G. Zimmermann

Allograft bone matrix versus synthetic bone graft substitutes.

Autologous bone is used very often in the treatment of fresh fractures, delayed unions and non-unions. Alternatives have included allografts and in recent years also demineralized bone matrix. The growing availability of good synthetic bone grafts and their advantages in safety and avoiding donor-site morbidity are the reasons that these products are being used more and more. There are on the market a wide variety of substitutes with different capabilities. Nevertheless autologous bone graft is still considered as the gold standard and will be discussed here in that context. Osteoconductive, osteogenic and osteoinductive products will also be classified and their advantages and disadvantages described.

Cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures.

Tibial shaft fracture is one of the most common types of bone fracture in young patients. In this prospective clinical cohort study, we investigated the effects of cigarette smoking on the clinical, functional, psychosocial and occupational outcomes after isolated lower-leg fracture. We examined 85 patients, including 61 men and 24 women, with a collective mean age of 46 years (range: 18-84 years). Thirty-nine patients had never smoked (G1) and 45 patients were current or previous smokers (G2). The G2 group displayed a significantly increased risk for delayed union or nonunion (G1=3 patients, G2=18 patients; P=0.0007) and increased time required for fracture healing (mean times: G1=11.9 weeks, G2=17.4 weeks; p=0.003) and a markedly increased time out of work (mean times: G1=16.1 weeks, G2=21.5 weeks; p=0.1177 (not significant)). The 18 negatively affected patients in G2 displayed a significant increase in the time required for fracture healing and time out of work (26 weeks (p=0.02) and 31 weeks (p=0.03), respectively). G2 group members had a 3- to 18-fold higher risk of impaired bone healing. The mean Short Form 36 (SF-36) was similar in both groups. The physical-function scores were G1=49.6 and G2=48.6; the mental scores were G1=52.7 and G2=52.8. These findings indicate that smoking significantly increases the risk of impaired fracture healing, which has clinical and occupational consequences for the affected patients. Based on our data, we developed a score to estimate the individual risk of impaired fracture healing. These types of patients must be informed and closely monitored to determine the need for timely re-intervention with additional therapy, such as BMP s or ultrasound.

Cigarette smoking decreases TGF-β1 serum concentrations after long bone fracture

TGF-b1 serum concentrations are considered to be one of the most promising markers of fracture healing. Previously, we demonstrated significant differences in the post-traumatic time courses of patients with timely and delayed fracture healing. The aim of this study was to evaluate possible differences in the serum concentrations of TGF-b1 in cigarette-smoking vs. non-smoking patients with timely and delayed fracture healing in order to understand pathophysiological pathways through which smoking impairs fracture healing.Serum samples were collected from 248 patients undergoing surgical treatment for long bone fractures within 1 year of surgery. Samples from 14 patients with atrophic-type delayed fracture healing were compared with 14 matched patients with normal bone healing. Each group included seven smokers and seven non-smokers. Post-operative serum concentrations were analysed at 1, 2, 4, 8, and 12 weeks as well as 1 year after surgery. The patients were monitored both clinically and radiologically for the entire duration of the study.All patients increased TGF-b1 serum concentrations after surgery. In patients with normal fracture healing, significantly higher TGF-b1 levels were observed in non-smokers (70 ng/ml) than in smokers(50 ng/ml) at the 4th week after surgery (p = 0.007). Also at the 4th week, in patients with delayed healing, significantly lower TGF-b1 levels were observed in smokers than in non-smokers (38 ng/ml vs.47 ng/ml, p = 0.021). However, no significant differences between non-smokers with delayed healing and smokers with normal healing (p = 0.151) were observed at the 4th week after surgery. TGF-b1 serum concentrations reached a plateau in all groups from the 6th to the 12th week after surgery, with a slight decrease observed in the final measurement taken 1 year after surgery.This study demonstrates that, after fracture, TGF-b1 serum concentrations are reduced by smoking,and this reduction is statistically significant during the 4th week after surgery. Our findings may help reveal the mechanism by which smoking impairs fracture healing. Furthermore, these results may help to establish a serological marker that predicts impaired fracture healing soon after the injury. Surgeons will not only be able to monitor the bone healing, but they will also be able to monitor the success of additional treatments such as ultrasound and bone morphologic proteins (BMPs).

Treatment of tibial shaft non-unions: bone morphogenetic proteins versus autologous bone graft

Fractures of the tibial shaft are likely to result in delayed union or non-union; 10-30% of these fractures will not heal properly and are commonly treated with autologous bone grafting. BMP-7 is a recombinant bone growth factor that can be applied locally as an alternative or in addition to autologous bone grafting, and this study aimed to compare the efficiency of the two procedures. From January 1995 to December 2002, 82 people with delayed union of a tibial fracture at least 4 months after primary stabilisation underwent autologous bone grafting. Successful healing was defined as radiological bony consolidation. Between May 2002 and June 2005, 26 similar cases were treated after the failure of the graft with local implantation of BMP-7, and were followed up for at least 1 year. Of the 82 people receiving autologous bone grafts only, 24 (28%) still had no signs of consolidation after 4 months and required revision surgery. Of the 26 people with BMP-7 implantation after failed graft, bony consolidation was seen after 4 months in 24 cases and only 2 (8%) required revision surgery. The BMP-7 group, although including more complicated cases, showed a significantly higher (p = 0.025) success rate compared with the group that did not receive BMP-7.

TRACP 5b and CTX as osteological markers of delayed fracture healing

Radiological studies are the standard method to monitor fracture healing but they do not allow a timely assessment of bone healing. Biochemical markers react rapidly to changes in bone metabolism during fracture healing and could be an additional tool to monitor this process. The goal of this study was to observe changes in serum biomarkers and evaluate the possible differences in the serum levels of tartrate-resistant acid phosphatase 5b (TRACP 5b), total N-terminal propeptide of type I collagen (PINP), bone-specific alkaline phosphatase (BAP), and C-terminal cross-linking telopeptide of type I collagen (CTX) in patients with normal and delayed fracture healing. Several serum samples were collected for one year after the surgical treatment of long bone fractures in 248 patients. From this large pool, 15 patients with atrophic nonunion were matched to 15 patients with normal bone healing. Post-operative changes in osteological markers were monitored during the 1st, 2nd, 4th, 8th, 12th and 52nd weeks. The patients were followed both clinically and radiologically for the entire one-year duration of the study. In the first week, the absolute values of CTX decreased significantly (p=0.0164) in cases of delayed fracture healing. The relative values of TRACP 5b were significantly decreased at weeks 4 (p=0.0066) and 8 (p=0.0043). BAP and PINP levels decreased in the first week followed by an increase, but there were no significant differences in the absolute or relative values during the healing process in both patient groups. For the first time, we have demonstrated changes in serum concentrations of TRACP 5b, PINP, BAP, and CTX during normal and delayed fracture healing. Characteristic changes in systemic TRACP 5b and CTX levels could reflect the initial process of successful fracture healing and may be used in clinical practice to monitor the healing process. Furthermore, it could be very important for determining the beneficial effects of additional treatments such as ultrasound or BMPs in clinical trials.

Cellular therapies for the treatment of non-union: The past, present and future

Non-union fracture is a pathological condition having some impairment of the cellular part of the repair: a reduction of MSC and of the osteoblastic activation. Non union is therefore a good indication for cell-based therapies using stem cells. We described the rational of this treatment and described the technique of autologous bone marrow concentrate implantation that was until now used. With the development of stem cell research and regenerative medicine, we believed that therapy based on cytotherapy has great potential. In this review, clinical applications of cytotherapy are summarized and analyzed. Current problems and future challenges are discussed.

Expression of TRAIL and the death receptors DR4 and DR5 correlates with progression of degeneration in human intervertebral disks.

Intervertebral disks degenerate far earlier than other musculoskeletal tissues and apoptosis has been suggested to have a vital function in promoting the degeneration process that is strongly associated with back pain. However, the molecular mediators of apoptosis in the intervertebral disk are poorly understood. Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-α/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand. We investigated which of these molecules are expressed in intervertebral disks and whether their expression correlates to disk degeneration. Intervertebral disks from 28 donors (age 12–70 years) suffering from scoliosis, vertebrae fracture or disk degeneration were scored histologically for degeneration and analyzed for gene expression of FasL/Fas, TRAIL/DR4, TNF-α/TNFR1 and caspase 8. Protein expression of FasL and TRAIL was assessed by immunohistology and apoptotic cell death was quantified by poly(ADP-ribose) polymerase (PARP) p85 staining. Isolated disk cells were analyzed by flow cytometry for Fas, FasL, TRAIL, DR4 and DR5 expression. Gene expression of TRAIL (P=0.002) and caspase 8 (P=0.027) significantly correlated with degeneration. TRAIL expression further correlated with cellularity (P=0.04), muccoid matrix changes (P=0.009) and tears and cleft formation (P=0.019). FasL and TRAIL expression was confirmed by immunohistology and PARP cleavage was significantly associated with degeneration (P=0.027). Flow cytometry on isolated disk cells revealed correlations between DR4 and degeneration (P=0.014), DR4/DR5 double-positive cells and degeneration (P=0.019), as well as DR5 and changes in tissue granularity (P=0.03). This is the first study that shows that intervertebral disk cells express TRAIL, DR4 and DR5, which correlate to the degenerative state of the disk. Therefore, disk cells inherit the molecular machinery to induce and undergo cellular apoptosis, and the frequency of cytokine expression suggests that the TRAIL/DR4/DR5 axis is an important molecular mediator of apoptosis induction in disk tissue.

Endoprothesenversorgung nach Radiusköpfchentrümmerfrakturen

BACKGROUND For many years, resection was the only therapy used for comminuted fractures of the radial head. When associated with an injury of the collateral ligament, the outcome was often unsatisfactory. Implantation of the modern radial head prosthesis promises a better outcome. METHODS Between June 2001 and January 2005, 30 patients were treated with a modular metallic radial head arthroplasty; 28 patients were available for follow-up. Their mean age was 49 years. The patients were followed for an average of 29 months. The outcomes were assessed on the basis of pain, motion, radiographic findings, and grip strength as measured with the Jamar Dynamometer. The overall outcome was rated using a pain visual analog scale, and the scoring systems described by Radin and Riseborough and by Broberg and Morrey. RESULTS 19 patients achieved excellent or good results, 8 had fair results, and 1 had a poor result as based on the Morrey score. 22 patients showed periprosthetic osteolysis on radiologic examination. CONCLUSION Arthroplasty with a modular metallic radial head combined with ligament reconstruction is an effective alternative to radial head resection. Compared with resection, the results using the EVOLVE prosthesis demonstrate definite advantages with regard to clinical outcome.

The value of laboratory and imaging studies in the evaluation of long-bone non-unions

Delayed union and non-union are common but definitive diagnosis is difficult. Few studies have evaluated imaging methods and laboratory parameters in the distinction between normal and prolonged heating specifically of long-bone fractures. The values of newer imaging methods have been analysed in some cases and should be the subject of further clinical trials. Biological markers may facilitate the earliest diagnosis of delayed union. Preliminary studies of these are limited and more trials are needed. To date it is still difficult to predict accurately a normal consolidation of bone.

Quantification of TGF-ß1, PDGF and IGF-1 cytokine expression after fracture treatment vs. non-union therapy via masquelet.

INTRODUCTION Biochemical processes during bone regeneration can be analysed via quantification of peripheral serum cytokine levels. To date, serum levels of cytokines in patients treated with masquelet technique and patients with normal bone healing have not been compared. This comparison is supposed to deliver novel insights into the process of bone regeneration. Our aim was to validate this established method in the monitoring of bone regeneration after non-union treatment in masquelet technique. MATERIALS AND METHODS Between 04/2008 and 01/2014 three groups were recruited: G1 (10 patients) with long bone non-unions, treated successfully with masquelet therapy, G2 (6 patients) with unsuccessful masquelet therapy and G3 (10 patients) with long bone fractures and normal bone healing. Peripheral blood samples were collected over a period of six months following a standardised time pattern in combination with clinical and radiologic follow up. TGF-ß1, PDGF-AB and IGF-1 were measured using commercially available immunoassays. RESULTS TGF-ß1 levels in G1 and G2 demonstrated a parallel and lower overall concentration over time compared to G3. G3 showed a significant TGF-ß1 peak 2 weeks after surgery compared to G1 (p=0.0054). PDGF-AB concentrations were always lower in G2 than in G1 and G3. G3 peaked at week 2 with a significant higher value than in G2 (p=0.0177). IGF-1 showed lower overall serum concentrations in G2 than in G1 and G3. G1 had a peak level during the fourth week of follow-up. Compared to G2 this peak was significant (p=0.0015). CONCLUSIONS This study shows that successful bone regeneration via masquelet technique only partially imitates cytokine expression of physiological bone healing. High expressions of IGF-1 correspond to a successful masquelet therapy while TGF-ß seems to play a minor role. These results assume that objective analysis of an effective non-union therapy with cytokine expression analysis is possible even with a small number of patients.