With an aging population and increase in total knee arthroplasty, periprosthetic distal femur fractures (PDFFs) have increased. The differences between these fractures and native distal femur fractures (NDFF) have not been comprehensively investigated. The purpose of this study was to compare the demographic, fracture, and treatment details of PDFFs compared to NDFFs.

A retrospective study of patients ≥ 18 years old who underwent surgical treatment for either a NDFF or a PDFF from 2010 to 2020 at a level 1 trauma center was performed. Demographics, AO/OTA fracture classification, quality of reduction, fixation constructs, and unplanned revision reoperation were compared between PDFF patients and NDFF patients using t-test and Fisher's exact test. 209 patients were identified with 70 patients having a PDFF and 139 patients having a NDFF. Of note, 48% of NDFF had a concomitant fracture of the ipsilateral knee (14%) or tibial plateau (15%). The most common AO/OTA classification for PDFFs was 33A3.3 (71%). NDFFs had two main AO/OTA classifications of 33C2.2 (28%) or 33A3.2. (25%). When controlling for patient age, bone quality, fracture classification, and fixation, the PDFF group had increased revision reoperation rate compared to NDFF (P < 0.05).

PDFFs tend to occur in elderly patients with low bone quality, have complete metaphyseal comminution, and be isolated; whereas, NDFF tend to occur in younger patients, have less metaphyseal comminution, and be associated with other fractures. When controlling for variables, PDFF are at increased risk of unplanned revision reoperation. Surgeons should be aware of these increased risks in PDFFs and future research should focus on these unique fracture characteristics to improve outcomes.

Determine the prevalence, etiologies, and risk factors of unplanned return to the OR (UROR) in adult orthopaedic trauma patients.

Retrospective review of a trauma prospective registry from 2014 – 2019 at a Level 1 academic hospital. An UROR was defined as a patient returning to OR unexpectedly following a planned definitive surgery to either readdress the presenting diagnosis or address a complication arising from the index procedure. Univariate and multivariate logistic regression was performed comparing those patients with an UROR versus those without.

A total of 1568 patients were reviewed. The rate of UROR was 9.8% (153 patients). Symptomatic implant was the leading cause of UROR (60%). Other significant UROR causes were infection (15%) and implant failure (9%). The median time between index procedure and UROR was 301 days.

For the univariate and multivariate analysis, open fracture (p< 0.05), fracture complexity (p<0.01), and weekend procedure (p< 0.01) were all associated with increased risk of UROR. All other variables were not statistically significant for any associations.

Those patients with an UROR for reasons other than symptomatic implants were more likely to have polyorthopaedic injuries (p < 0.05), ISS > 15 (p < 0.05), osteoporosis (p < 0.01), ICU status (p < 0.05), psychiatric history (p < 0.05), compartment syndrome (p < 0.05), neurovascular injury (p < 0.01), open fracture (p < 0.05), and fracture complexity (p < 0.05).

The rate of UROR in the orthopaedic trauma patient population is 10%. Most of these cases are due to implant-related issues. UROR for reasons other than symptomatic implants tend to be polytraumatized patients with higher-energy injuries, multiple complex fractures, and associated soft tissue injuries. Future focus on improved implant development and treatments for polytraumatized patients with complex fractures is warranted to decrease a relatively high UROR rate in orthopaedic trauma.

Mice are increasingly used for fracture healing research because of the possibility to use transgenic animals to conduct research on the molecular level. Mice from both sexes can be used, however, there is no consensus in the literature if fracture healing differs between female and male mice. Therefore, the aim of the present study was to analyze the similarities and differences in endochondral fracture healing between female and male C57BL/6J mice, since this mouse strain is mainly used in bone research. For that purpose, 12-weeks-old female and male mice received a standardized femur midshaft osteotomy stabilized by an external fixator. Mice were euthanized 10 and 21 days after fracture and bone regeneration was analyzed by biomechanical testing, µCT analysis, histology, immunohistochemistry and gene expression analysis. At day 21, male mice displayed a significantly larger fracture callus than female mice accompanied by higher number of osteoclasts, higher tissue mineral density and absolute values of bone volume, whereas relative bone volume to tissue volume ratio did not differ between the groups. Biomechanical testing revealed significantly increased bending stiffness in both fractured and intact femurs from male vs. female mice, whereas relative bending stiffness of fractured femurs related to the intact femurs did not differ. 10 days after fracture, male mice display significantly more cartilage and less fibrous tissue area in the fracture callus than female mice, whereas bone area did not differ. On the molecular level, male mice displayed increased active β-catenin expression in the fracture callus, whereas estrogen receptor α (ERα) expression was reduced. In conclusion, male mice showed more prominent cartilaginous callus formation, increased mineralization and whole callus tissue formation, whereas functional outcome after fracture did not differ from female mice. This might be due either to the heavier weight of male mice or because of differences in molecular signaling pathways.

Histone modifications critically contribute to the epigenetic orchestration of bone development - in part by modifying accessibility of genes to transcription factors. Based on the previous finding that histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue development, we here analyzed the molecular and cellular mechanisms of Mysm1-p53 interplay in bone development.

The bone phenotype of 4–5 week-old Mysm1-/- (MKO), Mysm1-/-p53-/- (DKO) and corresponding wildtype (WT) mice was determined using µCT and histology. Primary osteoblasts, mesenchymal stem cells (MSCs) and osteoclasts were isolated from long bones to assess cell proliferation, differentiation, apoptosis and activity. Statistics: one-way ANOVA, p<0.05.

MKO mice displayed an osteopenic bone phenotype compared to WT (BV/TV: 5.7±2.9 vs. 12.5±4.2, TbN: 1.3±0.6 vs. 2.7±0.7 1/mm, respectively), and these effects were abolished in DKO mice (BV/TV: 17.8±2.6, TbN: 3.7±0.4 1/mm). MKO mice compared to WT also showed both in vitro and in vivo disturbed osteoclast formation (in vitro: 1.5±1.2 vs. 9.9±1.8 OcN/mm2, in vivo OcN/BPm: 1.4±1.0 vs. 3.0±0.7 cells/mm, respectively) accompanied by increased apoptosis and DNA damage; additional p53 knockout attenuated these effects (7.8±1.8 OcN/mm2 and OcN/BPm: 2.2±1.0 cells/mm). Primary osteoblasts from both MKO and DKO mice showed decreased expression of the transcription factor Runx2 and of the osteogenic markers. ChIP-Seq analysis revealed direct binding of Mysm1 to Runx2 promoter regions in osteoblasts, implying that Mysm1 here regulates osteogenic differentiation. In contrast, MKO-MSCs differentiation did not differ from WT, but DKO-MSCs displayed a significantly increased expression of Alpl, Bglap and Runx2. The different effects of Mysm1-/- in MSCs and osteoblasts presumably resulted from the lower expression level of Mysm1 in MSCs in comparison to mature osteoblasts.

Thus, our data demonstrate that H2A deubiquitinase Mysm1 is essential for the epigenetic control of bone development via distinct mechanisms: 1) In osteoclasts, Mysm1 is involved in maturation of osteoclast progenitors and osteoclast survival. 2) In osteoblasts, Mysm1 directly controls Runx2 expression, thereby explaining osteopenic phenotype of MKO mice. 3) In MSCs, Mysm1 may play an inferior role due to low expression level. However, loss of p53 increases Runx2 expression during MSC differentiation, leading to normal bone formation in DKO mice.

Confirming clinical evidence, we recently demonstrated in a rodent model that a severe trauma which induces an acute systemic inflammation considerably impairs fracture healing. Interleukin-6 (IL-6) is a key cytokine in posttraumatic inflammation as its serum level correlates with injury severity and mortality. IL-6 signals are transmitted by the transmembrane glycoprotein 130 (gp130) via two distinct mechanisms: firstly, through classic signalling via the membrane-anchored IL-6 receptor and secondly, through trans-signalling using a soluble IL-6 receptor. Whereas IL-6 trans-signalling is considered a danger signal driving inflammation, classic signalling may mediate anti-inflammatory, pro-regenerative processes. The role of the two distinct pathways in bone healing has not yet been elucidated. Here, we studied the function of IL-6 in the pathophysiology of compromised bone healing induced by severe trauma.

Male C57BL/6J mice received an osteotomy of the right femur stabilized with an external fixator. Systemic inflammation was induced by additional blunt chest trauma (TxT) applied immediately after the osteotomy. Mice were injected with either fusion protein sgp130Fc, which selectively inhibits IL-6 trans-signalling, or a neutralizing anti-IL-6 antibody (IL-6 Ab), blocking both signalling pathways. Control mice received vehicle solution. Animals were euthanised 21 days after surgery. Fracture healing was analysed by biomechanical testing, μCT, and histomorphometry (n= 6–9; p=0.05; ANOVA/Fisher LSD post hoc).

Thoracic trauma significantly impaired fracture healing [bending stiffness (EI) −57%, p<0.00]. Treatment with sgp130Fc significantly attenuated bone regeneration as demonstrated by an increased EI (+110%, p<0.00) and a trend of augmented apparent Young”s modulus (+69%, p=0.13) compared to TxT control. Histomorphometric analysis could not detect differences in the amount of bone, confirming µCT results, but revealed a significantly decreased cartilage area after treatment with sgp130Fc (−76%, p=0.01). Inhibition of both signalling pathways with IL-6 Ab, however, did not have any effects.

In conclusion, severe trauma significantly impaired fracture healing, confirming previous studies. Treatment with sgp130Fc ameliorated the negative effects providing evidence that IL-6 trans-signalling triggers the excessive immune response after trauma impairing bone regeneration. Injection of IL-6 Ab did not improve fracture healing thereby implying that classic signalling may rather have beneficial effects.