OBJECTIVE: To investigate the prenatal manifestation and genetic basis for two fetuses suspected for Osteocraniostenosis (OCS). METHODS: Two fetuses undergoing invasive prenatal diagnosis at Cangzhou People's Hospital in April and August 2021 for short long bones and abnormal skull morphology were selected as the study subjects. Clinical data were collected and analyzed. Genomic DNA was extracted from amniotic fluid and peripheral blood samples of the two couples. Candidate variants were validated by Sanger sequencing. Literature was retrieved from CNKI, Wanfang Data Knowledge Service Platform and PubMed using keywords including "FAM111A gene", "gracile bone dysplasia", "FAM111A" and "osteocraniostenosis" from January 1, 2000 to June 30, 2025. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: K2020-049). RESULTS: Fetus 1 was found to have short limbs, abnormal skull morphology and shallow cerebral sulci. Fetus 2 showed short limbs, irregular skull halo, prominent forehead and bilateral frontal narrowing. Trio-WES revealed that fetus 1 has carried a heterozygous missense variant c.1582G>C (p.Asp528His) in exon 4 of the FAM111A gene, which was unreported previously. Fetus 2 has harbored a heterozygous in-frame deletion c.1020_1022delTTC (p.Ser343del) in exon 6 of the FAM111A gene, which has been recorded as likely pathogenic by the ClinVar and HGMD databases. Sanger sequencing confirmed that the parents of both fetuses were wild-type for the variant sites. A total of 9 previously reported patients with FAM111A-related gracile bone dysplasia/OCS from 4 publications were retrieved. The main clinical features included intrauterine growth restriction, hypomineralized skull, gracile long bones with narrow medullary cavities and characteristic facial anomalies, which were in large in keeping with the prenatal features of the two fetuses. CONCLUSION Both fetuses were diagnosed with FAM111A-related OCS based on the characteristic prenatal findings and identification of the FAM111A variants. Above finding expanded the phenotypic spectrum of FAM111A-associated disorders and provided clues for the prenatal diagnosis and genetic counseling.
Humans ; Female ; Pregnancy ; Prenatal Diagnosis ; Phenotype ; Fetus ; Male ; Bone Diseases, Developmental/genetics* ; Adult

OBJECTIVE: To analyze the clinical phenotype and pathogenic mechanism of the ARSL gene variant in a fetus with nasal bone aplasia. METHODS: A 34-year-old pregnant woman who attended Quzhou Maternal and Child Health Care Hospital on January 3, 2023 was selected as the study subject. Whole exome sequencing (WES) was performed on the fetus. Bioinformatics analysis was carried out to identify and prioritize candidate gene variants, followed by Sanger sequencing for familial validation. A mutant plasmid expression vector was constructed and subsequently transfected into HEK293T cells to preliminarily investigate the pathogenetic mechanism of the identified variant. Additionally, a comprehensive review of literature was conducted to systematically summarize the associated clinical phenotypes. This study was approved by the Medical Ethics Committee of Quzhou Maternal and Child Health Care Hospital (Ethics No.: KY-2023-11). RESULTS: WES revealed that the fetus harbored a c.827del (p.L276Rfs*48) variant of the ARSL gene, for which its mother was heterozygous. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic(PVS1+PM2_Supporting). In vitro cellular function studies demonstrated that this variant can result in a substantial decrease in the expression of mutant mRNA, thereby preventing the production of normal ARSL protein. Clinical phenotypes resulting from ARSL gene variants exhibited considerable diversity, with nasal hypoplasia being the most common manifestation. CONCLUSION The c.827del (p.L276Rfs*48) variant of the ARSL gene can lead to degradation of mRNA via the nonsense-mediated mRNA decay pathway, resulting in reduced levels of ARSL protein. The pathogenetic mechanism underlying the ARSL gene variant may be associated with its haploinsufficiency effect.
Humans ; Female ; Pregnancy ; Adult ; Frameshift Mutation ; HEK293 Cells ; Nasal Bone/abnormalities* ; Fetus/abnormalities* ; Exome Sequencing

OBJECTIVE

This review article aims to determine the properties, uses, toxicity, and other side effects of crosslinking agents in tissue scaffolds when applied in vitro and in vivo.

METHODS

A literature search was performed using the PubMed-NCBI (MEDLINE) database (https://pubmed.ncbi.nlm. nih.gov/) with keywords: crosslinking reagent, collagen, hydroxyapatite, and bone regeneration. GRADE criteria were used to assess the quality of evidence.

RESULTS

A total of six articles were included in the study. Improved mechanical properties of collagen-hydroxyapatite scaffolds with high porosity can be achieved by employing crosslinking methods, including physical dehydrothermal (DHT) treatment, chemical treatment with glutaraldehyde (GA), Microbial Transglutaminase (mTGase), 1‐ethyl‐3‐(3‐ dimethylaminopropyl) carbodiimide (EDAC), or a combination of both DHT and EDAC. Furthermore, the crosslinking of EDAC and DHT can lead to forming ester bonds between activated carboxyl groups and hydroxyl groups.

CONCLUSION

The combination of DHT and EDAC crosslinking can increase mechanical strength, make the pore size appropriate, make the scaffold more stable, and support cell adhesion so that new cells can grow, and the process of osteogenesis can run more optimally.

Cross-linking Reagents ; Collagen ; Durapatite ; Hydroxyapatite ; Bone Regeneration

BACKGROUND

In the Philippines and other developing countries, access to high-stability external fixators for traumainduced bone fracture management is limited, as modular external fixators, especially those with snap-on features, are manufactured overseas and are prohibitively expensive for most Filipino patients.

OBJECTIVE

This study aimed to assess the biomechanical performance of a locally-developed modular external fixator prototype for tibial diaphyseal fractures in comparison to available external fixators, such as Roger Anderson and Hoffmann. This provides an initial evaluation for the use of the external fixator as an alternative in terms of its stability.

METHODS

Using axial compression testing compliant with the ASTM F1541-24 standards, the ultimate strength, yield strength, safe strength, and stiffness were measured across various fixator types and tightening mechanisms, with or without the aid of a wrench. Statistical tools such as the t-test assuming equal variances, one-way analysis of variance, and Tukey-Kramer test with a 0.05 level of significance were used to determine any significant differences.

RESULTS

The mechanical performance of the external fixator prototype increased by a factor of 1.5 to 2.5 after the clamps were tightened with the wrench. However, when hand-tightened, it still performed sufficiently, showing a comparable mechanical performance with the Roger Anderson Fixator. In terms of the ultimate, safe, and yield strengths, it performed competitively in comparison with the Hoffmann system. However, there is a significant difference in stiffness between the prototype and the Hoffmann system.

CONCLUSION

The locally-developed external fixator was comparable biomechanically to the commercially available external fixators and the prototypes in different studies.

Evaluation Studies As Topic ; Developing Countries ; External Fixators ; Fractures, Bone ; Philippines ; Patients

BACKGROUND AND OBJECTIVES

Orthodontic tooth movement is driven by bone remodeling influenced by systemic factors, including caffeine and ethanol. This study aimed to investigate the effects of caffeine and ethanol on the expression of Receptor Activator of Nuclear Factor κβ (RANK) and Osteoprotegerin (OPG), key bone remodeling biomarkers, during orthodontic tooth movement.

METHODS

A laboratory experimental study was conducted on 30 male Wistar rats divided into three groups: K1 (orthodontic force only), K2 (force + caffeine), and K3 (force + ethanol). Orthodontic force was applied using Ni-Ti coil springs. Caffeine and ethanol were administered orally daily. On days 7 and 14, maxillary tissues were collected and analyzed via immunohistochemistry for RANK and OPG expression. Data were analyzed using One-Way ANOVA and Independent Sample T-tests with significance at pRESULTS

Caffeine and ethanol administration increased RANK and OPG expression compared to controls; however, only the ethanol group showed a significant increase in RANK expression on day 14 (p = 0.044). OPG expression was significantly higher in treatment groups at both time points (pCONCLUSION

Caffeine and ethanol modulate bone remodeling marker expression during orthodontic force application, with ethanol significantly increasing RANK expression at later stages. Further studies are needed to clarify the clinical implications for orthodontic treatment.

Animals ; Tooth Movement Techniques ; Tooth Movement ; Osteoprotegerin ; Role ; Movement ; Ethanol ; Bone Remodeling ; Caffeine ; Immunohistochemistry

Abstract Background: Nasopharyngeal cancer (NPC) is a malignancy of the nasopharyngeal mucosal epithelium. Primary and secondary metastases in nasopharyngeal cancer are generally prevalent in the bones. Gene expression plays a critical role in regulating fundamental cellular processes in cancer cells, including metastasis. Methods: A total of 29 patients with non-metastatic NPC were included in the study. Results: The mean age of the participants was 48.45±9.98 years old. Most participants were male (75.9%). More than half of the participants had T4 and N2, 52.7% and 51.0% respectively). Secondary metastasis was observed in 9 of the 29 participants within two years. Patients with secondary metastases had a higher proportion of T4 (7/9) and N2 (4/9) disease. Bone was the first site of secondary metastasis (6/9 patients). The median time to secondary bone metastasis was 14.0 (6.8-21.2) months. Based on the differential expression gene (DEG) analysis, the MMP9 gene was upregulated 12.50 (4.18–37.40), adjusted p <0.01, and the ADNP gene was downregulated 0.141 (0.04–0.43), adjusted p 0.04, among patients with secondary bone metastasis. Conclusion: Bones are the first site of metastasis, with a time to metastasis of 14.0 (6.8-21,2) months. MMP9 was upregulated, and ANDP was downregulated in patients with bone metastasis compared to those without metastasis.
MMP-9 ; ADNP ; nasopharyngeal cancer ; secondary bone metastasis

Introduction: Primary hyperparathyroidism (PHPT) is a common disorder that typically leads to increased bone turnover and reduced bone mineral density (BMD). Osteopetrosis, in contrast, is a rare, inherited disorder of defective osteoclast function, resulting in diffusely sclerotic but structurally fragile bones. The coexistence of both conditions is rare and can significantly alter the expected skeletal phenotype of PHPT. Case: We report a 77-year-old female with a previous history of resected ovarian carcinoma in remission, chronic iron deficiency anemia, and hypothyroidism. During a hospital admission for a lacunar infarct, an incidental finding of sclerotic skull lesions on computed tomography (CT) brain prompted further investigation. She had no history of fractures, hearing impairment, or family history of parathyroid or bone disorders. Biochemistry revealed parathyroid-dependent hypercalcemia with normal renal function. Bone turnover markers showed a normal resorption marker (BCTx) but an elevated formation marker (P1NP), with a mildly raised alkaline phosphatase. A sestamibi scan localized a probable left upper parathyroid adenoma, despite a negative neck ultrasound. Skeletal survey unexpectedly revealed widespread osteosclerosis of the skull, spine, and long bones, with a markedly elevated BMD on densitometry. Review of prior imaging confirmed that these sclerotic changes predated her current presentation, having been present on CTs from over a decade ago. Recurrent malignancy was excluded with repeat imaging and tumor markers. A diagnosis of PHPT secondary to parathyroid adenoma, coexisting with underlying, previously unrecognized osteopetrosis, was made. The patient declined both recommended parathyroidectomy and genetic studies. Conclusion This case demonstrates a rare coexistence of two pathologies with opposing effects on bone metabolism. The underlying osteopetrosis, characterized by defective osteoclasts, likely rendered the patient’s osteoclasts resistant to the catabolic effects of elevated PTH. This resulted in an atypically normal bone resorption marker and an unexpectedly high BMD, despite the diagnosis of PHPT.
Bone Density' ; Hyperparathyroidism ; Primary Osteopetrosis

Introduction: Metabolic bone disease of prematurity (MBDP) is characterized by biochemical and radiological findings related to bone demineralization in premature babies. Despite early recognition, MBDP is still a prevalent problem and is associated with significant morbidities in premature babies. This study aims to determine the prevalence and neonatal predictors of MBDP. Methodology: This retrospective cross-sectional study involved premature babies with gestational age ≤32 weeks and birth weight ≤1.5 kg, admitted to Hospital Tunku Azizah, Kuala Lumpur, between January 1, 2020, and January 31, 2024. Babies whose serum phosphate was ≤1.5 mmol/L and serum alkaline phosphatase >500 IU/L at 3–6 weeks of age fulfilled the diagnosis of MBDP. The maternal and neonatal characteristics of the study population were retrieved from the medical records. Neonatal predictors for MBDP were analyzed by simple and multiple logistic regression. Results: A total of 292 subjects were enrolled. The prevalence of MBDP was 13.4%. On simple logistic regression, male gender, low gestational age, poor APGAR score, delayed enteral feed initiation, prolonged TPN, delayed vitamin D supplementation, use of unfortified expressed breast milk, patent ductus arteriosus, and bronchopulmonary dysplasia, cholestasis, prolonged hospital stay, and prolonged ventilation were risk factors for MBDP (p <0.05). On multiple logistic regression, only cholestasis (p 0.014), prolonged TPN use (p <0.001), and prolonged hospitalization (p <0.001) were independent neonatal predictors for MBDP. Conclusion The risk of MBDP can be reduced by shortening TPN duration and hospitalization duration and preventing cholestasis. This may be achieved by early enteral feeding initiation and use of fortified EBM, thus preventing the development of MBDP.
Infant, Newborn ; Prevalence ; Bone Diseases, Metabolic ; Hospitals

Facing the requirements of promoting the healthy China initiative and improving people's health, the "bone health program" was proposed in 2024. In-depth development of a traditional Chinese medicine(TCM) prevention and control system is of strategic significance to the implementation of the "bone health program". Focusing on osteoporosis(OP), a representative disease affecting people's bone health, this paper concludes that accelerating the research on the prevention and control of OP by TCM is conducive to enhancing the knowledge and awareness of OP among the public, and it is beneficial to revealing the evolutionary pattern of OP and improving the understanding and management of this disease. Additionally, it can provide an overall framework for and strengthen the systematicity and completeness of the research on the prevention and treatment of OP by TCM. Meanwhile, it can help to explore new research paradigms and optimize the existing research model, so as to promote innovative breakthroughs in the prevention and treatment of bone health-related diseases by TCM. Under the overall layout of the "bone health program", importance should be attached to the early prevention and the innovation of very early diagnosis and intervention of OP. Emphasis should be put on the discovery of the target network of disease and treatment mechanism for revealing the core pathogenesis of OP and the therapeutic mechanism of TCM. In addition to local lesions of the bone and its clinical outcomes, attention should be paid to the development of multiple metabolic complications. The fusion of advanced interdisciplinary technologies should be promoted for OP and its complications, and thus a research and development system based on clinical application scenarios and driven by big data can be built. The measures above will facilitate the progress in the prevention and treatment of OP and other bone diseases by TCM and provide new momentum for enriching and deepening the research connotation of the "bone health program".
Osteoporosis/therapy* ; Humans ; Medicine, Chinese Traditional/methods* ; Drugs, Chinese Herbal/therapeutic use* ; China ; Bone and Bones/drug effects*

Recent studies have shown that an imbalance in iron metabolism can affect the composition and microstructural changes of bone, disrupting bone homeostasis and leading to osteoporosis(OP). The imbalance in iron metabolism, along with its induced local abnormal microenvironment and cellular iron death, has become a new focal point in OP research, drawing increasing attention from the academic community regarding the regulation of iron metabolism to prevent and manage OP. From the perspective of traditional Chinese medicine(TCM), iron metabolism imbalance has potential connections to TCM theories regarding internal organs, as well as treatments aimed at tonifying the kidney, strengthening the spleen, and activating blood circulation. Evidence is continually emerging that TCMs and effective components that tonify the kidney, strengthen the spleen, and activate blood circulation can prevent and manage OP by regulating iron metabolism. This article analyzes the relationship between iron and bone, as well as the effects of TCM formulations on improving iron metabolism and influencing bone metabolism, from the perspectives of iron metabolism mechanisms and TCM interventions, aiming to broaden existing clinical strategies for prevention and treatment and inject new momentum into the field of OP as it moves into a new era.
Osteoporosis/drug therapy* ; Humans ; Iron/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Medicine, Chinese Traditional ; Bone and Bones/drug effects*