Schönbeck Christian, Stutz Janine, Schreiber Sebastian T, Keller Lukas, Siep Chiara, Metzger Wolfgang, Giorgi Mario, Sartini Irene, Fritz Tobias, Pohlemann Tim, Menger Michael D, Liodakis Emmanouil, Laschke Matthias W, Orth Marcel
Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Germany.
Department of Veterinary Sciences, University of Pisa, Pisa, Italy.
Front Physiol. 2025 Jul 9;16:1630268. doi: 10.3389/fphys.2025.1630268. eCollection 2025.
Metamizole is a commonly used analgesic drug in clinical fracture management, which does not affect the healing process under physiological conditions. However, many fracture patients suffer from co-morbidities resulting in ischemic conditions with impaired bone healing. The effect of metamizole on fracture healing under ischemic conditions has not been analyzed so far. Accordingly, in this study 44 CD-1 mice underwent ligation of the deep femoral artery to induce mild ischemia in the right hind limb. The femur was then fractured and stabilized with an intramedullary lag screw and the animals were daily treated per os with 50 mg/kg metamizole (n = 23) or vehicle (control; n = 21). Serum concentrations of the active metamizole metabolites, 4-methyl-amino-antipyrine (4-MAA) and 4-amino-antipyrine (4-AA), were determined 30, 60 and 90 min after administration. Bone healing was analyzed by biomechanical, radiological, histomorphometrical and Western blot analysis at 2 and 5 weeks postoperatively. The plasma level of 4-MAA was high at all time points, whereas 4-AA peaked at 90 min after administration. Biomechanical, radiological and histomorphometrical analyses revealed no differences between metamizole-treated and control mice, while both groups showed a delayed fracture healing. Of interest, Western blot analyses of callus tissue showed an increased expression of the pro-angiogenic factor Cyr61 and the osteoanabolic runt-related transcription factor 2 (RUNX2) as well as the osteocatabolic receptor activator of NF-κB ligand (RANKL) in metamizole-treated animals when compared to controls. Taken together, these findings indicate that the application of metamizole does not affect fracture healing under ischemic conditions. Therefore, treatment with this analgesic drug may be also recommended in fracture patients suffering from co-morbidities resulting in tissue ischemia.
安乃近是临床骨折治疗中常用的镇痛药，在生理条件下不影响愈合过程。然而，许多骨折患者患有合并症，导致缺血状态，影响骨愈合。迄今为止，尚未分析安乃近在缺血条件下对骨折愈合的影响。因此，在本研究中，44只CD-1小鼠接受股深动脉结扎，以诱导右后肢轻度缺血。然后将股骨骨折，并用髓内拉力螺钉固定，动物每天口服50mg/kg安乃近（n = 23）或赋形剂（对照组；n = 21）。给药后30、60和90分钟测定活性安乃近代谢物4-甲基氨基安替比林（4-MAA）和4-氨基安替比林（4-AA）的血清浓度。术后2周和5周通过生物力学、放射学、组织形态计量学和蛋白质印迹分析来分析骨愈合情况。4-MAA的血浆水平在所有时间点都很高，而4-AA在给药后90分钟达到峰值。生物力学、放射学和组织形态计量学分析显示，安乃近治疗组和对照组小鼠之间没有差异，而两组均显示骨折愈合延迟。有趣的是，与对照组相比，蛋白质印迹分析显示，安乃近治疗组动物的骨痂组织中促血管生成因子Cyr61、骨合成代谢相关的矮小相关转录因子2（RUNX2）以及骨分解代谢的核因子κB受体激活剂配体（RANKL）的表达增加。综上所述，这些发现表明，在缺血条件下应用安乃近不影响骨折愈合。因此，对于患有导致组织缺血的合并症的骨折患者，也可能推荐使用这种镇痛药进行治疗。
