Effects of circulating inflammatory proteins on osteoporosis and fractures: evidence from genetic correlation and Mendelian randomization study.

Objective: There is a controversy in studies of circulating inflammatory proteins (CIPs) in association with osteoporosis (OP) and fractures, and it is unclear if these two conditions are causally related. This study used MR analyses to investigate the causal associations between 91 CIPs and OP and 9 types of fractures. Methods: Genetic variants data for CIPs, OP, and fractures were obtained from the publicly available genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary analysis, pleiotropy, and heterogeneity tests to analyze the validity and robustness of causality and reverse MR analysis to test for reverse causality. Results: The IVW results with Bonferroni correction indicated that CXCL11 (OR = 1.2049; 95% CI: 1.0308-1.4083; P = 0.0192) can increase the risk of OP; IL-4 (OR = 1.2877; 95% CI: 1.1003-1.5070; P = 0.0016), IL-7 (OR = 1.2572; 95% CI: 1.0401-1.5196; P = 0.0180), IL-15RA (OR = 1.1346; 95% CI: 1.0163-1.2668; P = 0.0246), IL-17C (OR = 1.1353; 95% CI: 1.0272-1.2547; P = 0.0129), CXCL10 (OR = 1.2479; 95% CI: 1.0832-1.4377; P = 0.0022), eotaxin/CCL11 (OR = 1.1552; 95% CI: 1.0525-1.2678; P = 0.0024), and FGF23 (OR = 1.9437; 95% CI: 1.1875-3.1816; P = 0.0082) can increase the risk of fractures; whereas IL-10RB (OR = 0.9006; 95% CI: 0.8335-0.9730; P = 0.0080), CCL4 (OR = 0.9101; 95% CI: 0.8385-0.9878; P = 0.0242), MCP-3/CCL7 (OR = 0.8579; 95% CI: 0.7506-0.9806; P = 0.0246), IFN-γ [shoulder and upper arm (OR = 0.7832; 95% CI: 0.6605-0.9287; P = 0.0049); rib(s), sternum and thoracic spine (OR = 0.7228; 95% CI: 0.5681-0.9197; P = 0.0083)], ß-NGF (OR = 0.8384; 95% CI: 0.7473-0.9407; P = 0.0027), and SIRT2 (OR = 0.5167; 95% CI: 0.3296-0.8100; P = 0.0040) can decrease fractures risk. Conclusion: Mendelian randomization (MR) analyses indicated the causal associations between multiple genetically predicted CIPs and the risk of OP and fractures.

The influence of COMT and ABCB1 gene polymorphisms on sufentanil analgesic effect for postoperative pain in children with fracture.

The aim of this observational study was to investigate the effects of catechol-O-methyltransferase (COMT) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on the postoperative analgesic effect of sufentanil in Chinese Han pediatric patients with fractures. A total of 185 pediatric patients who underwent fracture surgery were included. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the polymorphisms of COMT and ABCB1 genes. Sufentanil was used for postoperative analgesia. The pain level of the patients was evaluated using the face, legs, activity, cry, and consolability scale before surgery, during awakening, at 2, 6, 12, and 24 hours after surgery. The postoperative Ramsay sedation score, sufentanil consumption, and incidence of adverse reactions were also recorded. Pediatric patients with different genotypes of ABCB1 and COMT showed no statistically significant differences in general data such as age, gender, weight, height, surgical duration, and American Society of Anesthesiologists classification (P > .05). There were no statistically significant differences in sedation scores after surgery between different genotypes of ABCB1 and COMT (P > .05). Among patients with CC genotype in ABCB1, the pain scores and total consumption of sufentanil at awakening, 2 and 6 hours after surgery were higher compared to TT and CT genotypes (P < .05), while there were no statistically significant differences between TT and CT genotypes (P > .05). Among patients with AA genotype in COMT, the pain scores and total consumption of sufentanil at awakening, 2, 6, 12, and 24 hours after surgery were higher compared to AG and GG genotypes (P < .05), while there were no statistically significant differences between AG and GG genotypes (P > .05). There were no statistically significant differences in adverse reactions between different genotypes of ABCB1 and COMT (P > .05). The polymorphisms of COMT gene rs4680 and ABCB1 gene rs1045642 are associated with the analgesic effect and consumption of sufentanil in pediatric patients after fracture surgery.

Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence.

The 'diabetic bone paradox' suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

Bone health index in the assessment of bone health: The Generation R Study.

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10-14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture.

Complex interplay of neurodevelopmental disorders (NDDs), fractures, and osteoporosis: a mendelian randomization study.

BACKGROUND: Neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Tourette Syndrome (TS), have been extensively studied for their multifaceted impacts on social and emotional well-being. Recently, there has been growing interest in their potential relationship with fracture risks in adulthood. This study aims to explore the associations between these disorders and fracture rates, in order to facilitate better prevention and treatment. METHODS: Employing a novel approach, this study utilized Mendelian randomization (MR) analysis to investigate the complex interplay between ADHD, ASD, TS, and fractures. The MR framework, leveraging extensive genomic datasets, facilitated a systematic examination of potential causal relationships and genetic predispositions. RESULTS: The findings unveil intriguing bidirectional causal links between ADHD, ASD, and specific types of fractures. Notably, ADHD is identified as a risk factor for fractures, with pronounced associations in various anatomical regions, including the skull, trunk, and lower limbs. Conversely, individuals with specific fractures, notably those affecting the femur and lumbar spine, exhibit an increased genetic predisposition to ADHD and ASD. In this research, no correlation was found between TS and fractures, or osteoporosis.These results provide a genetic perspective on the complex relationships between NDDs and fractures, emphasizing the importance of early diagnosis, intervention, and a holistic approach to healthcare. CONCLUSION: This research sheds new light on the intricate connections between NDDs and fractures, offering valuable insights into potential risk factors and causal links. The bidirectional causal relationships between ADHD, ASD, and specific fractures highlight the need for comprehensive clinical approaches that consider both NDDs and physical well-being.

Exploring epigenetic strategies for the treatment of osteoporosis.

The worldwide trend toward an aging population has resulted in a higher incidence of chronic conditions, such as osteoporosis. Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mass and increased fracture risk, encompasses primary and secondary forms, each with distinct etiologies. Mechanistically, osteoporosis involves an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current pharmacological interventions for osteoporosis, such as bisphosphonates, denosumab, and teriparatide, aim to modulate bone turnover and preserve bone density. Hormone replacement therapy and lifestyle modifications are also recommended to manage the condition. While current medications offer therapeutic options, they are not devoid of limitations. Recent studies have highlighted the importance of epigenetic mechanisms, including DNA methylation and histone modifications, in regulating gene expression during bone remodeling. The use of epigenetic drugs, or epidrugs, to target these mechanisms offers a promising avenue for therapeutic intervention in osteoporosis. In this review, we comprehensively examine the recent advancements in the application of epidrugs for treating osteoporosis.

MicroRNAs in osteoblast differentiation and fracture healing: From pathogenesis to therapeutic implication.

The term "fracture" pertains to the occurrence of bones being either fully or partially disrupted as a result of external forces. Prolonged fracture healing can present a notable danger to the patient's general health and overall quality of life. The significance of osteoblasts in the process of new bone formation is widely recognized, and optimizing their function could be a desirable strategy. Therefore, the mending of bone fractures is intricately linked to the processes of osteogenic differentiation and mineralization. MicroRNAs (miRNAs) are RNA molecules that do not encode for proteins, but rather modulate the functioning of physiological processes by directly targeting proteins. The participation of microRNAs (miRNAs) in experimental investigations has been extensive, and their control functions have earned them the recognition as primary regulators of the human genome. Earlier studies have shown that modulating the expression of miRNAs, either by increasing or decreasing their levels, can initiate the differentiation of osteoblasts. This implies that miRNAs play a pivotal function in promoting osteogenesis, facilitating bone mineralization and formation, ultimately leading to an efficient healing of fractures. Hence, focusing on miRNAs can be considered a propitious therapeutic approach to accelerate the healing of fractures and forestall nonunion. In this manner, the information supplied by this investigation has the potential to aid in upcoming clinical utilization, including its possible use as biomarkers or as resources for devising innovative therapeutic tactics aimed at promoting fracture healing.

Mendelian-randomization study revealed causal relationship between nonalcoholic fatty liver disease and osteoporosis/fractures.

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have a higher risk of osteoporosis/fractures; however, the causal relationship remains unclear. METHODS: Publicly available genome-wide association studies (GWASs) were used for Mendelian randomization (MR) analysis. GWASs of NAFLD and fractures were obtained from the FinnGen Consortium. GWASs of bone mineral density (BMD) were derived from a meta-analysis. GWASs of obesity, diabetes, liver function, and serum lipid-related metrics were used to clarify whether the accompanying NAFLD symptoms contributed to fractures. Moreover, two additional GWASs of NAFLD were applied. RESULTS: A causal association was not observed between NAFLD and BMD using GWASs from the FinnGen Consortium. However, a causal relationship between NAFLD and femoral neck-BMD (FN-BMD), a suggestive relationship between fibrosis and FN-BMD, and between NAFLD and osteoporosis were identified in replication GWASs. Genetically proxied body mass index (BMI), high-density lipoprotein (HDL), and hip circumference increased the likelihood of lower limb fractures. The waist-to-hip ratio decreased, whereas glycated hemoglobin (HbA1C) and homeostasis model assessment of ß-cell function (HOMA-B) increased the risk of forearm fractures. Low-density lipoprotein (LDL) reduced, whereas HbA1C increased the incidence of femoral fractures. Alkaline phosphatase (ALP) raised the risk of foot fractures. However, after a multivariate MR analysis (adjusted for BMI), all the relationships became insignificant. CONCLUSIONS: NAFLD caused reduced BMD, and genetically predicted HDL, LDL, HbA1C, HOMA-B, ALP, hip circumference, and waist-to-hip ratio causally increased the risk of fractures. BMI may mediate causal relationships. Larger GWASs are required to verify this finding.

A new method regulates bone fracture tissue exosome lncRNA-mRNA to promote mesenchymal stem cell proliferation and migration.

Post-injury adaptation (PIA) is a simple and convenient method to promote bone healing, but its mechanism is unclear. This study was to discuss the role of fracture site tissue exosomes lncRNAs-mRNAs networks on PIA promoting bone mesenchymal stem cells (BMSCs) proliferation and migration. Firstly, the effects of PIA accelerating BMSCs proliferation and migration were confirmed by rat fracture model and bone fracture environment in vitro. Besides, the fracture site tissue exosomes were isolated and authenticated. Then the tissue exosomes were the key factor in PIA promoting BMSCs proliferation and migration authenticated by in vitro and in vivo experiments. The high throughput sequencing and RT-PCR were used to analyze the tissue exosomes lncRNAs-mRNAs networks. It was found that PIA treatment upregulated 118 lncRNAs, 295 mRNAs, and downregulated 111 lncRNAs, 2706 mRNAs in tissue exosomes. A total 12,211 genes were the target genes. Akt1, Actb and Uba52 were the hub mRNAs in tissue exosomes. In additions, tissue-derived exosomes of PIA treated rats upregulated 49 genes, 3 lncRNAs and downregulated 28 genes, 1 lncRNA in BMSCs. Kif11 was the hub gene. Overall, PIA promoted BMSCs proliferation and migration in the early stage of fracture healing, which was closely related to the fracture site tissue exosomes. Akt1, Actb and Uba52 were the hub mRNAs in the exosomes. Besides, Kif11 might be the key gene in BMSC regulated by tissue-derived exosomes of PIA treated rats.

Col1A-2 Mutation in Osteogenesis Imperfecta Mice Contributes to Long Bone Fragility by Modifying Cell-Matrix Organization.

Osteogenesis imperfecta (OI) is a rare congenital bone dysplasia generally caused by a mutation of one of the type I collagen genes and characterized by low bone mass, numerous fractures, and bone deformities. The collagen organization and osteocyte lacuna arrangement were investigated in the long bones of 17-week-old wildtype (WT, n = 17) and osteogenesis imperfecta mice (OIM, n = 16) that is a validated model of severe human OI in order to assess their possible role in bone fragility. Fractures were counted after in vivo scanning at weeks 5, 11, and 17. Humerus, femur, and tibia diaphyses from both groups were analyzed ex vivo with pQCT, polarized and ordinary light histology, and Nano-CT. The fractures observed in the OIM were more numerous in the humerus and femur than in the tibia, whereas the quantitative bone parameters were altered in different ways among these bones. Collagen fiber organization appeared disrupted, with a lower birefringence in OIM than WT bones, whereas the osteocyte lacunae were more numerous, more spherical, and not aligned in a lamellar pattern. These modifications, which are typical of immature and less mechanically competent bone, attest to the reciprocal alteration of collagen matrix and osteocyte lacuna organization in the OIM, thereby contributing to bone fragility.

DNA methylation-mediated Rbpjk suppression protects against fracture nonunion caused by systemic inflammation.

Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of the skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cells were one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via constitutive activation of Ikk2, Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, consequently leading to Rbpjk upregulation via hypomethylation within its promoter region. We also showed that Dnmt3b loss-of-function mice phenotypically recapitulated the fracture repair defects observed in Ikk2ca-transgenic mice, whereas Dnmt3b-transgenic mice alleviated fracture repair defects induced by Ikk2ca. Moreover, Rbpjk ablation restored fracture repair in both Ikk2ca mice and Dnmt3b loss-of-function mice. Altogether, this work elucidates a common mechanism involving a NF-κB/Dnmt3b/Rbpjk axis within the context of inflamed bone regeneration. Building on this mechanistic insight, we applied local treatment with epigenetically modified progenitor cells in a previously established mouse model of inflammation-mediated fracture nonunion and showed a functional restoration of bone regeneration under inflammatory conditions through an increase in progenitor differentiation potential.

Does enhanced cognitive performance reduce fracture risk? a Mendelian randomization study.

OBJECTIVE: While observational studies have suggested a link between cognitive performance and fracture risk, the causality and site-specific nature are unclear. We applied Mendelian randomization (MR) to elucidate these associations. METHODS: 147 single-nucleotide polymorphisms (SNPs) tied strongly to cognitive performance (p< 5e-8) were selected. We performed MR analysis to investigate the causal relationship between cognitive performance and fractures at specific sites, including the wrist, upper arm, shoulder, ribs, sternum, thoracic spine, lumbar spine, pelvis, femur, leg, and ankle. The primary estimate was determined using the inverse variance-weighted method. Additionally, we examined heterogeneity using the MR Pleiotropy RESidual Sum Outlier test and Cochran Q, and employed MR-Egger regression to identify horizontal pleiotropy. RESULTS: MR analysis identified a causal association between cognitive performance and fractures at the lumbar-spine-pelvis (odds ratio [OR] = 0.727, 95% CI = 0.552-0.956, p = 0.023), and ribs-sternum-thoracic spine sites (OR = 0.774, 95% CI = 0.615-0.974, p = 0.029). However, no causal association was found for fractures at other sites. CONCLUSIONS: This study provided evidence of a causal connection between cognitive performance and fracture risk at certain locations. These findings underline the potential of cognitive enhancement strategies as innovative and effective methods for fracture prevention.

Shape and fractures of carina sterni in chicken genotypes with different egg deposition rates reared indoor or free-range.

Commercial laying hens have high frequency of damage to the keel bone (KB), which causes negative effects on health and welfare. KB damage may consist in fractures (KBF) and deviations (KBD). The aim of the present study was to compare the KB shape, by means of Geometric Morphometric, and the occurrence of fractures in different chicken genotypes reared either free-range (FR) or in enriched cages. Moreover, the relationship between KB shape, genotype and rearing system was analysed. Sixty birds/genotype (2 Italian local breeds, Bionda Piemontese and Robusta Maculata, their crossbreeds with Sasso and Lohmann Brown) were used. All the hens fed the same commercial feed throughout the trial. Body weight, egg production, feed intake and mortality were recorded from 25 to 66 weeks of age. Ca intake (IN) and output (OUT) were estimated and Ca OUT/IN was calculated. FR affected the occurrence of KB deviations but not the shape, whereas the fractures were mainly affected by genotype. Local breeds had a lower prevalence of KBF with similar level of KBD but with different shapes. Crossbreeds seemed to be a suitable compromise between egg deposition rate and occurrence of KB damages.

An atlas of genetic determinants of forearm fracture.

Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.

Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis.

Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.

Genetic and Gene Expression Resources for Osteoporosis and Bone Biology Research.

PURPOSE OF REVIEW: The integration of data from multiple genomic assays from humans and non-human model organisms is an effective approach to identify genes involved in skeletal fragility and fracture risk due to osteoporosis and other conditions. This review summarizes genome-wide genetic variation and gene expression data resources relevant to the discovery of genes contributing to skeletal fragility and fracture risk. RECENT FINDINGS: Genome-wide association studies (GWAS) of osteoporosis-related traits are summarized, in addition to gene expression in bone tissues in humans and non-human organisms, with a focus on rodent models related to skeletal fragility and fracture risk. Gene discovery approaches using these genomic data resources are described. We also describe the Musculoskeletal Knowledge Portal (MSKKP) that integrates much of the available genomic data relevant to fracture risk. The available genomic resources provide a wealth of knowledge and can be analyzed to identify genes related to fracture risk. Genomic resources that would fill particular scientific gaps are discussed.

The causal effect of schizophrenia on fractures and bone mineral density: a comprehensive two-sample Mendelian randomization study of European ancestry.

BACKGROUND: Schizophrenia was clinically documented to co-occur with fractures and aberrant bone mineral density (BMD), but the potential causal relationship remained unclear. This study aimed to test the causal effects between schizophrenia and fractures as well as aberrant BMD by conducting Mendelian randomization (MR) analyses. METHODS: Two-sample MR was utilized, based on instrumental variables from large genome-wide association studies (GWAS) of schizophrenia as exposure, to identify the causal association of schizophrenia with mixed fractures, fractures at different body sites (including skull and facial bones, shoulder and upper arm, wrist and hand, and femur) and BMDs of forearm (FA), femoral neck (FN), lumbar spine (LS) and estimated BMD (eBMD). Multivariable Mendelian randomization (MVMR) analysis was performed to minimize the confounding effect of body mass index (BMI). RESULTS: Result from inverse variance weighting (IVW) method provided evidence schizophrenia increased the risk of fractures of skull and facial bones [odds ratio (OR) = 1.0006, 95% confidence interval (CI): 1.0003 to 1.0010] and femur [OR =1.0007, 95% CI: 1.0003 to 1.0011], whereas, decreased the level of eBMD [ß (95%CI): -0.013 (-0.021, -0.004)]. These causal effects still existed after adjusting for BMI. Sensitivity analyses showed similar results. However, no causal effect of schizophrenia on fracture or BMD in other parts was detected. CONCLUSION: The current finding confirmed that schizophrenia was causally associated with the fractures of skull, face and femur as well as eBMD, which might remind psychiatrists to pay close attention to the fracture risk in schizophrenic patients when formulating their treatment strategies.

The causal relationship between autoimmune diseases and osteoporosis: a study based on Mendelian randomization.

Objective: The relationship between different autoimmune diseases and bone mineral density (BMD) and fractures has been reported in epidemiological studies. This study aimed to explore the causal relationship between autoimmune diseases and BMD, falls, and fractures using Mendelian randomization (MR). Methods: The instrumental variables were selected from the aggregated statistical data of these diseases from the largest genome-wide association study in Europe. Specifically, 12 common autoimmune diseases were selected as exposure. Outcome variables included BMD, falls, and fractures. Multiple analysis methods were utilized to comprehensively evaluate the causal relationship between autoimmune diseases and BMD, falls, and fractures. Additionally, sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and one analysis, were conducted to verify the result's reliability. Results: Strong evidence was provided in the results of the negatively association of ulcerative colitis (UC) with forearm BMD. UC also had a negatively association with the total body BMD, while inflammatory bowel disease (IBD) depicted a negatively association with the total body BMD at the age of 45-60 years. Horizontal pleiotropy or heterogeneity was not detected through sensitivity analysis, indicating that the causal estimation was reliable. Conclusion: This study shows a negative causal relationship between UC and forearm and total body BMD, and between IBD and total body BMD at the age of 45-60 years. These results should be considered in future research and when public health measures and osteoporosis prevention strategies are formulated.

Assessing the Casual Association between Sex Hormone Levels and Fracture Risk: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone-binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome-wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two-sample MR approach. For the main analysis, the inverse-variance-weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR-Egger method were utilized. To evaluate potential pleiotropy, MR-Egger regression was conducted. Additionally, a leave-one-SNP-out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. RESULTS: The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52-3.85; p = 1.93 × 10-4 ]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10-4 ), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10-6 ). CONCLUSIONS: Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.

Association of trabecular bone score and bone mineral apparent density with the severity of bone fragility in children and adolescents with osteogenesis imperfecta: A cross-sectional study.

Osteogenesis imperfecta (OI) is a hereditary skeletal disease characterized by bone fragility. Areal bone mineral density (BMD), evaluated by dual-energy X-ray absorptiometry (DXA), is used to assess bone brittleness. The height-adjusted BMD Z-score (BMDHAZ) is calculated in children and adolescents with OI to reduce the confounding factor of short stature. However, even with the BMDHAZ, severity evaluation in children and adolescents with OI is challenging because certain abnormalities in bone quality cannot be accurately assessed by BMD analysis. The trabecular bone scores (TBS) and bone mineral apparent density (BMAD), which represent the structural integrity of bone and bone-size-associated BMD, respectively, are associated with fracture risk. Recently, age- and sex-specific reference ranges have been reported, enabling the calculation of Z-scores for children. To evaluate which density measurements show the highest correlation with fracture risk, we analyzed the associations between the Z-scores of TBS, BMAD, and BMDHAZ, fracture rate, and genetic variants. We retrospectively reviewed 42 participants with OI aged 5 to 20 years who underwent DXA. COL1A1/2 pathogenic variants were detected in 41 of the 42 participants. In participants with nonsense and frameshift variants (n = 17) resulting in haploinsufficiency and mild phenotype, the TBS Z-score was negatively correlated with fracture rate (FR) (r = -0.50, p = 0.042). In participants with glycine substitution (n = 9) causing the severe phenotype, the BMAD Z-scores were negatively correlated with FR (r = -0.74, p = 0.022). No correlation between the BMDHAZ and FR was observed in both groups. These findings suggest that the TBS and BMAD are useful in assessing children and adolescents with OI with specific genetic variants.