Bone aluminum accumulation in the current era / Acúmulo de alumínio no tecido ósseo na era atual

In the last few years, evidence from the Brazilian Registry of Bone Biopsy (REBRABO) has pointed out a high incidence of aluminum (Al) accumulation in the bones of patients with CKD under dialysis. This surprising finding does not appear to be merely a passive metal accumulation, as prospective data from REBRABO suggest that the presence of Al in bone may be independently associated with major adverse cardiovascular events. This information contrasts with the perception of epidemiologic control of this condition around the world. In this opinion paper, we discussed why the diagnosis of Al accumulation in bone is not reported in other parts of the world. We also discuss a range of possibilities to understand why bone Al accumulation still occurs, not as a classical syndrome with systemic signs of intoxication, as occurred it has in the past.

Nos últimos anos, evidências do Registro Brasileiro de Biópsia óssea (REBRABO) apontaram uma alta incidência de intoxicação por alumínio (Al) no tecido ósseo de pacientes com DRC em diálise. Essa surpreendente informação parece representar não apenas um acúmulo passivo deste metal, visto que dados prospectivos do REBRABO sugerem que a presença de Al no tecido ósseo pode estar independentemente relacionada a eventos cardiovasculares adversos maiores. Essas informações contrastam com a percepção mundial do controle epidemiológico dessa condição. Neste artigo de opinião, discutimos por que o diagnóstico de acúmulo ósseo de Al não é relatado em outras partes do mundo, e também discutimos uma gama de possibilidades para entender por que nós acreditamos que o acúmulo de Al no tecido ósseo ainda ocorre, não como se apresentava no passado, ou seja, como uma síndrome com sinais e sintomas sistêmicos de intoxicação.

Analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as inflammatory biomarkers in chronic kidney disease: impact of parathyroidectomy / Análise das relações neutrófilo/linfócito e plaqueta/linfócito como marcadores inflamatórios na doença renal crônica: impacto da paratireoidectomia

Abstract Introduction: Secondary hyperparathyroidism (SHPT) is one of the causes for inflammation in CKD. We assessed the impact of parathyroidectomy (PTX) on neutrophil-to-lymphocyte (N/L) and platelet-to-lymphocyte (P/L) ratios in SHPT patients. Methods: A total of 118 patients [hemodialysis (HD, n = 81), and transplant recipients (TX, n = 37)] undergoing PTX between 2015 and 2021 were analyzed. Results: There was a significant reduction in calcium and PTH levels in both groups, in addition to an increase in vitamin D. In the HD group, PTX did not alter N/L and P/L ratios. In the TX group, there was a reduction in N/L and P/L ratios followed by a significant increase in total lymphocyte count. Conclusion: N/L and P/L ratios are not reliable biomarkers of inflammation in SHPT patients undergoing PTX. Uremia, which induces a state of chronic inflammation in dialysis patients, and the use of immunosuppression in kidney transplant recipients are some of the confounding factors that prevent the use of this tool in clinical practice.

Resumo Introdução: O hiperparatireoidismo secundário (HPTS) é uma das causas de inflamação na DRC. Avaliamos o impacto da paratireoidectomia (PTX) nas relações neutrófilo/linfócito (N/L) e plaqueta/linfócito (P/L) em pacientes com HPTS. Métodos: Foram analisados 118 pacientes [hemodiálise (HD, n = 81) e transplantados (TX, n = 37)] submetidos à PTX entre 2015 e 2021. Resultados: Houve redução significativa de cálcio e PTH nos dois grupos, além de elevação de vitamina D. No grupo HD, a PTX não mudou as relações N/L e P/L. Já no grupo TX, houve redução nas relações N/L e P/L acompanhadas de elevação significativa do número de linfócitos totais. Conclusão: As relações N/L e P/L não são marcadores fidedignos de inflamação em pacientes com HPTS submetidos à PTX. A uremia, que induz um estado de inflamação crônica em pacientes dialíticos, e o uso de imunossupressão em pacientes transplantados renais são alguns dos fatores de confusão que impedem o uso dessa ferramenta na prática clínica.

Pubic bone osteomyelitis and fistulas after radiation therapy of the pelvic region: patient-reported outcomes and urological management of a rare but serious complication.

PURPOSE: This study investigated late urinary adverse events (UAEs) in patients who underwent pelvic radiation therapy, with a focus on occurrence, diagnostic characteristics and the impact of subsequent extirpative surgery with the need of urinary diversion on quality of life. METHODS: A retrospective analysis of 20 patients after pelvic radiotherapy (2016-2022) was conducted. Data included demographics, perioperative details, oncological parameters, and patient-reported outcomes. Imaging (CT, MRI) was examined for early manifestations of late UAEs. RESULTS: In the study cohort, prostate cancer was the primary malignancy in 85% with a mean radiation dose of 84 Gray over 35 days. Time to diagnosis of late UAEs was 4.0 years post-radiation. Radiological assessment demonstrated a progressive increase in typical CT and MRI features of pubic bone osteomyelitis over time. Surgical interventions, mainly cystectomy, were required with variable outcomes in patient-reported post-surgery quality of life. CONCLUSION: Diagnosing and managing late UAEs after pelvic radiation necessitate an understanding of their occurrence, diagnostic features and appropriate management strategies. Early imaging, particularly MRI, is crucial for timely diagnosis and treatment planning. Variable post-surgery quality of life underscores the importance of a multidisciplinary approach in managing late UAEs. The study contributes to understanding these complications and emphasizes their consideration in post-radiation follow-up care.

NAT10 promotes osteoclastogenesis in inflammatory bone loss by catalyzing Fos mRNA ac4C modification and upregulating MAPK signaling pathway.

INTRODUCTION: Excessive osteoclastogenesis is a key driver of inflammatory bone loss. Suppressing osteoclastogenesis has always been considered essential for the treatment of inflammatory bone loss. N-acetyltransferase 10 (NAT10) is the sole enzyme responsible for N4-acetylcytidine (ac4C) modification of mRNA, and is involved in cell development. However, its role in osteoclastogenesis and inflammatory bone loss remained elusive. OBJECTIVES: We aimed to clarify the regulatory mechanism of NAT10 and ac4C modification in osteoclastogenesis and inflammatory bone loss. METHODS: NAT10 expression and ac4C modification during osteoclastogenesis were determined by quantitative real-time PCR (qPCR), western blotting, dot blot and immunofluorescent staining, and the effect of NAT10 inhibition on osteoclast differentiation in vitro was measured by the tartrate-resistant acid phosphatase staining, podosome belts staining assay and bone resorption pit assay. Then, acRIP-qPCR and NAT10RIP-qPCR, ac4C site prediction, mRNA decay assay and luciferase reporter assay were performed to further study the underlying mechanisms. At last, mice models of inflammatory bone loss were applied to verify the therapeutic effect of NAT10 inhibition in vivo. RESULTS: NAT10 expression was upregulated during osteoclast differentiation and highly expressed in alveolar bone osteoclasts from periodontitis mice. Inhibition of NAT10 notably reduced osteoclast differentiation in vitro, as indicated by great reduction of tartrated resistant acid phosphatse positive multinuclear cells, osteoclast-specific gene expression, F-actin ring formation and bone resorption capacity. Mechanistically, NAT10 catalyzed ac4C modification of Fos (encoding AP-1 component c-Fos) mRNA and maintained its stabilization. Besides, NAT10 promoted MAPK signaling pathway and thereby activated AP-1 (c-Fos/c-Jun) transcription for osteoclastogenesis. Therapeutically, administration of Remodelin, the specific inhibitor of NAT10, remarkably impeded the ligature-induced alveolar bone loss and lipopolysaccharide-induced inflammatory calvarial osteolysis. CONCLUSIONS: Our study demonstrated that NAT10-mediated ac4C modification is an important epigenetic regulation of osteoclast differentiation and proposed a promising therapeutic target for inflammatory bone loss.

Systemic administration of Resolvin D1 reduces cancer-induced bone pain in mice: Lack of sex dependency in pain development and analgesia.

AIMS: Bone cancer produces severe pain that is treated with opioids, but serious side effects limit opioid utilization. There is therefore a need to develop effective and safe non-opioid alternatives. The lipid mediator, Resolvin D1 (RvD1), could be a prospective candidate for cancer pain treatment. To assess RvD1 and other potential candidates, appropriate animal models that recapitulate clinical features must be used. Although several preclinical models of cancer pain have been developed, the influence of sex on the development of cancer pain and the effectiveness of RvD1 have not been studied. RESULTS: Using a mouse model of fibrosarcoma growth in and around the calcaneus bone, we demonstrated that the mechanical hyperalgesia in the tumor-bearing hind paw develops independently of sex, except that it developed a little sooner in female mice. A single intravenous injection of RvD1 (0.001-10 µg/kg) decreased hyperalgesia in both sexes with similar potency (ED50 = 0.0015 µg/kg) and efficacy. Repeated daily administration of 10 µg/kg RvD1 prolonged the analgesic effect and completely abolished hyperalgesia. This was also independent of sex. CONCLUSION: In this preclinical mouse model of bone cancer pain, the development of pain and the analgesic effectiveness of RvD1 are not influenced by sex.

Potential Targeting Mechanisms for Bone-Directed Therapies.

Bone development is characterized by complex regulation mechanisms, including signal transduction and transcription factor-related pathways, glycobiological processes, cellular interactions, transportation mechanisms, and, importantly, chemical formation resulting from hydroxyapatite. Any abnormal regulation in the bone development processes causes skeletal system-related problems. To some extent, the avascularity of cartilage and bone makes drug delivery more challenging than that of soft tissues. Recent studies have implemented many novel bone-targeting approaches to overcome drawbacks. However, none of these strategies fully corrects skeletal dysfunction, particularly in growth plate-related ones. Although direct recombinant enzymes (e.g., Vimizim for Morquio, Cerezyme for Gaucher, Elaprase for Hunter, Mepsevii for Sly diseases) or hormone infusions (estrogen for osteoporosis and osteoarthritis), traditional gene delivery (e.g., direct infusion of viral or non-viral vectors with no modifications on capsid, envelope, or nanoparticles), and cell therapy strategies (healthy bone marrow or hematopoietic stem cell transplantation) partially improve bone lesions, novel delivery methods must be addressed regarding target specificity, less immunogenicity, and duration in circulation. In addition to improvements in bone delivery, potential regulation of bone development mechanisms involving receptor-regulated pathways has also been utilized. Targeted drug delivery using organic and inorganic compounds is a promising approach in mostly preclinical settings and future clinical translation. This review comprehensively summarizes the current bone-targeting strategies based on bone structure and remodeling concepts while emphasizing potential approaches for future bone-targeting systems.

Effect of Matrix Size and Acquisition Mode on Image Quality and Radiation Dose of Ultra-High-Resolution CT of the Temporal Bone: An Anatomical Study.

Purpose: To compare image quality and radiation exposure between super- and ultra-high-resolution helical and super-high-resolution volumetric CT of the temporal bone. Methods: Six cadaveric temporal bone specimens were used to evaluate key temporal bone structures using the following CT reconstruction and acquisition modes: helical and single-volume acquisition modes in super-high resolution (0.25-mm slice thickness, 10242 matrix), and helical mode in ultra-high resolution (0.25-mm slice thickness, 20482 matrix). Two observers performed 5 previously described preoperative measurements, measured noise and signal-to-noise ratios for air, and noise for bone, and rated the visualization of 5 anatomical structures on a 4-point scale, for each reconstruction mode. Radiation dose exposure was recorded for each examination. Results: There was no significant difference between any of the quantitative or qualitative measurements in any of the reconstruction and acquisition modes. There was a slight increase in noise and a decrease in signal-to-noise ratio in the air using the single-volume mode (115 ± 13.1 HU and 8.37 ± 0.91, respectively) compared to the helicoidal super-high-resolution (92.4 ± 11.8 HU and 10.8 ± 1.26, respectively) and helicoidal ultra-high-resolution (91.1 ± 10.7 HU and 10.9 ± 1.39, respectively) modes (P < .002). The volumic CT dose index was 50.9 mGy with helical acquisition and 29.8 mGy with single-volume acquisition mode (P < .0001). Conclusion: The single-volume super-high-resolution acquisition mode allows a reduction in radiation dose exposure without compromising image quality compared to helical scanning, but with a slightly lower signal-to-noise ratio in air with the single-volume mode, while there was no difference in image quality between the helical super- and ultra-high-resolution modes.

Frailty Status, Sedentary Behaviors, and Risk of Incident Bone Fractures.

BACKGROUND: The associations of physical pre-fraily and frailty with bone fractures and the modified effect of sedentary lifestyle remain uncertain. This study was performed to explore the association of physical pre-frailty and frailty with risk of incident bone fractures; and test the modification effects of sedentary lifestyle and other risk factors. METHODS: This cohort study included 413,630 participants without bone fractures at baseline in the UK Biobank study between 2006 and 2010 and followed up to 2021. The mean age of the participants was 56.5 years. A total of 224,351 (54.2%) enrolled participants were female and 376,053 (90.9%) included participants were white. Three Cox regression models were constructed to analyze the association of pre-frailty and frailty with total fractures, hip fractures, vertebrae fractures and other fractures. RESULTS: As compared with the physical non-frailty group, the multivariate adjusted Hazard Ratios (HRs) were 1.17 (95% CI: 1.14 to 1.21) and 1.63 (95% CI: 1.53 to 1.74) for the physical pre-frailty group and frailty group, respectively (P-trend<0.001). In addition, we found that sedentary behavior time significantly accentuated the associations of physical pre-frailty and frailty with total fractures (P-interaction<0.001), hip fractures (P-interaction=0.013) and other fractures (P-interaction<0.001). CONCLUSIONS: Our results indicate that physical pre-frailty and frailty are related to higher risks of bone fractures; such association was more pronounced among those with longer sedentary behavior time.

Comparative analysis of deep-learning-based bone age estimation between whole lateral cephalometric and the cervical vertebral region in children.

Bone age determination in individuals is important for the diagnosis and treatment of growing children. This study aimed to develop a deep-learning model for bone age estimation using lateral cephalometric radiographs (LCRs) and regions of interest (ROIs) in growing children and evaluate its performance. This retrospective study included 1050 patients aged 4-18 years who underwent LCR and hand-wrist radiography on the same day at Pusan National University Dental Hospital and Ulsan University Hospital between January 2014 and June 2023. Two pretrained convolutional neural networks, InceptionResNet-v2 and NasNet-Large, were employed to develop a deep-learning model for bone age estimation. The LCRs and ROIs, which were designated as the cervical vertebrae areas, were labeled according to the patient's bone age. Bone age was collected from the same patient's hand-wrist radiograph. Deep-learning models trained with five-fold cross-validation were tested using internal and external validations. The LCR-trained model outperformed the ROI-trained models. In addition, visualization of each deep learning model using the gradient-weighted regression activation mapping technique revealed a difference in focus in bone age estimation. The findings of this comparative study are significant because they demonstrate the feasibility of bone age estimation via deep learning with craniofacial bones and dentition, in addition to the cervical vertebrae on the LCR of growing children.

Do we need another screw? Sacroiliac screw fixation in open-book pelvic ring injuries (APC type II).

Purpose: To compare anterior plate fixation (SP fixation) both alone and in combination with an additional posterior sacroiliac screw (SP+SIS fixation) as a treatment for pelvic ring injuries with widening of the pubic symphysis and disruption to the anterior sacroiliac ligaments. Methods: To find studies with pelvic ring injuries (APC II; B2.3d) and SP or SP+SIS fixation, a systematic literature review was conducted by searching four databases. A protocol was published a priori at Open Science Framework (https://doi.org/10.17605/OSF.IO/3YHAV). Exclusion criteria included perineal injuries, chronic instability of the symphysis, complete sacroiliac separation, and pediatric patients (age <18 years). Primary outcomes of interest were defined as implant failure, health-related quality of life, and revision rate. Results: Altogether, 1861 studies were screened, and 40 studies qualified for full-text analysis. In total, 14 studies (two surveys, six biomechanical studies, and six retrospective clinical studies) were included. The surveys revealed that surgeons who had more recently begun practicing were more likely to use posterior fixation (SP+ISS). The biomechanical studies were heterogenous and did not yield a uniform pattern. In clinical studies, 117 patients (45%) received SP fixation, and 142 patients (55%) received SP+SIS fixation. Complications occurred in 31 SP patients (30%) and in five SP+SIS patients (3.5%). Conclusion: A high risk of bias was uncovered, and reporting was found to be incomplete. SP+SIS may have the potential to improve outcomes, but the evidence remains too inconclusive to draw reliable recommendations.

Zinc phosphate glass microspheres promoted mineralization and expression of BMP2 in MC3T3-E1 cells.

Degradable phosphate glasses have shown favorable properties for tissue engineering. By changing the composition of the glasses, the degradation rate, and ion release are controllable. Zinc oxide can function as a glass network modifier and has been shown to play a positive role in bone formation. Also, phosphate glasses can easily be processed into microspheres, which can be used as microcarriers. This study aims to develop zinc phosphate glasses microspheres and explore the optimized size and composition for applications in bone tissue engineering. Zinc-titanium-calcium-sodium phosphate glasses with 0, 1, 3, 5, or 10 mol % zinc oxide were prepared and processed into microspheres. The smaller microspheres ranged in size from 50 to 106 µm, while the larger ones ranged from 106 to 150 µm. The characteristics of glasses were examined. The osteoblastic cell line MC3T3-E1 was cultured on the surface of microspheres and the cell viability was examined. To evaluate osteogenic differentiation, Alizarin Red S staining, quantitative reverse transcription polymerase chain reaction, and western blot analysis were performed after 14 days. Different sizes of zinc phosphate glass microspheres were successfully made. The glass microspheres with <10 mol % zinc oxide were able to support the adhesion and proliferation of MC3T3-E1 cell lines. The relative gene expression of BMP2 was significantly upregulated in the smaller glass microspheres containing 3 mol % zinc oxide (26-fold, p < .001) and both sizes of microspheres containing 5 mol % zinc oxide (smaller: 27-fold, p < .001; larger: 35-fold, p < .001). Additionally, cluster formation was observed in glass microspheres after 14 days, and the mineralization of MC3T3-E1 cell lines was promoted. Based on these findings, the glass microspheres containing 3-5 mol % of zinc oxide can promote osteogenic differentiation for MC3T3-E1 cells.

The Diagnostic Value of PSMA PET-CT in Differentiating Medication-Related Osteonecrosis of the Jaw and Metastasis to the Jawbone.

INTRODUCTION: Medication-related osteonecrosis of the jaw (MRONJ) and jaw metastasis might share similar clinical and radiographic characteristics, with both demonstrating FDG uptake on PET-CT. Prostate-specific membrane antigen (PSMA) PET-CT is used to demonstrate prostate cancer dissemination. Unlike FDG PET-CT, PSMA PET-CT is more specific to cancer than to inflammation. Therefore, we hypothesized that it might be a useful tool to differentiate between MRONJ and jaw metastasis. MATERIALS AND METHODS: All files of prostate cancer patients diagnosed with MRONJ and with available PSMA PET-CT studies were retrieved. A similar number of solid cancer patients with MRONJ and with available FDG PET-CT studies served as a second study group. All studies were reviewed by two blinded co-investigators (LD, MF). RESULTS: Seventeen patients who underwent PSMA PET-CT (24 studies) and 15 patients who underwent FDG PET-CT (29 studies) met the inclusion criteria. All patients with FDG PET-CT studies showed pathological uptake at the site of MRONJ in at least one of their studies versus only 23.5% of patients in the PSMA PET-CT group (P < 0.001). FDG PET-CT studies showed pathological uptake in 89.6% of the studies compared to only 20.8% in the PSMA PET-CT group (P < 0.001). The mean standardized uptake value (SUVmax) and the mean uptake volume in the FDG PET-CT group were significantly higher compared to the PSMA PET-CT group (P < 0.001 and P < 0.005, respectively). The interclass correlation coefficient for all parameters was higher than 0.95. CONCLUSIONS: PSMA PET-CT is useful to differentiate between MRONJ and jaw metastasis.

Comparison of QCT and DEXA findings for lumbar vertebra in young adults and the elderly.

BACKGROUND: The use of dual-energy X-ray absorptiometry (DEXA) and quantitative computed tomography (QCT) methods are important for the diagnosis and follow-up of osteoporosis, and are used especially in cases to determine the degree of osteoporosis and the risk of fracture, monitoring the effectiveness of the treatment applied. PURPOSE: To compare the parameters measured using the DEXA method from the lumbar (L1-L4) vertebrae and the Hounsfield unit (HU) values measured with QCT at the same levels among young adults and the elderly. MATERIAL AND METHODS: The study included 155 patients (age range = 26-93 years). A total of 57 (36.8%) patients (age range = 26-64 years) were defined as the first group, and 98 (63.2%) patients (aged ≥65 years) were defined as the second group. T-test and correlation analysis were performed to compare bone mineral density (BMD), T score, and HU values measured using DEXA and QCT. RESULTS: A statistically significant difference was found between T score, lumbar total BMD, and HU values according to age and sex (P < 0.05). When the values measured from lumbar vertebrae were compared using both DEXA and CT, a high correlation was found between them. CONCLUSION: In the study, it was observed that QCT attenuation measurements of the lumbar spine measured between different age groups provided reliable results in terms of BMD scanning, as in DEXA. It should be noted that QCT has a longer imaging time and higher radiation dose compared to DEXA, and unnecessary scans should be avoided.

Ganoderic Acid A prevents bone loss in lipopolysaccharide-treated male rats by reducing oxidative stress and inflammatory.

Ganoderic Acid A (GAA) has demonstrated beneficial effects in anti-inflammatory and anti-oxidative stress studies. However, it remains unknown whether GAA exerts positive impacts on bone loss induced by lipopolysaccharide (LPS). This study aims to investigate the influence of GAA on bone loss in LPS-treated rats. The study assesses changes in the viability and osteogenic potential of MC3T3-E1 cells, as well as osteoclast differentiation in RAW264.7 cells in the presence of LPS using CCK-8, ALP staining, AR staining, and Tartrate-resistant acid phosphatase (TRAP) staining. In vitro experiments indicate that LPS-induced inhibition of osteoclasts (OC) and Superoxide Dismutase 2 (SOD2) correlates with heightened levels of inflammation and oxidative stress. Furthermore, GAA has displayed the ability to alleviate oxidative stress and inflammation, enhance osteogenic differentiation, and suppress osteoclast differentiation. Animal experiment also proves that GAA notably upregulates SOD2 expression and downregulates TNF-α expression, leading to the restoration of impaired bone metabolism, improved bone strength, and increased bone mineral density. The collective experimental findings strongly suggest that GAA can enhance osteogenic activity in the presence of LPS by reducing inflammation and oxidative stress, hindering osteoclast differentiation, and mitigating bone loss in LPS-treated rat models.

Cxcl10 and Cxcr3 regulate self-renewal and differentiation of hematopoietic stem cells.

BACKGROUND: The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. METHODS: We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3-/- and Cxcl10-/-) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3-/- and Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3-/-or Cxcl10-/- recipient mice (CD45.2) and examined donor-contributed hematopoiesis. RESULTS: Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10-/- donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. CONCLUSIONS: The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.

Remote actuation and on-demand activation of biomaterials pre-incorporated with physical cues for bone repair.

The high incidence of bone defect-related diseases caused by trauma, infection, and tumor resection has greatly stimulated research in the field of bone regeneration. Generally, bone healing is a long and complicated process wherein manipulating the biological activity of interventional scaffolds to support long-term bone regeneration is significant for treating bone-related diseases. It has been reported that some physical cues can act as growth factor substitutes to promote osteogenesis through continuous activation of endogenous signaling pathways. This review focuses on the latest progress in bone repair by remote actuation and on-demand activation of biomaterials pre-incorporated with physical cues (heat, electricity, and magnetism). As an alternative method to treat bone defects, physical cues show many advantages, including effectiveness, noninvasiveness, and remote manipulation. First, we introduce the impact of different physical cues on bone repair and potential internal regulatory mechanisms. Subsequently, biomaterials that mediate various physical cues in bone repair and their respective characteristics are summarized. Additionally, challenges are discussed, aiming to provide new insights and suggestions for developing intelligent biomaterials to treat bone defects and promote clinical translation.

A Rare Case of Multiple Bone Infarctions and Abnormal Pulmonary Function Tests in a Patient With Compound Heterozygous Hemoglobin S and Type 2 Hereditary Persistence of Fetal Hemoglobin.

Sickle cell disease (SCD) is a group of inherited blood disorders characterized by abnormal hemoglobin production, affecting individuals worldwide with varying prevalence across different populations. Manifestations vary, ranging from severe to mild. SCD is characterized by the presence of hemoglobin S (HbS), which distorts erythrocytes upon deoxygenation, leading to sickling. This results in hemolytic anemia, painful vaso-occlusive crises (VOC), and multiple organ damage, including bones, due to microinfarcts. Sickle cell trait (SCT), or carrier status, is not considered an SCD and often runs a benign course. We report a 44-year-old man of African descent presenting with a one-month history of pain in his ankles and feet. He had a prior diagnosis of sickle cell "trait" without previous VOC. Hematological indices were normal. Hemoglobin electrophoresis showed absent HbA, elevated HbS, elevated HbF, and normal HbA2. X-rays and MRI revealed bilateral bone infarction in diaphyses of right proximal and bilateral distal tibias. Molecular analysis of [Formula: see text]-globin revealed compound heterozygous hemoglobin S and type 2 deletion of persistence of fetal hemoglobin (HPFH). Pulmonary function tests revealed restrictive lung disease. A literature review from 1946 to May 2024 via PubMed, EMBASE, and Medline was performed, revealing two cases of HbS-HPFH with avascular necrosis affecting the femoral neck were briefly reported more than 60 years ago. Although pulmonary function tests in SCD typically show a mild restrictive pattern with decreased diffusion capacity and rarely an obstructive pattern, no cases of HbS-HPFH were identified. In conclusion, multiple bone infarctions are extremely rare in HbS-HPFH. Lung and bone diseases might be unrecognized in this unique disorder.

Study of long-term effects of pelvic radiotherapy on the function of bone marrow in recurrent cervical cancer patients.

Purpose: To study the effects of prior pelvic radiotherapy on bone marrow suppression in recurrent cervical cancer patients during chemotherapy. Methods and materials: The cases of 129 patients with recurrent cervical cancer were reviewed, of which 77 patients had pelvic radiotherapy history and another 52 patients with no pelvic radiotherapy history were used as control group. All patients received a chemotherapy regimen of paclitaxel combined with carboplatin (TC) per 21 days for 5-6 times. Hematologic toxicity, including count of red blood cell, white blood cell and neutrophil cell and platelet, was defined by using Common Terminology Criteria for Adverse Events (version 4.0). The relationship between age, body mass index, disease free survival, pathological types, FIGO stages, radiotherapy methods and the degree of bone marrow suppression during chemotherapy was statistically analyzed, respectively, for all recurrent cervical cancer patients. Results: Among 77 patients with previous radiotherapy history, 73 recurrent patients (94.8%) had bone marrow suppression followed by chemotherapy. Recurrent cervical cancer patients without prior radiotherapy (n=52) showed a lower risk of bone marrow suppression followed by chemotherapy (n=39, 75.0%, P < 0.05). The probability of severe bone marrow suppression (grade III-IV) after chemotherapy in recurrent cervical patients with or without history of radiotherapy was 41.6% and 13.5%, respectively (P < 0.05). In univariate analysis, radiotherapy methods were associated with the incidence of grade III-IV bone marrow suppression in recurrent cervical cancer patients (P=0.005). In multivariate analysis, radiotherapy methods and extended-field radiotherapy were the risk factor of grade III-IV bone marrow suppression (χ2=16.975, P=0.001). No significant differences in the counts of white blood cell, hemoglobin and platelet were observed before chemotherapy at relapse between patients with and without prior radiotherapy. Reduction of white blood cell counts, absolute value of neutrophil cell and platelet counts composited majority type of grade III and IV bone marrow suppression. Conclusions: The prior pelvic radiotherapy significantly increased the incidence of bone marrow suppression during chemotherapy in recurrent cervical cancer patients. When treating recurrent cervical cancer patients with chemotherapy who had prior radiotherapy, especially for those experienced external beam radiation therapy, essential attention and timely intervention are recommended to ensure completion of chemotherapy and clinical efficacy.

Semi-quantitative analysis on sea buckthorn phenolic-rich extract coating bone-like open porous NiTi-based alloy.

This study investigates the feasibility of coating Ni-Ti alloy with sea buckthorn extract via a hydrothermal method for targeted delivery of beneficial phenolic compounds to bone tissue. The qualitative analysis confirmed the presence of flavonoids and tannins in sea buckthorn extract, supporting its osteogenic potential. The microhardness of the NiTi alloy substrate was suitable for biomedical applications, and successful coating was achieved without compromising its properties. NiTi alloy samples were coated with 18.1, 20.1, and 12.4 mg of extract, respectively. Comprehensive evaluations confirmed the successful integration of the extract onto the alloy's surface. The coated system exhibited sustained release properties over five days, with the highest release occurring on the first day (on average 32.1 % for the first peak and 72.1 % for the second peak), as determined by HPLC analysis. The findings demonstrate the potential of this novel approach in developing dual-functionality implants for bone health promotion. Overall, this study underscores the promising potential of Ni-Ti alloy coated with sea buckthorn extract as a targeted drug delivery system for bone tissue.

Saikosaponin A attenuates osteoclastogenesis and bone loss by inducing ferroptosis.

To alleviate bone loss, most current drugs target osteoclasts. Saikosaponin A (Ssa), a triterpene saponin derived from Bupleurum falcatum (also known as Radix bupleuri), has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects. Recently, modulation of bone homeostasis was shown to involve ferroptosis. Herein, we aimed to determine Ssa's inhibitory effects on osteoclastogenesis and differentiation, whether ferroptosis is involved, and the underlying mechanisms. Tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and pit formation assays were conducted to confirm Ssa-mediated inhibition of RANKL-induced osteoclastogenesis in vitro. Ssa could promote osteoclast ferroptosis and increase mitochondrial damage by promoting lipid peroxidation, as measured by iron quantification, FerroOrange staining, Dichloro-dihydro-fluorescein diacetate, MitoSOX, malondialdehyde, glutathione, and boron-dipyrromethene 581/591 C11 assays. Pathway analysis showed that Ssa can promote osteoclasts ferroptosis by inhibiting the Nrf2/SCL7A11/GPX4 axis. Notably, we found that the ferroptosis inhibitor ferrostatin-1 and the Nrf2 activator tert-Butylhydroquinone reversed the inhibitory effects of Ssa on RANKL-induced osteoclastogenesis. In vivo, micro-computed tomography, hematoxylin and eosin staining, TRAP staining, enzyme-linked immunosorbent assays, and immunofluorescence confirmed that in rats with periodontitis induced by lipopolysaccharide, treatment with Ssa reduced alveolar bone resorption dose-dependently. The results suggested Ssa as a promising drug to treat osteolytic diseases.