Systemic acylcarnitine levels are affected in response to multiple injuries and hemorrhagic shock: An analysis of lipidomic changes in a standardized porcine model.

INTRODUCTION: Along with recent advances in analytical technologies, tricarboxylic acid-cycle intermediates are increasingly identified as promising makers for cellular ischemia and mitochondrial dysfunction during hemorrhagic shock. For traumatized patients, the knowledge of the role of lipid oxidation substrates is sparse. In this study, we aimed to analyze the dynamics of systemic acylcarnitine (AcCa) release in a standardized polytrauma model with hemorrhagic shock. METHODS: Fifty-two male pigs (50 ± 5 kg) were randomized into two groups: group isolated fracture was subject to a standardized femur shaft fracture, and group polytrauma was subject to a femur fracture, followed by blunt chest trauma, liver laceration, and a pressure-controlled hemorrhagic shock for 60 minutes. Resuscitation was performed with crystalloids. Fractures were stabilized by intramedullary nailing. Venous samples were collected at six time points (baseline, trauma, resuscitation, 2 hours, 4 hours, and 6 hours). Lipidomic analysis was performed via liquid chromatography coupled mass spectrometry. Measurements were collated with clinical markers and near-infrared spectrometry measurements of tissue perfusion. Longitudinal analyses were performed with linear mixed models, and Spearman's correlations were calculated. A p value of 0.05 was defined as threshold for statistical significance. RESULTS: From a total of 303 distinct lipids, we identified two species of long-chain AcCas. Both showed a highly significant ( p < 0.001) twofold increase after hemorrhagic shock in group polytrauma that promptly normalized after resuscitation. This increase was associated with a significant decrease of the base excess ( p = 0.005), but recovery after resuscitation was faster. For both AcCas, there were significant correlations with decreased muscle tissue oxygen delivery ( p = 0.008, p = 0.003) and significant time-lagged correlations with the increase of creatine kinase ( p < 0.001, p < 0.001). CONCLUSION: Our results point to plasma AcCas as a possible indicator for mitochondrial dysfunction and cellular ischemia in hemorrhagic shock. The more rapid normalization after resuscitation in comparison with acid base changes may warrant further investigation.

Prevalence of Low Serum Alkaline Phosphatase and Hypophosphatasia in Adult Patients with Atypical Femur Fractures.

Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP), its manifestations may include atypical femoral fractures (AFF). However, the prevalence of low serum ALP and HPP in patients with AFF remains unknown. We retrospectively analyzed ALP levels and clinical manifestations compatible with HPP in 72 adult patients with confirmed AFF by chart review. ALP values were compared with those of a control group of patients with prior proximal femoral fracture during antiresorptive treatment (n = 20). Among the AFF patients, 18 (25%) had at least one serum ALP value ≤ 40 IU/L, although in all but one case, at least one ALP value > 40 IU/L was also detected at another time point. Most low ALP values were associated with antiresorptive treatment (P = 0.049) and lowest levels of ALP did not differ between the AFF and the control groups (P = 0.129). However, low ALP values among AFF patients were associated with a higher rate of bilateral AFF (50% vs 22%, P = 0.025), metatarsal fracture (33% vs 7%, P = 0.006), and with trends for more frequent use of glucocorticoid (22% vs 8%, P = 0.089) and proton pump inhibitor (61% vs 44%, P = 0.220). In one AFF patient with low ALP and clinical suspicion of HPP, a rare pathogenic heterozygous variant of the ALPL gene was identified. In conclusion, low ALP values are common among subjects with AFF and mainly related to concomitant antiresorptive medication. Hence, low serum ALP has low specificity for HPP among AFF patients.

Serum albumin level predicts survival after surgical treatment of metastatic femur fractures: a retrospective study.

BACKGROUND: Surgical treatment for metastatic pathological femur fractures is associated with high mortality. Correct estimation of prognosis helps in determining the palliative value of surgical treatment and informs surgical decision. This study evaluates the risk factors for mortality in these patients who were surgically treated. METHODS: This is a retrospective study of 112 patients with surgical treatment of metastatic pathological femur fractures. Risk factors evaluated included age, ASA status, Charlson comorbidity index, preoperative serum albumin and haemoglobin, primary tumour site, presence of visceral metastases, presence of spinal metastases, time from diagnosis of cancer to occurrence of pathological fracture, type of surgical procedure performed, lesion and whether treatment was received for an actual or impending fracture. A Cox regression model was used to determine if these factors were independent significant factors for survival. RESULTS: Mortality at 2 years after surgical treatment of metastatic femoral fractures was 86%. Cox regression analysis of risk factors revealed that preoperative serum albumin and type primary tumour were independent risk factors for mortality. Presence of visceral metastases was strongly correlated to serum albumin levels. CONCLUSION: Preoperative serum albumin level and primary tumour site are independent risk factors of survival in patients treated for pathological femur fractures. Serum albumin level may be used as a prognostic tool to guide treatment in this cohort of patients with high mortality rates.

Vitamin D, calcium and albumin bloodserum levels in Belgian orthopedic patients - is systematic screening justified?

In the setting of fracture care, orthopedic surgeons are primarily focused on treating the fracture itself, but more and more attention is being paid to prevention of such fractures and identifying risk factors associated with worse postoperative prognoses. In our study we collected postoperative vitamin D, calcium and albumin bloodserum levels from 163 patients who were admitted with a femur fracture and from 233 patients who were admitted for an elective hip arthroplasty during the period of 365 days. Results : 84.21% of the fracture population had a vitamin D deficiency (< 20 ng/mL) as well as 77.30% of the elective hip arthroplasty population. There were no significant seasonal differences in the fracture population. 80.27% of the fracture population had an albumin deficiency (< 29 g/L) compared to 38.75% of the reference population. There were no significant statistical differences in vitamin D and albumin bloodserum levels between the under 75 years old age group and the over 75 years old age group. We can make the tentative assumption that systematic screening for all hip fracture patients and all elective hip arthroplasty patients admitted to our orthopedic ward - independent of their age, season or pathology - is justified and we advise other hospitals to implement this as well.

Hyponatremia in elderly patients with fragility fractures of the proximal femur: a cross-sectional study / Hiponatremia em pacientes idosos com fratura proximal de fêmur por fragilidade: um estudo transversal

ABSTRACT Introduction: Proximal femur fractures affect the mortality and morbidity of elderly individuals. Recent studies have shown an association between fragility fractures and hyponatremia, a common fluid and electrolyte balance disorder. Objectives: This study aimed to investigate the occurrence of hyponatremia in patients with fragility fractures of the proximal femur. Methods: The authors looked into the data from the medical records of patients admitted to the emergency unit of the Real Hospital Português for fragility fractures of the proximal femur from 2014 to 2017. The study included patients with serum sodium levels recorded in their charts. Results: Fourteen of 69 (20.3%) patients with proximal femur fractures had hyponatremia. The main factors linked to hyponatremia were lung disease, and prescription of amiodarone and/or antidepressants. Conclusion: In elderly individuals, fragility fractures of the proximal femur may correlate with hyponatremia, particularly among patients on amiodarone or antidepressants.

RESUMO Introdução: Fratura de fêmur proximal tem impacto na mortalidade e morbidade de idosos. Estudos recentes vêm demonstrando associação entre fratura por fragilidade e hiponatremia, um distúrbio hidroeletrolítico comum na prática médica. Objetivos: Investigar a ocorrência de hiponatremia em pacientes com fratura proximal de fêmur por fragilidade. Metodologia: Foram coletados dados a partir de prontuários de pacientes admitidos na emergência do Real Hospital Português devido à fratura proximal de fêmur por fragilidade, entre 2014 e 2017, e aqueles com natremia disponível no prontuário eletrônico foram incluídos no estudo. Resultado: Dentre os 69 pacientes com fratura de fêmur proximal, houve uma ocorrência de 14 pacientes com hiponatremia, o que corresponde a 20,3%. Os principais fatores associados à hiponatremia no estudo foram doença pulmonar, uso de amiodarona e antidepressivos. Conclusão: Em idosos, a fratura de fêmur proximal por fragilidade pode estar correlacionada com hiponatremia, principalmente quando estão sob uso de amiodarona ou antidepressivos.

Hyponatremia in elderly patients with fragility fractures of the proximal femur: a cross-sectional study.

INTRODUCTION: Proximal femur fractures affect the mortality and morbidity of elderly individuals. Recent studies have shown an association between fragility fractures and hyponatremia, a common fluid and electrolyte balance disorder. OBJECTIVES: This study aimed to investigate the occurrence of hyponatremia in patients with fragility fractures of the proximal femur. METHODS: The authors looked into the data from the medical records of patients admitted to the emergency unit of the Real Hospital Português for fragility fractures of the proximal femur from 2014 to 2017. The study included patients with serum sodium levels recorded in their charts. RESULTS: Fourteen of 69 (20.3%) patients with proximal femur fractures had hyponatremia. The main factors linked to hyponatremia were lung disease, and prescription of amiodarone and/or antidepressants. CONCLUSION: In elderly individuals, fragility fractures of the proximal femur may correlate with hyponatremia, particularly among patients on amiodarone or antidepressants.

Haematology panel biomarkers for humeral, femoral, and tibial diaphyseal fractures.

PURPOSE: The neutrophil to lymphocyte ratio (NLR) is a simple predictor used in oncology and cardiology. We aimed to analyze the NLR profile of patients with diaphyseal fractures of the humerus, femur, and tibia. METHODS: We performed a cross-sectional, consecutive-case population-based study including 148 patients (41.9% men respectively 58.1% women) with humeral (23.0%), femoral (30.4%), and tibial (46.6%) diaphyseal fractures, admitted for surgical treatment in our level 1 trauma centre over two years. RESULTS: The differences in NLR between the studied subgroups were not significant (p = 0.067), the highest value being observed in patients with femoral fracture (5.6) in contrast to patients with humeral fracture (4). In the global cohort, there was a significantly positive correlation between NLR and PLR (platelet to lymphocyte ratio; Spearman's r = 0.595; p < 0.001). The stratified subgroup analysis found significant association between NLR and duration of admission only for patients with femoral fracture (Spearman's r = - 0.308; p < 0.001). When compared with controls, all three fracture types had significantly higher neutrophil numbers and NLR and lower thrombocyte numbers. CONCLUSIONS: NLR are elevated in femur diaphyseal fractures compared with tibia and humerus, up to cut-off values with negative prediction of outcome in malignancy and cardiovascular patients. Increased NLR are predictive of longer hospital admissions for femur fractures.

Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression.

Delayed union and nonunion are a significant concern in long bone fractures and spinal fusions. Treatment of nonunion often entails multiple revision surgeries that further increase the financial, physical, and emotional burden on patients. The optimal treatment strategy for nonunions remains unclear in many cases, and the risk of complications after revision procedures remains high. This is in part due to our limited understanding of the biological mechanisms that inhibit proper bone healing and lead to nonunion. And yet, few preclinical models directly investigate how healing is impacted after establishment of nonunion, with most instead primarily focusing on treatment immediately after a fresh bone injury. Here, we utilized a critical size femoral defect model in rats where treatment was delayed 8 weeks post-injury, at which time nonunion was established. In this study, acute and delayed treatments with bone morphogenetic protein-2 (BMP-2) were assessed. We found that delayed treatment resulted in decreased bone formation and reduced mechanical strength compared to acute treatment, even when BMP-2 dose was increased by 2.5 times the acute treatment dose. Interestingly, serum cytokine analysis at 12 weeks post-treatment revealed signs of chronic immune dysregulation after delayed treatment. In particular, non-responders (rats that did not exhibit defect bridging) demonstrated higher overall expression of inflammatory cytokines, including TNFα and IL-1ß, compared to responders. These findings suggest that re-establishing long-term immune homeostasis may be critical for successful bone healing, particularly after nonunion. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:299-307, 2019.

Evaluation of matrix metalloproteases as early biomarkers for bone regeneration during the applied Masquelet therapy for non-unions.

INTRODUCTION: In the current study, we sought to determine if serum concentrations of MMPs correlate with bone regeneration occurring during the course of the Masquelet-therapy and to identify if MMPs may serve as early biomarkers reflecting successful bone regeneration and tissue remodeling. MATERIAL AND METHODS: This study was designed as a prospective clinical observer study. We compared serum samples over the time of treatment, as a matched-pair analysis, from 10 patients who were treated successfully with the Masquelet-therapy (Responder) with 10 patients who did not respond to the Masquelet-therapy (Non-Responder). The quantitative measurement was performed with Luminex Performance Human High Sensitivity Assays according to manufacturer's instructions. The lab technician performing the Luminex assays was blinded to both patient data and clinical outcome. RESULTS: Analysis of the expression pattern of MMP-2, -8 and -9 showed significant differences between groups. Two days after the first step of the Masquelet therapy Responder showed peak values of MMP-8 and MMP-9 that where significantly higher (p = 0.003 and p = 0.042, respectively) than in Non-Responder. In contrast serum levels of MMP-2 were lower after the first step of the Masquelet therapy in the Non-Responder group. The ratio of MMP-9 and MMP-2 was significantly higher in the Responder group two days after step I (p = 0.031) as well as 4 weeks after step II (p = 0.030). CONCLUSION: The findings of the current study emphasize the potential role of MMPs as biomarkers in bone remodeling. In particular, a distinct expression of MMP-2 correlates with successful bone regeneration, whereas initial overexpression of MMP-2 serum levels might identify patients that have a higher risk for a poor outcome of the Masquelet-therapy. Furthermore, we were able to introduce the serum analysis of the ratio of MMP-9 and MMP-2 as promising novel modality for early prediction of the outcome of the Masquelet therapy. Further analysis of this ratio over time subsequent to the second step might serve as an early indicator of a favorable response to the induced membrane technique.

An increase in myeloid cells after severe injury is associated with normal fracture healing: a retrospective study of 62 patients with a femoral fracture.

Background and purpose-Nonunion is common in femoral fractures. Previous studies suggested that the systemic immune response after trauma can interfere with fracture healing. Therefore, we investigated whether there is a relation between peripheral blood cell counts and healing of femur fractures. Patients and methods-62 multi-trauma patients with a femoral fracture presenting at the University Medical Centre Utrecht between 2007 and 2013 were retrospectively included. Peripheral blood cell counts from hematological analyzers were recorded from the 1st through the 14th day of the hospital stay. Generalized estimating equations were used to compare outcome groups. Results-12 of the 62 patients developed nonunion of the femoral fracture. The peripheral blood-count curves of total leukocytes, neutrophils, monocytes, lymphocytes, and platelets were all statistically significantly lower in patients with nonunion, coinciding with significantly higher CRP levels during the first 2 weeks after trauma in these patients. Interpretation-Patients who developed femoral nonunion after major trauma demonstrated lower numbers of myeloid cells in the peripheral blood than patients with normal fracture healing. This absent rise of myeloid cells seems to be related to a more severe post-traumatic immune response.

Temporary inhibition of the plasminogen activator inhibits periosteal chondrogenesis and promotes periosteal osteogenesis during appendicular bone fracture healing.

INTRODUCTION: Aminocaproic acid is approved as an anti-fibrinolytic for use in joint replacement and spinal fusion surgeries to limit perioperative blood loss. Previous animal studies have demonstrated a pro-osteogenic effect of aminocaproic acid in spine fusion models. Here, we tested if aminocaproic acid enhances appendicular bone healing and we sought to uncover the effect of aminocaproic acid on osteoprogenitor cells (OPCs) during bone regeneration. METHODS: We employed a well-established murine femur fracture model in adult C57BL/6J mice after receiving two peri-operative injections of aminocaproic acid. Routine histological assays, biomechanical testing and micro-CT analyses were utilized to assess callus volume, and strength, progenitor cell proliferation, differentiation, and remodeling in vivo. Two disparate ectopic transplantation models were used to study the effect of the growth factor milieu within the early fracture hematoma on osteoprogenitor cell fate decisions. RESULTS: Aminocaproic acid treated femur fractures healed with a significantly smaller cartilaginous callus, and this effect was also observed in the ectopic transplantation assays. We hypothesized that aminocaproic acid treatment resulted in a stabilization of the early fracture hematoma, leading to a change in the growth factor milieu created by the early hematoma. Gene and protein expression analysis confirmed that aminocaproic acid treatment resulted in an increase in Wnt and BMP signaling and a decrease in TGF-ß-signaling, resulting in a shift from chondrogenic to osteogenic differentiation in this model of endochondral bone formation. CONCLUSION: These experiments demonstrate for the first time that inhibition of the plasminogen activator during fracture healing using aminocaproic acid leads to a change in cell fate decision of periosteal osteoprogenitor cells, with a predominance of osteogenic differentiation, resulting in a larger and stronger bony callus. These findings may offer a promising new use of aminocaproic acid, which is already FDA-approved and offers a very safe risk profile.

Preoperative platelettolymphocyte ratio as a prognostic factor in geriatric patients with proximal femoral fractures.

INTRODUCTION: The aim of this study was to investigate whether the platelet to lymphocyte ratio is a prognostic factor in geriatric patients who underwent surgery for proximal femoral fractures. MATERIALS AND METHODS: Clinical and laboratory data of 288 patients who underwent surgery for proximal femoral fracture were analysed. The patients were divided into six groups on the basis of sex (male and female) and survival duration after the operation (death within the first 6 months, death between the 6 and 12 months, survival for more than 12 months). Pre-operative platelet/lymphocyte ratios of these groups were compared. RESULTS: Of 288 patients, 187 were female and 101 were male. There was no significant difference between the groups with regard to age (p = 0.123 female groups) (p = 0.207 male groups). Although the preoperative platelet to lymphocyte ratio was higher in patients who died within 12 months than in those who survived beyond that, this platelet/lymphocyte ratio was statistically significant in females who died in the first 6 months (p = 0.038). CONCLUSION: A high preoperative platelet to lymphocyte ratio may be associated with high risk of mortality in patients who were operated for proximal femoral fracture.

A new multiple trauma model of the mouse.

BACKGROUND: Blunt trauma is the most frequent mechanism of injury in multiple trauma, commonly resulting from road traffic collisions or falls. Two of the most frequent injuries in patients with multiple trauma are chest trauma and extremity fracture. Several trauma mouse models combine chest trauma and head injury, but no trauma mouse model to date includes the combination of long bone fractures and chest trauma. Outcome is essentially determined by the combination of these injuries. In this study, we attempted to establish a reproducible novel multiple trauma model in mice that combines blunt trauma, major injuries and simple practicability. METHODS: Ninety-six male C57BL/6 N mice (n = 8/group) were subjected to trauma for isolated femur fracture and a combination of femur fracture and chest injury. Serum samples of mice were obtained by heart puncture at defined time points of 0 h (hour), 6 h, 12 h, 24 h, 3 d (days), and 7 d. RESULTS: A tendency toward reduced weight and temperature was observed at 24 h after chest trauma and femur fracture. Blood analyses revealed a decrease in hemoglobin during the first 24 h after trauma. Some animals were killed by heart puncture immediately after chest contusion; these animals showed the most severe lung contusion and hemorrhage. The extent of structural lung injury varied in different mice but was evident in all animals. Representative H&E-stained (Haematoxylin and Eosin-stained) paraffin lung sections of mice with multiple trauma revealed hemorrhage and an inflammatory immune response. Plasma samples of mice with chest trauma and femur fracture showed an up-regulation of IL-1ß (Interleukin-1ß), IL-6, IL-10, IL-12p70 and TNF-α (Tumor necrosis factor- α) compared with the control group. Mice with femur fracture and chest trauma showed a significant up-regulation of IL-6 compared to group with isolated femur fracture. CONCLUSIONS: The multiple trauma mouse model comprising chest trauma and femur fracture enables many analogies to clinical cases of multiple trauma in humans and demonstrates associated characteristic clinical and pathophysiological changes. This model is easy to perform, is economical and can be used for further research examining specific immunological questions.

Hemorrhagic shock and tissue injury drive distinct plasma metabolome derangements in swine.

BACKGROUND: Tissue injury and hemorrhagic shock induce significant systemic metabolic reprogramming in animal models and critically injured patients. Recent expansions of the classic concepts of metabolomic aberrations in tissue injury and hemorrhage opened the way for novel resuscitative interventions based on the observed abnormal metabolic demands. We hypothesize that metabolic demands and resulting metabolic signatures in pig plasma will vary in response to isolated or combined tissue injury and hemorrhagic shock. METHODS: A total of 20 pigs underwent either isolated tissue injury, hemorrhagic shock, or combined tissue injury and hemorrhagic shock referenced to a sham protocol (n = 5/group). Plasma samples were analyzed by UHPLC-MS. RESULTS: Hemorrhagic shock promoted a hypermetabolic state. Tissue injury alone dampened metabolic responses in comparison to sham and hemorrhagic shock, and attenuated the hypermetabolic state triggered by shock with respect to energy metabolism (glycolysis, glutaminolysis, and Krebs cycle). Tissue injury and hemorrhagic shock had a more pronounced effect on nitrogen metabolism (arginine, polyamines, and purine metabolism) than hemorrhagic shock alone. CONCLUSION: Isolated or combined tissue injury and hemorrhagic shock result in distinct plasma metabolic signatures. These findings indicate that optimized resuscitative interventions in critically ill patients are possible based on identifying the severity of tissue injury and hemorrhage.

Interleukin-6 as possible early marker of stress response after femoral fracture.

Bone fracture healing is a complex process which at best results in full recovery of function and structure of injured bone tissue, but all the mechanisms involved in this process, and their mutual interaction, are not fully understood. Despite advancement of surgical procedures, this type of fractures is still a major public health concern. In the last few decades, a lot of attention is focused on the oxygen-free radicals and inflammatory response markers as important factors of skeletal injury. Thus, the aim of the present study was to follow the changes in redox balance and inflammatory response in elderly patients with femoral fractures during the earliest stages of fracture healing, by measuring the values of the observed markers immediately after fracture, as well as the first, third, and seventh postoperative day. Present study was performed on a group of 65 elderly patients with femoral neck fractures, recruited from the Orthopedic Clinic, Clinical Centre Kragujevac in the period from February to May 2015. Redox status was measured spectrophotometrically and evaluated by measuring the levels of index of lipid peroxidation (measured as TBARS), nitrite (NO2-), superoxide anion radical (O2-), and hydrogen peroxide (H2O2) in plasma, while activities of corresponding antioxidative enzymes, catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) were measured in erythrocytes. The cytokine concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were determined in plasma, using ELISA assays specific for human cytokines. Our study showed that redox status and TNF-α in elderly patients with femoral fractures did not show statistically significant changes during the early phase of fracture healing. On the other hand, IL-6 increased statistically in first day after intervention. This preliminary study has shown our observations, and we hope that these results may help in better understanding mechanisms which are included at fracture healing. More importantly, this study attempted to create a platform for further research.

Tissue injury suppresses fibrinolysis after hemorrhagic shock in nonhuman primates (rhesus macaque).

BACKGROUND: Hypoperfusion is associated with hyperfibrinolysis and early death from exsanguination, whereas tissue trauma is associated with hypofibrinolysis and delayed death from organ failure. We sought to elucidate the effects of injury patterns on fibrinolysis phenotypes using a nonhuman primate (NHP) model. METHODS: NHPs were randomized to three injury groups (n = 8/group): 60 minutes severe pressure-targeted controlled hemorrhagic shock (HS); HS + soft tissue injury (HS+); or HS + soft tissue injury + femur fracture (HS++). Animals were resuscitated and monitored for 360 minutes. Blood samples were collected at baseline, end-of-shock, end-of-resuscitation (EOR), and T = 360 minutes for assessments of: severity of shock (lactate) and coagulation via prothrombin time, partial thromboplastin time, D-dimer, fibrinogen, antithrombin-III, von Willebrand factor, and viscoelastic testing (ROTEM). Results are reported as mean ± SEM; statistics: two-way analysis of variance and t-tests (significance: p < 0.05). RESULTS: Blood loss, prothrombin time, partial thromboplastin time, antithrombin-III, fibrinogen, and von Willebrand factor were equivalent among groups and viscoelastic testing revealed few differences throughout the study. D-dimer increased approximately threefold, at EOR in the HS group, and at T = 360 minutes in the HS+ and HS++ groups (p < 0.05). At EOR, in the HS group compared with the HS+ and HS++ groups; the D-dimer-lactate ratio was twofold greater (2.2 ± 0.3 vs. 1.1 ± 0.3 and 1.1 ± 0.2, respectively; p < 0.05) and tissue factor-activated fibrin clot 30-minute lysis index was lower (98 ± 1% vs. 100 ± 0% and 100 ± 0%, respectively; p < 0.05). CONCLUSION: NHPs in HS exhibit acute suppression of fibrinolysis in the presence of tissue injury. Additional assessments to more comprehensively evaluate the mechanisms linking tissue injury with the observed fibrinolysis shutdown response are warranted.

Responses to Treatment With Teriparatide in Patients With Atypical Femur Fractures Previously Treated With Bisphosphonates.

If oversuppression of bone turnover explained the association between bisphosphonate use and atypical subtrochanteric femur fractures (AFF), this could be reversed with anabolic treatment such as teriparatide. We conducted a prospective, open-label study in patients previously treated with bisphosphonates who sustained AFF, examining the response to 24-month treatment with teriparatide on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers (BTM), and fracture healing as well as quantitative histomorphometry. We studied 14 patients. Baseline BMD, BTM, and TBS varied widely. On initial bone biopsies, 12 of 14 patients showed tetracycline labels, but mineralizing surface/bone surface was below published normal values in all but 2. Lumbar spine BMD increased significantly at month 24 (6.1% ± 4.3%, p < 0.05 versus baseline), whereas total hip BMD and TBS did not change significantly. Changes in BTM occurred as reported previously for patients without AFF treated with teriparatide after prior bisphosphonate treatment. At month 24, fractures were healed in 6 patients, showed partial healing in 3, were unchanged in 2, and showed nonunion in 1. In a patient with two fractures, the fracture that occurred before teriparatide treatment was reported as healed, but the fracture that occurred while on treatment showed only partial healing. Bisphosphonate-treated patients who sustain AFF show heterogeneity of bone turnover. Treatment with teriparatide resulted in increases in BTM and lumbar spine BMD, as has been reported for patients without AFF. There was no significant effect of teriparatide on hip BMD, mineralizing surface to bone surface (MS/BS), or TBS and no consistent effect on fracture healing. In the context of a patient who has experienced an AFF after receiving bisphosphonate treatment, therapy with teriparatide for 24 months would be expected to increase BMD and BTM (and probably reduce the risk of fractures resulting from osteoporosis) but should not be relied on to aid in healing of the AFF. © 2017 American Society for Bone and Mineral Research.

Evidence for Altered Canonical Wnt Signaling in the Trabecular Bone of Elderly Postmenopausal Women with Fragility Femoral Fracture.

Wnt signaling, a major regulator of bone formation and homeostasis, might be involved in the bone loss of osteoporotic patients and the consequent impaired response to fracture. Therefore we analyzed Wnt-related, osteogenic, and adipogenic genes in bone tissue of elderly postmenopausal women undergoing hip replacement for either femoral fracture or osteoarthritis. Bone specimens derived from the intertrochanteric region of the femurs of 25 women with fracture (F) and 29 with osteoarthritis without fracture (OA) were analyzed. Specific miRNAs were analyzed in bone and in matched blood samples. RUNX2, BGP, and OPG showed lower expression in F than in OA samples, while OSX, OPN, BSP, and RANKL were not different. Inhibitory genes of Wnt pathway were lower in F versus OA. ß-Catenin protein levels were higher in F versus OA, whereas its cotranscriptional regulator (Lef1) was lower in F group. miR-204, which targets RUNX2, and miR-130a, which inhibits PPARγ, were lower and higher, respectively, in F versus OA serum samples. The present study showed an inefficient Wnt signal transduction in F group despite higher ß-catenin protein levels, consistent with the expected overall postfracture systemic activation towards osteogenesis. This transcriptional inefficiency could contribute to the osteoporotic bone fragility.

Bone turnover markers and the factors associated with atypical femur fractures among Japanese patients.

Many previous reports have indicated that atypical femur fractures (AFFs) are associated with the administration of bisphosphonates (BPs). A number of risk factors and hypotheses regarding the pathogenesis of AFFs have been reported to date. The purpose of the present study was to identify the factors associated with AFFs in Japanese individuals and to elucidate the association between bone metabolism and AFFs by evaluating bone turnover markers (BTMs). We prospectively reviewed all patients with femur fractures and identified the patients with AFFs and typical femur fractures (TFFs). We collected the demographic and clinical data that were relevant to the present study, namely age, gender, affected side, affected site, concomitant medical history, and comorbid conditions, and measured the levels of BTMs within 24h after trauma. Welch's test and Fisher's exact probability test were used for the statistical analyses. A total of 338 patients, including 10 patients with AFFs and 328 patients with TFFs, were analyzed under the inclusion criteria. The use of BPs (p<0.001) and collagen disease and chronic granulomatous disease (CD/CGD) (p=0.025) were more frequently observed in patients with AFFs than in patients with TFFs, while the levels of BTMs, including N-terminal propeptides of type 1 procollagen (P1NP), isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) and undercarboxylated osteocalcin (ucOC) were significantly lower in patients with AFFs than in patients with TFFs. Furthermore, the level of TRACP-5b was found to be significantly lower in patients with atypical subtrochanteric fractures than in atypical diaphyseal fractures (p=0.025). Moreover, the levels of P1NP (p=0.016) and TRACP-5b (p=0.015) were found to be significantly lower in patients with AFFs than in patients with TFFs in a subgroup analysis of BPs users. The use of BPs was considered to be a factor associated with AFFs. Our comparison of the BTMs in patients with AFFs and TFFs indicated that the severe suppression of bone turnover was associated with the pathogenesis of AFFs. The extent of the influence of suppressed turnover on the pathogenesis of AFFs may differ depending on the fracture site.

Perioperative inflammatory response in major fracture: do geriatric patients behave differently?

PURPOSE: Interleukin-6 is a mainly proinflammatory interleukin and an indicator for the magnitude of surgery. The IL-6 serum concentration correlates with injury severity, the extent of tissue trauma and has negative impact on prognosis. To date it is unclear whether the immunologic changes assessed are age dependent. The aim of this study is to compare the surgical inflammatory response in different age groups. METHODS: Data were collected at a level-1 university trauma center in a prospective, consecutive cohort study. IL-6 levels were analyzed via ELISA from venous blood samples of cohorts of injuries with typical peak incidence: patients with unstable fractures of the spine (SP) for a middle-aged group and patients with fractures of the proximal femur (PF) for a geriatric group. Surgical treatment was performed using minimal-invasive instrumentation. RESULTS: 25 patients in group SP (age: 51 years ± 20) and 16 patients in the group PF (age: 73 years ± 16) were analysed. Group PF showed higher baseline IL-6 concentrations. Surgical treatment was followed by a significant increase of IL-6 levels in both groups 4 and 24 h postoperatively. Concentration profiles were similar, but increase was significantly higher in the PF group 4 h after surgery. CONCLUSION: Both the operative treatment of fractures in a middle-aged (SP) and a geriatric group (PF) lead to significant increasing of IL-6 levels. In view of a comparative surgical burden, these data suggest that age may be a confounding factor for a surgery induced pro-inflammatory response in the early postoperative stage.