JBMR Plus最新文献

Hypophosphatasia (HPP) is an inherited metabolic disease caused by deficiency of tissue nonspecific alkaline phosphatase (TNAP) caused by pathogenic variants of the ALPL gene (MIM 171760). The clinical manifestations of HPP vary, ranging from a lethal perinatal-onset type to a moderate late-onset type presenting with nonspecific symptoms, such as arthropathy and musculoskeletal pain. HPP is characterized by low TNAP activity and defective bone mineralization, leading to bone deformity and skeletal abnormalities. Moreover, this disease can cause systemic complications, such as muscle weakness, seizures, pain, and respiratory failure, leading to premature death in infants. This study aimed to evaluate whether measuring TNAP activity in dried blood spots (DBSs) can identify patients with HPP. We developed an assay to assess TNAP activity using DBSs and screened 45 632 newborns born between February 2019 and March 2022 in Kumamoto Prefecture in Japan for HPP. We detected a single heterozygous variant of the ALPL gene in 5 newborns. During the clinical course follow-up, one newborn presented with HPP-related clinical manifestations. This is the first study on newborn screening (NBS) for HPP worldwide. NBS for HPP using DBSs may be practical and beneficial, as it is a high-throughput method. Moreover, the DBSs used for the TNAP assay are the same as those used for public-funded NBS worldwide. In the future, this system may be implemented as standard NBS for HPP.

Mineralizing cells release a special class of extracellular vesicles known as matrix vesicles (MV), crucial for bone mineralization. Following their release, MV anchor to the extracellular matrix (ECM), where their highly specialized enzymatic machinery facilitates the formation of seed mineral within the MV's lumen, subsequently releasing it onto the ECM. However, how MV propagate mineral onto the collagenous ECM remains unclear. In this study, we address these questions by exploring the "protein corona" paradigm whereby nanoparticles entering a biological milieu become cloaked by a corona of soluble proteins modifying their biological functions. We isolated native MV from the growth plates of chicken embryos. After removing the protein corona from the native MV using high ionic strength buffer, we obtained shaved MV. Reconstituted MVs were produced by incubating shaved MV with the removed protein corona constituents. Our results show that both the removal and reconstitution of protein corona significantly affect the biochemical and physicochemical properties of MV, resulting in 3 well-defined groups. Shaved MV exhibited an increase in tissue nonspecific alkaline phosphatase (TNAP) activity and a decrease in mineral deposition compared to native MV. Reconstituted MV partially recovered these functions, showing a reduction of TNAP activity and mineral deposition compared to native MV. Furthermore, changes in the protein corona affect the MV ability to anchor to the collagenous ECM, which is crucial for initiating the propagation of the mineral phase within this organic matrix. Proteomic analyses revealed changes in the protein profile of the MV resulting from the removal of the protein corona, indicating that shaved proteins were primarily related to external structural and ECM organization and catabolism. These findings underscore the role of the protein corona in modulating the mineralization capabilities of MV. Understanding these interactions could lead to new therapeutic strategies for enhancing bone repair and regeneration.

Hypophosphatemic rickets is a rare bone disease characterized by short stature, bone deformities, impaired bone mineralization, and dental problems. Most commonly, hypophosphatemic rickets is caused by pathogenic variants in the X-chromosomal PHEX gene, but autosomal dominant and recessive forms also exist. We investigated a Finnish family in which the son (index, 29 yr) and mother (56 yr) had hypophosphatemia since childhood. Both patients had typical clinical, radiographic, and biochemical features of hypophosphatemic rickets, including a pathological fracture in the son. Gene panels and whole-exome sequencing did not reveal any pathogenic variants in the known hypophosphatemia genes. Therefore, we performed whole genome sequencing and identified a deep intronic variant (c.2147 + 1197A > G) in PHEX. Both the affected individuals, but none of the unaffected family members, had the same variant, as confirmed by Sanger sequencing. According to RT-PCR, whole transcriptomic data, and in silico analyses, the variant led to a new splice donor site in intron 21 and an 84 basepair pseudoexon between exons 21 and 22, likely leading to the synthesis of abnormal PHEX protein. Our study underscores the importance of intronic PHEX variants in X-linked hypophosphatemia (XLH). In patients with features of XLH but negative gene panel or whole-exome sequencing results, the combination of whole-genome sequencing and whole transcriptomics should be considered to detect possible deep intronic variants. The methodologies presented have the potential to be used more widely in other rare diseases.

Romosozumab is a potent treatment for osteoporosis, with significant effects on bone density and fracture prevention. This study evaluated the cardiovascular safety of romosozumab in a real-world cohort of postmenopausal women at high fracture risk. We retrospectively evaluated postmenopausal women who initiated treatment with romosozumab between January 1, 2020, and June 30, 2023. We examined the occurrence of a major adverse cardiovascular event (MACE) across two distinct segments during the treatment period and after its conclusion. After applying inclusion and exclusion criteria, 847 women were followed for a median of 729 days (IQR: 445-1060). The incidence rate of MACE was 24.0 (95% CI 17.7-32.5) per 1000 person-years during the study period. The change in the rate of MACE from 0-90 days and 90-365 days post-treatment initiation was 0.04 and 0.06 events per 1000 days, respectively. The difference in the rate between these intervals was not statistically significant (p = .09). After 1 yr of treatment, the slope of MACE increased to 0.10, differing significantly from the preceding 12 mo on treatment (p<.001). The incidence of MACE was higher in those with a background of previous cardiovascular disease or diabetes at all timepoints, as expected. The consistency in event rates during treatment suggests that romosozumab is not associated with an increase in MACE in postmenopausal women. This finding challenges reports suggesting an increase in cardiovascular events within the first year of romosozumab treatment.

Discoidin Domain Receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagen(s), including collagen type I. Ddr1 deletion in osteoblasts and chondrocytes has previously demonstrated the importance of this receptor in bone development. In this study, we examined the effect of DDR1 ablation on bone architecture and mechanics as a function of aging. Femurs were collected from female global Ddr1 knockout (KO) and wild-type (WT) mice at 2, 6, and 12 mo of age and analyzed by high-resolution micro-computed tomography (μCT), mechanical testing, and histology. Primary monocytes were collected for in vitro osteoclastogenesis assays. Our studies on younger (2 mo) mice revealed no significant differences between the two genotypes and the microarchitectural and mechanical features had a similar trend as those reported earlier for osteoblast or chondrocyte specific Ddr1 knockdown. At an advanced age (12 mo), significant differences were noted across the two genotypes. μCT analysis showed a decrease in medullary cavity area as well as increased trabeculation in cortical and trabecular bone in the Ddr1 KO vs. WT mice. In addition, Ddr1 KO mouse bones exhibited reduced mechanical properties (lower peak load, yield load, and energy to yield) at 12 mo. Histological analysis revealed reduced osteoclast count in Ddr1 KO femurs at 12 mo with no significant difference in osteocyte count between the genotypes. In vitro, osteoclastogenesis was impaired in Ddr1 KO bone marrow derived cells. These results suggest that DDR1 deficiency adversely impacts osteoclast differentiation and bone remodeling in an age-dependent manner.

Osteogenesis imperfecta (OI) is an uncommon bone disorder caused by mutations in type I collagen involved in bone matrix leading to increased fracture risk. There are several sub-categories within OI, with OI type I being the most common and mildest form. Women with OI considering pregnancy need to be aware of bone loss and fracture risk, particularly with lactation. We report the first case of a female with twin pregnancy and OI type I who presented with multiple vertebral fractures following delivery and postpartum lactation. Following endocrine review, she weaned breast-feeding but represented within weeks with further pain and magnetic resonance imaging (MRI) demonstrating new T12 and L1 fractures. Even after receiving intravenous zoledronic acid, she experienced further thoracic pain after lifting, and MRI demonstrated a further T7 fracture. Following modification of her treatment regimen to daily teriparatide injections for 12 months, repeat dual-energy X-ray absorptiometry scan showed a significant improvement in bone mineral density at the lumbar spine and left hip. Bone loss with lactation is an important consideration for women with OI considering pregnancy. Women with OI should be assessed by an endocrinologist prior to conception to optimize bone health and have an individualized plan to mitigate bone loss and fracture risk during pregnancy and the postpartum period.

Quantifying precision error for DXA, peripheral QCT (pQCT), and HR-pQCT is crucial for monitoring longitudinal changes in body composition and musculoskeletal outcomes. Agreement and associations between bone variables assessed using pQCT and second-generation HR-pQCT are unclear. This study aimed to determine the precision of, and agreement and associations between, bone variables assessed via DXA, pQCT, and second-generation HR-pQCT. Thirty older adults (mean age: 64.2 ± 8.0 yr; women: 67%) were recruited. DXA scans were performed at the total hip, lumbar spine, and whole body. Distal (4%) and proximal (30%/33%/66%) skeletal sites at the radius and tibia were scanned with pQCT and/or HR-pQCT. Root-mean-squared coefficients of variation (%CV_RMS) were calculated to define precision errors, and Bland-Altman plots assessed agreement between densitometric estimates. Pearson correlations and linear regression explored relationships between bone variables at different skeletal sites and proportional bias, respectively. Precision errors ranged between 0.55% and 1.6% for DXA, 0.40% and 4.8% for pQCT, and 0.13% and 30.7% for HR-pQCT. Systematic bias was identified between pQCT- and HR-pQCT-determined radius and tibia volumetric BMD (vBMD) estimates (all p<.001). Proportional bias was not observed between vBMD measures at any skeletal site (all p>.05). pQCT- and HR-pQCT-determined total, trabecular, and cortical vBMD and estimates of bone strength at the radius and tibia were strongly correlated (all p<.05). Precision error was low for most bone variables and within the expected range for all imaging modalities. We observed significant systematic bias, but no proportional bias, between pQCT- and second-generation HR-pQCT-determined vBMD estimates at the radius and tibia. Nevertheless, measures of bone density and strength were strongly correlated at all skeletal sites. These findings suggest that although bone density and strength estimates from both imaging modalities are not interchangeable, they are strongly related and likely have similar fracture prediction capabilities.

Costal cartilage plays an important functional role in the rib cage, but its mechanical properties have not been well characterized. The objective of this study is to characterize the properties of human costal cartilage and examine the effects of age, sex, rib level, and degree of calcification. We obtained cadaveric costal cartilage samples of ribs 3-6 with intact perichondrium from 24 donors (12 females and 12 males) evenly distributed by age (range 47-94 yr). Peripheral QCT scans were used to quantify geometric properties (area moments) and tissue calcification (as volume, length, and classified as central, peripheral, and mixed). Four-point bending tests were performed on each sample, and bending stiffness and modulus outcomes were evaluated by fitting data from mechanical testing with non-linear pseudo-elastic models (composed of linear and cubic components, separated into loading and unloading regimes). Effects of sex, age, rib level, and cartilage calcification on bending stiffness and modulus outcomes were assessed with mixed-effects regression models. Cartilage size (area moment) was larger in males than females and positively associated with age, while there was more calcification volume in cartilage of females than males. During loading, stiffness (linear and cubic) was larger in males, while modulus (linear and cubic) was larger in females. Linear stiffness and modulus were both negatively associated with age, positively associated with calcification, and varied between rib levels. Cubic (nonlinear) components of stiffness and modulus were positively associated with calcification and varied by rib, while modulus (but not stiffness) was negatively associated with age. During unloading, the linear stiffness and modulus values were much lower, though some similar associations were found. Overall, this study adds to our understanding of the behavior of costal cartilage as a nonlinear visco-elastic material, and the effects of sex, aging, and calcification on mechanical behavior.

Hormonal agents administered for metastatic castration-resistant prostate cancer (mCRPC) may lead to osteoporosis, skeletal events, reduced quality of life, and even reduced overall survival (OS). Bone-modifying agents may prevent those events but their effect on cancer-control outcomes remains uncertain. Relying on our institutional tertiary-care database, we explored the effect of bone-modifying agents (bisphosphonates such as zoledronic acid and denosumab) on OS and progression-free survival in patients with mCRPC with at least 1 bone metastasis using Kaplan-Meyer estimates and Cox regression models. Of 420 patients with mCRPC, 60% received bone-modifying agents who were younger (68 vs 69 years), with more systemic treatment lines for mCRPC (3 vs 2), and a higher proportion of initial de novo metastatic disease (72% vs 62%, all p ≤ .04) than patients without bone-modifying agents. In progression-free survival analyses, no significant differences were observed between both groups. In OS analyses, significant median OS differences were observed in favor of patients with bone-modifying agents (58 vs 45 months; hazard ratio [HR]: 0.66), even after multivariable adjustment (HR: 0.37; both p ≤ .01). In bone-modifying agent-stratified analyses, 57% received denosumab vs 43% bisphosphonates, with a significantly higher rate of Eastern Cooperative Oncology Group status of ≥2 in the bisphosphonates group. In progression-free and OS analyses, no significant differences were observed between bisphosphonates and denosumab patients, with numerically better results in progression-free survival analysis for denosumab after adjusting for covariates. The cumulative rate of osteonecrosis of the jaw at any treatment time was 12% in both groups and significantly decreased over time. Real-world data suggest a relatively low administration rate of bone-modifying agents in patients with osseous mCRPC. However, real-world data also suggest an OS benefit when bone-modifying agents are used, even after controlling for possible confounding patient and tumor characteristics.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by constitutive activation of parathyroid hormone type 1 receptor (PTH1R). We sought to characterize the craniofacial phenotype of patients with the disease. Six patients with genetically confirmed JMC underwent comprehensive craniofacial phenotyping revealing a distinct facial appearance that prompted a cephalometric analysis demonstrating a pattern of mandibular retrognathia. Oral examination was notable for flat and shallow palate, delayed eruption pattern, and impacted maxillary teeth. Subclinical and/or mild hearing loss was noted in 4 of 5 patients studied. The most common etiology was conductive, likely due to overcrowding of epitympanum which impedes the normal vibration of ossicles to sound. Paranasal sinus obliteration was noted in 5 of 6 patients. Computed tomography (CT) scan evaluation of craniofacial bones revealed bilaterally symmetric expansile lesions with predominant involvement of neural crest cell (NCC)-derived bones. Bilateral narrowing of facial nerve canals, particularly at the labyrinthine segment, was seen in 5 of 6 patients when compared to age-matched controls; 1 patient presented with progressive facial nerve palsy. Sagittal suture craniosynostosis was present in 5 of 6 patients-one of whom had a history of cranial reconstruction for pansynostosis in infancy. All patients demonstrated a significant degree of upper airway stenosis, as well as a more anterior hyoid bone displacement. Two patients had a diagnosis of obstructive sleep apnea. 18F-NaF Positron-emission tomography (PET)-CT revealed increased uptake associated with the skull base and gnathic bones in all patients. In conclusion, this first detailed systematic evaluation of the craniofacial phenotype of patients with JMC demonstrates a distinct and pronounced phenotype that predominantly affects the NCC-derived cranial bones indicating a critical role of PTH1R signaling in their development. These affects can result in significant disease-related morbidity, include hearing loss, nerve compression, craniosynostosis, dentoskeletal malocclusion, and airway compromise; all of which require close monitoring.