Journal of Bone and Mineral Research最新文献

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.

Zoledronic acid (ZA), cleared renally, carries a higher nephrotoxicity risk at doses≥4 mg, especially in patients with chronic kidney disease (CKD). While 5 mg is standard for osteoporosis, ZA increases bone mineral density at doses as low as 0.25 mg every 3 mo. Inpatient ZA (IP-ZA) in hip fracture patients reduces mortality and re-fracture risk, but its safety in those with advanced CKD [creatinine clearance rate (CrCl) < 35 mL/min] is unclear. We analyzed real-world data from a large academic healthcare system to assess the safety of reduced-dose IP-ZA (≤3 mg) in hip fracture patients with advanced CKD, compared to propensity-matched controls receiving no anti-osteoporosis medication during index hip fracture hospitalization. The study included 328 IP-ZA patients and 2308 controls, with a primary cohort of 46 IP-ZA patients and 98 matched untreated controls, predominantly female (77.8%), White (92.4%), with a mean age of 89.9 yr and CrCl of 31.1 ± 0.6 mL/min. The IP-ZA group received an average dose of 2.7 ± 0.1 mg (1 patient at 1 mg, 11 at 2 mg, 34 at 3 mg) on postoperative day 2.9 ± 0.3. All patients received standing acetaminophen, calcium (650-1000 mg/d), and vitamin D (1000-2500 IU/d) post-surgery. We monitored daily maximum body temperature, serum creatinine, and serum calcium for five days, starting the day before IP-ZA administration (or postoperative day 2 for controls). IP-ZA did not affect temperature, with new-onset fever (≥38.0 °C, days 2-4) in one IP-ZA patient and two controls. Serum creatinine level remained stable. Serum calcium level in the IP-ZA group decreased from 8.8 ± 0.1 mg/dL to 8.2 ± 0.2 mg/dL by day 5, unchanged in controls; no IP-ZA patient had serum calcium level < 7.5 mg/dL. Hospital length-of-stay (6.2 ± 0.4 vs. 6.5 ± 0.4 d, p = .41) and 30-d readmission rates were similar. This study suggests that reduced-dose IP-ZA is likely safe for patients with hip fracture and advanced CKD who are otherwise at high risk for being untreated.

Introduction: Fracture risk estimates can be used clinically to inform treatment decision-making in osteoporosis. Current fracture risk assessment tools have a low sensitivity in predicting fractures in males. This study aims to evaluate and validate the performance of a new fracture prediction tool - the Microarchitecture Fracture Risk Assessment Calculator (FRAC) - in a multi-centre cohort (MrOS) of older community-dwelling men.

Methods: The performance of FRAC was assessed in a population of 1586 men aged $geq 77$ years in the US. All participants underwent HR-pQCT scanning (61 m) of the distal radius and distal tibia. Incident fracture information was collected every 4 months from the study visit. The FRAC 5-year and 10-year risk of major osteoporotic fracture (MOF) and any osteoporotic fracture (AOF) was calculated for all participants. The model calibration was assessed by fitting Fine Gray competing risk regression models. The model discrimination was assessed using receiver operator characteristic curves (ROCs) and area under the curve (AUCs).

Results: Over the 10-year follow-up period, 129 men experienced an incident major osteoporotic fracture. The FRAC models showed good generalizability of the 5-year risk estimates (regression slope 0.8-1.1) to MrOS cohort. The FRAC models displayed an improved model performance (AUC = 0.685-0.703) relative to reference models of FRAX (AUC = 0.641) and FN aBMD alone (AUC = 0.636) for the 5-year MOF risk estimates. A sub-analysis on individuals classified as moderate risk by FRAX (10-20% MOF risk) found that FRAC aided in stratifying risk, particularly for the 5-year risk estimates (FRAC AUC = 0.691-0.706).

Conclusion: The FRAC models demonstrated strong performance and generalizability to an external cohort of older men. This validation of FRAC suggests its potential use as an alternate assessment tool for osteoporotic fracture risk and may have value in targeting moderate-risk subgroups to aid treatment decisions.

Osteoporosis is a major health concern in older individuals. Efficient case-finding is essential for timely risk assessment and treatment for high-risk patients. To prevent fractures and reduce the risk of subsequent disability, approaches offering clinically sufficient sensitivity with acceptable specificity are warranted. Although pharmaceutical osteoporosis treatment is effective, it is often diagnosed at a late stage, for instance, following a fracture. The aim of this study was to extend the existing Fracture Risk Evaluation Model (FREM), which identifies individuals at risk of an imminent (1-yr) major osteoporotic fracture (MOF) based on administrative health data. This extension (FREMVer2) included data on morbidity and medications and evaluated age-specific risk cut-offs to enhance the risk assessment of MOF and hip fracture (HF) risk, respectively. We included the entire population of Denmark aged ≥45 yr at baseline (2022; N = 2 493 180), not previously diagnosed with osteoporosis or receiving osteoporosis treatment. The cohort was divided into 4 groups stratified by sex and age (<65 yr, ≥65 yr). Each of the 4 groups was randomly split into a 60% development, a 20% model validation, and a 20% cut-off validation cohort. All diagnoses from Danish hospitals and filled prescriptions from Danish pharmacies from 2007 to 2021 were used as possible predictors for MOF. These predictors correspond to information that in Denmark is automatically transferred to general practitioner's electronic health records; hence, prediction would be possible in general practice. Models were constructed by logistic regression with LASSO regularization, determining the preferred regularization hyper parameter by cross-validation and forcing categorical age to be included. Across subgroups, the models obtained poor to acceptable area under the curves (AUCs) of 0.656-0.714 for MOF, and acceptable AUCs of 0.728-0.764 for HFs. Additionally, the models achieved sensitivities of around 80% or higher in almost all subgroups. This performance, together with the available predictors, makes FREMver2 a feasible decision support system as a step toward an opportunistic screening program in health care settings with access to administrative data.

Early-onset osteoporosis (EOOP) is diagnosed in premenopausal women or men under 50 yr of age when DXA-derived BMD is low (Z-score ≤ -2.0 or T-score ≤ -2.5) in the presence of a fragility fracture or a chronic disease. In young adult patients, it is essential to recognize EOOP and identify the underlying cause, including possible genetic defects, to optimize tailored treatments. Among monogenic causes, WNT1-related osteoporosis has been described in children and adults. We present two adults, a 27-yr-old male and his mother, who had no skeletal symptoms in childhood but presented as adults with back pain. Further studies revealed low BMD and multiple spinal fragility fractures, leading to rapid height loss and progressive kyphosis. Biochemistry was largely normal, but bone biopsies showed impaired bone metabolism with low bone turnover. Both were found to harbor a previously described pathogenic heterozygous variant in WNT1, which leads to impaired WNT signaling. We describe the challenges in their clinical care, sequence of treatments, and outcome. These patients highlight the value of a correct genetic diagnosis to better understand the mechanisms behind low bone mass and to enable early intervention. Furthermore, our study emphasizes the need for anabolic treatment options for both males and females with EOOP, and the importance of long-term treatment planning, including an exit strategy.

The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptors and act as universal adaptor proteins to mediate the activation of key downstream signaling pathways. However, it remains unclear whether and how Gαi1/3 proteins mediate Wnt/β-catenin signal transduction. In this study, we utilized single-cell sequencing analysis and employed viral transfection and gene editing techniques to alter the expression of Gαi1/3 in mouse embryonic osteoblast precursor cells. We examined the relationship between Gαi1/3 expression and the Wnt/β-catenin signaling pathway. Immunoprecipitation and confocal experiments were conducted to further explore the mechanisms by which Gαi1/3 exerts its functions. Osteogenic-related protein levels were detected by Western blotting, and the effects of Gαi1/3 proteins on osteogenic function were examined through alkaline phosphatase and Alizarin red staining. Additionally, micro-CT was used to compare bone mass in mice with different levels of Gαi1/3 expression, showing the relationship between Gαi1/3 and bone formation. Our findings indicate that Gαi1/3 proteins are significantly inversely correlated with age. Gαi1/3, rather than Gαi2, mediates the Wnt/β-catenin signaling pathway and promotes osteogenesis. Mechanistically, Gαi1/3 interacts with Axin1 and recruits it to the cell membrane, leading to inactivation of the β-catenin degradation complex. This results in β-catenin accumulation and nuclear translocation, where it activates the transcription of osteogenic genes. In vivo experiments further confirm that knockdown of Gαi1/3 significantly inhibits bone formation in mice. Our study identified Gαi1/3 as key regulatory proteins in Wnt/β-catenin signaling-mediated osteogenesis, and further elucidated its molecular mechanism in bone formation, which may provide a new therapeutic target for osteoporosis.