The role of gut microbiota in bone homeostasis.

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.

Elastic-band resistance exercise or vibration treatment in combination with hydroxymethylbutyrate (HMB) supplement for management of sarcopenia in older people: a study protocol for a single-blinded randomised controlled trial in Hong Kong.

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.

A systematic review on current osteosynthesis-associated infection animal fracture models.

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 â€‹CFU. Consistent and replicable infections were observed from 104 â€‹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 â€‹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.

How much do we know about the role of osteocytes in different phases of fracture healing? A systematic review.

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.

A study protocol for a randomized controlled trial evaluating vibration therapy as an intervention for postural training and fall prevention after distal radius fracture in elderly patients.

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.

Fragility fractures and imminent fracture risk in Hong Kong: one of the cities with longest life expectancies.

INTRODUCTION: Imminent fracture risk, or fractures within 2 years of an initial fracture, is a pressing issue worldwide. Hong Kong is a city with one of the longest life expectancies. The concern of fragility fractures and the imminent risk of a subsequent fracture is becoming a top priority. The objective of this study was to present the epidemiology of incident fragility fractures of all public acute hospitals and the imminent risk of a subsequent fracture in Hong Kong. METHODOLOGY: This was a retrospective population-based analysis. Patient records from all acute hospitals in Hong Kong from 1 January 2004 to 31 December 2018 were retrieved for patients ≥ 50 years of age with hip, distal radius, or proximal humerus fractures. Secondary fractures and falls were identified in the subsequent 5 years. Post hoc analysis in recent 2013-2018 period was performed. Overall survival (re-fracture incidence) on age subgroups using Kaplan survival analysis and variables was compared using the log-rank test. Cox proportional hazard regressions, obtaining the hazard ratios (HR) and their respective 95% confidence intervals (CI), were used. RESULTS: There is an overall increasing trend of fragility fractures (hip, distal radius, proximal humerus) from 5596 in 2004 to 8465 in 2018. The average cumulative imminent risk of fractures from recent 5 years is 3.87% at 1 year and 6.50% at 2 years. 49.5% of the patients with a secondary fracture occurred within 2 years since the initial major fragility fracture. Post hoc analysis in recent 2013-2018 period (N = 7039) showed male patients were 1.21 times more likely to have further fractures with time (HR = 1.21 (1.02, 1.45), p = 0.03) compared with female patients. Patients over age 95 were 2.01 times higher than patients of age under 75 to have further fracture over time. CONCLUSIONS: Following an initial fracture, prompt treatment strategies should be adopted to avoid imminent risk of fractures. This window of opportunity in the first 2 years is a golden period to treat osteoporosis and prevent falls. Our post hoc analysis has shown that male patients and patients older than 95 are at even higher risk. Clinicians and allied healthcare professionals should be alert on these patients.