Skeletal Sites Research Articles

Ultrasound propagation in cancellous bone: Dependence on mechanical, material, and structural properties

Critical skeletal sites for osteoporotic fractures include femur and vertebrae. However, many ultrasound devices designed for the management of osteoporosis instead target the calcaneus, which is far more accessible to ultrasound than femur or vertebrae. Calcaneus-based devices have been shown to be very effective for predicting osteoporotic fractures of the hip. MicroCT-based finite element models support targeting of calcaneus based on similar biomechanical structure-function relations in calcaneus compared with femoral neck, greater trochanter, proximal tibia, and vertebra. Finite element analysis can be used to relate these mechanical properties to ultrasonic properties such as broadband ultrasound attenuation, speed of sound, and broadband ultrasound backscatter. As an ultrasound beam propagates through cancellous bone, it loses energy to absorption, longitudinal-shear scattering, and longitudinal-longitudinal scattering. The relative roles of these mechanisms can be demonstrated in phantom models.

Identification of the metaphyseal skeletal stem cell building trabecular bone.

Skeletal stem cells (SSCs) that are capable of self-renewal and multipotent differentiation contribute to bone development and homeostasis. Several populations of SSCs at different skeletal sites have been reported. Here, we identify a metaphyseal SSC (mpSSC) population whose transcriptional landscape is distinct from other bone mesenchymal stromal cells (BMSCs). These mpSSCs are marked by Sstr2 or Pdgfrb+Kitl-, located just underneath the growth plate, and exclusively derived from hypertrophic chondrocytes (HCs). These HC-derived mpSSCs have properties of self-renewal and multipotency in vitro and in vivo, producing most HC offspring postnatally. HC-specific deletion of Hgs, a component of the endosomal sorting complex required for transport, impairs the HC-to-mpSSC conversion and compromises trabecular bone formation. Thus, mpSSC is the major source of BMSCs and osteoblasts in bone marrow, supporting the postnatal trabecular bone formation.

TNF-α promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis

Postmenopausal osteoporosis (PMOP) is a common kind of osteoporosis that is associated with excessive osteocyte death and bone loss. Previous studies have shown that TNF-α-induced osteocyte necroptosis might exert a stronger effect on PMOP than apoptosis, and TLR4 can also induce cell necroptosis, as confirmed by recent studies. However, little is known about the relationship between TNF-α-induced osteocyte necroptosis and TLR4. In the present study, we showed that TNF-α increased the expression of TLR4, which promoted osteocyte necroptosis in PMOP. In patients with PMOP, TLR4 was highly expressed at skeletal sites where exists osteocyte necroptosis, and high TLR4 expression is correlated with enhanced TNF-α expression. Osteocytes exhibited robust TLR4 expression upon exposure to necroptotic osteocytes in vivo and in vitro. Western blotting and immunofluorescence analyses demonstrated that TNF-α upregulated TLR4 expression in vitro, which might further promote osteocyte necroptosis. Furthermore, inhibition of TLR4 by TAK-242 in vitro effectively blocked osteocyte necroptosis induced by TNF-α. Collectively, these results suggest a novel TLR4-mediated process of osteocyte necroptosis, which might increase osteocyte death and bone loss in the process of PMOP.

Association of type 2 Diabetes Mellitus and bone mineral density: a two-sample Mendelian randomization study

BackgroundObservational studies have suggested that type 2 Diabetes Mellitus (DM2) is a potentially modifiable risk factor for lower BMD, but the causal relationship is unclear. This study aimed to examine whether the association of DM2 with lower BMD levels was causal by using Mendelian randomization (MR) analyses.MethodsWe collected genome-wide association study data for DM2 and BMD of total body and different skeletal sites from the IEU database. Subsequently, we performed a two-sample Mendelian randomization analysis using the Two Sample MR package.ResultsWe identified a positive association between DM2 risk (61,714 DM2 cases and 596,424 controls) and total BMD, and other skeletal sites BMD, such as femoral neck BMD, ultra-distal forearm BMD and heel BMD. However, non-significant trends were observed for the effects of DM2 on lumbar-spine BMD.ConclusionIn two-sample MR analyses, there was positive causal relationship between DM2 and BMD in both overall samples. In summary, while observational analyses consistently indicate a strong association between DM2 and low BMD, our MR analysis introduces a nuanced perspective. Contrary to the robust association observed in observational studies, our MR analysis suggests a significant link between DM2 and elevated BMD.

Association between BMD and coronary artery calcification: an observational and Mendelian randomization study.

Observational studies have reported inconsistent associations between bone mineral density (BMD) and coronary artery calcification (CAC). We examined the observational association of BMD with CAC in 2 large population-based studies and evaluated the evidence for a potential causal relation between BMD and CAC using polygenic risk scores (PRS), 1- and 2-sample Mendelian randomization (MR) approaches. Our study populations comprised 1414 individuals (mean age 69.9yr, 52.0% women) from the Rotterdam Study and 2233 individuals (mean age 56.5yr, 50.9% women) from the Framingham Heart Study with complete information on CAC and BMD measurements at the total body (TB-), lumbar spine (LS-), and femoral neck (FN-). We used linear regression models to evaluate the observational association between BMD and CAC. Subsequently, we compared the mean CAC across PRSBMD quintile groups at different skeletal sites. In addition, we used the 2-stage least squares regression and the inverse variance weighted (IVW) model as primary methods for 1- and 2-sample MR to test evidence for a potentially causal association. We did not observe robust associations between measured BMD levels and CAC. These results were consistent with a uniform random distribution of mean CAC across PRSBMD quintile groups (P-value > .05). Moreover, neither 1- nor 2-sample MR supported the possible causal association between BMD and CAC. Our results do not support the contention that lower BMD is (causally) associated with an increased CAC risk. These findings suggest that previously reported epidemiological associations of BMD with CAC are likely explained by unmeasured confounders or shared etiology, rather than by causal pathways underlying both osteoporosis and vascular calcification processes.

Prevalence of discordance between femoral and lumbar bone mineral density among older adults in a community-based setting.

T-score measurement via dual-energy X-ray absorptiometry (DXA) is the gold standard for assessing and classifying the bone mineral density status of patients as normal, osteopenic, or osteoporotic according to the World Health Organization criteria. However, the diagnostic accuracy may be affected by the skeletal site selected for DXA. Estimate the prevalence of femoral and lumbar BMD discordance in a community-based setting in Riyadh, Saudi Arabia. Cross-sectional. Polyclinics at a tertiary care center. This study included all patients aged ≥60 years who visited the Department of Family Medicine and underwent DXA screening between 2016 and 2022. Discordance was defined as a difference in BMD status between two skeletal sites. Minor discordance occurs when adjacent sites have different diagnoses; i.e., one site exhibits osteoporosis and the other exhibits osteopenia. In contrast, major discordance occurs when one site exhibits osteoporosis and the other exhibits normal BMD. 1429 older adults. The study patients had a median age of 66 years (60-99, minimum-maximum). The prevalence of discordance was 41.6%, with major discordance present in 2.2% of patients and minor discordance in 39.4%. The distribution of discordance did not differ significantly among the sociodemographic factors. Discordance is prevalent among the Saudi geriatric population. During the analysis of DXA results, physicians should account for discordance when diagnosing and ruling out osteoporosis in high-risk patients. All factors influencing discordance were not explored thoroughly; this study mainly focused on older adults. Furthermore, diverse age groups need to be investigated for a more comprehensive understanding of the analyzed factors.

Exploring causality between bone mineral density and frailty: A bidirectional Mendelian randomization study.

The bidirectional correlation between low bone mineral density (BMD) and frailty, despite its extensive documentation, still lacks a conclusive understanding. The objective of this Mendelian randomization (MR) study is to investigate the bidirectional causal relationship between BMD and frailty. We utilized summary statistics data for BMD at different skeletal sites-including heel BMD (e-BMD, N = 40,613), forearm BMD (FA-BMD, N = 8,143), femoral neck BMD (FN-BMD, N = 32,735), and lumbar spine BMD (LS-BMD, N = 28,489), alongside frailty index (FI, N = 175,226) data in participants of European ancestry. MR analysis in our study was conducted using well-established analytical methods, including inverse variance weighted (IVW), weighted median (WM), and MR-Egger approaches. We observed negative causal estimates between genetically predicted e-BMD (IVW β = - 0.020, 95% confidence interval (CI) = - 0.038, - 0.002, P = 0.029) and FA-BMD (IVW β = -0.035, 95% CI = -0.066, -0.004, P = 0.028) with FI. However, the results did not reach statistical significance after applying the Bonferroni correction, with a significance threshold set at P < 0.0125 (0.05/4). There was no causal effect of FN-BMD (IVW β = - 0.024, 95% CI = -0.052, 0.004, P = 0.088) and LS-BMD (IVW β = - 0.005, 95% CI = -0.034, 0.024, P = 0.749) on FI. In the reverse Mendelian randomization (MR) analysis, we observed no causal effect of FI on BMD at various skeletal sites. Our study provides support for the hypothesis that low BMD may be a potential causal risk factor for frailty, but further research is needed to confirm this relationship. However, our findings did not confirm reverse causality.

Damaged bone microarchitecture by Trabecular Bone Score (TBS) and low appendicular muscle mass: main risk factors for vertebral and non-vertebral fractures in women with long-standing rheumatoid arthritis.

To assess risk factors for fractures, including clinical, laboratory and dual energy X-ray absorptiometry (DXA) parameters (bone mass, trabecular bone score-TBS, muscle mass) in women with established rheumatoid arthritis (RA). Three hundred females with RA (ACR, 2010) were studied. Clinical data were obtained by questionnaire and disease activity by composite indices (DAS28, CDAI, SDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Bone mineral density (BMD), TBS, body composition and Vertebral Fracture Assessment (VFA) were performed by DXA. Logistic regression models were constructed to identify factors independently associated with vertebral (VF) and non-vertebral fractures (NVF), separately. Through rigorous eligibility criteria, a total of 265 women were yielded for final data analysis (median age, 55 [22-86] years; mean disease duration, 16.2years). Prevalence of VF and NVF were 30.6% and 17.4%, respectively. In multivariate analyzes, TBS (OR = 1.6, 95%CI = 1.09-2.36, p = 0.017), CRP (OR = 1.54, 95%CI = 1.15-2.08, p = 0.004), and parathormone (OR = 1.24, 95%CI = 1.05-1.45, p = 0.009) were risk factors for VF, whereas low appendicular muscle mass (OR = 2.71; 95%CI = 1.01-7,28; p = 0.048), body mass index (BMI) (OR = 0.90, 95%CI = 0.82-0.99; p = 0.025), ESR (OR = 1.18, 95%CI = 1.01-1,38, p = 0,038) and hip BMD (OR = 1.82, 95%CI = 1.10-3.03, p = 0.02) were associated with NVF. In women with long-term RA, markers of fractures differed between distinct skeletal sites (vertebral and non-vertebral). The magnitude of association of bone/muscle parameters with fracture (TBS for VF and appendicular muscle mass for NVF) was greater than that of the association between RA activity and fracture. TBS seems to have greater discriminative power than BMD to identify subjects with VF in long-standing RA.

Effect of magnesium deficiency on bone health

Objective. To assess the impact of magnesium deficiency on bone metabolism based on an analytical analysis of current literature, as well as to systematize data on the impact of magnesium deficiency on the development of osteoporosis, bone regeneration, and to consider it as a risk factor for fracture. Methods. The review is based on the analysis of literature sources from PubMed, Scopus, Web of Science, Cochrane Library, Google, Google Scholar, and RLNS. The search was conducted by keywords: magnesium, deficiency, magnesium and bone tissue, magnesium and osteoporosis, magnesium and fractures, magnesium and bone regeneration. Results. Magnesium is a key element in the metabolic and regulatory processes of the body. Its effects on bone tissue are direct and indirect. The direct magnesium effect on genes involved in osteogenesis is accompanied by proliferation of mesenchymal stem cells and osteoblasts, but magnesium deficiency leads to their reduction and apoptosis. In case of magnesium deficiency, the number and activity of osteoclasts increases. Magnesium regulates bone mineralization in a concentration-dependent manner. Magnesium deficiency increases bone resorption and affects osteopenia and osteoporosis, which can occur indirectly through decreased vitamin D levels, increased biosynthesis of parathyroid hormone, increased oxidative stress and biosynthesis of proinflammatory cytokines. However, data on bone mineral density at different skeletal sites in magnesium deficiency are ambiguous. Magnesium deficiency is considered a risk factor for fracture. It is of great importance for bone regeneration, affecting in various ways: it stimulates the proliferation and differentiation of mesenchymal stem cells and osteoblasts, periosteum cells, increases the movement of osteoblasts to the area of traumatic bone injury, and activates signaling pathways. At the early stage of regeneration magnesium has a positive effect on macrophages, its specificity of action is inhibition of transformation of M2 macrophages into M1 at the tissue-specific stage of regeneration. One of the mechanisms stimulating regeneration may be the effect of magnesium on axons, release and increase of calcitonin-related polypeptide α. Conclusions. Since hypomagnesemia is a potentially modifiable factor, this opens up prospects for maintaining bone health and requires further research in this area.

Rapid bone microarchitecture decline in older men with high bone turnover-the prospective STRAMBO study.

Older men with high bone turnover have faster bone loss. We assessed the link between the baseline levels of bone turnover markers (BTMs) and the prospectively assessed bone microarchitecture decline in men. In 825 men aged 60-87yr, we measured the serum osteocalcin (OC), bone alkaline phosphatase (BAP), N-terminal propeptide of type I procollagen (PINP), and C-terminal telopeptide of type I collagen (CTX-I), and urinary total deoxypyridinoline (tDPD). Bone microarchitecture and strength (distal radius and distal tibia) were estimated by high-resolution pQCT (XtremeCT, Scanco Medical) at baseline and then after 4 and 8yr. Thirty-seven men took medications affecting bone metabolism. Statistical models were adjusted for age and BMI. At the distal radius, the decrease in the total bone mineral density (Tt.BMD), cortical BMD (Ct.BMD), cortical thickness (Ct.Thd), and cortical area (Ct.Ar) and failure load was faster in the highest vs the lowest CTX-I quartile (failure load: -0.94 vs -0.31% yr-1, P < .001). Patterns were similar for distal tibia. At the distal tibia, bone decline (Tt.BMD, Ct.Thd, Ct.Ar, Ct.BMD, and failure load) was faster in the highest vs the lowest tDPD quartile. At each skeletal site, the rate of decrease in Tb.BMD differed between the extreme OC quartiles (P < .001). Men in the highest BAP quartile had a faster loss of Tt.BMD, Tb.BMD, reaction force, and failure load vs the lowest quartile. The link between PINP and bone decline was poor. The BTM score is the sum of the nos. of the quartiles for each BTM. Men in the highest quartile of the score had a faster loss of cortical bone and bone strength vs the lowest quartile. Thus, in the older men followed prospectively for 8yr, the rate of decline in bone microarchitecture and estimated bone strength was 50%-215% greater in men with high bone turnover (highest quartile, CTX-I above the median) compared to the men with low bone turnover (lowest quartile, CTX-I below the median).

Muscle ultrasound to diagnose sarcopenia in chronic kidney disease: a systematic review and bayesian bivariate meta-analysis

ObjectiveThe aim of this systematic review was to assess the diagnostic test accuracy of muscle ultrasound for sarcopenia among chronic kidney disease (CKD) populations.BackgroundSarcopenia has become a worldwide health issue, especially for CKD patients. Conventional techniques of muscle mass assessment often prove limited, thus prompts increasing interest in ultrasound suitability.MethodsWe searched the Cochrane Library, PubMed and Embase for literature published up to June 2023. Ultrasound diagnosis of sarcopenia in CKD patients was included. Two independent investigators used the Quality Assessment Tool for Diagnosis Accuracy Studies (QUADAS-2) to assess the quality. We extracted valuable information from eligible studies. Using a Bayesian bivariate model, we pooled sensitivity and specificity values and summary receiver operating characteristic (SROC) curves.ResultsFive articles, involving 428 participants at various stages of CKD were included. Three studies diagnosed by the cross-sectional area (CSA) of the rectus femoris, while two others by muscle thickness (MT) and shear wave elastography (SWE) from the same muscle, separately. Overall, CSA or SWE had a pooled sensitivity of 0.95 (95% CrI, 0.80, 1.00), and the specificity was 0.73 (95% CrI, 0.55, 0.88) for diagnosing sarcopenia in CKD patients.ConclusionsUltrasound measurements of CSA and SWE were more sensitive for diagnosing sarcopenia in the CKD population than in the general population. Ultrasound assessment from a single peripheral skeletal muscle site may serve as a rapid screening tool for identifying sarcopenic individuals within the CKD population, if a specific cut-off value could be determined.

Τhe story of sclerostin inhibition: the past, the present, and the future.

Sclerostin inhibits osteoblast activity by hampering activation of the canonical Wnt signaling pathway and simultaneously stimulates osteoclastogenesis through upregulation of the receptor activator of NFκB ligand (RANKL). Thus, antibodies against sclerostin (Scl-Abs), besides promoting bone formation, suppress bone resorption and dissociate bone formation from resorption. This dual action results in remarkable increases of bone mineral density which are of a greater magnitude compared to the other antiosteoporotic treatments and are accompanied by decreases of fracture risk at all skeletal sites. The anabolic effect subsides after the first few months of treatment and a predominantly antiresorptive effect remains after this period, limiting its use to 12months. Furthermore, these effects are largely reversible upon discontinuation; therefore, subsequent treatment with antiresorptives is indicated to maintain or further increase the bone gains achieved. Romosozumab is currently the only Scl-Ab approved for the treatment of severe postmenopausal osteoporosis. Indications for use in other populations, such as males, premenopausal women, and patients with glucocorticoid-induced osteoporosis, are pending. Additionally, the efficacy of Scl-Abs in other bone diseases, such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemia, and bone loss associated with malignancies, is under thorough investigation. Cardiovascular safety concerns currently exclude patients at high cardiovascular risk from this treatment.

Causal relationship between reproductive factors and female bone density: a univariate and multivariate mendelian randomization study.

Observational studies have found associations between reproductive factors and bone density in women. However, the causal relationships are not well understood. This study aims to investigate whether various reproductive factors are causally related to bone density at different skeletal sites using both univariable and multivariable Mendelian randomization (MR) methods. The study incorporated four reproductive factors, namely, age at menarche (AAM), age at first live birth (AFB), age at menopause (ANM), and age at last live birth (ALB), as well as five distinct skeletal sites, including bone mineral density (BMD), heel calcaneus BMD, ultradistal forearm bone mineral density (FA-BMD), lumbar spine bone mineral density (LS-BMD), and femoral neck bone mineral density (FN-BMD). Univariable two-sample MR and multivariable MR analyses were conducted using data from published genome-wide association studies (GWASs). A total of 150 single nucleotide polymorphisms (SNPs) associated with the four reproductive factors were extracted from GWAS databases. The primary statistical analysis method utilized in this study was the inverse variance weighted (IVW) method. In the univariate MR analysis, we observed causal connections between four reproductive factors and bone density. Specifically, AAM had a significant impact on BMD and heel calcaneus BMD. Age at first live birth was negatively associated with FA-BMD. Age at last live birth showed a negative correlation with BMD and heel calcaneus BMD. ANM exhibited positive associations with BMD, heel calcaneus BMD, FA-BMD, and LS-BMD. Subsequently, we performed a multivariable MR analysis to examine the combined effects of multiple variables, which confirmed the persistence of associations between age at menopause and bone density at various sites. Additionally, we found a negative correlation between age at last live birth and heel calcaneus BMD. This study offers a fresh perspective on the prevention of osteoporosis in women, explicitly stating that reproductive factors such as early menopause and late childbirth play a significant predictive role in individual bone density decline. Therefore, when developing osteoporosis screening and management protocols, reproductive factors should be included for a more comprehensive guidance of clinical practice.

Strukturne determinante povećane koštane fragilnosti kod starijih osoba - višestruke perspektive

Numerous epidemiological studies have shown that increased bone fragility and a higher risk of fractures are present in the aged, which reduces their quality of life and represents a significant socio-economic burden for the healthcare system. However, morphological and structural determinants underlying increased bone fragility have yet to be fully explained. This paper aimed to provide an overview of modern studies that dealt with determinants of increased bone fragility, analyzing different hierarchical levels of bone tissue organization (macro-, micro-, and nano-levels) in aged individuals and individuals with chronic comorbidities (mainly in individuals with chronic liver disease, renal disorders, and type 2 diabetes mellitus). Also, variable frequency of fractures at different skeletal sites in aged persons and individuals with chronic diseases was shown, indicating that aging-related bone loss is not a uniform process. A complete understanding of the spatial pattern of impaired bone quality can aid in the targeted evaluation of individualized fracture risk. Establishing a firm connection between the results of the clinical assessment of bone status and the analysis of numerous structural and mechanical bone properties (on various hierarchical levels) can represent a solid base for developing adequate guidelines and algorithms for prevention and treatment of increased bone fragility in aged individuals and individuals with chronic diseases.

Comparison of bone mineral density of runners with inactive males: A cross-sectional 4HAIE study.

The purpose of the study was to determine whether running is associated with greater bone mineral density (BMD) by comparing the BMD of regularly active male runners (AR) with inactive nonrunner male controls (INC). This cross-sectional study recruited 327 male AR and 212 male INC (aged 18-65) via a stratified recruitment strategy. BMD of the whole body (WB) and partial segments (spine, lumbar spine (LS), leg, hip, femoral neck (FN), and arm for each side) were measured by dual-energy x-ray absorptiometry (DXA) and lower leg dominance (dominant-D/nondominant-ND) was established by functional testing. An ANCOVA was used to compare AR and INC. The AR had greater BMD for all segments of the lower limb (p<0.05), but similar BMD for all segments of the upper limb (p>0.05) compared with INC. Based on the pairwise comparison of age groups, AR had greater BMD of the ND leg in every age group compared with INC (p<0.05). AR had grater BMD of the D leg in every age group except for (26-35 and 56-65) compare with INC (p<0.05). In the youngest age group (18-25), AR had greater BMD in every measured part of lower extremities (legs, hips, femoral necks) compared with INC (p<0.05). In the 46-55 age group AR had greater BMD than INC (p < 0.05) only in the WB, D Leg, D neck, and ND leg. In the 56-65 age group AR had greater BMD than INC (p<0.05) only in the ND leg. Overall, AR had greater BMD compared with INC in all examined sites except for the upper limbs, supporting the notion that running may positively affect bone parameters. However, the benefits differ in the skeletal sites specifically, as the legs had the highest BMD difference between AR and INC. Moreover, the increase in BMD from running decreased with age.

Causal relationship between glycemic traits and bone mineral density in different age groups and skeletal sites: a Mendelian randomization analysis.

Previous research has confirmed that patients with type 2 diabetes mellitus tend to have higher bone mineral density (BMD), but it is unknown whether this pattern holds true for individuals without diabetes. This Mendelian randomization (MR) study aims to investigate the potential causal relationship between various glycemic trait (including fasting glucose, fasting insulin, 2-h postprandial glucose, and glycated hemoglobin) and BMD in non-diabetic individuals. The investigation focuses on different age groups (15-30, 30-45, 45-60, and 60 + years) and various skeletal sites (forearm, lumbar spine, and hip). We utilized genome-wide association study data from large population-based cohorts to identify robust instrumental variables for each glycemic traits parameter. Our primary analysis employed the inverse-variance weighted method, with sensitivity analyses conducted using MR-Egger, weighted median, MR-PRESSO, and multivariable MR methods to assess the robustness and potential horizontal pleiotropy of the study results. Fasting insulin showed a negative modulating relationship on both lumbar spine and forearm. However, these associations were only nominally significant. No significant causal association was observed between blood glucose traits and BMD across the different age groups. The direction of fasting insulin's causal effects on BMD showed inconsistency between genders, with potentially decreased BMD in women with high fasting insulin levels and an increasing trend in BMD in men. In the non-diabetic population, currently available evidence does not support a causal relationship between glycemic traits and BMD. However, further investigation is warranted considering the observed gender differences.

Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density.

It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss. The objective of this study was to investigate the risk of fracture and BMD of sequence variants in GIPR that reduce the activity of the GIP receptor and have been associated with reduced body mass index (BMI). We analyzed the association of 3 missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and 2 rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss-of-function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analyzed associations with fractures at different skeletal sites in the general population: any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically nonvertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy x-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD). None of the 3 missense variants in GIPR was significantly associated with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR was not associated with fractures or with BMD measured with clinically validated DXA, but was associated with eBMD. Missense variants in GIPR, or burden of LoF variants in the gene, are not associated with risk of fractures or with lower BMD.

The association of lipid metabolism with bone metabolism and the role of human traits: a Mendelian randomization study.

The impact of lipid metabolism on bone metabolism remains controversial, and the extent to which human traits mediate the effects of lipid metabolism on bone metabolism remains unclear. This study utilized mendelian randomization to investigate the effects of blood lipids on bone mineral density (BMD) at various skeletal sites and examined the mediating role of human traits in this process. We leveraged genetic data from large-scale genome-wide association studies on blood lipids (n=1,320,016), forearm bone mineral density (FA-BMD) (n=10,805), lumbar spine bone mineral density (LS-BMD) (n=44,731), and femoral neck bone mineral density (FN-BMD) (n=49,988) to infer causal relationships between lipid and bone metabolism. The coefficient product method was employed to calculate the indirect effects of human traits and the proportion of mediating effects. The results showed that a 1 standard deviation(SD) increase in HDL-C, LDL-C and TC was associated with a decrease in LS-BMD of 0.039 g/cm2, 0.045 g/cm2 and 0.054 g/cm2, respectively. The proportion of mediating effects of systolic blood pressure (SBP) on HDL-C to LS-BMD was 3.17%, but suppression effects occurred in the causal relationship of LDL-C and TC to LS-BMD. Additionally, the proportion of mediating effects of hand grip strength (HGS) on the TC to LS-BMD pathway were 6.90% and 4.60% for the left and right hands, respectively. In conclusion, a negative causal relationship was established between lipid metabolism and bone metabolism. Our results indicated that SBP and HGS served as mediators for the effects of lipid metabolism on bone metabolism.

Osteoporosis and Obesity.

This article concisely overviews the complex relationship between obesity and bone health. Obesity, characterized by excessive fat accumulation, has been traditionally associated with higher bone mineral density. Also, recent data suggest a favorable bone microarchitecture profile in these patients. However, the increase in bone mineral density does not necessarily confer protection against fractures, and the risk of fractures may vary depending on the skeletal sites. Various factors, including mechanical factors, hormones, cytokines, inflammation, and bone marrow adiposity, contribute to the adverse effect of obesity on bone. The article explores these factors alongside non-invasive techniques and tools like the Fracture Risk Assessment (FRAX) to evaluate fracture risk. This article also highlights the essential roles of hormones such as vitamin D, Parathormone (PTH), FGF-23 (Fibroblast Growth Factor 23), which affect bone health, and some of the hormones secreted from the adipose tissues such as adiponectin and leptin. The article delves into the intriguing obesity paradox, where an increased BMI correlates with higher bone mineral density but not necessarily reduced fracture risk. Sarcopenic obesity, a combination of excessive fat accumulation and reduced muscle mass, further complicates the relationship between obesity and bone health. Physicians should keep a comprehensive approach to treating obese patients with osteoporosis, including lifestyle modifications, weight management, fall prevention strategies, and pharmacological interventions. Further research is needed to better understand the relationship between obesity and bone health.

Вычислительный фантом для дозиметрии красного костного мозга пятилетнего ребенка от инкорпорированных бета-излучателей

The red bone marrow (RBM) exposure due to bone-seeking radionuclides can lead to grave medical consequences. In particular, the increased risk of leukemia in people exposed due to contamination of the Techa River in 1950s is associated with the RBM exposure due to 89,90Sr. Improvement of the internal RBM dosimetry methods includes the development of computational phantoms that represent 3D models of the skeletal sites. Modeling radiation transport within such phantoms enables estimation of conversion factors from the radionuclide activity in the bone to the RBM dose rate. This paper is an extension study focused on generating a set of computational phantoms representing skeletons of individuals of different ages. The aim was to develop a computational phantom representing a 5-yearold child for internal RBM dosimetry from incorporated beta emitters. The phantoms of the skeletal sites with active hematopoiesis were created using the original Stochastic Parametric Skeletal Dosimetry (SPSD) method. With this method, every such site represented a set of smaller phantoms of simple geometric shape. RBM distribution across the skeleton, bone size, characteristics of bone micro-architecture, as well as density and chemical composition of the simulated media (RBM, bone) were determined based on the published data. As a result, a computational phantom of the major skeletal sites with active hematopoiesis representing a 5-year-old child was generated that included 43 phantoms of bone fragments. Linear dimensions of phantoms were within 3–75 mm. Micro-architecture parameters varied greatly: BV/TV ratio —13–52%, Tb. Th. — 0.09–0.29 mm, Tb. Sp. —0.48–0.98 mm.