A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures.

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.

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing.

PURPOSE: The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW. METHODS: Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by µCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits. RESULTS: Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number. CONCLUSIONS: Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.

Internal fixation with locking plate of 3- and 4-part proximal humeral fractures in elderly patients: complications and functional outcome.

Despite recent advances in operative techniques, internal fixation of (3- and 4-part) displaced proximal humeral fractures in elderly patients with osteoporotic bone remains controversial, sometimes followed by poor results. The aim of the present study was to evaluate outcomes of internal fixation with locking plate of multi-fragment proximal humeral fractures in elderly patients. The study cohort comprised 59 consecutive patients (mean age 70.1) with 3- and 4-part fractures who had undergone open reduction and internal fixation with locked plate at Sestre milosrdnice University Hospital Center in Zagreb, Croatia. All patients were invited for follow-up examinations and underwent standard x-ray examination preoperatively to assess fracture pattern in the operating theatre as well as at 6 weeks, 3 and 6 months, 1 year, and then annually after surgery to assess fracture healing or complications. Clinical outcomes were measured by constant score. Patients were followed-up for 14 to 36 months. The overall complication rate was 27.1%. The mean constant score at 1-year follow-up was 70.2 points for 3-part fractures vs. 64.2 for 4-part fractures (p < 0.0001). In conclusion, despite a relatively high overall complication rate, internal fixation with locking plate provided moderate to good functional results in the treatment of osteoporotic complex proximal humeral fractures.

Approach to distal femur by osteotomy of the patellar distal pole and internal fixation with basket plate in complex articular fracture: report of five cases.

According to AO classification, 33-C3 (complete articular multifragmentary) fracture of distal femur is characterized by complex articular involvement, along with short distal femoral block with multiple small fragments and usually with severe soft tissue abruption. In such cases of complex articular fracture of distal femur with extensive comminution of the femur condyle that is often seen in these fractures, anatomical reduction is quite difficult. Minimal fixation strategies sometimes do not provide an optimal degree of reduction and stability of the distal femoral block osteosynthesis. We describe 5 cases of treatment of the 33-C3 distal femoral fractures using arthrotomy of the knee joint by osteotomy of the distal pole of the patella and internal fixation with basket plate as an alternative approach for anatomical reduction of the comminuted articular surface.

Bone morphogenetic protein (BMP)1-3 enhances bone repair.

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFß, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. Invitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E(1) osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair.

Detection of bone and cartilage-related proteins in plasma of patients with a bone fracture using liquid chromatography-mass spectrometry.

Following bone fracture, a large number of growth factors, cytokines, and their cognate receptors involved in the repair process are active at the fracture site. To determine whether they appear in patients' blood as candidate biomarkers for following the outcome of healing, we analysed the plasma of 25 patients with an acute bone fracture following affinity plasma purification, SDS gel electrophoresis and liquid chromatography - tandem mass spectrometry (LC-MS/MS). Two hundred and thirteen nonredundant proteins were identified in the in-gel analysis of pooled plasma proteins. Gene ontology (GO) analysis indicated that a majority of detected proteins were of extracellular origin, whereas only a small number were of intracellular (cytosol and nucleus) origin. A significant proportion of detected proteins was involved in the cell growth and proliferation, transport and coagulation. Twelve proteins were potentially related to bone and cartilage metabolism, and several have not been previously identified in the plasma, including: TGF-beta induced protein IG-H(3), cartilage acidic protein 1, procollagen C proteinase enhancer protein and TGF-beta receptor III.