Low Bone Mass Research Articles

Bone phenotyping of murine hemochromatosis models with deficiencies of Hjv, Alk2, or Alk3: The influence of sex and the bone compartment.

Osteopenia is frequently observed in patients with iron overload, especially in those with HFE-dependent hereditary hemochromatosis (HH). Interestingly, not all mouse models of HH show bone loss, suggesting that iron overload alone may not suffice to induce bone loss. In this study, the bone phenotypes of Hjv-/- and hepatocyte-specific Alk2- and Alk3-deficient mice as additional mouse models of HH were investigated to further clarify, how high iron levels lead to bone loss and which signaling mechanisms are operational. Neither male nor female 12-week-old Hjv-/- mice had an altered trabecular or cortical bone mass or bone turnover, despite severe iron overload. Male 12-month-old Hjv-/- mice even presented with a higher femoral trabecular bone volume compared to wildtype mice. Similarly, female mice with hepatocyte-specific Alk2 or Alk3 deficiency did not show an altered bone phenotype at 3, 6, and 12 months of age. Male hepatocyte-specific Alk3-deficient mice also had a normal trabecular bone mass at all ages analyzed, despite showing increased bone resorption and decreased bone formation parameters. Interestingly, hepatocyte-specific Alk2-deficient mice showed reduced femoral trabecular bone at 6 months of age due to suppressed bone formation. Cortical thickness at the femur was reduced in both, 6-month-old male hepatocyte-specific Alk2- and Alk3-deficient mice. Raising hepatocyte-specific Alk2-deficient male mice on an iron-deficient diet rescued the bone phenotype. Taken together, despite iron overload, trabecular bone microarchitecture was not altered in mice deficient of Hjv or Alk3. Only male hepatocyte-specific Alk2-deficient mice showed site-specific lower trabecular and cortical bone mass at the femur, which was dependent on iron. Thus, bone loss does not correlate with the extent of iron overload in these mouse models, but may relate to the amount of iron-loaded macrophages, as precursors of osteoclasts, in the bone marrow.

Sex hormone deficiency in male and female mice expressing the Alzheimer’s disease-associated risk-factor TREM2 R47H variant impacts the musculoskeletal system in a sex- and genotype-dependent manner

Abstract The R47H variant of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a risk factor for Alzheimer’s disease in humans and leads to lower bone mass accrual in female but not male 12-month-old mice. To determine whether, as with aging, gonadectomy results in sex-specific musculoskeletal effects, gonad removal or SHAM surgery were performed in 4-month-old TREM2R47H/+ mice and wild type (WT) male and female littermates (n = 10-12/group), with sexes analyzed separately. Body weight was lower in males, but higher in females after gonadectomy, independently of their genotype. Gonadectomy also lead to decreased BMD in males at all sites and in whole body (total) and spine in female mice for both genotypes. Total and femur BMD was lower in gonadectomized male mice 6-weeks post-surgery, independently of the genotype. On the other hand, BMD was only lower in ovariectomized WT but not TREM2R47H/+ mice in all sites measured at this time point. Bone formation and resorption markers levels were not affected by orchiectomy, whereas CTX was higher 3 weeks after surgery and P1NP showed a tendency towards lower values at the 6 weeks timepoint only in ovariectomized WT mice. μCT analyses showed no differences resulting from gonadectomy in structural parameters in femoral cortical bone for either sex, but lower tissue mineral density in males of either genotype 6 weeks post-surgery. Nevertheless, biomechanical properties were overall lower in gonadectomized males of either genotype, and only for WT ovariectomized mice. Distal femur cancellous bone structure was also affected by gonadectomy in a genotype- and sex-dependent manner, with genotype-independent changes in males, and only in WT female mice. Thus, expression of the TREM2 R47H variant minimally alters the impact of gonadectomy in the musculoskeletal system in males, whereas it partially ameliorates the consequences of ovariectomy in female mice.

Loss of Runx2 in Gli1 + Osteogenic Progenitors Prevents Bone Loss Following Ovariectomy

Abstract Osteoporosis is a metabolic bone disorder characterized by low bone mass and bone mineral density. It is the most prevalent bone disease and a common cause of fracture in aging adults. Low bone mass, as seen in osteoporosis, results from an imbalance between osteoblast and osteoclast activity. Gli1+ cells are indispensable to the maintenance of bone tissue homeostasis. These cells give rise to osteoprogenitors and are present at the osteogenic fronts of long bones in adult mice. Runx2 is a key regulator of osteogenesis and plays a crucial role in osteoblastic differentiation and maturation during development. However, its function in maintaining adult bone tissue homeostasis remains unclear. In this study, we investigated the role of Runx2 in maintaining adult bone homeostasis in the context of ovariectomy-induced estrogen deficiency, a model for postmenopausal osteoporosis. Our results show that deletion of Runx2 in the Gli1+ osteogenic progenitor population prevents loss of both cortical and trabecular bone mass and mineralization after ovariectomy. At the cellular level, loss of Runx2 leads to a decrease in osteoclast activity. Our study indicates that Runx2 is essential for maintaining adult bone tissue homeostasis by regulating osteoclast differentiation.

Height prediction of individuals with osteogenesis imperfecta by machine learning

BackgroundOsteogenesis imperfecta (OI) is a genetic disorder characterized by low bone mass, bone fragility and short stature. There is a significant gap in knowledge regarding the growth patterns across different types of OI, and the prediction of height in individuals with OI was not adequately addressed. In this study, we described the growth patterns and predicted the height of individuals with OI employing multiple machine learning (ML) models. Accurate height prediction enables effective monitoring and facilitates the development of personalized intervention plans for managing OI.MethodThis study included cross-sectional data for 323 participants with OI, and the median height Z-score for OI types I, III and IV were − 0.62 (-5.93 ~ 3.24), -3.97 (-10.44 ~ -0.02) and − 1.64 (-6.67 ~ 2.44), respectively. Based on the cross-sectional data of participants, the height curves across different gender and OI types were plotted and compared. Subsequently, feature selection techniques, specifically the filter and wrapper methods, were employed to identify predictive factors for the height of participants. Finally, multiple machine learning (ML) models were constructed for height prediction, and the performance of each model was systematically evaluated.ResultsThe analysis of height curves revealed that male with OI are significantly taller than female with OI from the age of 14 (p = 0.045), individuals with OI type III are statistically shorter than those with OI types I and IV starting from 3 years old (p = 0.006), and those with OI type IV are statistically shorter than those with OI type I from the age of 10 (p = 0.028). The application of filter and wrapper methods identified gender (p = 0.001), age (p < 0.001), Sillence types (p = 0.007), weight Z-score (p < 0.001) and aBMD Z-score (p = 0.021) as significant predictive factors for height. The optimal performance of predictive models was registered by gradient boosting classifier (GB) (bias = 5.783, accuracy = 92.59%, R2 = 0.828), random forest (RF) (bias = 6.155, accuracy = 90.12%, R2 = 0.788), ensemble machine learning (EML) (bias = 6.250, accuracy = 91.36%, R2 = 0.825) and deep neuron networks (DNNs) (bias = 6.223, accuracy = 90.12%, R2 = 0.821).ConclusionThis study analyzed a large cohort of individuals with OI and provided detailed height patterns across different gender and OI types that are crucial for assessing overall growth. Gender, age, Sillence types, weight Z-score and aBMD Z-score were identified as predictive factors for height. The predictive models of GB, RF, EML and DNNs had higher accuracy to evaluate the height of individuals with OI. This study allows guardians and physicians to timely monitor the height parameters, and facilitate the creation of personalized intervention schedules tailored to the needs of individuals with OI.

Shen Gu An Capsule Inhibition of Postmenopausal Osteoporosis in Ovariectomized Mice Using Network Pharmacology-Based Mechanism Prediction and Pharmacological Validation

Background Postmenopausal osteoporosis (PMOP) is characterized by low bone mass and increased bone fragility in postmenopausal women. Shen Gu An capsule (SGA) has been clinically used to treat bone diseases, especially PMOP with kidney Yang deficiency. Objectives We aimed to study the effect of SGA on the treatment of PMOP. Methodology The key candidate targets and pathways of SGA for treating PMOP were predicted by Network pharmacology analysis. Then, in vivo validation using bilaterally ovariectomized C57BL/6 mice was performed, and the bone quality was analyzed by Micro-CT and histological analysis. Results In this study, we obtained 113 active compounds and 82 targets via the database of Traditional Chinese Medicine Systems Pharmacology. Subsequently, compound-target and protein−protein interaction networks were constructed. Then GO and KEGG analysis revealed that NF-κB signaling pathway might be the underlying mechanism as its well-known function in osteoclastogenesis. Furthermore, the in vivo experiments using ovariectomized mice demonstrated that SGA could decrease the number of osteoclasts and preserve bone mass through inhibiting the NF-κB signaling pathway. Conclusions SGA could prevent postmenopausal osteoporosis in ovariectomized mice through inhibiting NF-κB signaling pathway. The finding of this study provides more evidence for the clinical application of SGA to treat osteoporosis.

Bone turnover, areal BMD, and bone microarchitecture by second-generation high-resolution peripheral quantitative computed tomography in transfusion-dependent thalassemia.

Thalassemic osteopathy includes low bone mass and impaired bone microarchitecture. We aimed to evaluate the prevalence and determinants of bone quantity (osteoporosis) and quality (microarchitecture) in a cohort of adult patients with transfusion-dependent thalassemia (TDT). Patients with TDT (n = 63) and age- and BMI-matched controls (n = 63) were recruited in the study. Areal bone mineral density (BMD) was measured using DXA Hologic scanner. P1NP and β-CTX were estimated by electrochemiluminescence assay. Bone geometry and volumetric BMD (vBMD) were estimated by second-generation high-resolution peripheral quantitative computed tomography. Bone turnover marker β-CTX was significantly lower in the TDT group, but there was no difference in P1NP levels. Low bone mass (Z ≤ -2) was present in greater proportion of patients both at lumbar spine (LS) (54 vs 0%; p = .001) and femoral neck (FN) (33 vs 8%; p = .001). Hypogonadism was associated with low BMD at FN (OR 10.0; 95% CI, 1.2-86; p = .01) and low hemoglobin with low BMD at LS (OR 1.58; 95% CI, 0.96-2.60; p = .07). The mean trabecular bone score was also significantly lower in patients compared with controls (1.261 ± 0.072 vs 1.389 ± 0.058). Total, cortical and trabecular vBMD were significantly lower in cases than controls. The trabecular number and cortical thickness were significantly lower and trabecular separation higher in cases than controls. Adults with TDT have significantly lower areal, cortical and trabecular vBMD. The bone microarchitecture is also significantly impaired in terms of lower number and wider spacing of trabeculae as well as lower cortical thickness and area at both radius and tibia.

La pratique du cyclisme de haut niveau impacte-t-elle la masse osseuse ?

Background : Elite cyclists may be at risk for osteopenia. Many factors can lead to bone loss in cycling, including low energy availability, low grade of inflammation, and a weak mechanical osteogenic stimulus. Thus we wanted to assess bone health in one elite team of professional cyclists, and to identify correlations between BMD and potential risks factors.Methods : Thirty-three adult male cyclists were recruited from one international team. Total body, hip femur and lumbar spine BMD had been measured by DXA and was compared to standard values for a healthy population of same age and sex. Training characteristics, morphometrics, body lean mass, fat mass, history, medication and results of recent blood and stool analysis were collected and compared between the cyclists having low BMD and those with unaltered BMD. Univariate and multivariate correlation analyses were carried out to identify predictive factors for low BMD.Results : Twenty-one (64%) out of 33 cyclists presented a Z score < -1 at one site, and five of them (15%) had densitometric osteoporosis. Lumbar spine was involved every time ‘Z score = -b 1,23 +/- 0,94). Age, history, and training characteristics were significantly and negatively linked to BMD. After multiple regression, no variable had an independent correlation with BMD. No correlation was found with biomarkers or with training characteristics.Conclusion : Our study shows a worrying proposition of low bone mass in our population of young male and otherwise healthy cyclists. Low energy availability, as the missing point of our study, might be the main causal factor. Great attention should be paid in bone status in elite cyclists of any age.

Unveiling the Metabolic Challenges in Pulmonary Arterial Hypertension: Insights into Thyroid, Glycemic, Lipid, and Bone Disorders

This study aimed to evaluate the prevalence of thyroid, glycemic, lipid and metabolic bone disorders among adult patients with pulmonary arterial hypertension (PAH). MethodsThis was an observational cross-sectional clinical study with patients with PAH, matched by sex and age with a control group without PAH. All individuals were enrolled into a clinical assessment, metabolic workup, thyroid ultrasound, and bone densitometry protocol. ResultsThe PAH group included 35 participants (34 females, 46 ± 15.5 years), and the control group, 40 (39 females, 41.8 ± 13.1 years). There was no difference in body mass index (BMI) between PAH and control group (27.5 ± 5.9 and 26.9 ± 4.3 kg/m2, respectively; p = 0.63; 95% CI = -1.8, 2.94), neither in physical activity time per week (60.3 ± 103.3, 98.9 ±137.6, respectively; p = 0.17; 95% CI = -95.23, 18.06). Although there was no difference in the prevalence of insulin resistance between the PAH (51.4%) and the control group (47.5%), p=0.74, patients with PAH had a higher median of glycated hemoglobin (A1c) than the control group (6.1% and 5.57%, respectively), p=0.006; 95% CI = -0.14, 1.22. PAH group presented lower mean total cholesterol (170.46 ± 35.51 mg/dL) and median LDL-cholesterol [105 (46) mg/dL, median (interquartile range)] levels than the control group [192.1 ± 34.44 mg/dL, p = 0.009; 95% CI = -37.76, 5.52; 121.6 (35.02) mg/dL, p=0.012; 95% CI = -34.08, 0.77, respectively]. It was found a higher prevalence of hypothyroidism (22.9%) in PAH group than in control group (2.5%), p = 0.007. We found hyperparathyroidism (HPT) among 8 patients of PAH group (23%), but none in the control group. Considering bone mineral density disorders, 12 patients from PAH group presented low bone mass, osteopenia, or osteoporosis (34%), and 8 individuals in the control group (20%), p =0.032, which represented a 2.13 higher relative risk for those conditions for the former group. The patients with HPT presented a higher creatinine level (0.98 ± 0.12 mg/dL) than the PAH patients with normal parathyroid hormone (0.76 ± 0.14 mg/dL), p = 0.0004; 95% CI = 0.12, 0.33. The PAH group also presented lower total hip (-0.15 ± 1.25) and femoral neck (-0.14 ± 1.07) bone mineral density (BMD) Z-scores than the control group (0.50 ± 1.13, p = 0.021; 95% CI = -0.18, -0.027; 0.35 ± 0.94, p = 0.038; 95% CI = -0.16, -0.01, respectively). ConclusionIn this cohort, the findings of higher A1c levels, hypothyroidism prevalence, lower LDL and total cholesterol levels, and a higher prevalence of hyperparathyroidism, as well as lower total hip and femoral neck BMD Z-scores in the PAH group, compared to the control group and highlighting the dysregulation of various metabolic pathways in patients with HAP, suggesting the need for targeted interventions to enhance patient care. Additionally, they underscore the importance of gaining a deeper understanding of the mechanisms driving these changes and their potential pathophysiological connections to the disease.

Interrelationships of cervical spine sagittal alignment and whole spinopelvic alignment under implications of musculoskeletal health among independent elderly women in Taiwan: A cross-sectional study.

Older women are at increased risk of spinal misalignment and its associated complications. This study investigated the influence of age, grip strength, and various sagittal spinal parameters on spinal alignment. The results indicate the need for comprehensive management strategies. This cross-sectional study included 200 older women who underwent bone health evaluations at the orthopedic department of a hospital. The study participants underwent dual-energy X-ray absorptiometry, grip strength measurement, and full-length spine radiography. Clinical and radiographic parameters were analyzed through Pearson correlation and linear regression analyses. Significant correlations were identified between grip strength and spinal parameters such as C7 slope and global tilt, indicating that muscle strength affects spinal alignment. Advanced age was associated with changes in sagittal spinal parameters, indicating that changes occur in body compensation over time. Furthermore, pelvic parameters such as pelvic tilt and sacral slope were significantly correlated with spinal curvature, indicating their critical roles in maintaining spinal stability. This study revealed the critical roles of muscle strength and pelvic alignment in the management of spinal health in older women with low bone mass. Targeted interventions for increasing muscle strength, correcting posture, and achieving hormonal balance can notably improve spinal stability and reduce the risk of associated complications. Longitudinal studies should be conducted to validate and refine the intervention strategies and to extend the study findings.

Prevalence and Risk Factors of Osteoporosis among Postmenopausal Women Visiting a District Hospital of Nepal: An Observational Study

Introduction: Osteoporosis and low bone mass affect millions of people worldwide, leading to severe consequences ranging from disability to mortality. This study aimed to determine the prevalence and risk factors of osteoporosis among postmenopausal women in a district of Nepal.Methods: An analytical cross-sectional study involving postmenopausal women from Nuwakot, Dhading, and Rasuwa districts in Nepal was conducted at Trishuli Hospital, Nuwakot. Ethical approval was taken from the Institutional Review Board of Nepal Health Research Council(Reference number: 1768). The prevalence of osteoporosis was determined, and the associated factors were analyzed using multivariate logistic regression. Dual-Energy X-ray Absorptiometry (GE-Lunar Prodigy) was used to measure Bone Mineral Density (g/cm2) at the proximal femur and lumbar spine. Various factors related to osteoporosis were also analyzed.Results: There were 384 postmenopausal women and the prevalence of osteoporosis was 82 (21.35%; 95% CI: 17.25%-25.45%)e. The mean age of female with osteoporosis was 67.52±8.84 years and that without osteoporosis was 55.70±7.69 years (p &lt;0.001). The multivariate logistic regression showed aOR 0.82 for body mass index.Conclusions: The study reports a lower prevalence of osteoporosis than expected in postmenopausal women. There was a significant inverse relationship between osteoporosis and body mass index. However, no significant association was observed between Bone Mineral Density, biochemical variables, smoking, and parity.

Opportunistic Bone Mineral Density Measurement Using Photon-Counting Detector CT Spectral Localizer Images: A Prospective Study.

Background: Spectral localizer images from photon-counting detector (PCD) CT can be used for bone mineral density (BMD) evaluation given their 2D-projectional nature and material decomposition capability. As all CT examinations include localizer images, this approach could allow opportunistic osteoporosis screening in patients undergoing clinically indicated imaging by PCD CT. Objective: To assess the utility of PCD-CT spectral localizer images for opportunistic derivation of area BMD (aBMD) values and T-scores, using dual-energy X-ray absorptiometry (DXA) as the reference standard. Methods: This prospective study included patients ≥18 years old scheduled for clinically indicated lumbar spine CT between October 2023 and February 2024 and who underwent DXA within the 13 prior months or were scheduled for DXA within the subsequent 13 months. Participants underwent lumbar spine CT by PCD CT including spectral localizer images. Lumbar spine aBMD was extracted from clinical DXA reports. ROIs were placed on lumbar vertebral bodies and background soft tissues to extract areal densities from spectral localizer images using material decomposition; areal densities were used to derive lumbar spine aBMD values. The aBMD values were used to derive T-scores, which were classified as representing normal (≥-1) or abnormal (<-1) bone mass. DXA-derived and PCD-CT derived measurements were compared. Results: The study included 51 participants (mean age: 62 years [range, 28-83 years]; 31 female, 20 male). Mean DXA-derived T-score was 0.39±1.64; mean PCD-CT derived T-score was 0.28±1.77 (p=.29). Lin's concordance correlation coefficient between DXA-derived and PCD-CT T-scores was 0.90. The difference between DXA-derived and PCD-CT derived T-scores showed a small correlation with patient age (r=-0.13), absolute interval between DXA and PCD CT (r=.15), and BMI (r=0.28); this difference in scores did not show a significant difference between male and female patients (0.08 vs 0.13, respectively; p=.81). PCD-CT T-scores had sensitivity of 97%, specificity of 71%, PPV of 90%, and NPV of 91% for detecting abnormal bone mass using DXA-derived T-scores as the reference standard. Conclusion: PCD-CT spectral localizers showed clinical utility for deriving aBMD values and, consequently, T-scores. Clinical Impact: The T-score derived from PCD-CT spectral localizers may serve as an opportunistic screening tool for low bone mass and osteoporosis.

A cross-sectional study in adiponectin, glucose metabolism, and body composition in cystic fibrosis.

We hypothesized that the insulin-sensitizing adipokine adiponectin (ADP) is upregulated in cystic fibrosis (CF) related diabetes (CFRD) and underweight adults with CF. We aimed to assess correlations between glucose metabolism, body composition and ADP in CF. We performed a cross-sectional study among adults with CF at the Copenhagen CF Center. The study included a fasting level of ADP, an oral glucose tolerance test (OGTT), and a dual energy-x-ray absorptiometry scan. In total, 115 patients were included of whom 104 had an OGTT performed. Glucose intolerance was not correlated with ADP in multivariable analysis, while increased hepatic insulin resistance (i.e., HOMA-IR) was correlated with reduced ADP levels. ADP declined by 4% (eβ 0.96, 95% CI: 0.94, 0.98), 5% (eβ 0.95, 95% CI: 0.93, 0.98), 9% (eβ 0.91, 95% CI: 0.87, 0.95), and 83% (eβ 0.17, 95% CI: 0.08, 0.37) for each one unit (kg/m2) increase in body mass index, fat mass index, muscle mass index, and bone mineral content index, respectively. In CF, ADP was negatively correlated with hepatic insulin resistance as well as low fat, muscle, and bone mass, but not with glucose intolerance. This suggests that malnutrition leads to higher ADP levels in CF.

Evaluation of the information quality related to osteoporosis on TikTok

BackgroundOsteoporosis is currently considered the most common bone disease in the world and is characterized by low bone mass, deterioration of the bone tissue microstructure, and decreased bone strength. With the increasing popularity of smartphones and short videos, many patients search for various types of health information through social media, such as short videos. As one of China’s short video giants, TikTok has played a significant role in spreading health information. We found that there are many videos about osteoporosis on TikTok; however, the quality of these short videos has not yet been evaluated.ObjectiveThe purpose of this study was to evaluate the information quality of osteoporosis videos on the domestic TikTok platform.MethodsWe retrieved and screened 100 videos about osteoporosis from TikTok, extracted the basic information, encoded the video content, and recorded the source of each video. Two independent raters evaluated the information quality of each video via the DISCERN rating scale.ResultThe videos were divided into three groups according to their source: medical personnel, science communicators, and news media, with medical personnel posting the most videos. The content of the video is divided into 7 groups, namely, disease prevention, disease diagnosis, disease symptoms, disease overview, life-style, drug knowledge, and drug treatment, with the most videos related to disease overview. The average DISCERN score of the videos is 37.69 (SD = 6.78), mainly within the ‘poor’ (54/100, 54%) and ‘appropriate’ (43/100, 43%) rating ranges, with overall quality being low. Further analysis revealed a positive correlation between the number of shares, comments, likes, and favorites, and a positive correlation between the DISCERN score and the number of shares and favorites.ConclusionThe overall quality of videos concerning osteoporosis on TikTok is lower, but the quality of videos varies significantly across different sources. We should be selective and cautious when watching videos about osteoporosis on TikTok.

Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis.

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (MTNR1A) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [MTNR1Ac.184+1G>T (MTNR1Ac.184+1G>T)] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.

A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass

Cellular communication network factor 2 (CCN2) is a secreted extracellular matrix-associated protein, and its aberrantly increased expression has been implicated in a diversity of diseases involving pathological processes of fibrosis, chronic inflammation, or tissue injury, which has promoted the evaluation of CCN2 as therapeutic targets for multiple disorders. However, human phenotypes associated with CCN2 deficiency have remained enigmatic; variants in CCN2 have not yet been associated with a human phenotype. Here, we collected families diagnosed with spondyloepimetaphyseal dysplasia (SEMD), and screened candidate pathogenic genes for families without known genetic causes using next-generation sequencing. We identified a monoallelic variant in signal peptide of CCN2 (NM_001901.2: c.65 G > C [p.Arg22Pro]) as the cause of SEMD in 14 subjects presenting with different degree of short stature, premature osteoarthritis, and osteoporosis. Affected subjects showed decreased serum CCN2 levels. Cell lines harboring the variant displayed decreased amount of CCN2 proteins in culture medium and an increased intracellular retention, indicating impaired protein secretion. And the variant weakened the stimulation effect of CCN2 on osteogenesis of bone marrow mesenchymal stem cells. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice (Ccn2fl/fl;Prx1Cre) partially recapitulated the phenotypes including low bone mass observed in affected subjects. Pathological mechanism implicated in the skeletal abnormality in Ccn2fl/fl;Prx1Cre mice involved decreased bone formation, increased bone resorption, and abnormal growth plate formation. Collectively, our study indicate that monoallelic variants in CCN2 lead to a human inherited skeletal dysplasia, and highlight the critical role of CCN2 in osteogenesis in human.

Association of serum fatty acids with bone health in rural elderly population in Qingdao, China: A cross-sectional study.

As a type of macronutrient, fatty acids (FA) play significant roles in the bone health of elderly people. However, the specific association between different types of FA and bone health is not fully understood, especially in rural elderly populations. To address this gap, a study was conducted in rural areas of Qingdao, China. Participants aged 65 and older were randomly recruited from 11 rural villages in Licha town, Qingdao City. The levels of serum FA in their serum were measured to investigate the associations between FA and bone mass. The results showed that levels of saturated fatty acids (SFA), n-3 polyunsaturated fatty acids (n-3 PUFA), and n-6 polyunsaturated fatty acids (n-6 PUFA) were all significantly associated with bone mass. Specifically, higher levels of SFA were positively correlated with low bone mass (LBM), while PUFA levels were inversely correlated with LBM. Furthermore, the odds ratio (OR) for LBM exhibited a significant nonlinear dose-response relationship (pnonlinearity = 0.1989) with SFA levels, and a significant nonlinear dose-dependent relationship was also observed with the levels of n-3PUFA and n-6PUFA (pnonlinearity = 0.6183, 0.5808, respectively), indicating that increasing dietary PUFA intake appropriately and controlling SFA intake may benefit the bone health of elderly individuals in rural areas.

9175 Pretransplant Clinical Characteristics Related To Change In Bone Mineral Density In Adults 1 Year After Allogeneic Hematopoietic Stem Cell Transplantation At Bucaramanga, Colombia Reference Center

Abstract Disclosure: G.A. Parra-Serrano: None. C.L. Sossa: None. K.J. Moreno Medina: None. M. Ochoa: None. A. Reyes Gonzalez: None. A. Plata: None. P. Mantilla Mantilla: None. Introduction: Hematopoietic stem cell transplantation (HSCT) , refractory to pharmacological management, increases 10-year survival by 80%, Chronic complications include alterations in bone metabolism, that increase appearance of osteoporosis (13.8 - 17%), non traumatic fractures, and loss of Bone mineral density (BMD) at the hip -4.2%, L1L4 -2% and femoral neck-9%. Methods Calculate Change at (BMD) in adults undergoing allogenic (HSCT) after 1y and determine pretransplant factors related to this change. Composite endpoint osteoporosis/lowbonemass (osteoporosis Tscore&amp;lt;-2.5 and/or low bone mass Zscore-2.0) 1 year after transplant, Adult patients Retrospective cohort study, ethical comittee approval, anonymized database, undergoing allogeneic (HSCT) between 2009 and 2022, (BMD) measured at lumbar spine (L1L4) and femoral neck before and one year after transplant; Also paraclinical variables: TSH, vitaminD, kidney function, glucocorticoid, Graft vs host disease, disease relapse, diabetes. Descriptive analisis performed, simple linear regresion analisis for delta L1L4 and femoral neck BMD before and 1 year after transplant, and multivariate regresion analisis for variables p&amp;lt;0.2 on simple lineal regression analysis . Results 123 patients, (48 included, 73 excluded (22 died, 50 densitometry data not suitable)). BMD change At lumbar spine, -4.7% (NS) , and at femoral neck -9.8% (p&amp;lt;0.05), Simple regression analysis no correlation for preclinical variables at lumbar spine. negative correlation between prednisolone dose at femoral neck BMD (p 0.007, coefficient B -0.0086 [IC95% -0.014, 0.0025]). Mutivariate regression analysis performed for BMD diference at femoral neck, after adjusting for variables p&amp;lt;0.2 on simple regression analysis, model that include (prednisone dose, diabetes and relapse before transplant showed Rsquare 0.19 coefficient 0.0092 p 0.003. For every gram of glucocorticoid (prednisolone) bone loss decrease -0.9% of BMD at femoral neck at 1 year follow up. Proportion of patients with composite osteoporosis/lowbonemass at femoral neck pre-transplant (n2) 4.17%, postransplant (n14) 29.17%. * p 0.0005. no difference observed at lumbar spine. Fracture incidence n2 (4%) at lumbar spine and n1 (2%) at femoral neck. Conclusions At femoral neck, People with HSCT present significant decrease in (BMD) and higuer incidence of Osteoporosis or low bone mass, not observed at lumbar spine, after adjusting for multiple variables. for every 1gr of prednisolone equivalent dose, (BMD) decrease -0.9%, at femoral neck p0.003. The model only explain 19% of change of BMD at femoral neck, that suggest immune response caused by allogenic transplantation might be responsible, in part, of BMD change. Presentation: 6/3/2024

6820 Assessing The Efficacy And Safety Of Setrusumab For Osteogenesis Imperfecta: Updated Phase 2 Data From The Phase 2/3 Orbit Study

Abstract Disclosure: G.S. Gottesman: Advisory Board Member; Self; Ultragenyx, Kyowa Kirin, Inc. Consulting Fee; Self; Ultragenyx. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Ultragenyx. T.O. Carpenter: Advisory Board Member; Self; Ultragenyx. Consulting Fee; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. M. Wallace: Advisory Board Member; Self; Ultragenyx. Consulting Fee; Self; Novosteo. P. Smith: Grant Recipient; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. E.A. Imel: Consulting Fee; Self; Ultragenyx. Grant Recipient; Self; Ultragenyx. Research Investigator; Self; Ultragenyx. H. Wang: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. H.M. Byers: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. S. Krolczyk: Employee; Self; Ultragenyx. Stock Owner; Self; Ultragenyx. E.M. Lewiecki: Consulting Fee; Self; Amgen Inc, Radius Health, Inc. Grant Recipient; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Research Investigator; Self; Amgen Inc, Radius Health, Inc, Ultragenyx. Speaker; Self; Amgen Inc, Kyowa Kirin, Inc. Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and low bone mass with no universally accepted treatment. Setrusumab is a fully human anti-sclerostin monoclonal antibody that improved bone mineral density (BMD), bone strength, and bone turnover markers in adults with OI (ASTEROID; NCT03118570). In the ongoing Phase 2/3 Orbit study (NCT05125809), Phase 2 evaluated the efficacy and safety of setrusumab in pediatric and young-adult cohorts with OI based on PK/PD, safety, and BMD data, to determine the dosing strategy for the Phase 3 portion. Subjects with OI Types I, III, or IV, ages 5 to &amp;lt;26 years, were randomized 1:1 to receive 20 or 40 mg/kg setrusumab intravenously monthly. Six-month data as of August 2023 are presented. Twenty-four subjects (50% female, 75% &amp;lt;18 years of age) with OI Type I (n=17/24, 71%) or III/IV (n=7/24, 29%) were enrolled and randomized to receive 20 mg/kg (n=14/24) or 40 mg/kg (n=10/24) of setrusumab. The mean (SD) baseline-corrected area under the effect curve (AUEC) for serum P1NP in the 20 mg/kg setrusumab group was 4153 (4407) µg/(L*day) over month one of treatment, and 5256 (5521) µg/(L*day) in the 40 mg/kg group. Mean (SE) change from baseline in lumbar spine BMD in the 20 mg/kg group was 9.1% (1.8%) and 12.8% (2.5%) at M3 and M6, respectively (all p&amp;lt;0.05 vs baseline) and 9.3% (2.4%) and 16.1% (3.9%) in the 40 mg/kg group (M6 p&amp;lt;0.05 vs baseline). Mean (SE) baseline BMD Z-score in the 20 mg/kg group of 2.1 (0.8) improved by 0.6 (0.8) at M3 and 0.9 (0.8) at M6, and improved from 1.1 (0.4) at baseline by 0.5 (0.4) and 0.9 (0.4) at M3 and M6, respectively, in the 40 mg/kg group (all p&amp;lt;0.05 vs baseline). The median annualized fracture rate (excluding fingers, toes, face, and skull) was reduced significantly from 0.7 to 0 (p=0.042) after setrusumab initiation (calculated reduction of 67%). No new radiographically confirmed fractures excluding fingers, toes, face, and skull were reported in 20/24 (83%) subjects after starting setrusumab, while only 4/24 (17%) reported fractures (precipitating events: one subject: slipped on ice, stubbed toe, one subject each: fell off of tricycle, bending over in bed, tripped and fell). Setrusumab treatment resulted in no unexpected adverse events. Treatment-related adverse events included infusion-related reaction (7/24, 29%), headache (3/24, 13%) infusion site pain, bone pain, and upper respiratory tract infection (each 1/24, 4%). In Orbit Phase 2, we observed significant improvements from baseline in lumbar spine BMD at M3 and M6 at both 20 and 40 mg/kg doses, with no marked differences between dose groups. Fracture rates significantly decreased with setrusumab initiation, with 83% of subjects reporting no new fractures. Presentation: 6/1/2024

9397 Shatter Proofing Bones: Revamping Osteoporosis Screening

Abstract Disclosure: R. Subramani: None. T. Gupta: None. M. Anwar: None. J. Pamula: None. Background: Osteoporosis is a common disease characterized by low bone mass, structural deterioration of bone tissue, and increased risk of fractures. The World Health Organization (WHO) has defined osteoporosis based on bone density measurements. According to their definition, osteoporosis is diagnosed when the bone density at the hip or spine is at least 2.5 standard deviations (SDs) below the mean bone density of a reference population of young, healthy women (T score ≤ -2.5). According to NHANES data from 2017-2018, the overall prevalence of osteoporosis among adults over 50 was found to be 12.6%. It was observed that the prevalence of osteoporosis was higher among women (19.6%) compared to men (4.4%). According to US Preventative Services Task Force (USPSTF), the guidelines for screening are as follows: BMD Testing (DEXA) for all women aged 65 and older, postmenopausal women younger than 65 with clinical risk factors for fracture including advancing age, previous fracture, glucocorticoid therapy, parental history of hip fracture, low body weight, current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, secondary osteoporosis. BMD Testing for Men is not recommended. The most used bone measurement test to screen for osteoporosis is central DXA which measures BMD at the hip and lumbar spine. Goal: To improve the osteoporosis screening using DXA scan in the outpatient internal medicine resident patient panel by 5% Study Design:Subjects were identified by an EPIC report and will include retrospective chart review of records from July 2022 and prospective screening until April 2024 for the outpatient IM clinic list of patients including both resident panel. Methods: Pre-intervention data analysis of current rates; Educating residents about appropriate screening; Utilization of osteoporosis screening as care-gap in EPIC ;Calling patients who are due for screening from IM residents patient panels; Post-interventional data analysis Results: The total number of patients on the residents panel was 196. Before interventions, screening rate for osteoporosis were 71.2% among residents' patients. After intervention, screening rates increased to 75.5%. There was a 4.3 % improvement in screening rate. Conclusion: Resident education, addressing Osteoporosis care gaps in EPIC and patient outreach are effective interventions to improve screening rates. Discussion: Osteoporosis screening remains an area of needed improvement in IM clinic. EPIC system should not only take age for prompting osteoporosis screening but also other factors such as family history, pre-mature fractures, steroid use, etc. Adding osteoporosis screening into the metric system are few steps to be considered for future directions. Presentation: 6/3/2024

7172 Osteoporosis Associated with Antiretroviral Therapy - Case report

Abstract Disclosure: C.E. Guillen Lopez: None. L.A. Sanchez Ato: None. A. Patel: None. A. Molkina: None. T. Ayub: None. L. Robles: None. A. Arce Gastelum: None. Osteoporosis presents a substantial public health challenge, contributing significantly to morbidity and mortality through fractures. While postmenopausal osteoporosis is common, secondary osteoporosis affects a significant number of patients, including over 30% of postmenopausal and 50-80% of men. People living with HIV (PLWH) experience age-related medical comorbidities earlier and more extensively than those without HIV. The compromised bone health in PLWH is attributed to factors associated with the virus, antiretroviral therapy (ART) side effects, and health disparities such as inadequate nutrition, low body weight, hypogonadism, vitamin D deficiency, and increased recreational substance use. More recently, it has become apparent that vertebral fractures are more common in PLWH, with a prevalence of 11.1% and a 2.30-fold more significant risk than the general population. Low bone mass density (BMD) is twice as common in PLWH, increasing to 3 times as common in PLWH on ART. ART initiation leads to transient bone loss with nucleotide reverse transcriptase inhibitors such as tenofovir disoproxil fumarate (TDF) and protease inhibitors, causing higher BMD loss. In contrast, integrase and specific reverse-transcriptase inhibitors have minimal adverse effects on BMD. The newer formulation, tenofovir alafenamide (TAF), is believed to have a more favorable impact on bone health than TDF. The repercussions of diminished bone health, particularly osteoporotic fractures, have significant medical and economic implications. They are leading to early mortality, disability, and a loss of independence. The HIV Medicine Association (HIVMA) and Infectious Diseases Society of America (IDSA) recommend BMD screening for all HIV-infected patients at 50 years. 58-year-old male PLWH reveals a history of osteoporosis with multiple spinal (L1, L4-5, S1) and bilateral wrist fractures on TDF for 15 years. The patient has been treated with bisphosphonates. Alendronate was initially prescribed, but due to acid reflux side effects, zoledronic acid was a better option. Despite various ART regimens, Dolutegravir/Lamivudine was started four years ago without further fractures. Recent bone density assessments showed improvement in the lumbar spine, returning to a normal range with a T-score of 0.6. However, the left femoral neck remains at -2.5, and the right femoral neck is at -2.2, showing minimal change. To enhance BMD in PLWH on ART, transitioning to alternatives with lower bone loss associations and using bisphosphonates as tolerated are suggested. As the HIV-infected population ages, proactive screening for low BMD is vital to manage evolving health needs and prevent bone-related complications. A holistic approach includes evaluation for secondary etiologies of osteoporosis, medical treatment, and vitamin D and calcium supplementation. Presentation: 6/3/2024