Effects of Tranexamic Acid on Human Osteoblasts as Proxy for Fracture Healing.

OBJECTIVES: To investigate the effect of tranexamic acid (TXA) through in vitro culture of primary human osteoblasts (HOB) and in vivo using an operative rat femur fracture model. It was hypothesized that there would not be any effect on fracture healing in both studies. METHODS: Primary HOBs were exposed to varying concentrations of TXA over different time periods. Cells were assessed for viability, metabolism, and mineralization. For the in vivo model, fractures were created in the femora of adult rats, exposed to either TXA or saline, and then assessed for healing at different time points. A modified radiographic union score for tibia was used to evaluate radiographs, callus mineralization was assessed with microcomputed tomography, and biomechanical tests were performed. RESULTS: Overall, HOB viability and metabolism decreased as TXA concentration and exposure time increased. However, at concentrations below 56.44 mg/mL, HOB viability was not affected. Similarly, mineralization also decreased as TXA concentration and exposure time increased. In both groups, in vivo results demonstrated increasing radiographic healing, callus mineralization, and biomechanical strength as a function of time. There was a trend for increased healing in the TXA group at 6 weeks after fracture; however, the difference compared with untreated animals was not statistically significant. CONCLUSIONS: Although a degradation of HOB viability and metabolism occurred with increased TXA concentrations and exposure times, clinically relevant concentrations do not adversely affect HOB viability, metabolism, or mineralization. In addition, there were no noticeable adverse effects of TXA administration in the in vivo model.

The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.

The comparative stability of screw versus plate versus screw and plate coronoid fixation.

PURPOSE: To compare the biomechanical characteristics of screw versus plate versus both screw and plate fixation for large, type 3 O'Driscoll coronoid fractures. METHODS: Synthetic ulnas had 70% of their coronoids cut. Fixation was performed with either a cannulated screw, a plate, or both a screw and a plate. Energy to failure, force at failure, first cycle stiffness, and stiffness at failure were measured on a servohydraulic testing machine under cyclic posterior axial loading. RESULTS: The combination of a plate and screw had significantly greater energy to failure (83 Nm), force required to cause failure (634 N), and stiffness at failure (387 N/mm) compared to either an isolated plate (38 Nm, 474 N, 237 N/mm, respectively) or a screw (10 Nm, 279 N, 149 N/mm, respectively). For energy to failure and force required to cause failure, the plate group significantly outperformed the screw group. There was no significant difference in stiffness at the time of failure between the plate and screw groups. CONCLUSIONS: For type 3 O'Driscoll coronoid fractures or nonunions when both a screw and a plate can be placed, the combination of these 2 fixation devices appears to produce significantly greater biomechanical stability than either fixation device alone.