[Importance of local antibiotics in the prophylaxis and treatment of fracture-associated infections]. / Stellenwert lokaler Antibiotika für die Prophylaxe und Therapie frakturassoziierter Infektionen.

BACKGROUND: Fracture-associated infections (FRI) are a severe complication that lead to higher morbidity and high costs for the healthcare system. An effective prophylaxis and treatment of FRI are therefore of great interest. OBJECTIVE: The aim of this review is to summarize the available evidence on the use of local antibiotics for the prophylaxis and treatment of FRI. MATERIAL AND METHODS: A thorough search and a narrative synthesis of the available literature were performed. Their depiction is supplemented by an illustrative presentation of a case report. RESULTS: A robust consensus definition of FRI has existed since 2018. The current use of local antibiotics for the prophylaxis and treatment of FRI in Germany is heterogeneous. There is no consensus on local antibiotic treatment of FRI. The available literature shows an advantage for the additive local antibiotic treatment of open fractures. In closed fractures there is a tendency towards an advantage especially in the presence of further risk factors (long duration of external fixation, higher degree of closed tissue damage, compartment syndrome). According to analogous data from the field of endoprosthetics, additive local antibiotic treatment could also be advantageous under closed soft tissue conditions. The evidence is insufficient to enable the recommendation for a specific antibiotic or a specific mode of application. Local and systemic adverse reactions are frequently discussed in the literature but their incidence is low. CONCLUSION: Overall, additive local antibiotic treatment is to be recommended for open fractures and in closed fractures in the presence of other risk factors. Local and systemic adverse reactions as well as the development of antibiotic resistance must be weighed up in individual cases.

Cordycepin promotes osteogenesis of bone marrow-derived mesenchymal stem cells and accelerates fracture healing via hypoxia in a rat model of closed femur fracture.

Fracture is the most frequently encountered traumatic large-organ injury observed in human patients. Cordycepin possesses beneficial effects in osteogenesis of mesenchymal stem cells (MSCs), but its effect on fracture healing is largely unknown. A rat model of closed femur fracture was established, and treated with therapy using bone marrow-derived MSCs (BMMSCs). The effect of cordycepin on the osteogenic process of BMMSCs in vitro was evaluated by Alizarin Red S (ARS) staining and expressions of osteogenic marker genes. Radiographic evaluations and four-point bending mechanical testing were performed on model rats after BMMSC treatment, to assess the effect of cordycepin on fracture healing. Cordycepin promoted osteogenesis of BMMSCs in vitro, and enhanced radiographic parameters and mechanical properties in rat closed femur fracture model using BMMSC therapy in vivo. A hypoxia inhibitor echinomycin could negate the above-mentioned therapeutic effects of cordycepin, indicating that the beneficial effects of cordycepin were mediated via hypoxic response pathway. This study demonstrates that cordycepin promotes osteogenesis of BMMSCs and accelerates fracture healing via hypoxia in a rat model of closed femur fracture, and proposes the clinical potential of cordycepin in bone fracture treatments.

Pretreatment with Pamidronate Decreases Bone Formation but Increases Callus Bone Volume in a Rat Closed Fracture Model.

Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46-79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38-63%, p < 0.01) and reduced MAR (32-49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.

The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model.

PURPOSE: To evaluate the therapeutic efficiency of a micellar prodrug formulation of simvastatin (SIM/SIM-mPEG) and explore its safety in a closed femoral fracture mouse model. METHODS: The amphiphilic macromolecular prodrug of simvastatin (SIM-mPEG) was synthesized and formulated together with free simvastatin into micelles. It was also labeled with a near infrared dye for in vivo imaging purpose. A closed femoral fracture mouse model was established using a three-points bending device. The mice with established closed femoral fractures were treated with SIM/SIM-mPEG micelles, using free simvastatin and saline as controls. The therapeutic efficacy of the micelles was evaluated using a high-resolution micro-CT. Serum biochemistry and histology analyses were performed to explore the potential toxicity of the micelle formulation. RESULTS: Near Infrared Fluorescence (NIRF) imaging confirmed the passive targeting of SIM/SIM-mPEG micelles to the bone lesion of the mice with closed femoral fractures. The micelle was found to promote fracture healing with an excellent safety profile. In addition, the accelerated healing of the femoral fracture also helped to prevent disuse-associated ipsilateral tibia bone loss. CONCLUSION: SIM/SIM-mPEG micelles were found to be an effective and safe treatment for closed femoral fracture repair in mice. The evidence obtained in this study suggests that it may have the potential to be translated into a novel therapy for clinical management of skeletal fractures and non-union.

The effect of teicoplanin on fracture healing: an experimental study.

OBJECTIVES: This study aims to investigate the effect of teicoplanin on fracture healing stereologically and histopatologically. MATERIALS AND METHODS: Twenty male Wistar albino rats were separated into two as the study (teicoplanin) and control groups. After intramedullary fixation of the right tibia of all the rats with 0.5 mm Kirschner wire under general anesthesia, standard closed shaft fractures were created using fracture formation apparatus. Teicoplanin (10 mg/kg) and saline were administered intraperitoneally to the study and control groups, respectively. Control radiographs were taken at the end of the procedure and the rats were sacrificed after 28 days. New bone and connective tissue volumes were calculated on obtained tissue samples using unbiased stereological and histopathological techniques. RESULTS: It was observed that teicoplanin increased the formation of bone, vascularization, and connective tissue. There was a statistically significant difference between the two groups in respect of bone and vascular total volume (p<0.05). Although an increase was observed in connective tissue total volume, no statistically significant difference was detected between the two groups (p>0.05). CONCLUSION: In addition to its antibacterial effect, teicoplanin may increase new bone formation; thus, it may be used safely in the treatment of bone defects accompanied with infection.

Parameters for lithium treatment are critical in its enhancement of fracture-healing in rodents.

BACKGROUND: Lithium, a treatment for bipolar disorder, is not clinically indicated for use in fracture management but has been reported to positively influence bone biology. It is hypothesized that lithium dosing for beneficial effects on bone health may be much lower than the dosing required for psychotropic benefits in patients with bipolar disorder. A preclinical study with a rodent fracture model was utilized to best define the lowest effective dose, best timing of treatment onset, and optimal treatment duration for the use of lithium as a new treatment in fracture care. METHODS: A design-of-experiments approach was used to assess the parameters of dose, timing of treatment onset, and treatment duration. Closed femoral shaft fractures were generated and analyzed with use of destructive torsional mechanical testing and microcomputed tomography-based image analysis. Eleven different outcome measures were quantified, with maximum yield torque as the primary study outcome, to assess the quality of long-bone fracture-healing. RESULTS: Fracture-healing was maximized with a lithium treatment combination of a low dose (twenty milligrams per kilogram of body weight per day), later onset of lithium treatment (seven days after fracture), and longer treatment duration (two weeks), with maximum yield torque displaying a 46% increase compared with nontreated and sham-treated controls (481.1 ± 104.0 N-mm compared with 329.9 ± 135.8 N-mm; p = 0.04). Design-of-experiments analysis determined the timing of treatment onset to be the most influential parameter for improving fracture-healing, with femora treated at a later onset (seven days after fracture) showing a significant (21%) increase in maximum yield torque compared with those treated at an earlier onset (three days after fracture) (p = 0.01). CONCLUSIONS: A later onset of lithium administration significantly improved femoral fracture-healing. Trends indicated that a lower dose and longer treatment duration also had a positive effect on fracture repair. CLINICAL RELEVANCE: Orally administered low-dose lithium therapy with a large postfracture administration window has the potential to yield a safe, reliable, and cost-effective treatment to enhance bone-healing and restore earlier function and mobility pending appropriate large-animal proof-of-concept models, safety data, and U.S. Food and Drug Administration clinical trials approval.

Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture: a double-blind, randomized, controlled phase-II/III trial.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation. METHODS: Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone. RESULTS: Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups. CONCLUSIONS: In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. 24306696

Implementation of a short course of prophylactic antibiotic treatment for prevention of postoperative infections in clean orthopaedic surgeries.

BACKGROUND & OBJECTIVES: Perioperative antimicrobial prophylaxis constitutes the bulk of antimicrobial consumption in any hospital. This study was conducted at a level 1 Trauma Centre of a tertiary care hospital of India to assess the efficacy of a short (24 h) course of perioperative antibiotic prophylactic regimen in preventing surgical site infections (SSI) in open reduction and internal fixation (ORIF) of closed fractures of limbs and to assess if the same can be implemented as a general policy. METHODS: Patients of either sex, aged 18 yr or more, who were scheduled for ORIF and were willing and able to give informed consent, were included in the study. Patients were randomly allocated into two groups. Group 1 (n=100) received 3 doses of 1 g i.v. cefuroxime perioperatively spaced 12 h apart and group 2 (n=97) received the conventional existing regimen [5 days of i.v. antibiotics (cefuroxime 1 g twice daily along with amikacin 15 mg/kg in 2 divided doses), followed by oral cefuroxime, 500 mg twice daily till suture removal]. RESULTS: Of the 197 patients, four patients developed a surgical site infection (three with methicillin resistant Staphylococcus aureus and one Acinetobacter baumanii). Of these, two patients were in group 1 and the remaining two in group 2. These patients were treated with i.v. antibiotics based on the culture and antimicrobial sensitivity reports. The cost of the short course treatment was ` 150 per patient as compared to ` 1,900 per patient for conventional regimen. INTERPRETATION & CONCLUSIONS: There was no significant difference in rates of SSI among the two groups in our study. Cost evaluation revealed that shorter course was less expensive than conventional long course regimen. Implementation of a short course perioperative regimen will go a long way in reducing antimicrobial resistance, cost and adverse reactions to antimicrobials.

A novel low-molecular-weight compound enhances ectopic bone formation and fracture repair.

BACKGROUND: Use of recombinant human bone morphogenetic protein-2 (rhBMP-2) is expensive and may cause local side effects. A small synthetic molecule, SVAK-12, has recently been shown in vitro to potentiate rhBMP-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype. The aims of this study were to test the ability of SVAK-12 to enhance bone formation in a rodent ectopic model and to test whether a single percutaneous injection of SVAK-12 can accelerate callus formation in a rodent femoral fracture model. METHODS: Collagen disks with rhBMP-2 alone or with rhBMP-2 and SVAK-12 were implanted in a standard athymic rat chest ectopic model, and radiographic analysis was performed at four weeks. In a second set of rats (Sprague-Dawley), SVAK-12 was percutaneously injected into the site of a closed femoral fracture. The fractures were analyzed radiographically and biomechanically (with torsional testing) five weeks after surgery. RESULTS: In the ectopic model, there was dose-dependent enhancement of rhBMP-2 activity with use of SVAK-12 at doses of 100 to 500 µg. In the fracture model, the SVAK-12-treated group had significantly higher radiographic healing scores than the untreated group (p = 0.028). Biomechanical testing revealed that the fractured femora in the 200 to 250-µg SVAK-12 group were 43% stronger (p = 0.008) and 93% stiffer (p = 0.014) than those in the control group. In summary, at five weeks the femoral fracture group injected with SVAK-12 showed significantly improved radiographic and biomechanical evidence of healing compared with the controls. CONCLUSIONS: A single local dose of a low-molecular-weight compound, SVAK-12, enhanced bone-healing in the presence of low-dose exogenous rhBMP-2 (in the ectopic model) and endogenous rhBMPs (in the femoral fracture model). CLINICAL RELEVANCE: This study demonstrates that rhBMP-2 responsiveness can be enhanced by a novel small molecule, SVAK-12. Local application of anabolic small molecules has the potential for potentiating and accelerating fracture-healing. Use of this small molecule to lower required doses of rhBMPs might both decrease their cost and improve their safety profile.

Experimental stimulation of bone healing with teriparatide: histomorphometric and microhardness analysis in a mouse model of closed fracture.

Fracture consolidation is a crucial goal to achieve as early as possible, but pharmacological stimulation has been neglected so far. Teriparatide has been considered for this purpose for its anabolic properties. We set up a murine model of closed tibial fracture on which different doses of teriparatide were tested. Closed fracture treatment avoids any bias introduced by surgical manipulations. Teriparatide's effect on callus formation was monitored during the first 4 weeks from fracture. Callus evolution was determined by histomorphometric and microhardness assessment. Daily administration of 40 µg/kg of teriparatide accelerated callus mineralization from day 9 onward without significant increase of sizes, and at day 15 the microhardness properties of treated callus were similar to those of bone tissue. Teriparatide considerably improved callus consolidation in the very early phases of bone healing.

Single percutaneous injection of stromal cell-derived factor-1 induces bone repair in mouse closed tibial fracture model.

Stromal cell-derived factor-1 is a dominant chemokine in bone marrow that is known to be involved in inflammatory diseases, including rheumatoid arthritis. Its role in bone repair has recently been demonstrated. The purpose of this study was to investigate the role of extraneous stromal cell-derived factor-1 in fracture healing.

The effects of leukotriene receptor antagonist montelukast on histological, radiological and densitometric parameters of fracture healing.

OBJECTIVES: In this study we evaluated the effects of montelukast, a leukotriene-receptor antagonist, on fracture healing, and investigated the hypothesis that enhanced fracture healing would be observed with montelukast in a rat tibia fracture model. MATERIALS AND METHODS: Sixty adult (6 months old) female Wistar albino rats (mean weight 220 g, range 210-270 g) were randomly divided into two groups: a montelukast group (n=30) and a control group (n=30). Closed tibia fractures were created and fixed by intramedullary Kirschner wire. The rats were sacrificed three and six weeks after the fractures. Radiological and histological evaluations were performed, and bone mineral density was measured. RESULTS: Three rats died in the montelukast group, whereas only one died in the control group during the study. Initial weight and weight gain at the 3rd and 6th weeks were not significantly different between the groups (p>0.05). Bone mineral densities in the control and study groups were 0.13±0.009 gr/cm2, and 0.13±0.01 gr/cm2 at week three and 0.16±0.02 gr/cm2, and 0.13±0.01 gr/cm2 at week six, respectively. Histopathological scores in the control and study groups were 3.42±0.6, and 3.0±0.0 at week three and 3.5±0.5, and 3.4±0.8 at week six, respectively. Radiological scores in the control and study groups were 1.19±0.6, and 1.0±0.6 at week three and 3.0±0.8, and 2.9±0.9 at week six, respectively. There were no significant differences between the two groups in any parameters evaluated at either time interval (p>0.05). CONCLUSION: Our study failed to show a possible positive effect of leukotriene receptor inhibition on fracture healing at the 3rd and 6th postoperative weeks.

[Analysis of the effects of different medicines on hypercoagulability state variations of femoral shaft fracture and after its operation].

OBJECTIVE: To explore the role of Tong Mai Tang & Lornoxicam on the serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL-6) , D-dipolymer( D-Di), Platelet count (PLC) in treatment of femoral shaft fracture among period surgery time. METHODS: We selected 120 cases of traumatic femoral shaft fracture patients according to the inclusion criteria and exclusion criteria, which were randomized dividend into four groups (I, II, III, IV respectively) of the same size based on the random number table method of 30 patients each. Therapeutic methods of four groups following as: Group I, Tpanax Notoginseng Pills PO; Group II, Tpanax Notoginseng Pills PO, Lornoxicam For Injection, 8 mg IM; Group III, Tpanax Notoginseng Pills PO, Tong Mai Decoctions 200 mL PO; Group IV, Tpanax Notoginseng Pills PO, Lornoxicam For Injection 8 mg IM, Tong Mai Decoctions 200 mL PO. The above medications were administered to the four groups after admission to hospital the next day. Peripheral blood samples were taken for immune determination of pro-inflammatory cytokines of TNF-alpha, IL-6, D-Di, PLC in blood serum on the 2nd and 6th day before operation and on the 8th and 13th day after operation in the morning. And all patients received liver and kidney function examination 2nd and 13th day after admission. Analysis of variance and least significant difference-test were done with the help of SPSS 17.0 statistic software. RESULTS: The difference among four groups in TNF-alpha and IL-6 were significant (P < 0.05). And there were also significant statistic difference between group II/III/IV and group I group (P < 0.05). But the difference between group II and group III was insignificant (P > 0.05). However, the group contrast result between group IV and group II/III had statistics difference (P < 0.05). The difference in D-Di PLC at 6th day and 8th day were significant (P < 0.05). The group comparisons in group I/II/IV were also significant. There were non-statistics significance in group II compared 6th day/8th day with 2nd day (P > 0.05). The comparison between the 13th day with the first three time sections had statistics significance. And there were statistics significance at the 13th day between group IV and group II (P < 0.05). CONCLUSION: The serum concentrations of TNF-alpha, IL-6, D-Di and PLC level were significantly increased in peroperative period, These results seem to indicate that the Tong Mai Decoctions & Lornoxicam may play an important role in inhibiting the release of TNF-alpha, IL-6, D-Di and PLC into the blood stream and decreasing the incunabula complication at early traumatic stage. The Tong Mai Decoctions & Lornoxicam was the worth promoting screened China and the West union medication combination.

[Effects of Tongmai decoction on the perioperative changes of plasma TNF-alpha and IL-6 in patients with femoral fractures].

OBJECTIVE: To explore the effects of Tongmai decoction on the perioperative changes of serum concentrations of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 in patients with femoral fractures, and conform the effectiveness of Tongmai decoction on inflammatory factors in patients with femoral fractures, providing the theoretical evidence for the clinical use of Tongmai decoction. METHODS: From October 2007 to May 2009, 60 patients with closed traumatic femoral fractures were selected according to the inclusion criterias and exclusion criterias. All the patients were randomly divided into three groups (group A, group B and group C). Twenty patients in group A (Tpanax Notoginseng pill group), 13 patients were male and 7 patients were female; ranging in age from 20 to 45 years, averaged 32.0 years; the disease course ranged from 2.0 to 26.0 h, with an average of 9.5 h. Twenty patients in group B (Tpanax Notoginseng pills and Lornoxicam injection group),12 patients were male and 8 patients were female; ranging in age from 23 to 42 years, averaged 31.0 years; the disease course ranged from 3.5 to 25.0 h, with an average of 13.6 h. Twenty patients in group C (Tpanax Notoginseng pill, Lornoxicam injection and Tongmai decoction group), 14 patients were male and 6 patients were female; ranging in age from 21 to 44 years, averaged 31.5 years; the disease course ranged from 4.6 to 29.0 h, with an average of 13.3 h. Among all the patients, 42 patients with fractures were fixed with femoral intramedullary nailing, and other 18 patients with femoral locking plate fixation. The patients in group A took Tpanax Notoginseng pills orally, 4 g each time and twice daily; the patients in group B took Tpanax Notoginseng pills orally as group A, and at the same time received intramuscular injection of Lornoxicam, 8 mg each time and once daily; the patients in group C took Tpanax Notoginseng pills orally and received intramuscular injection of Lornoxicam as group B, and at the same time took Tongmai decoction (R ) orally, 200 ml each time and twice daily. The above medications were administered to the three groups on the second day after admission to hospital. Peripheral blood samples were taken for determination of pro-inflammatory cytokines of TNF-alpha and IL-6 in blood serum on the 2nd and 6th days before operation and on the 8th and 13th days after operation. And all the patients were evaluated liver and kidney function at the 2nd and 7th days after admission. Analysis of variance and least significant difference-test were done with the help of SPSS 17.0 statistic software. RESULTS: The differences among three groups of TNF-alpha and IL-6 in blood serum at the 2nd day after admission and 2 days after operation had no statistical significance (P > 0.05). The TNF-alpha and IL-6 levels among 3 groups had statistical differences at the 7th day after admission and at the 7th day after operation (P < 0.05, P < 0.01). There were significant differences of TNF-alpha and IL-6 levels between the 7th day after admission and the 2nd day after admission, the 7th day after operation and the 2nd day after admission (P < 0.01). There were also significant differences of TNF-alpha and IL-6 levels between group C compared with group A and B at the 7th day after admission and the 7th day after operation(P < 0.05, P < 0.01). CONCLUSION: The serum concentrations of TNF-alpha and IL-6 level significantly increased in perioperative period. The results indicate that the Tongmai decoction may play an important role in inhibiting the release of TNF-alpha and IL-6 into the blood stream and decreasing the incunabula complication at early traumatic stage.

BMP-7 in combination with estrogen enhances bone formation in a fracture callus explant culture.

In postmenopausal women, estrogen withdrawal results in decrease in bone density or osteoporosis. Osteoporosis leads to fracture and retards bone-healing response. Bone morphogenetic protein-7 (BMP-7), a member of the transforming-growth factor-beta superfamily, has been shown as a promising candidate that stimulates bone growth in its application to fracture healing. The purpose of this study was to determine whether BMP-7 could enhance bone formation in the absence of estrogen. Female rats underwent a controlled closed fracture at the midshaft of the right femur. The callus tissues were harvested from the fracture site eight days following the fracture, and were cultured in serum-free media. The explanted callus tissues were then treated with BMP-7, estrogen (E2) or both. We assessed bone formation by measuring alkaline phosphatase (AP) activity, expression of an osteogenic transcription factor, Runt-related transcription factor-2 (Runx2), production of nitric oxide (NO), and calcium mineralization. Supplementation of serum-free cultures with BMP-7 alone increased cell proliferation by twofold, caused a 6.5-fold increase in AP activity, and enhanced calcium mineralization after 48 h. Moreover, BMP-7 in combination with E2 caused a 8.2-fold increase in the AP activity. Runx2 protein expression was increased following stimulation with BMP-7 and E2. Interestingly, E2 induced the amount of NO production by twofold, whereas BMP-7 did not, either alone or with E2. Thus, BMP-7 could enhance early and late markers of bone fracture healing in callus explant cultures, except for NO. BMP-7 could be a promising growth factor in the treatment of fractures as a consequence of osteoporosis.

Intermittent PTH(1-34) does not increase union rates in open rat femoral fractures and exhibits attenuated anabolic effects compared to closed fractures.

Intermittent Parathyroid Hormone (PTH)((1-34)) has an established place in osteoporosis treatment, but also shows promising results in models of bone repair. Previous studies have been dominated by closed fracture models, where union is certain. One of the major clinical needs for anabolic therapies is the treatment of open and high energy fractures at risk of non-union. In the present study we therefore compared PTH((1-34)) treatment in models of both open and closed fractures. 108 male Wistar rats were randomly assigned to undergo standardized closed fractures or open osteotomies with periosteal stripping. 27 rats in each group were treated s.c. with PTH((1-34)) at a dose of 50 mug/kg 5 days a week, the other 27 receiving saline. Specimens were harvested at 6 weeks for mechanical testing (n=17) or histological analysis (n=10). In closed fractures, union by any definition was 100% in both PTH((1-34)) and saline groups at 6 weeks. In open fractures, the union rate was significantly lower (p<0.05), regardless of treatment. In open fractures the mechanically defined union rate was 10/16 (63%) in saline and 11/17 (65%) in PTH((1-34)) treated fractures. By histology, the union rate was 3/9 (33%) with saline and 5/10 (50%) with PTH((1-34)). Radiological union was seen in 13/25 (52%) for saline and 15/26 (58%) with PTH((1-34)). Open fractures were associated with decreases in bone mineral content (BMC) and volumetric bone mineral density (vBMD) on quantitative computerized tomography (QCT) analysis compared to closed fractures. PTH((1-34)) treatment in both models led to significant increases in callus BMC and volume as well as trabecular bone volume/total volume (BV/TV), as assessed histologically (p<0.01). In closed fractures, PTH((1-34)) had a robust effect on callus size and strength, with a 60% increase in peak torque (p<0.05). In the open fractures that united and could be tested, PTH((1-34)) treatment also increased peak torque by 49% compared to saline (p<0.05). In conclusion, intermittent PTH((1-34)) produced significant increases in callus size and strength in closed fractures, but failed to increase the rate of union in an open fracture model. In the open fractures that did unite, a muted response to PTH was seen compared to closed fractures. Further research is required to determine if PTH((1-34)) is an appropriate anabolic treatment for open fractures.

Osteogenic protein-1 overcomes inhibition of fracture healing in the diabetic rat: a pilot study.

Type I diabetes mellitus inhibits fracture healing and leads to an increase in complications. As a pilot study, we used a closed fracture model in the diabetic rat to address the question of whether osteogenic protein-1 (OP-1) in a collagen carrier can overcome this inhibition by increasing the area of the newly mineralized callus and femoral torque to failure compared with diabetic animals with fractures treated without OP-1. Diabetes was created in 54 rats by injection of streptozotocin. After 2 weeks, a closed femur fracture was created using a drop-weight impaction device. Each fracture site was immediately opened and treated with or without 25 microg OP-1 in a collagen carrier. Animals were euthanized after 2 or 4 weeks. Fracture healing was assessed by callus area from high-resolution radiographs, callus strength from torsional failure testing, and undecalcified histologic analysis. The area of newly mineralized callus was greater in diabetic animals treated with 25 microg OP-1/carrier compared with diabetic animals with untreated fractures and with fractures treated with carrier alone. This increase in callus area did not translate into an equivalent increase in torque to failure. Osteogenic protein-1 showed some evidence of overcoming the inhibition of fracture healing in the diabetic rat.

Single- versus multiple-dose antibiotic prophylaxis in the surgical treatment of closed fractures: a meta-analysis.

OBJECTIVES: The use of prophylactic antibiotics in the surgical treatment of closed long bone fractures is well established. The duration and dosage of prophylaxis, however, vary significantly among surgeons. A systematic review and meta-analysis were performed to determine if multiple-dose perioperative antibiotic prophylaxis is more effective than a single preoperative dose in the prevention of surgical wound infections during the treatment of closed long bone fractures. DATA SOURCES: Articles were identified by searching the following medical databases: Medline, Medline In Process & Other Non-indexed Citations, Embase, CENTRAL, and the Cochrane Database of Systematic Reviews. Relevant conference proceedings and the reference section of selected manuscripts were also searched for additional studies. STUDY SELECTION: Studies were included if they were prospective randomized controlled trials of patients with closed fractures treated with surgical fixation or arthroplasty. The interventions must have directly compared a single preoperative prophylactic dose to a multiple-dose perioperative strategy. Studies were excluded if they involved open fractures. DATA EXTRACTION: The demographic information, prophylaxis strategy, wound infection rate, and risk ratio were extracted from each article. DATA SYNTHESIS: Seven trials and 3,808 patients were pooled using a random effects model. When compared to a regimen of multiple doses of prophylactic antibiotics, administration of a single preoperative dose has a risk ratio of 1.24 (95% CI 0.60-2.60). The pooled risk difference between the 2 strategies is 0.005 (95% CI -0.011-0.021). Neither result is significant. CONCLUSIONS: In the setting of closed long bone fractures, the pooled results failed to demonstrate superiority of multiple-dose prophylaxis over a single-dose strategy. The pooled estimates suggest that surgical wound infections are relatively rare events and that any potential difference in infection rates between prophylaxis strategies is likely quite small. However, because the confidence interval surrounding the pooled risk ratio spans 1.0 by such a large amount, we are unable to definitively recommend a preferred dosing regimen to prevent surgical wound infections. Although future research is required to ensure our prophylaxis decisions continue to be evidence based and cost-effective, it is unlikely that a single clinical trial will be able to provide the answer. The use of other quantitative methods, such as cost-effectiveness analysis, may be helpful in modeling an optimal prophylaxis strategy.