Surgical Complications Associated With Atypical Femur Fractures Attributed to Bisphosphonate Use.

Complications of atypical femur fractures (AFFs) are common. AFFs often receive the same treatment as other femoral fractures; however, there appears to be a higher rate of adverse outcomes. Nine patients sustained a total of 13 AFFs, had documented bisphosphonate use before fracture, and had surgery between 2006 and 2012. Complications included continued pain, surgical revision, nonunion, malunion, deformity, or heterotopic ossification. The overall complication rate was 33.3%, with four of the 12 surgeries performed at this institution resulting in one nonunion and three minor complications. None of the primary fixations required revision. There was a higher complication rate for AFFs when compared with non-bisphosphonate-related intramedullary nail femur fracture fixations. This cohort demonstrated a lower rate of major complications compared to the literature. Using a reamed, statically locked nail, halting bisphosphonate medication, and allowing early weight bearing is a safe and efficacious method to treat atypical femur fractures. (Journal of Surgical Orthopaedic Advances 27(1):14-20, 2018).

Methotrexate-mediated inhibition of nuclear factor κB activation by distinct pathways in T cells and fibroblast-like synoviocytes.

OBJECTIVES: Nuclear factor κB (NF-κB) is a critical activator of inflammatory processes and MTX is one of the most commonly prescribed DMARDs for treatment of RA. We sought to determine whether MTX inhibited NF-κB activity in RA and in lymphocytes and fibroblast-like synoviocytes (FLSs) and to define underlying mechanisms of action. METHODS: An NF-κB luciferase reporter plasmid was used to measure NF-κB activation across experimental stimuli. Flow cytometry was used to quantify changes in intracellular protein levels, measure levels of reactive oxygen species and determine apoptosis. Quantitative RT-PCR was used to identify changes in MTX target genes. RESULTS: In T cell lines, MTX (0.1 µM) inhibited activation of NF-κB via depletion of tetrahydrobiopterin (BH4) and increased Jun-N-terminal kinase (JNK)-dependent p53 activity. Inhibitors of BH4 activity or synthesis also inhibited NF-κB activation and, similar to MTX, increased JNK, p53, p21 and JUN activity. Patients with RA expressed increased levels of phosphorylated or active RelA (p65) compared with controls. Levels of phosphorylated RelA were reduced in patients receiving low-dose MTX therapy. In contrast, inhibition of NF-κB activation by MTX was not mediated via BH4 depletion and JNK activation in FLSs, but rather was completely prevented by adenosine receptor antagonists. CONCLUSION: Our findings support a model whereby distinct pathways are activated by MTX in T cells and FLSs to inhibit NF-κB activation.