Definitive proof is lacking on mesenchymal stem cell (MSCs) cellular therapy to regenerate bone if biological potential is insufficient. High number of MSCs after GMP expansion may solve the progenitor insufficiency at the injury but clinical trials are pending. A prospective, multicenter, multinational Phase I/IIa interventional clinical trial was designed under the EU-FP7 REBORNE Project to evaluate safety and early efficacy of autologous expanded MSCs loaded on biomaterial at the fracture site in diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus) nonunions. The trial included 30 recruited patients among 5 European centres in France, Spain, Germany, and Italy. Safety endpoints (local and general complication rate) and secondary endpoints for early efficacy (number of patients with clinically and radiologically proven bone healing at 12 and 24 weeks) were established. Cultured MSCs from autologous bone marrow, expanded under GMP protocol was the Investigational Medicinal Product, standardised in the participating countries confirming equivalent cell production in all the contributing GMP facilities. Cells were mixed with CE-marked biphasic calcium phosphate biomaterial in the surgical setting, at an implanted dose of 20−106 cells per cc of biomaterial (total 10cc per case) in a single administration, after debridement of the nonunion.Background
Methods
Beside spine and pelvis surgery, computer-assisted guidance systems are not used frequently for musculoskeletal injuries. Main reason is the dependence on a fixed reference array that must be firmly attached to all moving parts. We investigated a novel fluoroscopy-based image guidance system in orthopaedic trauma surgery that uses a different technique. This was a prospective, not randomised single centre case series at a level I trauma centre. 45 patients with 46 injuries (foot 12, shoulder 10, long bones 7, hand and wrist 7, ankle 7, spine and pelvis 4) were included. Different surgical procedures were examined following the basic principles of the AO/ASIF. Main outcome measurements were the number of trials for implant placement, total surgery time, usability via user questionnaire and system failure rate. Furthermore we wanted to test the ability of the new system to be integrated in existing surgical workflows. In all cases, the trajectory function was used, inserting a total of 56 guided implants. The trajectory was the most popular feature used by surgeons (n=43, 93.5%), followed by the length measurement tool (n=29, 63%) and the bending function (n=17, 37%). The functions could be freely activated by the performing surgeon. The system failed when used in pelvic and spinal injuries, resulting in a total failure rate of 6.5% (n=3) of all included cases. The overall usability was rated as good, scoring 84.3%. This study examined the clinical application of a fluoroscopy-based image guidance system for different musculoskeletal injuries. Its major advantage is the high integrability in the accustomed surgical workflow and its connectivity with existing technical equipment. It can hardly be compared to known navigation solutions, since instruments are not tracked and fixed reference arrays are not required. Expected advantages should be explored in randomised studies.
Minimally invasive placement of iliosacral screws (SI-screw) is becoming the standard surgical procedure for sacrum fractures. Computer navigation seems to increase screw accuracy and reduce intraoperative radiation compared to conventional radiographic placement. In 2012 an interdisciplinary hybrid operating theatre was installed at the University of Ulm. A floor-based robotic flat panel 3D c-arm (Artis zeego, Siemens, Germany) is linked to a navigation system (BrainLab Curve, BrainLab, Germany). With a single intraoperative 3D scan the whole pelvis can be visualised in CT-like quality. The aim of this study was to analyse the accuracy of SI-screws using this hybrid operating theater. 32 SI-screws (30 patients) were included in this study. Indications ranged from bone tumour resection with consecutive stabilisation to pelvic ring fractures. All screws were implanted using the hybrid operating theatre at the University of Ulm. We analysed the intraoperative 3D scan or postoperative computed tomography and classified the grade of perforation of the screws in the neural foramina and the grade of deviation of the screws to the cranial S1 endplate according to Smith et al. Grade 0 stands for no perforation and a deviation of less than 5 °. Grade 1 implies a perforation of less than 2 mm and a deviation of 5–10°, grade 2 a perforation of 2–4 mm and a deviation of 10–15° and grade 3 a perforation of more than 4 mm and a deviation of more than 15°. All patients were tested for intra- and postoperative neurologic complications and infections. The statistical analysis was executed using Microsoft Excel 2010. 32 SI-screws were implanted in the first 20 months after the hybrid operating theatre had been established in 2012. All 30 patients were included in this study (15 men, 15 women). The mean age was 59 years ±23 (13–95 years). 20 patients received a single screw in S1 (66.7%), 1 patient 2 unilateral screws in S1 and S2 (3.3%), one patient 2 bilateral screws in S1 (3.3%) and 8 patients a single screw stabilising both SI-joints (26.7%). 27 screws showed no perforation (84.4%), 1 screw a grade 1 perforation (3.1%) and 4 screws a grade 2 perforation (12.5%). There was no grade 3 perforation. Furthermore there was no perforation of the neural foramina or the ventral cortex in the axial plane of the SI-screws stabilising one SI-joint (24 screws). Only single SI-screws bridging both SI joints showed a perforation of the neural foramina (37% grade 0, 12.5% grade 1, 50% grade 2, 0% grade 3). In the frontal plane 23 screws (71.9%) showed a deviation of less than 5°. In 5 screws a grade 1 deviation (15.6%) and in 4 screws a grade 2 deviation (12.5%) could be found. There was no grade 3 deviation. There were no infections or neurological complications. The high image quality and large field of view in combination with an advanced navigation system is a great benefit for the surgeon. All SI-screws stabilising only one joint showed completely intraosseous placement. Single SI-screws bridging 2 SI-joints intentionally perforated the neural foramina ventrally in 5 cases because of dysmorphic sacral anatomy. This makes image-guided implantation of SI-screws in a hybrid operating theatre a very safe procedure.
The internal fixation of scaphoid bone fractures remains technically difficult due to the size of the bone and its three- dimensional shape. Early rigid fixation, e.g with a screw, has been shown to support good functional outcome. In terms of stability of the fracture, biomechanical studies have shown a superior result with central screw placement in the scaphoid in comparison with an eccentric position, which can lead to delayed or non-union. Image-based navigation could be helpful for these cases. The main limitation of reference-based navigation systems is their dependence on fixed markers like used in modern navigation systems. Therefore it is limited in treatment of small bone fractures. In former experimental studies 20 artificial hand specimens were randomised into two groups and blinded with polyurethane foam: 10 were treated conventionally and 10 were image guided. For trajectory guidance a reduction of duration of surgery, radiation exposure and perforation rate compared to the conventional technique could be found. Accuracy was not improved by the new technique. The purpose of this study was to identify the possible advantages of the new guidance technique in a clinical setting. In this prospective, non-randomised case series we tested the feasibility of the system into the accommodated surgical workflow. There was no control group. Three cases of scaphoid fractures were included. All of the patients were treated with a cannulated screw following K-wire placement via the percutaneous volar approach described. In addition, length measurements and screw sizes were determined using special features of the system. The performing surgeon and two attending assistant doctors (one assisting the surgical procedure, one handling the guidance system) had to rate the system following each procedure via a user questionnaire. They had to rate the system's integration in the workflow and its contribution to the success of the surgical procedure in percentages (0 %: totally unsuccessful; 100 %: perfect integration and excellent contribution). All of the clinical procedures were performed by the same surgeon. The surgeons rated the system's contribution and integration as very good (91 and 94 % of 100 %). No adverse event occurred. An average of 1.3 trials ± 0.6 (1; 2) was required to place the K-wire in the fractured scaphoid bone. The dose-area product was 19 cGycm2 ± 3 (16; 22). The mean incision until suture time was 36.7 min ± 5.7 (30; 40). For clinical cases, the system was integrated and rated as very helpful by users. The system is simple and can be easily integrated into the surgical workflow. Therefore it should be evaluated further in prospective clinical series.
Isolated injuries of the sacral bone are rare. The pathomechanism of these injuries are usually high velocity accidents or falls from large heights. The computer-assisted implantation of iliosacral screws (SI-screw) becomes more important in the treatment of dorsal pelvic ring fractures. The advantage of the minimal-invasive screw placement is the reduction of the non-union and deep wound infection rate. Another advantage of computer-navigated SI-screw placement is the reduction of intraoperative radiation for the patient and the surgical staff. The purpose of this study was to analyse the position of navigated iliosacral screws. In the study group 74 screws (49 patients) were included and radiologically analysed. All screws were implanted using 3D-navigation (BrainLAB Vector Vision, Brainlab, Germany). Navigation was always executed with the same 3D c-arm (ARCADIS Orbic 3D, Siemens, Germany) and navigation system. We determined the grade of perforation and angular deviation in the postoperative CT-scans in all screws. The classification was performed according to Smith et al in 4 grades. Grade 0 implies no perforation and grade 1 a perforation less than 2 mm. Grade 2 correlates a perforation of 2–4 mm and grade 3 a perforation of more than 4 mm. Furthermore the intra- and postoperative complications as well as the body-mass-index, the co-morbidities and the duration of radiation were documented. The statistical analysis was executed using Microsoft Excel 2003.INTRODUCTION
METHODS
In orthopaedic surgery, as in many other surgical fields, there is a clear tendency towards the use of minimally invasive procedures. These techniques are increasingly being implemented almost routinely for procedures such as spine and pelvis surgery. However, for fracture treatment and for applications involving small bones, such as hand and foot surgery, these systems are hardly ever used. We introduce a new system for image based guidance in traumatology. We included 20 patients with a fracture of the fifth metatarsal. They were randomised on admission into two groups. Ten patients in the metatarsal group were operated conventionally and ten were operated with the assistance of a new image guidance system. This system is based on 2D-fluoro images which are acquired with a conventional c-arm and are transferred to the system workstation. After detecting marked tools, it can be used to display trajectories for K-wire guidance in the c-arm shot. The average duration of surgery (time from incision to suture) in the image-based group was 12.7 minutes ± 5.5 (min. 6, max. 23), in the conventional group it was 17 minutes ± 6.5 (min. 7, max. 28) (p=0.086). The average duration of radiation was 18 seconds ± 8.5 (min. 6, max 36) in the image-based group vs. 32.4 seconds ± 19.4 (min. 12, max. 66) in the conventional group (p=0.057). An average of 4.7 C-arm shots ± 2 (min 2, max 9) were necessary in the image-based group to position the K-wire. For the conventional group, 8.2 shots ± 2.3 (min 4, max 12) were used (p=0.0073). It took 1.6 trials ± 0.7 (min.1, max. 3) to position the K-wire for the image-based procedures, in the conventional group 2.7 trials ± 0.9 (min. 1, max 4) were necessary (p=0.0084). There were no malfunctions or adverse events in any of the image-based navigational cases. No screws needed to be replaced in the image-based group. In the conventional group, two screws were replaced intra-operatively because they were too short in the control c-arm shot, and the screw threads did not bridge the fracture gap completely, leading to insufficient compression. In this pilot study with only a small sample size, the image-based guidance system could be integrated into the existing surgical workflow and was used for applications, where existing navigation systems are not commonly used. The technology gives the surgeon additional information and can reduce the number of trials for perfect implant positioning. This potentially increases the safety of the surgical procedure and spares intact bone substance which is essential for the footing of implants in small bones and fragment fixation. Whether these factors contribute to a reduction in complications or revision rate must be confirmed in larger prospective studies.
In polytrauma patients invasive surgeries can potentiate the posttraumatic systemic inflammation thus increasing the risk of multi organ dysfunction. Therefore, fractures are initially treated by external fixators, which later are replaced by intramedullary nails. We showed that a severe trauma impaired the healing of fractures stabilized by external fixation. Here we studied, whether the conversion to an intramedullary nail increases posttraumatic inflammation and leads to further impairment of healing. 44 rats received a femur osteotomy stabilized by an external fixator (FixEx). Half of the rats underwent a thoracic trauma (TXT) at the same time. After 4 days the fixator was replaced by an intramedullary nail (IMN) in half of the rats of each group. The rats were killed after 40 and 47 days. C5a serum levels were measured 0, 6, 24, and 72h after the 1st as well as the 2nd surgery. The calli were evaluated by three-point-bending test, μCT and histomorphometry. The TXT significantly increased serum C5a levels after the 2nd surgical intervention. After 40 days the switch from FixEx to IMN significantly decreased bending stiffness in rats with and without TXT. After 47 days flexural rigidity in rats subjected to conversion was significantly decreased compared to rats treated only with a FixEx, particularly in combination with TXT. This study showed that after a severe trauma the conversion of the fixation could provoke a second hit and contribute to delayed fracture healing.
There is evidence that fracture healing is delayed in severely injured patients. We recently demonstrated that a blunt chest trauma, which induced posttraumatic systemic inflammation, considerably impaired fracture healing in rats. Because the complement anaphylatoxin C5a is an important trigger of systemic inflammation, we tested the hypothesis, whether the impairment of fracture healing observed after a severe trauma resulted from systemically activated complement. 16 male Wistar rats received a thoracic trauma and a femur osteotomy stabilized by an external fixator. Immediately and 12 h after the trauma, half of the animals received a C5aR-antagonist to prevent the C5a-dependent systemic inflammation. Control rats received a nonsense peptide, which does not provoke any biological effect. The animals were killed after 35 days and the calli were analyzed by three point bending testing, μCT and histomorphometry. Statistics: Mann-Whitney U test, level of significance to p<0.05. The treatment with the C5aR-antagonist increased flexural rigidity significantly by 55%, improved bony bridging of the fracture gap and led to a slightly larger and qualitatively improved callus as evaluated by μCT and histological measurements. This study shows, that the immunomodulation by a C5aR-antagonist significantly reduced the deleterious effects of a thoracic trauma on fracture healing. C5a could possibly represent a target to prevent delayed bone healing in patients with severe trauma.
Since osteoimmunology is gaining increasingly interest and evidence for involvement of complement in bone biology was found, the role of complement in bone biology and fracture healing was evaluated. After characterizing the bone phenotype, a fracture healing experiment with C3- and C5- deficient mice was performed. After osteotomy of the right femur and external fixation, healing was analyzed after 1, 3, 7 and 21 days. Bone characterization revealed a reduced number of osteoclasts in C5-deficient animals with a significantly reduced resorption activity. While bone mineral density was significantly higher in complement-deficient strains, stiffness was significantly reduced. After 21 days of fracture healing, C5-deficient animals showed reduced stiffness and a smaller callus volume compared to controls. Interestingly, C3- more than C5-deficient animals showed reduced bone formation. Altogether, bone phenotype of complement-deficient animals resembles a mild form of osteopetrosis. This might be due to the resorption defect seen in C5-deficient mice. A reason for the minor involvement of C3-deficient mice compared to the C5-deficient animals could be the cross-talk between the coagulation cascade with side activation of complement factor C5 by thrombin. These results indicate for the first time an essential role of complement in bone biology and fracture healing. Future studies should focus on the molecular basis of complement involvement and the osteoclastic resorption defect.
Fractures of the femoral head are a challenging problem. The most often performed head preserving procedure worldwide is closed reduction and insertion of cannulated screws under fluoroscopic control. The use of navigation is still experimental in general trauma since rigid reference markers must be attached to all fragments. The examined system (Surgix®, Tel Aviv, Israel) is a fluoroscopy based image analysing system. It consists of a workstation and X-ray opaque markers in surgical tools. When the tool is visible in a C-arm shot a trajectory is displayed as additional layer in the image to serve as guidance for the surgeon. Forty synthetic femurs (Synbone®, Malans, Switzerland) were used and placed inside foam to simulate the soft tissue of the thigh. The models were equipped with 4.5mm radio-opaque markers at the fovea capitis femoris as target point. The aim was to bring the tip of a K-wire as close as possible to the target point entering the bone at the lateral base of the greater trochanter in a center-center position. Twenty were done under image guidance and 20 were operated the conventional way. Outcome measures included the accuracy (the distance between the tip of the wire and the target in a CT), the number of guide wire insertions, procedure duration, radiation exposure and learning curve. In the image guided group optimal guide wire placement was accomplished on first pass in 65% of the cases as compared to 5% in the conventional group (p = < 0.0001). The average number of trial and error was significantly lower in the guided group (1.7 vs. 5.8, p = < 0.0001). Consequently the average duration of the guided procedure was significantly shorter (p = 0.0008) along with radiation exposure time reduced by over 70% (p = 0.0002). The guidance system hit averaged 5.8 mm off target as compared to 5.3 mm for the freehand method (p = 0.3319). Image based guidance significantly shortened the procedure, reduced the radiation exposure and the number of trials without changing the surgeons workflow and can be used in trauma cases were reference marker based navigation is not applicable.
Computer assisted surgery (CAS) is used in trauma surgery to reduce radiation and improve accuracy but it is time consuming. Some trials for navigation in small bone fractures were made, but they are still experimental. One major problem is the fixation of the dynamic reference base for navigation. We evaluated the benefit of a new image based guidance-system (Surgix®, Tel Aviv, Israel) for fracture treatment in scaphoid bones compared to the conventional method without navigation. The system consists of a workstation and surgical devices with embedded radio opaque markers. These markers as well as the object of interest must be on the same C-arm shot. If a tool is detected in an image by the attached workstation additional information such as trajectories are displayed in the original fluoroscopic image to serve the surgeon as aiming device. The system needs no referencing and no change of the workflow. For this study 20 synthetic hand models (Synbone®, Malans, Switzerland) were randomised in two groups. Aim of this study was a central guide-wire placement in the scaphoid bone, which was blindly measured by using postoperative CT-scans. Significant distinctions related to the duration of surgery, emission of radiation, radiation dose, and trials of guide-wire positioning were observed. By using the system the surgery duration was with 50 % shortened (p = 0.0054) compared to the conventional group. One reason might be the significant reduction of trials to achieve a central guide-wire placement in the bone (p = 0.0032). Consequently the radiation exposure for the surgeon and the patient could be shortened by reduction of radiation emission (p = 0.0014) and radiation dose (p = 0.0019). By using the imaged based guidance system a reduction of surgery duration, radiation exposure for the patient and the surgeon can be achieved. By a reduced number of trials for achieving a central guide-wire position the risk of weakening the bone structure can be minimised as well by using the system. The system seems helpful where navigation is not applicable up to now. The surgical workflow does not have to be chanced.
We report on a patient with an unusual pulmonary infection after resection of a high-grade osteosarcoma. In March 2007 a 30-year old female with pain and swelling of the left proximal humerus was submitted to the orthopaedic department. Rx and CT revealed a tumour with destruction and invasion of the surrounding soft tissue. Incision biopsy led to the diagnosis of osteoblastic osteosarcoma. She was enrolled into the EURAMOS protocol and received neoadjuvant chemotherapy. In July 2007 an extra-articular resection of the proximal humerus with modular endoprosthetic replacement was performed. The sarcoma had responded well to chemotherapy (regression grade 3 according to Salzer-Kunts-chik). Surprisingly, the resection specimen demonstrated a “skip lesion” of vital sarcoma in the resection line not been detected by preoperative PET or MRT. After consultation of the German study group she was stratified into the standard risk group. 12 months later a control CT revealed multiple foci in both lungs, which were highly suspicious for pulmonary metastases. All clinical parameters were normal. A lung biopsy was performed by thoracotomy and a granulomatous infection was diagnosed, which was suspicious for tuberculosis. Extended microbiological investigations by culture and PCR analysis revealed an infection by Myco-bacterium Xenopi, which is a rare form of an atypical mycobacteriosis. Since then she is treated accordingly, however the infection has progressed and involvement of the liver has been diagnosed by cutting needle biopsy.
In our outpatient clinic we have assessed the clinical follow-up as clinical examination (Enneking-score) and standardized radiological follow-up for 5 years, then once per year. In the focus of interest were aseptic loosening of the stems, wear of polyethylene, and mechanical problems as implant failure
We conclude that in tumour patients with major osseous reconstruction after wide resection a certain loss ob function cannot be avoided, but the rate of complications in the long-term-follow-up after implantation of modular tumour prosthesis is acceptable.
Although IL-6 mRNA expression in rat is restricted to the first day post-fracture, the inflammatory phase, the protein has been observed later in the healing process, indicating additional roles. The importance of IL-6 was demonstrated by delayed healing in knockout mice through diminished osteoclast numbers, formation thereof being stimulated by IL-6. The aim of our study was to investigate with which cells this cytokine is associated and when during fracture healing. A closed fracture of the lower right limb was created in rats. The tibia was obtained from six animals at each of 1, 3, 7, 14 and 28 days post-fracture, decalcified and prepared for standard immunohistochemistry with an IL-6-specific polyclonal antibody. The number and types of cells positively stained for IL-6 along the whole length of the periosteal callus on one surface and in the fracture was evaluated. Mostly inflammatory cells were initially stained, becoming virtually absent by day 7 when this phase has normally ended. Within the immediate vicinity of the fracture where endochondrial ossification occurred, staining of chondrocytes was significant (69%) by day 7 when this cell was laying down cartilaginous tissue that was also calcified. Distally to the fracture where direct bone formation occurred through intra-membranous ossification by osteoblasts, staining of these cells was observed, peaking at day 14 (56%). As this bone started to take on the appearance of cortex and surviving embedded osteoblasts differentiated to osteocytes, the latter cells were stained, suggesting a role in remodelling. At the fracture as bone replaced the cartilaginous tissue and union occurred, staining of chondrocytes decreased, whereas local osteoblasts were positive. IL-6 appears to play a role throughout fracture healing, in endochondrial and intra-membranous ossification. The level of staining of each cell type reflected the degree of their activity with respect to production of related tissue.
Especially, no cases of lesions of the axillary nerve or frozen shoulder were seen. The latter we believe is due to the MI procedure and the early functional treatment due to high primary stability of the NCB-PH® plate. Despite good functional outcome, younger patients with higher levels of activity compared to the average patient sustaining proximal humeral fractures tend to feel subjective problems with the plate in situ demanding surgical removal of hardware. The long-term results also prove the NCB-PH® plate to be a safe and effective method of treatment reaching a functional outcome that enables the mostly old patients to regain an acceptable level of activity. Removal of hardware is easy to perform and offers especially in the younger patient a possibility to at least improve patients’ subjective outcome
The degree of correction was controlled during the operation with the navigation system and compared with pre- and postoperative 2.5D ultrasound measurements to avoid projection errors of long standing x-rays.
The postoperative 2.5D ultrasound leg axis analysis showed a maximum of +/− 2° difference between the pre-, intra- and postoperative measurements.
This first results show a promising increase of accuracy while radiation can be reduced. The actual values show that the main goal to increase the intraoperative accuracy in corrective osteotomies can be achieved with computer aided surgery.
In vitro experiments have shown, that stabilisation of the fibula in complete fractures of the lower leg give more stability compared to a single stabilisation of the tibia. However it is not known how this biomechanical conditions influence the bone healing process. To investigate the effect of fibula stability in tibia fracture healing tibial osteotomies in rats with and without fibula fractures were compared. Male wistar rats (n=18) were operated by a transverse osteotomy of the proximal tibia of the left leg. Fracture was stabilised by intramedullary nailing. In 8 cases an additional closed fibula fracture was performed. The healing period was 21 days. Each whole leg was examined by x-ray. After explantation of the tibia and removing of the nail and the fibula, the tibia was examined by CT-Scan, three-point-bending and histological evaluation. Animals, who had a fibula fracture along with the tibia fracture presented with delayed healing. Density in CT-scan was 30% lower (p=0,0002) in animals with a fibula fracture (405mg/ccm, SD:64) compared to those without a fibula fracture (mean=577mg/ccm, SD:17). In three point bending the bending stiffness was 79% lower (p=0,0006) in animals with a fibula fracture (mean=252Nmm/mm, SD:118) compared to animals without a fibula fracture (mean=1219Nmm/mm, SD:478). The breaking force was 59% lower (p=0,0004) in animals with a fibula fracture (mean=17,5N, SD:6) compared to animals without a fibula fracture (mean=42,4N, SD:14). Complete fractures of the lower leg healed considerably worse than solitary fractures of the tibia. We conclude that the missing of rotational stability of our k-wire fixation of the tibia with a unfixed fibula fracture is one of the reasons for the delay in fracture repair. The results support the in vitro findings of the biomechanical importance of the fibula for the stability of tibia fractures.
Non-steroidal anti-rheumatics (NSAR) are often used in patients with fractured bones for analgetic reasons. This animal experiment was performed to determine the influence of NSAR on the process of fracture healing. As an alternative central acting analgetic without peripheral effect Tramadol was included in this experiment. Wistar rats were operated by a transverse osteotomy of the proximal tibia of the left leg, fracture was stabilized by intramedullary nailing (healing period 21 days). All therapeutics were applied orally, twice a day. The animals were divided in 4 groups, 10 rats each: Group 1 was treated with placebo, group2 with tramadol (20mg/kg bodyweight/day), group3 with Diclofenac-Colestyramin (5mg/kg/bw./day) over 7 days followed by 14 days placebo, group4 with Diclofenac-Colestyramin (5mg/kg/bw./day) over 21 days. On day 21 the rats were sacrificed and each leg was examined by x-ray, than the tibia was examined by CT-Scan, three-point-bending and histological evaluation. There were no significant differences between group1 and 2 and between group3 and 4, respectively. Therefore the data of group1 and 2 as well as group3 and 4 are put together. The results of CT and 3-point-bending showed, that rats treated by Diclofenac presented with delayed fracture healing compared to those treated by placebo or Tramadol. Bone density was 30% lower (p = 0,0001) in animals treated with Diclofenac (mean = 577mg/ccm, SD:53,1 in group1 and 2 vs. mean = 404,3mg/ccm, SD:27,3 in group3 and 4). The breaking force was 45% (p = 0,0009) lower (mean = 42,4N, SD:14,2 vs. mean = 23,3N, SD:8,2) and the bending stiffness 56% (p = 0,0039) lower (mean = 1218,9Nmm/mm, SD:477,9 vs. mean = 532,6Nmm/mm, SD:389,9) in animals, treated with diclofenac. Diclofenacserumlevels on day 21 in rats with longtime diclofenac application (mean = 242ng/ml, SD:47,7) were comparable to those in humans. Oral application of Diclofenac significantly delayed fracture healing in rats. This effect might be comparable to other NSAR and fracture healing in humans.