Interaction between MARK3 (rs11623869), PLCB4 (rs6086746) and GEMIN2 (rs2277458) variants with bone mineral density and serum 25-hidroxivitamin D levels in Mexican Mestizo women.

Introduction: Understanding the genetic factors contributing to variations in bone mineral density (BMD) and vitamin D could provide valuable insights into the pathogenesis of osteoporosis. This study aimed to evaluate the association of single nucleotide variants in MARK3 (rs11623869), PLCB4 (rs6086746), and GEMIN2 (rs2277458) with BMD in Mexican women. Methods: The gene-gene interaction was evaluated in these variants in serum 25(OH)D levels and BMD. A genetic risk score (GRS) was created on the basis of the three genetic variants. Genotyping was performed using predesigned TaqMan assays. Results: A significant association was found between the rs6086746-A variant and BMD at the total hip, femoral neck, and lumbar spine, in women aged 45 years or older. However, no association was observed between the variants rs11623869 and rs2277458. The rs11623869 × rs2277458 interaction was associated with total hip (p=0.002) and femoral neck BMD (p=0.013). Similarly, for vitamin D levels, we observed an interaction between the variants rs6086746 × rs2277458 (p=0.021). GRS revealed a significant association with total hip BMD (p trend=0.003) and femoral neck BMD (p trend=0.006), as well as increased vitamin D levels (p trend=0.0003). These findings provide evidence of the individual and joint effect of the MARK3, PLCB4, and GEMIN2 variants on BMD and serum vitamin D levels in Mexican women. Discussion: This knowledge could help to elucidate the interaction mechanism between BMD-related genetic variants and 25OHD, contributing to the determination of the pathogenesis of osteoporosis and its potential implications during early interventions.

Use of data-independent acquisition mass spectrometry to identify an objective serum indicator of the need for osteoporotic therapeutic intervention.

Osteoporosis is characterized by weakened bone microstructure and loss of bone mass. Current diagnostic criteria for osteoporosis are based on the T-score, which is a measure of bone mineral density. However, osteoporotic fragility fractures can occur regardless of the T-score, underscoring the need for additional criteria for the early detection of patients at fracture risk. To identify indicators of reduced bone strength, we performed serum proteomic analysis using data-independent acquisition mass spectrometry with serum samples from two patient groups, one with osteoporosis but no fractures and the other with osteopenia and fragility fractures. Collective evaluation of the results identified six serum proteins that changed to a similar extent in both patient groups compared with controls. Of these, extracellular matrix protein 1 (ECM1), which contributes to bone formation, showed the most significant increase in serum levels in both patient groups. An ELISA-based assay suggested that ECM1 could serve as a serum indicator of the need for therapeutic intervention; however, further prospective studies with a larger sample size are necessary to confirm these results. The present findings may contribute to the provision of early and appropriate therapeutic strategies for patients at risk of osteoporotic fractures. SIGNIFICANCE: This study aimed to identify objective serum indicators of the need for therapeutic intervention in individuals at risk of osteoporotic fracture. Comprehensive proteome analyses of serum collected from patients with osteoporosis but no fractures, patients with osteopenia and fragility fractures, and controls were performed by data-independent acquisition mass spectrometry. Collective evaluation of the proteome analysis data and ELISA-based assays identified serum ECM1 as a potential objective marker of the risk of fragility fractures in patients with osteoporosis or osteopenia. The findings are an important step toward the development of appropriate bone health management methods to improve well-being and maintain quality of life.

Association between hepatitis A seropositivity and bone mineral density in adolescents and adults: a cross-sectional study using NHANES data.

BACKGROUND: Osteoporosis, characterized by decreased bone density and increased fracture risk, imposes significant physical, psychosocial, and financial burdens. Early detection and prevention are crucial for managing osteoporosis and reducing the risk of fractures. OBJECTIVES: To investigate the relationship between Hepatitis A seropositivity and bone mineral density (BMD) in adolescents and adults and to explore the potential link between Hepatitis A infection and osteoporosis risk. DESIGN AND SETTING: This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 to evaluate the association between hepatitis A seropositivity and BMD in 15,693 participants. METHODS: Multivariable regression analysis was used to calculate the mean BMD and standard error for adolescents and adults, followed by an independent z-test to determine whether there was a significant difference between the seropositive and seronegative groups. RESULTS: Hepatitis A seropositive adolescents and adults had lower BMD than their seronegative counterparts, with significant differences in lumber spine (mean difference = -0.03 g/cm2, P < 0.01 for both age groups) and pelvis BMDs (mean difference = -0.02 g/cm2, P < 0.01 for the adult age groups), after adjusting for various covariates. CONCLUSIONS: This study confirmed that both adolescent and adult individuals seropositive for Hepatitis A antibodies had reduced BMD among both adolescents and adults, especially in the adult group. This finding suggests a possible link between Hepatitis A infection and risk of osteoporosis.

The prevention effect of pulsed electromagnetic fields treatment on senile osteoporosis in vivo via improving the inflammatory bone microenvironment.

This study aimed to assess PEMF in a rat model of senile osteoporosis and its relationship with NLRP3-mediated low-grade inflammation in the bone marrow microenvironment. A total of 24 Sprague Dawley (SD) rats were included in this study. Sixteen of them were 24-month natural-aged male SD rats, which were randomly distributed into the Aged group and the PEMF group (n = 8 per group). The remaining 8 3-month -old rats were used as the Young positive control group (n = 8). Rats in the PEMF group received 12 weeks of PEMF with 40 min/day, five days per week, while the other rats received placebo PEMF intervention. Bone mineral density/microarchitecture, serum levels of CTX-1 and P1CP, and NLRP3-related signaling genes and proteins in rat bone marrow were then analyzed. The 12-week of PEMF showed significant mitigation of aging-induced bone loss and bone microarchitecture deterioration, i.e. PEMF increased the bone mineral density of the proximal femur and L5 vertebral body and improved parameters of the proximal tibia and L4 vertebral body. Further analysis showed that PEMF reversed aging-induced bone turnover, specifically, decreased serum CTX-1 and elevated serum P1CP. Furthermore, PEMF also dramatically inhibited NLRP3-mediated low-grade inflammation in the bone marrow, i.e. PEMF inhibited the levels of NLRP3, proCaspase1, cleaved Caspase1, IL-1ß, and GSDMD-N. The study demonstrated that PEMF could mitigate the aging-induced bone loss and reverses the deterioration of bone microarchitecture probably through inhibiting NLRP3-mediated low-grade chronic inflammation to improve the inflammatory bone microenvironment in aged rats.

Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease.

PURPOSE: Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison's disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement. METHODS: Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). RESULTS: Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10-6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient's age (p = 1.038 × 10-5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD. CONCLUSION: Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

Circulating Hsa-miR499a-5p as markers in dysmobility syndrome patients: a new index for diagnosing dysmobility syndrome based on osteoporosis and predicting fracture risk.

BACKGROUND: Dysmobility syndrome based on osteoporosis (ODS) is a disease characterized by low bone mass and low muscle mass. Its features are high fracture and high fall risk. Falls and fractures are the most important factors affecting the quality of life and lifespan of ODS. However, there is no serum marker for the evaluation of ODS patients.Our previous studies have shown that the expression of circulating miRNA is stable and is a good marker for disease diagnosis. Therefore, this study aims to explore potential serum markers of ODS. METHODS: A total of 78 subjects were included in this study. The data including appendicular skeletal muscle mass index, bone mineral density, bone metabolism markers, and other relevant information were collected for analysis. Real-time quantitative polymerase chain reaction was used to detect 19 miRNAs associated with muscle mass reduction. The correlation of quantitative data was analyzed by Pearson. The receiver operating characteristic curve was used to evaluate the performance of miRNA as a biomarker. RESULTS: In this study, we found that the muscle mass and strength of patients with ODS are significantly reduced and are negatively correlated with the risk of fracture. The hsa-miR-499a-5p is specifically downregulated in ODS, and is positively correlated with muscle mass and strength, and negatively correlated with the risk of fracture. Compared with muscle mass and strength, hsa-miR-499a-5p has better sensitivity and specificity as a diagnostic marker. CONCLUSION: hsa-miR-499a-5p is a potential serum biomarker for assessing muscle function and predicting fall or fracture risk in the ODS population.

Association of blood heavy metal levels with osteocalcin abnormality and incidence of osteoporosis in Saudi subjects / Associação de anormalidades de osteocalcina nos níveis de metais pesados no sangue e incidência de osteoporose em indivíduos sauditas

Serum toxic metals have been implicated in development of many diseases. This study investigated the association between blood levels of lead and cadmium with abnormal bone mineral density (BMD) and incidence of osteoporosis. Sixty Saudi male adults age matching were assigned into two groups: A healthy control group (n = 30) and osteoporosis patients diagnosed according to T-score (n = 30). Serum calcium, vitamin D, osteocalcin, lead, cadmium were measured. Osteoporotic group showed a highly significant elevation of blood lead and cadmium levels compared to the control group (p <0.001). BMD was negatively correlated with serum osteocalcin level compared with control. There was a significant negative correlation between the cadmium and lead levels (r=-0.465 and p-value = 0.01) and calcium (p < 0.004). Our findings suggested that high cadmium and lead were negative correlated to BMD and increased the risk factor for osteoporosis.

Os metais tóxicos do soro têm sido implicados no desenvolvimento de muitas doenças. Este estudo investigou a associação entre os níveis sanguíneos de chumbo e cádmio com densidade mineral óssea anormal (DMO) e incidência de osteoporose. Sessenta adultos sauditas do sexo masculino com idades iguais foram divididos em dois grupos: um grupo de controle saudável (n = 30) e pacientes com osteoporose diagnosticados de acordo com o T-score (n = 30). Cálcio sérico, vitamina D, osteocalcina, chumbo, cádmio foram medidos. O grupo osteoporótico apresentou elevação altamente significativa dos níveis de chumbo e cádmio no sangue em comparação ao grupo controle (p < 0,001). A DMO foi negativamente correlacionada com o nível de osteocalcina sérica em comparação com o controle. Houve correlação negativa significativa entre os níveis de cádmio e chumbo (r = -0,465 ep = 0,01) e cálcio (p < 0,004). Nossos achados sugeriram que cádmio e chumbo elevados foram correlacionados negativamente à DMO e aumentaram o fator de risco para osteoporose.

Circulating MicroRNAs as Biomarkers of Osteoporosis and Fragility Fractures.

CONTEXT: Measurement of circulating microRNAs (miRNAs) as potential biomarkers of fragility fracture risk has recently become a subject of investigation. OBJECTIVE: Measure by next-generation sequencing (NGS), global miRNA expression in serum samples of osteoporotic subjects vs individuals with normal bone mineral density (BMD). DESIGN: Samples were collected from patients with different bone phenotypes and/or fragility fractures who did not receive any antiresorptive and/or bone-forming drug at the time of blood collection. SETTING: Samples and data were collected at 7 medical centers in Italy. PATIENTS: NGS prescreening: 50 osteoporotic patients vs 30 individuals with normal BMD. Droplet digital polymerase chain reaction (ddPCR) validation: 213 patients with different bone phenotypes, including the NGS-analyzed cohort. RESULTS: NGS identified 5 miRNAs (miR-8085, miR-320a-3p, miR-23a-3p, miR-4497, miR-145-5p) differentially expressed in osteoporosis cases without fractures vs controls. ddPCR validation confirmed lower c-miR-23a-3p expression in osteoporotic patients, with or without fracture, than in osteopenic and normal subjects and increased c-miR-320a-3p expression in osteoporotic patients with fracture and lower expression in osteoporotic patients without fracture. ddPCR analysis showed a significantly increased expression of miR-21-5p in osteoporotic patients, with or without fracture, than in osteopenic and normal subjects, not evidenced by the NGS prescreening. DISCUSSION: Our study confirmed levels of c-miR-23a-3p and c-miR-21-5p as able to distinguish osteoporotic patients and subjects with normal BMD. Increased levels of c-miR-320a-3p specifically associated with fractures, independently by BMD, suggesting c-miR-320a-3p as a prognostic indicator of fracture risk in osteoporotic patients, to be confirmed in prospective studies on incident fractures.

Serum osteocalcin concentration as an independent biomarker of osteoporosis in patients with chronic kidney disease.

OBJECTIVES: Osteocalcin, an osteoblast-derived hormone, is associated with the development of osteoporosis and arteriosclerosis in the general population. However, its role on the pathogenesis of osteoporosis and vascular calcification in patients with chronic kidney disease (CKD) is unclear. Here, we investigated the connection between osteocalcin, bone mineral density (BMD), and abdominal aortic calcification (AAC) in CKD patients. MATERIALS AND METHODS: In total, 95 patients with stage 2 to stage 5 CKD were enrolled. Serum osteocalcin levels were measured using an electrochemiluminescence immunoassay. BMD was determined by dual-energy X-ray absorptiometry, and AAC scores were generated from lateral lumbar radiograph findings. RESULTS: 95 patients were assigned into normal bone density (30.5%, n = 29), osteopenia (45.3%, n = 43), and osteoporosis (24.2%, n = 23) groups. The osteoporosis group was characterized by older age, higher female-to-male ratio, phosphorous levels, calcification scores, osteocalcin levels, and intact parathyroid hormone (PTH) levels, while with lower hemoglobin levels as compared to normal and osteopenia groups. Multivariate multinominal regression analysis showed age, female sex, intact PTH, and serum osteocalcin level were independent determinants of osteoporosis severity in CKD patients. Furthermore, serum osteocalcin level is positively correlated to intact PTH in multivariate linear regression model, indicating that osteocalcin might be a bone turnover marker in patients with CKD. Multivariate stepwise linear regression analysis revealed that age, diabetes mellitus, poorer renal function, rather than osteocalcin, have independent associations with AAC score. CONCLUSION: Elevated serum osteocalcin levels could be considered as a marker of osteoporosis rather than that of vascular calcification in patients with CKD.

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

Liquid chromatography-mass spectrometry method for discovering the metabolic markers to reveal the potential therapeutic effects of naringin on osteoporosis.

The pharmacological effects and therapeutic targets of naringin (NG) against osteoporosis (OP) is still unclear. Liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) based non-targeted metabonomics has been used to explore the differentiated metabolites and potential biological pathways of NG in the pathological process of OP. Using network pharmacology analysis, the key protein targets of NG against OP were also screened. By the metabonomics analysis, a total of 33 differentiated metabolites in serum were discovered, of which 21 were significantly regulated by NG treatment. These metabolites majorly associated with to amino acid metabolism,polyunsaturated fatty acid metabolism, pyruvate metabolism and glycerophospholipidmetabolism. Using the network pharmacology prediction analysis, NG was related to the expression changes of 13 important protein targets. It showed that high-throughput metabonomics strategy integrated with network pharmacology could insight into molecular mechanisms of natural products.

Circ_0006873 Sponges miR-142-5p to Inhibit Osteoblastic Differentiation of hBMSCs via Regulating PTEN/Akt Signaling Pathway.

OBJECTIVE: Osteoporosis is likely becoming a new disease challenge with increasing aging population. Circ_0006873 dysregulation may serve as an event linked to osteoporosis. Thus, this study sought to evaluate the function and mechanism of circ_0006873 on osteoporosis. METHODS: Clinical serum samples collected from 30 osteoporosis patients were utilized to obtain circ_0006873 and miR-142-5p expression data. The link between circ_0006873, miR-142-5p, and phosphatase and tensin homolog (PTEN) was demonstrated via online tools (starBase, circinteractome), RNA Immunoprecipitation (RIP) and dual-Luciferase reporter assays. After knockdown or overexpression, cell counting kit-8 (CCK-8) assay measured cell viability. Alizarin red S (ARS) staining as well Alkaline phosphatase (ALP) staining detected osteoblastic differentiation levels. Quantitative real-time PCR (qRT-PCR) and western blot analyzed expression of RNAs and proteins after transfection or during osteoblastic differentiation. RESULTS: circ_0006873 was upregulated in osteoporosis patients and decreased during osteoblastic differentiation. Following experiments revealed that cell viability, proliferation-related factors, osteogenic marker genes (ALP, Runx2, Bglap) and osteoblastic differentiation degree were promoted after circ_0006873 knockdown but inhibited after overexpression. Circ_0006873 sponged miR-142-5p, which was downregulated in osteoporosis patients and became higher during osteoblastic differentiation. Rescue assay indicated miR-142-5p mimic could reverse the effects of circ_0006873 overexpression on cell viability and osteogenic markers, and also could activate Akt pathway. Furthermore, circ_0006873 can negatively target miR-142-5p via regulating PTEN to inhibit osteoblastic differentiation. CONCLUSION: Circ_0006873 sponges miR-142-5p thereby enhances PTEN expression to suppress osteoblastic differentiation via regulation of Akt signaling pathway, thus, may provide a treatment approach for osteoporosis.

Positive association between high-density lipoprotein cholesterol and bone mineral density in U.S. adults: the NHANES 2011-2018.

BACKGROUND: Serum lipids are highly inheritable and play a major role in bone health. However, the relationship between high-density lipoprotein cholesterol (HDL-C) and bone mineral density (BMD) remains uncertain. The goal of this study was to see if there was a link between HDL-C levels and BMD in persons aged 20-59. METHODS: Multivariate logistic regression models were used to determine the link between HDL-C and lumbar BMD using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. Generalized additive models and fitted smoothing curves were also used. RESULTS: The analysis included a total of 10,635 adults. After controlling for various variables, we discovered that HDL-C was positively linked with lumbar BMD. The favorable connection of HDL-C with lumbar BMD was maintained in subgroup analyses stratified by sex and race in women, but not in men, and in blacks, but not in whites. The relationship between HDL-C and lumbar BMD in men and whites was a U-shaped curve with the same inflection point: 0.98 mmol/L. CONCLUSIONS: In people aged 20 to 59, our research discovered a positive relationship among HDL-C and lumbar BMD. Among males and whites, this relationship followed a U-shaped curve (inflection point: 0.98 mmol/L). HDL-C measurement might be used as a responsive biomarker for detecting osteoporosis early and guiding therapy.

The Short-Term Effect of Prunes in Improving Bone in Men.

Osteoporosis is a major health concern in aging populations, where 54% of the U.S. population aged 50 and older have low bone mineral density (BMD). Increases in inflammation and oxidative stress play a major role in the development of osteoporosis. Men are at a greater risk of mortality due to osteoporosis-related fractures. Our earlier findings in rodent male and female models of osteoporosis, as well as postmenopausal women strongly suggest the efficacy of prunes (dried plum) in reducing inflammation and preventing/reversing bone loss. The objective of this study was to examine the effects of two doses of prunes, daily, on biomarkers of inflammation and bone metabolism in men with some degree of bone loss (BMD; t-score between -0.1 and -2.5 SD), for three months. Thirty-five men between the ages of 55 and 80 years were randomized into one of three groups: 100 g prunes, 50 g prunes, or control. Consumption of 100 g prunes led to a significant decrease in serum osteocalcin (p < 0.001). Consumption of 50 g prunes led to significant decreases in serum osteoprotegerin (OPG) (p = 0.003) and serum osteocalcin (p = 0.040), and an increase in the OPG:RANKL ratio (p = 0.041). Regular consumption of either 100 g or 50 g prunes for three months may positively affect bone turnover.

Clinical, biochemical and genetic findings in adult patients with chronic hypophosphatasemia.

PURPOSE: The study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP). METHODS: Twenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5'-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies. RESULTS: Pathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive breast cancer. Mineral and bone markers were similar in the three groups. Mean urine PEA levels were significantly higher in patients harboring pALPL than those detected in patients harboring bALPL and wtALPL; by contrast, serum PLP levels were similar in the three groups. A 6-points score, considering clinical and biochemical features, was predictive of pALPL detection [P = 0.060, OR 1.92 (95% CI 0.972, 3.794)], and more significantly of pALPL or bALPL [P = 0.025, OR 14.33 (95% CI 1.401, 14.605)]. CONCLUSION: In osteopenic/osteoporotic patients, single clinical or biochemical factors did not distinguish hypophosphatasemic patients harboring pALPL or bALPL from those harboring wtALPL. Occurrence of multiple clinical and biochemical features is predictive of ALPL anomalies, and, therefore, they should be carefully identified. Tamoxifen emerged as a hypophosphatasemic drug.

Relationship Between Serum Amino Acid Levels and Bone Mineral Density: A Mendelian Randomization Study.

Background: This study aimed to explore the association between serum amino acids (AAs) levels and bone mineral density (BMD). Methods: We performed a two-sample Mendelian randomization (MR) analysis to analyze the associations between the levels of eight AAs and BMD values by using summary-level genome-wide association study (GWAS) data. We applied the MR Steiger filtering method and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test to check for and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. The associations were estimated with the inverse variance weighted (IVW), MR-Egger, weighted median and MR Robust Adjusted Profile Score (MR.RAPS) methods. Results: Our study found that genetically increased isoleucine (Ile) [IVW: effect = 0.1601, 95% confidence interval (CI) = 0.0604 ~ 0.2597, p = 0.0016] and valine (Val) levels (IVW: effect = 0.0953, 95% CI = 0.0251 ~ 0.1655, p = 0.0078) were positively associated with total body BMD (TB-BMD). The results also revealed that genetically increased tyrosine (Tyr) levels were negatively associated with TB-BMD (IVW: effect = -0.1091, 95% CI = -0.1863 ~ -0.0320, p = 0.0055). Conclusions: In this study, associations between serum AA levels and BMD were established. These findings underscore the important role that serum AAs play in the development of osteoporosis and provide evidence that osteoporosis can be prevented and treated by the intake of certain AAs.

Chondroitin Sulfate Alleviates Diabetic Osteoporosis and Repairs Bone Microstructure via Anti-Oxidation, Anti-Inflammation, and Regulating Bone Metabolism.

Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.

Vitamin B6 as a novel risk biomarker of fractured ankles.

ABSTRACT: Ankle fractures are the most common intra-articular fractures. Osteoporosis is a common and frequent disease among the elderly with a poor prognosis and high risk of fractured ankles. However, the relationship between vitamin B6 and the incidence of fractured ankles in patients with osteoporosis is unclear.A total of 101 patients with osteoporosis were recruited. Clinical and followed-up information was recorded. And the vitamin B6, albumin, globulin, and hemoglobin in the blood were tested. Pearson's chi-squared and spearman test were performed to analyze the correlation between fractured ankles and relative parameters. Univariate and multivariate logistic regression, receiver operating characteristic curve analysis, univariate and multivariate Cox proportional hazards regression analysis, and Kaplan-Meier method were also performed.There exist strong relation between the expression level of vitamin B6 and fractured ankle (P < .001). The expression of vitamin B6 [Odd ratio (OR) = 12.071, 95% confidence interval (CI): 4.69-31.143, P < .001] has a clear correlation with whether the patients have fractured ankles via the univariate logistic regression analysis. In terms of multivariate logistic regression level, vitamin B6 (OR = 15.384, 95% CI:5.195-45.556, P < .001) was significantly associated with fractured ankle. In addition, expression level of vitamin B6 [hazard ratio (HR) = 11.684, 95% CI: 6.419-21.267, P < .001] was significantly associated with Maintenance time from recovery to recurrence (MRTT) of patients with osteoporosis.Enhanced vitamin B6 is significantly correlated with the poor prognosis of patients with osteoporosis and the increasing incidence of fractured ankles.

Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.