Osteoporosis related to WNT1 variants: a not infrequent cause of osteoporosis.

Nearly 10% of subjects with severe idiopathic osteoporosis present pathogenic WNT1 mutations. Clinical characteristics include a family history of osteoporosis, early adulthood onset, and fragility fractures which may evolve to pseudoarthrosis. WNT1 should be genetically screened in these patients as the phenotype is often variable and therapeutic approaches may differ. INTRODUCTION: Recent studies have shown that homozygous WNT1 gene mutations may be related to severe osteoporosis resembling osteogenesis imperfecta (OI). Conversely, heterozygous WNT1 mutations are linked to a milder phenotype of early-onset osteoporosis. Treatment with bisphosphonates is reported to be unsatisfactory. Our aim was to analyze the presence and prevalence of WNT1 mutations and the main associated clinical characteristics in subjects with primary early-onset osteoporosis. METHODS: A cohort comprising 56 subjects (aged 19-60 years) with severe, early-onset osteoporosis was screened by massive parallel sequencing with a 23-gene panel. The gene panel included 19 genes known to cause OI (including the WNT1 gene), three genes related to osteoporosis, and the gene related to hypophosphatasia (ALPL). RESULTS: We identified five patients (3 men) with heterozygous WNT1 variants. All presented severe osteoporosis with early fracture onset and a family history of fragility fractures. None presented a characteristic phenotype of OI or skeletal deformities. One patient was previously treated with bisphosphonates, presenting inadequate response to treatment and two developed pseudoarthrosis after upper arm fractures. All subjects were diagnosed in adulthood. CONCLUSIONS: Nearly 1/10 adult subjects with severe idiopathic osteoporosis may present pathogenic WNT1 mutations. Clinical characteristics commonly include a family history of osteoporosis, onset in early adulthood, marked decrease in bone mass, and prevalent fractures, particularly vertebral. WNT1 should be genetically screened in these subjects as the phenotype is often variable and the therapeutic approach may differ. The role of WNT1 mutations in the development of pseudoarthrosis should also be elucidated.

Case of femoral pseudarthrosis due to Scedosporium apiospermum in an immunocompetent patient with successful conservative treatment and review of literature.

Scedosporium apiospermum is a ubiquitous filamentous fungus, commonly found in soil, sewage and polluted waters. It is rarely pathogenic but can cause a broad spectrum of clinical diseases, which can be localised or disseminate to distant organs. The disseminated form of the disease is mostly seen among immunocompromised patients. However, some rare cases of disseminated disease have been reported in immunocompetent individuals. Treatment of these infections is challenging because of their natural resistance to many antifungal agents. Here, we report the case of a 57-year-old immunocompetent patient diagnosed with femoral pseudarthrosis due to S. apiospermum, despite having no obvious clinical sign of infection. Previously, the patient had undergone four iterative femoral surgeries following a road traffic accident which occurred 20 years before. During its last surgery for pseudarthrosis, no clinical or biological signs of infection were present. Per operative samples tested positive for S. apiospermum. The patient was successfully treated with oral voriconazole during 6 months with an excellent tolerance. We also provide a review of literature on bone and joint infections due to Scedosporium spp. (S. apiospermum, Scedosporium boydii and Scedosporium aurantiacum), discussing the evolution of their management and outcome which seems to improve since the use of voriconazole.

Infections caused by Tissierella praeacuta: A report of two cases and literature review.

Herein we report two cases of infections caused by Tissierella praeacuta and a review of the literature. The first case was a septic pseudarthrosis of the left femur after multiple fractures. Two per-operative samples were positive with T. praeacuta. The patient was successfully treated by piperacillin - tazobactam and metronidazole. The second case was a bacteremia in a patient suffering from pyonephrosis and a hepatic abscess. The treatment was meropenem. No relapses were observed in both cases. Identification of the strains using MALDI-TOF coupled to mass spectrometry (MS) (Beckman coulter, France) was inconclusive in the two cases. Identification by 16S rRNA sequencing was then performed. This bacterium was susceptible to beta-lactams, chloramphenicol, rifampicine and metronidazole.

Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice.

Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to debilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseudarthrosis (nonunion fracture). Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progenitors and mesenchymal stem cells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPK as a critical pathway underlying the pathogenesis of NF1-associated fracture repair deficits. Nf1-deficient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase activating-related domain (NF1 GAP-related domain) in vitro is sufficient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1(-/-) pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-deficient murine pro-OBLs. Similarly, MEK inhibition enhances OBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclast maturation in Nf1 haploinsufficient bone marrow mononuclear cells (BMMNCs). Importantly, MEK inhibitor significantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1(flox/-). Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis related to NF1 mutations. These studies provide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.

[Improvement of fracture healing with teriparatide: series of 22 cases and review of the literature]. / Accélération de la guérison fracturaire par le tériparatide: série de 22 cas et revue de la littérature.

Pseudoarthrosis is defined as a non healing fracture 9 months after trauma and without radiological progression within the last three months. Osteoporotic fractures have a greater risk of chirurgical complications. The question of giving a medical treatment in the purpose of accelerating fracture healing is an increasing concern. There are data showing that with teriparatide (bone anabolic treatment derived from the parathyroid hormone) bone healing and functional status are improved, with or without surgery, in the case of either typical or atypical fractures. The risks of this treatment are low but health insurance agreement is needed in this indication. We report our experience with the use of this molecule, out of the official indication, in complex situations of non healing fractures.

Osteoanabolic therapy: a non-surgical option of treatment for Kümmell's disease?

Kümmell's disease is the current eponym of avascular osteonecrosis (AVN) of a vertebral body leading to a delayed non-healing vertebral compression fracture (VCF) and thus pseudo-arthrosis. AVN is characterized by production of gas that outlines a radiolucent zone in the vertebral body, called vacuum cleft sign (VCS) or "Kümmell's sign". This sign has been observed in up to one-third of VCFs and is often associated with osteoporosis and never with malignant or inflammatory diseases. Generally, treatment strategies are conservative management and percutaneous vertebroplasty. Teriparatide (rhPTH [1-34]) is an osteoanabolic agent approved for treatment of osteoporosis and helpful in fracture's healing too. Here, we describe the case of an 81-year-old osteoporotic woman presented with a 1-year history of persistent low back pain onset after a trauma. A lumbar spine Computer Tomography (CT) scan performed 2 months after the injury (November 2006) showed the VCS within a VCF of the first lumbar vertebra; a control CT scan 1 year later showed persistence of the finding. After 12 months of treatment with teriparatide 20 mcg/day, symptoms disappeared and vacuum was significantly reduced. In conclusion, Kümmell's disease may be hypothesized in patients with chronic spinal symptoms, especially in the presence of osteoporosis. Moreover in this condition, osteoanabolic treatment may be used in patients with Kümmell's disease to enhance vertebral fracture's healing and contribute to back pain relief.

[Augmentation in surgical sepsis : Chances and limitations in the treatment of osteitis with calcium hydroxyapatite containing antibiotics]. / Augmentation in der septischen Chirurgie : Chancen und Limitationen in der Behandlung der Osteitis mit antibiotikahaltigem Kalziumhydroxylapatit.

BACKGROUND: The surgical treatment of osteitis or fracture-related infections (FRI) is often associated with large bone defects. The treatment of these defects remains a major challenge in trauma surgery. Within the concept of tissue engineering, the development of various hybrid bone graft substitutes, such as calcium hydroxyapatite with added antibiotics, is continuously progressing. OBJECTIVE: Chances and limitations in the treatment of osteitis with calcium hydroxyapatite containing antibiotics. MATERIAL AND METHODS: Overview of the results of a 2-stage (infection) pseudarthrosis model on rat femurs treated with Cerament® G (Bonesupport, Lund, Schweden). Evaluation of the clinical experiences based on three case examples of osteitis treated with calcium hydroxyapatite containing antibiotics (Cerament® G or Cerament® V). RESULTS: After establishment of a 2­stage pseudarthrosis model on the rat femur, the osteoconductive and osteoinductive potential of calcium hydroxyapatite containing antibiotics could be confirmed. In the clinical application, the use of Cerament® G seems to lead to a more favorable outcome in small cavitary defects. The recurrence rates are higher than previously described, especially for larger segmental defects. CONCLUSION: Taking the clinical and experimental results into consideration, a stricter evaluation of the indications for the use of Cerament® G is necessary to achieve the best possible outcome for patients.

[Therapy-resistant, atrophic and septic femoral pseudarthrosis]. / Therapieresistente, Atrophe und Infizierte Femorale Pseudarthrose.

Non-union is a common and serious complication in orthopaedic surgery with high socioeconomic importance. In addition to conventional methods for the treatment of non-unions bone morphogenetic protein (BMP)-7 for the induction of bone tissue is available. The case report demonstrates successful treatment of a septic and atrophic femoral non-union by combination therapy with BMP-7 and autologous spongiosa graft after multiple revision surgeries.

Enhancement of difficult nonunion in children with osteogenic protein-1 (OP-1): early experience.

UNLABELLED: Numerous studies have described the use of osteogenic protein-1 (OP-1) in adults, but there are few reports in children. The objectives of this short-term followup cohort study were (1) to examine clinical and radiographic healing of persistent nonunions after OP-1 application in children; and (2) to determine the safety of OP-1 use in this sample. Clinical healing was defined by absence of pain and tenderness at the nonunion site and the ability to fully weight bear on the affected limb. Radiographic healing was determined by bony bridging of the nonunion site in at least one view. Safety was defined as the absence of major adverse events, including allergic reactions, infections, local inflammatory reactions, and heterotopic ossification. OP-1 was used in 19 patients who had an operative procedure for the bridging of persistent nonunions between 1999 and 2007. The mean age was 11.6 years (range, 4.8-20.3 years). Thirteen patients had persistent nonunion after one or more previous surgeries, prior to the initial OP-1 application. A single dose of 3.5 mg of OP-1 mixed with 1 g of Type I bovine collagen was applied to 23 sites of 19 patients. Three patients received additional OP-1 applications. Healing occurred clinically and radiographically in 17 of the 23 sites. Complications included four superficial pin site infections, one deep infection, and two fractures. No major local adverse event related to OP-1 application was noted in our sample. Our findings suggest OP-1 stimulates healing of persistent nonunions without major adverse events in our patient population. LEVEL OF EVIDENCE: Level IV, case series. See the guidelines online for a complete description of levels of evidence.

Effects of single and cyclical local injections of basic fibroblast growth factor on cancellous bone defects in rabbits.

BACKGROUND: Local administration of basic fibroblast growth factor (bFGF) has anabolic effects on bone formation. A delivery system for local treatment is required to increase efficacy because of its short half-life. However, little is known about the effects of cyclical local injection of bFGF. We evaluated the effects of single and cyclical local injection of bFGF at a cancellous bone defect in the femoral condyle in rabbits. METHODS: Using the "vehicle only" as a control, a single low dose (40 microg), single high dose (120 microg), or cyclical low dose (40 microg, three times) of bFGF was injected percutaneously into a bone defect implanted with a gelatin sponge. The rabbits were killed at 4 weeks after surgery and the femurs were harvested for evaluation. RESULTS: Both single and cyclical administration of bFGF dose-dependently increased the amount of new bone formation in the bone defect using radiographs (P < 0.01) and bone mineral density (BMD) measurements (P < 0.01) compared to controls. However, only high-dose bFGF injection significantly increased the cancellous bone volume at the bone defect (P < 0.05) compared to controls, using bone histomorphometry. Cyclical injection of bFGF significantly increased the number of runt-related transcription factor-2 (Runx2)-positive cells compared to single low- and high-dose bFGF administration (P < 0.01 and P < 0.05, respectively), and single high-dose and cyclical administration significantly increased the number of osteopontin-positive cells compared to controls (P < 0.01), based on immunohistochemical analysis. CONCLUSIONS: These results suggest that high-dose injection of bFGF, at the very early stage of cancellous bone healing, is more effective in increasing cancellous bone volume, and cyclical injection of bFGF may stimulate osteoprogenitor cells.

The Effect of Proton Pump Inhibitors on Bone Formation in a Rat Spinal Arthrodesis Model.

STUDY DESIGN: Rat posterolateral arthrodesis model. OBJECTIVE: Quantify the impact of administration of a proton pump inhibitor on spine fusion. SUMMARY OF BACKGROUND DATA: Proton pump inhibitors (PPIs) are widely used for gastrointestinal disorders and for ulcer prophylaxis in patients taking non-steroidal anti-inflammatory drugs. PPIs cause chronic acid suppression which has been found to result in decreased bone mineral density, increased fracture risk, and impaired fracture healing. Despite advances in surgical techniques, pseudarthrosis still occurs in up to 24% of patients requiring revision surgery following spinal fusion procedures. Thus, there are likely many unidentified risk factors. While PPIs have been hypothesized to impact fracture healing, no study has evaluated their effect on spine arthrodesis rates. METHODS: Thirty-eight female rats underwent posterolateral lumbar spinal fusion. Rats were divided into two groups: normal saline control and pantroprazole, which was administered by daily intraperitoneal injections. At 8 weeks postoperative spines were evaluated with manual palpation, microCT, histologic analysis, and biomechanical testing. RESULTS: Fusion rates of the control group and PPI group were not significantly different (100% vs. 94%). Average fusion scores were significantly lower in the pantoprazole group. New bone formation identified on microCT imaging of bilaterally fused specimens demonstrated a lower average volume of newly generated bone in the PPI group, but this difference was not significant. Biomechanical testing demonstrated no significant difference in strength or stiffness of the fusion mass between the groups. CONCLUSION: This study demonstrates that administration of PPIs does not inhibit fusion rates, bone formation, or affect biomechanical integrity of fusion. However, lower fusion scores in the PPI group suggest that a negative impact may still exist. Future studies will explore growth factor and protein expression in the fusion masses as well as utilize higher doses of PPI to fully discern their effect on spine fusion. LEVEL OF EVIDENCE: N/A.

Glycopeptide bone penetration in patients with septic pseudoarthrosis of the tibia.

BACKGROUND AND OBJECTIVE: In the treatment of bone infections, a major determinant of the clinical response is the active drug concentration at the infected site. Because of the high prevalence of meticillin (methicillin)-resistant staphylococci and enterococci, glycopeptides are widely used for the treatment of bone and joint infections, but data on their penetration into human bone are lacking. The aim of our study was to measure vancomycin and teicoplanin concentrations in infected human bone under steady-state conditions and verify their relationship with inflammatory markers, patient demographic characteristics and pharmacodynamic microbiological markers. METHODS AND PATIENTS: Twenty-seven adult orthopaedic patients undergoing surgical debridement for septic pseudoarthrosis of the tibia and receiving either intravenous vancomycin (Vancocina) 1 g twice daily) or teicoplanin (Targosid) 10 mg/kg/day) were studied from January 2004 to January 2008. Plasma and bone specimens were simultaneously collected during surgery for pharmacokinetic and microbiological assays at a variable interval after antimicrobial administration. Bone samples were dissected into cortical and cancellous bone, cleaned of soft tissues, crushed and eluted into phosphate buffer. Necrotic samples and sequestra were not analysed.Plasma and bone antimicrobial concentrations were measured by a validated method of high-performance liquid chromatography with UV detection, and bone/plasma concentration ratios were calculated. Cortical and cancellous bone area under the concentration-time curve (AUC) over 24 hours (AUC(24)) values were measured by the linear-log trapezoidal rule, using WinNonlin) software, and were compared with the minimum inhibitory concentrations (MICs) of the infecting agents. RESULTS: For vancomycin, the mean +/- SD concentrations were 2.66 +/- 1.2 mg/L in cortical bone and 11.53 +/- 7.8 mg/L in cancellous bone (corresponding to 20.67% and 89.39% of intraoperative plasma concentrations), and the mean +/- SD tissue AUC(24) values were 55.15 +/- 25.26 h . mg/L for cortical bone and 299.16 +/- 299.54 h . mg/L for cancellous bone. For teicoplanin, the mean +/- SD concentrations were 2.01 +/- 1.7 and 7.51 +/- 7.0 mg/L in cortical and cancellous bone, respectively (12.35% and 48.6% of intraoperative plasma concentrations), and the mean +/- SD teicoplanin tissue AUC(24) values were 34.08 +/- 23.6 h . mg/L and 155.17 +/- 132.8 h . mg/L for cortical bone and cancellous bone, respectively. The mean vancomycin AUC(24)/MIC ratios were 215.02 for plasma, 47.14 for cortical bone and 268.95 for cancellous bone. The mean teicoplanin AUC(24)/MIC ratios were 336.48, 36.27 and 197.21 for plasma, cortical bone and cancellous bone, respectively. CONCLUSIONS: Bone penetration of both glycopeptides ranged from poor (<15%) to satisfactory (15-30%) in the cortical compartment, while it was far higher into the highly vascularized cancellous tissue. Vancomycin bone penetration was slightly higher than with teicoplanin, but the difference was not statistically significant. Higher bone concentrations were observed with higher inflammatory markers, possibly as a result of increased vascularization and vascular permeability under inflammatory conditions. Bone concentrations over the MIC and AUC/MIC ratios suggested that both glycopeptides achieve a satisfactory pharmacokinetic exposure in the cancellous bone, as far as Gram-positive pathogens are concerned. On the other hand, cortical bone exposure was suboptimal in most patients. Furthermore, as antimicrobial penetration may be affected by impaired blood supply, the role of radical surgical removal of purulent and necrotic tissues appears to be essential in order to shorten treatment duration and to reduce the risk of treatment failure.

Treatment of congenital pseudarthrosis of the tibia with native bovine BMP: a case report.

Bone morphogenetic proteins (BMP) have been shown to induce bone formation and union in long bone defects and nonunions. We report a case of congenital pseudarthrosis of the tibia treated with a composite implant consisting of a biocoral frame, collagen carrier, and native bovine BMP extract. A six-year-old boy had persisting congenital proximal tibial pseudarthrosis despite six prior operations. At surgery, the sclerotic surfaces of both fragments were excised, fixation was performed using Ilizarov's device, and the composite implant and an autograft were applied to the nonunion site. Three months after the operation, radiographs showed union, and at four months, the Ilizarov device was removed. Two years later, the proximal pseudarthrosis remained clinically and radiologically united. It is concluded that BMP may contribute to the healing of congenital tibial pseudarthrosis of the tibia.

The Effect of Ketorolac on Thoracolumbar Posterolateral Fusion: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: The purpose of this study was to evaluate the effect of postoperative ketorolac administration (ie, dosage and duration of use) on pseudarthrosis following thoracolumbar posterolateral spinal fusions. SUMMARY OF BACKGROUND DATA: Ketorolac is a nonsteroidal anti-inflammatory drug often administered for pain control after spine surgery. The main concern with ketorolac is the risk of pseudarthrosis following fusion. MATERIALS AND METHODS: A systematic search of multiple medical reference databases was conducted for studies detailing postoperative ketorolac use in lumbar fusion and scoliosis surgery in adult and pediatric patients, respectively. Meta-analysis was performed using the random-effects model for heterogeneity as this study analyzes heterogenous patient populations undergoing variable approaches to fusion and variable numbers of levels with variable means of detection of pseudarthrosis. Outcome measure was pseudarthrosis. RESULTS: Overall, 6 studies totaling 1558 patients were reviewed. Pseudarthrosis was observed in 119 (7.6%) patients. Pseudarthrosis were observed in adults with ketorolac administered for >2 days [odds ratio (OR), 3.44, 95% confidence interval (95% CI), 1.87-6.36; P<0.001], adults with doses of ≥120 mg/d (OR, 2.93, 95% CI, 1.06-8.12; P=0.039), and adults with ketorolac administered for >2 days and at doses ≥120 mg/d (OR, 4.75, 95% CI, 2.34-9.62; P<0.001). Ketorolac use in smokers was associated with pseudarthrosis (OR, 8.71, 95% CI, 2.23-34.0; P=0.002). CONCLUSION: Ketorolac, when administered for >2 days and/or at a dose of ≥120 mg/d, is associated with pseudarthrosis in adults after posterolateral lumbar fusion. Ketorolac use in smokers is also associated with pseudarthrosis.

Tratamiento de pseudoartrosis postquirúrgica en la base del segundo metatarsiano mediante autoinjerto de calcáneo: caso clínico / Treatment of postsurgical pseudoarthrosis in the base of the second metatarsal with calcaneus autograft: a case report

Los procesos de no-unión postquirúrgicos en pie y tobillo no son infrecuentes debido a la gran cantidad de procedimientos quirúrgicos mediante osteotomías o artrodesis que se realizan anualmente. Ocasionalmente, estos procedimientos no tienen una estabilización óptima del foco de fractura y pueden acabar degenerando en un proceso de no-unión. Presentamos el caso de una paciente a la que se le realizaron osteotomías en la base de los metatarsianos menores por cirugía mínimamente invasiva para el tratamiento de metatarsalgia, que derivó en el desarrollo de pseudoartrosis dolorosa en la base del segundo metatarsiano y de no-unión en el 4.º metatarsiano. Se realizó tratamiento quirúrgico consistente en la utilización de autoinjerto corticoesponjoso de calcáneo y estabilización con placa de bloqueo dorsal para 2.º metatarsiano y estabilización con placa dorsal de bloqueo para el 4.º metatarsiano. La radiología mostró integración del injerto a las 8 semanas y los resultados clínicos fueron muy satisfactorios tras 5 años de seguimiento. El autoinjerto de calcáneo con estabilización rígida por medio de placa de bloqueo dorsal puede ser un tratamiento efectivo para el tratamiento de la no unión y pseudoartrosis en la base de los metatarsianos.(AU)

Postsurgical nonunions of the foot and ankle are not uncommon because of the large number of procedures by means of osteotomies and arthrodesis that are performed annually. We present a clinical case of a patient who developed a painful nonunion in the base of the second metatarsal after a minimally invasive surgical procedure for metatarsalgia within a base osteotomy that developed a painful pseudoartrhosis of the 2nd metatarsal and also a nonunion of the 4th metatarsal. The patient was treated with the use of an autograft of corticocancellous bone from ipsilateral calcaneus that was fixated with a dorsal locking plate for the 3rd metatarsal and also with stabilization by means of a dorsal locking plate of the 4th metatarsal. Radiology showed good integration of the graft at 8 weeks and clinical results were excellent after 5 years of followup. Autograft from calcaneus fixed with a locking dorsal plate can be an effective treatment of nonunions in the base of the metatarsals.(AU)

In silico clinical trials for pediatric orphan diseases.

To date poor treatment options are available for patients with congenital pseudarthrosis of the tibia (CPT), a pediatric orphan disease. In this study we have performed an in silico clinical trial on 200 virtual subjects, generated from a previously established model of murine bone regeneration, to tackle the challenges associated with the small, pediatric patient population. Each virtual subject was simulated to receive no treatment and bone morphogenetic protein (BMP) treatment. We have shown that the degree of severity of CPT is significantly reduced with BMP treatment, although the effect is highly subject-specific. Using machine learning techniques we were also able to stratify the virtual subject population in adverse responders, non-responders, responders and asymptomatic. In summary, this study shows the potential of in silico medicine technologies as well as their implications for other orphan diseases.

Improved union and bone strength in a mouse model of NF1 pseudarthrosis treated with recombinant human bone morphogenetic protein-2 and zoledronic acid.

Tibial pseudarthrosis associated with Neurofibromatosis type 1 (NF1) is an orthopedic condition with consistently poor clinical outcomes. Using a murine model that features localized double inactivation of the Nf1 gene in an experimental tibial fracture, we tested the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and/or the bisphosphonate zoledronic acid (ZA). Tibiae were harvested at 3 weeks for analysis, at which time there was negligible healing in un-treated control fractures (7% union). In contrast, rhBMP-2 and rhBMP-2/ZA groups showed significantly greater union (87% and 93%, p < 0.01 for both). Treatment with rhBMP-2 led to a 12-fold increase in callus bone volume and this was further increased in the rhBMP-2/ZA group. Mechanical testing of the healed rhBMP-2 and rhBMP-2/ZA fractures showed that the latter group had significantly higher mechanical strength and was restored to that of the un-fractured contralateral leg. Co-treatment with rhBMP-2/ZA also reduced fibrous tissue infiltration at the fracture site compared to rhBMP alone (p = 0.068). These data support the future clinical investigation of this combination of anabolic and anti-resorptive agents for the treatment of NF1 pseudarthrosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:930-936, 2018.

[Application of gentamycini impregnated polymethylmethacrylate (PMMA) (Septopal) in treatment of infected nonunion. Own experiments]. / Wykorzystanie implantów z polimetylmetakrylanu (PMMA) jako nosnika gentamycyny (Septopal) w leczeniu zakazonych stawów rzekomych. Badania wlasne.

INTRODUCTION: Treatment techniques of osteomyelitis and infected nonunion require local antibiotic-therapy in the infection places because of the necessity of achievement of a very high concentration of antibiotic. Among the methods of local application of antibiotic we have the possibility of non-absorbale carriers application where polymethylmethacrylate (PMMA) is the carrier. Aminoglycosides are the most commonly employed antibiotics for use with PMMA. PURPOSE OF THE WORK: Estimation of the possibility of use gentamycini-impregnated polymethylmethacrylate (PMMA) (Septopal) in treatment of infected nonunion. MATERIAL AND METHODS: In the years 2001-2006 in Clinic of Traumatology and Hand Surgery in Wroclaw Medical University, 16 patients were treated because of osteomyelitis and infected nonunion of the long bone. Osteomeylitis, according to the Cierny-Mader's classification, was determined as type IVA in 8 patients, as type IIIA in 4 patients, as type IVB in 4 patients. In stage I surgical cleaning focus of the infected nonunion, external stabilization and implantation of PMMA with gentamycyni were performed, in stage II bone graft with length from 2 to 5 cm was applied. RESULTS: Eradication of the inflammatory process was achieved 13 patients, bone union-in 12 patients. The mean time of bone union achievement was 9 months. The failures concerned mainly patients with type IVB of osteomyelitis according to Cierny-Mader's classification. CONCLUSIONS: Application of PMMA with gentamycini is an efficient method in the treatment of traumatic osteomyelitis. The reults of osteomyelitis treatment correspond to the osteomyelitis classification according to Cierny-Mader. Application of PMMA with gentamycyni in connection with surgery of nonunion prevents possible infection and creates the space for bone grafts.

Bone morphogenetic protein 7 in the treatment of congenital pseudarthrosis of the tibia.

We describe a 13-year-old boy with atrophic tibial pseudarthrosis associated with neurofibromatosis who had undergone nine unsuccessful operations. Eventually, union was obtained by the use of bone morphogenetic protein 7 in conjunction with intramedullary stabilisation and autologous bone graft.

rhBMP-2 protects against reoperation for pseudoarthrosis and/or instrumentation failure: A matched case-control study of 448 patients.

The objective of this independent study is to determine the impact of recombinant human bone morphogenetic protein 2 (rhBMP-2) on reoperation for pseudarthrosis and/or instrumentation failure. A nested case-control study of first-time posterolateral, instrumented fusion of the lumbar spine for degenerative spinal disease was undertaken. Cases of reoperation for pseudoarthrosis and/or instrumentation failure were assigned to controls, who did not experience the primary outcome measure at the time of reoperation. Cases and controls were matched on number of interspaces fused and inclusion of interbody. Predictors of reoperation for pseudoarthrosis and/or instrumentation failure were assessed with a conditional logistical regression controlling for rhBMP-2, age, obesity, and smoking. Of the 448 patients, 155 cases of reoperation for pseudoarthrosis and/or instrumentation were matched with 293 controls. Twenty-six percent of first-time surgeries included rhBMP-2, which was statistically more commonly used in the control cohort (33.11%) versus the case cohort (12.90%) (Unadjusted odds ratio [ORunadj]=0.28) (95% confidence interval [CI]: 0.16-0.49). Following a multivariate analysis controlling for age, obesity, and smoking, the rhBMP-2 recipients incurred a 73% lower odds of reoperation for pseudoarthrosis and/or instrumentation failure (95% CI, 0.15-0.48). Neither sarcomatous nor osseous neoplasm was detected in the study population. Mean follow up did not differ between the cases (81.57±standard deviation [SD] 4.98months) versus controls (74.75±2.49month) (ORunadj=1.01) (95% CI: 1.00-1.01). rhBMP-2 in lumbar fusion constructs protects against reoperation for pseudoarthrosis and/or instrumentation failure. However, the decision to include fusion supplements should be weighted between surgical determinants and clinical outcomes.