Performance of HR-pQCT, DXA, and FRAX in the discrimination of asymptomatic vertebral fracture in postmenopausal Chinese women.

Volumetric bone density (vBMD) and trabecular microarchitecture measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) can discriminate the patients with high risk of asymptomatic vertebral fracture (VF) in postmenopausal Chinese women. These findings suggested that HR-pQCT could provide additional information on bone quality of the patients with asymptomatic VF. INTRODUCTION: Although there were several studies using HR-pQCT to investigate asymptomatic VF, it remains uncertain if HR-pQCT parameters can discriminate asymptomatic VF patients, especially in Chinese population. The purpose of this study was to investigate whether bone quality measured by HR-pQCT could discriminate asymptomatic VF independent of hip areal bone mineral density (aBMD) measured by dual-energy x-ray absorptiometry (DXA) and fracture risks evaluated using built-in Fracture Risk Assessment Tool (FRAXBMD). METHODS: This is a nested case-control study. One hundred seventy-five ambulatory Chinese postmenopausal women aged 60-79 years were retrieved from Normative Reference Standards (NRS) cohort in Hong Kong. DXA was used to identify VF from lateral spine images (VFA) using Genant's semi-quantitative method. Major osteoporotic fracture risk was calculated using FRAX tool. HR-pQCT was used to assess vBMD, microarchitecture, and estimated strength at both distal radius and tibia. Comparison of HR-pQCT parameters between asymptomatic VF and control was performed using covariance analysis. Logistic regression analysis was performed for calculating the adjusted odds ratio (OR) with 95% confidence intervals (CI) of fracture status as per SD decrease in HR-pQCT parameters. RESULTS: Women with asymptomatic VF were older than those of the control in our NRS cohort. Nevertheless, after adjusted for covariance, asymptomatic VF showed significantly lower trabecular vBMD (Tb.vBMD) at radius but higher SMI at tibia as compared with those of the control. Tb.vBMD at radius yielded the highest value of area under the curve (AUC) as compared with total hip aBMD and FRAXBMD. However, no significant difference was found among each other. CONCLUSION: Tb.vBMD at the radius and SMI at the tibia provided by HR-pQCT can discriminate asymptomatic VF independent of hip aBMD and FRAXBMD by DXA in postmenopausal women.

Fibrinolysis as a target to enhance osteoporotic fracture healing by vibration therapy in a metaphyseal fracture model.

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.

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.