Low-energy shock waves promote the cisplatin chemosensitivity of human osteosarcoma MNNG/HOS cells via the P2X7/Akt/mTOR pathway.

Background: The current dilemma of osteosarcoma treatment is the resistance of chemotherapeutic drugs after long-term usage, which also introduces life-threatening side effects. Methods and results: To minimize chemoresistance in osteosarcoma patients, the authors applied shock waves (SWs) to human osteosarcoma MNNG/HOS cells, then evaluated the cell viability and extracellular ATP levels, and further investigated the effect of SWs on cisplatin (DDP) cytotoxicity in MNNG/HOS cells. The authors' results showed that 400 SW pulses at 0.21 mJ/mm2 exhibited little influence on the MNNG/HOS cell viability. In addition, this SW condition significantly promoted the extracellular ATP release in MNNG/HOS cells. Importantly, low-energy SWs obviously increased Akt and mammalian target of rapamycin (mTOR) phosphorylation and activation in MNNG/HOS cells, which could be partially reversed in the presence of P2X7 siRNA. The authors also found that low-energy SWs strongly increased the DDP sensitivity of MNNG/HOS cells in the absence of P2X7. Conclusions: For the first time, the authors found that SW therapy reduced the DDP resistance of MNNG/HOS osteosarcoma cells when the ATP receptor P2X7 was downregulated. SW therapy may provide a novel treatment strategy for chemoresistant human osteosarcoma.

Shock wave assisted intracellular delivery of antibiotics against bone infection with Staphylococcus aureus via P2X7 receptors.

Background: Treatment of chronic osteomyelitis (bone infection) remains a clinical challenge; in particular, it requires enhanced delivery of antibiotic drugs for the treatment of intracellular Staphylococcus aureus (S. aureus), which prevents infection recurrence and resistance. Previous studies have found that noninvasive shock waves used to treat musculoskeletal diseases can alter cell permeability, however, it is unclear whether shock waves alter cell membrane permeability in chronic osteomyelitis. Furthermore, it remains unknown whether such changes in permeability promote the entry of antibiotics into osteoblasts to exert antibacterial effects. Methods: In our study, trypan blue staining was used to determine the shock wave parameters that had no obvious damage to the osteoblast model; the effect of shocks waves on the cell membrane permeability of osteoblast model was detected by BODIPY®FL vancomycin; high performance liquid chromatography-mass spectrometry (HLPC-MS) was used to detect the effect of shock wave on the entry of antibiotics into the osteoblast model; plate colony counting method was used to detect the clearance effect of shock wave assisted antibiotics on S. aureus in the osteoblast model. To explore the mechanism, the effect of different pulses of shock waves on S. aureus was examined by plate colony counting method, besides, P2X7 receptor in osteoblast was detected by immunofluorescence and the extracellular ATP levels was detected. Furthermore, the effect of P2X7 receptor antagonists KN-62 or A740003 on the intracellular antibacterial activity of shock-assisted antibiotics was observed. Then, we used S. aureus to establish a rat model of chronic tibial osteomyelitis and investigated the efficacy and safety of shock-wave assisted antibiotics in the treatment of chronic osteomyelitis in rats. Results: The viability of the osteoblast models of intracellular S. aureus infection was not significantly affected by the application of up to 400 shock wave pulses at 0.21 mJ/mm2. Surprisingly, the delivery of BODIPY®FL vancomycin to osteoblast model cells was markedly enhanced by this shock wave treatment. Furthermore, the shock wave therapy increased the delivery of hydrophilic antibiotics (vancomycin and cefuroxime sodium), but not lipophilic antibiotics (rifampicin and levofloxacin), which improved the intracellular antibacterial effect. Afterwards, we discovered that shock wave treatment increased the extracellular concentration of ATP (the P2X7 receptor activator)， while KN-62 or A740003, a P2X7 receptor inhibitor, decreased intracellular antibacterial activity. We then found that 0.1 mL of 1 × 1011 CFU/mL ATCC25923 S. aureus was suitable for modeling chronic osteomyelitis in rats. Besides, the shock wave-assisted vancomycin treatment with the strongest antibacterial and osteogenic effects among the tested treatments was confirmed in vivo by imaging examination, microbiological cultures, and histopathology, with favorable safety. Conclusions: Our results suggest that shock waves can promote the entry of antibiotics into osteoblasts for antibacteria by changing the cell membrane permeability in a P2X7 receptor-dependent manner. Besides, considering antibacterial and osteogenic efficiency and a high degree of safety in rat osteomyelitis model, shock wave-assisted vancomycin treatment may thus represent a possible adjuvant therapy for chronic osteomyelitis.

Causal effects of osteoporosis on structural changes in specific brain regions: a Mendelian randomization study.

Observational studies have reported that osteoporosis is associated with cortical changes in the brain. However, the inherent limitations of observational studies pose challenges in eliminating confounding factors and establishing causal relationships. And previous observational studies have not reported changes in specific brain regions. By employing Mendelian randomization, we have been able to infer a causal relationship between osteoporosis and a reduction in the surficial area (SA) of the brain cortical. This effect is partially mediated by vascular calcification. We found that osteoporosis significantly decreased the SA of global brain cortical (ß = -1587.62 mm2, 95%CI: -2645.94 mm2 to -529.32 mm2, P = 0.003) as well as the paracentral gyrus without global weighted (ß = - 19.42 mm2, 95%CI: -28.90 mm2 to -9.95 mm2, P = 5.85 × 10-5). Furthermore, we estimated that 42.25% and 47.21% of the aforementioned effects are mediated through vascular calcification, respectively. Osteoporosis leads to a reduction in the SA of the brain cortical, suggesting the presence of the bone-brain axis. Vascular calcification plays a role in mediating this process to a certain extent. These findings establish a theoretical foundation for further investigations into the intricate interplay between bone, blood vessels, and the brain.

Silicone rubber sealed channel induced self-healing of large bone defects: Where is the limit of self-healing of bone?

Background: Large defects of long tubular bones due to severe trauma, bone tumor resection, or osteomyelitis debridement are challenging in orthopedics. Bone non-union and other complications often lead to serious consequences. At present, autologous bone graft is still the gold standard for the treatment of large bone defects. However, autologous bone graft sources are limited. Silicon rubber (SR) materials are widely used in biomedical fields, due to their safety and biocompatibility, and even shown to induce nerve regeneration. Materials and methods: We extracted rat bone marrow mesenchymal stem cells (BMMSCs) in vitro and verified the biocompatibility of silicone rubber through cell experiments. Then we designed a rabbit radius critical sized bone defect model to verify the effect of silicone rubber sealed channel inducing bone repair in vivo. Results: SR sealed channel could prevent the fibrous tissue from entering the fracture end and forming bone nonunion, thereby inducing self-healing of long tubular bone through endochondral osteogenesis. The hematoma tissue formed in the early stage was rich in osteogenesis and angiogenesis related proteins, and gradually turned into vascularization and endochondral osteogenesis, and finally realized bone regeneration. Conclusions: In summary, our study proved that SR sealed channel could prevent the fibrous tissue from entering the fracture end and induce self-healing of long tubular bone through endochondral osteogenesis. In this process, the sealed environment provided by the SR channel was key, and this might indicate that the limit of self-healing of bone exceeded the previously thought. The translational potential of this article: This study investigated a new concept to induce the self-healing of large bone defects. It could avoid trauma caused by autologous bone extraction and possible rejection reactions caused by bone graft materials. Further research based on this study, including the innovation of induction materials, might invent a new type of bone inducing production, which could bring convenience to patients. We believed that this study had significant meaning for the treatment of large bone defects in clinical practice.

Risk of osteoporosis in patients treated with direct oral anticoagulants vs. warfarin: an analysis of observational studies.

Aims: Evidence on the association between the risk of new-onset osteoporosis and oral anticoagulants remains controversial. We aimed to compare the risk of osteoporosis associated with the use of direct oral anticoagulants (DOACs) with that associated with warfarin use. Methods: Studies published up to 15 March 2023 that investigated the association between the use of DOACs and warfarin and the incidence of osteoporosis were identified by online searches in PubMed, Embase, the Cochrane Library, and Web of Science conducted by two independent investigators. Random-effects or fixed-effect models were employed to synthesize hazard ratios (HRs)/relative ratios (RRs) with 95% confidence intervals (CIs) for estimating the risk of osteoporosis correlated with DOAC and warfarin prescriptions (PROSPERO No. CRD42023401199). Results: Our meta-analysis ultimately included four studies involving 74,338 patients. The results suggested that DOAC use was associated with a significantly lower incidence of new-onset osteoporosis than warfarin use (pooled HR: 0.71, 95% CI: 0.57 to 0.88, p < 0.001, I 2: 85.1%). Subanalyses revealed that rivaroxaban was associated with a lower risk of osteoporosis than both warfarin and dabigatran. In addition, DOACs were associated with a lower risk of developing osteoporosis than warfarin in both male and female patients, in patients with atrial fibrillation (AF), and in patients who underwent therapy for > 365 days. Conclusion: DOAC users experienced a lower incidence of osteoporosis than warfarin users. This study may give us insight into safe anticoagulation strategies for patients who are at high risk of developing osteoporosis. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023401199.

Gamma Nail Combined with One Cannulated Compression Screw Fixation for Treating Pauwels Type III Femoral Neck Fractures in Young and Middle-Aged Adults: Clinical Follow-Up and Biomechanical Studies.

OBJECTIVE: Recently, some clinical studies have reported the use of an intramedullary nailing system for treating unstable femoral neck fractures or femoral neck fractures combined with femoral shaft fractures in young adults, and the results have indicated certain advantages. However, no study has investigated the mechanical properties of this method. We aimed to evaluate the mechanical stability and clinical efficacy of the Gamma nail combined with one cannulated compression screw (CCS) fixation for treating Pauwels type III femoral neck fracture in young and middle-aged adults. METHODS: This study consists of two parts: a clinical retrospective study and randomized controlled biomechanical test. Twelve adult cadaver femora were used to test and compare the biomechanical properties among three fixation methods: three parallel CCS (group A), Gamma nail (group B), and Gamma nail combined with one cannulated compression screw (group C). The single continuous compression test, cyclic load test, and ultimate vertical load test were used to evaluate the biomechanical performance of the three fixation methods. We also conducted a retrospective study of 31 patients with Pauwels type III femoral neck fractures, including 16 patients with fractures fixed with three parallel CCS (CCS group) and 15 patients with fractures fixed with Gamma nail combined with one CCS (Gamma nail + CCS group). The patients were followed up for at least 3 years, and all were evaluated for surgical time (from skin incision to closure), surgical blood loss, hospital stay, and the Harris hip score. RESULTS: In mechanical experiments, we have found that the mechanical advantages of Gamma nail fixation are not as good as those of conventional CCS fixation. However, the mechanical properties of Gamma nail fixation combined with one cannulated screw perpendicular to the fracture line are much better than those of Gamma nail fixation and CCS fixation. No significant difference was found in the incidence of femoral head necrosis and nonunion between the CCS and Gamma nail + CCS groups. Moreover, there was no statistically significant difference in the Harris hip scores between the two groups. One patient in the CCS group showed significant withdrawal of cannulated screws at 5 months after surgery, whereas in the Gamma nail + CCS group, all patients, including those with femoral neck necrosis, showed no loss of stability of the fixation. CONCLUSION: Among the two fixation methods evaluated in this study, Gamma nail combined with one CCS fixation showed better biomechanical properties and may reduce complications associated with unstable fixation devices.

Cardiovascular risk factors mediating the protective effect of education on cervical spondylosis risk.

The causal association between education and cervical spondylosis may be mediated partly through risk factors of cardiovascular disease. The identification of the protective effect of education and the evaluation of risk factors will help to optimize disease prevention at both clinical and public health levels. In this study, we applied several different Mendelian randomization (MR) methods to identify which cardiovascular factors underlie the clustering of cervical spondylosis with cardiovascular disease, and the degree to which these mediate an effect of education. Univariable MR analyses provided evidence supporting a protective effect of genetically predicted education on cervical spondylosis risk, and MVMR further identified the direct effect of education level. Our results also provided evidence supporting the detrimental effects of BMI and smoking on cervical spondylosis risk, with evidence that the effect of education is mediated through BMI and smoking. The proportions of the effect of education mediated through BMI and smoking were 12% and 3%, respectively. These findings highlight education, obesity, and smoking as common mechanisms underlying the clustering of cervical spondylosis with risk factors of cardiovascular disease, which might represent clinical and public health targets for reducing multi-morbidity and the burden of these common conditions.

Causal associations of anthropometric measurements with osteoarthritis: A Mendelian randomization study.

OBJECTIVE: We believe that there is a causal relationship between waist circumference and knee osteoarthritis. To confirm the hypothesis, we have conducted this study. METHODS: Genetic variants associated with the five anthropometric variables were obtained from previous large-scale genomewide association studies. Summary-level data on osteoarthritis were obtained from the UK Biobank. The univariable and multivariable MR framework were used to evaluate the associations. The two-sided p value was considered to be statistically significant at 0.01 (where p = 0.05/5) after Bonferroni correction for the five exposure variables. RESULTS: In the univariable MR, there was evidence of a detrimental effect of height, weight, BMI, waist circumference, and hip circumference on osteoarthritis risk in the main IVW analyses (height: OR 1.115, 95% CI 1.054-1.180; weight: OR 1.765, 95% CI 1.650-1.889; BMI: OR 1.952, 95%CI 1.841-2.068; waist circumference: OR 2.140, 95% CI 1.994-2.296; hip circumference: OR 1.719, 95% CI 1.600-1.846). And the analyses on knee osteoarthritis and hip osteoarthritis yielded similar results. However, the multivariable MR showed that only waist circumference was causally associated with osteoarthritis, after adjusting for the confounding exposure effects (waist circumference: OR 1.877, 95% CI 1.286-2.739). Such association was also repeated in the analyses on knee osteoarthritis but not hip osteoarthritis. CONCLUSION: Our study highlighted the causal associations between waist circumference and knee osteoarthritis risk.

Non-antibiotic strategies for prevention and treatment of internalized Staphylococcus aureus.

Staphylococcus aureus (S. aureus) infections are often difficult to cure completely. One of the main reasons for this difficulty is that S. aureus can be internalized into cells after infecting tissue. Because conventional antibiotics and immune cells have difficulty entering cells, the bacteria can survive long enough to cause recurrent infections, which poses a serious burden in healthcare settings because repeated infections drastically increase treatment costs. Therefore, preventing and treating S. aureus internalization is becoming a research hotspot. S. aureus internalization can essentially be divided into three phases: (1) S. aureus binds to the extracellular matrix (ECM), (2) fibronectin (Fn) receptors mediate S. aureus internalization into cells, and (3) intracellular S. aureus and persistence into cells. Different phases require different treatments. Many studies have reported on different treatments at different phases of bacterial infection. In the first and second phases, the latest research results show that the cell wall-anchored protein vaccine and some microbial agents can inhibit the adhesion of S. aureus to host cells. In the third phase, nanoparticles, photochemical internalization (PCI), cell-penetrating peptides (CPPs), antimicrobial peptides (AMPs), and bacteriophage therapy can effectively eliminate bacteria from cells. In this paper, the recent progress in the infection process and the prevention and treatment of S. aureus internalization is summarized by reviewing a large number of studies.

Effects of Bisphosphonates Treatments in Osteopenic Older Women: A Systematic Review and Meta-Analysis.

Aims: To review the effects of bisphosphonates on bone density, fractures, and bone markers in osteopenic older women. Methods: Relevant articles published before February 2022 were searched in PubMed, EMBASE, and the Cochrane Library. All randomized controlled trials that reported incident fractures, bone mineral density (BMD), bone markers, or adverse events with bisphosphonates in osteopenic older women were included. The quality of included studies was assessed using the Cochrane Risk of Bias tool. The risk ratios (RRs) for fractures, net percent change in bone mineral density and differences in bone markers were calculated using a meta-analysis. Results: A total of 11 studies were included in our meta-analysis. Bisphosphonates significantly increased the percent changes in the lumbar spine BMD (WMD, 5.60; 95% CI, 4.16-7.03; I 2 = 93.6%), hip BMD (WMD, 4.80; 95% CI, 2.93 to 6.66; I 2 = 97.1%), total body BMD (WMD, 3.24; 95% CI, 2.12-4.35; I 2 = 90.9%), femoral neck BMD (WMD, 4.02; 95% CI, 1.70-6.35; I 2 = 91.8%) and trochanter BMD (WMD, 5.22; 95% CI, 3.51-6.93; I 2 = 83.6%) when compared to placebo. Zoledronate was associated with a great treatment effect on fragility fracture (RR, 0.63; 95% CI, 0.50-0.79), clinical vertebral fracture (RR, 0.41; 95% CI, 0.22-0.76), and radiographic vertebral fracture (RR, 0.60; 95% CI, 0.27-1.35) compared to placebo. Meanwhile, alendronate was also associated with beneficial effects on fragility fracture (RR, 0.40; 95% CI, 0.15-1.07), clinical vertebral fracture (RR, 0.46; 95% CI, 0.17-1.24), and radiographic vertebral fracture (RR, 0.64; 95% CI, 0.38-1.09). In addition, the use of bisphosphonates reduced the concentration of procollagen type I N-terminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX) over placebo by 15.79 (95% CI, -18.92 to -12.66; I 2 = 28.4%), -0.23 (95% CI, -0.35 to -0.10; I 2 = 91.3%), respectively. Although there was insufficient evidence to determine their safety, these bisphosphonates may have an effect on cancer, cardiac events, and mortality in osteopenic older women. Conclusion: All bisphosphonates examined were associated with beneficial effects on fractures, BMD, and bone markers in women with osteopenia. Further randomized controlled trials are necessary to clarify the safety of bisphosphonates in women with osteopenia.

Efficacy of the Combination of Teriparatide and Denosumab in the Treatment of Postmenopausal Osteoporosis: A Meta-Analysis.

Aim: Evidence on the efficacy of combination treatment of teriparatide and denosumab for osteoporosis remains controversial. We aim to compare the efficacy between the combination treatment and monotherapy among patients with postmenopausal osteoporosis. Methods and results: We systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science up to 26 January 2022, for relevant studies. This meta-analysis reviewed all randomized controlled trials (RCTs) that reported on the combination treatment of teriparatide and denosumab in patients with postmenopausal osteoporosis. The articles were examined individually by two reviewers, and the relevant data was extracted. We combined weighted mean difference (WMD) for bone mineral density (BMD) using random- or fixed- effect models and conducted subgroup analyses. Sensitivity analyses were performed, and possible publication bias was also assessed. Overall, combination treatment enhanced the mean percent change of bone mineral density in lumbar spine than monotherapy (WMD = 2.91, 95%CI: 1.983.83; p = 0.00). And, combination treatment has been beneficial for enhancing the mean percent change of BMD in hip (WMD = 3.19, 95%CI: 2.25∼4.13; p = 0.00). There was no significant difference between combination treatment and monotherapy in terms of the adverse events (RR = 0.81, 95%CI: 0.45∼1.45; p = 0.472). Conclusion: The meta-analysis indicates that combination treatment led to greater BMD at the lumbar spine and hip in comparison to monotherapy, without an increased incidence of adverse events. Systematic Review Registration: (https://inplasy.com/), identifier (Inplasy Protocol 2734).

Minimally Invasive Percutaneous TightRope® System Fixation for an Unstable Posterior Pelvic Ring: Clinical Follow-up and Biomechanical Studies.

OBJECTIVE: To evaluate the mechanical stability and clinical efficacy of minimally invasive percutaneous TightRope® systems applied via gun-shaped reduction forceps for unstable posterior pelvic ring fractures. MATERIALS AND METHODS: This study consists of two parts: a clinical retrospective study and a randomized controlled biomechanical test. For the clinical study, a retrospective analysis of posterior pelvic ring fractures was performed between June 2015 and May 2020. Eighteen patients underwent surgery using two TightRope® systems to fix a broken posterior pelvic ring because of unstable AO type C1 and C2 pelvic ring fractures. The patients were followed up for at least 2 years, and all patients were evaluated using the Majeed scoring system and vertical displacement. In the biomechanical tests, six embalmed adult pelvic specimens were used. The fractures were subjected to TightRope®, IS screw, and TBP fixation in a randomized block design. The specimens were placed in a biomechanical testing machine in a standing neutral posture. A cyclic vertical load of up to 500 N was applied, and the displacement of the specimens was recorded by the testing machine. The ultimate load in each group of specimens was recorded. The displacement and ultimate load were compared and analyzed by statistical methods. RESULTS: At a mean follow-up of 38.89 ± 8.72 months, the functional Majeed score was excellent in 14 patients and good in four patients. The final radiological examinations showed that the outcome was excellent in 14 patients and good in four patients. In these patients, no serious clinical complications were found. Weight-bearing was delayed in four patients. In biomechanical tests, the displacement of the specimens fixed with TightRope® was significantly lower than that of the specimens fixed with TBP (P < 0.05) when the load ranged from 300 to 500 N. The displacement in the IS screw group was significantly lower than that in either the TBP or TightRope® group (P < 0.05) when the load ranged from 0 to 500 N. The ultimate load in the IS screw group (1798 ± 83.53 N) was significantly greater than that in the TBP group (1352 ± 74.41 N) (t = 9.78, P < 0.0001) and the TightRope® group (1347 ± 54.28 N) (t = 11.11, P < 0.0001). However, no significant difference was observed between the TightRope® and TBP groups (t = 0.13, P = 0.90). CONCLUSION: Percutaneous posterior TightRope® system shows strong stability in mechanical experiments and shows good results in clinical follow-up while this system has certain advantages in lower surgical requirements and lower risk of related nerve and vascular structural damage.

Fracture risks in patients with atrial fibrillation treated with different oral anticoagulants: a meta-analysis and systematic review.

AIMS: evidence on the difference in fracture risks for patients with atrial fibrillation (AF) receiving direct oral anticoagulants (DOACs) versus warfarin remains controversial. We aim to compare the fracture risks between the DOAC and warfarin prescriptions among the AF patients. METHODS AND RESULTS: we systematically searched PubMed, EMBASE, the Cochrane Library and Web of Science up to 19 April 2021 for relevant studies. And the observational studies regarding the relationship between the DAOC versus warfarin prescriptions and fracture risks among the patients with AF were included in this meta-analysis. Two investigators independently screened the articles and extracted the relevant data. A random- or fixed-effect model was applied to calculate the pooled hazard ratio/relative ratios with 95% confidence intervals of fracture risks associated with the DOAC and warfarin prescriptions. Six studies comprising 351,208 patients and 9,424 fractures were included in this meta-analysis. Overall, the AF patients treated with DOACs tend to present a lower risk of any fracture compared with those treated with warfarin (relative ratio: 0.82, 95% confidence interval (CI): 0.74-0.91). Sub-analyses for each individual DOAC indicate that apixaban and rivaroxan are associated with lower risk of any fracture compared with warfarin (HR: 0.75, 95% CI: 0.60-0.92, and HR: 0.79, 95% CI: 0.71-0.88, respectively). CONCLUSION: this meta-analysis suggests that DOAC users have a lower risk of fractures than the warfarin users. The results of this study may provide optimal anticoagulation opportunities for AF patients with high fracture risk factors.

Changes of Migration, Immunoregulation and Osteogenic Differentiation of Mesenchymal Stem Cells in Different Stages of Inflammation.

Bone infection has always been the focus of orthopedic research. Mesenchymal stem cells (MSCs) are the natural progenitors of osteoblasts, and the process of osteogenesis is triggered in response to different signals from the extracellular matrix. MSCs exert important functions including secretion and immune regulation and also play a key role in bone regeneration. The biological behavior of MSCs in acute and chronic inflammation, especially the transformation between acute inflammation and chronic inflammation, has aroused great interest among researchers. This paper reviews the recent literature and summarizes the behavior and biological characteristics of MSCs in acute and chronic inflammation to stimulate further research on MSCs and treatment of bone diseases.

Recent Advances in Osteoclast Biological Behavior.

With the progress of the aging population, bone-related diseases such as osteoporosis and osteoarthritis have become urgent problems. Recent studies have demonstrated the importance of osteoclasts in bone homeostasis, implying these will be an important mediator in the treatment of bone-related diseases. Up to now, several reviews have been performed on part of osteoclast biological behaviors such as differentiation, function, or apoptosis. However, few reviews have shown the complete osteoclast biology and research advances in recent years. Therefore, in this review, we focus on the origin, differentiation, apoptosis, behavior changes and coupling signals with osteoblasts, providing a simple but comprehensive overview of osteoclasts for subsequent studies.

Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups.

Cellular associations in the bone microenvironment are involved in modulating the balance between bone remodeling and resorption, which is necessary for maintaining a normal bone morphology. Macrophages and osteoclasts are both vital components of the bone marrow. Macrophages can interact with osteoclasts and regulate bone metabolism by secreting a variety of cytokines, which make a significant contribution to the associations. Although, recent studies have fully explored either macrophages or osteoclasts, indicating the significance of these two types of cells. However, it is of high importance to report the latest discoveries on the relationships between these two myeloid-derived cells in the field of osteoimmunology. Therefore, this paper reviews this topic from three novel aspects of the origin, polarization, and subgroups based on the previous work, to provide a reference for future research and treatment of bone-related diseases.

MicroRNAs as Biomarkers for the Diagnosis of Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

Background: Abnormal expression levels of microRNAs (miRNAs) were observed in ankylosing spondylitis (AS) in recent articles, suggesting that miRNAs may be used as biomarkers for AS diagnoses. In this paper, we conducted a meta-analysis to identify the overall diagnostic accuracy of miRNA biomarkers in AS patients. Methods: An extensive search was undertaken in PubMed, Embase, Cochrane databases, and Wan Fang database up to 30 December 2020 using the following key words: ("microRNAs" or "microRNA" or "miRNA" or "miR" or "RNA, Micro" or "Primary MicroRNA") and ("Spondylitis Ankylosing" or "Spondyloarthritis Ankylopoietica" or "Ankylosing Spondylarthritis" or "Ankylosing Spondylarthritides" or "Spondylarthritides Ankylosing" or "Ankylosing Spondylitis") and ("blood" or "serum" or "plasma"). Statistical evaluation of dysregulated miRNAs using the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the curve (AUC). Results: Twenty-nine articles reporting on the miRNAs of AS were included. A total of 42 miRNAs were observed to be up-regulated and 45 miRNAs were down-regulated in the AS cases compared with the controls. Besides, 29 studies from nine articles were included in our meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0. 76 (95% CI, 0.70-0.81), 0.80 (95% CI, 0.74-0.85), 3.75 (95% CI, 2.82-5.01), 0.30 (95% CI, 0.24-0.39), 12.32 (95% CI, 7.65-19.83), 0.85 (95% CI, 0.81-0.88), respectively, suggesting a good diagnostic accuracy of miRNAs for AS. Conclusions: Circulating miRNAs are deregulated in AS patients. miRNAs may be used as a relatively non-invasive biomarkers for the detection of AS.

Acid-Suppressive Drugs and Risk of Fracture in Children and Young Adults: A Meta-Analysis of Observational Studies.

Background: Recent studies have suggested that proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) may increase the risk of fracture. We performed a meta-analysis to evaluate the risk of fracture with PPIs and H2RAs use in children and young adults. Methods: PubMed, EMBASE database, Cochrane Library, and Web of Science for relevant articles published before May 2021 were searched. We included all the observational studies reporting on the risk of fracture with acid-suppressive drug (PPIs and H2RAs) use in children and young adults. We calculated pooled risk ratios (RRs) for fracture using random-effects models and conducted subgroup analyses. Results: A total of six studies were included in our analysis. Pooled analysis of PPIs use showed significant risk for fracture (RR = 1.23; 95% CI, 1.12-1.34; I 2 = 79.3), but not significant for PPIs combined with H2RAs use (RR = 1.22; 95% CI, 0.94-1.60; I 2 = 44.0%), as well as for H2RAs use alone (RR = 1.08; 95% CI, 0.94-1.24; I 2 = 84.1%). Grouping of studies by region showed a significantly increased fracture risk with PPIs use in North America (RR = 1.24; 95% CI, 1.16-1.32; I 2 =0.0%) than in Europe (RR = 1.23; 95% CI, 1.00-1.52; I 2 = 94.6%) and Asia (RR = 1.10; 95% CI, 0.96-1.25). However, there was no significant association between the H2RAs use and the fracture risk in North America (RR = 1.08; 95% CI, 1.00-1.09; I 2 = 0.0%). Moreover, PPIs use showed an increased risk of fracture in women (RR = 1.13; 95% CI, 1.07-1.19; I 2 = 0.0%), whereas there was no significant association between the PPIs use and the risk of fracture in men (RR = 0.93; 95% CI, 0.66-1.31; I 2 = 0.0%). Conclusion: PPIs use alone could increase the risk of fracture in children and young adults, but not for PPIs combined with H2RAs use or H2RAs use alone. Clinicians should exercise caution when prescribing PPIs for patients.

Genetic Determinants for Bacterial Osteomyelitis: A Focused Systematic Review of Published Literature.

Background: Osteomyelitis is an inflammatory process characterized by progressive bone destruction. Moreover, chronic bacterial osteomyelitis is regarded as a difficult-to-treat clinical entity due to its long-standing course and frequent infection recurrence. However, the role of genetic factors in the occurrence and development of bacterial osteomyelitis is poorly understood. Methods: We performed a systematic review to assess the frequency of individual alleles and genotypes of single-nucleotide polymorphisms (SNPs) among patients with bacterial osteomyelitis and healthy people to identify whether the SNPs are associated with the risk of developing bacterial osteomyelitis. Then, gene ontology and Kyoto Encyclopedia of Gene and Genomes analyses were performed to identify the potential biological effects of these genes on the pathogenesis of bacterial osteomyelitis. Result: Fourteen eligible studies containing 25 genes were analyzed. In this review, we discovered that the SNPs in IL1B, IL6, IL4, IL10, IL12B, IL1A, IFNG, TNF, PTGS2, CTSG, vitamin D receptor (VDR), MMP1, PLAT, and BAX increased the risk of bacterial osteomyelitis, whereas those in IL1RN and TLR2 could protect against osteomyelitis. The bioinformatic analysis indicated that these osteomyelitis-related genes were mainly enriched in inflammatory reaction pathways, suggesting that inflammation plays a vital role in the development of bacterial osteomyelitis. Furthermore, functional notation for 25 SNPs in 17 significant genes was performed using the RegulomeDB and NCBI databases. Four SNPs (rs1143627, rs16944, rs2430561, and rs2070874) had smaller scores from regulome analysis, implying significant biological function. Conclusion: We systematically summarized several SNPs linked to bacterial osteomyelitis and discovered that these gene polymorphisms could be a genetic factor for bacterial osteomyelitis. Moreover, further large-scale cohort studies are needed to enhance our comprehensive understanding of the development of osteomyelitis to provide earlier individualized preventions and interventions for patients with osteomyelitis in clinical practice.

Brachial muscle injury resulting in acute compartment syndrome of the upper arm: a case report and literature review.

BACKGROUND: Acute compartment syndrome (ACS) is a potentially devastating condition. ACS is rare in the upper arm. CASE PRESENTATION: We report a case of acute compartment syndrome of the anterior compartment of the upper arm due to brachial muscle injury. The patient experienced abnormal progressive swelling and pain in his right upper arm, and passive pulling pain of the right wrist and right hand. It was highly suspected to be right upper arm compartment syndrome, and was confirmed by surgery. The patient transferred to the emergency operating room for fasciotomy that was performed under general anesthesia using the anterolateral approach. The brachial muscle was found to be heavily swollen and had the greatest tension. The brachial muscle fibers were split lengthwise, and a large amount of hematoma was cleared. The brachial muscles were injured and partly ruptured. After full decompression, a negative pressure drainage device was used to cover the wound in the first stage. Ten days after injury, the swelling of the affected limb subsided and the wound was sutured. The patient's limbs completely recovered to normal. The shoulder and elbow joints could move freely and the patient resumed normal farming work ability. CONCLUSION: Clinicians should fully recognize the fact that acute compartment syndrome can occur in the upper arm, rather than only the forearm and leg, and therefore avoid serious consequences caused by missed diagnosis and misdiagnosis.