The effects of hydroxychloroquine-induced oxidative stress on fracture healing in an experimental rat model.

OBJECTIVES: The purpose of this study was to investigate whether hydroxychloroquine (HCQ) sulfate causes oxidative stress (OS) and its effect on fracture healing in an experimental rat model. MATERIALS AND METHODS: In this experimental study, open diaphyseal femur fractures were induced in 24 eight-week-old male rats (mean weight: 225±25 g; range, 200 to 250 g) and then fixed with K-wire. The rats were divided into four groups: HCQ-2, control-2 (C-2), HCQ-4, and control-4 (C-4). During the study period, rats in the HCQ groups received an HCQ solution (160 mg/kg/day), whereas rats in the control groups received saline. The HCQ-2 and C-2 groups were sacrificed on the 14th day, and the HCQ-4 and C-4 groups were sacrificed on the 28th day. After sacrifice, malondialdehyde levels induced by OS were calculated for each rat, and fracture healing was evaluated radiographically, histomorphometrically, histopathologically, and immunohistochemically. RESULTS: Malondialdehyde levels were higher in the HCQ groups than in the control groups (p<0.05). Hydroxychloroquine caused OS in rats. The ratio of total callus diameter to femur bone diameter was lower in HCQ groups compared to control groups (p<0.05). No differences were observed when comparing radiological and histological healing results between the control and HCQ groups. Alkaline phosphatase levels were lower in the HCQ-4 group than the C-4 group at week four (p<0.05), although osteocalcin and osteopontin levels did not differ between groups (p>0.05). Oxidative stress had no adverse effects on histologic healing outcomes and osteoblast functions. Cathepsin K and tartrate-resistant acid phosphatase-5b levels were higher in the HCQ-4 group than in the C-4 group (p<0.05). While the number and function of osteoclasts increased due to OS in callus tissue, a decrease in the number of chondrocytes was observed. CONCLUSION: Hydroxychloroquine-induced OS increases the number and function of osteoclasts and decreases the number of hypertrophic chondrocytes and endochondral ossification but has no significant effect on mid-late osteoblast products and histological fracture healing scores.

The effects of cephalexin on fracture healing in a rat femur fracture model.

OBJECTIVES: The aim of this study was to examine the effects of cephalexin on the fracture union histomorphometrically, radiologically, biomechanically, immunohistochemically, and histopathologically in a rat femur fracture model and to evaluate the effects of the antibiotics to be used in the prophylaxis of fracture infection on the union of the fracture. MATERIALS AND METHODS: A total of 48 male Wistar rats were divided into four groups as two-week control (C2) and cephalexin (CEP2) and four-week control (C4) and cephalexin (CEP4). After establishment of standard fracture model on right femurs, 60 mg/kg/day of cephalexin was applied to CEP2 and CEP4 by oral gavage. Radiological, biomechanical, histopathological, immunohistochemical, and histomorphometric examinations were performed on amputated femurs. RESULTS: Callus volume of CEP4 group significantly increased compared to CEP2 group (p=0.005), while no significant difference was found in the bone mineral density and callus/bone volume among the groups (p>0.05). There was no significant difference in flexural strength between the C4 and CEP4 groups (p=0.093). Histological healing scores increased from Week 2 to Week 4 (p=0.002) and inflammation scores decreased in both control and cephalexin groups (p=0.010 and p=0.008); however, no significant difference was found in healing and inflammation scores (p>0.05). The CD34+ immunoreactivity in the CEP2 group was significantly higher than the C2 group (p=0.029). Collagen type III level was significantly lower in the CEP2 and CEP4 groups compared to the corresponding control groups (p=0.008 and p=0.016, respectively). CONCLUSION: Cephalexin did not exert any radiological, histopathological, histomorphometric, biomechanical, and immunohistochemical adverse effects on the femoral fracture healing model in rats; however, it showed positive effects on CD34 and Collagen type III levels. Based on these findings, antibiotherapy with cephalexin may be considered as a safe treatment for fracture union.

Antibiotic cement-coated rigid locked nails in infected femoral and tibial nonunion. Reoperation rates of commercial versus custom-made nails.

INTRODUCTION: The objective of this study is to assess bone union, infection control, and reoperation rates in a series of patients with infected femoral or tibial nonunion treated with antibiotic-cement-coated rigid nails and to compare the results obtained with custom-made nails versus commercial nails. METHODS: We retrospectively analyzed a series of consecutive patients with infected nonunion of the femur or the tibia treated with antibiotic-cement-coated rigid nails between January 2010 and 2020. We assessed patients' distinctive characteristics, initial injury, type of nail used (custom-made nail with vancomycin or commercial nail with gentamicin), success rate (bone union + infection control), reoperation rate, and failure rate. Comparative analyses were conducted between reoperated and non-reoperated patients regarding the type of nail used. A multivariate regression analysis was performed to assess the risk variables that impacted reoperation rates. RESULTS: We included 54 patients with 22 (40.74%) infected femoral nonunions and 32 (59.25%) tibial nonunions, who were treated with 38 (70.37%) custom-made antibiotic-cement coated nails and 16 (29.62%) commercial nails. Bone union and infection control were achieved in 51 (94.44%) cases. The reoperation rate was 40.74% (n = 22), and the failure rate was 5.55% (n = 3). The use of custom-made nails was associated with a higher risk of reoperation (Odds Ratio 4.71; 95% Confidence Interval 1.10 - 20.17; p = 0.036). CONCLUSION: Antibiotic-cement-coated nails reached a 94.44% success rate. Nails manufactured in the OR coated with vancomycin cement were associated with a higher risk of reoperation than commercial nails loaded with gentamicin cement. LEVEL OF EVIDENCE: III comparative, observational, non-randomized.

Effect of Vancomycin Applied to the Surgical Site on Fracture Healing in a Diabetic Rat Model.

BACKGROUND: Prophylactic vancomycin treatment decreases the prevalence of surgical site and deep infections by >70% in diabetic patients undergoing reconstructive foot and ankle surgery. Thus, determining whether clinically relevant local vancomycin doses affect diabetic fracture healing is of medical interest. We hypothesized that application of vancomycin powder to the fracture site during surgery would not affect healing outcomes, but continuous exposure of vancomycin would inhibit differentiation of osteoblast precursor cells and their osteogenic activity in vitro. METHODS: The vancomycin dose used to treat the diabetic rats was a modest increase to routine surgical site vancomycin application of 1 to 2 g for a 70-kg adult (21 mg/kg). After femur fracture in BB-Wistar type 1 diabetic rats, powdered vancomycin (25 mg/kg) was administered to the fracture site. Bone marrow and periosteal cells isolated from diabetic bones were cultured and treated with increasing levels of vancomycin (0, 5, 50, 500, or 5000 µg/mL). RESULTS: Radiographic scoring, micro-computed tomography (µCT) analysis, and torsion mechanical testing failed to identify any statistical difference between the vancomycin-treated and the untreated fractured femurs 6 weeks postfracture. Low to moderate levels of vancomycin treatment (5 and 50 µg/mL) did not impair cell viability, osteoblast differentiation, or calcium deposition in either the periosteum or bone marrow-derived cell cultures. In contrast, high doses of vancomycin (5000 µg/mL) did impair viability, differentiation, and calcium deposition. CLINICAL RELEVANCE: In this diabetic rodent fracture model, vancomycin powder application at clinically relevant doses did not affect fracture healing or osteogenesis.

Race, Gender, and Primary Language Were Not Associated With Changes in Opioid Prescribing in Children: Results From a Single Institution, 2010 to 2020.

BACKGROUND: Patients should be prescribed medication based on their medical condition, without prejudice because of their race, gender, or primary language. However, previous research has shown that men are prescribed more medication than women, patients who are White are prescribed more medications than patients who are non-White, and English-speaking people are prescribed more medications than non-English-speaking patients. However, it is unclear whether these differences also occur in pediatric orthopaedic populations. QUESTIONS/PURPOSES: We asked: (1) Was the amount of opiates prescribed at discharge associated with patient age, gender, race, or primary language? (2) Did the amount of opiates prescribed to patients at discharge change from 2010 to 2020? METHODS: In a single center, between January 2010 and December 2019, we treated 331 patients younger than 18 years surgically for upper and lower long-bone extremity fractures. Patients were considered eligible if they had a nonpathologic fracture. Femur fractures were not included. Based on these criteria, all patients were eligible. The mean age was 12 ± 4 years. The mean weight was 57 ± 33 kg. Among these patients, 76% (253 of 331) were boys and 24% (78 of 331) were girls. From the hospital discharge records, we recorded the amount of opiates prescribed at the time of discharge as measured by morphine milligram equivalents (MMEs). We examined the association of age, gender, race, primary language, weight, and year of treatment using this measurement. We determined a patient's race retrospectively by information given by their parents at time of admission. We did not attempt to contact patients to obtain more nuanced information about their racial background. These data were obtained from the electronic health record. The Wilcoxon rank sum test, t-test, or chi-square test was used to assess associations depending on the distribution of variables, as appropriate. Because opioids as measured in MMEs is zero-inflated, a two-part model analysis was used to adjust for confounding variables. One component of the model was for the probability of having any opiate prescription and another was for the mean number of opioids received. Findings were considered statistically significant if p values were < 0.05. RESULTS: In total, 57% (189 of 331) of children were prescribed opiates at discharge after surgery for long-bone fractures. Opiate MMEs increased with patient age (r = 0.38; p < 0.01). Boys and girls showed no difference in the amounts of pain medication (adjusted odds ratio [OR] 1.38 [95% confidence interval (CI) 0.80 to 2.39]; p = 0.71; adjusted opioid difference: 0.35 MME [95% CI -51.7 to 52.4]; p = 0.99), nor were there differences between patients who were White and those who were non-White (adjusted OR 0.78 [95% CI 0.49 to 1.23]; p = 0.28; adjusted opioid difference: 21.5 MME [95% CI -19.3 to 62.4]; p = 0.30), or between patients for whom English was there primary language and those for whom English was not their primary language (adjusted OR 1.16 [95% CI 0.52 to 2.57]; p = 0.71; adjusted opioid difference: 22.7 MME [95% CI -55.7 to 101.3]; p = 0.57) when adjusted for age and weight. There was no change in opioid prescription amounts from 2010 to 2020 after adjusting for changes in patient age across years (Spearman r = -0.08; p = 0.16). CONCLUSION: Fairness in opioid prescribing based on race, gender, or primary language is possible. Additional research is needed to determine what factors in our institution led to this result. We suggest that prescribers should apply consistent protocols based on factors such as weight or injury type rather than making individual decisions for each patient. This will lead to fairer opioid prescribing to patients from different race and gender groups. LEVEL OF EVIDENCE: Level III, therapeutic study.

Sedative use and incidence of falls and hip fractures among older adults in an outpatient geriatric clinic / Perfil de uso de sedativos e ocorrência de quedas e fratura de fêmur entre idosos em um ambulatório de geriatria

OBJECTIVE: To investigate the use of sedatives by older adults attending a private outpatient geriatric clinic in Belo Horizonte (MG), Brazil, and its association with falls and hip fractures. METHODS: Using a longitudinal design, the prevalence of benzodiazepine and nonbenzodiazepine ("z-drugs") intake by older adults was described and their association with the incidence of falls and fractures (30 days after the initial visit) was evaluated through logistic regression. RESULTS: A total of 7821 older adults were included in the study, most of them women (72.50%), with a mean age of 77.5 years and a mean Clinical-Functional Vulnerability Index (IVCF-20) score of 16.5. The overall prevalence of sedative use (any sedative) was 6.19%, with 4.48% benzodiazepines and 1.98% z-drugs. The most widely used sedatives were clonazepam (29.04%), zolpidem (28.65%), and alprazolam (23.44%). Falls were reported for 182 patients (2.33%), with a higher incidence among users of any sedatives (4.34; p = 0.002; OR = 1.94, adjusted for sex, age, and IVCF-20) and benzodiazepines (5.14%; p < 0.001; OR = 2.28) than among non-users (2.19%). Hip fractures occurred in 33 patients (0.42%), and again were more frequent among users of sedatives (1.03%; p = 0.032; OR = 2.57) and benzodiazepines (1.43%; p = 0.003; OR = 3.45) than among non-users (0.38%). CONCLUSIONS: The use of sedatives, especially benzodiazepines, is associated with an increased incidence of falls and hip fractures in older adults

OBJETIVO: Investigar a utilização de sedativos entre idosos atendidos em ambulatório privado de geriatria em Belo Horizonte (MG), bem como sua associação com quedas e fraturas de fêmur. METODOLOGIA: Trata-se de estudo longitudinal, no qual foi descrita a prevalência de uso de benzodiazepínicos e drogas Z entre idosos (60 anos ou mais) e avaliada sua associação com a incidência de queda e fratura (30 dias após consulta inicial) por meio de regressão logística. RESULTADOS: Foram incluídos no estudo 7821 idosos, com maioria feminina (72,50%), idade média de 77,5 anos e Índice de Vulnerabilidade Clínico Funcional (IVCF-20) médio de 16,5 pontos. A prevalência de uso de sedativos em geral foi de 6,19%, sendo 4,48% de benzodiazepínicos e 1,98% de drogas Z. Os medicamentos sedativos mais utilizados foram clonazepam (29,04%), zolpidem (28,65%) e alprazolam (23,44%). Relatou-se queda para 182 idosos (2,33%), com incidência maior entre usuários de sedativos (4,34; p = 0,002; OR = 1,94 ajustada por sexo, idade e IVCF-20) e de benzodiazepínicos (5,14%; p < 0,001; OR = 2,28) do que entre não usuários (2,19%). Identificou-se fratura de fêmur em 33 idosos (0,42%), sendo mais frequente entre usuários de sedativos (1,03%; p = 0,032; OR = 2,57) e de benzodiazepínicos (1,43%; p = 0,003; OR = 3,45) do que entre não usuários (0,38%). CONCLUSÃO: Concluiu-se que a incidência de quedas e fraturas de fêmur em idosos possui associação com o uso de medicamentos sedativos, em especial os benzodiazepínicos

Case report: Clinical characteristics and treatment of secondary osteoporosis induced by X-linked congenital adrenal dysplasia.

Objective: To summarize the clinical features and bone complications in a patient from a large family with X-linked congenital adrenocortical hypoplasia (AHC) and evaluate the efficacy of different treatment regimens on the prognosis of secondary osteoporosis caused by AHC at a 5-year follow-up. Methods: A large family with AHC was recruited, and the causative gene mutation was identified by Sanger sequencing in the proband. Clinical features as well as radiological examinations and laboratory indices of osteoporosis secondary to AHC were analyzed in this study. Meanwhile, the proband was treated with classical antiresorptive drugs (bisphosphonates) for 2 years and switched to a vitamin K2 analogue for another 3 years, during which the efficacy of the drugs was evaluated. Results: The proband was identified as carrying a homozygous insertion mutation (p. Thr193GlyfsX13) in the NR0B1 (nuclear receptor subfamily 0, group B, member 1) gene, resulting in a premature stop codon due to a frameshift mutation. During treatment and follow-up, the proband did not respond well to bisphosphonate and developed atypical femoral fractures. Vitamin K2 improved clinical symptoms. In terms of bone mineral density (BMD), there is no evidence of any effect of vitamin K2 on the neck of femur, though some minor effects on spinal BMD cannot be excluded. Conclusions: Secondary osteoporosis induced by AHC deserves clinical attention. Unlike in primary osteoporosis, the curative effect of bisphosphonates was unsatisfactory and was more likely to cause atypical femoral fractures in long-term treatment. It is suggested that bone anabolic drugs may be better alternatives.

The effect of combined drug therapy in lateral fragility fractures of the femur: a prospective observational study.

OBJECTIVE: Due to a growing number of lateral fragility fractures, and their high economic and social impact, we evaluated the combined drug therapy effectiveness in lateral fragility femur fractures treated by intramedullary nailing surgery comparing the clinical and radiological results of two groups of patients. PATIENTS AND METHODS: From May 2019 to March 2020, we carried out a prospective observational study comparing the results of patients with femoral lateral fractures treated by the same intramedullary nail (PFNA Synthes®) using Clodronic acid and Vitamin D (study group, 25 patients) compared to patients with the same fractures treated with Vitamin D alone (control group, 25 patients). The evaluations were based on bone biochemical markers (serum calcium level, serum phosphate level, parathyroid hormone, Vitamin D, serum C-terminal telopeptide), Visual Analogic Scale and HHS (Harris Hip Score) score, and femur densitometric views. In order to evaluate the femur neck mineral bone density (BMD), two areas have been identified on the Anterior-Posterior view: the Region of Interest (ROI)1 (under the head screw) and the ROI2 (above the femoral screw). The BMD has been calculated using femur densitometric views at T0 (1st day post-surgery) and at T1 (12 months later). RESULTS: As far as the BMD average of ROI1 is concerned, we found a significant statistical increase at T1 in the study group (0.93±0.07 gr/cm2) vs. control group (0.88±0.08 gr/cm2), p=0.04. Both biochemical and densitometric values were statistically increased in the study group from T0 to T1 (p<0.05), while control group showed an improvement in the biochemical values only. CONCLUSIONS: Thanks to a one year follow-up, we are able to demonstrate that the administration of an adequate drug therapy after surgery can lead to a better control of the bone remodeling and reabsorption process.

Kefir peptides promote osteogenic differentiation to enhance bone fracture healing in rats.

AIMS: Fractures are the result of fragile bone structures after trauma caused by direct or indirect external impact or strong muscular contraction. Most fracture patients undergo surgical fixation to accelerate the healing process and restore the function of mutilated bone. Promoting the healing process remains an important issue for the treatment of bone fractures. Our previous studies demonstrated the remarkable bone-protective effects of kefir peptides (KPs) in ovariectomized rats and mice. In this study, we further evaluate the efficacy of KPs on fracture healing using a rat model of femoral fracture. MAIN METHODS: Fifteen 8-week-old male Sprague Dawley (SD) rats were divided into the sham, mock, and KPs groups, in which the mock and the KPs groups underwent femur-fracture surgery with nail fixation, while the sham group underwent a sham operation. The next day, rats were orally administered with daily 400 mg/kg of KPs (KPs group) or distilled water (sham and mock groups) for four weeks. X-ray imaging, histochemical staining and serum osteogenic markers were applied for fracture healing evaluation. In vitro, mouse bone marrow mesenchymal stem cells (BMMSCs) and MC3T3-E1 line were subjected to osteoblast differentiation in the presence of KPs and compared with no KPs treatment. KEY FINDINGS: The results demonstrated that KPs treatment improved the progression of the fracture healing process (p < 0.05) and significantly increased the expressions of Col1a1, Alp, Spp1, Vegfa and Cox2 mRNA in the femurs of the KPs-treated fractured rats compared to those of the mock-treated fracture rats. In vitro, KPs treatment promoted bone regeneration factor (Col1a1, Alp, M-csf and Phospho1) expression in MC3T3-E1-derived osteoblast cultures (on Day 3) and enhanced osteogenic differentiation and mineralization in BMMSC-derived osteoblast cultures (on Day 17 and Day 21). SIGNIFICANCE: This is the first study to show that KPs can help with fracture healing by promoting osteogenic differentiation, and it also suggests that KPs can be used as a nutritional supplement to accelerate fracture healing.

Atypical femoral fracture in a bisphosphonate-naïve patient on denosumab for osteoporosis.

A post-menopausal Caucasian woman sustained an atypical femoral fracture (AFF) after 5-years continuous denosumab for osteoporosis without prior bisphosphonate exposure. This is only the fifth case reported of AFF in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should consider AFF in patients taking denosumab even without prior bisphosphonate exposure. INTRODUCTION: Denosumab has demonstrated overwhelmingly favourable skeletal benefit/risk profile in managing post-menopausal osteoporosis with up to 10-year exposure in the extension of the pivotal FREEDOM randomised placebo-controlled trial. Four previous cases of atypical femoral fracture have been reported in bisphosphonate-naïve patients receiving denosumab for osteoporosis. METHODS: We present an 85-year-old Caucasian post-menopausal woman without prior fragility fracture who sustained unilateral atypical femoral fracture after 5-years continuous subcutaneous denosumab for osteoporosis. She had no prior bisphosphonate or glucocorticoid exposure and had known chronic kidney disease. RESULTS: X-ray scan demonstrated complete, non-comminuted left proximal femoral shaft fracture meeting radiographic criteria for an atypical femoral fracture. Computed tomography (CT) scan lower limbs revealed unusual side-by-side appearance of proximal and distal fragments of left proximal femur. DXA BMD was artefactually elevated at lumbar spine (1.504 g/cm2, T-score + 2.5) and low-normal at right femoral neck (0.856 g/cm2, T-score -1.0). Serum biochemistry showed renal impairment at baseline (eGFR 30 mL/min/1.73m2). Low-normal serum C telopeptide of type 1 collagen (CTX) (230 ng/L) indicated therapeutic suppression of bone resorption. CONCLUSION: The patient underwent intramedullary nailing of the femur and denosumab was ceased. This is only the fifth case reported of atypical femoral fracture in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should maintain a high index of suspicion for atypical femoral fracture in a patient taking denosumab even without prior bisphosphonate exposure.

Effects of bisphosphonates on appendicular fracture repair in rodents.

The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite their strength, bones do break and the main cause of fractures are trauma and decreased bone mineral density as a result of aging and/or pathology that weakens the bone's microarchitecture and subsequently, its material properties. Osteoporosis is a disease marked by increased osteoclast activity and decreased osteoblastic activity tipping the remodeling balance in favor of bone resorption and can be caused by aging, glucocorticoids, disuse and estrogen-deficiency. Ultimately, this leads to brittle and weaker bones which become more prone to trauma or stress-induced fractures. The current treatment for preventing and treating osteoporotic fractures is the use of antiresorptive drugs such as bisphosphonates (BPs) and denosumab, but unfortunately, their long-term use, especially with alendronate and ibandronate, has been associated with increased risk of atypical femoral fractures (AFFs); femoral diaphyseal fractures distal to the lesser trochanter but proximal to the supracondylar flare. The purpose of this review is to examine the information that exists in the literature examining the effects of BPs on fracture repair of long bones in rodent (rat and mouse) models. The focus on rodents stems from the scientific community's unresolved need to develop small animal models to examine the molecular, cellular, tissue and biomechanical mechanisms responsible for the development of AFFs and how best they can be treated.

The effect of cigarette smoke versus vaporized nicotine on healing of a rat femur.

INTRODUCTION: Little data exists regarding the effects of vaporized nicotine on healing. Our goal was to compare vaporized nicotine, combusted nicotine and control with respect to bone healing in a rat femur fracture model. MATERIALS AND METHODS: Forty-five male Sprague Dawley rats were divided into three equal cohorts. Rats were exposed to two cigarettes daily, an equivalent dose of vaporized nicotine, or control, six days a week. Exposures occurred for 4 weeks prior to iatrogenic femur fracture and intramedullary repair. Four additional weeks of exposure occurred prior to sacrifice. Radiographic, biomechanical and histologic analysis was conducted. RESULTS: No significant difference between the three groups was identified for total mineralized bone volume (p = 0.14), total volume of mature bone (p = 0.12) or immature bone (p = 0.15). Importantly, less total mineralized bone volume and immature bone volume was seen in the vaporized nicotine group compared to combusted tobacco, but results were not significant. Biomechanical testing revealed no significant difference in group torsional stiffness (p = 0.92) or maximum torque (p = 0.31) between the three groups. On histologic analysis, chi-square testing showed no significant difference in any category. CONCLUSIONS: This exploratory study compared combusted nicotine, vaporized nicotine and a control on rat femur fractures. While no statistically significant differences were identified, there were trends showing less total mineralized bone volume and immature bone volume in the vaporized nicotine group compared to the other groups. Additional study is warranted based on our findings.

Treatment of sirolimus in the pathological femoral fracture related to blue rubber bleb nevus syndrome: A case report.

RATIONALE: Blue rubber bleb nevus syndrome (BRBNS) is a rare condition with characteristic vascular malformations of the skin, most frequently lesions of the gastrointestinal tract and central nervous system, and less often, the musculoskeletal system. We report a 5-year case of BRBNS complicated with pathological femoral fracture that was successfully treated with sirolimus. PATIENT CONCERNS: We report the case of a 1-week-old girl with a diagnosis of BRBNS who had multiple venous malformations over her body. She also presented with right lower-limb swelling and complicated with a pathological femoral fracture. DIAGNOSES: BRBNS with the complication of pathological femoral fracture. INTERVENTIONS: Treatment with low-dose sirolimus as an antiangiogenic agent was administered, combined with hip spica protection. OUTCOMES: The vascular lesion was reduced after about 6 months and the fracture site had healed around 2.5 years after initiation of sirolimus therapy. There were no drug adverse effects at the 5-year follow-up point. The patient showed excellent spirit and no obvious sequelae were found. LESSONS: To the best of our knowledge, this is the first report of the successful use of sirolimus in a patient with a pathological femoral fracture related to BRBNS complications.

The effect of theranekron on femur fracture healing in an experimental rat model.

OBJECTIVES: The aim of this study was to investigate the radiological, biomechanical, histopathological and immunohistochemical effects of theranekron on fracture healing in an experimental rat model. MATERIALS AND METHODS: Forty-eight male albino Wistar rats were used. Four groups were formed, with 12 rats in each of theranekron groups 1 and 2, and control groups 1 and 2. After a fracture was created in the right femur of the rats included in the study, fixation was performed with an intramedullary Kirschner wire. Theranekron was administered subcutaneously to theranekron groups 1 and 2 at a dose of 0.3 mg/kg on days 0, 5 and 10. After radiographic analysis of the femurs of theranekron group 1 and control group 1 rats at four weeks of the study was performed, both groups were divided into two equal subgroups (six femurs in each group). Histopathological and immunohistochemical examinations were performed in one subgroup and biomechanical examination in the other subgroup. At the end of six weeks, the rats in theranekron group 2 and control group 2 were evaluated after applying the same procedure as in the fourth week. RESULTS: When the mean radiological scores of the theranekron and control groups were compared, a statistically significant difference was found in favor of the theranekron group at four and six weeks (p=0.028 and p=0.006, respectively). At four weeks, statistically significant higher biomechanical forces were obtained in the theranekron group compared to the control group (p=0.030). In the histopathological evaluation, the inflammation value of the control group at four weeks was statistically significantly higher than the theranekron group (p=0.027). The angiogenesis, osteoblast proliferation, and bone formation values of the theranekron group were significantly higher than the control group (p=0.014, p=0.014, and p=0.005, respectively). At six weeks, the bone formation values of the theranekron group were statistically significantly higher than the control group (p=0.021). The difference between the theranekron group and the control group scores of the immunohistochemical evaluation were statistically significantly different at four and six weeks (p=0.006 and p=0.011, respectively). CONCLUSION: Theranekron may play a role in accelerating fracture healing by reducing acute inflammation process in the early period of fracture union, increasing fracture strength, angiogenesis, osteoblast proliferation, and bone formation.

Effect of Low-Dose Dexmedetomidine Combined with Lumbosacral Plexus Block Guided by Ultrasound Imaging Based on Image Segmentation Algorithm in Fracture Surgery.

The aim of this study was to analyze the application of ultrasound-guided low-dose dexmedetomidine combined with lumbosacral plexus block based on artificial intelligence algorithm in the surgical treatment of proximal femoral fractures. 104 patients with proximal femoral fractures were divided into 52 cases in the experimental group (ultrasound-guided lumbosacral plexus block combined with dexmedetomidine based on local fitting image segmentation algorithm) and 52 cases in the routine group (endotracheal intubation and inhalation combined with general anesthesia). An image segmentation algorithm based on local fitting was constructed to enhance the ultrasound image. It was found that in the routine group, the heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) at the beginning of intravenous injection of dexmedetomidine, during skin incision, and half an hour after skin incision were significantly lower than those at admission (P < 0.05). The pressing times of patient-controlled intravenous analgesia (PCIA) in the conventional group (17.05 ± 6.85 times) were significantly higher than that in the experimental group (8.55 ± 4.12 times), and the difference was statistically significant (P < 0.05). The visual analogue scale (VAS) scores at 1, 5, 10, and 15 after operation in the routine group were significantly higher than those in the experimental group (P < 0.05). The number of dizziness, nausea, and vomiting, venous thrombosis of lower limbs, cardiovascular events, and pulmonary infection in the routine group on the 1st, 2nd, and 3rd days after operation were significantly higher than those in the experimental group (P < 0.05). In summary, the ultrasound-guided lumbar plexus-sacral plexus block combined with dexmedetomidine anesthesia based on image segmentation algorithm can effectively maintain the hemodynamic stability of patients, with remarkable analgesic effect and high safety.

Protective effect of Du-Zhong-Wan against osteoporotic fracture by targeting the osteoblastogenesis and angiogenesis couple factor SLIT3.

ETHNOPHARMACOLOGICAL RELEVANCE: Du-Zhong-Wan (DZW) is a traditional Chinese medicine (TCM) composed of Eucommia ulmoides Oliv. and Dipsacus asper Wall. ex C.B. Clarke in the ratio 1:1. Based on the TCM theory, DZW nourishes the kidney to strengthen the bones. The literature research revealed that DZW possesses anti-fatigue, anti-depressant, and anti-osteoporotic properties. However, the action and mechanism of DZW on osteoporotic fracture remains slightly unclear. AIM OF THE STUDY: To evaluate the pharmacological effect of DZW on ovariectomized mice with an open femoral fracture and reveal the underlying mechanism. MATERIALS AND METHODS: We conducted ovariectomy for 5 weeks, followed by unilateral open transverse femoral fracture for another 3 weeks in C57BL/6 mice; during this process, DZW was administrated. The femur bone and vertebra tissues were collected and analyzed by micro-computed tomography, histomorphometry, mechanical strength testing, immunohistochemistry staining, and qRT-PCR analyses. In addition, alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to determine the extent of osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs). Western blotting was performed to examine the protein expression. RESULTS: DZW treatment significantly improved the bone histomorphometric parameters in mice undergoing ovariectomy when combined with the femoral fracture, including an increase in the bone volume, trabecular number, and bone formation rate and a decrease in the bone erosion area. Simultaneously, DZW treatment histologically promoted fractured callus formation. Mechanical strength testing revealed significantly higher stiffness and an ultimate load after treatment with DZW. The angiogenesis of H-type vessels was enhanced by DZW, as evidenced by increased levels of CD31 and endomucin (EMCN), the H-type vessel endothelium markers, at the fractured endosteum and metaphysis regions. Relative to the osteoporotic fracture mice, the DZW treatment group showed an increased proangiogenic factor SLIT3 level. The increased level of SLIT3 was also recorded during the process of DZW-stimulated osteoblastogenesis from BMSCs. CONCLUSIONS: For the first time, we demonstrated that DZW promoted osteoporotic fracture healing by enhancing osteoblastogenesis and angiogenesis of the H-type vessels. This enhanced combination of osteoblastogenesis and angiogenesis was possibly related to the production of proangiogenic factor SLIT3 induced by DZW.

Tetracalcium phosphate treatment on experimental fracture model in rats.

OBJECTIVES: This study aims to investigate the efficacy of tetracalcium phosphate (TTCP) on fracture healing in rat femurs. MATERIALS AND METHODS: Forty-two female Wistar Albino rats were randomized into two groups (Group 1 and Group 2, n=21 for each). The left femur of all animals was fractured by osteotomy after deep anesthesia with ketamine. Additional procedure was not applied to the rats in Group 1. Rats in Group 2, following osteotomy, were applied to the fracture line approximately 2 mL TTCP. The animals were sacrificed at Weeks 1, 2, and 3 after surgery (seven animals were sacrificed from each group each week) and the broken femurs were removed. The femurs were examined first radiographically and second histopathologically. RESULTS: Radiologically, callus maturity and bone union increased with time in both groups. However, no significant differences were found regarding callus maturity and bone union in weekly comparisons (anteroposterior plain: p=0.53, p=0.37, p=0.42, lateral plain: p=0.26, p=0.42, p=0.87). Histopathologically, the fractures healed normally as the weeks progressed in both groups. The histological scores of Group 2 were higher at Weeks 1, 2, and 3. In the evaluation, no significant difference was found between the groups in terms of histological scores except for the first week (p=0.024, p=104, p=462, respectively). CONCLUSION: Although there was no statistically significant difference in the histological evaluation of both groups, except for the first week, the histological scores of Group 2, which underwent TTCP in all weeks, were higher. According to the results of this study, we believe that TTCP may be beneficial, particularly in the early stages of fracture healing.

An investigation of the effect of acrylamide on fracture healing in rats.

BACKGROUND: The aim of this study was to investigate the effects of acrylamide (AA) on fracture healing histologically, biochemically, and radiologically in a rat femur fracture model. METHODS: Scanning electron microscopy (SEM) imaging and Fourier transform infrared spectroscopy (FTIR), and UV (ultraviolet)-Vis (visible) spectrophotometer examination were performed for acrylamide characterization. In this study, after the femur fracture model was created, the groups were formed to include eight rats in each group (G) as follows: G1: 15th-day control, G2: 15th-day AA, G3: 30th-day control, G4: 30th-day AA. In G2 and G4, 5mg/kg acrylamide was administered 3 times a week by gastric gavage. The fracture was evaluated radiologically according to Lane-Sandhu scoring and histologically according to Huo scoring. The weight changes of the rats were recorded. Albumin, total protein, cholesterol, HDL, LDL, triglyceride, ALP, LDH, vit. D, PTH, Ca, P, WBC, Hb, Plt values were examined in the blood samples. The data were analyzed using the SPSS program. RESULTS: The characterization properties of acrylamide were confirmed. No significant weight change was observed in the rats during the study. When blood values were compared, a statistically significant difference was determined between albumin, total protein, phosphorus, white blood cell (WBC), and hemoglobin groups (p=0.41, p=0.00, p=0.003, p=0.019, and p=0,017, respectively). According to the histological score comparisons, G3 was significantly different from G1, G2, and G4 (p<0.05), and G4 was significantly different from G1 and G2 (p<0.05). According to Lane-Sandhu scoring, there was a significant difference between G2 and G3 and G4 (p: 0.0, p: 0.034), G1 and G3 (p: 0.001), respectively. CONCLUSION: AA adversely affects fracture healing even at low doses, as in the present study. According to the results of this study, the authors recommend a diet poor in acrylamide during fracture treatment. Therefore, further human studies are required to find out the complex effect of AA on bone healing and the body.

Dynamic Effects of the Third Generation Bisphosphonate of Risedronate on Rat Osteoporotic Fractures for Clinical Usage Guidance.

OBJECTIVE: To better understand the risks of bisphosphonates in order to develop guidance for appropriate clinical usage, to compared femoral fracture healing at different time points and to explore the effects of Residronate on fracture healing. METHODS: Osteoporosis model was achieved by ovariectomy surgery, followed by surgical incision of left femoral shaft 4 weeks after ovariectomy surgery. Three days after fracture surgery, risedronateor saline was fed by intragastric administration. X ray examination was used to check the callus formation, Bone Mineral Density (BMD), Bone Mineral Content (BMC), biomechanical, imaging and micromorphological of bone tissue as well as the trabecular bone parameters were all examined. The femoral pathology tissue of each rat was used to analyze trabecular bone parameters, including trabecular bone volume/tissue volume (Tb. BV/TV), bone surface to tissue volume ratio (BS/TV), trabecular bone mineral density (Tb. BMD), trabecular bone number (Tb. N), trabecular bone thickness (Tb. Th) and small bone Trabecular bone space (Tb. Sp). RESULTS: Via X-ray and pathologically, risedronate treatment promoted the callus forming at the fracture site during the following 6 weeks after osteoporotic fracture by X-ray (P < 0.01), increased the local bone mineral density (P < 0.01), and accelerated the fracture healing during the first 3 weeks (P <0.01), but delayed facture healing in the later 3 weeks (P < 0.01). Risedronate increased the bone continuity of fracture at 7th week, but this phenomenon was not found at the 10th week (P < 0.01). Delayed fracture healing occurred locally at the fracture site. At 7th week, Risedronate may promote cartilage cells proliferating at fracture site, increase the dense of bone trabeculae and the connection of bone trabeculae, thicken the bone cortex showing better fracture healing than OPF-Saline groups (P < 0.01). However, these parameter did not continue during the 7th and 10th weeks. Comparing the first and the later 3 weeks, the rats in group Osteoporotic Fracture-Risedronate (OPF-RD) accelerated the local fracture healing in the first 3 weeks but not in the last 3 weeks, which is consistent for the BMD and BMC among each group (P < 0.05). Through evaluation of bone mineral density and bone mineral content, risedronate dramatically increased the BMD at the fracture site and resulted in reduction of BMC by risedronate at the fracture site (P < 0.05) among each group still exist, indicating dramatic (P < 0.05). Through load testing, Risedronate increased the structural strength and mechanical indexes of the new callus (P < 0.01). CONCLUSION: Risedronate can improve the structural strength and mechanical index of newborn callus. Longer than 7 weeks usage of third generation bisphosphonate of risedronate does not contribute to osteoporotic fracture.