osteoporosis, a health concern of postmenopausal women. This study aimed to evaluate the impacts of nanomicelle curcumin (CUR), Nigella sativa oil (NS), and their combination on bone turnover biomarkers and assess their safety. This triple‐blind randomized controlled trial was performed on 120 postmenopausal women aged 50–65 with primary osteoporosis or osteopenia. The subjects were randomly allocated to receive microcrystalline cellulose (placebo), 80 mg of CUR, 1000 mg of NS, or their combination (CUR‐NS) for 6 months. All patients were also treated with alendronate (70 mg) and calcium (500 mg), vitamin D (400 IU) supplements. The serum levels of alkaline phosphatase (ALP), osteocalcin (OC), and osteopontin (OP) were measured at the baseline and after the intervention. For safety assessment, the hepatic enzyme levels of aspartate transaminase and alanine transaminase as well as serum urea and creatinine were evaluated. ALP levels were significantly reduced in the NS (p = .029) and CUR‐NS (p = .015) groups compared with those in the placebo. After adjustment for the covariates, this effect was still significant in the CUR‐NS group (p = .004). The OC levels were decreased in the placebo, CUR, and NS groups, and the OP concentration also was attenuated in all groups through the trial. However, the intergroup differences were not significant for both biomarkers. Evaluating the key renal metabolites and hepatic enzyme levels indicated no toxicity of the administered doses. This study reveals the beneficial effects of CUR‐NS on the improvement of some bone turnover biomarkers. These compounds seem to be safe at the current dosage for supplementation in postmenopausal women.

Serum Osteocalcin and Bone Mineral Density as Markers of Post-menopausal Osteoporosis: A Meta-analysis

Osteocalcin (OC) and bone mineral density (BMD) measurements determine the bone mass and microarchitecture of bone. Both are used for diagnosing osteoporosis and their role as a biomarker in postmenopausal osteoporosis (PMO) remains controversial. To determine the relationship between serum OC and PMO and compare BMD vs OC, a metaanalysis was carried forward with case-control studies. Studies reporting mean/median and standard deviation of osteocalcin in post-menopausal women with and without osteoporosis were included. From the same studies, BMD measurements in both groups were included. Fifteen studies were included with 1864 postmenopausal women. We found significant increase in serum OC (Standardized Mean Difference of 0.918 and SE of 0.476 (p=0.054), confidence interval (CI) (-0.015 to 1.852) and significant decrease in BMD values (SMD of -2.321 and SE of 0.345 (p= &lt;0.001) (CI - 2.998 to -1.643)) in PMO. T score also significantly decreased in PMO (SMD &lt;0 (-3.785). Heterogeneity was observed in all parameters analyzed for more than 90%. We concluded that in our metanalysis, there was a significant increase in serum osteocalcin levels with SMD&gt; 0 and significantly low BMD/t score levels with SMD &lt;0 in postmenopausal osteoporotic women as compared to healthy postmenopausal women. Osteocalcin gives the current status of bone remodeling and is not influenced by multiple factors whereas BMD measures the bone mass, yet techniques vary and are influenced by many factors. SMD &lt; 0 alone cannot be used to detect osteoporosis or predict osteoporotic fractures. Increased osteocalcin and low BMD/T score after menopause together are good indicators to detect osteoporosis. This conjunction can economically burden the patient and thus our study concludes that SMD &gt; 0 serum osteocalcin solely can be implemented as a promising marker for diagnosing osteoporosis.

Bone microarchitecture, bone mineral density and bone turnover in association with glycemia and insulin action in women with prior gestational diabetes.

The aim of this cross-sectional study was to comprehensively assess bone health in women with prior gestational diabetes mellitus, including bone microarchitecture (TBS), bone mineral density (BMD, DXA) and bone turnover (osteocalcin). Study participants underwent a detailed anthropometric, biochemical and hormone assessment, including insulin and osteocalcin measurement. BMD was measured at lumbar spine, femur neck and total hip using DXA and TBS derived from lumbar spine DXA images using TBS iNsight software. A total of 240 women (mean age: 33.3 ± 5.0 years; median postpartum duration: 34 [interquartile range 13.0-54.5] months were evaluated. At the current visit, 115 (47.9%) and 36 (15%) women had prediabetes and diabetes, respectively. Women with dysglycemia (diabetes/prediabetes) had a higher BMD at all three sites, compared to those with normoglycemia; however, the difference was not statistically significant. Women with dysglycemia had a significantly lower TBS (1.32 ± 0.09 vs. 1.35 ± 0.09; p = .038). In the fully adjusted model, the odds ratio for association between diabetes and low TBS was 2.92 (95% confidence interval: 1.20, 7.08; p = .018). Women with dysglycemia had significantly lower serum osteocalcin levels (18.6 ± 8.5 ng/ml vs. 21.5 ± 9.7 ng/ml; p = .018). HOMA-IR (r = -.285, p < .001) was negatively correlated, while Matsuda index (r = .274, p < .001) and disposition index (r = .159, p = .016) were positively correlated with serum osteocalcin levels. Bone health is affected early in the natural history of diabetes and is associated with an overall low bone turnover state.

Serum osteocalcin levels at 4months of age were associated with neurodevelopment at 4years of age in term-born children.

The hormone osteocalcin influenced neurodevelopment and cognition in mice models; this human study explored potential associations between total serum levels in human infants and neurodevelopment at 4years of age. The data were based on two Swedish birth cohorts from 2008 to 2009. We followed 158healthy full-term vaginal births (51% girls) by measuring serum osteocalcin in cord blood and at 4, 12 and 36months. The values were compared with neurodevelopment tests at 4years of age. There was an association between osteocalcin at 4months and later full-scale intelligence quotient (IQ; r2 0.031, p<0.05). Children with osteocalcin levels in the highest quartile scored 5.6 (95% confidence interval [1.3, 9.9]) points higher than those in the lowest quartile, with mean scores of 118.8±8.8 and 113.2±9.2 (p<0.05). They also scored higher on gross motor skills (p<0.05) and showed greater ability during the drawing trail test (p<0.005). Cord levels of osteocalcin were negatively associated with processing speed and fine motor development at 4years, but levels at 12 and 36months were not associated with later neurodevelopment. Osteocalcin levels in infancy appeared to be associated with later IQ and motor development, but more research is needed.

Effect of Non-alcoholic Fatty Liver Disease on Some of Bone Biomarkers in Men

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the common liver diseases worldwide that is not associated with alcohol consumption; it is a group of disorders caused by fat accumulation in the liver. AIM: The research aims to assess the levels of serum sialoprotein, sclerostin, and osteocalcin in men with NAFLD. METHODS: The current study was conducted in Basra city, Iraq in 2020, which includes 400 men with NAFLD, age ranges between (30 and 50) years, and 400 matched health men as controls, serum levels of study parameters were measured using the ELISA method. RESULTS: The results showed a significant decrease in the levels of serum osteocalcin but a non-significant difference in sclerostin and bone sialoprotein in men with NAFLD comparing with the control group, also age and disease severity factors did not show any significant effect on study parameters in the patient’s group. CONCLUSION: In conclusion, men with NAFLD may be prone to some disturbances in the bone health regardless of disease progression and age in Basrah city.

Mature Osteoblasts Are Critical Bone Marrow Niche Cells Regulating Multiple Myeloma Cell Growth, at Least in Part, By Affecting the Local Immune Microenvironment

Despite high response rates to new therapies, most multiple myeloma (MM) patients relapse and become refractory to treatment. This is likely because MM cells enter dormancy and reactivate only under permissive conditions. Cellular dormancy is ubiquitous in normal tissues as well as in malignant, non-malignant, and metastasizing tumors. Dormant tumor cells (DTC) are protected from therapies which can reactivate later at the time of disease progression, resulting in relapsed refractory MM (RRMM). The tumor microenvironment (TME) is a key determinant of tumor dormancy and reactivation. We have previously shown that inhibition of Activin A in SCID mice transplanted with human MM.1S increased osteoblast numbers and resulted in inhibition of MM growth (Vallet et al., PNAS). We hypothesize that MM-DTCs reside in osteoblastic niche in the BM TME. Our long-term goal is to identify factors regulating DTCs in MM and develop strategies for long term disease control.We have generated mice in which mature osteoblasts can be postnatally deleted in an inducible and reversible manner. To achieve this, mice carrying floxed diphtheria toxin receptor (DTR) alleles were mated with mice expressing Cre-recombinase driven by the osteocalcin promoter (OC-Cre). This led to the expression of DTR in mature osteoblasts (OC-Cre/iDTR) only. The control mice were littermates lacking the OC-Cre allele (iDTR). Until the treatment with diphtheria toxin (DT), the OC-Cre/iDTR mice were immunocompetent compared to iDTR mice, as they did not show any differences in immune cell populations by flow cytometry, and did not show any skeletal phenotype, as measured by micro-computed CT (micro-CT).We chose to induce mature osteoblast-deficiency at 8-weeks of age to allow skeletal maturation which is assumed to be completed by 6-7weeks of age. To induce postnatal deletion of mature osteoblasts, the OC-Cre/iDTR and control mice both were treated with 50 µg/kg DT once a week, beginning at 8-weeks of age. Micro-CT analysis showed a significant increase in cortical porosity within 1-week after DT injection. 8-weeks of DT treatment significantly reduced trabecular bone fraction (BV/TV), trabecular numbers (Tb.N), and bone mineral density (BMD) with a significant increase in trabecular spacing (Tb.Sp). Immunohistochemistry for osteocalcin showed rapid loss of mature and endosteal osteoblasts (N.Ob/T.Ar). This was accompanied with a marked decreased in serum sclerostin and serum osteocalcin levels suggesting reduced osteocytes and mature osteoblasts, respectively. Importantly, serum CTX levels or numbers of osteoclasts (N.Oc/T.Ar) were unchanged. To study MM engraftment and progression, 3x10 6 5TGM1 luciferase tdTomato positive (5TGM1-Luc-Tom) MM cells were injected into the tibia of OC-Cre/iDTR and control iDTR mice followed by weekly injection of DT for 8-weeks. Flow cytometry analysis showed a 4-fold increase in the 5TGM1-Tom cells in the BM from OC-Cre/iDTR mice compared to controls. Bioluminescence imaging (BLI) for 5TGM1-Luc-Tom cells at 4-weeks showed dramatic increase in the OC-Cre/iDTR mice compared to controls. Interestingly, by 8-weeks, the BLI imaging showed 5TGM1-Luc-Tom cells in other long-bones of OC-Cre/iDTR mice but not the controls. To identify local BM TME changes, we assessed the levels of 200 cytokines and growth factors in the BM from these mice. The levels of immune regulatory cytokines, such as IL-17F and IL-21, were found to be decreased in the OC-Cre/iDTR mice compared to control iDTR mice, both after 4-weeks from intratibial 5TGM1 cell injection. This was accompanied by significant decrease in the fraction of CD4+ T-helper and Th17+ cells in the OC-Cre/iDTR mice compared to controls, as assessed by flow cytometry.These data show that MM cells engraft and proliferate rapidly within the BM in the absence of mature osteoblasts and have a propensity to migrate to other long bones with time. This may be partially mediated by the altered immune cell profile in the BM in the absence of mature osteoblasts. These data further suggest that expanding the mature osteoblast niche may provide novel therapeutic avenues and reduce disease burden creating an environment for long term tumor control. Importantly, this model will allow us to understand the osteoblastic niche for MM and the mechanisms of activation and dormancy, at least in part, via a role of the immune cells. DisclosuresFulzele: Constellation Pharma: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other.

The Effect of Genetically Modified Lactobacillus plantarum Carrying Bone Morphogenetic Protein 2 Gene on an Ovariectomized Rat.

ObjectiveOsteoporosis result from age-related decline in the number of osteoblast progenitors in the bone marrow. Probiotics have beneficial effects on the host, when administered in appropriate amounts. This study investigated the effects of probiotics expressing specific genes, especially the effects of genetically modified bone morphogenetic protein (BMP)-2-expressing Lactobacillus plantarum CJNU 3003 (LP) on ovariectomized rats. MethodsTwenty-eight female Wistar rats (250–300 g, 12 weeks old) were divided into four groups : the sham (control), the ovariectomy (OVX)-induced osteoporosis group (OVX), the OVX and LP (OVX/LP), OVX and genetically modified BMP-2-expressing LP (OVX/LP with BMP) groups. The three groups underwent bilateral OVX and two of these groups were administered two different types of LP via oral gavage daily. At 16 weeks post-OVX, blood was collected from the heart and the bilateral tibiae were extracted and were scanned by ex-vivo micro-computed tomography and stained with hematoxylin-and-eosin (H&E) and Masson’s trichrome stain for pathological assessment. The serum levels of osteocalcin (OC), rat C-telopeptide of type I collagen (CTX-I), BMP-2, and receptor activator of nuclear factor-ĸB ligand (RANKL) were measured. ResultsThe 3D-micro-computed tomography images showed that the trabecular structure in the OVX/LP with BMP group was maintained compared with OVX and OVX/LP groups. No significant differences were detected in trabecular thickness (Tb.Th) between control and OVX/LP with BMP groups (p>0.05). Furthermore, a tendency toward increased BMD, trabecular bone volume, Tb.Th, and trabecular number and decreased trabecular separation was found in rats in the OVX/LP with BMP groups when compared with the OVX and OVX/LP groups (p>0.05). The H&E and Masson’s trichrome stained sections showed a thicker trabecular bone in the OVX/LP with BMP group compared with the OVX and OVX/LP groups. There was no difference in serum levels of OC, CTX and RANKL control and OVX/LP with BMP groups (p>0.05). In contrast, significant differences were found in OC and CTX-1 levels between the OVX and OVX/LP with BMP groups (p<0.05). ConclusionOur results showed that the expression of genetically modified BMP-2 showed inhibition effect for bone loss in a rat model of osteoporosis.

Abnormal Bone Metabolism May Be a Primary Causative Factor of Keel Bone Fractures in Laying Hens.

Simple SummaryKeel is an essential structural bone, providing anchorage for the attachment of large breast muscles in birds, allowing them to flap wings and provide proper ventilation for their lungs during flight. Previous studies reported that keel bone damage (especially fractures) negatively affects the welfare, health, production performance, eggshell quality, and mobility of laying hens contained in different housing systems. Furthermore, various factors affect keel bone damage, including nutrition, age, housing systems, and strains of laying hens. However, studies on the effects of abnormal bone metabolism and development on keel bone damage in laying hens are limited. Therefore, this study aimed to investigate the impacts of bone metabolism and development status on keel bone damage by determining the levels of serum bone turnover markers in laying hens. The results showed that laying hens with impaired keel bone had significantly altered levels of serum Ca and P metabolism-related and osteoblast and osteoclast activity-related markers compared to those in laying hens with normal keel bone. Thus, these results indicated that abnormal bone metabolism before keel bone damage reflected by varying levels of serum bone turnover markers might be a pivotal factor causing keel bone damage in laying hens. Our results also provide new insights into the occurrence of keel bone damage in laying hens.Keel bone damage negatively affects the welfare, production performance, egg quality, and mobility of laying hens. This study aimed to investigate whether abnormal bone metabolism causes keel bone damage in laying hens. Eighty Hy-line Brown laying hens were housed in eight furnished cages with 10 birds per cage and studied from 18 to 29 weeks of age (WOA). Accordingly, keel bone status was assessed at 18, 22, 25, and 29 WOA using the X-ray method, and the serum samples of laying hens with normal keel (NK), deviated keel (DK), and fractured keel (FK) that occurred at 29 WOA were collected across all the time-points. Subsequently, the serum samples were used to measure markers related to the metabolism of Ca and P and activities of osteoblast and osteoclast. The results showed that FK laying hens had lighter bodyweight than NK and DK birds throughout the trial (p < 0.05), while the keel bone length and weight were not different in NK, DK, and FK hens at 29 WOA (p > 0.05). Moreover, bone hematoxylin and eosin (H&E) staining and tartrate-resistant acid phosphatase (TRAP) staining indicated that damaged keel bone had evident pathological changes. In the FK hens, serum P level was reduced but serum 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3) and 25-hydroxyvitamin D3 (25-OHD3) levels were elevated compared to NK hens (p < 0.05). Additionally, DK hens had higher levels of serum 1,25-(OH)2D3, parathyroid hormone (PTH) and calcitonin (CT), and lower level of serum 25-OHD3 than the NK birds (p < 0.05). Furthermore, serum alkaline phosphatase (ALP), osteocalcin (OC), osteoprotegerin (OPG), TRAP, and corticosterone (CORT) levels were elevated in DK and FK hens compared to NK hens (p < 0.05). The levels of serum Ca, P, PTH, ALP, TRAP, OPG, OC, and CORT in laying hens fluctuated with the age of the birds. Generally, the results of this study indicate that keel bone damage, especially fractures, could be associated with abnormal bone metabolism in laying hens.

What happens to the bone structure after normocalcemic primary hyperparathyroidism surgery?

BackgroundBone disease in primary hyperparathyroidism is a clear indication for surgical treatment. However, it is not known whether surgery benefits hypercalcemic primary hyperparathyroidism and normocalcemic primary hyperparathyroidism equally. The aim of our study was to evaluate the bone changes in patients undergoing parathyroidectomy based on the biochemical profile 1 and 2 years after surgery. MethodsThis prospective study included 87 consecutive patients diagnosed with primary hyperparathyroidism who underwent surgery between 2016 and 2018. Bone densitometry (1/3 distal radius, lumbar, and femur) and bone remodeling markers (osteocalcin, type 1 procollagen [P1NP], β-cross-linked telopeptide of type I collagen [BCTX]) were performed preoperatively and postoperatively. Postoperative changes in bone mineral density and bone markers were compared and evaluated according to the clinical characteristics and the individual biochemical profile. ResultsOne year after surgery, all patients showed an increase in bone mineral density at the lumbar site (mean, 0.029 g/cm2; range, 0.017–0.04; P < .001) and femur neck (mean, 0.025 g/cm2; range, 0.002–0.05; P < .001); however, there were no changes in the distal third of the radius (mean, -0.003 g/cm2; range, -0.008 to 0.002; P = NS). There were no significant differences when comparing normocalcemic primary hyperparathyroidism and hypercalcemic primary hyperparathyroidism. Serum osteocalcin (37 ± 17.41), P1NP (67.53 ± 31.81) and BCTX (0.64 ± 0.37) levels were elevated before surgery. One year after the surgery, we observed a significant decrease in P1NP (33.05 ± 13.16, P = .001), osteocalcin (15.80 ± 6.19, P = .001), and BCTX (0.26 ± 0.32, P < .001) levels. ConclusionOur findings indicate that parathyroidectomy has similar benefits for normocalcemic primary hyperparathyroidism and hypercalcemic primary hyperparathyroidism in terms of bone improvement. Although the most substantial improvement occurred during the first postoperative year in both groups, we consider that studies with longer follow-up are warranted.

The Effect of Lactobacillus gasseri BNR17 on Postmenopausal Symptoms in Ovariectomized Rats.

Clinical and preclinical studies have reported that Lactobacillus gasseri BNR17, a probiotic bacterial strain isolated from human breast milk, reduces body weight and white adipose tissue volume. In order to further explore the actions of L. gasseri BNR17, we investigated the anti-menopausal effects of L. gasseri BNR17 in an ovariectomized (OVX) rat model. The serum alanine aminotransferase levels of the rats in the OVX-BNR17 group were lower than those of the rats in the OVX-vehicle only (OVX-Veh) group. Upon administration of L. gasseri BNR17 after ovariectomy, calcitonin and Serotonin 2A levels increased significantly, whereas serum osteocalcin levels showed a decreasing tendency. Compared to the rats in the OVX-Veh group, those in the OVX-BNR17 group showed lower urine deoxypyridinoline levels, lower pain sensitivity, and improved vaginal cornification. Furthermore, L. gasseri BNR17 administration increased bone mineral density in the rats with OVX-induced femoral bone loss. These results suggest that L. gasseri BNR17 administration could alleviate menopausal symptoms, indicating that this bacterium could be a good functional probiotic for managing the health of older women.

Low serum osteocalcin levels are associated with diabetes mellitus in glucocorticoid treated patients.

Osteocalcin (OC) is involved in the regulation of glucose homeostasis. Glucocorticoid (GC) treatment is associated with impaired osteoblast function, decreased OC levels, and the development and/or worsening of pre-existing diabetes mellitus (DM). Whether decreased OC levels in GC-treated subjects contribute to DM is not well known. The aim of this study was to analyse whether OC levels in GC-treated patients are associated with the presence of DM. One hundred twenty-seven patients (aged 61.5 ± 17.9years) on GC treatment were included. GC dose, treatment duration, presence of DM and bone formation (OC, bone ALP, PINP) and resorption markers (urinary NTX, serum CTX) were analysed. The cut-offs of each bone turnover marker (BTM) for the presence of DM were evaluated and optimised with the Youden index and included in the logistic regression analysis. Among the patients, 17.3% presented DM. No differences were observed in GC dose or duration or the presence of fractures. Diabetics showed lower levels of OC (7.57 ± 1.01 vs. 11.56 ± 1; p < 0.001), PINP (21.48 ± 1.01 vs. 28.39 ± 1; p = 0.0048), NTX (24.91 ± 1.01 vs. 31.7 ± 1; p = 0.036) and CTX (0.2 ± 1.01 vs. 0.3 ± 1; p = 0.0016). The discriminating BTM cut-offs for DM presence were < 9.25ng/mL for OC, < 24ng/mL for PINP, < 27.5nMol/mM for NTX and < 0.25ng/mL for CTX. In a multivariate logistic regression model adjusted for GC dose, BMI, age and the above four BTMs, only OC remained independently associated with DM presence. Thus, in a model adjusted for GC dose, BMI and age, OC was significantly associated with DM (OR: 6.1; 95%CI 1.87-19.89; p = 0.001). Decreased OC levels in GC-treated patients are associated with increased odds of DM, and only OC was independently associated with DM in a model including four BTMs.

Correlation between Serum hs-CRP and Magnesium Ion with Osteocalcin in Acute Leukemia Patients

Acute leukemia is a proliferation of immature cells in the bone marrow that affects peripheral blood or other organs. Inflammation has a vital role in cancer pathophysiology. Inflammation in leukemia occurs through two mechanisms: intrinsic and extrinsic. Magnesium deficiency leads to inflammation in acute leukemia patients. Manifestation of inflammation in acute leukemia are abnormalities in musculoskeletal systems such as osteopenia, osteoporosis, osteonecrosis, and pathological fractures. Increased inflammation in the bone remodeling process increases osteoclast (OC) regulation and decreases osteoblast (OB) activity resulting in reduced osteocalcin (OCN) production. Osteocalcin, also known as gamma-carboxy glutamic acid-containing protein or bone Gla-protein, is a small, non-collagen protein associated with the bone matrix. Osteocalcin is known as bone formation. This study aimed to analyze the correlation between hs-CRP, ion Mg and serum OCN levels in acute leukemia. A cross-sectional observational analytic study in acute leukemia subjects was conducted at Clinical Pathology Installation of Dr. Moewardi Hospital. Surakarta from August to September 2020. Normality test of Shapiro-Wilk was used to determine data distribution, Pearson correlation test was used to analyze the correlation strength between variables. From a total of 35 subjects, there was a significant negative correlation between hs-CRP and serum OCN in acute leukemia (r= -0.46; p=0.06), but no correlation was found between Mg ion and serum OCN in acute leukemia patients (r=0.09; p=0.957). The mean of hs-CRP, Mg ion, and OCN was 2.95±4.95 mg/dL, 0.49±0.05 mmol/L, and 16.32±19.46 ng/mL, respectively. Advanced research with chronic leukemia population and other variants as needed.