Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in vivo CD-1 mice. Further, we identified dysregulated NF-κB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

Study Design.: Prospective cohort study. Objective.: Determine whether epigenetic age (EA), calculated via DNA methylation analysis, is associated with early postoperative complications in adult spinal deformity (ASD) surgery. Background.: ASD is increasingly prevalent in the aging population, with postoperative complication rates ranging from 37% to 71%. While chronological age (CA) and frailty scores are known predictors of poor outcomes, they may not fully capture biological vulnerability. EA, derived from DNA methylation patterns, may better reflect a patient’s physiological reserve and stress response capacity. Methods.: Thirty patients undergoing ASD surgery were prospectively enrolled and provided peripheral blood samples on the day of surgery. DNA methylation of peripheral blood mononuclear cells (PBMCs) was analyzed using the Illumina EPIC v2.0 array. EA was computed using the Horvath DNAmAge algorithm. Associations between EA, CA, and the Edmonton Frailty Index (EFI) with postoperative complications at 30 days were assessed using appropriate parametric and non-parametric statistical tests. Differentially methylated positions (DMPs) were identified between complication and non-complication group. Results.: Of the 30 enrolled patients (mean CA: 68.4 y, 21 female), 14 (47%) experienced postoperative complications. Sixty-three DMPs were found between the two groups, with 35 hypomethylated and 28 hypermethylated CpG sites in the complication group. Genes affected were linked to immune response, including LRBA and NFACT2. Regulators of EGFR and WNT pathways were also differentially methylated. Patients with EA greater than CA were significantly more likely to experience complications (86% vs. 14%, P =0.038). The difference between EA and CA was greater in the complication group (5.07 vs. 0.87 y, P =0.029). No significant differences were found in mean CA, EA, or EFI alone between the groups. Conclusion.: Postoperative complications in ASD patients were associated with epigenetic alterations and elevated EA relative to CA. These findings suggest EA may be a novel biomarker for preoperative risk stratification in ASD surgery.

Study Design: Retrospective cohort study.Purpose: Using latent profile analysis (LPA) to multidimensionally profile trunk muscles, we aimed to identify muscle phenotypes, compare LPA-based classification with sarcopenia definitions for explaining sagittal alignment, and examine malalignment patterns across LPA-derived subtypes.Overview of Literature: Paraspinal sarcopenia is closely associated with sagittal malalignment in adult spinal deformity (ASD), but traditional single-muscle or single-metric definitions fail to capture heterogeneous muscle degeneration.Methods: This retrospective cohort study included 145 patients with ASD undergoing long-segment fusion (≥5 levels; upper instrumented vertebra T1–L1) with ≥1-year follow-up. We measured muscle quantity using the psoas vertebral body index (PVBI) and paralumbar vertebral body index (PLVBI), and muscle quality using fatty infiltration (FI) of the psoas and paralumbar (multifidus and erector spinae) muscles. LPA was applied to PVBI, PLVBI, and psoas and paralumbar FI to identify clusters. For comparison, sarcopenia was defined by each metric. We compared LPA with single-metric definitions for predicting sagittal measures and examined clinical, radiographic (pre/ post), and surgical outcomes across LPA subtypes.Results: LPA explained sagittal alignment better than any single measure and revealed four phenotypes: Mild-Deg (high quantity, low FI; n=49), Mod-Deg (moderate; n=39), Seve-Deg (low quantity, high FI; n=34), and Hete-Deg (low quantity, high paralumbar FI but low psoas FI; n=23). Preoperative deformity progressively worsened from Mild-Deg to Seve-Deg, while Hete-Deg also showed pronounced malalignment. Postoperatively, most metrics were similar across groups. At last follow-up, however, Mod-Deg/Seve-Deg had greater pelvic incidence (PI)–lumbar lordosis (LL), and LL in Seve-Deg trended toward progressive worsening from postoperative to follow-up (PI–LL and T4 pelvic angle).Conclusions: Multidimensional LPA muscle phenotyping outperformed single-metric sarcopenia definitions in explaining sagittal alignment. It also identified a heterogeneous Hete-Deg subtype suggestive of functional compensation despite severe preoperative deformity, whereas Seve-Deg reflected irreversible muscle loss with progressive imbalance.

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in-vivo CD-1 mice. Further, we identified dysregulated NFB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. Finally, we found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy of bone marrow cells and activated NFB signaling genes in bone marrow-derived cells. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NFB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.