Journal of Bone and Mineral Research最新文献

Transgender individuals are increasingly seeking gender-affirming therapy. For children and adolescents, this typically involves puberty suppression followed by hormone treatment. However, potential long-term adverse effects on the growing skeleton remain poorly characterized, largely due to the lack of appropriate preclinical animal models. Existing models often rely on surgical puberty suppression and, in the case of estradiol (E2) administration, cause a high bone mass-phenotype that is not observed in the clinical setting. To address this, we developed a novel preclinical mouse model that mimics the medical approach used in transgirls and analyzed the effects of gender-affirming therapy on bone. Four-week-old male mice were treated with the gonadotropin-releasing hormone analogue degarelix (DGX) for pharmacological puberty suppression. After 4 weeks, E2 was administered at different doses, and bone properties were analyzed after an additional 8 weeks. DGX treatment effectively suppressed sex steroid signaling, leading to reduced bone mass and strength, which were dose-dependently restored by E2. While high E2 doses resulted in an excessive increase in bone mass, thereby precluding further mechanistic study, lower doses resulted in a bone phenotype resembling that of native females. At the cellular level, DGX-mediated puberty suppression resulted in increased bone resorption that exceeded bone formation, and also caused an accumulation of marrow adipocytes. Subsequent low-dose E2 administration reduced bone resorption, stimulated bone formation, and prevented the increase in bone marrow adiposity. In summary, we established and validated a mouse model that accurately mimics gender-affirming therapy initiated during early puberty and enables the study of its effects on bone.

Vertebral fractures represent a growing health issue in our aging societies. We performed a large-scale quantitative assessment of the geometric, densitometric, and biomechanical characteristics of the aging thoracolumbar spine using quantitative computed tomography (QCT) and homogenized finite element (hFE) analysis. A total of 9,298 intact vertebral bodies from T1 to L5 were evaluated across 629 radiologically healthy post-mortem spines (194 female, 435 male). We quantified vertebral height, cross-sectional area (CSA), bone mineral content (BMC), bone mineral density (BMD), synthetic areal bone mineral density (aBMD) and hFE-derived yield strength and applied a mixed linear regression model to investigate their dependence on age, sex, body mass index (BMI), and spinal level. We found that vertebral height was greatest in the lumbar region, while CSA increased caudally and showed positive associations with both age and BMI. Both BMD and yield strength declined with advancing age, with significantly steeper reductions observed in females and in individuals with lower BMI. Interestingly, not yield force, but yield strength was found to be minimal at the thoracolumbar junction (T12-L1), which coincides with the highest occurrence of vertebral fractures. Despite inter-individual variability, BMD demonstrated strong segmental correlations, particularly between adjacent vertebrae, with correlation strength increasing with anatomical proximity. We established a robust power-law relationship (R2 = 0.91) between BMD and yield strength, which generalized across all vertebral levels. Collectively, these findings delineate spatial and demographic patterns in vertebral strength degeneration and provide normative QCT-based reference data for biomechanical modeling. The derived regression framework enables non-invasive estimation of vertebral yield strength, supporting future applications in fracture risk prediction and spine biomechanics research.

Cleidocranial dysplasia is a rare genetic condition negatively impacting skeletal development. Clinical guidelines for patients, their family members, and clinicians on the diagnosis, treatment, and management of this disease are lacking. The aim of this study was to align expert opinion on standard of care medical recommendations for patients with cleidocranial dysplasia, primarily for adults and children (≥2 years of age). A modified Delphi panel comprised of a three-round survey was used to determine consensus among a multidisciplinary team of thirteen experts with experience treating patients with cleidocranial dysplasia. Statements for Round 1 were generated from a targeted literature review and received input from a steering committee of two experts within the panel. Expert discussion held after Round 2 helped refine statements for Round 3; the steering committee also reviewed statements before dissemination in each round. The consensus threshold was pre-defined as ≥70% agreement or disagreement for Likert-scale statements or ≥70% of experts selecting the same response for a multiple-choice option. For statements wherein consensus was measured, 79% (n/N=26/33), 91% (n/N=21/23), and 100% (n/N=12/12) of statements reached consensus, respectively, in Round 1, Round 2, and Round 3. Overall, consensus was reached on 37 standard of care recommendations for patients with cleidocranial dysplasia: 9 regarding diagnosis, 24 regarding treatment and management, consisting of 7 dental/orthodontic and 17 other medical (non-dental/orthodontic), and 4 regarding care providers. The expert consensus reached in this panel informs the first comprehensive best practice guidelines for patients, their family members, and healthcare providers to diagnose, treat, and manage the dental/orthodontic and other medical complications of cleidocranial dysplasia.

A 38-yr-old primigravida presented at 30 + 2 wk' gestation with pregnancy-induced hypertension and was found to have severe hypercalcaemia (adjusted calcium 3.19 mmol/L). Intravenous fluid therapy produced only transient improvement, and recurrent hypercalcaemia required repeated inpatient management. Parathyroid hormone (PTH) was suppressed, while both 25(OH)D₃ and 1,25(OH)₂D₃ (calcitriol) were elevated. Imaging and laboratory investigations revealed no evidence of malignancy or granulomatous disease. Delivery by elective caesarean section was undertaken at 35 wk' gestation. The neonate developed transient hypocalcaemia with suppressed PTH, requiring brief intravenous calcium supplementation. Maternal hypercalcaemia persisted postpartum, and renal imaging revealed nephrolithiasis and nephrocalcinosis. Serum calcium remained elevated during lactation but normalized after weaning. Extended vitamin D metabolite profiling showed an increased 25(OH)D₃:24,25(OH)₂D₃ ratio, and genetic analysis confirmed compound heterozygous pathogenic variants in CYP24A1, encoding vitamin D 24-hydroxylase, the enzyme responsible for calcitriol degradation. The findings established a diagnosis of gestational hypercalcaemia due to CYP24A1 deficiency. Normal pregnancy is associated with physiological rises in calcitriol, reduced PTH, and hypercalciuria, features that can mimic or mask this disorder. This case illustrates the diagnostic challenges of recognizing CYP24A1 deficiency in pregnancy.

The endoplasmic reticulum (ER) orchestrates the folding of the large amounts of membrane and secretory proteins that are synthesized during the process of osteogenesis. The Unfolded Protein Response (UPR) resulting from accumulation of misfolded proteins in the ER lumen either promotes or inhibits osteoblast differentiation in vitro depending on magnitude and duration. All three transducers of the UPR, namely, IRE, PERK, and ATF6 proteins, have been implicated in skeletal biology, yet their specific contribution to osteoblast differentiation and function in vivo has not been investigated systematically. Here, the skeletal consequences of deleting each of them (i.e. Ire1α, Perk, or Atf6) in the osteoblast lineage using the Osx1-Cre transgene were determined. Mice with deletion of Ire1α in Osx1+ osteoblast precursors exhibited a marked reduction in osteoblast number, bone mass, and strength. Primary bone marrow cultures of osteoprogenitors lacking Ire1α had significantly reduced proliferation, alkaline phosphatase activity, and survival. Analyses of bulk RNA-seq data revealed suppression of osteogenic signature by Ire1α deletion in Osx1+ cells and predicted suppression of β-catenin activity. Mechanistically, Ire1α augments nuclear translocation and transcriptional activity of β-catenin in Osx1+ cells. In contrast, deletion of Perk or Atf6 genes in the osteoblast lineage using the Osx1-Cre transgene did not alter bone mass or strength. Collectively, these studies demonstrate that IRE1, but not other UPR transducers, promote physiological bone accrual in part by boosting β-catenin activity in osteoprogenitors.

Osteonecrosis of the femoral head (ONFH) is a debilitating condition often leading to joint collapse. While corticosteroids use and alcohol consumption are known risk factors, the pathophysiology, especially in idiopathic cases, which account for one-third population, remains unclear. This study aimed to investigate the potential role of human cytomegalovirus (HCMV) reactivation in the pathogenesis of ONFH, focusing on its presence, distribution, and reactivation status. Blood and femoral head samples were obtained from ONFH patients and fracture controls. HCMV exposure was assessed through serology and viral DNA quantification, and reactivation was confirmed by gB immunohistochemistry and IE-1 mRNA RT-qPCR. Tissue samples from different regions of the femoral head (necrotic, transitional, and healthy zones) were analyzed for viral content, reactivation and localization. Results revealed showed significantly higher HCMV DNA levels in necrotic and transitional zones of ONFH, strongly correlated with lesion volume. Furthermore, gB localization was predominantly found in the microvascular structures, such as small vessels and capillaries, suggesting that HCMV reactivation may contribute to microvascular damage and ischemia. IE-1 transcripts, markers of viral reactivation, further confirmed reactivation. Notably, HCMV reactivation was observed across all ONFH etiologies-corticosteroid-related, alcohol-related, and idiopathic-indicating its broad involvement in ONFH progression. This study provides the first clinical evidence linking HCMV reactivation to ONFH, offering potential therapeutic avenues, including antiviral treatments, to address this condition.