Introduction:There is no universally-utilized classification system for avascular necrosis of the femoral head (AVNFH), a debilitating condition that arises due to impaired blood supply resulting in cortical collapse. AVNFH may require early intervention to prevent irreversible damage leading to total hip arthroplasty. The purpose of this study is to assess the variability in classification, management, and outcomes reported in randomized controlled trials (RCTs) related to AVNFH. Methods:PubMed, Embase, and Medline were queried for RCTs on the treatment of AVNFH (2010-2023). The number of patients, number of femoral heads, minimum follow-up, AVNFH classification system, treatment interventions, and outcome measures were extracted. Variability in classification, management approach, and reporting of outcomes was evaluated. Results:A total of 30 RCTs met inclusion criteria, encompassing 1891 total patients. The mean number of patients in each study was 63 (SD = 41), with a mean minimum follow-up of 30 months (SD = 17). The Association Research Circulation Osseous classification system was utilized in 63 % (n = 19) of studies, Ficat and Arlet in 20 % (n = 6) of studies, Steinberg in 10 % (n = 3), Mitchell in 3 % (n = 1), and the China-Japan Friendship Hospital classifications in 3 % (n = 1). There were 61 treatment interventions, stratified into nine categories. Radiographic imaging was most commonly used to evaluate patients at follow-up. Conclusion:There are a variety of classification systems, treatments, and outcome measures utilized in the literature to categorize and quantify AVNFH. The utilization of a universally-accepted classification system and standardized outcome reporting may help to ensure reproducibility and accuracy given a continued lack of consensus.

AbstractWithout intervention, 80% of hips with osteonecrosis (ON) will progress. Core decompression (CD) has shown favorable results (60–80% survivorship) in early stage ON, and recently, bone marrow aspirate concentration (BMAC) injection into the decompressed femoral head has been proposed to stimulate healing of the necrotic lesion and improve outcomes and survivorship. We reviewed the clinical and radiographic outcomes of 51 Steinberg stage 2 hips in 31 patients who underwent CD + BMAC for ON with a minimum of 1 year follow-up. We evaluated preoperative visual analog pain scores (VAS), Steinberg stage based on radiographs, and Kerboul angle as measured on magnetic resonance imaging. Clinical outcomes were reported as a change in VAS at final follow-up, hip and disability osteoarthritis score for joint replacements (HOOS, JR) score at final follow-up, advancement in Steinberg stage based on radiographs, or decision to proceed with total hip arthroplasty (THA). At an average of 27 months, VAS scores improved from 7 to 2.3 (p < 0.001). In total, 38 of 51 hips (75%) had stable radiographs, while 13 of 51 hips (25%) progressed radiographically or proceeded to THA. The average HOOS JR score in patients at final follow-up was 87.5, indicating excellent hip function. Of the patients that went on to THA, all were preoperative Steinberg stage 2C and the preoperative Kerboul angle in this cohort was 241, compared with 163 in those hips that did not go on to THA (p < 0.001). In preoperative hips that were Steinberg stage 2B or less, there was no advancement in the radiographic stage, whereas 67% of patients with preoperative stage 2C hips progressed (p < 0.001). CD + BMAC significantly improves pain and helps prevent the progression of ON when performed on patients in whom ON is classified as Steinberg stage 2B or less or in whom the Kerboul angle is 180 or less. Level of evidence was level III.

The passage of a decade is a milestone worthy of note, encouraging reflection on what we have accomplished and what lies ahead. In that spirit, it is with great pleasure that we celebrate the 10-year anniversary of JBJS Reviews. In 2013, finding that Current Concepts Reviews in JBJS were among the journal's highest-rated articles, we sought to provide readers globally with more information in this format while also taking advantage of digital access, which a weekly online journal could allow. So began JBJS Reviews. Since its launch, Reviews has consistently provided authoritative, evidence-based review articles upholding the JBJS standard of quality. Thanks are extended to our authors, the Board of Associate Editors, our reviewers, and all who have worked to ensure the steady and timely publication of high-quality manuscripts. Reviews now follows a continuous publication model, offering readers new content on a regular basis and is indexed in MEDLINE/PubMed. Readers also turn to Reviews for trusted content in earning continuing medical education credits. To commemorate the journal's 10-year anniversary, we have compiled a collection of the 10 most popular JBJS Reviews articles published since the journal's inception1–10. We invite readers to explore this special edition collection, which is currently available at JBJS.org and represents expert insights into a range of topics of interest to orthopaedic surgeons. While Narrative Reviews and Systematic Reviews continue to serve as mainstay content of the journal, 2 other article types help to distinguish JBJS Reviews: Critical Analysis Reviews and Team Approach articles. Critical Analysis Reviews feature clinical care recommendations derived from a comprehensive evaluation of appropriate literature along with Grades of Recommendation summarizing the quality of the literature. Team Approach articles, introduced in 2016, present a clinical scenario and then outline important aspects of diagnosis and treatment from the perspectives of various members of the treatment team. Both of these well-received article types aim to optimize the value of reviews for our readers and will continue to be preferred submissions11. As we reflect on 10 years, we naturally consider the impact that Reviews is making. Among journals, one measurable benchmark is the impact factor, which Reviews has now received for the first time, earning an impact factor of 2.3. While just one measure of a publication's performance, such metrics will continue to offer important insight into how we are doing. Our 10-year anniversary arrives at a time of great change more broadly in the emergence of artificial intelligence (AI). The challenge for all of us is to both understand and appreciate the appropriate role of AI in publishing while ensuring the integrity of patient-focused content on our pages12. Perhaps it is fair to say that there are more questions than answers at this point given the rapid rollout of AI tools, but this area will remain of key interest to us. Looking ahead, we will continue to provide high-quality, peer-reviewed articles of benefit to the orthopaedic community and the patients we treat. This is as good a time as any to double-down on our core commitments and ready ourselves for the future. I look forward to reading the next 10 years' “top 10” articles and to measuring their effects on the evolution of our specialty.

Everyone appreciates a good review article. When comprehensive, well researched, well organized, and well written, a review article can be an essential part of every reader’s portfolio of knowledge. However, while the narrative or systematic format of most review articles may meet these qualifications, there are often missed opportunities for readers to derive the maximum benefit from these methods of communication. This is why JBJS Reviews provides 2 types of articles that take information in the literature to the next level of value: the Critical Analysis Review and the Team Approach article. Critical Analysis Review articles communicate clinical care recommendations that are derived from a complete evaluation of appropriate literature and are made explicit in a standard format known as a Recommendations for Care Table1. The added value of this information, which can pertain to treatment, diagnosis, or prognosis, is supported by the JBJS Levels of Evidence. As a result, the reader learns not only what information is current but also how reliable the information is and thus how dependable it may be for guiding clinical care. Team Approach articles focus on the multidisciplinary nature of musculoskeletal care by creating a clinical scenario and reviewing the potential input and involvement of key medical professionals in a co-management format2. A treatment recommendation from each specialist is presented in a logical sequence that reflects both the continuity of care and the collaborative approach. Although the Editor and the Board of Associate Editors are charged with making recommendations for invited articles, manuscripts submitted to JBJS Reviews need not always be invited. In fact, the majority of articles published to date have not been invited, which we view as a desirable trend. However, while the most outstanding narrative and Systematic Review articles will continue to be accepted, Critical Analysis Review and Team Approach articles will be preferred.

Background: Risk stratification of individual patients who are prone to infection would allow surgeons to monitor high-risk patients more closely and intervene early when needed. This could reduce infection-related consequences such as increased health-care costs. The purpose of this study was to develop a machine learning (ML)-derived risk-stratification tool using the SPRINT (Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures) and FLOW (Fluid Lavage of Open Wounds) trial databases to estimate the probability of infection in patients with operatively treated tibial shaft fractures (TSFs). Methods: Patients with unilateral TSFs from the SPRINT and FLOW trials were randomly split into derivation (80%) and validation (20%) cohorts. Random forest algorithms were used to select features that are relevant to predicting infection. These features were included for algorithm training. Five ML algorithms were trained in recognizing patterns associated with infection. The performance of each ML algorithm was evaluated and compared based on (1) the area under the ROC (receiver operating characteristic) curve (AUC), (2) the calibration slope and the intercept, and (3) the Brier score. Results: There were 1,822 patients included in this study: 170 patients (9%) developed an infection that required treatment, 62 patients (3%) received nonoperative treatment with oral or intravenous antibiotics, and 108 patients (6%) underwent subsequent surgery in addition to antibiotic therapy. Random forest algorithms identified 7 variables that were relevant for predicting infection: (1) Gustilo-Anderson or Tscherne classification, (2) bone loss, (3) mechanism of injury, (4) multitrauma, (5) AO/OTA fracture classification, (6) age, and (7) fracture location. Training of the penalized logistic regression algorithm resulted in the best-performing prediction model, with AUC, calibration slope, calibration intercept, and Brier scores of 0.75, 0.94, 0.00, and 0.076, respectively, in the derivation cohort and 0.81, 1.07, 0.09, and 0.079, respectively, in the validation cohort. Conclusions: We developed an ML prediction model that can estimate the probability of infection for individual patients with TSFs based on patient and fracture characteristics that are readily available at hospital admission.

As practicing orthopaedic surgeons, we strive to improve our patients’ outcomes. However, surgical technique, perioperative measures, and modern implant designs can only accomplish small to moderate improvements. Knowledge of the biological foundation that results in orthopaedic maladies and an understanding of the cellular and molecular mechanisms that govern regeneration will eventually result in orthobiological treatments that may affect thousands of patients and accelerate and ease their return to function after an orthopaedic injury. Here we will highlight some of the most groundbreaking and relevant basic science articles that were published in the past year. This summary aimed to be inclusive, yet, due to the sheer number of publications, had to be limited to certain topics. Basic science breakthroughs in musculoskeletal oncology are not covered herein, as they are part of a separate update in The Journal of Bone & Joint Surgery. Fracture Healing The skeleton has a remarkable ability to regenerate in response to injury without forming scars. Although this process is successful in the large majority of fractures, a certain percentage of fractures still fail to unite, and it is this fraction that would benefit either from early recognition using radiographic or biological readouts or from therapeutic adjuvants that could jumpstart or guide successful regeneration. Skeletal stem and progenitor cells are the cornerstone of fracture repair. Although extensive research in the past has focused on the marrow-derived skeletal stem and progenitor cells, more recent efforts have focused on the periosteum as a source for stem cells. In fact, one could argue that the periosteum is the prime source of skeletal stem and progenitor cells during fracture repair. In a recent paper, Kegelman et al. nicely highlighted the role of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) in promoting periosteal progenitor cell expansion and differentiation during fracture healing1. Utilizing a transgenic mouse strategy, they showed that YAP/TAZ deletion in Osterix-expressing cells (osteoprogenitor cells) during adult fracture healing did not affect the development of the chondrogenic soft callus; however, the deletion yielded impaired osteoprogenitor cell expansion and osteogenic differentiation resulting in delayed callus mineralization and thus impaired fracture healing. Julien et al. further elevated the importance of periosteal stem and progenitor cells as the key for successful bone-healing2. Using a transgenic mouse line (Prx1Cre;Fgfr3Y367/+) in which fibroblast growth factor receptor 3 (FGFR3) signaling is overactivated in periosteal progenitor cells, the authors demonstrated that the cartilage-to-bone transformation by periosteal cells during bone regeneration is regulated by FGFR3 signaling. In addition, using elegant transplantation models, they showed that periosteal cells transplanted into a nonunion site can overcome the detrimental microenvironment that led to the failure of union and can therefore be considered as a potentially powerful, cell-based therapy for the treatment of delayed union or nonunion. Novak et al. examined the role of Notch signaling in periosteal cells during fracture healing3. Increased Notch signaling in osteochondroprogenitor cells in the periosteum resulted in increased proliferation, decreased soft callus size, increased mineralized tissue, and an overall stronger and stiffer callus, promoting Notch signaling as a potential therapeutic target to augment fracture healing. Aging is a known risk factor for poor fracture healing, and there is ample evidence now that the aging innate and adaptive immune system exerts a detrimental effect on all aspects of fracture healing. Clark et al. recently identified aging macrophages as culprits for delayed fracture healing4. Using RNA sequencing analysis, they demonstrated a clear shift toward an M1/pro-inflammatory phenotype in the aging fracture callus in addition to a general dysregulation of immune-related genes. When they prevented migration of macrophages into the aging fracture callus, they observed improved fracture healing, suggesting a negative impact of circulating monocytes and infiltrating macrophages during fracture healing in the aging animal. Precision medicine has entered the clinical arena in cancer treatment, but orthopaedic care is still relying on the same methods and techniques that we used decades ago. We still use radiographs and clinical examination to define union of a long-bone fracture, and we have not made any substantial strides toward predicting the development of a nonunion rather than diagnosing it when it has already happened. For the affected patients, this decades-old diagnostic approach means waiting for up to 9 months before a decision is made to proceed with a revision surgical procedure. Working et al. recently demonstrated that the collagen X degradation fragments (collagen X marker [CXM]) can be measured in serum and correlated with the progression of endochondral fracture healing in mice5. Together with a human study showing that CXM can serve as a real-time marker for bone growth6, one can imagine a precision medicine approach utilizing blood tests in addition to serial radiographs during the early stages of fracture repair to predict fracture union, and, in the untoward event of predicted aberrant union, early intervention could be initiated. Cartilage and Osteoarthritis Surgical management of isolated cartilage defects still represents a challenging task, and procedures such as microfracture have only resulted in temporary restoration of the articular surface by forming fibrocartilage. In a groundbreaking study, Murphy et al. demonstrated that the skeletal stem cells that are recruited to the microfracture site can be triggered to regenerate articular cartilage by delivering bone morphogenetic protein-2 (BMP-2) and a soluble vascular endothelial growth factor receptor 1 (VEGFR1)7. Atomic force microscopy revealed that the cartilage regenerate had a similar elastic modulus compared with uninjured cartilage, and animals showed improved mobility parameters as measured by gait analysis. This study showed, for the first time, that biochemical manipulation of the local stem cell niche environment can activate a regenerative response of resident skeletal stem cells that results in a durable articular cartilage regenerate. Heterotopic Ossification Wound-healing relies on a well-orchestrated sequence of molecular events that result in the correct programming of adult progenitor cells within the wound environment. In some instances (for example, after burns, brain injury, or massive trauma), this programming can be misguided, resulting in heterotopic bone formation. Recent discoveries have shed light on the cell type and the molecular pathways that are responsible for this aberrant regenerative response. Using transgenic reporter mice and single-cell RNA (scRNA) sequencing, Pagani et al. demonstrated that regionally specific multipotent progenitor cells respond to trauma and form heterotopic bone8. Mechanistically, Lee et al. identified the role of nerve growth factor-tropomyosin receptor kinase A (NGF-TrkA) signaling as an essential regulator of neural ingrowth and subsequent formation of heterotopic ossification following soft-tissue trauma9. After NGF expression in the zone of injury, NGF-responsive axons invade the site and induce osteocartilaginous differentiation. Surgical denervation and biochemical manipulation of NGF-TrkA signaling resulted in delays in axonal ingrowth, which then caused delayed osteochondral differentiation. Clinical observation has demonstrated an effect of joint mobilization on heterotopic ossification formation. Using an in vivo mouse model of severe trauma and joint immobilization, Huber et al. showed that the altered physical environment after immobilization results in extracellular matrix changes that trigger mesenchymal progenitor cell fate changes10. This study provided promising evidence that aberrant wound-healing and heterotopic ossification formation can be prevented by modulating mechanotransductive pathways using immobilization or pharmacologic inhibitors. Tendon Tendon injuries represent one of the most common orthopaedic injuries, often seen in young, active patients. Despite being so common in young patients with presumably favorable regenerative capacity, tendon injuries are often plagued by improper regeneration with resultant loss of strength, decreased range of motion, and joint instability. Therefore, research focusing on improved tendon regeneration has gained meaningful momentum in the past decade. In addition to this, in a recent publication, Wang et al. demonstrated the influence of the extracellular matrix protein periostin on the tendon stem and progenitor cell maintenance and proliferation11. The incorporation of recombinant periostin (rPOSTN) into a biomimetic parallel-aligned collagen scaffold resulted in improved tendon regeneration in a rat Achilles tendon defect model. The authors showed that the rPOSTN-loaded scaffold resulted in enhanced tendon stem and progenitor cell (TSPC) recruitment, tendon regeneration, and repair with native-like hierarchically organized collagen fibers. Also, the rPOSTN-treated tendon demonstrated recovery of mechanical properties and locomotion functions. Using rPOSTN treatment to initiate and promote endogenous stem cell recruitment to a tendon injury site has potential advantages with regard to clinical translation, as it avoids the regulatory hurdles associated with cell therapy. Scleraxis-lineage cells play an essential role during tendon development, and, because regeneration often utilizes developmental processes, one could assume that this cell lineage contributes to adult tendon regeneration. In a surprising finding, Best et al.12 revealed that genetic ablation of the scleraxis lineage prior to tendon injury and repair resulted in enhanced tendon regeneration with improved mechanical properties. However, the depletion during postnatal tendon growth and adult tendon homeostasis resulted in changes in matrix alignment and organization with an as-yet-unknown effect on the mechanical properties of the adult tendon. These findings add to our fundamental knowledge of tendon homeostasis and repair and further highlight the complexities encountered during adult tissue regeneration. Understanding the Cellular Bone Marrow Landscape Using Single-Cell Transcriptomics In the past few years, our understanding of skeletal stem cell identity and hierarchy has increased to a great degree. With the advent of scRNA sequencing, we are now in the position to unravel the skeletal stem cell field with detailed transcriptomic resolution, offering new insight into the workings of these now well-defined cell types within the bone and bone marrow and their computationally predicted differentiation trajectories. Zhong et al. provided detailed insight into the bone marrow mesenchymal lineage using scRNA sequencing13. Using trajectory analysis, they identified a population of cells as the most primitive of the mesenchymal lineage, which they called early mesenchymal progenitors, expressing common stem cell markers such as Sca1, CD34, and Thy1. The authors also identified a previously uncharacterized type of fat cell without lipid droplets that controls bone marrow osteoblast and vasculature homeostasis called marrow adipogenic lineage precursors, and these cells are marked by Lepr, which was previously identified as a skeletal stem cell marker (Zhou et al.14). The scRNA sequencing analysis of older mice, 16 months of age, revealed an expansion of the adipocyte clusters as well as a reduction in early mesenchymal progenitor number and a drift toward adipogenic status. This observation confirms a fate shift of marrow cells toward an adipogenic lineage with age that was previously observed. Similarly, Baccin et al. performed a detailed single-cell-level survey of bone marrow niches by integrating both scRNA sequencing and spatially resolved transcriptomics15. They developed a method of laser-capture microdissection on fixed bone marrow sections coupled with bulk RNA sequencing to provide detailed information on bone marrow cell types, their subtypes, and their location within the bone marrow. They found that Cxc12-abundant reticular (CAR) cells could be split into 2 subsets, Adipo-CAR cells, which differentially localize to sinusoidal endothelia, and Osteo-CAR cells, which differentially localize to arteriolar endothelia or nonvascular regions, providing evidence that CAR cells with different transcriptional potential can occupy distinct spatial niches. One shortcoming of scRNA sequencing technology is the loss of spatial information. However, Baccin et al. offered an approach to combine transcriptional and spatial information, providing a platform for a more detailed and complete picture of the bone microenvironment that includes both transcriptional data and spatial data. Finally, Matsushita et al. used scRNA sequencing, lineaging tracing, and genetic manipulation to define the role of Cxcl12-creER+ labeled reticular cells during regeneration and found that these cells represent quiescent perisinusoidal Cxcl12+ cells16. They found that these labeled cells express cytokines and adipocyte-related genes, have little colony-forming activity, and give rise to adipocytes but not osteoblasts during homeostasis. By using a drill-hole cortical injury, they demonstrated through lineage tracing, in combination with scRNA sequencing, that these cells adapt a stem cell identity and give rise to new osteoblasts during injury through activation of canonical Wnt signaling in their trajectory to osteoblasts. Using genetic ablation, they found that β-catenin deficiency in these cells caused deficits in healing, confirming the role of Wnt signaling in the activation of these cells during regeneration. This finding also demonstrates that, although perisinusoidal cells have an adipogenic signature, as also noted by Baccin et al., these cells can change their transcriptional profile and fate in response to injury. This highlights the need for a combination of scRNA sequencing with techniques such as lineage tracing and genetic manipulation to fully understand the function of heterogenous cell types within bone both during homeostasis and during regeneration. Muscle Regeneration and Aging Although considerable efforts have been mobilized to better understand the regenerative ability of skeletal muscle, we are still lacking a clinically applicable therapeutic that would allow our patients to recover faster and more reliably after muscle injury. Recent advances have identified an altered immune response to muscle injury during aging as a potential culprit for the poor healing response. Blanc et al. identified inflammatory-related CC-chemokine-receptor 2 (Ccr2) expression in myogenic progenitors during regeneration, which resulted in impaired myogenic progenitor fusion, a hallmark of successful muscle regeneration17. Inhibition of Ccr2 during muscle injury in older individuals revealed enhanced muscle regeneration and functional recovery in those older individuals. Edwards et al. examined the role of toll-like receptor (TLR) signaling in muscle fibrosis after ischemia-reperfusion injury18. Using hydroxychloroquine, a small molecule inhibitor of TLR7/8/9, resulted in decreased muscle fibrosis and increased myofiber regeneration after ischemia-reperfusion injury. The role of satellite cells in muscle regeneration has been extensively studied. Leung et al. identified a subset of satellite cells that express Lgr5 (leucine-rich repeat-containing G protein-coupled receptor 5), a receptor for Rspo1-Rpo4, which are potent Wnt signaling enhancers19. These Lgr5-positive cells are contributing only to muscle regeneration but not to muscle homeostasis. In response to injury, Lgr5 is upregulated in this subset of Pax7-positive cells and results in regeneration of muscle fibers and replenishment of the quiescent stem cell pool. Upcoming Meetings and Events Related to Orthopaedic Basic Science The Gordon Research Conference, “Bones and Teeth,” will be held on January 16 to 21, 2022, in Galveston, Texas. The 2022 Annual Meeting of the Orthopaedic Research Society (ORS) will be held on February 4 to 8, 2022, in Tampa, Florida. The annual meeting of the International Society for Stem Cell Research (ISSCR) will be held on June 15 to 18, 2022, in San Francisco, California. The American Society for Bone and Mineral Research (ASBMR) 2022 Annual Meeting will be held on September 9 to 12, 2022, in Austin, Texas. The World Orthopaedic Research Congress will be held on September 7 to 9, 2022, in Edinburgh, United Kingdom.

Type 2 diabetes mellitus (T2DM) significantly increases bone fragility and fracture risk. Progranulin (PGRN) promotes bone fracture healing in both physiological and type 1 diabetic conditions. The present study aimed to investigate the role of PGRN in T2DM bone fracture healing. MKR mice (with an FVB/N genetic background) were used as the T2DM model. Drill-hole and Bonnarens and Einhorn models were used to investigate the role of PGRN in T2DM fracture healing in vivo. Primary bone marrow cells were isolated for molecular and signaling studies, and reverse transcription-polymerase chain reaction, immunohistochemical staining, and western blotting were performed to assess PGRN effects in vitro. PGRN mRNA and protein expression were upregulated in the T2DM model. Local administration of recombinant PGRN effectively promoted T2DM bone fracture healing in vivo. Additionally, PGRN could induce anabolic metabolism during endochondral ossification through the TNFR2-Akt and Erk1/2 pathways. Furthermore, PGRN showed anti-inflammatory activity in the T2DM bone regeneration process. These findings suggest that local administration of exogenous PGRN may be an alternative strategy to support bone regeneration in patients with T2DM. Additionally, PGRN might hold therapeutic potential for other TNFR-related metabolic disorders.

Objectives: In the SPRINT trial, 18% of patients with a tibial shaft fracture (TSF) treated with intramedullary nailing (IMN) had one or more unplanned subsequent surgical procedures. It is clinically relevant for surgeon and patient to anticipate unplanned secondary procedures, other than operations that can be readily expected such as reconstructive procedures for soft tissue defects. Therefore, the objective of this study was to develop a machine learning (ML) prediction model using the SPRINT data that can give individual patients and their care team an estimate of their particular probability of an unplanned second surgery. Methods: Patients from the SPRINT trial with unilateral TSFs were randomly divided into a training set (80%) and test set (20%). Five ML algorithms were trained in recognizing patterns associated with subsequent surgery in the training set based on a subset of variables identified by random forest algorithms. Performance of each ML algorithm was evaluated and compared based on (1) area under the ROC curve, (2) calibration slope and intercept, and (3) the Brier score. Results: Total data set comprised 1198 patients, of whom 214 patients (18%) underwent subsequent surgery. Seven variables were used to train ML algorithms: (1) Gustilo-Anderson classification, (2) Tscherne classification, (3) fracture location, (4) fracture gap, (5) polytrauma, (6) injury mechanism, and (7) OTA/AO classification. The best-performing ML algorithm had an area under the ROC curve, calibration slope, calibration intercept, and the Brier score of 0.766, 0.954, -0.002, and 0.120 in the training set and 0.773, 0.922, 0, and 0.119 in the test set, respectively. Conclusions: An ML algorithm was developed to predict the probability of subsequent surgery after IMN for TSFs. This ML algorithm may assist surgeons to inform patients about the probability of subsequent surgery and might help to identify patients who need a different perioperative plan or a more intensive approach.

A wide variety of drug classes exists that are used to treat osteoporosis and prevent fragility fractures. Currently, ongoing efforts are being made to develop sophisticated, convenient agents that increase clinical efficacy while minimizing the risk of adverse events. Progress in this emerging field of medicine is rapid, particularly at the speed to which novel targets become effective pharmacologic agents. The challenge will be to most appropriately use these new medications to effectively treat osteoporotic patients.

Implant alignment and soft-tissue balancing are important factors in total knee arthroplasty (TKA). The purpose of this study was to design a mechanical balancing device, which measures deflections resulting from forces applied on each condyle to provide numerical data indicating the extent of ligament release needed, or angular changes in the bone cuts required to achieve a balanced knee. Two mechanical devices were designed and 3D printed, Pistol Grip and In-line. The Pistol Grip design consisted of a lever system that indicated the difference between lateral and medial forces with a single pointer. The In-line design allows for the quantification of the absolute force applied on each individual condyle. The two designs were evaluated on a test rig designed to model balance and imbalance conditions in the knee. For the Pistol Grip design maximum pointer deflection indicates a 2 mm change in elevation per condyle and/or a 3 degrees angular change of the condyles which can be corrected by adjusting the ligament lengths equivalent to 2 mm and/or by modifying the proximal or distal femur bone cut by 3 degrees. For the In-line design, maximum pointer deflection represented a 40 N load on the condyle. Our mechanical balancer designs were successful in providing information that can guide surgeons to accurately achieve balance through ligamentous releases and/or modification to bone cuts. The balancer designs are easy to use, do not require any electronics or software, and can be incorporated into the surgical procedure.

Fracture haematoma forms immediately after fracture and is considered essential for the bone healing process. Its molecular composition has been briefly investigated with our current understanding being based on animal studies. This study aims to analyse the inflammatory cytokine content of fracture haematoma in humans and determine its effect on osteoprogenitor cells. Twenty-three patients were recruited following informed consent. Peripheral blood, fracture haematoma and bone were collected. A Luminex assay on the levels of 34 cytokines was performed and autologous peripheral blood samples served as control. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays were performed. Gene expression analysis of 84 key osteogenic molecules was performed. Thirty-three inflammatory cytokines were found to be significantly raised in fracture haematoma when compared to peripheral serum (p < 0.05). Amongst the most raised molecules were IL-8, IL-11 and MMP1, -2 and -3. Fracture haematoma did not significantly affect MSC proliferation, but ALP activity and calcium deposition were significantly increased in the MSCs undergoing osteogenic differentiation. Medium supplementations with fracture haematoma resulted in a statistically significant upregulation of osteogenic genes including the EGF, FGF2 and VEGFA. This seems to be the pathway involved in the osteogenic effect of fracture haematoma on bone cells. In conclusion, fracture haematoma is found to be a medium rich in inflammatory and immunomodulatory mediators. At the same time, it contains high levels of anti-inflammatory molecules, regulates osteoclastogenesis, induces angiogenesis and the production of the extracellular matrix. It appears that fracture haematoma does not affect osteoprogenitor cells proliferation as previously thought, but induces an osteogenic phenotype.

AIMS:This aim of this study was to assess the feasibility of designing and introducing generic 3D-printed instrumentation for routine use in total knee arthroplasty.MATERIALS AND METHODS:Instruments were designed to take advantage of 3D-printing technology, particularly ensuring that all parts were pre-assembled, to theoretically reduce the time and skill required during surgery. Concerning functionality, ranges of resection angle and distance were restricted within a safe zone, while accommodating either mechanical or anatomical alignment goals. To identify the most suitable biocompatible materials, typical instrument shapes and mating parts, such as dovetails and screws, were designed and produced.RESULTS:Before and after steam sterilization, dimensional analysis showed that acrylonitrile butadiene styrene could not withstand the temperatures without dimensional changes. Oscillating saw tests with slotted cutting blocks produced debris, fractures, or further dimensional changes in the shape of Nylon-12 and polymethylmethacrylate (MED610), but polyetherimide ULTEM 1010 was least affected.CONCLUSION:The study showed that 3D-printed instrumentation was technically feasible and had some advantages. However, other factors, such as whether all procedural steps can be accomplished with a set of 3D-printed instruments, the logistics of delivery, and the economic aspects, require further study. Cite this article: Bone Joint J 2019;101-B(7 Supple C):115-120.

BACKGROUND:The minimum clinically important difference (MCID) was developed to ascertain the smallest change in an outcome that patients perceive as beneficial. The objectives of the present review were (1) to compare the MCIDs for pain assessments used among guidelines and meta-analyses investigating different nonsurgical therapies for knee osteoarthritis and (2) to compare the effect estimates of different nonsurgical interventions against a single commonly-utilized MCID threshold. METHODS:Systematic and manual searches were conducted to identify guidelines and meta-analyses evaluating pain outcomes for nonsurgical knee osteoarthritis interventions. Individual treatment effects for pain were presented on a common scale (the standardized mean difference [SMD]). To evaluate the perception of the relative benefit of each nonsurgical treatment, the variation in MCIDs selected from the published MCID literature was assessed. RESULTS:Thirty-seven guidelines and meta-analyses were included. MCIDs were often presented as an SMD or a mean difference (MD) on a validated scale and varied in magnitude across sources. This analysis demonstrated that intra-articular hyaluronic acid, intra-articular corticosteroids, and acetaminophen all had relatively larger effect sizes than topical nonsteroidal anti-inflammatory drugs (NSAIDs). Higher-molecular-weight intra-articular hyaluronic acid had a greater relative effect compared with both non-selective and cyclooxygenase-2-selective oral NSAIDs. Evaluating the treatment effect estimates against a commonly utilized MCID revealed similarities in which observations attained clinical significance among treatments; however, this observation varied across the range of reported MCIDs. CONCLUSIONS:The present review confirmed the variability in the MCIDs for pain assessments that are used across guidelines and meta-analyses evaluating nonsurgical interventions for knee osteoarthritis. This variability may yield conflicting treatment recommendations, ranging from rejecting treatments that are indeed efficacious to accepting treatments that may not be beneficial. Additional research is required to determine why some nonsurgical therapies are more consistently recommended in knee osteoarthritis guidelines than others as these findings suggest similarities in their effect estimates for pain. Relevant stakeholders need to reach a consensus on a standard approach to determining the MCIDs for these therapies to ensure that appropriate and effective treatment options are available to patients prior to invasive surgical intervention. LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.

AbstractOsteonecrosis of the femoral head (ONFH) is a rapidly progressive degenerative disease frequently affecting individuals within their fourth and fifth decade of life. Though often asymptomatic, patients with ONFH may present with a wide range of symptoms, including deep groin pain. There are many classification systems used to stratify disease severity, of which the Association of Research Circulation Osseous (ARCO) classification system is currently the most comprehensive. Once diagnosed, an estimated 75% of patients will experience femoral head collapse within three years of diagnosis if left untreated. Currently, the only definitive intervention available for ONFH is total hip arthroplasty (THA). However, recent advancements have been made with respect to the available treatment modalities. In this article, the author review the management of ONFH, providing clinicians with the necessary information to counsel their patients.

Bisphosphonates (BPs) are highly effective in treating osteoporosis and reducing hip, vertebral, and other fractures by as much as 50% to 70%. However, since 2006, atypical femur fractures (AFFs) emerged as potential side effects of BPs and other treatments. These fractures have unusual radiologic features and occur with little trauma. Public concern has led to a >50% decrease in BP usage. AFFs are rare: for each AFF, >1200 fractures, including 135 hip fractures, are prevented. Case definition criteria were updated by the American Society of Bone and Mineral Research in 2014. Many epidemiologic studies have been reported, and although methodologically challenging, generally support a BP-AFF association. However, the magnitude of the association between BPs and AFFs is uncertain: estimates of relative risk for AFFs among BP users vs nonusers range from 1 to 65 with a meta-analysis estimate of 1.7. Although mechanistic studies have proposed several hypotheses explaining how BPs might decrease bone strength, AFF pathogenesis remains uncertain and cannot explain the paradox of efficacy of reduction of common fractures while increasing risk for rare fractures at one site. There are several consistent risk factors, including Asian race (in North America), femoral bowing, and glucocorticoid use, whereas others remain unclear. Consensus is emerging about strategies to prevent AFFs in BP users (including drug holidays after 5 years' use in some patients). In conclusion, AFFs can be devastating, but even under the most pessimistic assumptions, the benefit/risk ratio is highly positive for BPs, particularly during 3 to 5 years of use. As understanding of AFFs increases, it is becoming increasingly possible to maximize BP benefits while minimizing AFF risk.