Yuichiro Ukon

Background: This study aims to investigate the risk factors and onset timing of second contralateral hip fractures (SHFx) following initial femoral fractures, with a particular focus on early events occurring within one year. Methods: This retrospective study utilized a nationwide hospital claims database (Medical Data Vision, MDV) covering over 30% of all Diagnosis Procedure Combination (DPC) hospitals in Japan. MDV data combining patients who had visited a healthcare facility for osteoporosis with fractures (International Classification of Diseases, 10th Revision [ICD-10] code M80) or femoral fractures (ICD-10 code S72) were used. Patients aged 40 years and older who underwent bipolar hip arthroplasty or open reduction and internal fixation between April 2008 and September 2024 were included ( n = 370,227). Clinical and demographic data were collected, including comorbidities and medications related to QFracture, FRAX, and fall risk. Results: The incidence of early second contralateral hip fractures (eSHFx) was 2.7% ( n = 10,136). Multivariate logistic regression identified female, age (70–79, 80–89, ≥ 90 years), Bone Mass Index (BMI) < 18.5 kg/m2, Charlson Comorbidity Index (CCI) = 1 point, dementia, delirium, fracture history, steroid use, and sleeping pill use as significant risk factors for eSHFx. Among patients who developed SHFx, male, age ≥ 90 years, BMI < 18.5 kg/m2, CCI (1, ≥ 3 points), dementia, delirium, steroid use, and sleeping pill use were significantly associated with early rather than late onset. Fall-related factors were risk factors for eSHFx and factors that predisposed to eSHFx. Female was a risk factor for eSHFx, but the timing of SHFx was late. Conclusion: This study identified risk factors for eSHFx and factors influencing their timing. It is crucial to determine the optimal timing and method of intervention for each patient to select the most appropriate therapy.

Xenotransplantation has emerged as a potential solution to the critical shortage of donor organs, with recent breakthroughs demonstrating transplantation of genetically modified porcine organs into humans. In Japan, the Ministry of Health, Labour and Welfare has advanced the regulatory review framework to accelerate research and enable the nation's first clinical xenotransplantation. Unlike conventional pharmaceutical pathways, the Act on the Safety of Regenerative Medicine provides a distinctive framework that allows xenotransplantation to be delivered as a medical procedure rather than as a medicinal product. Under this law, a multi‐step review process and adherence to specific guidelines, this framework may facilitate early‐phase clinical research while safeguarding public health, offering an alternative model to regulatory systems in the other countries.

Osteoporosis is characterized by reduced bone mass and structural deterioration, leading to increased fracture risk, particularly in older adults. Parathyroid hormone (PTH) is a widely used anabolic therapy for osteoporosis; however, rapid bone loss after treatment discontinuation presents a significant clinical challenge. Cellular senescence has been implicated in age‐related bone fragility. However, its role in PTH‐induced bone remodeling and post‐treatment bone loss remains unclear. This study aimed to investigate the effects of PTH administration frequency on bone microarchitecture and cellular senescence in young and aged mice. High‐frequency PTH administration improved trabecular bone volume in both age groups, but caused cortical bone thinning, increased porosity, and elevated osteoclast activity in aged mice. PTH induces senescent osteoblast‐lineage‐enriched cell accumulation in aged, but not young mice, accompanied by upregulation of senescence‐associated markers and activation of the mechanistic Target of Rapamycin Complex 1 pathway. Co‐administration of the senolytic agents dasatinib and quercetin during PTH treatment reduced senescent cell burden, improved cortical porosity, and mitigated rapid bone loss after PTH discontinuation in aged mice. These findings indicate that senescent osteoblast‐lineage‐enriched cells contribute to bone fragility and post‐treatment bone loss in aged individuals, suggesting that targeting senescence may enhance the efficacy and sustainability of PTH therapy for osteoporosis.

Aims: Nonunion occurs when a fracture fails to heal permanently, often necessitating surgical intervention to stimulate the bone healing response. Current animal models of long-bone nonunion do not adequately replicate human pathological conditions. This study was intended as a preliminary investigation of a novel rat nonunion model using a two-stage surgical intervention, and to evaluate the efficacy of a selective prostaglandin E2 receptor 4 agonist (AKDS001) as a novel nonunion therapeutic agent compared with existing treatments.Methods: Initially, Sprague-Dawley rats underwent intramedullary Kirschner wire (K-wire) fixation of a femoral fracture with the interposition of a 2 mm-thick silicon disc. After three weeks, the silicon disc was removed, and the intramedullary K-wire was replaced with plate fixation while maintaining the 2 mm defect. Contrary to the control group (1) that received no treatment, the following therapeutic interventions were performed at injury sites after freshening: (2) freshening group: no grafting; (3) iliac bone (IB) group: IB grafting; (4) AKDS group: AKDS001-loaded microspheres (MS) combined with IB (0.75 mg/ml); and (5) bone morphogenetic protein (BMP) group: grafting of a BMP-2-loaded collagen sponge (10 μg; 0.10 mg/ml). After six weeks, micro-CT (μCT) and histological analysis was performed.Results: In the control group, the radiological union rate was 0%, and histological findings showed that fracture sites comprised fibrous scar tissue, resembling the histology of human nonunion. The union rates in the freshening, IB, AKDS, and BMP groups were 16.7%, 0%, 62.5%, and 50.0%, respectively. The AKDS group demonstrated a significantly higher union rate than the IB group (p = 0.026). μCT and histological analysis indicated that the quality of newly formed bone was superior in the AKDS group than in the BMP group.Conclusion: We developed a novel long-bone nonunion model. The co-therapy of AKDS001-MS and IB grafting presents a promising new treatment for nonunion.Cite this article: Bone Joint Res 2025;14(3):166–175.

Bone morphogenetic protein 2 (BMP2) is clinically applied for treating intractable fractures and promoting spinal fusion because of its osteogenic potency. However, adverse effects following the release of supraphysiological doses of BMP2 from collagen carriers are widely reported. Nanoclay gel (NC) is attracting attention as a biomaterial, given the potential for localized efficacy of administered agents. However, the efficacy and mechanism of action of NC/BMP2 remain unclear. This study explored the efficacy of NC as a BMP2 carrier in bone regeneration and the enhancement mechanism. Subfascial implantation of NC containing BMP2 elicited superior bone formation compared with collagen sponge (CS). Cartilage was uniformly formed inside the NC, whereas CS formed cartilage only on the perimeter. Additionally, CS induced a dose-dependent inflammatory response around the implantation site, whereas NC induced a minor response, and inflammatory cells were observed inside the NC. In a rat spinal fusion model, NC promoted high-quality bony fusion compared to CS. In vitro, NC enhanced chondrogenic and osteogenic differentiation of hBMSCs and ATDC5 cells while inhibiting osteoclastogenesis. Overall, NC/BMP2 facilitates spatially controlled, high-quality endochondral bone formation without BMP2-induced inflammation and promotes high-density new bone, functioning as a next-generation BMP2 carrier.

Study Design: Retrospective cohort study using prospective database. Objective: This study aimed to establish a risk-scoring system for predicting severe complications after pyogenic spondylodiscitis surgery. Summary of Background data: Pyogenic spondylodiscitis surgery can cause severe complications. Methods: Grades III, IV, and V complications in the CD classification were defined as severe complications. A predictive scoring system for severe complications was developed using 7 risk factors identified from a cohort of 143 PS surgery patients from January 2013 to December 2017 described in a previous study. External validation used a separate cohort of 70 patients from 9 institutions identified from January 2018 to December 2021. Results: This first study proposed a risk predictive scoring system for severe complications [updated Charlson comorbidity index (≥3), 2; chronic pulmonary disease, 3; diabetes, 1; Gram-negative bacteria, 3; pyogenic osteoarthritis, 3; preoperative white blood count (≥1.0×10⁴/μL), 2; preoperative platelet count (≤2.4×10⁵/μL), 2]. The scoring system could well predict severe complications [area under the receiver operating curve (AUROC) value of 0.851]. There was classification into 3 risk groups: low–moderate risk (≤4), high risk (5 or 6), and very high risk (≥7), further simplified by the scoring system. Complication rates were 5.2% (low–moderate), 40.1% (high), and 84.2% (very high). In addition, external validation showed a very good AUROC value of 0.820. Conclusions: We developed a simple, externally validated scoring system for predicting severe complications after pyogenic spondylodiscitis surgery that will be helpful for clinicians involved in informed consent and intensive care unit management of high-risk patients.