Improve Fracture Healing Research Articles

Short-term effectiveness of robot-guided femoral neck system combined with cannulated compression screw fixation in treatment of femoral neck fracture in young and middle-aged patients

To investigate short-term effectiveness of robot-guided femoral neck system (FNS) combined with cannulated compression screw (CCS) fixation in treatment of femoral neck fracture in young and middle-aged patients. A clinical data of 49 young and middle-aged patients with femoral neck fractures, who met the selection criteria and admitted between January 2021 and June 2023, was retrospectively analyzed. After reduction of femoral neck fractures, 27 cases were treated with robot-guided FNS fixation (FNS group) and 22 cases with robot-guided FNS and CCS fixation (FNS+CCS group). There was no significant difference in baseline data such as gender, age, cause of fracture, time from fracture to operation, fracture side, and classification (Garden classification and Pauwels classification) between the two groups ( P>0.05). The operation time, intraoperative blood loss, intraoperative fluoroscopy frequency, the time when the patient began bearing weight, and hip joint pain and functional scores (VAS score and Harris score) at last follow-up for two groups were recorded. Imaging re-examination was taken to evaluate the quality of fracture reduction, fracture healing, as well as the occurrence of fracture non-union, osteonecrosis of the femoral head, and femoral neck shortening. All operations were successfully completed and the incisions healed by first intention. There was no significant difference in operation time and intraoperative blood loss between the two groups ( P>0.05), and the intraoperative fluoroscopy frequency in FNS+CCS group significantly increased compared to FNS group ( P<0.05). All patients were followed up 12-18 months (mean, 14.1 months). Imaging re-examination showed that there was no significant difference in fracture reduction quality between the two groups ( P>0.05), but the fracture healing time was significantly shorter in FNS+CCS group than in FNS group, and weight-bearing began earlier ( P<0.05). The incidences of femoral neck shortening, fracture non-union, and osteonecrosis of the femoral head were lower in FNS+CCS group than in FNS group, and there was significant difference in the incidence of femoral neck shortening between groups ( P<0.05). At last follow-up, there was no significant difference in VAS scores between the two groups ( P>0.05). However, the Harris score was significantly higher in FNS+CCS group than in FNS group ( P<0.05). Compared with FNS fixation alone, robot-guided FNS combined with CCS fixation in the treatment of femoral neck fractures in young and middle-aged patients has obvious advantages in terms of early weight bearing and fracture healing, improves fracture healing rate, effectively prevents postoperative complications, and can obtain good short-term effectiveness.

Anti-Microbial Drug Metronidazole Promotes Fracture Healing: Enhancement in the Bone Regenerative Efficacy of the Drug by a Biodegradable Sustained-Release In Situ Gel Formulation.

Nitroimidazoles comprise a class of broad-spectrum anti-microbial drugs with efficacy against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. Among these drugs, metronidazole (MTZ) is commonly used with other antibiotics to prevent infection in open fractures. However, the effect of MTZ on bone remains understudied. In this paper, we evaluated six nitroimidazole drugs for their impact on osteoblast differentiation and identified MTZ as having the highest osteogenic effect. MTZ enhanced bone regeneration at the femur osteotomy site in osteopenic ovariectomized (OVX) rats at the human equivalent dose. Moreover, in OVX rats, MTZ significantly improved bone mass and strength and improved microarchitecture compared to the vehicle-treated rats, which was likely achieved by an osteogenic mechanism attributed to the stimulation of the Wnt pathway in osteoblasts. To mitigate the reported neurological and genotoxic effects of MTZ, we designed an injectable sustained-release in situ gel formulation of the drug that improved fracture healing efficacy by 3.5-fold compared to oral administration. This enhanced potency was achieved through a significant increase in the circulating half-life and bioavailability of MTZ. We conclude that MTZ exhibits osteogenic effects, further accentuated by our sustained-release delivery system, which holds promise for enhancing bone regeneration in open fractures.

PANORAMIC REVIEW OF ACUTE SCAPHOID FRACTURES: DESCRIPTION, EPIDEMIOLOGY, ETIOLOGY, PRESENTATION, DIAGNOSIS, TREATMENT AND PROGNOSIS

Introduction: Scaphoid fractures are the most common fractures of the carpal bone and commonly occur in young males. Inadequate treatment of these fractures commonly leads to pseudarthrosis, resulting in pain and significant disability. Tenderness to palpation and/or pain with axial loading of the thumb should be managed as if it were a scaphoid fracture until proven otherwise. Objective: to detail current information related to scaphoid fractures, description, epidemiology, etiology, presentation, diagnosis, treatment and prognosis. Methodology: a total of 37 articles were analyzed in this review, including review and original articles, as well as clinical cases, of which 20 bibliographies were used because the other articles were not relevant to this study. The sources of information were PubMed, Google Scholar and Cochrane; the terms used to search for information in Spanish, Portuguese and English were: fracture, scaphoid, carpal bones, trauma, surgery. Results: Scaphoid fractures account for 2% to 7% of all fractures and 60% to 70% of carpal bone fractures. They are infrequent in children with approximately 3% of all pediatric hand and wrist fractures. Non-displaced fractures have high healing rates with cast treatment. Radiographs may miss fractures up to 25% of the time. Physical therapy is important in both operative and nonoperative treatment. Conclusions: Knowledge of the clinical presentation, diagnosis and treatment of scaphoid fractures is of utmost importance, because sometimes this type of fracture can go undetected on radiographs, which can lead to complications such as pseudarthrosis. The diagnosis of scaphoid fractures is sometimes complicated, so when there is clinical suspicion, appropriate complementary examinations should be performed to better determine the pathological condition, as is the case of computed tomography. Conservative or surgical management will depend on the type of fracture. Smoking cessation is recommended to improve fracture healing and physiotherapy both after surgical and non-surgical treatment. KEY WORDS: fracture, scaphoid, carpal bones, trauma, surgery.

Chinese expert consensus on treatment of osteoporotic fractures with teriparatide (2024 edition)

Osteoporotic fracture is the most serious complication of osteoporosis, which is a special type of pathologic fracture of the skeleton that occurs because of osteoporosis. It is characterized by delayed fracture healing, high risk of re-fracture, high rate of disability and death, difficulty in treatment and long treatment time, and re-fracture has a"cascade effect". Guidelines in different countries recommend that patients with osteoporotic fractures and those at very high risk of fracture should consider anabolic agents as first treatment choice. Teriparatide is the only anabolic agent approved by National Medical Products Administration (NMPA), and it has the clinical efficacy of improving fracture healing, reducing the risk of re-fracture, and improving bone microstructure in the treatment of osteoporotic fracture. Due to deficiencies in the current standardization of clinical use of teriparatide, Committee of Accelerated Rehabilitation After Osteoporotic Fractures of China Association of Rehabilitation Technology Transformation and Promotion, Bone and Joint Group of Chinese Society of Osteoporosis and Bone Mineral Research and Osteoporosis Working Committee of Chinese Association of Orthopedic Surgeons developed this consensus. The development of this consensus follows the modified Delphi method and forms 8 evidence-based medical recommendations, aiming to propose methods and precautions for standardizing the application of teriparatide, and to emphasize the importance of teriparatide application for the treatment of patients with osteoporotic fracture.

Arthroscopic Assisted Reduction of Talus Fractures Leads to Improved Clinical Outcomes at Mid- Term Follow-Up

Introduction/Purpose: Talus fracture is an uncommon and challenging pathology to treat due to its relationship with articular cartilage, ligamentous network, and avascular nature. The purpose of this systematic review was to evaluate the clinical outcomes after arthroscopic talar fracture fixation, compare to conventional open reduction and internal fixation (ORIF), and analyze the quality and level of evidence of the included studies. Methods: A systematic review of the MEDLINE, EMBASE, and Cochrane Library databases was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in June 2023. Articles were included if they evaluated outcomes following arthroscopic treatment of talus fractures, were written in English, were peer-reviewed, had a minimum of 2 patients per cohort, had human patients, and had a minimum 6-month follow-up. Inclusion criteria consisted of: Studies reporting clinical data following arthroscopy for the treatment of talus fractures were included and assessed. Results: Seven studies were analyzed, including 4 case series, 1 retrospective cohort, and 2 retrospective comparative studies. 237 patients treated with arthroscopic assisted reduction were compared to 76 patients treated with ORIF. Amongst arthroscopically treated patients, the AOFAS score improved from 71.2 ± 5.2 preoperatively to 89.9 ± 4.3 postoperatively. The SF-36 score improved from 73.2 ± 30.3 preoperatively to 104.5 ± 19.3 postoperatively. In total, 6 complications (3.0%) were observed in arthroscopically treated patients, of which the most common was peri-talar osteoarthritis in 2 patients (0.84%). In comparative cohorts, ORIF patients experienced a 13.0% complication rate in 6 patients (talar necrosis, malunion, nonunion, infection, and post-traumatic arthritis), compared to 2.2% in 1 patient (malunion) in the arthroscopic cohort. Conclusion: This study demonstrates that arthroscopic assisted reduction of talar fractures results in good clinical outcomes with lower complication rates. This minimally invasive approach had lower complications than ORIF, with no cases of talar necrosis and decreased postoperative traumatic arthritis. This technique provides adequate exposure without additional osteotomy, while decreasing trauma to local anatomical trauma, minimizing the risk of postoperative complications, and improving fracture healing assessment of concomitant lesions. These findings indicate arthroscopic treatment of talus fractures is an efficacious and safe procedure with comparable or improved clinical and postoperative outcomes as compared to conventional ORIF.

Subperiosteal delivery of transforming growth factor beta 1and human growth hormone from mineralized PCL films.

The ability to locally deliver bioactive molecules to distinct regions of the skeleton may provide a novel means by which to improve fracture healing, treat neoplasms or infections, or modulate growth. In this study, we constructed single-sided mineral-coated poly-ε-caprolactone membranes capable of binding and releasing transforming growth factor beta 1 (TGF-β1) and human growth hormone (hGH). After demonstrating biological activity in vitro and characterization of their release, these thin bioabsorbable membranes were surgically implanted using an immature rabbit model. Membranes were circumferentially wrapped under the periosteum, thus placed in direct contact with the proximal metaphysis to assess its bioactivity in vivo. The direct effects on the metaphyseal bone, bone marrow, and overlying periosteum were assessed using radiography and histology. Effects of membrane placement at the tibial growth plate were assessed via physeal heights, tibial growth rates (pulsed fluorochrome labeling), and tibial lengths. Subperiosteal placement of the mineralized membranes induced greater local chondrogenesis in the plain mineral and TGF-β1 samples than the hGH. More exuberant and circumferential ossification was seen in the TGF-β1 treated tibiae. The TGF-β1 membranes also induced hypocellularity of the bone marrow with characteristics of gelatinous degeneration not seen in the other groups. While the proximal tibial growth plates were taller in the hGH treated than TGF-β1, no differences in growth rates or overall tibial lengths were found. In conclusion, these data demonstrate the feasibility of using bioabsorbable mineral coated membranes to deliver biologically active compounds subperiosteally in a sustained fashion to affect cells at the insertion site, bone marrow, and even growth plate.

Silencing p75NTR regulates osteogenic differentiation and angiogenesis of BMSCs to enhance bone healing in fractured rats

BackgroundFractures heal through a process that involves angiogenesis and osteogenesis but may also lead to non-union or delayed healing. Bone marrow mesenchymal stem cells (BMSCs) have been reported to play a pivotal role in bone formation and vascular regeneration and the p75 neurotrophin receptor (p75NTR) as being an important regulator of osteogenesis. Herein, we aim to determine the potential mediation of BMSCs by p75NTR in bone healing.MethodsRat BMSCs were identified by flow cytometry (FCM) to detect cell cycle and surface markers. Then transfection of si/oe-p75NTR was performed in BMSCs, followed by Alizarin red staining to detect osteogenic differentiation of cells, immunofluorescence double staining was performed to detect the expression of p75NTR and sortilin, co-immunoprecipitation (CO-IP) was conducted to analyze the interaction between p75NTR and sortilin, and EdU staining and cell scratch assay to assess the proliferation and migration of human umbilical vein endothelial cells (HUVECs). The expression of HIF-1α, VEGF, and apoptosis-related proteins were also detected. In addition, a rat fracture healing model was constructed, and BMSCs-si-p75NTR were injected, following which the fracture condition was observed using micro-CT imaging, and the expression of platelet/endothelial cell adhesion molecule-1 (CD31) was assessed.ResultsThe results showed that BMSCs were successfully isolated, p75NTR inhibited apoptosis and the osteogenic differentiation of BMSCs, while si-p75NTR led to a decrease in sortilin expression in BMSCs, increased proliferation and migration in HUVECs, and upregulation of HIF-1α and VEGF expression. In addition, an interaction was observed between p75NTR and sortilin. The knockdown of p75NTR was found to reduce the severity of fracture in rats and increase the expression of CD31 and osteogenesis-related proteins.ConclusionSilencing p75NTR effectively modulates BMSCs to promote osteogenic differentiation and angiogenesis, offering a novel perspective for improving fracture healing.

The impact of age and sex on the inflammatory response during bone fracture healing.

Inflammation is thought to be dysregulated with age leading to impaired bone fracture healing. However, broad analyses of inflammatory processes during homeostatic bone aging and during repair are lacking. Here, we assessed changes in inflammatory cell and cytokine profiles in circulation and in bone tissue to identify age- and sex-dependent differences during homeostasis and repair. During homeostatic aging, male mice demonstrated accumulation of CD4+ helper T cells and CD8+ cytotoxic T cells within bone while both pro-inflammatory "M1" and anti-inflammatory "M2" macrophage numbers decreased. Female mice saw no age-associated changes in immune-cell population in homeostatic bone. Concentrations of IL-1β, IL-9, IFNγ, and CCL3/MIP-1α increased with age in both male and female mice, whereas concentrations of IL-2, TNFα, TNFR1, IL-4, and IL-10 increased only in female mice - thus we termed these "age-accumulated" cytokines. There were no notable changes in immune cell populations nor cytokines within circulation during aging. Sex-dependent analysis demonstrated slight changes in immune cell and cytokine levels within bone and circulation, which were lost upon fracture injury. Fracture in young male mice caused a sharp decrease in number of M1 macrophages; however, this was not seen in aged male mice nor in female mice of any age. Injury itself induced a decrease in the number of CD8+ T cells within the local tissue of aged male and of female mice but not of young mice. Cytokine analysis of fractured mice revealed that age-accumulated cytokines quickly dissipated after fracture injury, and did not re-accumulate in newly regenerated tissue. Conversely, CXCL1/KC-GRO, CXCL2/MIP-2, IL-6, and CCL2/MCP-1 acted as "fracture response" cytokines: increasing sharply after fracture, eventually returning to baseline. Collectively, we classify measured cytokines into three groups: (1) age-accumulated cytokines, (2) female-specific age-accumulated cytokines, and (3) fracture response cytokines. These inflammatory molecules represent potential points of intervention to improve fracture healing outcome.

Therapeutic Effects of a Placental Tissue-Derived Allograft on Fracture Healing

Background:As 5-10% of fractures will not heal without medical intervention, there is an ongoing need for effective treatments to promote fracture healing. CTM Biomedical produces human placental tissue-derived allografts that are used clinically and may assist in healing; however, no pre-clinical studies assessing these products have been performed. Our study investigating the impact of CTM products on the healing of a standard femoral fracture and a critical sized femoral defect (CSD) aims to fill this gap. We hypothesize that CTM product application will improve fracture healing and reduce pain-related behaviors.&#x0D; Methods:Femoral fractures were induced in 45 mice. CTM membrane, CTM paste, a combination of CTM membrane and paste, or saline was applied to each fracture. X-rays were taken twice weekly over 22 days, and blinded modified Radiological Union Scale for Tibia (mRUST) fracture scoring was performed. Complete blood analysis was conducted weekly. Following euthanasia 23 days post-surgery, μCT and histomorphometric analyses were conducted. CSDs have also been surgically induced in the femurs of 95 mice, with plans for similar fracture analyses.&#x0D; Results:CTM product application did not significantly alter the levels of inflammatory cells, suggesting that the mice did not undergo immunological reactions. mRUST scoring indicated that CTM products may not alter fracture healing rates. However, combined application of CTM membrane and paste significantly increased the fracture callus’s mineralized volume (by ~90%) and the percent of the callus that was bone. CTM membrane and paste application also led to an increased threshold for hind paw withdrawal, suggesting that CTM products may decrease pain-related behaviors.&#x0D; Future Directions:We hypothesize that in our CSD model, mice treated with the combination of CTM membrane and paste will display improved fracture healing and decreased pain-related behaviors. If shown to be effective, CTM product use may decrease fracture nonunion risk and increase comfort.

Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells.

Delayed or failed bone healing is a significant clinical challenge worldwide. Bone marrow mesenchymal stem cells (BMSCs) offer a promising approach for improving fracture healing. Isomangiferin, a xanthone C-glucoside, is known for its pharmacological activities, but its role in fracture healing remains unclear. In this study, we investigated the effects of isomangiferin on BMSCs under oxidative stress conditions induced by hydrogen peroxide (H2O2). Our results showed that isomangiferin promotes osteogenic differentiation and migration of H2O2-treated BMSCs, reduces apoptosis and reactive oxygen species production, and activates the AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) pathway. These findings suggest that isomangiferin may be a potential therapeutic agent for enhancing bone healing by modulating BMSC function.

How to Improve Fracture Healing in Atypical Femoral Fractures

How to Improve Fracture Healing in Atypical Femoral Fractures

Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing.

Despite decades of progress, developing minimally invasive bone-specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) functionalized with a peptide that targets tartrate-resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase-3 beta (GSK3β) inhibitor, via the TRAP binding peptide-NP (TBP-NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture-associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP-NP is comprehensively investigated herein. TBP-NPAR28 promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast-macrophage co-cultures in vitro. Longitudinal analysis of TBP-NPAR28 -mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti-inflammatory and downregulated pro-inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone-targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone-associated diseases.

Key Trace Elements Zinc and Magnesium Levels Decline After Fracture in a Rat Model

Category: Basic Sciences/Biologics; Basic Sciences/Biologics Introduction/Purpose: Zinc and magnesium are crucial for bone health, and their deficiencies can lead to impaired bone metabolism and repair. Although enhancing their bioavailability has been linked to better fracture healing, their levels during healing have not been studied. We hypothesized that zinc and magnesium levels transiently decrease at the fracture site compared to intact bone. This study is the first to explore temporal trace element levels during the initial stages of fracture healing. The findings will reveal when each element changes its concentration at the fracture site, which is associated with specific functions necessary for appropriate healing. Understanding the connection between trace element concentration and repair processes could lead to more effective treatment or supplementation during fracture healing. Methods: Following induction of a femur fracture in male BB Wistar rats, injured and intact contralateral femurs were harvested at 1- (n=3), 3- (n=4), and 7-days (n=3) after fracture. Fracture segments 10mm in length were resected 5mm from the center of the callus in either direction. Contralateral non-fractured femur segments were resected from the same region within the femoral diaphysis. Samples were analyzed via inductively coupled mass spectrometry using an Agilent ICP-MS 7900 (Agilent Technologies, Santa Clara, CA). Data was converted from ppb to percent weight zinc and magnesium per weight of bone (w/w%). The difference between zinc and magnesium in contralateral intact bone vs. fractured bone was calculated and averaged (∆) for each group. The average % change were also determined. An independent sample two-tailed t-test was performed comparing average w/w% of zinc and magnesium between fracture and contralateral samples. A p-value of &lt; 0.05 was considered significant. Results: After 1-day post-fracture, there was a -29.09 average % change in zinc levels (∆ 6.90x10^-03 ± 5.05x10^-03) (p = 0.033) and a -25.76 average % change in magnesium levels (∆ 1.21x10^-01 ± 7.36x10^-02 w/w%) (p = 0.241) between fractured and non- fractured femurs. After 3-days post-fracture, there was a -22.51 average % change in zinc levels (∆ 5.45x10^-03 ± 3.95x10^-03 w/w%) (p = 0.022) and a -33.07 average % change in magnesium levels (∆ 1.84x10^-01 ± 1.05x10^-01 w/w%) (p = 0.025). After 7- days post-fracture, there was a -9.40 average % change in zinc levels (∆ 1.90x10^-03 ± 3.98x10^-03) (p = 0.377) and a -17.88 average % change in magnesium levels (∆ 9.04x10^-02 ± 1.24x10^-01 w/w%) (p = 0.159) between fractured and non-fractured femurs. Conclusion: Previous research has established the significance of trace elements, namely zinc and magnesium, in the process of fracture healing. Zinc has been shown to improve fracture healing, while magnesium has been found to play a role regulating inflammation during early fracture healing. The findings of this study corroborate our hypothesis that levels of these elements transiently decline following fracture. By evaluating these changes in trace element levels, we can gain a better understanding of their function in the fracture healing process. These observations may offer insight into potential therapeutic approaches utilizing zinc and magnesium for fracture healing in the future.

Parathyroid hormone therapy improves MRSA-infected fracture healing in a murine diabetic model.

Diabetes mellitus (DM) impairs fracture healing and is associated with susceptibility to infection, which further inhibits fracture healing. While intermittent parathyroid hormone (1-34) (iPTH) effectively improves fracture healing, it is unknown whether infection-associated impaired fracture healing can be rescued with PTH (teriparatide). A chronic diet-induced type 2 diabetic mouse model was used to yield mice with decreased glucose tolerance and increased blood glucose levels compared to lean-fed controls. Methicillin-resistant Staphylococcus aureus (MRSA) was inoculated in a surgical tibia fracture model to simulate infected fracture, after which mice were treated with a combination of antibiotics and adjunctive teriparatide treatment. Fracture healing was assessed by Radiographic Union Scale in Tibial Fractures (RUST), micro-computed tomography (μCT), biomechanical testing, and histology. RUST score was significantly poorer in diabetic mice compared to their lean nondiabetic counterparts. There were concomitant reductions in micro-computed tomography (μCT) parameters of callus architecture including bone volume/total volume, trabecular thickness, and total mineral density in type 2 diabetes mellitus (T2DM) mice. Biomechanicaltesting of fractured femora demonstrated diminished torsional rigidity, stiffness, and toughness to max torque. Adjuvant teriparatide treatment with systemic antibiotic therapy improved numerous parameters of bone microarchitecture bone volume, increased connectivity density, and increased trabecular number in both the lean and T2DM group. Despite the observation that poor fracture healing in T2DM mice was further impaired by MRSA infection, adjuvant iPTH treatment significantly improved fracture healing compared to antibiotic treatment alone in infected T2DM fractures. Our results suggest that teriparatide may constitute a viable adjuvant therapeutic agent to improve bony union and bone microarchitecture to prevent the development of septic nonunion under diabetic conditions.

OA07 A case of severe osteoporosis treated with teriparatide following the development of bilateral atypical femoral fractures due to IV zoledronic acid

Abstract Introduction Atypical femoral fractures (AFF) are a rare complication of long-term anti-resorptive therapy. A literature review of 310 cases of AFF did reveal a median duration of bisphosphonate therapy of 7 years. Additionally, simultaneous glucocorticoid use was seen in 34% of the cases and was reported to have a 5-fold increase in one case series. Around 70% of patients do describe a prodrome of thigh pain and around quarter of all cases will have bilateral involvement. Case description A 59-year-old lady with a background diagnosis of Behçet’s disease was referred for continuation of osteoporosis care. History of Fractures 2003- left-sided distal radial fracture; 2017 - refractured again after a fall; left 5th metatarsal fracture a few months later. 2019 - right navicular fracture, left pubic rami fracture and left iliac wing fracture, after a fall from the bus In 2023, she has tripped and fell from the standing height resulting in a left femoral shaft fracture, which had radiological features of an atypical femoral fracture. She denied any prodromal thigh pain. The orthopaedic team did an intramedullary nailing to the left femoral shaft. X-ray of the right femur shaft revealed cortical thickening of right mid femoral shaft. Treatment History In 2009, she was started on oral bisphosphonate therapy and from 2020 to 2022 received 3 doses of IV zoledronic acid at the national Behçet’s centre in Birmingham. She has been on long-term steroid therapy due to the underlying Behçet's disease and was on prednisolone 7mg daily when she was referred to us. Management of AFF The orthopaedic team initially recommended a watch and wait policy for the right side; however, following discussions with the patient and with us, prophylactic nailing of the right femoral shaft was done 2 months later. Investigations DXA scan in 2022: spine T-score of−3.3 (L2 −3.6, L3 −3.9, L4 −3.7); femoral neck T-score of −2.5. Despite treatment with oral and then parenteral bisphosphonates for the last 12 years, there is a significant reduction in BMD with 18.2% decrease in the spine and 7.1% decrease in the femoral neck compared to the last DEXA in 2019. Management plan The next step was to treat her with teriparatide, which she is currently having without any problems. We shall continue it for 24 months. Discussion Atypical femoral fractures are rare. Anti-resorptive medication including bisphosphonates and denosumab are known to cause atypical femoral fractures. Teriparatide, being anabolic agent, is not associated with the increased risk of atypical femoral fractures. While there are no randomised controlled studies about the use of teriparatide in healing atypical femoral fractures, there are some case reports where teriparatide had shown improved fracture healing in AFF. After the 24 months, to ‘lock in the effects’ of teriparatide, an anti-resorptive medication will be required. Because both femoral shafts have received intramedullary nailing, we would consider IV zoledronic acid after the 24 months of teriparatide. This is the approach supported by the European Calcified Tissue Society in their systemic review and recommendations on ‘Medical Management of Patients After Atypical Femur Fractures’ (https://doi.org/10.1210/clinem/dgz295). Key learning points Consider atypical femoral fracture in patients who are on anti-resorptive therapy and complain of thigh/groin pain. Atypical femoral fractures can be bilateral; therefore, evaluate both sides. Teriparatide can be used to treat osteoporosis in patients with atypical femoral fracture, but considerations will have to be made in relation to subsequent therapy.

Probiotics: Can it modulate fracture healing?

Fractures remain a huge burden and their management adversely affects individuals' function and productivity during the lengthy healing period. Gut microbiota exerts a systemic influence on diverse aspects of host physiology, including bone. The primary objective of this study was to evaluate if oral probiotic treatment before or after a fracture in a mouse model could increase cytokines and biomarkers essential for bone healing with subsequent improvement in the biomechanical properties of the healed callus. Femoral osteotomy and intramedullary pinning were performed on C57BL/6 mice. Group 1 received either control PBS or probiotic via oral gavage for 5 weeks before fracture (pre-fracture). Group 2 received equivalent treatments for 4 weeks only after fracture (post-fracture). Fracture calluses were harvested on day 3 and 7 for RT-qPCR to quantify osteogenic-related inflammatory cytokines and bone biomarkers. Fractured femurs were evaluated day 28 post-osteotomy via microstructural analysis (μCT) and biomechanical testing (torsion). Mice treated with probiotics pre-fracture (group 1) showed significantly increased gene expression on day 3 of cytokines TGF-β, IL-6 and IL-17F and a corresponding increase in gene expression on day 7 for Col1 and Runx2. Significant improvement was also seen in bone volume fraction, bone mineral density, tissue mineral density, maximum yield torque, stiffness and strain energy. Mice treated with probiotics post-fracture (group 2), demonstrated no changes in cytokine or bone marker gene expression with no significant changes on microstructural analysis. However, significant increases were seen in twist angle at failure and strain energy, with a corresponding reduction in torsional stiffness. Our results suggest that oral probiotic administration, before or after a fracture, may sufficiently alter the gut flora microenvironment leading to improved bone healing biomechanical properties. The use of probiotics may provide a cost-effective and low-risk adjunctive therapy to improve fracture healing.

Multicenter consensus statements on the use of low-intensity pulsed ultrasound (LIPUS) in Hand Surgery.

The purpose of this agreement was to establish consensus statements on the use of low-intensity pulsed ultrasound (LIPUS) in hand surgery. Based on Delphi consensus methodology, a preliminary list of questions on the use of LIPUS in hand surgery was developed by an interdisciplinary team of hand and plastic surgeons as well as psychologists and experts from communications science. Based on these, questionnaires were invented and a total of three Delphi rounds have been conducted. Delphi panelists consisted of 11 German hand surgeons with a mean experience in hand surgery of 15years (7-23years). Questions and statements were revised during this process, resulting in a consensus at the end of round three. After three Delphi rounds, the following recommendations could be derived. LIPUS can be applied for impaired fracture healing of the digits, metacarpals, carpal bones as well as a prophylactic procedure in order to avoid further revision surgery. LIPUS therapy can be useful in addition to revision surgery for delayed union and non-unions. In the case of certain risk factors (replantation, revascularization, osteoporosis, smoking), it can be applied directly postoperatively in order to prevent impaired fracture healing. It should be applied for 90-120days. There is a consensus among German hand surgeons, when and how LIPUS can be applied for improving fracture healing of the hand. Randomized controlled trials with direct comparison of fracture treatment with and without LIPUS are needed to support these statements with objective data.

Effects of Piper sarmentosum on Bone Health and Fracture Healing: A Scoping Review.

Piper sarmentosum (PS) is a traditional herb used by Southeast Asian communities to treat various illnesses. Recent pharmacological studies have discovered that PS possesses antioxidant and anti-inflammatory activities. Since oxidative stress and inflammation are two important processes driving the pathogenesis of bone loss, PS may have potential therapeutic effects against osteoporosis. This review systematically summarised the therapeutic effects of PS on preventing osteoporosis and promoting fracture healing. A systematic literature search was performed in November 2021 using 4 electronic databases and the search string "Piper sarmentosum" AND (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes). Nine unique articles were identified from the literature. The efficacy of PS has been studied in animal models of osteoporosis induced by ovariectomy and glucocorticoids, as well as bone fracture models. PS prevented deterioration of bone histomorphometric indices, improved fracture healing and restored the biomechanical properties of healed bone in ovariectomised rats. PS also prevented osteoblast/osteocyte apoptosis, increased bone formation and mineralisation and subsequently improved trabecular bone microstructures and strength of rats with osteoporosis induced by glucocorticoids. Apart from its antioxidant and anti-inflammatory activity, PS also suppressed circulating and skeletal expression of corticosterone and skeletal expression of 11β hydroxysteroid dehydrogenase type 1 but increased the enzyme activity in the glucocorticoid osteoporosis model. This review also identified several research gaps about the skeletal effects of PS and suggested future studies to bridge these gaps. PS may be of therapeutic benefit to bone health. However, further research is required to validate this claim.

Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair.

Introduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures. Here, we describe poly (ethylene glycol) dimethacrylate (PEGDMA)-based microparticles, in the shape of microrods, loaded with beta nerve growth factor (β-NGF) for the purpose of promoting fracture repair. Methods: Herein, PEGDMA microrods were fabricated through photolithography. PEGDMA microrods were loaded with β-NGF and in vitro release was examined. Subsequently, bioactivity assays were evaluated in vitro using the TF-1 tyrosine receptor kinase A (Trk-A) expressing cell line. Finally, in vivo studies using our well-established murine tibia fracture model were performed and a single injection of the β-NGF loaded PEGDMA microrods, non-loaded PEGDMA microrods, or soluble β-NGF was administered to assess the extent of fracture healing using Micro-computed tomography (µCT) and histomorphometry. Results: In vitro release studies showed there is significant retention of protein within the polymer matrix over 168 hours through physiochemical interactions. Bioactivity of protein post-loading was confirmed with the TF-1 cell line. In vivo studies using our murine tibia fracture model show that PEGDMA microrods injected at the site of fracture remained adjacent to the callus for over 7 days. Importantly, a single injection of β-NGF loaded PEGDMA microrods resulted in improved fracture healing as indicated by a significant increase in the percent bone in the fracture callus, trabecular connective density, and bone mineral density relative to soluble β-NGF control indicating improved drug retention within the tissue. The concomitant decrease in cartilage fraction supports our prior work showing that β-NGF promotes endochondral conversion of cartilage to bone to accelerate healing. Discussion: We demonstrate a novel and translational method wherein β-NGF can be encapsulated within PEGDMA microrods for local delivery and that β-NGF bioactivity is maintained resulting in improved bone fracture repair.

Taohong Siwu Decoction enhances human bone marrow mesenchymal stem cells proliferation, migration and osteogenic differentiation via VEGF-FAK signaling in vitro.

Taohong Siwu Decoction (THSWD) is a conventional traditional Chinese prescription aiming at promoting blood circulation and alleviating blood stasis. It is widely prescribed in instances of ischemic strokes, cardiovascular diseases, osteoporosis and bone fracture. However, its molecular functions in bone formation remain uncharacterized. This study aims to explore the potential effects of THSWD treatment on human bone marrow mesenchymal stem cells (BMSCs) proliferation, osteogenic differentiation, and migration. BMSCs undergo osteogenic, adipogenic, and chondrogenic differentiation to determine cell stemness. BMSCs were treated with low dose (200μg/ml), medium dose (400μg/ml) and high dose (600μg/ml) THSWD. The cell viability was determined by CCK-8 assays, the osteogenic differentiation ability was determined by alizarin red staining and ALP staining, and cell migration was determined by wound healing and transwell assays. The effect of THSWD on the vascular endothelial growth factor (VEGF)/focal adhesion kinase (FAK) pathway was determined by immunoblotting. THSWD time-dependently and dose-dependently promoted BMSC viability. Moreover, THSWD also promoted BMSC osteogenic differentiation and migration. As opposed to THSWD, VEGF receptor inhibitor Bevacizumab suppressed BMSC osteogenic differentiation and migration. In BMSCs that have been co-treated with THSWD and Bevacizumab, THSWD effects on BMSC functions were partially eliminated by Bevacizumab. Moreover, THSWD treatment boosted VEGF content in the supernatant and was conducive to the phosphorylation of FAK and Src, whereas Bevacizumab exerted opposite effects; similarly, Bevacizumab partially abolished THSWD effects on VEGF and FAK (Tyr397) and Src (Tyr418) phosphorylation. THSWD enhances the capacities of BMSCs to proliferate, differentiate, and migrate, possibly through VEGF and the FAK-Src, thereby improving fracture healing.