Tranexamic Acid Attenuates the Progression of Posttraumatic Osteoarthritis in Mice

Abstract

Background: Posttraumatic osteoarthritis (OA) is a common disorder associated with a high socioeconomic burden, particularly in young, physically active, and working patients. Tranexamic acid (TXA) is commonly used in orthopaedic trauma surgery as an antifibrinolytic agent to control excessive bleeding. Previous studies have reported that TXA modulates inflammation and bone cell function, both of which are dysregulated during posttraumatic OA disease progression. Purpose: To evaluate the therapeutic effects of systemic and topical TXA treatment on the progression of posttraumatic OA in the knee of mice. Study Design: Controlled laboratory study. Methods: OA was induced via anterior cruciate ligament (ACL) transection on the right knee of female mice. Mice were treated with TXA or vehicle intraperitoneally daily or intra-articularly weekly for 4 weeks, starting on the day of surgery. Articular cartilage degeneration, synovitis, bone erosion, and osteophyte formation were scored histologically. Micro−computed tomography evaluation was conducted to measure the subchondral bone microstructure and osteophyte volume. Cartilage thickness and bone remodeling were assessed histomorphometrically. Results: Both systemic and topical TXA treatment significantly reduced cartilage degeneration, synovitis, and bone erosion scores and increased the ratio of hyaline to calcified cartilage thickness in posttraumatic OA. Systemic TXA reversed ACL transection-induced subchondral bone loss and osteophyte formation, whereas topical treatment had no effect. Systemic TXA decreased the number and surface area of osteoclasts, whereas those of osteoblasts were not affected. No effect of topical TXA on osteoblast or osteoclast parameters was observed. Conclusion: Both systemic and topical TXA exerted protective effects on the progression of posttraumatic OA. Drug repurposing of TXA may, therefore, be useful for the prevention or treatment of posttraumatic OA, particularly after ACL surgery. Clinical Relevance: TXA might be beneficial in patients with posttraumatic OA of the knee.

The emerging role of tranexamic acid and its principal target, plasminogen, in skeletal health

“…A recent animal study with a sample size of 6 showed that both systemic and topical TXA treatment protected cartilage from degeneration and lowered inflammatory responses of the synovial tissue in mice with post-traumatic osteoarthritis after anterior cruciate ligament transection. Moreover, systemic TXA beneficially affected pathological subchondral bone remodeling and reduced osteophyte formation in wild-type mice that underwent anterior cruciate ligament transection 22 , overall suggesting a potentially beneficial effect of TXA in patients with osteoarthritis. Thus, the results of a current phase II double-blinded RCT investigating the effects of systemic TXA on joint inflammation and cartilage health in anterior cruciate ligament reconstruction are eagerly awaited 77 .…”

“…Collectively, the current evidence from animal experiments suggests beneficial effects of TXA on osteoporosis 21 and osteoarthritis 22 , while the underlying mechanisms however, require further clarification. In terms of bone regeneration, the results from one preclinical study support a positive effect of TXA application on fracture healing 70 , whereas the other two available studies suggest no influence 72 or even negative outcomes 71 .…”

“…In vitro , TXA was shown to directly promote osteogenesis of bone marrow-derived osteoblasts, inhibit osteoclastogenesis, and reduce the expression of inflammatory cytokines in macrophages 20 . Furthermore, several animal studies have reported that TXA treatment exerts beneficial effects on osteoporosis and osteoarthritis 21 , 22 . Thus, TXA may potentially alter bone and immune cell function in skeletal diseases via PLG-dependent or -independent manners, as discussed below.…”