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Human fracture healing is a complex interaction of several cytokines that regulate osteoblast and osteoclast activity. By monitoring OPG (osteoprotegerin) and sRANKL we aimed to possibly predict normal or impaired fracture healing. In 64 patients with a fracture of a long bone serum level of sRANKL and OPG were evaluated with respect to bony union (n=57) or pseudarthrosis (n=7). Measurements were carried out at admission and at 1, 2, 4, 6, 8, 12, 24, and 48 weeks after the injury. Patients' serum levels were compared to 33 healthy controls. Fracture hematoma contained significantly higher sRANKL and OPG concentrations compared to patients serum (p=0.005, p=0.028). OPG level in fracture hematoma was higher compared to the unions serum level (p=0.028). sRANKL was decreased in unions during the observation period. In non-unions sRANKL and OPG levels showed a variable course, with no statistical significance. This is the first study to document the course of OPG and sRANKL in normal and delayed human fracture healing emphasizing its local and systemic involvement. We provide evidence of strongly enhanced OPG levels in patients with a long bone fracture compared to healthy controls. Further, levels of free sRANKL were decreased during regular fracture repair., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Sclerostin (SOST), an antagonist of Wnt signaling, is an important negative regulator of bone formation. However, no data on the role of SOST in the human fracture healing have been published so far. This study addressed this issue. Seventy-five patients with long bone fractures were included into the study and divided in two groups. The first group contained 69 patients with normal fracture healing. Six patients with impaired fracture healing formed the second group. Thirty-four volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SOST levels were measured in fracture hematoma and serum of 16 patients with bone fractures. Fracture hematoma contained significantly higher SOST concentrations compared to patient's serum. SOST levels in fracture hematoma and in patient's serum were both significantly higher than in the serum of controls. Highly elevated SOST serum concentrations were found in patients with physiological fracture healing. SOST levels were decreased in patients with impaired fracture healing. However, this difference was not statistically significant. This is the first study to provide evidence of strongly enhanced SOST levels in patients with bone fracture. The results indicate local and systemic involvement of SOST in humans during fracture healing., (Copyright © 2012 Orthopaedic Research Society.)

Despite clinical efforts to treat growth disturbances only little is known about the growth potential of the different zones of the growth plate. The aim of this study was to investigate the growth potential of different zones of the growth plate. A total of 20 New Zealand White rabbits were used for this experiment. The right and left ulna of each animal were used resulting in a total of 40 ulnae. Animals were assigned into five groups. In groups I and II resection of the metaphyseal (n = 12) or the epiphyseal (n = 6) segment of the growth plate was performed. In group III resection of the growth plate and re-implantation was performed (n = 6). In group IV the growth plate was resected and re-implanted after a 180° rotation (n = 6). Animals in group V served as controls. Histologic and radiologic examinations were performed to evaluate the growth process at 1, 2, 4, and 12 weeks following surgery. In group I, III, and IV temporary growth disturbance which was compensated within a short time was observed. Resection of the epiphyseal part resulted in growth arrest of the distal ulna in combination with normal growth of the radius which led to and valgus deformity of the limb. The results of this study indicate the importance of the reserve zone for the functioning of the growth plate., (Copyright © 2011 Orthopaedic Research Society.)

Injury of the growth plate is a specific problem in traumatology and can cause limb deformity and length discrepancy as a result of growth arrest. The purpose of this study was to evaluate alterations of the growth plate after artificially created injuries. A total of 14 New Zealand White rabbits were used for this experiment. The right and left ulna of each animal was used resulting in a total of 28 ulnae. In six animals drill holes were driven into the growth plate either from the distal/epiphyseal side or from the proximal/metaphyseal side of the physis. In six animals a fracture of the distal ulna corresponding to a Salter-Harris fracture type IV was created. This fracture was fixed by screws from either the epiphyseal or the metaphyseal side. Two animals served as controls. Histologic and radiologic examinations were performed to evaluate the growth process at 1, 2, 4, and 12 weeks following surgery. Drilling or fixation of the growth plate from the metaphyseal side resulted in temporary growth disturbance which was compensated within a short time. In contrast fixation from the epiphyseal side caused severe growth disturbances. Based on our findings K-wires or screws should be inserted from the metaphyseal side and be placed in the center of the growth plate., (Copyright © 2011 Orthopaedic Research Society.)

Macrophage colony-stimulating factor (M-CSF) plays a unique role in bone remodeling. However, to our knowledge, no data on the role of M-CSF in fracture healing in humans have been published so far. This study addressed this issue. One hundred and thirteen patients with long-bone fractures were included in the study and divided into two groups, according to their course of fracture healing. The first group contained 103 patients with normal fracture healing. Ten patients with impaired fracture healing formed the second group of the study. Volunteers donated blood samples as control. Serum samples were collected over a period of 6 months, following a standardized time schedule. In addition, M-CSF levels were measured in fracture hematoma and serum of 11 patients with bone fractures. M-CSF concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Fracture hematoma contained significantly higher M-CSF concentrations compared to M-CSF concentrations in patient's serum. M-CSF levels in fracture hematoma and in patient's serum were both significantly higher than M-CSF concentrations measured in serum of healthy controls. Highly elevated M-CSF serum concentrations were found in patients with physiological fracture healing over the entire observation period. Significant differences in the M-CSF serum concentration between patients with normal fracture healing and patients with impaired fracture healing were not observed. This study indicates, for the first time, to our knowledge, a possible local and systemic involvement of M-CSF in humans during fracture healing., (Copyright (c) 2009 Orthopaedic Research Society.)

Vascular endothelial growth factor (VEGF) plays an important role in the bone repair process as a potent mediator of angiogenesis and it influences directly osteoblast differentiation. Inhibiting VEGF suppresses angiogenesis and callus mineralization in animals. However, no data exist so far on systemic expression of VEGF with regard to delayed or failed fracture healing in humans. One hundred fourteen patients with long bone fractures were included in the study. Serum samples were collected over a period of 6 months following a standardized time schedule. VEGF serum concentrations were measured. Patients were assigned to one of two groups according to their course of fracture healing. The first group contained 103 patients with physiological fracture healing. Eleven patients with delayed or nonunions formed the second group of the study. In addition, 33 healthy volunteers served as controls. An increase of VEGF serum concentration within the first 2 weeks after fracture in both groups with a following decrease within 6 months after trauma was observed. Serum VEGF concentrations in patients with impaired fracture healing were higher compared to the patients with physiological healing during the entire observation period. However, statistically significant differences were not observed at any time point between both groups. VEGF concentrations in both groups were significantly higher than those in controls. The present results show significantly elevated serum concentrations of VEGF in patients after fracture of long bones especially at the initial healing phase, indicating the importance of VEGF in the process of fracture healing in humans., ((c) 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The role of colony stimulating factor-1 (CSF-1) in the regulation of osteoclasts and bone remodeling suggests that CSF-1 may also be involved in regulation of bone healing. The ability of CSF-1 to promote healing of bone defects was tested in a rabbit model. Twenty-four New Zeeland rabbits were included in the study. Animals were assigned to two groups: the control group (n = 12) was treated by plate fixation. The animals in the second group (n = 12) were also stabilized by conventional plating and received additionally CSF-1 for 2 weeks systemically. Histologic, histomorphometric, and radiologic examinations were performed to evaluate the healing process at 4, 8, and 12 weeks following surgery. Animals that were treated by CSF-1 produced a significantly higher amount of mineralized bone over the first 8 weeks after fracture compared to the control animals. Furthermore, a higher number of osteoclasts was found in CSF-1-treated animals within the first 8 weeks, compared to the controls. The present data emphasize for the first time the importance of CSF-1 in the bone healing. The use of CSF-1 in addition to conventional fixation might be a novel approach for the treatment of bone defects.

Anorganic bovine-derived hydroxyapatite (ABM) in combination with binding peptid (P-15) has demonstrated the capacity to improve the healing of periodontal defects. This study evaluated the benefit of ABM/P-15 to promote healing of cortical long bone defects in a rabbit model. A 5-mm segmental bone defect was created in the femur and fixed with a plate. There were two treatment groups: no implant (n = 12) and ABM/P-15 (n = 12). At 4, 8, and 12 weeks, healing of the defect was evaluated with radiographs and histomorphometric examination of the treated femora. After 4 weeks, radiographs showed bone formation without signs of complete consolidation in three of four animals in the control group and two of four ABM/P-15 treated animals. At the later course of the treatment, no radiologic difference was evident between the treatment groups. Histomorphometric evaluation revealed an area of 1.29 +/- 0.11 mm(2) and 0.97 +/- 0.21 mm(2) of newly produced bone in animals of the control group and ABM/P-15 group after 4 weeks. After 8 and 12 weeks, animals in the control group had an area of 2.44 +/- 0.62 mm(2) and 2.5 +/- 0.2 mm(2) of newly produced bone within the osteotomy gap compared to 1.6 +/- 0.65 mm(2) and 1.56 +/- 0.27 mm(2) in the ABM/P-15 group (p = 0.0004). An enhanced or accelerated ingrowth of bone, as reported in previous studies, was not observed. Our results imply that the ABM/P-15 is not a suitable graft for the treatment of critical-sized segmental defects in long bones.