Recombinant Human BMP6 Applied Within Autologous Blood Coagulum Accelerates Bone Healing: Randomized Controlled Trial in High Tibial Osteotomy Patients

Abstract

Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo-controlled, double-blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow-up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm 3 ; p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm 3 ; p = 0.006) follow-up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC-treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP-based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system.

A novel autologous bone graft substitute containing rhBMP6 in autologous blood coagulum with synthetic ceramics for reconstruction of a large humerus segmental gunshot defect in a dog: The first veterinary patient to receive a novel osteoinductive therapy

“…BMP6 is superior to BMP2 and BMP7 in stimulating bone formation both in vitro and in vivo ( Song et al, 2010 ; Vukicevic and Grgurevic, 2009 ) because it acts via all BMP type I receptors. In addition, BMP6 is, unlike BMP2 and BMP7, resistant to Noggin which is the main BMP antagonist present in an increased amount in bone ( Song et al, 2010 ) allowing the use of low BMP6 concentration per mL of ABC ( Grgurevic et al, 2019 ; Sampath and Vukicevic, 2020 ; Grgurevic et al, 2020 ; Durdevic et al, 2020 ; Chiari et al, 2020 ). BMP2 with bovine collagen has been used previously in dogs with long bone non-unions; however, the follow-up period of mostly 5–8 weeks was not long enough to pronounce successful healing since large defects need at least 4–8 months to demonstrate the cortical rebridgment and biomechanical stability after osteosynthesis removal ( Itoh et al, 1998 ; Milovancev et al, 2007 ; Peric et al, 2015 ).…”

“…We have recently demonstrated that an autologous bone graft substitute (ABGS) containing recombinant human bone morphogenetic protein 6 (rhBMP6) within ABC with and without allograft as a CRM was safe and efficacious in the rabbit ulnar segmental defect model ( Grgurevic et al, 2019 ), rabbit and ovine posterolateral spinal fusion (PLF) and sheep anterior lumbar interbody fusion (ALIF) models ( Vukicevic et al, 2020a ; Grgurevic et al, 2020 ). In continuation, the ABGS was tested in Phase I clinical trials in patients with distal radial fracture ( Durdevic et al, 2020 ), and Phase I/II trial in patients undergoing high tibial osteotomy ( Chiari et al, 2020 ) and was proven safe and efficacious as compared to placebo and standard of care treated patients. ABGS with the addition of allograft as a CRM is currently used in a posterolateral lumbar interbody fusion (PLIF) clinical study in patients with lumbar back pain due to a degenerative disc disease (EudraCT number 2017-000860-14).…”

Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions

“…Furthermore, higher osteoinductive activity of BMP-6 and BMP-9, compared to BMP-2 or BMP-7, make them promising candidates for promoting bone repair or filling, as shown by several recent studies [ 399 , 400 , 401 ]. For example, a recent randomized, double-blinded, placebo-controlled phase I/II clinical trial revealed that autologous blood coagulum combined with rhBMP-6 (1.0 mg/10 mL) promoted bone healing in patients with high tibial osteotomy [ 401 ].…”

Bone morphogenetic proteins: From discovery to development of a novel autologous bone graft substitute consisting of recombinant human BMP6 delivered in autologous blood coagulum carrier

“…In clinical trials we tested whether the low quantities of BMP6 in an autologous carrier support trabecular bone healing of the compartment in which BMP2 and BMP7 were ineffective 14,15 . ABGS has so far been tested in Phase I study in patients with distal radial fractures 14 and Phase I/II study in patients undergoing high tibial osteotomy 15 .…”

“…Thus, the animal-derived collagen has been replaced with ABC which reduces the inflammatory response and serves as a physiological carrier for rhBMP6 adjustable to the desired shape 11,12 . Based on the results from the preclinical studies, clinical studies/trials in patients with a distal radial fracture, high tibal osteotomy and posterolateral spinal fusion were approved [13][14][15] . This review covers BMP discovery, biology and their use in clinical studies with particular reference to new BMP6 based ABGS.…”