Clinical Hospital Center "Sisters of Mercy", Clinic of Traumatology, Draskoviceva 19, 10000 Zagreb, Croatia.
Laboratory for Mineralized Tissues, Centre for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000 Zagreb, Croatia.
Bone. 2020 Nov;140:115551. doi: 10.1016/j.bone.2020.115551. Epub 2020 Jul 27.
Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
骨形态发生蛋白（BMPs）已知可在体内诱导新骨形成，但用基于 BMP 的治疗方法治疗小梁骨缺损仍存在争议。在这里，我们评估了一种新型的自体骨移植物替代物（ABGS）的安全性和有效性，该替代物由重组人 BMP6（rhBMP6）分散在自体血凝块（ABC）中组成，作为一种生理性天然载体，用于治疗闭合性桡骨远端骨折（DRF）患者。我们招募了 32 名患者，进行了一项随机、标准治疗（SoC）和安慰剂（PBO）对照、双盲的 I 期首次人体（FiH）临床试验。ABGS 是从外周血中制备的，rhBMP6 浓度为 250μg/mL ABC 或 PBO（1mL ABC 仅含有赋形剂），并通过注射器注射到骨折部位，然后用 3 根克氏针闭合固定骨折。患者携带固定器 5 周，并通过临床检查、安全性、连续影像学分析和 CT 随访 0 至 26 周。在 13 周的随访和研究后 26 周，没有记录到严重的不良反应。结果表明，在治疗后 13-26 周，32 名患者中的任何一名患者的血液中均未检测到抗 rhBMP6 抗体。用 ABGS 治疗的患者的血浆药代动力学分析显示，在给药后 24 小时内的任何时间点均未检测到 rhBMP6。用 AGBS 治疗的患者的 CT 图像和影像学分析评分显示，与 PBO 和 SoC 相比，在 5 和 9 周时（具有高效果大小和 P=0.027），骨愈合明显加快，而在 13 周时，所有患者的愈合结果相似。总之，我们表明，将 ABGS（250μg rhBMP6/mL ABC）注入桡骨远端骨折部位的骨内，与对照 PBO 和 SoC 患者相比，具有良好的耐受性，无严重不良反应，并且早期加速小梁骨愈合。
