Antibiotic Therapy for 6 or 12 Weeks for Prosthetic Joint Infection.

BACKGROUND: The management of prosthetic joint infection usually consists of a combination of surgery and antimicrobial therapy. The appropriate duration of antimicrobial therapy for this indication remains unclear. METHODS: We performed an open-label, randomized, controlled, noninferiority trial to compare 6 weeks with 12 weeks of antibiotic therapy in patients with microbiologically confirmed prosthetic joint infection that had been managed with an appropriate surgical procedure. The primary outcome was persistent infection (defined as the persistence or recurrence of infection with the initial causative bacteria, with an antibiotic susceptibility pattern that was phenotypically indistinguishable from that at enrollment) within 2 years after the completion of antibiotic therapy. Noninferiority of 6 weeks of therapy to 12 weeks of therapy would be shown if the upper boundary of the 95% confidence interval for the absolute between-group difference (the value in the 6-week group minus the value in the 12-week group) in the percentage of patients with persistent infection within 2 years was not greater than 10 percentage points. RESULTS: A total of 410 patients from 28 French centers were randomly assigned to receive antibiotic therapy for 6 weeks (205 patients) or for 12 weeks (205 patients). Six patients who withdrew consent were not included in the analysis. In the main analysis, 20 patients who died during follow-up were excluded, and missing outcomes for 6 patients who were lost to follow-up were considered to be persistent infection. Persistent infection occurred in 35 of 193 patients (18.1%) in the 6-week group and in 18 of 191 patients (9.4%) in the 12-week group (risk difference, 8.7 percentage points; 95% confidence interval, 1.8 to 15.6); thus, noninferiority was not shown. Noninferiority was also not shown in the per-protocol and sensitivity analyses. We found no evidence of between-group differences in the percentage of patients with treatment failure due to a new infection, probable treatment failure, or serious adverse events. CONCLUSIONS: Among patients with microbiologically confirmed prosthetic joint infections that were managed with standard surgical procedures, antibiotic therapy for 6 weeks was not shown to be noninferior to antibiotic therapy for 12 weeks and resulted in a higher percentage of patients with unfavorable outcomes. (Funded by Programme Hospitalier de Recherche Clinique, French Ministry of Health; DATIPO ClinicalTrials.gov number, NCT01816009.).

Periprosthetic joint infection in aseptic total hip arthroplasty revision.

PURPOSE: There is no consensus regarding systematic screening for infection in aseptic revision total hip arthroplasty (THA). The rationale for systematic intra-operative samples is to increase the sensitivity of latent infections detection, which may require specific treatment. However, the incidence of occult infection in revision THAs is not precisely known. As such, the aim of the study was to evaluate the incidence of occult infection in presumed aseptic revision THAs and identify associated risk factors. METHOD: Bacteriological samples from 523 aseptic THA revisions performed for five years were analyzed. Revisions performed for periprosthetic joint infection (PJI) or clinical suspicion of PJI were excluded. Microbiological cultures were performed using tissue samples in 505 cases (97%), synovial fluid in blood culture vials in 158 (30%), and in dry tubes in 263 (50%). Implants were sent for sonication in 12 cases (2.6%). The mean number of microbiological samples per patient was 3.6 (range, 1-15). Histology samples were collected for 300 patients (57%). RESULTS: The incidence of occult infection was 7% (36 cases) and contamination 8% (42 cases). Among occult infections, the primary reasons for revision were dislocation (42%), aseptic loosening (25%), fracture (19%), and others (14%). The infection rate in the dislocation group was significantly higher than that of other reasons for revision (p < 0.001). Among the patients determined with PJI, the revision THA was performed less than a year after primary in 19 (53%). CONCLUSION: The incidence of occult PJI justifies systematic intraoperative sampling. A short time between primary arthroplasty and revision or an early postoperative dislocation is a factor to suspect infections.

Laterality and grip strength influence hand bone micro-architecture in modern humans, an HRpQCT study.

It is widely hypothesized that mechanical loading, specifically repetitive low-intensity tasks, influences the inner structure of cancellous bone. As such, there is likely a relationship between handedness and bone morphology. The aim of this study is to determine patterns in trabecular bone between dominant and non-dominant hands in modern humans. Seventeen healthy patients between 22 and 32 years old were included in the study. Radial carpal bones (lunate, capitate, scaphoid, trapezium, trapezoid, 1st, 2nd and 3rd metacarpals) were analyzed with high-resolution micro-computed tomography. Additionally, crush and pinch grip were recorded. Factorial analysis indicated that bone volume ratio, trabeculae number (Tb.N), bone surface to volume ratio (BS.BV), body weight, stature and crush grip were all positively correlated with principal components 1 and 2 explaining 78.7% of the variance. Volumetric and trabecular endostructural parameters (BV/TV, BS/BV or Tb.Th, Tb.N) explain the observed inter-individual variability better than anthropometric or clinical parameters. Factors analysis regressions showed correlations between these parameters and the dominant side for crush strength for the lunate (r2 = 0.640, P < 0.0001), trapezium (r2 = 0.836, P < 0.0001) and third metacarpal (r2 = 0.763). However, despite a significant lateralization in grip strength for all patients, the endostructural variability between dominant and non-dominant sides was limited in perspective to inter-individual differences. In conclusion, handedness is unlikely to generate trabecular patterns of asymmetry. It appears, however, that crush strength can be considered for endostructural analysis in the modern human wrist.

Cadaveric Study Comparing the Biomechanical Properties of Grafts Used for Knee Anterolateral Ligament Reconstruction.

PURPOSE: To measure the biomechanical properties (maximum load, stiffness, and elongation) of the anterolateral ligament (ALL), gracilis, and iliotibial band (ITB) within the same subject. METHODS: Thirteen unpaired knees were used (7 women, 6 men). The donors had a mean age at death of 54 years (range: 37 to 70 years). The mechanical properties of two types of ALL grafts were evaluated: ITB and two-strand gracilis. The mechanical properties of ALL were also measured. Validated methods were used to perform the tensile tests to failure and to record the results. Student's t-test was used to compare the various samples. RESULTS: The maximum load to failure was 141 N (±40.6) for the ALL, 200.7 N (±48.7) for the gracilis, and 161.1 N (±27.1) for the ITB. Only the gracilis had a significantly higher failure load than ITB and ALL (P = .001 and P = .03). The stiffness was 21 N mm-1 (±8.2) for the ALL, 131.7 N mm-1 (±43.7) for the gracilis, and 39.9 N mm-1 (±6) for the ITB. The elongation at failure was 6.2 mm (±3.2) for the ALL, 19.9 mm (±6.5) for the gracilis, and 20.8 mm (±14.7) for the ITB. CONCLUSIONS: The gracilis had the highest maximum load to failure. The ITB's mechanical properties most closely resemble those of the ALL. CLINICAL RELEVANCE: The biomechanical properties of each potential ALL graft can be factored in when deciding which type of graft to use.

Can the gracilis replace the anterior cruciate ligament in the knee? A biomechanical study.

PURPOSE: The purpose of this study was to determine whether a four-strand gracilis-only construct possesses the biomechanical properties needed to act as an anterior cruciate ligament (ACL) reconstruction graft. METHODS: This was a pilot study with 32 cadaver specimens. The biomechanical properties of three types of grafts were determined using validated tensile testing methods: patellar tendon (BTB), both hamstring tendons together (GST4) and gracilis alone (G4). RESULTS: The maximum load at failure of the G4 was 416.4 N (±187.7). The GST4 and BTB had a maximum load at failure of 473.5 N (±176.9) and 413.3 N (±120.4), respectively. The three groups had similar mean maximum load and stiffness values. The patellar tendon had significantly less elongation at failure than the other two graft types. CONCLUSIONS: The biomechanical properties of a four-strand gracilis construct are comparable to the ones of standard grafts. This type of graft would be useful in the reconstruction of the anteromedial bundle in patients with partial ACL ruptures.

Reverse shoulder arthroplasty for malignant tumors of proximal humerus.

BACKGROUND: Reverse shoulder arthroplasty (RSA) provides an alternative for shoulder girdle reconstruction after wide transarticular resection of the proximal humerus for malignant tumor. The aim of this study was to evaluate midterm outcomes of this therapeutic option. METHODS: Ten patients with RSA were included and reviewed with 24 months of minimum follow-up. Proximal resection of malignant tumor included the "V" deltoid insertion in 4 patients. The humeral stem was coated (with an allograft in 2 patients and a cement mantel in 3) or left uncoated (5 patients). RESULTS: At a mean follow-up of 42 months, among 8 prosthesis available for evaluation (2 patients died), the Constant and Murley score averaged 52 points, the 11-item version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) score averaged 29.5 points, the Subjective Shoulder Value averaged 58%, and the Musculoskeletal Tumor Society score averaged 20.25 points. Mean forward active elevation reached 122°, external rotation at side was -2°, and internal rotation was to L4. Three prostheses were unstable. The involvement of "V" deltoid insertion at surgery trended to worsen the clinical outcome. Atrophy of the anterior deltoid occurred in most of patients who had a previous transdeltoid biopsy. Radiographic evaluation found 1 stem loosening, 1 stem at risk, and 3 scapular notches without glenoid loosening. CONCLUSION: Use of RSA after resection of a malignant tumor of the proximal humerus seems to be an acceptable option to preserve function. However, radiographic evolution is worrisome, and long-term study remains necessary to validate this therapeutic option with follow-up.

Evaluation of the accuracy of patient-specific cutting blocks for total knee arthroplasty: a meta-analysis.

PURPOSE: Because published studies on the accuracy achieved with patient-specific guides during total knee arthroplasty (TKA) contradict each other, this systematic review and meta-analysis sought to compare radiological TKA outcomes when patient-specific cutting blocks (PSCB) were used to the outcomes when standard manual instrumentation was used. METHODS: The meta-analysis was implemented according to PRISMA Statement Criteria. The primary endpoint was the hip-knee-ankle (HKA) angle, which represents the leg's mechanical axis. The accuracy of component placement in the coronal and sagittal planes, and the accuracy of femoral component rotation were also compiled. After testing for publication bias and heterogeneity across studies, data were aggregated random-effects modeling when necessary. RESULTS: Fifteen articles were included: 916 total knee arthroplasty cases in the PSCB group and 998 in the MI group. The mechanical axis did not differ between the two groups (weighted mean difference 0.07°; 95 % CI, -0.5° to 0.65°; p = 0.8). Risk ratio analysis revealed no protective effect of using PSCB relative to the appearance of HKA angle outliers (RR = 0.88; 95 % CI, 0.68-1.13; p = 0.3). There was a trend towards a protective effect with PSCB for the risk of femoral component outliers, but the opposite was observed for the tibial component. The implantation procedure was stopped in 30 cases because the surgeon-authors found excessive discrepancies between the intra-operative observations and the pre-operative plan. CONCLUSIONS: This meta-analysis found no evidence that using patient-specific cutting blocks provides superior accuracy to using manual instrumentation during TKA.

Obesity is no longer a risk factor for dislocation after total hip arthroplasty with a double-mobility cup.

PURPOSE: Dislocation is one of the most feared complications after total hip arthroplasty (THA). This risk is greater in obese patients compared with the general population. METHODS: We performed a retrospective cohort study in which the main objective was to compare the dislocation rate between obese patients (BMI > 30 kg/m²) (exposed group) and non-obese patients (BMI ≤ 30 kg/m²) (unexposed group) after primary THA with a double-mobility acetabular cup. The patients had a minimum follow-up of 24 months. RESULTS: The 'obese' group consisted of 77 THA cases and the 'non-obese' group of 425 cases; the two groups were similar in terms of age, gender and ASA score. After a mean follow-up of 58.3 ± 27 months (range 27-159), 43 patients had been lost to follow-up and 56 had died; the two groups had similar mean values. One patient in the 'obese' group had suffered a dislocation due to a fall 16 months after the THA. One patient in the 'non-obese' group had suffered a dislocation after a periprosthetic femur fracture with stem subsidence two months after the THA procedure. Both patients underwent surgical revision where the double-mobility cup was preserved; there were no further dislocation events as of the last follow-up. The dislocation rate in the two groups was similar (1.3 % versus 0.23%, p > 0.05). No cases of loosening were found. Revisions were secondary to deep or superficial infection (n = 22), periprosthetic femur fracture (n = 10) or haematoma (n = 3). CONCLUSION: These findings imply that double-mobility cups are a reliable way of reducing the risk of dislocation in obese patients after primary THA.

Radiological validation of a fluoroscopic guided technique for femoral implant positioning during hip resurfacing.

PURPOSE: The positioning of the femoral cup in hip resurfacing is essential for the survival of the implant. We described a technique in 2005 to position the femoral cup guided by fluoroscopy independent of the approach performed. The main objectives were to study the positioning of the femoral components of the implant and the accuracy of the technique. METHODS: Between 2003 and 2011 we conducted a prospective study of 160 consecutive hip resurfacings all operated with this fluoroscopic-guided technique. Three independent observers performed a radiographic analysis at the pre-operative planning stage and on postoperative radiographs using OsiriX software. The statistical analysis was based on comparison of two groups by Student's t test. RESULTS: The entire implant was positioned in valgus, with an average of 7.816° valgus (p <0.001). All implants were positioned in neutral or anteverted with a mean of 1.98° (p <0.001). The risk of malpositioning on the antero-posterior plane was less than 1.41° with p <0.019. The risk of profile positioning error was lower than 0.80° with p <0.047. CONCLUSION: This study validates a technique of femoral implant positioning for resurfacing. It is simple, precise and independent of the approach performed.

Hip resurfacing: a systematic review of literature.

PURPOSE: We conducted a systematic review of the literature in order to take stock of hip resurfacing according to the principle of "evidence based medicine". Our main objective was to compare the rate of revision of resurfacing implants with survival limits set by the National Institute of Clinical Excellence (NICE). METHODS: A systematic review was undertaken of all published (Medline, Cochrane, EMBASE) literature research databases up to July 2012 as recommended by the PRISMA statement. Data extraction focused on functional outcomes, complications and survival rates. The survival rates of implants were analysed according to the mean of the series in comparison to the NICE criteria. RESULTS: Fifty-three studies were identified and included 26,456 cases with an average of 499.17 ± 856.7 (range, 38-5000) cases per study. The median survival was 95.57 % ± 3.7 % (range, 84-100). The percentage of studies which satisfied the criteria set by NICE was 69.8 %. In terms of cumulative revision rates pondered by the number of implants, BHR®, Conserve Plus® and Cormet® showed the best results. The mean postoperative score was 91.2 ± 7.72 (range, 68.3-98.6). There was no statistically significant difference between implants in terms of functional outcomes. CONCLUSION: On the basis of the current evidence base, this review of the literature emphasises the importance of certain parameters that can improve the results of resurfacing. The type of implant seems to play an important role as does patient selection.

Experimental study of an original radiographic view for diagnosis of cam-type anterior femoroacetabular impingement.

PURPOSE: Primary paraclinical investigation to look for femoral morphological abnormality consistent with cam-type anterior femoroacetabular impingement (FAI) must include specific radiographic projections of the hip from the following: cross-table, frog-leg or Dunn (90° and 45° flexion). We use a frog-leg type view with fixed angles as described by Chiron, obtained with the patient in a supine position, with the hip in 45° flexion-abduction and 30° external rotation. The X-ray beam is anteroposterior and centred on the femoral head. We evaluated this view by comparing it with other views in common use. METHODS: In this experimental study, we created artificial radio-opaque morphological abnormalities secured onto normal femoral necks. The femurs were placed in relation to a fixed pelvis using orthogonal landmarks, in the positions of the various radiographic views. The digital radiographs were analysed by two observers. Nineteen femurs were included to reveal a difference of 5° between the alpha angle of Nötzli et al. [11] measured on the Dunn view and the frog-leg 45/45/30 view (Student's paired test). RESULTS: The highest mean values of the alpha angle of Nötzli were always obtained with the frog-leg 45/45/30 view (87.4°, 86.2°, 84.5°) and the lowest with the cross-table view. We found a mean difference of 8.95° with the 90° Dunn view (P = 0.00007), 3.44° with the 45° Dunn view (P = 0.004) and 13.47° with the cross-table view (P = 0.002). CONCLUSIONS: This experimental study confirmed the value of the frog-leg 45/45/30 view in assisting diagnosis of cam-type FAI.

Hypesthesia after anterolateral versus midline skin incision in TKA: a randomized study.

BACKGROUND: The anterior midline skin incision in a TKA provides excellent surgical exposure. However, it usually requires sectioning the infrapatellar branch of the saphenous nerve which may be associated with lateral cutaneous hypesthesia and neuroma formation. QUESTIONS/PURPOSES: We asked whether an anterolateral skin incision to the knee would decrease the area of skin hypesthesia and associated postoperative discomfort. PATIENTS AND METHODS: We randomized 69 knees to receive a TKA through either a midline or an anterolateral skin incision. We assessed skin sensitivity by application of the Semmes-Weinstein monofilament at 13 reference points at 6 weeks and 6 and 12 months postoperatively. The area of hypesthesia was measured using Mesurim Pro 9(®) software. Patient knee ROM, Knee Injury and Osteoarthritis Outcome Score (KOOS), and WOMAC clinical score also were assessed. RESULTS: The area of hypesthesia was less after an anterolateral compared with a midline incision up to 1 year after surgery: the areas of hypesthesia were, respectively, 32 cm(2) versus 76 cm(2) at 6 weeks, 14 cm(2) versus 29 cm(2) at 6 months, and 7 cm(2) versus 19 cm(2) at 1 year. Clinical scores and knee ROM were similar in both groups at each followup. At 1 year, in the entire group we observed a correlation between a smaller area of paresthesia and better WOMAC and KOOS scores and greater knee flexion. CONCLUSIONS: Compared with the midline skin incision, the anterolateral incision is associated with fewer sensory disturbances and appears to be a reasonable alternative in TKA. LEVEL OF EVIDENCE: Level I, therapeutic study. See the guidelines for authors for a complete description of levels of evidence.

The anconeus, an active lateral ligament of the elbow: new anatomical arguments.

PURPOSE: As there are a few detailed anatomical studies of the active function of anconeus muscle in stabilizing the elbow, we aimed to look for anatomical features confirming its role as an active stabilizer of the humero-ulnar joint. METHODS: Thirty fresh unembalmed elbows from 15 cadavers were dissected. We examined the anatomy, insertions, relationships and orientation of the muscle fibres of the anconeus. RESULTS: The anconeus lies in a separate compartment from the other forearm muscles, but in continuity with the extensor (triceps) compartment of the arm. In all the cases, at its proximal extremity we observed continuity of muscle and tendon with the vastus lateralis of the triceps brachii. The muscle fibres run downward and backward, parallel to the fibres of vastus lateralis of the triceps, when the elbow is in extension. Its deep aspect adheres closely to the lateral joint capsule of the humero-ulnar joint. CONCLUSION: The new anatomical characteristics of the anconeus revealed in this study make this muscle a digastric head of triceps brachii that coapts the ulna to the humerus and so reduces varus instability. The close relationships between triceps brachii and the anconeus on one hand and between the joint capsule and the anconeus on the other make the latter muscle an active lateral stabilizer of the elbow.

Preoperative use of epoietin beta in total hip replacement: a prospective study.

OBJECTIVE: Epoietin (EPO) effectively decreases perioperative blood transfusion requirements. We evaluated the feasibility of using EPO beta to increase haemoglobin levels before total hip replacement (THR) and reduce transfusion. MATERIALS AND METHODS: One hundred and seventy-one patients undergoing primary THR were included in this prospective observational study. Patients with initial haemoglobin level <130 g l−1 received EPO beta subcutaneously in a four-dose regimen. Haemoglobin levels were measured at baseline, before surgery, and at postoperative days 1 and 5. RESULTS: Twenty-eight patients received EPO beta preoperatively, 143 were not treated including 42 with initial haemoglobin level <130 g l−1. Haemoglobin increased by 29 ± 9 g l−1 in the low Hb + EPO group versus 2 ± 1 g l−1 for the other patients. In the low Hb + EPO group 3.6% were transfused, in the low HB group 45.2% (P = 0.001) and in the normal Hb group 11.9% (P = 0.2). CONCLUSIONS: Preoperative EPO beta increases haemoglobin level and reduces transfusion frequency in anaemic patients before total joint replacement. It could play a major role in the management of perioperative blood loss in orthopaedic surgery.

Micro-computed tomography study of the subchondral bone of the vertebral endplates in a porcine model: correlations with histomorphometric parameters.

PURPOSE: Subchondral bone (SCB) of the vertebral endplates (VEP) is the principal site of changes in vertebral trabecular microarchitecture secondary to intervertebral disc degeneration. However, the microstructure of this region has not yet been clearly characterized. METHODS: One thoracic and one lumbar vertebral unit (vertebra-disc-vertebra) was removed in nine pigs aged 4 months. Three samples (one central and two laterals) were taken from each VEP. Micro-CT examination and histomorphometric measurements of the subchondral trabecular bone of the VEP were carried out. Correlations between micro-CT and histological parameters were sought. RESULTS: Trabecular network was significantly denser [increased bone volume fraction (BV/TV) and trabecular number (Tb.N), decreased intertrabecular separation (Tb.Sp)] in the cranial endplates of the vertebral units. It was also significantly denser and less well organized [increased degree of anisotropy (DA)] in the centre of the VEP. The thickness of the cartilage endplate (CEP), SCB and growth cartilage were significantly lower in the centre of the VEP. There was a significant negative correlation between BV/TV, Tb.N and DA with the thicknesses of the CEP and SCB whereas Tb.Sp was positively correlated with these two parameters. CONCLUSION: We observed densification of the trabecular network in the centre of the VEP overlying the nucleus pulposus, partly related to thinner hyaline cartilage. Densification is associated with more anisotropic architecture that could cause lower mechanical strength in this area. This study provides new information on the microarchitecture of the SCB of the VEP which will make it possible to validate future models.

Influence of asymmetric tether on the macroscopic permeability of the vertebral end plate.

We implemented an experimental model of asymmetrical compression loading of the vertebral end plate (VEP) in vivo. The macroscopic permeability of the VEP was measured. We hypothesized that static asymmetrical loading on vertebrae altered the macroscopic permeability of the VEP. In scoliosis, solute transport to and from the disc is dramatically decreased especially at the apical intervertebral disc. The decrease in permeability could be induced by mechanical stress. Nine skeletally immature pigs were instrumented with left pedicle screws and compression rod at the T5/T6 and L1/L2 levels. After 3 months, three cylindrical specimens of the VEP were obtained from each of the tethered levels. A previously validated method for measuring permeability, based on the relaxation pressure due to a transient-flow rate was used. A pistoning device generated a fluid flow that fully saturated the cylindrical specimen. The decrease in upstream pressure was measured using a pressure transducer, which allowed the macroscopic permeability to be derived. A microscopic study completed the approach. Overall macroscopic permeability was lower for the tethered VEPs than for the VEPs of the control group, respectively -47% for flow-in (p = 0.0001) and -46% for flow-out (p = 0.0001). In the tethered group, macroscopic permeability of the specimens from the tethered side was lower than macroscopic permeability of those from the non-tethered side, -39% for flow-out (p = 0.024) and -47% for flow-in (p = 0.13). In the control group, the macroscopic permeability was greater in the center of the VEP than in its lateral parts for flow-out (p = 0.004). Macroscopic permeability of the center of the VEPs was greater for flow-out than for flow-in (p = 0.02). There was no significant difference between thoracic and lumbar. This study demonstrated that compression loading applied to a growing spine results in decreased permeability of the VEP. This result could be explained by local remodeling, such as calcification of the cartilage end plate or sclerosis of the underlying bone.

Surgical correction of Madelung's deformity by combined corrective radioulnar osteotomy: 14 cases with four-year minimum follow-up.

Fourteen wrists in 11 girls, mean age 13.3 years (range 9-16) at surgery, were treated for Madelung's deformity. The presenting complaint was incapacitating pain. All were treated by radial closing wedge osteotomy and ulnar shortening osteotomy. The dorsal retinaculum was also surgically repaired in six cases. At a mean follow-up of 5.1 years (range 4-8.75), we observed improved range of motion in both flexion/extension and pronation/supination and absence of pain during daily activity. Radiographically, positioning of the distal radial articular surface and lunate subsidence were improved. Union was obtained after all osteotomies without secondary procedures. Posterior displacement of the ulnar head persisted in two wrists. Combined radioulnar osteotomy restored the anatomy to as near normal as possible. This technique provides satisfactory and encouraging results and does not compromise the surgical future of the wrist. However, longer follow-up is required to assess recurrence or possible long-term degenerative consequences.

Mouse model of fracture pain.

BACKGROUND: The aim of this study was to validate a model of postfracture pain in mice, which was evaluated in the presence and the absence of morphine and ketoprofen. METHODS: The study was divided into two parts: protocol A, the effects of closed fracture; and protocol B, the effects of morphine and ketoprofen on fracture pain. In protocol A, mice were assigned to three groups: group 1, sham incision; group 2, sham pinning; or group 3, fracture. In protocol B, mice were randomly assigned to four groups to receive morphine (3 or 10 mg/kg body weight), ketoprofen (50 mg/kg body weight), or placebo (vehicle). Three tests were used to assess pain behavior: von Frey filament application, hot plate test, and a subjective pain scale. RESULTS: In protocol A, thermal nociception, mechanical nociception, and subjective pain were significantly modified in group 3 (fractured) compared with control groups 1 and 2 (sham groups). In protocol B, when tests were repeated for 240 min in morphine-treated animals and in ketoprofen-treated animals, reduction of mechanical nociception, thermal nociception, and subjective pain scale score were observed. Morphine and ketoprofen administration provided the same effect on behavioral testing on postoperative days 1 and 2. CONCLUSION: This mouse model seems to be a reliable and reproducible tool to investigate the effect of closed bone fracture on several parameters, such as pain, remodeling, and recovery. Moreover, it allows studying the effects of various pharmacologic treatments as well as the involvement of various systems using different genetically modified strains of mice.

A Multicentric, Open-Label, Randomized, Comparative Clinical Trial of Two Different Doses of Expanded hBM-MSCs Plus Biomaterial versus Iliac Crest Autograft, for Bone Healing in Nonunions after Long Bone Fractures: Study Protocol.

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n = 108) will be randomly assigned to either the experimental low dose (n = 36), the experimental high dose (n = 36), or the comparator arm (n = 36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use.