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All fracture repairs start with the innate immune system with the inflammatory response known as the inflammatory stage guided and driven by the secretion of chemokine by the ruptured tissue, followed by the sequential recruitment of neutrophils, monocytes and macrophages. These innate immune cells would infiltrate the fracture site and secrete inflammatory cytokines to stimulate recruitment of more immune cells to arrive at the fracture site coordinating subsequent stages of the repair process. In which, subsidence of pro-inflammatory M1 macrophage and transformation to anti-inflammatory M2 macrophages promotes osteogenesis that marks the start of the anabolic endochondral stage.Literature search was performed on Pubmed, Embase, and Web of Science databases (last accessed 15th April 2021) using "macrophage AND fracture". Review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.Eleven pre-clinical animal studies out of 429 articles were included in this systematic review according to our inclusion and exclusion criteria. All of which investigated interventions targeting to modulate the acute inflammatory response and macrophage polarization as evident by various markers in association with fracture healing outcomes.This systematic review summarizes attempts to modulate the innate immune response with focuses on promoting macrophage polarization from M1 to M2 phenotype targeting the enhancement of fracture injury repair. Methods used to achieve the goal may include applications of damage-associated molecular pattern (DAMP), pathogen-associated molecular pattern (PAMP) or mechanical stimulation that hold high translational potentials for clinical application in the near future.

Sarcopenia is a hallmark of the ageing process, which is characterized by the decline in muscle mass and strength. Growing evidence indicates that mitochondria dysfunction play core roles in this process. Meanwhile, physical exercise is regarded as one of the efficiency therapies to attenuate sarcopenia via regulating mitochondrial function during ageing. However, the specific mechanisms among exercise, mitochondrial function and sarcopenia are still unclear. The aim of this systematic review is to delineate the effects of physical exercise on mitochondria during ageing in order to explore potential target for rescuing sarcopenia.A systematic literature search was performed in PubMed, Embase and Web of Science. Information was extracted from the included studies for review.In this review, 16 pre-clinical studies were included and 105 clinical studies that were not mechanistic research were excluded. 16 pre-clinical studies provided evidence that physical exercise could affect mitochondrial quality control to attenuate sarcopenia. Most of the included studies described the important role of mitochondrial dynamic equilibrium in sarcopenia and showed that effective physical exercise could influence mitochondrial biogenesis, fusion, fission and mitophagy to attenuate sarcopenia in aged animal.This systematic review provides an up-to-date sequential overview and highlights the link in the potential mitochondria-related target and physical exercise in aged animal.Currently, there is no standard treatment method for sarcopenia. This systematic review revealed the underlying mechanisms for how physical exercise improved muscle performance via regulating mitochondrial dynamic equilibrium, which could provide scientific support for using exercise as a timely intervention for sarcopenia. Additionally, this systematic review allows a better understanding of mitochondrial dynamic equilibrium and exercise for future development of new therapeutic interventions to attenuate sarcopenia.

BackgroundElderly people with low lean and high fat mass, are diagnosed with sarcopenic obesity (SO), and often have poor clinical outcomes. This study aimed to explore the relationship between obesity and sarcopenia, and the optimal proportion of fat and muscle for old individuals.MethodsParticipants aged 60 years or above were instructed to perform bioelectrical impedance analysis to obtain the muscle and fat indicators, and handgrip strength was also performed. Sarcopenia was diagnosed according to predicted appendicular skeletal muscle mass and function. Body mass index (BMI) and body fat percentage (BF%) were used to define obesity. The association of muscle and fat indicators were analyzed by Pearson’s correlation coefficient. Pearson Chi-Square test was utilized to estimate odds ratios (OR) and 95% confidence intervals (CI) on the risk of sarcopenia according to obesity status.Results1637 old subjects (74.8 ± 7.8 years) participated in this study. Not only fat mass, but also muscle indicators were positively correlated to BMI and body weight (p < 0.05). Absolute muscle and fat mass in different positions had positive associations (p < 0.05). Muscle mass and strength were negatively related to appendicular fat mass percentage (p < 0.05). When defined by BMI (OR = 0.69, 95% CI [0.56, 0.86]; p = 0.001), obesity was a protective factor for sarcopenia, whilst it was a risk factor when using BF% (OR = 1.38, 95% CI [1.13, 1.69]; p = 0.002) as the definition. The risk of sarcopenia reduced with the increase of BMI in both genders. It was increased with raised BF% in males but displayed a U-shaped curve for females. BF% 26.0–34.6% in old females and lower than 23.9% in old males are recommended for sarcopenia and obesity prevention.ConclusionSkeletal muscle mass had strong positive relationship with absolute fat mass but negative associations with the percentage of appendicular fat mass. Obesity was a risk factor of sarcopenia when defined by BF% instead of BMI. The management of BF% can accurately help elderly people prevent against both sarcopenia and obesity.

Aims With the ageing population, fragility fractures have become one of the most common conditions. The objective of this study was to investigate whether microbiological outcomes and fracture-healing in osteoporotic bone is worse than normal bone with fracture-related infection (FRI). Methods A total of 120 six-month-old Sprague-Dawley (SD) rats were randomized to six groups: Sham, sham + infection (Sham-Inf), sham with infection + antibiotics (Sham-Inf-A), ovariectomized (OVX), OVX + infection (OVX-Inf), and OVX + infection + antibiotics (OVX-Inf-A). Open femoral diaphysis fractures with Kirschner wire fixation were performed. Staphylococcus aureus at 4 × 104 colony-forming units (CFU)/ml was inoculated. Rats were euthanized at four and eight weeks post-surgery. Radiography, micro-CT, haematoxylin-eosin, mechanical testing, immunohistochemistry (IHC), gram staining, agar plating, crystal violet staining, and scanning electron microscopy were performed. Results Agar plating analysis revealed a higher bacterial load in bone (p = 0.002), and gram staining showed higher cortical bone colonization (p = 0.039) in OVX-Inf compared to Sham-Inf. OVX-Inf showed significantly increased callus area (p = 0.013), but decreased high-density bone volume (p = 0.023) compared to Sham-Inf. IHC staining showed a significantly increased expression of TNF-α in OVX-Inf compared to OVX (p = 0.049). Significantly reduced bacterial load on bone (p = 0.001), enhanced ultimate load (p = 0.001), and energy to failure were observed in Sham-Inf-A compared to Sham-Inf (p = 0.028), but not in OVX-Inf-A compared to OVX-Inf. Conclusion In osteoporotic bone with FRI, infection was more severe with more bone lysis and higher bacterial load, and fracture-healing was further delayed. Systemic antibiotics significantly reduced bacterial load and enhanced callus quality and strength in normal bone with FRI, but not in osteoporotic bone. Cite this article: Bone Joint Res 2022;11(2):49–60.

ObjectivesThe aim of this study was to discover the role of fat and muscle in bone structures, as well as the relationship between obesity and sarcopenia on age-related osteoporosis.MethodsA total of 400 participants (65.0 ± 8.2 years old, 42.3% women) were recruited. Fat, muscle, bone parameters, basic demographics, medical history, physical performance and activity, and calcium intake of participants were obtained from datasets. The diagnosis of osteoporosis, sarcopenia, and obesity was based on current recommendations. Pearson correlation, non-linear regression models, and decision tree analyses were performed to study the relationship between fat, muscle, and bone. Logistic regression analyses were used to explore the risk of osteoporosis in old people with obesity or sarcopenia via Model 1 (unadjusted) and Model 2 (adjusted by age, physical activity, and calcium intake).ResultsCorrelation analysis showed that limb muscle mass and index, and age were best related to bone mineral density (BMD) (|r| = 0.386–0.632, p < 0.001). On the contrary, body mass index (BMI) and increased body fat percentage (BF%) were harmful for bone health. An increase of BMI and fat mass index slowed the increase of BMD in the spine, while skeletal muscle mass index accelerated the increase. People with sarcopenia had low muscle mass and strength. When separating subjects into sarcopenia and non-sarcopenia status, sarcopenia was independently related to higher risks of osteoporosis in both models (OR > 1, p < 0.05). BMI-defined obesity in Model 1 as well as BF%-defined obesity in both models did not reduce the risk of osteoporosis in both models (p > 0.05). The decision tree classification (85% accuracy) showed that greater body weight and larger lower limb muscle performance were negatively related to osteoporosis, while fat mass and percentage did not play roles in this prediction.ConclusionLow muscle mass and function were harmful to bone health. Obesity defined by both BMI and BF% had limited protective roles in osteoporosis. The benefits for bone from increased muscle mass and function play a more superior role than increased fat mass in old people. Sarcopenia prevention and treatment instead of controlling obesity should be recommended as an approach to reduce the risks of age-related osteoporosis and fragility fracture for elderly people.

Background Gut microbiota dysbiosis and sarcopenia commonly occur in the elderly. Although the concept of the gut–muscle axis has been raised, the casual relationship is still unclear. This systematic review analyses the current evidence of gut microbiota effects on muscle/sarcopenia. Methods A systematic review was performed in PubMed, Embase, Web of Science, and The Cochrane Library databases using the keywords (microbiota* OR microbiome*) AND (sarcopen* OR muscle). Studies reporting the alterations of gut microbiota and muscle/physical performance were analysed. Results A total of 26 pre‐clinical and 10 clinical studies were included. For animal studies, three revealed age‐related changes and relationships between gut microbiota and muscle. Three studies focused on muscle characteristics of germ‐free mice. Seventy‐five per cent of eight faecal microbiota transplantation studies showed that the recipient mice successfully replicated the muscle phenotype of donors. There were positive effects on muscle from seven probiotics, two prebiotics, and short‐chain fatty acids (SCFAs). Ten studies investigated on other dietary supplements, antibiotics, exercise, and food withdrawal that affected both muscle and gut microbiota. Twelve studies explored the potential mechanisms of the gut–muscle axis. For clinical studies, 6 studies recruited 676 elderly people (72.8 ± 5.6 years, 57.8% female), while 4 studies focused on 244 young adults (29.7 ± 7.8 years, 55.4% female). The associations of gut microbiota and muscle had been shown in four observational studies. Probiotics, prebiotics, synbiotics, fermented milk, caloric restriction, and exercise in six studies displayed inconsistent effects on muscle mass, function, and gut microbiota. Conclusions Altering the gut microbiota through bacteria depletion, faecal transplantation, and various supplements was shown to directly affect muscle phenotypes. Probiotics, prebiotics, SCFAs, and bacterial products are potential novel therapies to enhance muscle mass and physical performance. Lactobacillus and Bifidobacterium strains restored age‐related muscle loss. Potential mechanisms of microbiome modulating muscle mainly include protein, energy, lipid, and glucose metabolism, inflammation level, neuromuscular junction, and mitochondrial function. The role of the gut microbiota in the development of muscle loss during aging is a crucial area that requires further studies for translation to patients.

Aims The use of 3D printing has become increasingly popular and has been widely used in orthopaedic surgery. There has been a trend towards an increasing number of publications in this field, but existing literature incorporates limited high-quality studies, and there is a lack of reports on outcomes. The aim of this study was to perform a scoping review with Level I evidence on the application and effectiveness of 3D printing. Methods A literature search was performed in PubMed, Embase, and Web of Science databases. The keywords used for the search criteria were ((3d print*) OR (rapid prototyp*) OR (additive manufactur*)) AND (orthopaedic). The inclusion criteria were: 1) use of 3D printing in orthopaedics, 2) randomized controlled trials, and 3) studies with participants/patients. Risk of bias was assessed with Cochrane Collaboration Tool and PEDro Score. Pooled analysis was performed. Results Overall, 21 studies were included in our study with a pooled total of 932 participants. Pooled analysis showed that operating time (p < 0.001), blood loss (p < 0.001), fluoroscopy times (p < 0.001), bone union time (p < 0.001), pain (p = 0.040), accuracy (p < 0.001), and functional scores (p < 0.001) were significantly improved with 3D printing compared to the control group. There were no significant differences in complications. Conclusion 3D printing is a rapidly developing field in orthopaedics. Our findings show that 3D printing is advantageous in terms of operating time, blood loss, fluoroscopy times, bone union time, pain, accuracy, and function. The use of 3D printing did not increase the risk of complications. Cite this article: Bone Joint Res 2021;10(12):807–819.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and bone structural deterioration that may result in fragility fractures. Use of bone imaging modalities to accurately predict fragility fractures is always an important issue, yet the current gold standard of dual-energy X-ray absorptiometry (DXA) for diagnosis of osteoporosis cannot fully satisfy this purpose. The latest high-resolution peripheral quantitative computed tomography (HR-pQCT) is a three-dimensional (3D) imaging device to measure not only volumetric bone density, but also the bone microarchitecture in a noninvasive manner that may provide a better fracture prediction power. This systematic review and meta-analysis was designed to investigate which HR-pQCT parameters at the distal radius and/or distal tibia could best predict fragility fractures. A systematic literature search was conducted in Embase, PubMed, and Web of Science with relevant keywords by two independent reviewers. Original clinical studies using HR-pQCT to predict fragility fractures with available full text in English were included. Information was extracted from the included studies for further review. In total, 25 articles were included for the systematic review, and 16 articles for meta-analysis. HR-pQCT was shown to significantly predict incident fractures and/or major osteoporotic fractures (MOFs). Of all the HR-pQCT parameters, our meta-analysis revealed that cortical volumetric bone mineral density (Ct.vBMD), trabecular thickness (Tb.Th), and stiffness were better predictors. Meanwhile, HR-pQCT parameters indicated better performance in predicting MOFs than incident fractures. Between the two standard measurement sites of HR-pQCT, the non-weight-bearing distal radius was a more preferable site than distal tibia for fracture prediction. Furthermore, most of the included studies were white-based, whereas very few studies were from Asia or South America. These regions should build up their densitometric databases and conduct related prediction studies. It is expected that HR-pQCT can be used widely for the diagnosis of osteoporosis and prediction of future fragility fractures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Background This study aimed to adjust and cross‐validate skeletal muscle mass measurements between bioimpedance analysis (BIA) and dual‐energy X‐ray absorptiometry (DXA) for the screening of sarcopenia in the community and to estimate the prevalence of sarcopenia in Hong Kong. Methods Screening of sarcopenia was provided to community‐dwelling older adults. Appendicular skeletal muscle mass (ASM) was evaluated by BIA (InBody 120 or 720) and/or DXA. Handgrip strength and/or gait speed were assessed. Diagnosis of sarcopenia was based on the 2019 revised Asian Working Group for Sarcopenia cut‐offs. Agreement analysis was performed to cross‐validate ASM measurements by BIA and DXA. Multiple regression was used to explore contribution of measured parameters in predicting DXA ASM from BIA. Results A total of 1587 participants (age = 72 ± 12 years) were recruited; 1065 participants were screened by BIA (InBody 120) with 18 followed up by DXA, while the remaining 522 participants were assessed by the BIA (InBody 720) and DXA. The appendicular skeletal muscle mass index (ASMI) evaluated by BIA showed a mean difference of 2.89 ± 0.38 kg/m2 (InBody 120) and 2.97 ± 0.45 kg/m2 (InBody 720) against DXA gold standard. A significant overestimation of muscle mass was measured by BIA compared with DXA (P

Aging and obesity are two global concerns in public health. Sarcopenic obesity (SO), defined as the combination of age-related sarcopenia and obesity, has become a pressing issue. This systematic review and meta-analysis summarize the current clinical evidence relevant to SO. PubMed, Embase, and Web of Science were searched, and 106 clinical studies with 167,151 elderlies were included. The estimated prevalence of SO was 9% in both men and women. Obesity was associated with 34% reduced risk of sarcopenia (odds ratio [OR] 0.66, 95% CI 0.48-0.91; p 0.001). The pooled hazard ratio (HR) of all-cause mortality was 1.51 (95% CI 1.14-2.02; p 0.001) for people with SO compared with healthy individuals. SO was associated with increased risk of cardiovascular disease and related mortality, metabolic disorders, cognitive impairment, arthritis, functional limitation, and lung diseases (all ORs 1.0, p 0.05). The attenuated risk of sarcopenia in elderlies with obesity ("obesity paradox") was dependent on higher muscle mass and strength. Apart from unifying the diagnosis of SO, more research is needed to subphenotype people with obesity and sarcopenia for individualized treatment. Meanwhile, the maintenance of proper body composition of muscle and fat may delay or attenuate the adverse outcomes of aging.

The prevalence of osteoporotic fracture is high due to global aging problem. Delayed and impaired healing in osteoporotic fractures increase the socioeconomic burden significantly. Through intensive animal and clinical research in recent years, the pathogenesis of osteoporotic fracture healing is unveiled, including decreased inflammatory response, reduced mesenchymal stem cells and deteriorated angiogenesis, etc. The enhancement of osteoporotic fracture healing is important in shortening hospitalization, thus reducing related complications. Mechanical stimulation is currently the most well-accepted approach for rehabilitation of osteoporotic fracture patients. Some new interventions providing mechanical signals were explored extensively in recent years, including vibration treatment, and osteoporotic fracture healing was found to respond very well to these signals. Vibration treatment could accelerate osteoporotic fracture healing with improved callus formation, mineralization and remodeling. However, the mechanism of how osteoporotic fracture bones sense mechanical signals and relay to bone formation remains unanswered. Osteocytes are the most abundant cells in bone tissues. Cumulative evidence confirm that osteocyte is a type of mechanosensory cell and shows altered morphology and reduced cell density during aging. Meanwhile, osteocytes serve as endocrine cells to regulate bone and mineral homeostasis. However, the contribution of osteocytes in osteoporotic fracture healing is largely unknown. A recent in vivo study was conducted to examine the morphological and functional changes of osteocytes after vibration treatment in an osteoporotic metaphyseal fracture rat model. The findings demonstrated that vibration treatment induced significant outgrowth of canaliculi and altered expression of various proteins (E11, DMP1, FGF23 and sclerostin), particularly osteocyte-specific dentin matrix protein 1 (DMP1) which was greatly increased. DMP1 may play a major role in relaying mechanical signals to bone formation, which may require further experiments to consolidate. Most importantly, vibration treatment significantly increased the mineralization and accelerated the osteoporotic fracture healing in metaphyseal fracture model. In summary, osteocyte is the major cell type to sense mechanical signals and facilitate downstream healing in osteoporotic fracture bone. Vibration treatment has good potential to be translated for clinical application to benefit osteoporotic fracture patients, while randomized controlled trials are required to validate its efficacy.

Low-intensity pulsed ultrasound (LIPUS) is a developing technology, which has been proven to improve fracture healing process with minimal thermal effects. This noninvasive treatment accelerates bone formation through various molecular, biological, and biomechanical interactions with tissues and cells. Although LIPUS treatment has shown beneficial effects on different bone fracture locations, only very few studies have examined its effects on deeper bones. This study provides an overview on therapeutic ultrasound for fractured bones, possible mechanisms of action, clinical evidences, current limitations, and its future prospects.

Aims The effect of the gut microbiota (GM) and its metabolite on bone health is termed the gut-bone axis. Multiple studies have elucidated the mechanisms but findings vary greatly. A systematic review was performed to analyze current animal models and explore the effect of GM on bone. Methods Literature search was performed on PubMed and Embase databases. Information on the types and strains of animals, induction of osteoporosis, intervention strategies, determination of GM, assessment on bone mineral density (BMD) and bone quality, and key findings were extracted. Results A total of 30 studies were included, of which six studies used rats and 24 studies used mice. Osteoporosis or bone loss was induced in 14 studies. Interventions included ten with probiotics, three with prebiotics, nine with antibiotics, two with short-chain fatty acid (SCFA), six with vitamins and proteins, two with traditional Chinese medicine (TCM), and one with neuropeptide Y1R antagonist. In general, probiotics, prebiotics, nutritional interventions, and TCM were found to reverse the GM dysbiosis and rescue bone loss. Conclusion Despite the positive therapeutic effect of probiotics, prebiotics, and nutritional or pharmaceutical interventions on osteoporosis, there is still a critical knowledge gap regarding the role of GM in rescuing bone loss and its related pathways. Cite this article: Bone Joint Res 2021;10(1):51–59.

Aims Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing. Methods A total of 144 rats were randomized to four groups: sham control; sham and LMHFV; ovariectomized (OVX); and ovariectomized and LMHFV (OVX-VT). Fibrinolytic potential was evaluated by quantifying fibrin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) along with healing outcomes at three days, one week, two weeks, and six weeks post-fracture. Results All rats achieved healing, and x-ray relative radiopacity for OVX-VT was significantly higher compared to OVX at week 2. Martius Scarlet Blue (MSB) staining revealed a significant decrease of fibrin content in the callus in OVX-VT compared with OVX on day 3 (p = 0.020). Mean tPA from muscle was significantly higher for OVX-VT compared to OVX (p = 0.020) on day 3. Mechanical testing revealed the mean energy to failure was significantly higher for OVX-VT at 37.6 N mm (SD 8.4) and 71.9 N mm (SD 30.7) compared with OVX at 5.76 N mm (SD 7.1) (p = 0.010) and 17.7 N mm (SD 11.5) (p = 0.030) at week 2 and week 6, respectively. Conclusion Metaphyseal fracture healing is enhanced by LMHFV, and one of the important molecular pathways it acts on is fibrinolysis. LMHFV is a promising intervention for osteoporotic metaphyseal fracture healing. The improved mechanical properties, acceleration of fracture healing, and safety justify its role into translation to future clinical studies. Cite this article: Bone Joint Res 2021;10(1):41–50.

Summary: Objective: To analyze the effectiveness of exercise interventions on falls and fall-related fracture prevention among community-dwelling elderlies. Methods: Literature search was conducted in Pubmed and Embase. Keywords used for literature search were “fracture” AND “fall” AND “exercise”. Randomized controlled trials involving community-dwelling elderlies older than 60 years old with physical exercises as intervention were included. A systematic review and meta-analysis was performed. The primary outcomes were falls and fractures. Results: Twelve studies were included and 4784 participants were involved with a mean age of 75.4. The most common exercise interventions were strength and balance exercises. The results of meta-analysis of 11 studies showed that exercise intervention had beneficial effect on fall prevention (RR = 0.71, 95% CI, 0.62–0.82; I2 = 24%, p < 0.0001). The effect was better when exercise intervention applied to women participants (RR = 0.64, 95% CI, 0.49–0.83; I2 = 28%, p = 0.00009) compared to men and women participants (RR = 0.75, 95% CI, 0.64–0.89; I2 = 24%, p = 0.001). The results of meta-analysis of seven studies showed that physical exercise had significant effect on fracture prevention (RR = 0.54, 95% CI, 0.35–0.83; I2 = 25%, p = 0.005). However, the effect was significant when exercise intervention applied to women participants only (RR = 0.37, 95% CI, 0.20–0.67; I2 = 0%, p = 0.001) but not significant when exercise intervention applied to both genders (RR = 0.80, 95% CI, 0.58–1.09; I2 = 0%, p = 0.15). Conclusion: Exercise interventions, especially the combination of strength and balance training, were effective in preventing falls. Resistance exercises and jumping exercises were effective for fracture prevention among community-dwelling older population. The effectiveness of exercise interventions on fracture prevention have more significant effect on women. Further studies are needed to test the effectiveness of exercise interventions in men. Translational potential: The use of effective exercises or biophysical interventions including vibration therapy can be incorporated into Fracture Liaison Services to prevent future fall and fracture.

Objective Osteosynthesis-associated infection is a challenging complication post fracture fixation, burdening the patients and the orthopaedic surgeons alike. A clinically relevant animal model is critical in devising new therapeutic strategies. Our aim was to perform a systematic review to evaluate existing preclinical models and identify their applications in aspects of animal selection, bacterial induction, fracture fixation and complications. Methods A systematic literature research was conducted in PubMed and Embase up to February 2020. A total of 31 studies were included. Information on the animal, bacterial induction, fracture fixation, healing result and complications were extracted. Results Animals selected included murine (23), rabbit (6), ewe (1) and goat (1). Larger animals had enabled the use of human-sized implant, however small animals were more economical and easier in handling. Staphylococcus aureus (S. aureus) was the most frequently chosen bacteria for induction. Bacterial inoculation dose ranged from 102−8 ​CFU. Consistent and replicable infections were observed from 104 ​CFU in general. Methods of inoculation included injections of bacterial suspension (20), placement of foreign objects (8) and pretreatment of implants with established biofilm (3). Intramedullary implants (13), plates and screws (18) were used in most models. Radiological (29) and histological evaluations (24) in osseous healing were performed. Complications such as instability of fracture fixation (7), unexpected surgical death (5), sepsis (1) and persistent lameness (1) were encountered. Conclusion The most common animal model is the S. aureus infected open fracture internally fixated. Replicable infections were mainly from 104 ​CFU of bacteria. However, with the increase in antibiotic resistance, future directions should explore polymicrobial and antibiotic resistant strains, as these will no doubt play a major role in bone infection. Currently, there is also a lack of osteoporotic bone infection models and the pathophysiology is unexplored, which would be important with our aging population. The translational potential of this article This systematic review provides an updated overview and compares the currently available animal models of osteosynthesis-associated infections. A discussion on future research directions and suggestion of animal model settings were made, which is expected to advance the research in this field.

Background: Although emerging studies have provided evidence that osteocytes are actively involved in fracture healing, there is a general lack of a detailed understanding of the mechanistic pathway, cellular events and expression of markers at different phases of healing. Methods: This systematic review describes the role of osteocytes in fracture healing from early to late phase. Literature search was performed in PubMed and Embase. Original animal and clinical studies with available English full-text were included. Information was retrieved from the selected studies. Results: A total of 23 articles were selected in this systematic review. Most of the studies investigated changes of various genes and proteins expression patterns related to osteocytes. Several studies have described a constant expression of osteocyte-specific marker genes throughout the fracture healing cascade followed by decline phase with the progress of healing, denoting the important physiological role of the osteocyte and the osteocyte lacuno-canalicular network in fracture healing. The reports of various markers suggested that osteocytes could trigger coordinated bone healing responses from cell death and expression of proinflammatory markers cyclooxygenase-2 and interleukin 6 at early phase of fracture healing. This is followed by the expression of growth factors bone morphogenetic protein-2 and cysteine-rich angiogenic inducer 61 that matched with the neo-angiogenesis, chondrogenesis and callus formation during the intermediate phase. Tightly controlled regulation of osteocyte-specific markers E11/Podoplanin (E11), dentin matrix protein 1 and sclerostin modulate and promote osteogenesis, mineralisation and remodelling across different phases of fracture healing. Stabilised fixation was associated with the finding of higher number of osteocytes with little detectable bone morphogenetic proteins expressions in osteocytes. Sclerostin-antibody treatment was found to result in improvement in bone mass, bone strength and mineralisation. Conclusion: To further illustrate the function of osteocytes, additional longitudinal studies with appropriate clinically relevant model to study osteoporotic fractures are crucial. Future investigations on the morphological changes of osteocyte lacuno-canalicular network during healing, osteocyte-mediated signalling molecules in the transforming growth factor-beta-Smad3 pathway, perilacunar remodelling, type of fixation and putative biomarkers to monitor fracture healing are highly desirable to bridge the current gaps of knowledge.The translational potential of this article: This systematic review provides an up-to-date chronological overview and highlights the osteocyte-regulated events at gene, protein, cellular and tissue levels throughout the fracture healing cascade, with the hope of informing and developing potential new therapeutic strategies that could improve the timing and quality of fracture healing in the future. Keywords: Dentin matrix protein 1, Fracture healing, Lacuno-canalicular network, Osteocyte, Sclerostin, TGF-Beta-Smad3

Fragility fractures are related to the loss of bone integrity and deteriorated morphology of osteocytes. Our previous studies have reported that low-magnitude high-frequency vibration (LMHFV) promoted osteoporotic fracture healing. As osteocytes are known for mechanosensing and initiating bone repair, we hypothesized that LMHFV could enhance osteoporotic fracture healing through enhancing morphological changes in the osteocyte lacuna-canalicular network (LCN) and mineralization. A metaphyseal fracture model was established in female Sprague-Dawley rats to investigate changes in osteocytes and healing outcomes from early to late phase post-fracture. Our results showed that the LCN exhibited an exuberant outgrowth of canaliculi in the osteoporotic fractured bone at day 14 after LMHFV. LMHFV upregulated the E11, dentin matrix protein 1 (DMP1), and fibroblast growth factor 23 (FGF23), but downregulated sclerostin (Sost) in osteocytes. Moreover, LMHFV promoted mineralization with significant enhancements of Ca/P ratio, mineral apposition rate (MAR), mineralizing surface (MS/BS), and bone mineral density (BMD) in the osteoporotic group. Consistently, better healing was confirmed by microarchitecture and mechanical properties, whereas the enhancement in osteoporotic group was comparable or even greater than the normal group. This is the first report to reveal the enhancement effect of LMHFV on the osteocytes' morphology and functions in osteoporotic fracture healing.

Background Sarcopenia is an aging‐induced deterioration of skeletal muscle mass and function. Low‐magnitude high‐frequency vibration (LMHFV) was shown to improve muscle functions and β‐hydroxy‐β‐methylbutyrate (HMB) to increase muscle mass and strength. Muscle‐derived stem cells (MDSCs) are progenitor cells important for muscle regeneration. We hypothesized that LMHFV and HMB could retard sarcopenia by reducing fat infiltration through inhibiting adipogenesis in MDSCs. Methods Senescence‐accelerated mouse P8 male mice were randomized into control (CTL), HMB, LMHFV (VIB), and combined (COM) groups. Interventions started at age of month 7 and assessed at 1, 2, and 3 months post‐intervention by densitometry, histology, and functional tests. In vitro, MDSCs isolated from gastrocnemius of senescence‐accelerated mouse P8 mice were characterized, randomized into CTL, VIB, HMB, and COM groups, and assessed by oil red O staining, mRNA, and protein expression. Results At 2 months post‐intervention, percentage lean mass of HMB, VIB, and COM groups were significantly higher than CTL group. Twitch, tetanic, and specific tetanic forces of COM group were higher, while specific twitch force of both VIB and COM groups were higher. Grip strength of HMB, VIB, and COM groups were higher. Histologically, both VIB and COM groups presented lower oil red O area than CTL group. Type I muscle fibre in CTL group was higher than HMB, VIB, and COM groups. MDSC were detected in situ by immunofluorescence stain with stem cell antigen‐1 signals confirmed with higher β‐catenin expression in the COM group. The observations were also confirmed in vitro, MDSCs in the HMB, VIB, and COM groups presented lower adipogenesis vs. the CTL group. β‐Catenin mRNA and protein expressions were lower in the CTL group while their relationship was further validated through β‐catenin knock‐down approach. Conclusions Our results showed that combined LMHFV and HMB interventions enhanced muscle strength and decreased percentage fat mass and intramuscular fat infiltration as compared with either treatment alone. Additive effect of LMHFV and HMB was demonstrated in β‐catenin expression than either treatment in MDSCs and altered cell fate from adipogenesis to myogenesis, leading to inhibition of intramuscular lipid accumulation. Wnt/β‐catenin signalling pathway was found to be the predominant regulatory mechanism through which LMHFV and HMB combined treatment suppressed MDSCs adipogenesis.

Fracture liaison services (FLS) have been implemented worldwide, but we present one of the first reported experiences in China. Only 1 out of 226 patients had a secondary fracture within 1 year. This serves as a platform to improving solutions and decreasing imminent fractures for future use nationwide in China. INTRODUCTION Fracture liaison services (FLS) have been implemented worldwide but we present one of the first reported experiences in China. Vertebral fragility fracture is one of the earliest fracture to occur. The objective of this study was to implement a dedicated fracture service to decrease imminent fractures for future use nationwide in China. METHODS Patients 50 years or older with a recent vertebral compression fracture were recruited. All patients were offered investigation with DXA scan and blood taking. Treatment was provided with calcium and vitamin D supplements and denosumab injections. The primary outcome was the imminent fracture rate or the re-fracture rate occurring within 2 years of the initial one. Secondary outcomes were bone mineral density (BMD), treatment initiation, adherence to drug, compliance to follow-up, falls, mortality, pain, quality of life, pain-related disability with Roland-Morris Disability Questionnaire (RMDQ), and Oswestry Disability Index (ODI). RESULTS Two hundred twenty-six patients (n = 226) were analyzed. 0.4% (n = 1) had an imminent fracture within 2 years. 11.1% (n = 25) had a fall within 2 years, in which 1 resulted in a major osteoporotic fracture. 7.1% died (n = 16) within the 2-year time period. 97.8% (n = 221) underwent BMD investigation with an initial DXA scan. One hundred percent (n = 226) had treatment initiation and were prescribed with Denosumab injections. 89.8% (n = 203) were compliant and showed complete adherence to drug therapy over the 2 years. Pain, quality of life, and disability were significantly improved. CONCLUSION This is the first reported fracture liaison service for vertebral fracture patients reported in China. Future FLS should incorporate muscle and sarcopenic assessments as a routine, and also research on novel interventions in this area would significantly improve patient outcomes.

Cement arterio-venogram is a rare event with cement extrusion into femoral nutrient vessels. In literature it is known to be benign with no significant clinical sequelae. It is postulated that it is due to high cement implantation pressure, that results in optimal cement filling quality. All previously reported cases were female patients, and it is thought to be a female only phenomenon due to the relatively narrow femoral canal leading to higher pressures during cementation. In this case series we report 3 cases different to existing literature. All 3 patients showed a cement arterio-venogram together with bone cement implantation syndrome and hypotension intraoperatively. It was also observed that during implantation the cement was of low viscosity. We postulate low cement viscosity during implantation with pressurization is also a contributing factor to these phenomena. This case series also demonstrates the first 2 male cases, showing this the even can occur in males too. The cement arteriovenogram is located at 41%-42% femur length which is within the 'third sixth' of the length of the femur. Good cementation techniques and prevention is also highlighted in this report.

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

Background There are more than 300,000 hip fractures yearly in the USA with mortality rates of 20% within 1 year. The treatment of osteoporotic fractures is a major challenge as bone quality is poor, and healing is expected to delay due to the impaired healing properties with respect to bone formation, angiogenesis, and mineralization. Enhancement of osteoporotic fracture healing and function is therefore critical as a major goal in modern fracture management. Previous pre-clinical studies have shown that low-magnitude high-frequency vibration (LMHFV) accelerates osteoporotic fracture healing. The objective of this study is to investigate the effect of LMHFV on accelerating trochanteric hip fracture healing and functional recovery. Methods This is a randomized, double-blinded, placebo-controlled clinical trial to evaluate the effect of LMHFV in accelerating trochanteric hip fracture healing. All fractures undergo cephalomedullary nail fixation. The primary outcome of this study is time to fracture healing by X-ray. Computed tomography (CT) and dual-energy X-ray absorptiometry (DXA) will also be performed. Blood circulation at the fracture site will be assessed by dynamic perfusion magnetic resonance (MR). Clinical results include functional recovery by muscle strength, timed up and go test (TUG), quality of life questionnaire (SF-36), balancing, falls, and mortality. Discussion Previous animal studies have demonstrated LMHFV to improve both normal and osteoporotic fracture healing by accelerating callus formation and mineralization. The mechanical stimulation stimulates angiogenesis by significantly enhancing vascular volume and blood flow velocity. This is the first study to translate LMHFV to enhancing hip fracture healing clinically. Positive results would provide a huge impact in the recovery of hip fracture patients and save healthcare costs. Trial registration Clinicaltrials.gov NCT04063891. Registered on August 21, 2019

Fracture liaison services (FLS) have been implemented worldwide, but we present one of the first reported experiences in China. Only 1 out of 226 patients had a secondary fracture within 1 year. This serves as a platform to improving solutions and decreasing imminent fractures for future use nationwide in China.Fracture liaison services (FLS) have been implemented worldwide but we present one of the first reported experiences in China. Vertebral fragility fracture is one of the earliest fracture to occur. The objective of this study was to implement a dedicated fracture service to decrease imminent fractures for future use nationwide in China.Patients 50 years or older with a recent vertebral compression fracture were recruited. All patients were offered investigation with DXA scan and blood taking. Treatment was provided with calcium and vitamin D supplements and denosumab injections. The primary outcome was the imminent fracture rate or the re-fracture rate occurring within 2 years of the initial one. Secondary outcomes were bone mineral density (BMD), treatment initiation, adherence to drug, compliance to follow-up, falls, mortality, pain, quality of life, pain-related disability with Roland-Morris Disability Questionnaire (RMDQ), and Oswestry Disability Index (ODI).Two hundred twenty-six patients (n = 226) were analyzed. 0.4% (n = 1) had an imminent fracture within 2 years. 11.1% (n = 25) had a fall within 2 years, in which 1 resulted in a major osteoporotic fracture. 7.1% died (n = 16) within the 2-year time period. 97.8% (n = 221) underwent BMD investigation with an initial DXA scan. One hundred percent (n = 226) had treatment initiation and were prescribed with Denosumab injections. 89.8% (n = 203) were compliant and showed complete adherence to drug therapy over the 2 years. Pain, quality of life, and disability were significantly improved.This is the first reported fracture liaison service for vertebral fracture patients reported in China. Future FLS should incorporate muscle and sarcopenic assessments as a routine, and also research on novel interventions in this area would significantly improve patient outcomes.

Sarcopenia is highly prevalent in fragility fracture patients and is associated with delayed healing. In this study, we investigated the effect of low-magnitude high-frequency vibration (LMHFV) on osteoporotic fracture with sarcopenia and the potential role of myostatin. Osteoporotic fractures created in sarcopenic SAMP8, non-sarcopenic SAMR1 were randomized to control or LMHFV (SAMP8, SAMR1, SAMP8-V, or SAMR1-V) groups. Healing and myostatin expression were evaluated at 2, 4, and 6 weeks post-fracture. In vitro, conditioned-media were collected from myofibers isolated from aged and young SAMP8 or C2C12 myoblasts with or without LMHFV. Osteoblastic MC3T3-E1 under osteogenic differentiation were treated with plain or conditioned-medium (±myostatin propeptide). LMHFV significantly enhanced callus formation was in non-sarcopenic SAMR1 mice; but the enhancement effect was not significant in SAMP8 mice at week 2. Myostatin expressions in callus and biceps femoris of SAMP8 group were significantly higher all groups with significant negative correlation with callus size (R2 = 0.7256; p = 0.0004). Mechanical properties (week 4) and callus remodeling (week 6) were inferior in SAMP8 versus SAMR1 and were significantly enhanced by LMHFV. Alkaline Phosphatase (ALP) and Runx2 expression of MC3T3-E1 was lower in aged myofiber compared with young, but upregulated by LMHFV or myostatin inhibition; also confirmed with C2C12. LMHFV enhanced early callus formation, microarchitecture, callus remodeling and mechanical properties of fracture healing in both SAMP8 and SAMR1; however, more effective in non-sarcopenic SAMR1 mice. Impaired fracture healing in sarcopenic SAMP8 mice is attributed by elevated myostatin expression in callus and muscle, which correlated negatively with callus formation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:277-287, 2020.

Most osteoporotic fractures occur at metaphyseal regions of long bones. The present study proposed a clinically relevant animal model that satisfied: i) induction of osteoporosis, ii) unilateral complete osteotomy at metaphysis, iii) internal fixation. 6 months old female Sprague-Dawley rats (n = 64) were randomly divided into the ovariectomised-metaphyseal osteotomy (OVX, n = 32) and metaphyseal osteotomy (SHAM, n = 32) groups. The metaphyseal-osteotomy model was created with a plate-fixation of the osteotomy and assessed by X-ray, micro-computed tomography, histomorphometry and mechanical testing at weeks 1, 3 and 6. X-ray results showed complete healing of metaphyseal osteotomy at week 6. Histology showed 3 stages of metaphyseal healing. Stage 1 was characterised by fibrous tissue, consisting of disorganised orientation of collagen fibres, and infiltration of immune cells. At stage 2, a transitional zone consisting of maturing fibrous tissue and differentiating mesenchymal cells with early trabecular bone formation and disorganised woven bone were observed. During stage 3, cortical bone ends unified and woven bone underwent transformation to lamellar bone. OVX group healing was significantly delayed when compared to SHAM samples. The study demonstrated that healing of osteoporotic osteotomy at the metaphyseal region was delayed in terms of radiography, histomorphometry and mechanical strength. These quantitative evaluations, along with histological features, may provide key references for future studies. The animal model may provide additional clinical relevance as most osteoporotic fracture in humans occurs at metaphyseal regions.

Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in patients. The endplate, the post-synaptic part of the neuromuscular junction (NMJ), occupies 0.1% of the myofiber surface area only, but is composed of millions of acetylcholine receptors (AChRs) that are efficient in binding to acetylcholine (ACh) and triggering skeletal muscle contraction. This systematic review aims to examine aging-associated alterations of post-synaptic AChRs, including morphology, function and related gene expression. A systematic literature search was conducted in PubMed, Embase and Web of Science with relevant keywords by two independent reviewers. Original pre-clinical and clinical studies regarding AChRs changes during aging with available full text and written in English were included. Information was extracted from the included studies for further review. In total, 30 articles were included. Various parameters assessing AChRs alterations by radioassay, immunofluorescence, electrophysiology and mechanical test were reported. Endplate fragmentation and denervation were common in old skeletal muscles during aging. To ensure efficient NMJ transmission and force generation, type I or IIb muscle fibers tended to have increased ACh quanta releasing after electrical stimulations, while type IIa muscle fibers tended to have stronger binding between ACh and AChRs, but the overall function of AChRs was reduced during aging. Alterations of AChRs area depended on muscle type, species and the progress of muscle atrophy and type I muscles fibers tended to demonstrate enlarging AChRs areas. Myogenic regulator factors (MRFs) can regulate the expression of AChRs subunits, while decreased MRF4 may lead to expression changes of AChRs subunits during aging. Sarcoglycan-α can delay low-density lipoprotein receptor-related protein 4 (LRP4) degradation. This protein was increased in old muscles but still cannot suppress the degradation of LRP4. Investigating the role of these AChRs-related genes in the process of aging may provide a potential target to treat sarcopenia.

BackgroundOsteoporosis is an age-related disease with progressive loss of bone, leading to fragile bone. It is one of the major health issues in older adults and causes medical, social and economic impacts globally. Patients with osteoporosis have high risk of osteoporotic fractures. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical intervention providing whole-body mechanical stimulation. Previous studies showed that LMHFV is beneficial to muscle strength, postural control, balancing ability, new bone formation, spinal bone mineral density (BMD) and blood circulation. During the LMHFV treatment, older adults need to stand upright on the platform for 20 min/day. However, some physically weak elderlies with poor musculoskeletal ability cannot stand for a long period. Therefore, the design of vibration platform is modified for the disabled patients to treat at sitting position and the efficacy of LMHFV on this group of elderlies will be verified. It is hypothesised that new design of LMHFV is beneficial to wheelchair users in terms of vertebral BMD, muscle health and musculoskeletal functions.MethodsThis study is a single-blinded randomised controlled trial to investigate the effect of LMHFV on vertebral BMD, muscle health, balancing ability and functional ability in wheelchair users (mainly on wheelchair for outdoor activities). Healthy elderlies aged 65 years or above with walking difficulties and using wheelchair are eligible. Exclusion criteria are those: (1) who cannot stand and walk independently, (2) who have vibration treatment before, (3) with malignancy, (4) with acute fractures or severe osteoarthritis, (5) with cardiovascular concern such as with pacemaker in situ, (6) with chronic inflammatory conditions known to affect muscle metabolism such as rheumatoid arthritis and (7) with high frequency of physical activities, such as participants who participated in regular exercise five times a week or more. Recruited participants will be randomised to either LMHFV or control group. Participant assigned to LMHFV group will receive LMHFV (35 Hz, 0.3g (g=gravitational acceleration), 20 min/day, at least three times/week) for 6 months. The primary outcome is BMD at the lumbar spine to be assessed by dual-energy X-ray absorptiometry that is clinically recommended for the diagnosis of osteoporosis. All primary and secondary outcome assessments for all groups will be performed in the investigators’ institute at baseline and 6 months post treatment.DiscussionThis study aims to investigate the effects of LMHFV on wheelchair users. The findings of this study will help to confirm the efficacy of LMHFV on vertebral BMD, muscle health, balancing ability and functional outcomes in wheelchair using elderlies. LMHFV therapy is an intervention strategy that is easy to implement at the community healthcare level or individually at home that has previously been proven to reduce fall risk and muscle strength at the lower limb. The ultimate goal is to improve their bone and muscle quality of wheelchair users, as well as enhancing their quality of life.Trial registration numberClinicalTrials.gov (NCT04180267).