Abnormal Bone Mineral Research Articles

Insights into skeletal involvement in adult Gaucher disease: a single-center experience.

Gaucher disease (GD) is a lysosomal storage disorder causing systemic and skeletal complications. This study evaluates bone health in adult GD type 1 patients, focusing on skeletal complications, bone mineral density (BMD), and biochemical markers. A cohort of adult GD type 1 patients followed up at Ege University Pediatric Metabolism Department were retrospectively examined. This study included 32 patients with GD type 1, comprising 11 males (34.4%) and 21 females (65.6%). The median age at diagnosis was 20.5years (min: 3-max:65), and at enrolment, it was 35years (min:18-max:71). Most patients (93.8%) had organomegaly, and 93.8% had cytopenia. Common genetic variants were p.Asn409Ser (60.9%), p.Leu483Pro (7.8%), and p.Asp448His(4.7%). All patients were on enzyme replacement therapy (ERT) for a median of 11years (min:2-max:18). Bone complications included pathologic fractures in six patients (19%) and avascular necrosis in 12 patients (37.5%). Bone pain was reported by 93.7% of patients at admission and persisted in 59.4% during follow-up. DXA scans showed abnormal bone mineral density (BMD) in 62.5% of patients initially, with a significantly low bone density in 3.1% and reduced bone density in 59.3%. BMD improved with treatment, as evidenced by a significant increase in Z scores (p < 0.05). Elevated chitotriosidase (75%), ferritin (50%), and immunoglobulin G (21.9%) levels were noted but did not correlate with BMD. Seven patients (22%) were splenectomized, all with bone issues. Bone health in GD involves multiple factors beyond biochemical markers. While ERT improves BMD, bone pain and fractures remain significant issues. Comprehensive management, including regular BMD monitoring and better vitamin D supplementation adherence, is crucial. Further research is needed to improve treatments for bone complications in GD.

MicroRNAs in fluorosis pathogenesis: impact on dental, skeletal, and soft tissues.

Fluoride-induced toxicity (fluorosis) poses a significant health concern globally, affecting millions of individuals. Understanding the molecular mechanisms underlying fluorosis, particularly the role of microRNAs (miRNAs), is crucial for developing effective preventive and therapeutic strategies. This review explores the pivotal role of miRNAs in the pathogenesis of fluorosis, particularly examining its impact on both hard (skeletal and dental) and soft (brain, liver, kidney, heart, and reproductive organs) tissues. Skeletal fluorosis manifests as abnormal bone mineralization and structure, while dental fluorosis affects enamel formation. In vitro and in vivo studies suggest a significant involvement of miRNAs in the progression of these conditions. For skeletal fluorosis, miR-124, miR-155, and miR-200c-3phave been identified askeyregulators, while miR-296-5p and miR-214-3pare implicatedin dental fluorosis.Moreover, soft tissue fluorosis encompasses a spectrum of adverse effects on various organs, including the brain, liver, kidneys, heart, and reproductive system. In soft tissues, miRNAs, such as miR-124, miR-200c-3p, miR-132, and miR-34b-5p, havebeen linkedto cellular damage and dysfunction. Notably, miRNAs exert their effectsthrough the modulation ofcritical pathways involved in fluorosis pathology, including Wnt signaling, apoptosis, cell cycle, and autophagy. Understanding the regulatory roles of miRNAs in fluorosis pathogenesis holds promise for identifying biomarkers and therapeutic targets. However, further research is needed to elucidate the molecular mechanisms underlying miRNA-mediated responses to fluoride exposure.Integration ofmiRNA research into fluorosis studies could facilitate the development of diagnostic tools and therapeutic interventions, thus mitigating the detrimental effects of fluorosis on both hard and soft tissues.

Thoracolumbar Fractures: Factors Predicting Failure of Percutaneous Short- and Long-Segment Posterior Fixation

IntroductionThoracolumbar (TL) transition trauma is frequent and challenging. Although short- (SSPF) and long-segment posterior fixation (LSPF) are its mainstay treatment, little is known about their failure rates and reasons behind it. Research questionunderstand why TL instrumentations fail and what factors influence it. Materials and methodsRetrospective, cohort, unicentric analysis on adult patients with acute TL trauma treated with percutaneous transpedicular SSPF or LSPF. Two groups were created, according to the presence of treatment failure at follow-up. We analysed whether age ≥ 65 years old, fracture segment, posterior ligamentous complex (PLC) injury, load sharing classification (LSC) score > 6, type of instrumentation (SSPF vs LSPF) and abnormal bone mineral density (BMD) were associated with failure. To achieve this, we evaluated radiological parameters at the preoperative, postoperative and follow-up appointments. Results87 patients were included: 60 (69.0%) without failure and 27 (31.0%) with. Age ≥ 65 years old (aOR = 3.66, p = 0.020), PLC injury (aOR = 2.94, p = 0.048) and SSPF (aOR = 6.75, p = 0.013) were statistically significant factors contributing to failure. The first two also presented shorter times to failure (35.2 vs 69.1 months, p = 0.013, and 25.2 vs 69.1 months, p = 0.037, respectively). In PLC injured patients, there was no statistically significant difference between SSPF vs LSPF. Discussion and conclusionsWe conclude that age >65 years old, PLC injury and SSPF may be correlated with instrumentation failure. The first two factors were also associated with a shorter time to failure.

Abnormally low serum albumin levels are associated with abnormal bone mineral density and osteoporotic fractures: a retrospective studies

BackgroundMany studies have indicated that abnormal bone mineral density (BMD) is related to abnormal liver and kidney function, but the effect of serum albumin level on abnormal BMD and osteoporotic fracture is still controversial. The aim of this retrospective study was to investigate the effects of serum albumin levels on abnormal BMD and osteoporotic fractures.MethodsThe study included 538 patients through the electronic medical records of inpatients and outpatients stored at Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology. A multivariate logistic regression model was employed to test the relationship between serum albumin levels and abnormal BMD, and the effect of serum albumin levels on osteoporotic fractures was verified through the U test. Correlation between age, sex, kidney stones, coronary heart disease, hypertension, diabetes, fatty liver disease, haemoglobin (HB), mean corpuscular haemoglobin concentration (MCHC), platelets (PLT), platelet distribution width (PDW), lymphocytes (LYMP), alanine aminotransferase (ALT), total protein (TP), albumin (ALB), uric acid (UA), total bilirubin (TBIL), total cholesterol (TC), high-density lipoprotein (HDL) and abnormal BMD were analysed by logistic regression modelling after excluding confounding factors.ResultsThe ALB level in osteoporotic patients was 41.70 (36.40–45.00) g/L, which was significantly lower than those in the normal BMD and reduced BMD groups. The odds ratio (OR) (95% confidence interval [CI]) between the osteoporosis and normal BMD groups was 0.445 (0.394–0.502); the OR (95% CI) between the osteoporosis and reduced BMD groups was 0.395 (0.341–0.459). In the subgroup analysis by whether or not a fracture was present, the OR (95% CI) was 0.073 (0.045–0.119).ConclusionsALB is a protective factor against osteoporosis and osteoporotic fractures, suggesting that it may have the potential to predict osteoporosis onset and fractures.

Assessment of Bone Mineral Density in Chronic Obstructive Pulmonary Disease Patients

Background: Main co-morbidities of chronic obstructive pulmonary disease that restricts physical exercise is osteoporosis. In this study we assess chronic obstructive pulmonary disease patients for osteoporosis, osteopenia and determine correlation of body mass index, number of pack years, severity of chronic obstructive pulmonary disease with bone mineral density Method and patients: This cross-sectional study was carried out on 61 chronic obstructive pulmonary disease patients.. Dual energy x-ray absorptiometry was used to evaluate the bone mineral densities at lumbar spine. According to WHO guidelines, patients with a T score greater than -1 were classified as having normal bone density, those with a T score of (-1 )to (-2) as having osteopenia, and those with a T score of less than -2.5 as having osteoporotic bone density. Results: Sixty - one chronic obstructive pulmonary disease patients were included in this study, 11 patients (18%) had normal bone mineral density, fifty patients had abnormal bone mineral density .Also thirty - two patients had osteoporosis(52.5%) and 18 (29.5%) had osteopenia. .BMD correlated directly with BMI (P value=0.009) and inversely with number of pack years (P = 0.000), ,BMD correlated inversely with severity of COPD (P = 0.001) . Conclusion: Patients with chronic obstructive lung disease had a higher chance of osteoporotic fractures and decreased bone mineral density.A lower BMI, more pack years, and a rise in the severity of the condition raised chance of osteoporosis..

The role of humerus cortical thickness in predicting osteoporosis in MR imaging.

This study aims to evaluate the efficacy of humerus cortical thickness on coronal T1-weighted images of the humerus in distinguishing patients with normal vs. abnormal bone mineral density (BMD). Patients (n:138) with shoulder magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) scans were evaluated. Patients were grouped into normal and low BMD (osteopenia and osteoporosis) according to DXA. An average cortical bone thickness (CBTavg) and gauge cortical bone thickness (CBTg) were calculated from the proximal humerus on coronal T1W MRI. Sensitivity and specificity for the prediction of osteoporosis were determined for several cortical bone thickness thresholds. Proximal humerus average cortical bone thickness measurements strongly correlated with DXA femur and lumbar scores (p < 0.01). Gauge cortical thickness measurements also correlated with DXA femur and lumbar scores (p < 0.01). Average cortical bone thickness measurement of 4.52 mm was determined to be a potential marker for predicting osteoporosis, with a sensitivity of 92.3% and a specificity of 84.9%. Average cortical bone thickness measurements obtained from shoulder MRI are correlated with DXA. It appears to be effective in differentiating patients with normal and abnormal BMD and may help to opportunistically predict patients with osteoporosis in a rapid, simple and practical way, potentially guiding further diagnostic assessments.

Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2)

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2; MIM #613312) is a very rare disorder caused by biallelic loss-of-function mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene. ENPP1 deficiency encompasses a spectrum of phenotypes that includes, in addition to ARHR2, generalized arterial calcification of infancy (GACI), ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum. ARHR2 can be found in GACI survivors, but it may also be the first manifestation of ENPP1 deficiency. Although the precise mechanisms are not fully elucidated, patients with GACI and ARHR2 have elevated serum FGF23 levels, leading to renal phosphate wasting and hypophosphatemia. As a result, the clinical and radiological phenotype of ARHR2 patients is very similar to that of patients affected with other forms of hypophosphatemic rickets, such as X-linked hypophosphatemia. Patients show signs of rickets (abnormal mineralization of growth plates in children) and osteomalacia (abnormal bone mineralization in children and adults) of varying severity. Clinical manifestations specific to ENPP1 loss-of-function mutations and common to GACI, such as ectopic calcifications (valvular, arterial, or periarticular), deafness, OPLL, and PXE, may also be found. Genetic confirmation of the disease is important so as to ensure that patients receive the appropriate treatment or have the opportunity to participate in clinical trials to evaluate the safety and efficacy of novel and promising recombinant enzyme therapies.

Enzyme replacement therapy for hypophosphatasia-The current paradigm.

Hypophosphatasia (HPP) is a rare, inherited, and systemic disorder characterized by impaired skeletal mineralization and low tissue nonspecific serum alkaline phosphatase (TNSALP) activity. It is caused by either autosomal recessive or dominant-negative mutations in the gene that encodes TNSALP. The phenotype of HPP is very broad including abnormal bone mineralization, disturbances of calcium and phosphate metabolism, pain, recurrent fracture, short stature, respiratory impairment, developmental delay, tooth loss, seizures, and premature death. Other than supportive care, there has been no disease-specific treatment available for those with HPP. Asfotase alfa is a fully humanized, recombinant enzyme replacement therapy for the management of HPP. It is available in several countries for the treatment of the more severe forms of HPP, namely perinatal and infantile HPP. This review will summarize the preclinical data on asfotase alfa and highlight the data from clinical trials and case reports. These data show the transformative nature of asfotase alfa when administered as part of an interdisciplinary treatment model.

Quantitative calcium-based assessment of osteoporosis in dual-layer spectral CT

ObjectivesTo evaluate a novel calcium-only imaging technique (VCa) with subtracted bone marrow in osteoporosis in dual-layer CT (DLCT) compared to conventional CT images (CI) and dual-energy X-ray absorptiometry (DXA). Material and methodsImages of a multi-energy CT phantom with calcium inserts, quantitative CT calibration phantom, and of 55 patients (mean age: 64.6 ± 11.5 years) were acquired on a DLCT to evaluate bone mineral density (BMD). CI, calcium-suppressed images, and VCa were calculated. For investigating the association of VCa and CI with DXA a subsample of 30 patients (<90 days between DXA and CT) was used. Multiple regression analysis was performed to identify further factors improving the prediction of DXA BMD. ResultsThe calcium concentrations of the CT phantom inserts were significantly associated with CT numbers from VCa (R2 = 0.94) and from CI (R2 = 0.89–0.92). VCa showed significantly higher CT numbers than CI in the phantom (p ≤ 0.001) and clinical setting (p < 0.001). CT numbers from VCa were significantly associated with CI (R2 = 0.95, p < 0.001) and with DXA (R2 = 0.31, p = 0.007), whereas no significant association between DXA and CI was found. Prediction of DXA BMD based on CT numbers derived from VCa yielded R2 = 0.76 in multiple regression analysis. ROC for the differentiation of normal from pathologic BMD in VCa yielded an AUC of 0.7, and a cut-off value of 126HU (sensitivity: 0.90; specificity: 0.47). ConclusionVCa images showed better agreement with DXA and known calcium concentrations than CI, and could be used to estimate BMD. A VCa cut-off of 126HU could be used to identify abnormal bone mineral density.

Preoperative abnormal bone mineral density as a prognostic indicator in patients undergoing gastrectomy for gastric cancer: A cohort study.

Predicting postgastrectomy relapse and mortality in patients with gastric cancer (GC) remains challenging, with limitations to traditional staging systems such as the tumor-node-metastasis (TNM) system. This study aimed to investigate the impact of preoperative Hounsfield unit (HU) values, which serve as a surrogate marker for bone mineral density (BMD), in predicting survival outcomes in patients with GC. A retrospective analysis was conducted on data from patients with GC who underwent curative-intent gastrectomy. Opportunistic abdominopelvic computed tomography images were used to assess HU values at the 3rd lumbar vertebra (L3). These values were then categorized using a cutoff value of 110 HU, which has been established in previous studies as a determinant for abnormal versus normal BMD. Cox regression analysis established predictor models for overall survival (OS). Among 501 initial patients, 478 met the inclusion criteria. Multivariate analyses revealed HU values (hazard ratio, 1.51), along with other factors (the 5-factor modified frailty index, type of gastrectomy, TNM stage, anemia, and serum albumin level), as significant predictors of OS. The full model (FM) incorporating these variables demonstrated superior discrimination ability compared to the baseline model (BM), which is based solely on the TNM stage (concordance index: 0.807 vs 0.709; P < .001). Furthermore, the FM outperformed the BM in predicting OS risks at 36- and 60-months post-surgery. In conclusion, among patients undergoing gastrectomy for GC, those with HU values ≤ 110 (indicating abnormal BMD) at the L3 level, as determined through opportunistic CT scans, exhibited a poorer prognosis than those with HU values > 110 (indicating normal BMD). Integrating HU with other clinicopathological parameters enhances predictive accuracy, facilitating individualized risk stratification and treatment decision-making, which could potentially lead to improved survival outcomes.

#911 A mice model of SHPT with bone abnormalities in CKD and potential functional role of sphingolipid in renal osteodystrophy

Abstract Background and Aims Renal osteodystrophy (ROD) is the skeletal disease of chronic kidney disease associated mineral and bone disorder (CKD-MBD). ROD is characterized by abnormal bone mineralization and impaired bone remodeling, leading to increased risk of fractures and mortality in patients with CKD. To date, the pathology of ROD remains poorly understood due to the lack of a suitable animal model. Hence, we successfully established a stable mouse model of ROD using an optimized adenine diet and explored the possible signaling based on RNA-seq expression analyses. Method Blood biochemical analysis, micro-computed tomography (micro-CT) and bone histomorphometry were performed to analyze the skeletal characteristics. RNA sequencing (RNA-seq) was used to investigate the mechanisms involved in ROD. The functions of differentially expressed genes (DEGs) were evaluated by Gene Ontology (GO) analyses, Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and Gene Set Enrichment Analyses (GSEA). DEGs were validated by quantitative real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results The mice with ROD induced by optimized adenine diet showed severe abnormalities in serum creatinine (Scr) and blood urea nitrogen (BUN) along with marked hyperparathyroidism and hyperphosphatemia. The bone mineral density (BMD) of femurs was significantly lower in the ROD mice than that in the control (CTL) mice. The trabecular and cortical bone parameters of femurs significantly showed bone loss and severe cortical porosity. ROD mice showed high bone turnover with increased osteoid, eroded, osteoblast, and osteoclast perimeters as well as increased bone formation rate and mineral apposition rate. Transcriptomic profiling identified 1286 genes were upregulated in the femurs of ROD mice compared to the CTL mice and 333 genes that were downregulated. GO, KEGG and GSEA pathway analyses indicated that these genes were highly enriched in functions related to lipid metabolism pathway, sphingolipid signaling pathway, among others. The differential expression of alkaline ceramidase 1(Acer1), ceramide synthase 4 (Cers4) sphingomyelin phosphodiesterase 3 (Smpd3), sphingosine-1-phosphate phosphatase 2 (Sgpp2) in skeletal tissue and serum of CKD patients were validated by qRT-PCR. Since sphingolipid pathways have been recently implicated in bone metabolism, these genes are potential target genes in the settings of ROD. Conclusion In conclusion, our findings demonstrated that the CKD mice with bone abnormalities induced by optimized adenine diet may serve as a useful model for skeletal analysis in ROD. Based on the RNA-seq, we identified that sphingolipid might play a crucial role in the pathogenesis of ROD and provided new therapeutic targets for future study.

#2034 CKD-MBD management: results from a national survey on bone turnover biomarkers practice and therapeutic strategies among Italian nephrologists

Abstract Background and Aims Advanced stages of chronic kidney disease (CKD) are constantly characterized by a mineral and bone disorders (MBD) syndrome concerning a complex systemic condition that includes laboratory abnormalities of bone and mineral metabolism involving calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; abnormalities in bone turnover, mineralization, volume, or strength; extra-skeletal calcifications, such as vascular or other soft tissue. CKD-MBD syndrome determines relevant consequences in terms of fragility fractures, cardiovascular events and higher mortality. The nephrologist's awareness of CKD-MBD diagnostic and management tools and therapeutic strategies is key to improving CKD patients’ prognosis and outcomes. Method A new national survey (composed of 17 online questions) was conducted among Italian nephrologists to investigate the reference laboratory availability of bone turnover markers (BTMs), the clinical attitude on secondary hyperparathyroidism (sHPT) management, and the CKD-MBD therapeutic approach in different stages of CKD and dialysis patients. Results 89 Italian nephrologists participated in the survey. The reference laboratories largely fulfill the biomarkers request of ionized calcium (97.7%), phosphorus (100%), PTH (100%), alkaline phosphatase (ALP) (100%), magnesium (100%), 25-OH and 1,25-OH vitamin D levels (92.1%; 53.9%); while most of the hospital laboratories do not regularly support the availability of specific BTMs, both for diagnosis and monitoring the bone resorption and formation (Fig. 1)—such as bone ALP (75.3%), calcifediol (37.1%), calcitriol (40.5%), fibroblast growth factor-23 (FGF-23) (intact 9% and c-terminal 4.5%), vitamin K (33.7%), Klotho (6.75%, soluble 4.5%), osteocalcin (38.2%), matrix gla protein (10.1%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (6.75%), cross-linked collagen type I peptide (CTX) (32.6%) and procollagen type 1 n-terminal propeptide (P1NP) (10.1%). The nephrologist's attitude to start management and treatment of sHPT is revealed to be mainly led by KDOQI (n = 42, 47%) and KDIGO (n = 39, 44%) guidelines considering their PTH cut-off values; in 53.9% of clinicians the measure of PTH levels is then performed every 3 months according to KDOQI guidelines. In relation to the definition of high turnover metabolic bone disease by BTMs, this metabolic pattern is identified in &amp;gt; 50% and 30-40% of patients with CKD 4-5D by 31.5% and 21.4% of nephrologists, respectively. 65% of clinicians currently considered ALP of equal importance as alterations of PTH as a predictor of fracture events. Other biomarkers, such as FGF-23, P1NP or TRAP-5b, emerge to not be still used in regular clinical practice. In patients diagnosed with CKD-MBD and skeletal fragility, 76.4% of nephrologists consider the AIFA (Italian Medicines Agency) note 79 to support osteoporosis treatment. The therapeutic strategies of CKD-MBD include the administration of vitamin D (e.g. cholecalciferol 27-37.1%, calcifediol 9-12.4%, calcitriol 42.7-55.1%) and its analogues (e.g. paricalcitol 23.6-52.8%) and the use of antiresorptive agents (e.g. alendronate 3.4%-23.6%, denosumab 22.5%-30.3%) with variable frequencies among different advanced CKD stages and for those patients on peritoneal or hemodialysis (Fig. 2). Conclusion Results present a suboptimal use of BTMs and a current heterogeneous therapeutic management of CKD-MBD syndrome and renal osteodystrophy in Italian clinical practice. The survey represents a starting point of work to further implement awareness of diagnostic and therapeutic issues of CKD-MBD.

Does ethnicity influence bone health index in children? A pilot study.

Several pathological conditions can lead to variations in bone mineral content during growth. When assessing bone age, bone mineral content can be estimated without supplementary cost and irradiation. Manual assessment of bone quality using the Exton-Smith index (ESI) and automated assessment of the bone health index (BHI) provided by the BoneXpert® software are available but still not validated in different ethnic groups. Our aim is to provide normative values of the ESI and BHI for healthy European Caucasian and first-generation children of North Africans living in Europe. A sex- and aged-match population of 214 girls (107 European-Caucasian and 107 North African) and 220 boys (111 European-Caucasian and 109 North African) were retrospectively and consecutively included in the study. Normal radiographs of the left hand and wrist from healthy children were retrieved from those performed in a single institution from 2008 to 2017 to rule out a left-hand fracture. Radiographs were processed by BoneXpert® to obtain the BHI and BHI standard deviation score (SDS). One radiologist, blinded to BHI values, manually calculated ESI for each patient. The variability for both methods was assessed and compared using the standard deviation (SD) of the median (%) for each class of age and sex, and ESI and BHI trends were compared by sex and ethnic group. The final population comprised 434 children ages 3 to 15 years (214 girls). Overall, BHI was lower in North African children (mean = 4.23 for girls and 4.17 in boys) than in European Caucasians (mean = 4.50 for girls and 4.68 in boys) (P < 0.001). Regardless of ethnicity, 29 girls (13.6%) and 34 boys (15.5%) had BHI more than 2 SD from the mean. While correlated to BHI, ESI has a higher variability than BHI and is more pronounced from 8-12 years for both sexes (mean ESI in European Caucasian girls and boys17.47 and 20.87, respectively) (P < 0.001). ESI showed more than 15% variability in European girls from 8-12 years and a plateau in North African boys from 12 yearsto 16 years. However, the BHI has less than 15% variability regardless of age and ethnic group. BHI may be a reliable tool to detect children with abnormal bone mineral content, with lower variability compared to ESI andwith specific trends depending on sex and ethnicity.

An FGFR2 mutation as the potential cause of a new phenotype including early-onset osteoporosis and bone fractures: a case report

Osteoporosis is a systemic, multifactorial disorder of bone mineralization. Many factors contributing to the development of osteoporosis have been identified so far, including gender, age, nutrition, lifestyle, exercise, drug use, as well as a range of comorbidities. In addition to environmental and lifestyle factors, molecular genetic factors account for 50–85% of osteoporosis cases. For example, the vitamin D receptor (VDR), collagen type I (COL1), estrogen receptor (ER), apolypoprotein Е (ApoE), bone morphogenetic protein (BMP), and Low-density lipoprotein receptor-related protein 5 (LRP5) are all involved in the pathogenesis of osteoporosis. Among the candidate genes, the pathogenic variants in which are involved in the pathogenesis of osteoporosis is FGFR2. Additionally, FGFs/FGFRs-dependent signaling has been shown to regulate skeletal development and has been linked to a plethora of heritable disorders of the musculoskeletal system. In this study we present the clinical, biochemical and radiological findings, as well as results of molecular genetic testing of a 13-year-old male proband with heritable osteoporosis, arthralgia and multiple fractures and a family history of abnormal bone mineralization and fractures. Whole exome sequencing found a heterozygous previously undescribed variant in the FGFR2 gene (NM_000141.5) (GRCh37.p13 ENSG00000066468.16: g.123298133dup; ENST00000358487.5:c.722dup; ENSP00000351276.5:p.Asn241LysfsTer43). The same variant was found in two affected relatives. These data lead us to believe that the variant in FGFR2 found in our proband and his relatives could be related to their phenotype. Therefore, modern methods of molecular genetic testing can allow us to differentiate between osteogenesis imperfecta and other bone mineralization disorders.

Breast Cancer and Bone Mineral Density in a U.S. Cohort of Middle-Aged Women: Associations with Phosphate Toxicity.

Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition. Based on shared associations with dysregulated phosphate metabolism and phosphate toxicity, a hypothesis proposed in the present mixed methods-grounded theory study posits that middle-aged women with incidence of breast cancer had a greater magnitude of changes in bone mineral density over time compared with women who remained cancer-free. To test this hypothesis, a mixed-effects model was used to analyze the associations of breast cancer incidence with spinal bone mineral density changes in the U.S. Study of Women's Health Across the Nation. Compared with women in the cohort who remained cancer-free, women who self-reported breast cancer had higher bone mineral density at baseline, but had more rapid losses in bone mineral density during follow-up visits. These findings agree with the hypothesis that a greater magnitude of changes in bone mineral density over time is associated with breast cancer in a cohort of middle-aged women. The findings also have implications for studies investigating dysregulated phosphate metabolism and phosphate toxicity as causative factors of bone metastasis in metastatic breast cancer. Additionally, the authors previously found increased breast cancer risk associated with high dietary phosphate intake in the same cohort of middle-aged women, and more studies should investigate a low-phosphorus diet to reduce bone mineral abnormalities and tumorigenesis in breast cancer patients.

Can the greater trochanter/femoral neck signal intensity ratio on coronal T1 weighted images of the hip differentiate normal-abnormal bone mineral density?

The aim of this study is to evaluate the efficacy of the greater trochanter/femoral neck (T/N) signal intensity (SI) ratio on T1 weighted images of the hip in differentiating patients with normal vs. abnormal bone mineral density (BMD) using hip dual-energy x-ray absorptiometry (DXA) as the reference. Three BMD groups according to the T score of the femoral neck (i.e., normal, osteopenia, and osteoporosis) were created, and 20 patients were included for each group. The T/N ratio was calculated by dividing the greater trochanter SI by that of the femoral neck on coronal T1-weighted images. Receiver-operator characteristic (ROC) analysis was performed to determine diagnostic efficacy. The mean age was 59.2±9.4; there were 57 women and 3 men. The mean BMD was 0.67±0.14 g/cm2. The mean T/N ratio for the normal, osteopenia, and osteoporosis groups were 1.37 (±0.12), 1.19 (±0.10), and 1.18 (±0.13), respectively. When the osteopenia and osteoporosis groups were combined into one group, i.e., low BMD group, the mean T/N ratio was 1.18 (±0.11), and it was significantly different from that of the normal BMD group (p<0.00001). In ROC analysis, the area under curve (AUC) for the T/N ratio in the diagnosis of low BMD was 0.870. An optimal cutoff value of 1.28 was found for the differentiation of normal vs. abnormal BMD with 80% sensitivity and 80% specificity. The T/N ratio seems to be effective at differentiating patients with normal vs. abnormal BMD and may help triage patients for additional evaluation.

T2*-corrected Q-Dixon and reduced-FOV diffusion kurtosis imaging (DKI) parameters: correlation with QCT-derived bone mineral density (BMD) and ability to identify abnormal BMD and osteoporosis in postmenopausal women.

Bone marrow fat increases when the bone volume decreases. The composition of the bone marrow microenvironment can also become altered. Assessments of bone marrow fat and bone marrow structural heterogeneity have the potential to predict abnormal bone mineral density (BMD) and osteoporosis. This study aimed to investigate the diagnostic performance of T2*-corrected Q-Dixon and reduced-field-of-view (FOV) diffusion kurtosis imaging (DKI) parameters in determining abnormal BMD and osteoporosis in postmenopausal women. In this prospective study, the individuals who were eligible for inclusion included postmenopausal women (over 50-year-old) with suspected osteoporosis based on experiencing low back pain. This mono-center study was conducted in tertiary care in China. All of the patients were recruited by using the consecutive sampling method. Subjects who underwent T2*-corrected Q-Dixon and reduced-FOV DKI sequences were enrolled. Fat fraction (FF), T2*, mean kurtosis (MK), and mean diffusivity (MD) values were measured on L1, L2, and L3 vertebral bodies. Quantitative computed tomography (QCT) examinations served as the reference standard. All of the subjects were divided into three groups: normal (BMD >120 mg/cm3), osteopenia (BMD 80-120 mg/cm3), and osteoporosis (BMD <80 mg/cm3). One-way analysis of variance, correlation coefficient analysis, and receiver operating characteristic curve analysis were performed. Among all of the enrolled subjects, 52 were in the normal group, 51 were in the osteopenia group, and 52 were in the osteoporosis group. There were significant differences in FF, T2*, MK, and MD values between the three groups (P<0.001, P<0.001, P<0.001, and P=0.003, respectively). FF, T2*, and MK values exhibited significant negative correlations with BMD values (r=-0.739, P<0.001; r=-0,676, P<0.001; and r=-0.626, P<0.001, respectively). Excellent discriminatory capacity was observed in the Q-Dixon [area under the curve (AUC): 0.976, 95% confidence interval (CI): 0.955-0.997] differentiation between normal and abnormal BMD subjects. It was significantly better than the DKI (AUC: 0.812, 95% CI: 0.741-0.882) parameter combination (P<0.001), whereas the DKI model (AUC: 0.825, 95% CI: 0.739-0.910) performed comparably to the Q-Dixon model (AUC: 0.798, 95% CI: 0.710-0.886) for screening osteoporosis (P=0.57). FF and T2* values measured by using T2*-corrected Q-Dixon, as well as MK and MD values measured by using reduced-FOV DKI, may serve as potential imaging biomarkers in assessing abnormal BMD and osteoporosis in postmenopausal women.

Abstract #1399545: Calcification of Left Atrial Appendage in Autosomal Recessive Hypophosphatemic Rickets Type 2 (ENPP1 Mutation)

Autosomal Recessive Hypophosphatemic Rickets type 2 (ARHR2) is a rare genetic condition secondary to a loss-of-function mutation in ENPP1 gene. ARHR2 is associated with renal phosphate wasting and suppressed 1,25-dihydroxyvitamin D due to increased FGF-23 levels and causing abnormal bone mineralization. Furthermore, as ENPP1 is implicated in the generation of PPi (inorganic pyrophosphate) which inhibits hydroxyapatite deposition, some ARHR2 patients present with life-treating generalized arterial calcification of infancy (GACI). We reported the case of a 32-year-old woman with a known diagnosis of ARHR2 since the age of seven. At that time, she presented a growth failure, bowed legs but no GACI history. She was treated from the age of 7 to 18 with phosphate supplements and calcitriol. She had ten surgeries for her leg deformities and had a subtotal parathyroidectomy at age 13 for primary hyperparathyroidism. She was referred to a tertiary centre for management of hypophosphatemia and diffuse bone pain. The alkaline phosphatase was at the upper limit of normal but imagings, including computed tomography scans and bone scintigraphy, did not show pseudofractures. Her chronic pain was associated with osteoarthritis and periarticular calcifications. She was treated for hypertension, and had a history of preeclampsia at 33 weeks of pregnancy. At the physical exam, a 30 mm Hg systolic blood pressure differential was noted between the right and left arms, suspect of severe subclavian artery stenosis. Additional investigations demonstrated a normal cardiac ultrasound (US), an Agatson score of 0 (coronary calcium scan) but extensive calcifications of the left atrial appendage, dense calcifications of the mitral valve and numerous calcifications in the ascending aortic wall. The spectrum of clinical manifestations associated with ENPP1-related conditions (GACI and ARHR2) is still unclear. In some patients who survive GACI, resolution of vascular calcifications has been reported. Furthermore, this case raises the possibility of undetected vascular calcifications in the infancy uncovered only after the diagnosis of ARHR2. Previous cases reported pulmonary stenosis, thickening of the aortic valve, and increased carotid intima-media thickness in patients with ARHR2 phenotype. Left atrial calcifications have been described in mechanical valve replacement, mitral stenosis, post-radiotherapy and in chronic kidney disease. Recommendations of cardiac US and kidney US have been proposed at the diagnosis of AHRH2. We further suggest vascular screening with cardiac scans to examine large vessels, and calcium score in these patients.

The WNT/β-catenin system in chronic kidney disease-mineral bone disorder syndrome.

The WNT/β-catenin system is an evolutionarily conserved signaling pathway that plays a crucial role in morphogenesis and cell tissue formation during embryogenesis. Although usually suppressed in adulthood, it can be reactivated during organ damage and regeneration. Transient activation of the WNT/β-catenin pathway stimulates tissue regeneration after acute kidney injury, while persistent (uncontrolled) activation can promote the development of chronic kidney disease (CKD). CKD-MBD is a clinical syndrome that develops with systemic mineral and bone metabolism disorders caused by CKD, characterized by abnormal bone mineral metabolism and/or extraosseous calcification, as well as cardiovascular disease associated with CKD, including vascular stiffness and calcification. This paper aims to comprehensively review the WNT/β-catenin signaling pathway in relation to CKD-MBD, focusing on its components, regulatory molecules, and regulatory mechanisms. Additionally, this review highlights the challenges and opportunities for using small molecular compounds to target the WNT/β-catenin signaling pathway in CKD-MBD therapy. We conducted a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science, to identify relevant articles. We searched for articles that discussed the WNT/β-catenin signaling pathway, CKD-MBD, and their relationship. We also reviewed articles that discussed the components of the WNT/β-catenin signaling pathway, its regulatory molecules, and regulatory mechanisms. The WNT/β-catenin signaling pathway plays a crucial role in CKD-MBD by promoting vascular calcification and bone mineral metabolism disorders. The pathway's components include WNT ligands, Frizzled receptors, and LRP5/6 co-receptors, which initiate downstream signaling cascades leading to the activation of β-catenin. Several regulatory molecules, including GSK-3β, APC, and Axin, modulate β-catenin activation. The WNT/β-catenin signaling pathway also interacts with other signaling pathways, such as the BMP pathway, to regulate CKD-MBD. The WNT/β-catenin signaling pathway is a potential therapeutic target for CKD-MBD. Small molecular compounds that target the components or regulatory molecules of the pathway may provide a promising approach to treat CKD-MBD. However, more research is needed to identify safe and effective compounds and to determine the optimal dosages and treatment regimens.

Young XLH Patients-Reported Experience with a Supportive Care Program.

X-linked hypophosphatemia (XLH) is a rare, chronic, genetic condition characterized by renal phosphate wasting and abnormal bone and teeth mineralization. It represents a challenging and multifaceted disease that causes wide-ranging impacts on patients' lives. In this context, a scientific committee has designed a support initiative for patients treated for XLH: the aXess program. We sought to determine if a patient support program (PSP) could help XLH patients cope with their condition. During the 12 months of participation in the aXess program, XLH patients were contacted by phone by a nurse to coordinate their treatment, ensure treatment adherence, and provide motivational interviews. A Pediatric QOL inventory was conducted on all participants at enrollment (D0), at month 6, and month 12. Altogether, a total of 59 patients were enrolled in the program. Most patients reported an improvement in QOL in all examined dimensions by month 12 (physical, emotional, social, and school, 85.4 ± 0.2 at month 12 versus 75.6 ± 0.3 at enrollment, p<0.05). Patients were very satisfied with the program, with a mean overall satisfaction score of 9.8 ± 0.6 (on a scale from 0 to 10) at month 6 and 9.2 ± 1.5 at month 12. Our findings indicate that this program might improve the QOL for patients with chronic conditions such as XLH through patient education, therapy adherence, motivational interviews, and frequent follow-up. It links the home environment and overall illness management, bringing patients, families, and caregivers together.