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Abstract Sarcopenia is a complex age-associated syndrome of progressive loss of muscle mass and strength. Although this condition is influenced by many factors, age-related changes in immune function including immune cell dynamics, and chronic inflammation contribute to its progression. The complex interplay between the immune system, gut-muscle axis, and autophagy further underscores their important roles in sarcopenia pathogenesis. Immunomodulation has emerged as a promising strategy to counteract sarcopenia. Traditional management approaches to treat sarcopenia including physical exercise and nutritional supplementation, and the emerging technologies of biophysical stimulation demonstrated the importance of immunomodulation and regulation of macrophages and T cells and reduction of chronic inflammation. Treatments to alleviate low-grade inflammation in older adults by modulating gut microbial composition and diversity further combat sarcopenia. Furthermore, some pharmacological interventions, nano-medicine, and cell therapies targeting muscle, gut microbiota, or autophagy present additional avenues for immunomodulation in sarcopenia. This narrative review explores the immunological underpinnings of sarcopenia, elucidating the relationship between the immune system and muscle during ageing. Additionally, the review discusses new areas such as the gut-muscle axis and autophagy, which bridge immune system function and muscle health. Insights into current and potential approaches for sarcopenia management through modulation of the immune system are provided, along with suggestions for future research directions and therapeutic strategies. We aim to guide further investigation into clinical immunological biomarkers and identify indicators for sarcopenia diagnosis and potential treatment targets to combat this condition. We also aim to draw attention to the importance of considering immunomodulation in the clinical management of sarcopenia.

The neuromuscular junction (NMJ) is a specialized chemical synapse that converts neural impulses into muscle action. Age-associated NMJ degeneration, which involves nerve terminal and postsynaptic decline, denervation, and loss of motor units, significantly contributes to muscle weakness and dysfunction. Although physical training has been shown to make substantial modifications in NMJ of both young and aged animals, the results are often influenced by methodological variables in existing studies. Moreover, there is still lack of strong consensus on the specific effects of exercise on improving the morphology and function of the ageing NMJ. Consequently, the purpose of this study was to conduct a systematic review to elucidate the effects of exercise training on NMJ compartments in the elderly.We conducted a systematic review using PubMed, Embase, and Web of Science databases, employing relevant keywords. Two independent reviewers selected studies that detailed NMJ changes during exercise in ageing, written in English, and available in full text.In total, 20 papers were included. We examined the altered adaptation of the NMJ to exercise, focusing on presynaptic and postsynaptic structures and myofibers in older animals or humans. Our findings indicated that aged NMJs exhibited different adaptive responses to physical exercise compared to younger counterparts. Endurance training, compared with resistance and voluntary exercise regimens, was found to have a more pronounced effect on NMJ structural remodeling, particularly in fast twitch muscle fibers. Physical exercise was observed to promote the formation and maintenance of acetylcholine receptor (AChR) clusters by increasing the recombinant docking protein 7 (Dok7) expression and stabilizing Agrin and lipoprotein receptor-related protein 4 (LRP4). These insights suggest that research on exercise-related therapies could potentially attenuate the progression of neuromuscular degeneration.Translational potential of this article: This systematic review provides a detailed overview of the effects of different types of physical exercise on improving NMJ in the elderly, providing scientific support for the timely intervention of muscle degeneration in the elderly by physical exercise, and providing help for the development of new therapeutic interventions in the future.

Abstract Aging of the global population increases the incidence of osteoporosis and associated fragility fractures, significantly impacting patient quality of life and healthcare costs. The acute inflammatory reaction is essential to initiate healing after injury. However, aging is associated with “inflammaging”, referring to the presence of systemic low-level chronic inflammation. Chronic inflammation impairs the initiation of bone regeneration in elderly patients. This review examines current knowledge of the bone regeneration process and potential immunomodulatory therapies to facilitate bone healing in inflammaging. Aged macrophages show increased sensitivity and responsiveness to inflammatory signals. While M1 macrophages are activated during the acute inflammatory response, proper resolution of the inflammatory phase involves repolarizing pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype associated with tissue regeneration. In aging, persistent chronic inflammation resulting from the failure of M1 to M2 repolarization leads to increased osteoclast activation and decreased osteoblast formation, thus increasing bone resorption and decreasing bone formation during healing. Inflammaging can impair the ability of stem cells to support bone regeneration and contributes to the decline in bone mass and strength that occurs with aging. Therefore, modulating inflammaging is a promising approach for improving bone health in the aging population. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may benefit bone regeneration in inflammation. Preconditioning MSCs with pro-inflammatory cytokines affects MSCs’ secretory profile and osteogenic ability. MSCs cultured under hypoxic conditions show increased proliferation rates and secretion of growth factors. Resolution of inflammation via local delivery of anti-inflammatory cytokines is also a potential therapy for bone regeneration in inflammaging. Scaffolds containing anti-inflammatory cytokines, unaltered MSCs, and genetically modified MSCs can also have therapeutic potential. MSC exosomes can increase the migration of MSCs to the fracture site and enhance osteogenic differentiation and angiogenesis. In conclusion, inflammaging can impair the proper initiation of bone regeneration in the elderly. Modulating inflammaging is a promising approach for improving compromised bone healing in the aging population.

Max L. Lee was not included as an author in the original publication [...]

BackgroundDysregulated inflammation is associated with many skeletal diseases and disorders, such as osteolysis, non-union of fractures, osteonecrosis, osteoarthritis and orthopaedic infections. We previously showed that continuous infusion of lipopolysaccharide (LPS) contaminated polyethylene particles (cPE) caused prolonged inflammation and impaired bone formation. However, the metabolic and bioenergetic processes associated with inflammation of bone are unknown. Mitochondria are highly dynamic organelles that modulate cell metabolism and orchestrate the inflammatory responses that involve both resident and recruited cells. Glycolytic reprogramming, the shift from oxidative phosphorylation (OXPHOS) to glycolysis causes inappropriate cell activation and function, resulting in dysfunctional cellular metabolism. We hypothesized that impaired immunoregulation and bone regeneration from inflammatory states are associated with glycolytic reprogramming and mitochondrial dysfunction in macrophages (Mφ) and mesenchymal stromal cells (MSCs).MethodsWe used the Seahorse XF96 analyzer and real-time qPCR to study the bioenergetics of Mφ and MSCs exposed to cPE. To understand the oxygen consumption rate (OCR), we used Seahorse XF Cell Mito Stress Test Kit with Seahorse XF96 analyzer. Similarly, Seahorse XF Glycolytic Rate Assay Kit was used to detect the extracellular acidification rate (ECAR) and Seahorse XF Real-Time ATP Rate Assay kit was used to detect the real-time ATP production rates from OXPHOS and glycolysis. Real-time qPCR was performed to analyze the gene expression of key enzymes in glycolysis and mitochondrial biogenesis. We further detected the gene expression of proinflammatory cytokines in Mφ and genes related to cell differentiation in MSC during the challenge of cPE.ResultsOur results demonstrated that the oxidative phosphorylation of Mφ exposed to cPE was significantly decreased when compared with the control group. We found reduced basal, maximal and ATP-production coupled respiration rates, and decreased proton leak in Mφ during challenge with cPE. Meanwhile, Mφ showed increased basal glycolysis and proton efflux rates (PER) when exposed to cPE. The percentage (%) of PER from glycolysis was higher in Mφ exposed to cPE, indicating that the contribution of the glycolytic pathway to total extracellular acidification was elevated during the challenge of cPE. In line with the results of OCR and ECAR, we found Mφ during cPE challenge showed higher glycolytic ATP (glycoATP) production rates and lower mitochondrial ATP (mitoATP) production rates which is mainly from OXPHOS. Interestingly, MSCs showed enhanced glycolysis during challenge with cPE, but no significant changes in oxygen consumption rates (OCR). In accordance, seahorse assay of real-time ATP revealed glycoATP rates were elevated while mitoATP rates showed no significant differences in MSC during challenge with cPE. Furthermore, Mφ and MSCs exposed to cPE showed upregulated gene expression levels of glycolytic regulators and Mφ exposed to cPE expressed higher levels of pro-inflammatory cytokines.ConclusionThis study demonstrated the dysfunctional bioenergetic activity of bone marrow-derived Mφ and MSCs exposed to cPE, which could impair the immunoregulatory properties of cells in the bone niche. The underlying molecular defect related to disordered mitochondrial function could represent a potential therapeutic target during the resolution of inflammation.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Novel minimally invasive strategies are needed to obtain robust bone healing in complex fractures and bone defects in the elderly population. Local cell therapy is one potential option for future treatment. Mesenchymal stromal cells (MSCs) are not only involved in osteogenesis but also help direct the recruitment of macrophages during bone regeneration via MSC-macrophage crosstalk. The C-C motif chemokine ligand 2 (CCL2) is an inflammatory chemokine that is associated with the migration of macrophages and MSCs during inflammation. This study investigated the use of CCL2 as a therapeutic target for local cell therapy. MSCs and macrophages were isolated from 10 to 12 week-old BALB/c male mice. Genetically modified CCL2 over-expressing MSCs were produced using murine CCL2-secreting pCDH-CMV-mCCL2-copGFP expressing lentivirus vector. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture. Cell migration assays were also performed. MSCs transfected with murine CCL2-secreting pCDH-CMV-mCCL2-copGFP expressing lentivirus vector showed higher levels of CCL2 secretion compared to unaltered MSCs (p < 0.05). Genetic manipulation did not affect cell proliferation. CCL2 did not affect the osteogenic ability of MSCs alone. However, acute (1 day) but not sustained (7 days) stimulation with CCL2 increased the alizarin red-positive area when MSCs were co-cultured with macrophages (p < 0.001). Both recombinant CCL2 (p < 0.05) and CCL2 released from MSCs (p < 0.05) facilitated macrophage migration. We demonstrated that acute CCL2 stimulation promoted subsequent osteogenesis in co-culture of MSCs and macrophages. Acute CCL2 stimulation potentially facilitates osteogenesis during the acute inflammatory phase of bone healing by directing local macrophage migration, fostering macrophage-MSC crosstalk, and subsequently, by activating or licensing of MSCs by macrophage pro-inflammatory cytokines. The combination of CCL2, MSCs, and macrophages could be a potential strategy for local cell therapy in compromised bone healing.

Joint replacement is a common surgery and is predominantly utilized for treatment of osteoarthritis in the aging population. The longevity of many of these implants depends on bony ingrowth. Here, we provide an overview of current techniques in osteogenesis (inducing bone growth onto an implant), which is affected by aging and inflammation. In this review we cover the biologic underpinnings of these processes as well as the clinical applications. Overall, aging has a significant effect at the cellular and macroscopic level that impacts osteosynthesis at bone-metal interfaces after joint arthroplasty; potential solutions include targeting prolonged inflammation, preventing microbial adhesion, and enhancing osteoinductive and osteoconductive properties.

Local cell therapy has recently gained attention for the treatment of joint diseases and fractures. Mesenchymal stem cells (MSCs) are not only involved in osteogenesis and angiogenesis, but they also have immunomodulatory functions, such as inducing macrophage migration during bone regeneration via macrophage crosstalk. C-C motif chemokine ligand 2 (CCL2), a known inflammatory mediator, is associated with the migration of macrophages during inflammation. This study examined the utility of CCL2 as a therapeutic target for local cell therapy. Using lentiviral vectors for rabbit MSCs, genetically modified CCL2 overexpressing MSCs were generated. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture, and cell migration assays were also performed. Additionally, co-cultures were performed with endothelial cells (ECs), and angiogenesis was evaluated using a tube formation assay. Overexpression of CCL2 did not affect bone formation under monoculture conditions but promoted chemotaxis and osteogenesis when co-cultured with macrophages. Furthermore, CCL2-overexpression promoted tube formation in co-culture with ECs. These results suggest that CCL2 induces macrophage chemotaxis and osteogenesis by promoting crosstalk between MSCs and macrophages; CCL2 also stimulates ECs to induce angiogenesis. These findings indicate that CCL2 may be a useful therapeutic target for local cell therapy in areas of bone loss.

Background: 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. Methods: A systematic literature search was performed in PubMed, Embase and Web of Science. Information was extracted from the included studies for review. Results: 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. Conclusions: 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. Translation of this article: 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.

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.

Abstract 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.

Abstract 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

Abstract The objective of this study was to investigate the prognostic factors predicting the ambulation recovery of fragility hip fracture patients. 2286 fragility hip fracture patients were collected from the Fragility Fracture Registry in Hong Kong. Predictive factors of ambulation deterioration including age, gender, pre-operation American Society of Anesthesiologists grade, pre-fracture mobility, delay to surgery, length of stay, fracture type, type of surgery, discharge destination and complications were identified. Patients with outdoor unassisted and outdoor with aids ambulatory function before fracture had 3- and 1.5-times increased risk of mobility deterioration, respectively (Odds Ratio (OR) = 2.556 and 1.480, 95% Confidence Interval (CI) 2.101–3.111 and 1.246–1.757, both p 14 days), early discharge (less than 6 days), and length of stay also did not increased risk of mobility decline. Male patients performed worse in terms of their mobility function after surgery compared to female patients (OR = 1.195, 95% CI 1.070–1.335, p = 0.002). This study identified that better premorbid good function, discharge to old age homes especially newly institutionalized patients, increased age, lower ASA score, and male patients, correlate with mobility deterioration at 1-year post-surgery. With the aging population and development of FLS, prompt identification of at-risk patients should be performed for prevention of deterioration.

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.

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.

Abstract 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.

Abstract Background Fractures of the distal radius are one of the most common osteoporotic fractures in elderly men and women. These fractures are a particular health concern amongst the elderly, who are at risk of fragility fractures, and are associated with long-term functional impairment, pain and a variety of complications. This is a sentinel event, as these fractures are associated with a two to four times increased risk of subsequent hip fractures in elderly patients. This is an important concept, as it is well established that these patients have an increased risk of falling. Fall prevention is therefore crucial to decrease further morbidity and mortality. The purpose of this study is to investigate the effect of low-magnitude high-frequency vibration (LMHFV) on postural stability and prevention of falls in elderly patients post distal radius fracture. Methods This is a prospective single-blinded randomized controlled trial. Two hundred patients will be recruited consecutively with consent, and randomized to either LMHFV (n = 100) or a control group (n = 100). The primary outcome is postural stability measured by the static and dynamic ability of patients to maintain centre of balance on the Biodex Balance System SD. Secondary outcomes are the occurrence of fall(s), the health-related quality of life 36-item short form instrument, the Timed Up and Go test for basic mobility skills, compliance and adverse events. Outcome assessments for both groups will be performed at baseline (0 month) and at 6 weeks, 3 months and 6 months time points. Discussion Previous studies have stressed the importance of reducing falls after distal radius fracture has occurred in elderly patients, and an effective intervention is crucial. Numerous studies have proven vibration therapy to be effective in improving balancing ability in normal patients; However, no previous study has applied the device for patients with fractures. Our study will attempt to translate LMHFV to patients with fractures to improve postural stability and prevent recurrent falls. Positive results would provide a large impact on the prevention of secondary fractures and save healthcare costs. Trial registration ClinicalTrials.gov, NCT03380884. Registered on 21 December 2017.

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.

The medical system of Hong Kong has been heavily affected by COVID-19. Adaptations are necessary to continue clinical care, education, and research, while minimising the risk of infection of our staff and students. Here, we report our early experience in response to the challenge posed by the COVID-19 pandemic. The translational potential of this article: This perspective can help to disseminate knowledge from an orthopaedic unit in a university hospital on overcoming the challenges of the COVID-19 pandemic, including clinical practice, education of medical students, and research.

Sarcopenia is an age-related geriatric syndrome characterized by the gradual loss of muscle mass and function. Low-magnitude high-frequency vibration (LMHFV) was shown to be beneficial to structural and functional outcomes of skeletal muscles, while magnesium (Mg) is a cofactor associated with better indices of skeletal muscle mass and strength. We hypothesized that LMHFV, Mg and their combinations could suppress inflammation and sarcopenic atrophy, promote myogenesis via PI3k/Akt/mTOR pathway in senescence-accelerated mouse P8 (SAMP8) mice and C2C12 myoblasts. Results showed that Mg treatment and LMHFV could significantly decrease inflammatory expression (C/EBPα and LYVE1) and modulate a CD206-positive M2 macrophage population at month four. Mg treatment also showed significant inhibitory effects on FOXO3, MuRF1 and MAFbx mRNA expression. Coapplication showed a synergistic effect on suppression of type I fiber atrophy, with significantly higher IGF-1, MyoD, MyoG mRNA (p < 0.05) and pAkt protein expression (p < 0.0001) during sarcopenia. In vitro inhibition of PI3K/Akt and mTOR abolished the enhancement effects on myotube formation and inhibited MRF mRNA and p85, Akt, pAkt and mTOR protein expressions. The present study demonstrated that the PI3K/Akt/mTOR pathway is the predominant regulatory mechanism through which LMHFV and Mg enhanced muscle regeneration and suppressed atrogene upregulation.

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.

Introduction Sarcopenia is a geriatric syndrome characterised by progressive loss of skeletal muscle mass and function with risks of adverse outcomes and becomes more prevalent due to ageing population. Elastic-band exercise, vibration treatment and hydroxymethylbutyrate (HMB) supplementation were previously proven to have positive effects on the control of sarcopenia. The purpose of this study is to evaluate the effectiveness of elastic-band exercise or vibration treatment with HMB supplementation in managing sarcopenia. Our findings will provide a safe and efficient strategy to mitigate the progression of sarcopenia in older people and contribute to higher quality of life as well as improved long-term health outcomes of elderly people.Methods and analysis In this single-blinded, randomised controlled trial (RCT), subjects will be screened for sarcopenia based on the Asian Working Group for Sarcopenia (AWGS) definition and 144 sarcopenic subjects aged 65 or above will be recruited. This RCT will have three groups evaluated at two time points to measure changes over 3 months—the control and the groups with combined HMB supplement and elastic-band resistance exercise or vibration treatment. Changes in muscle strength in lower extremity will be the primary outcome. Muscle strength in the upper extremity, gait speed, muscle mass (based on AWGS definition), functional performance in terms of balancing ability and time-up-and-go test and quality of life will be taken as secondary outcomes. In addition, each participant’s daily activity will be monitored by a wrist-worn activity tracker. Repeated-measures analysis of variance will be performed to compare within-subject changes between control and treatment groups at two time points of pretreatments and post-treatments.Ethics and dissemination The procedures have been approved by the Joint CUHK-NTEC Clinical Research Management Office (Ref. CREC 2018.602) and conformed to the Declaration of Helsinki. Results will be disseminated through peer-reviewed publications, conferences and workshops.Trial registration number NCT04028206.

Abstract Background The purpose of this registry-based retrospective study was to investigate the risk factors related to one-year mortality in displaced intracapsular fragility hip fracture patients. Methods Patients were screened from the Fragility Fracture Registry. Inclusion criterion was displaced intracapsular hip fracture patients with atypical or pathological fractures excluded. One-year mortality was investigated against risk factors including age, gender, past medical history, pre-fracture mobility (PFM), pre-operation ASA grade, delayed surgery over 48 h, post-surgical complications, and length of stay at acute orthopedic ward (LOS). Results A total of 1050 patients were included for further analysis. Gross one-year mortality was 14.9%. One-year mortality was significantly higher in patients who received non-operative treatment and those who received surgery but delayed over 48 h after admission (both p

Ageing is accompanied by chronic inflammatory responses due to elevated circulatory inflammatory cytokine production. Several inflammatory cytokines have been shown to be responsible for a decrease in muscle mass. However, little is known about the possible relationship between inflammation and sarcopaenia. This review aims to summarise the existing evidence about inflammation and sarcopaenia. Sarcopaenia is defined as an age-related decrease of muscle mass and/or muscle strength; it is caused by multiple factors, such as skeletal muscle atrophy, neuromuscular junction degeneration, hormone imbalance, cytokine imbalance, protein synthesis and proteolysis. Several inflammatory cytokines have been considered to promote muscle loss; C-reactive protein levels are significantly upregulated in sarcopaenia and sarcopenic obesity, and high levels of interleukin-6 are associated with reduced muscle mass and muscle strength (the administration of interleukin-6 could lead to a reduction in muscle mass). Up-regulation of tumour necrosis factor-α expression is also related to the development of sarcopaenia. Signalling pathways, such as protein kinase B/mammalian target of rapamycin, Janus kinase/signal transducer and activator of transcription-5 and signal transducer and activator of transcription 3 signalling, involved in muscle metabolism are regulated by insulin-like growth factor-1, tumour necrosis factor-α and interleukin-6 respectively. In conclusion, the inflammatory cytokines produced during chronic inflammation due to ageing, may influence their respective related pathways, thus leading to age-related muscle deterioration. The translational potential of this article: This review can provide more information for sarcopaenia medicine research in terms of anti-inflammation therapy.

Ultrasound is an inaudible form of acoustic sound wave at 20 kHz or above that is widely used in the medical field with applications including medical imaging and therapeutic stimulation. In therapeutic ultrasound, low-intensity pulsed ultrasound (LIPUS) is the most widely used and studied form that generally uses acoustic waves at an intensity of 30 mW/cm2, with 200 ms pulses and 1.5 MHz. In orthopaedic applications, it is used as a biophysical stimulus for musculoskeletal tissue repair to enhance tissue regeneration. LIPUS has been shown to enhance fracture healing by shortening the time to heal and reestablishment of mechanical properties through enhancing different phases of the healing process, including the inflammatory phase, callus formation, and callus remodelling phase. Reports from in vitro studies reveal insights in the mechanism through which acoustic stimulations activate cell surface integrins that, in turn, activate various mechanical transduction pathways including FAK (focal adhesion kinase), ERK (extracellular signal-regulated kinase), PI3K, and Akt. It is then followed by the production of cyclooxygenase 2 and prostaglandin E2 to stimulate further downstream angiogenic, osteogenic, and chondrogenic cytokines, explaining the different enhancements observed in animal and clinical studies. Furthermore, LIPUS has also been shown to have remarkable effects on mesenchymal stem cells (MSCs) in musculoskeletal injuries and tissue regeneration. The recruitment of MSCs to injury sites by LIPUS requires the SDF-1 (stromal cell derived factor-1)/CXCR-4 signalling axis. MSCs would then differentiate differently, and this is regulated by the presence of different cytokines, which determines their fates. Other musculoskeletal applications including bone–tendon junction healing, and distraction osteogenesis are also explored, and the results are promising. However, the use of LIPUS is controversial in treating osteoporosis, with negative findings in clinical settings, which may be attributable to the absence of an injury entry point for the acoustic signal to propagate, strong attenuation effect of cortical bone and the insufficient intensity for penetration, whereas in some animal studies it has proven effective.

Low intensity pulsed ultrasound (LIPUS) has been proven effective in promoting fracture healing but the underlying mechanisms are not fully depicted. We examined the effect of LIPUS on the recruitment of mesenchymal stem cells (MSCs) and the pivotal role of stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) pathway in response to LIPUS stimulation, which are essential factors in bone fracture healing. For in vitro study, isolated rat MSCs were divided into control or LIPUS group. LIPUS treatment was given 20 minutes/day at 37 °C for 3 days. Control group received sham LIPUS treatment. After treatment, intracellular CXCR4 mRNA, SDF-1 mRNA and secreted SDF-1 protein levels were quantified, and MSCs migration was evaluated with or without blocking SDF-1/CXCR4 pathway by AMD3100. For in vivo study, fractured 8-week-old young rats received intracardiac administration of MSCs were assigned to LIPUS treatment, LIPUS+AMD3100 treatment or vehicle control group. The migration of transplanted MSC to the fracture site was investigated by ex vivo fluorescent imaging. SDF-1 protein levels at fracture site and in serum were examined. Fracture healing parameters, including callus morphology, micro-architecture of the callus and biomechanical properties of the healing bone were investigated. The in vitro results showed that LIPUS upregulated SDF-1 and CXCR4 expressions in MSCs, and elevated SDF-1 protein level in the conditioned medium. MSCs migration was promoted by LIPUS and partially inhibited by AMD3100. In vivo study demonstrated that LIPUS promoted MSCs migration to the fracture site, which was associated with an increase of local and serum SDF-1 level, the changes in callus formation, and the improvement of callus microarchitecture and mechanical properties; whereas the blockade of SDF-1/CXCR4 signaling attenuated the LIPUS effects on the fractured bones. These results suggested SDF-1 mediated MSCs migration might be one of the crucial mechanisms through which LIPUS exerted influence on fracture healing.