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Abstract. Objectives:. To develop and validate a prediction model for a deep surgical site infection (SSI) after fixation of a tibial plateau or pilon fracture. Design:. Pooled data from 2 randomized trials (VANCO and OXYGEN). Setting:. Fifty-two US trauma centers. Patients:. In total, 1847 adult patients with operatively treated tibial plateau or pilon fractures who met criteria for a high risk of infection. Intervention:. We considered 13 baseline patient characteristics and developed and externally validated prediction models using 3 approaches (logistic regression, stepwise elimination, and machine learning). Main Outcomes and Measures:. The primary prediction model outcome was a deep SSI requiring operative debridement within 182 days of definitive fixation. Our primary prognostic performance metric for evaluating the models was area under the receiver operating characteristic curve (AUC) with clinical utility set at 0.7. Results:. Deep SSI occurred in 75 VANCO patients (8%) and in 56 OXYGEN patients (6%). The machine learning model for VANCO (AUC = 0.65) and stepwise elimination model for OXYGEN (AUC = 0.62) had the highest internal validation AUCs. However, none of the external validation AUCs exceeded 0.64 (range, 0.58 to 0.64). Conclusions:. The predictive models did not reach the prespecified clinical utility threshold. Our models' inability to distinguish high-risk from low-risk patients is likely due to strict eligibility criteria and, therefore, homogeneous patient populations.

Background:. Orthopaedic academic partnerships between high-income countries (HICs) and low and middle-income countries (LMICs) are an effective method to increase research and scholarly support. The purpose of this study was to perform a systematic literature review of the current state of partnerships worldwide and assess the quality, quantity, and content of their research output. Methods:. A systematic review was conducted using 4 academic databases: PubMed, MEDLINE, Embase, and CENTRAL. Article eligibility criteria included articles published between January 2017 and 2022, with orthopaedic authors from at least 1 HIC and LMIC. Articles related to global orthopaedic surgery with exclusively HIC or LMIC authors were excluded. Results:. The database search yielded 25,928 articles, and after deduplication, 21,145 articles were included in the screening. After title and abstract screening, 408 articles underwent full-text review for eligibility. The final list of eligible articles for extraction included 310 publications in 127 journals. Published articles increased over time (46 in 2017 to 88 in 2021) and were most commonly published in the Journal of Bone and Joint Surgery (20, 6.5%). Open-access articles (203, 65.5%) had a significantly greater Journal Citation Indicator (p = 0.024) than non-open-access articles. Most studies (40.7%) were observational, with few (3.6%) randomized controlled trials. Orthopaedic trauma (38.1%) was the most common subspecialty, followed by spine (14.8%) and pediatrics (14.2%). Most partnerships were sponsored by North American authors in 65 LMICs, primarily China, India, and the sub-Saharan African region. Conclusion:. This study identified 310 articles published by orthopaedic international academic partnerships in 106 countries over the past 5 years, demonstrating that collaborations between LMIC/HIC partners nearly doubled over the study period. Sixty-five percent of the articles were published in open-access journals.

Abstract. Background:. Despite the recent emphasis on promoting international collaborations within orthopaedic surgery, criteria for determining the strengths of such partnerships has not been established. The purpose of this study was to evaluate orthopaedic experts' perceptions of the most valuable characteristics of international academic partnerships. Methods:. This study was conducted using a modified Delphi methodology. Experts were identified through the Consortium of Orthopaedic Academic Traumatologists (COACT). Responses were collected from February to September 2022. Three rounds of surveys listing possible topics on a 5-point Likert scale were used to develop consensus among a group of experts. Consensus criteria for topic inclusion in the final scale was determined as a rating of “strongly agree” or “agree” by ≥70% of the participants in the third survey. Results:. The Round 1 survey was distributed to 96 invited participants within the COACT network, of which 50 experts (52.1%) completed the first survey. Consensus was reached on 54 topics organized into the following 5 categories: Research, Advocacy/Leadership, Training/Surgical Skills, Education/Knowledge Exchange, and Sustainability and Safety (RATES Criteria). Conclusions:. Determining the most valuable characteristics of successful international academic partnerships can lead to more sustainable, mutually beneficial collaborations. The criteria identified in this study can provide the foundation for developing new partnerships and assessing existing ones.

Abstract. Open fractures continue to be a challenging clinical problem throughout the world, and Japan is no exception. Surgeons are faced with critical decisions throughout the care of these injuries that can have significant effects in clinical outcome, ranging from the type and timing of antibiotic administration, fixation, soft-tissue management, and interventions for postfracture complications. In October 2022, the Japanese Society for Fracture Repair (JSFR) was invited to represent Japan as the Guest Nation society at the 38th Annual Meeting of the Orthopaedic Trauma Society held in Tampa, Florida. The JSFR organized a symposium, entitled “Management of Open Fracture and related complications—the Japanese way,” that featured cutting-edge approaches to open fractures in their country, including presentations on the “fix-and-flap” approach, local antibiotics perfusion delivery, and a “chipping” method for the stimulation of bone healing. This article summarizes the content of these 3 presentations from that symposium.

ABSTRACT Objective: To report on the experience and impressions of the Brazilian orthopedic trauma surgeons attending the Leadership Development Program (LDP) hosted by the Sociedade Brasileira do Trauma Ortopédico (SBTO) in Sao Paulo, Brazil on November 4, 2022. Methods: Forty-eight orthopedic trauma surgeons from five different regions throughout Brazil were provided a link to complete The Big Five Test, a validated online personality assessment. The questionnaire was available in Portuguese and was intended to provide a background on individual personality traits and their influence on interpersonal interactions. The LDP integrated content from literature reviews specific to Latin America, established leadership programs from leading business schools, and various subject matter experts. Prior to the start of the LDP, participants received a pre-course survey evaluating demographic information, a needs assessment, and the prioritization of leadership topics utilizing a 5-point Likert-scale. Attendees participated in the one-day, interactive LDP focusing on the fundamental principles of leadership development, communication, personal development, emotional intelligence and negotiation. Following the LDP, a post-course evaluation was administered to determine the participants’ overall experience, and suggestions for LDP improvement. Results: Forty-one of the forty-eight course participants completed the pre-course evaluation, whereas forty-six of the forty-eight participants completed the post-course evaluations. Overwhelmingly, the lack of opportunity was most prevalently reported as the main obstacle to attending a leadership course, as cited by 56% of respondents. Conclusion: Expanding the accessibility, diversity, and customizability of leadership programs can facilitate the development of personal tools needed to move healthcare forward. Critical topics include emotional intelligence and other differentiating leadership qualities that distinguish true transformational and servant leaders. Advancing leadership skills can stimulate networking, expose learners to experiential learning styles, inspire others to create positive change, and engender creative solutions for systematic improvements and health outcomes. Level of Evidence III; Individual Case-Control Studies.

Background:. Fracture-related infection is one of the most challenging complications in orthopaedic trauma surgery. However, the effect of infection on functional and pain-related outcomes has not been well established. The aims of this study were to evaluate functional recovery for patients with fracture and a deep surgical site infection compared with patients with fracture without infection and to evaluate whether pain severity, social support, and preinjury mental health have a moderating effect on the magnitude and direction of the relationship between deep surgical site infection and functional recovery. Methods:. This is a secondary retrospective cohort study using prospectively collected data from the VANCO trial (Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection) and the OXYGEN (Supplemental Perioperative Oxygen to Reduce Surgical Site Infection After High Energy Fracture Surgery) trial. In this study, 2,116 patients with tibial plateau, pilon, or calcaneal fractures at high risk for infection were included. Patients were divided into cohorts of patients who experienced a deep surgical site infection and those who did not. The primary outcome measure was the functional outcome using the Veterans RAND 12-Item Health Survey (VR-12). Results:. After controlling for covariates, deep surgical site infection was independently associated with functional outcome, with a 3.3-point reduction in the VR-12 Physical Component Score, and pain severity was independently associated with functional outcome, with a 2.5-point reduction in the VR-12 Physical Component Score. Furthermore, the Brief Pain Inventory pain severity demonstrated an important moderating effect on the relationship between infection and functional outcome. In patients with lower pain scores, infection had a large negative impact on functional outcome, whereas, in patients with higher pain scores, infection had no significant impact on functional outcome. Furthermore, the functional outcome in the entire cohort remains at only 61% of baseline. Conclusions:. This study documents the negative impact of postoperative infection on functional recovery after injury, as well as the novel finding of pain severity as an important moderating factor. This study emphasizes not only the importance of developing effective interventions designed to reduce postoperative infection, but also the role that factors that moderate pain severity plays in limiting recovery of physical function. Level of evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Purpose:. This study examined the leadership development themes that global orthopaedic surgeons in differently resourced countries perceive as essential components and evaluated barriers to attending leadership development programs. Methods:. This multinational, 45-question survey engaged orthopaedic surgeons (one expert per country). The questionnaire collected participants' demographics, perception of effective leadership traits, and valuation of various leadership themes based on importance and interest. Results:. The survey was completed by 110 orthopaedic surgeons worldwide. Respondents most commonly reported holding a leadership position (87%) in hospital settings (62%), clinical settings (47%), and national orthopaedic societies (46%). The greatest proportion of participants reported having never attended a leadership course (42%). Participants regarded “high performing team-building,” “professional ethics,” and “organizational structure and ability to lead” as the most important leadership themes. No significant (P ≤ 0.05) differences were identified among perceived importance or interest in leadership themes between income levels; however, statistically significant differences were identified in the questionnaire; respondents in low- and middle-income countries (LICs/LMICs) demonstrated a stronger interest in attending a leadership course than those in high-income countries (HICs) (98% vs. 79%, P = 0.013), and fewer surgeons in LICs/LMICs had taken personality assessment tests than those in HICs (22% vs. 49%, P = 0.019). The most common barriers to attending leadership courses were lack of opportunities and invitations (57%), difficulty missing work (22%), and cost of course attendance (22%). Conclusions:. These findings can better inform the development of effective curricula and provide a framework for a successful model for the future. Level of Evidence:. V.

Introduction:. Fragility fractures of the pelvis (FFP) in elderly patients are an underappreciated injury with a significant impact on mobility, independency, and mortality of affected patients and is a growing burden for society/health care. Given the lack of clinical practice guidelines for these injuries, the authors postulate there is heterogeneity in the current use of diagnostic modalities, treatment strategies (both operative and nonoperative), and follow-up of patients with FFP. The goal of this study was to assess international variation in the management of FFP. Methods:. All International Orthopaedic Trauma Association (IOTA) steering committee members were asked to select 15 to 20 experts in the field of pelvic surgery to complete a case-driven international survey. The survey addresses the definition of FFP, use of diagnostic modalities, timing of imaging, mobilization protocols, and indications for surgical management. Results:. In total, 143 experts within 16 IOTA societies responded to the survey. Among the experts, 86% have >10 years of experience and 80% works in a referral center for pelvic fractures. However, only 44% of experts reported having an institutional protocol for the management of FFP. More than 89% of experts feel the need for a (inter)national evidence-based guideline. Of all experts, 73% use both radiographs and computed tomography (CT) to diagnose FFP, of which 63% routinely use CT and 35% used CT imaging selectively. Treatment strategies of anterior ring fractures were compared with combined (anterior and posterior ring) fractures. Thirty-seven percent of patients with anterior ring fractures get admitted to the hospital compared with 75% of patients with combined fractures. Experts allow pain-guided mobilization in 72% after anterior ring fracture but propose restricted weight-bearing in case of a combined fracture in 44% of patients. Surgical indications are primarily based on the inability to mobilize during hospital admission (33%) or persistent pain after 2 weeks (25%). Over 92% plan outpatient follow-up independent of the type of fracture or treatment. Conclusion:. This study shows that there is a great worldwide heterogeneity in the current use of diagnostic modalities and both nonoperative and surgical management of FFP, emphasizing the need for a consensus meeting or guideline.

Summary:. Severe open fractures present challenges to orthopaedic surgeons worldwide, with increased risks of significant complications. Although different global regions have different resources and systems, there continue to be many consistent approaches to open fracture care. Management of these complex injures continues to evolve in areas ranging from timing of initial operative debridement to the management of critical-sized bone defects. This review, compiled by representative members of the International Orthopaedic Trauma Association, focuses on several critical areas of open fracture management, including antibiotic administration, timing of debridement, bone loss, soft tissue management, and areas of need for future investigation.

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.

Abstract. The incidence of periprosthetic fractures (PPFs) continues to increase worldwide. The goal of management is to restore mobility early while minimizing potential treatment complications. The general medical frailty of patients sustaining PPFs complicates the management of these conditions, with many of those affected being highly susceptible to the consequences of impaired mobilization. Outcomes depend on patient-related (eg, age, physiological condition, medical comorbidities, quality of bone, presence of osteolysis, previous procedures, sex) and surgeon-related (eg, diagnosis, choice of procedure, selected implant, and surgical technique) factors, and preventative measures to decrease the risk of PPFs should be pursued whenever possible. The articles in this supplement address the treatment of the most commonly encountered PPFs, specifically those in the proximal humerus, acetabulum, proximal femur, distal femur, and proximal tibia. This work represents a collaborative effort of the member societies of the International Orthopaedic Trauma Association, an international association of orthopaedic organizations dedicated to the promotion of musculoskeletal trauma care through advancements in patient care, research, and education. The expectation is that the information provided in this supplement will improve the care of patients with PPFs.

Objective:. International observerships are one of many efforts aimed at addressing disparities in orthopaedic trauma care globally. However, their impact on visiting surgeons and their home countries, as well as the challenges faced by participating surgeons, are not well-documented. Methods:. A survey was distributed to overseas surgeons who participated in an orthopaedic trauma observership from 2009 to 2020. Surgeons were identified through North American institutions previously recognized by the authors as having hosted international observerships. Information gathered included participant demographics, details of and perceived impact of the observership, and barriers faced before, during, and after the program. Responses from 148 international surgeons (ISs) from 49 countries were analyzed. Results:. Sixty percent of observerships were at academic programs, 57% lasted 1–3 months, and 60% were self-funded. Participants identified cost and housing as primary barriers. After completing their observership, lack of funding, equipment and support staff, and excessive workload prevented participants from implementing changes at their clinical practice. Most observers believed that they gained relevant clinical (89%) and surgical knowledge (67%) and developed a professional network of North American hosts (63%). The most common suggested changes to the observership were greater hands-on experience in the operating room and structured goal setting relevant to the visiting surgeon. Conclusions:. Visiting surgeons find North American orthopaedic trauma observerships helpful in improving their surgical and clinical skills. However, financial constraints and resource limitations at their clinical practice and limited operative experience during the observership present barriers to maximizing this clinical experience. To enhance the relevance of clinical observerships for ISs and impact global orthopaedic trauma care, the unique needs and challenges facing ISs must be addressed. Level of Evidence:. IV—Cross-Sectional Study.

IntroductionClinical and preclinical data suggest accelerated bone fracture healing in subjects with an additional traumatic brain injury (TBI). Mechanistically, altered metabolism and neuro-endocrine regulations have been shown to influence bone formation after combined fracture and TBI, thereby increasing the bone content in the fracture callus. However, the early inflammatory response towards fracture and TBI has not been investigated in detail so far. This is of great importance, since the early inflammatory phase of fracture healing is known to be essential for the initiation of downstream regenerative processes for adequate fracture repair.MethodsTherefore, we analyzed systemic and local inflammatory mediators and immune cells in mice which were exposed to fracture only or fracture + TBI 6h and 24h after injury.ResultsWe found a dysregulated systemic immune response and significantly fewer neutrophils and mast cells locally in the fracture hematoma. Further, local CXCL10 expression was significantly decreased in the animals with combined trauma, which correlated significantly with the reduced mast cell numbers.DiscussionSince mast cells and mast cell-derived CXCL10 have been shown to increase osteoclastogenesis, the reduced mast cell numbers might contribute to higher bone content in the fracture callus of fracture + TBI mice due to decreased callus remodeling.

Abstract. Introduction: The use of national databases for orthopaedic research has increased significantly in the past decade. The purpose of this study was to report on the current state of orthopaedic trauma registries in 21 countries represented by 20 member societies of the International Orthopaedic Trauma Association (IOTA). Methods: A web-based survey was circulated to all IOTA member societies. The survey consisted of 10 questions (five open-ended and five multiple-choice). Results: Representatives from all 21 countries replied. Five countries (24%) do not currently have or plan to start a registry. One country (5%) had a registry that is now closed. Two countries (10%) are building a registry. Thirteen countries (62%) reported at least one active registry, including four countries with more than one registry. Of the 14 countries that reported the existence of a registry, there were 17 registries noted that included patients with fracture. There were seven registries dedicated to high-energy trauma and four registries that included elderly hip fractures. In addition, 9/17 representatives reported the utilization of a fracture classification and 9/17 noted some level of mandate from medical providers. All responders but one reported that data were manually entered into their registries. Conclusions: Despite the shared vision of quality control and outcome optimization, IOTA society representatives reported significant variability in the depth and format of the orthopaedic trauma registry among IOTA members. These findings represent an opportunity for collaboration across organizations in creating fracture registries. Level of Evidence: Level IV.

Abstract. Background:. Argentina is a country with varying access to orthopedic surgical care. The Argentine Association of Trauma and Orthopedics (AATO) “Interior Committee” was developed to address potential regional differences and promote standardization of orthopedic trauma care. The paper assesses the level of national standardization of the management of open tibia fractures across 9 provinces in Argentina. Methods:. Utilizing a matched-comparison group design, management of these injuries were assessed and compared between 3 groups: an “AATO Exterior Committee” consisting of surgeons that practice in Buenos Aires, and 2 “Interior Committees,” comprising surgeons that practice in outlying provinces, 1 of which is affiliated with the AATO, and 1 that is not affiliated with the AATO. The study was conducted in 2 phases: phase 1 assessed open tibia fracture management characteristics, and phase 2 evaluated the management of soft-tissue wound coverage following open fractures. Results:. Soft-tissue coverage procedures for Gustilo Anderson Type IIIB fractures were more commonly performed by orthopedic surgeons in Interior Committees than the AATO Exterior Committee. Greater rates of definitive wound coverage within 7 days post-injury were reported in both Interior Committees compared to the Exterior Committee. Plastic surgeons were reported as more available to those in the AATO Exterior Committee group than in the AATO Interior Committees. Conclusion:. While treatment patterns were evident among groups, differences were identified in the management and timing of soft-tissue coverage in Gustilo Anderson Type IIIB fractures between the Exterior Committee and both Interior Committees. Future targeted educational and surgical hands-on training opportunities that emphasize challenges faced in resource-limited settings may improve the management of open tibia fractures in Argentina.

BackgroundCardiac injuries following trauma are associated with a worse clinical outcome. So-called trauma-induced secondary cardiac injuries have been recently described after experimental long bone fracture even in absence of direct heart damage. With the progressive aging of our society, the number of elderly trauma victims rises and therefore the incidence of hip fractures increases. Hip fractures were previously shown to be associated with adverse cardiac events in elderly individuals, which have mainly been attributed to pre-conditioned cardiac diseases. The aim of the present study was to investigate the effect of hip fractures on the heart in healthy young and middle-aged mice.Materials and MethodsYoung (12-week-old) and middle-aged (52-week-old) female C57BL/6 mice either received an intramedullary stabilized proximal femur fracture or sham treatment. The observation time points included 6 and 24 h. Systemic levels of pro-inflammatory mediators as well as local inflammation and alterations in myocardial structure, metabolism and calcium homeostasis in left ventricular tissue was analyzed following hip fracture by multiplex analysis, RT-qPCR and immunohistochemistry.ResultsAfter hip fracture young and middle-aged mice showed increased systemic IL-6 and KC levels, which were significantly elevated in the middle-aged animals. Furthermore, the middle-aged mice showed enhanced myocardial expression of HMGB1, TLR2/4, TNF, IL1β and NLRP3 as well as considerable alterations in the myocardial expression of glucose- and fatty acid transporters (HFABP, GLUT4), calcium homeostasis proteins (SERCA) and cardiac structure proteins (desmin, troponin I) compared to the young animals following hip fracture.ConclusionYoung and middle-aged mice showed local myocardial alterations, which might predispose for the development of secondary cardiac injury following hip fracture. Age and the age-associated phenomenon of ‘inflammaging’ seemed to be an independent risk factor aggravating and accelerating cardiac alterations following hip fracture.

Background: Trauma is the leading cause of death and disability worldwide, especially in the young population. Cardiac injuries are an independent predictor for a poor overall outcome after trauma. The aim of the present study was to analyze systemic inflammation as well as local cardiac inflammation after experimental limb-, neuro- and combined trauma in mice. Methods: Male C57BL/6 mice received either a closed tibia fracture (Fx), isolated traumatic brain injury (TBI) or a combination of both (Fx ​+ ​TBI). Control animals underwent sham procedure. After 6 and 24 ​h, systemic levels of inflammatory mediators were analyzed, respectively. Locally, cardiac inflammation and cardiac structural alterations were investigated in left ventricular tissue of mice 6 and 24 ​h after trauma. Results: Mice showed enhanced systemic inflammation after combined trauma, which was manifested by increased levels of KC, MCP-1 and G-CSF. Locally, mice exhibited increased expression of inflammatory cytokines (IL-1β, TNF) in heart tissue, which was probably mediated via toll-like receptor (TLR) signaling. Furthermore, mice demonstrated a redistribution of connexin 43 in cardiac tissue, which appeared predominantly after combined trauma. Besides inflammation and structural cardiac alterations, expression of glucose transporter 4 (GLUT4) mRNA was increased in the heart early after TBI and after combination of TBI and limb fracture, indicating a modification of energy metabolism. Early after combination of TBI and tibia fracture, nitrosative stress was increased, manifested by elevation of nitrotyrosine in cardiac tissue. Finally, mice showed a trend of increased systemic levels of cardiac troponin I and heart-fatty acid binding protein (HFABP) after combined trauma, which was associated with a significant decrease of troponin I and HFABP mRNA expression in cardiac tissue after TBI and combination of TBI and limb fracture. Conclusion: Mice exhibited early cardiac alterations as well as alterations in cardiac glucose transporter expression, indicating a modification of energy metabolism, which might be linked to increased systemic- and local cardiac inflammation after limb-, neuro- and combined trauma. These cardiac alterations might predispose individuals for secondary cardiac damage after trauma that might compromise cardiac function after TBI and long bone fracture. Translational potential statement: Injuries to the head and extremities frequently occur after severe trauma. In our study, we analyzed the effects of closed tibia fracture, isolated TBI, and the combination of both injuries with regard to the development of post-traumatic secondary cardiac injuries.

Abstract Musculoskeletal injuries are the most common reason for surgery in severely injured patients. In addition to direct cardiac damage after physical trauma, there is rising evidence that trauma induces secondary cardiac structural and functional damage. Previous research associates hip fractures with the appearance of coronary heart disease: As 25% of elderly patients developed a major adverse cardiac event after hip fracture. 20 male pigs underwent femur fracture with operative stabilization via nailing (unreamed, reamed, RIA I and a new RIA II; each group n = 5). Blood samples were collected 6 h after trauma and the concentration of troponin I and heart-type fatty acid binding protein (HFABP) as biomarkers for EMD were measured. At baseline and 6 h after trauma, transesophageal ECHO (TOE) was performed; and invasive arterial and left ventricular blood pressure were measured to evaluate the cardiac function after femur fracture. A systemic elevation of troponin I and HFABP indicate an early myocardial damage after femur fracture in pigs. Furthermore, various changes in systolic (ejection fraction and cardiac output) and diastolic (left ventricular end-diastolic pressure, mitral valve deceleration time and E/A ratio) parameters illustrate the functional impairment of the heart. These findings were accompanied by the development of valvular dysfunction (pulmonary and tricuspid valve). To the best of our knowledge, we described for the first time the development of functional impairment of the heart in the context of EMD after long bone fracture in pigs. Next to troponin and HFABP elevation, alterations in the systolic and diastolic function occurred and were accompanied by pulmonary and tricuspid valvular insufficiency. Regarding EMD, none of the fracture stabilization techniques (unreamed nailing, reaming, RIA I and RIA II) was superior.

Abstract. Osteoporotic fractures often result in reduced function after healing, with associated pain, disability, loss of independence, and reduced quality of life. Following osteoporotic fractures, it is common for older adults to sustain subsequent, or secondary, fractures. These fractures include those of the proximal femur, vertebrae, distal radius, proximal humerus, and other sites. Although widely recognized as a gap in care, the implementation of appropriate secondary fracture prevention programs has been carried out in most countries. A Fracture Liaison Service represents the best secondary fracture prevention model of care for managing osteoporosis following fragility fractures and falls. These programs have proven to be cost-effective, and represent a major advancement in patient care over those “usual care practices” seen in most community and academic medical centers. Key Fracture Liaison Service programmatic functions include case finding, patient assessment, osteoporosis assessment, initiation of osteoporosis treatment, falls prevention, education, and exercise.

Abstract. Osteoporotic fractures, a major cause of disability and associated medical care expenditures, are expected to continue to increase worldwide. Adults who sustain primary osteoporotic fractures are more likely to sustain additional subsequent fractures, but few receive interventions to prevent those secondary fractures. Fracture liaison service models have been developed to systematically streamline preventative care for patients who have sustained a primary fragility fracture, proving cost-effective and efficacious. These programs have been developed in many countries, with varying degrees of success. There continues to be a need to better understand the various approaches to fracture liaison service programs in different regions enabling best practices to be adopted, successful approaches to be shared, and common obstacles to be addressed. The reports in this supplement address the status of fracture liaison service programs in different countries, focusing on national standards and guidelines, successes and barriers, and future directions. This work represents a collaborative effort of member societies of the International Orthopaedic Trauma Association (IOTA), an international association of orthopaedic societies dedicated to the promotion of musculoskeletal trauma care through advancements in patient care, research, and education. The expectation is that the information in these reports will aid efforts to address the growing need for fragility fracture programs.

Background:. The purposes of the present study were (1) to characterize open tibial fractures and their treatment in trauma centers located across different regions of Argentina and (2) to evaluate the rates of and indications for reoperation after the surgical treatment of such fractures. Methods:. This retrospective multicenter study evaluated open tibial fractures in Argentina that were operatively treated by experienced orthopaedic trauma surgeon-members of the Argentine Association of Orthopedic Trauma (AATO) between January 2015 and June 2020. Data were collected from 13 hospital databases; 8 hospitals were designated as “interior,” and 5 hospitals were designated as “exterior.” The study included 701 skeletally mature patients, all of whom had a minimum of 12 months of follow-up. Information was collected on patient demographics, injury pattern and mechanism, fracture classification, treatment modality, reoperation rates, time between definitive fixation and reoperation, and indications for reoperation. Results:. Seventy-six percent of presenting injuries were the result of a high-energy mechanism. Intramedullary nailing represented the most common type of fixation (88%). One hundred and fifty patients (21%) required reoperation. Delayed union/nonunion was the most common indication for reoperation in patients who had been previously treated with intramedullary nail fixation (31%; 39 of 126), and infection was the most common indication for reoperation in patients who had been treated with plate fixation (43%; 3 of 7). The time between the injury and definitive fixation was significantly different between the interior and exterior trauma centers (13.8 versus 4.7 days; p < 0.001), as was the time between definitive fixation and reoperation (69.3 versus 25.2 days; p = 0.004). The reoperation rates for the interior and exterior trauma centers were similar (20% versus 24%; p = 0.2). Infection, delayed union/nonunion, and implant removal were the most common indications for reoperation across groups. Conclusions:. An improved understanding of the factors that influence treatment may help to guide future areas for improvement, establish educational goals, and create additional nationwide guidelines for open tibial fracture treatment. Level of Evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Abstract There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF’s ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.

Introduction: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. Methods: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. Results: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. Discussion: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.

Introduction: Pragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow. Methods: Given the broad eligibility criteria and high fracture volume at participating clinical sites in the PREPARE trial, a pragmatic sampling strategy was needed. Using data from PREPARE, descriptive statistics were used to describe the use of the sampling strategy across clinical sites. A Chi-square test was performed to explore whether use of the sampling strategy was associated with a reduction in the number of missed eligible patients. Results: 7 of 20 clinical sites (35%) elected to adopt a sampling strategy. There were 1539 patients excluded due to the use of the sampling strategy, which represents 30% of all excluded patients and 20% of all patients screened for participation. Use of the sampling strategy was associated with lower odds of missed eligible patients (297/4545 (6.5%) versus 341/3200 (10.7%) p

Abstract. The coronavirus disease 2019 (COVID-19) has significantly affected the treatment of patients with surgical conditions, including those with acute and chronic musculoskeletal issues. While different global regions experienced different levels of COVID-19 activity and had different resources with which to deal with the pandemic, there were many consistent approaches to injury care and musculoskeletal trauma management. Understanding these approaches is necessary to improve current and future strategies to taking care of orthopaedic trauma patients in an infectious disease outbreak. This supplement focuses on approaches to musculoskeletal trauma care during the first months of the COVID-19 pandemic in 19 countries from 6 continents. This work represents a collaborative work of member societies of the International Orthopaedic Trauma Association (IOTA), an international association of orthopaedic societies dedicated to the promotion of musculoskeletal trauma care through advancements in patient care, research, and education. The information in these reports will aid efforts to understand and ultimately better address musculoskeletal trauma care worldwide during the first waves of the pandemic.

Pelvic ring injuries (PRI) are among the most difficult injuries to deal with in orthopedic trauma. When these injuries are accompanied by hemodynamic instability their management becomes significantly more complex. A methodical assessment and expeditious triage are required for these patients followed by adequate resuscitation. A major triage decision is whether these patients should undergo arterial embolization in the angiography suit or prompt packing and pelvic stabilization in the operating room. Patient characteristics, fracture type and injury characteristics are taken into consideration in the decision-making process. In this review we discuss the acute evaluation, triage and management of PRIs associated with hemodynamic instability. An evidence based and protocol driven approach is necessary in order to achieve optimal outcomes in these patients.

Abstract. Background:. While the global burden of musculoskeletal injury is increasingly recognized, few epidemiologic studies have specifically recorded its incidence or prevalence, particularly in low- and middle-income countries. Understanding the burden of musculoskeletal injury relative to other health conditions is critical to effective allocation of resources to mitigate the disability that results from trauma. The current study aims to systematically review the existing primary literature on the incidence and prevalence of pelvic and appendicular fractures, a major component of musculoskeletal injury, in low- and lower-middle income countries (LMICs). Methods:. This study conforms to the systematic review and traditional meta-analysis guidelines outlined in the PRISMA-P statement. Incidence rates were calculated as the occurrence of new fracture cases per 100,000 person-years, and prevalence as total fracture cases per population sample, reported as percentages. Results:. The literature search yielded 3497 total citations. There were 21 full-text articles, representing 14 different countries, selected for data extraction. Included studies reported a wide range of incidence and prevalence rates, with an overall mean fracture incidence ranging from 779 (95% CI: 483.0–1188.7) to 1574 (95% CI: 1285.1–1915.1) per 100,000 person-years. Conclusion:. Better understanding the unmet burden of musculoskeletal injury in LMICs is critical to effectively allocating resources and advocating for underserved populations. To address existing gaps and heterogeneity within the literature, future research should incorporate population-based sampling with broader geographic representation in LMICs to more accurately capture the burden of disease.

Summary: Background: The Lancet Commission on Global Surgery established the Three Delays framework, categorising delays in accessing timely surgical care into delays in seeking care (First Delay), reaching care (Second Delay), and receiving care (Third Delay). Globally, knowledge gaps regarding delays for fracture care, and the lack of large prospective studies informed the rationale for our international observational study. We investigated delays in hospital admission as a surrogate for accessing timely fracture care and explored factors associated with delayed hospital admission. Methods: In this prospective observational substudy of the ongoing International Orthopaedic Multicenter Study in Fracture Care (INORMUS), we enrolled patients with fracture across 49 hospitals in 18 low-income and middle-income countries, categorised into the regions of China, Africa, India, south and east Asia, and Latin America. Eligible patients were aged 18 years or older and had been admitted to a hospital within 3 months of sustaining an orthopaedic trauma. We collected demographic injury data and time to hospital admission. Our primary outcome was the number of patients with open and closed fractures who were delayed in their admission to a treating hospital. Delays for patients with open fractures were defined as being more than 2 h from the time of injury (in accordance with the Lancet Commission on Global Surgery) and for those with closed fractures as being a delay of more than 24 h. Secondary outcomes were reasons for delay for all patients with either open or closed fractures who were delayed for more than 24 h. We did logistic regression analyses to identify risk factors of delays of more than 2 h in patients with open fractures and delays of more than 24 h in patients with closed fractures. Logistic regressions were adjusted for region, age, employment, urban living, health insurance, interfacility referral, method of transportation, number of fractures, mechanism of injury, and fracture location. We further calculated adjusted relative risk (RR) from adjusted odds ratios, adjusted for the same variables. This study was registered with ClinicalTrials.gov, NCT02150980, and is ongoing. Findings: Between April 3, 2014, and May 10, 2019, we enrolled 31 255 patients with fractures, with a median age of 45 years (IQR 31–62), of whom 19 937 (63·8%) were men, and 14 524 (46·5%) had lower limb fractures, making them the most common fractures. Of 5256 patients with open fractures, 3778 (71·9%) were not admitted to hospital within 2 h. Of 25 999 patients with closed fractures, 7141 (27·5%) were delayed by more than 24 h. Of all regions, Latin America had the greatest proportions of patients with delays (173 [88·7%] of 195 patients with open fractures; 426 [44·7%] of 952 with closed fractures). Among patients delayed by more than 24 h, the most common reason for delays were interfacility referrals (3755 [47·7%] of 7875) and Third Delays (cumulatively interfacility referral and delay in emergency department: 3974 [50·5%]), while Second Delays (delays in reaching care) were the least common (423 [5·4%]). Compared with other methods of transportation (eg, walking, rickshaw), ambulances led to delay in transporting patients with open fractures to a treating hospital (adjusted RR 0·66, 99% CI 0·46–0·93). Compared with patients with closed lower limb fractures, patients with closed spine (adjusted RR 2·47, 99% CI 2·17–2·81) and pelvic (1·35, 1·10–1·66) fractures were most likely to have delays of more than 24 h before admission to hospital. Interpretation: In low-income and middle-income countries, timely hospital admission remains largely inaccessible, especially among patients with open fractures. Reducing hospital-based delays in receiving care, and, in particular, improving interfacility referral systems are the most substantial tools for reducing delays in admissions to hospital. Funding: National Health and Medical Research Council of Australia, Canadian Institutes of Health Research, McMaster Surgical Associates, and Hamilton Health Sciences.

Abstract. Hip fractures, among the most common geriatric injuries, are associated with adverse patient outcomes and significant costs. The incidence of these fractures continues to rise with an aging population worldwide. While many factors that negatively impact patient outcomes are nonmodifiable, others, which include pre- and postoperative medical management, timing of surgical stabilization, and fracture fixation methods, are modifiable and have been shown to affect outcomes. Treatment pathways are dependent upon available resources and established systems, and comparative guidelines from different regions and countries are not well documented. This special issue seeks to highlight regional differences in hip fracture care globally and represents a collaborative work of member societies of the International Orthopaedic Trauma Association, an international association of orthopaedic societies dedicated to the promotion of musculoskeletal trauma care through advancements in patient care, research, and education. The expectation is that better understanding these differences will aid efforts to better understand, improve, and standardize existing approaches to hip fracture management worldwide.

Abstract. Open fractures are commonly encountered injuries worldwide and are often complicated by infection. Many present significant treatment challenges, where surgeons’ early decision-making can affect long-term outcomes. While evidence-based recommendations exist to guide some of these decisions, several treatment areas continue to be controversial. This supplement seeks to outline critical treatment elements for open fractures, including antibiotic administration, surgical timing, bone defect management, and soft-tissue coverage as well as management of fracture-related infections. The expectation is that a better understanding of these issues will help improve the future care of these potentially disabling injuries.

Abstract. Open fractures are complex presentations with elevated risks of infection and nonunion due to a multitude of factors. Along with early surgical debridement, antibiotics have been heavily utilized and have become part of standard of care to reduce the risks of fracture-related infections. Many aspects of their use have been studied and debated. The early administration of intravenous antibiotics has been shown to significantly reduce the incidence of infection. Furthermore, current standards do not recommend prolonged antibiotic administration post wound closure. Recently, an increasing number of studies have assessed the utility of locally administered antibiotics. Clinical and basic science studies have been relatively supportive of their usage, but further studies are still warranted to further delineate their effects.

Abstract. Background:. An increasing number of traumatic injuries in low- and low-middle-income countries (LICs/LMICs) have coexisting injuries requiring soft-tissue coverage (flaps). Yet, there is a lack of subspecialty care and flap training in Latin America. This study assesses the effectiveness of a surgical skills training course in improving rotational and free flap knowledge and identifies barriers to performing these types of flaps. Methods:. Participants attending a surgical skills training course in Guadalajara, Mexico completed a pre/postcourse flaps knowledge survey consisting of 15 questions from the plastic surgery in-training examination and also completed a 7-point Likert survey regarding perceived barriers to performing flaps at their institution. Results:. Of the course participants, 17 (44.7%) completed the precourse knowledge survey, 24 (63.2%) completed the postcourse survey, and 37 (97.4%) completed the barriers survey. Scores improved from pre- to postcourse knowledge surveys (39.6% to 53.6%, P = .005). Plastic surgery subsection scores also improved (39.0% to 60.4%, P = .003). Twenty-five percent of attendees received prior flap training and had plastic surgeons available to perform flaps. Few participants (38.9%) reported flap procedures being commonly completed at their hospitals. Participants stating that flaps were uncommon in their hospital reported more institutional barriers and less access to dermatomes. These participants also reported lack of operating room and surgical personnel availability. Conclusion:. A surgical skills training course may be useful in improving knowledge of soft-tissue coverage procedures. There are also modifiable physician and institutional barriers that can improve the ability to perform rotational and free flaps as identified by the course participants.

Abstract. Trauma is a leading cause of death worldwide. Many more survive their injuries and face lifelong disabilities, including limiting musculoskeletal conditions that significantly impact individuals and societies. According to the World Health Organization, the burden of injury resulting from trauma will continue to increase. Despite this expected increase, trauma systems remain poorly described and understood. This supplement, which represents a collaboration of member societies of the International Orthopaedic Trauma Association, will describe trauma systems in countries from 5 different continents. The expectation is that this work will assist in identifying existing trauma systems and developing strategies for improvements in post-injury care worldwide.

The majority of fractures heal through the process of endochondral ossification, in which a cartilage intermediate forms between the fractured bone ends and is gradually replaced with bone. Recent studies have provided genetic evidence demonstrating that a significant portion of callus chondrocytes transform into osteoblasts that derive the new bone. This evidence has opened a new field of research aimed at identifying the regulatory mechanisms that govern chondrocyte transformation in the hope of developing improved fracture therapies. In this article, we review known and candidate molecular pathways that may stimulate chondrocyte-to-osteoblast transformation during endochondral fracture repair. We also examine additional extrinsic factors that may play a role in modulating chondrocyte and osteoblast fate during fracture healing such as angiogenesis and mineralization of the extracellular matrix. Taken together the mechanisms reviewed here demonstrate the promising potential of using developmental engineering to design therapeutic approaches that activate endogenous healing pathways to stimulate fracture repair.

Musculoskeletal injury confers an enormous burden of preventable disability and mortality in low- and moderate-income countries (LMICs). Appropriate orthopedic and trauma care services are lacking. Leading international health agencies emphasize the critical need to create and sustain research capacity in the developing world as a strategic factor in the establishment of functional, independent health systems. One aspect of building research capacity is partnership between developing and developed countries, and knowledge sharing via these collaborations. This study evaluated the efficacy of a short, intensive course designed to educate surgeons on fundamental aspects of clinical research using evidence-based medicine (EBM) principles. Orthopedic surgeons from the United States and Canada presented a one-day course on the fundamentals of clinical research in Havana, Cuba. Knowledge acquisition was assessed on the part of course participants and surveyed current involvement with and attitudes toward clinical research. Questionnaires were presented to participants immediately preceding and following the course. The mean pre-test score was 43.9% (95% CI: 41.1–46.6%). The mean post-test score was 59.3% (95% CI: 56.5–62.1%). There were relative score increases in each subgroup based on professional level, subjective level of familiarity with EBM concepts, and subjective level of experience in research. This study establishes the short-term efficacy of an intensive course designed to impart knowledge in EBM and clinical research. Further study is necessary to determine the long-term benefits of this type of course. This may be a useful part of an overall strategy to build health research capacity in LMICs, ultimately contributing to improved access to high-quality surgical care.

Bone fractures represent an enormous societal and economic burden as one of the most prevalent causes of disability worldwide. Each year, nearly 15 million people are affected by fractures in the United States alone. Data indicate that the blood supply is critical for fracture healing; as data indicate that concomitant bone and vascular injury are major risk factors for non-union. However, the various role(s) that the vasculature plays remains speculative. Fracture stabilization dictates stem cell fate choices during repair. In stabilized fractures stem cells differentiate directly into osteoblasts and heal the injury by intramembranous ossification. In contrast, in non-stable fractures stem cells differentiate into chondrocytes and the bone heals through endochondral ossification, where a cartilage template transforms into bone as the chondrocytes transform into osteoblasts. One suggested role of the vasculature has been to participate in the stem cell fate decisions due to delivery of oxygen. In stable fractures, the blood vessels are thought to remain intact and promote osteogenesis, while in non-stable fractures, continual disruption of the vasculature creates hypoxia that favors formation of cartilage, which is avascular. However, recent data suggests that non-stable fractures are more vascularized than stable fractures, that oxygen does not appear associated with differentiation of stem cells into chondrocytes and osteoblasts, that cartilage is not hypoxic, and that oxygen, not sustained hypoxia, is required for angiogenesis. These unexpected results, which contrast other published studies, are indicative of the need to better understand the complex, spatio-temporal regulation of vascularization and oxygenation in fracture healing. This work has also revealed that oxygen, along with the promotion of angiogenesis, may be novel adjuvants that can stimulate healing in select patient populations.

In October 2013, the International Combined Orthopaedic Research Societies (ICORS; http://i-cors.org) was founded with inaugural member organisations from the previous Combined Orthopaedic Research Society, which had sponsored combined meetings for more than 2 decades. The ICORS is dedicated to the stimulation of orthopaedic and musculoskeletal research in fields such as biomedical engineering, biology, chemistry, and veterinary and human clinical research. The ICORS seeks to facilitate communication with member organisations to enhance international research collaborations and to promote the development of new international orthopaedic and musculoskeletal research organisations. Through new categories of membership, the ICORS represents the broadest coalition of orthopaedic research organisations globally.

SUMMARY The matrix metalloproteinase (MMP) family of extracellular proteases performs crucial roles in development and repair of the skeleton owing to their ability to remodel the extracellular matrix (ECM) and release bioactive molecules. Most MMP-null skeletal phenotypes that have been previously described are mild, thus permitting the assessment of their functions during bone repair in the adult. In humans and mice, MMP2 deficiency causes a musculoskeletal phenotype. In this study, we assessed the role of MMP2 during mouse fracture repair and compared it with the roles of MMP9 and MMP13. Mmp2 was expressed at low levels in the normal skeleton and was broadly expressed in the fracture callus. Treatment of wild-type mice with a general MMP inhibitor, GM6001, caused delayed cartilage remodeling and bone formation during fracture repair, which resembles the defect observed in Mmp9–/– mice. Unlike Mmp9- and Mmp13-null mutations, which affect both cartilage and bone in the callus, the Mmp2-null mutation delayed bone remodeling but not cartilage remodeling. This remodeling defect occurred without changes in either osteoclast recruitment or vascular invasion of the fracture callus compared with wild type. However, we did not detect changes in expression of Mmp9, Mmp13 or Mt1-Mmp (Mmp14) in the calluses of Mmp2-null mice compared with wild type by in situ hybridization, but we observed decreased expression of Timp2 in the calluses of Mmp2-, Mmp9- and Mmp13-null mice. In keeping with the skeletal phenotype of Mmp2-null mice, MMP2 plays a role in the remodeling of new bone within the fracture callus and impacts later stages of bone repair compared with MMP9 and MMP13. Taken together, our results indicate that MMPs play unique and distinct roles in regulating skeletal tissue deposition and remodeling during fracture repair.

Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading, inflammation and exogenous molecules. Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of metabolic bone diseases. Zoledronate (ZA), a nitrogen-containing bisphosphonate (N-BP), is the most potent bisphosphonate among the clinically approved bisphosphonates. Cases of bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet, osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized tibial fractures and a new model of mandibular fracture repair. Contrary to tibial fractures, which heal mainly through endochondral ossification, mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones.

Extracellular matrix (ECM) remodeling is important during bone development and repair. Because matrix metalloproteinase 13 (MMP13, collagenase-3) plays a role in long bone development, we have examined its role during adult skeletal repair. In this study we find that MMP13 is expressed by hypertrophic chondrocytes and osteoblasts in the fracture callus. We demonstrate that MMP13 is required for proper resorption of hypertrophic cartilage and for normal bone remodeling during non-stabilized fracture healing, which occurs via endochondral ossification. However, no difference in callus strength was detected in the absence of MMP13. Transplant of wild-type bone marrow, which reconstitutes cells only of the hematopoietic lineage, did not rescue the endochondral repair defect, indicating that impaired healing in Mmp13-/- mice is intrinsic to cartilage and bone. Mmp13-/- mice also exhibited altered bone remodeling during healing of stabilized fractures and cortical defects via intramembranous ossification. This indicates that the bone phenotype occurs independently from the cartilage phenotype. Taken together, our findings demonstrate that MMP13 is involved in normal remodeling of bone and cartilage during adult skeletal repair, and that MMP13 may act directly in the initial stages of ECM degradation in these tissues prior to invasion of blood vessels and osteoclasts.