Andreas Leonidou

Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing

Background: Platelet-derived growth factor (PDGF) has been shown in vivo to increase bone formation and supplement fracture healing, and may have a role as a therapeutic agent in the treatment of bone loss and fracture healing in humans. Objective: A comprehensive review of the recent literature on the effect of PDGF on bone mineral density and fracture healing. Methods: In vitro and in vivo evidence was systematically collected using medical search engines MEDLINE/OVID (1950 to March 2008) and EMBASE (1980 to March 2008) databases. Results/conclusion: Evidence to date suggests that PDGF-BB, and to a lesser extent PDGF-AA, may have potential therapeutic use in the treatment of osteoporosis and bone healing in humans. Additionally, by targeting α-receptors on osteoblasts, a potential anabolic effect on bone metabolism in humans can be anticipated; however, more research needs to be done to assess the role of β-receptors in human bone.

Patellar resurfacing in total knee arthroplasty: does design matter? A meta-analysis of 7075 cases.

BACKGROUND Patellar resurfacing in total knee arthroplasty remains controversial. The aim of this study was to compare outcomes following total knee arthroplasty with patellar resurfacing with those following total knee arthroplasty without patellar resurfacing. We also sought to identify any correlation between outcomes and prosthetic design. METHODS Eighteen Level-I randomized controlled trials with a cumulative sample size of 7075 knees (3463 in the resurfacing group and 3612 in the non-resurfacing group) satisfied the inclusion criteria. In the primary analysis, patellar resurfacing total knee arthroplasty was compared with non-resurfacing total knee arthroplasty, with use of reoperation rates, incidence of anterior knee pain, and functional scores as outcome measures. The secondary analysis focused on comparing patella-friendly and non-patella-friendly total knee arthroplasty designs with regard to the same three outcome measures. RESULTS No significant differences were found between the resurfacing and non-resurfacing groups with regard to the incidence of anterior knee pain. A higher rate of reoperations was observed in the non-resurfacing group. Analysis of homogeneous data comparing patella-friendly with non-patella-friendly total knee arthroplasty designs demonstrated no differences in the incidence of reoperations. CONCLUSIONS No evidence was found to suggest that either patellar resurfacing or the prosthetic design affects the clinical outcome of a total knee arthroplasty. The higher incidence of reoperations in the non-resurfacing group may be attributed to the fact that secondary patellar resurfacing adds a surgical option for the treatment of anterior knee pain following total knee arthroplasty, thus artificially increasing the rate of reoperations in the non-resurfacing group.

Biological therapy of bone defects: the immunology of bone allo-transplantation

Importance of the field: Bone is one of the most transplanted tissues worldwide. Autograft is the ideal bone graft but is not widely used because of donor site morbidity and restricted availability. Allograft is easily accessible but can transmit infections and elicit an immune response. Areas covered in this review: This review identifies all in vitro and in vivo evidence of immune responses following bone transplantation and highlights methods of improving host tolerance to bone allotransplantation. What the reader will gain: In humans, the presence of anti-HLA specific antibodies against freeze-dried and fresh-frozen bone allografts has been demonstrated. Fresh-frozen bone allograft can still generate immune reactions whilst freeze-dried bone allografts present with less immunogenicity but have less structural integrity. This immune response can have an adverse effect on the grafts incorporation and increase the incidence of rejection. Decreasing the immune reaction against the allograft by lowering the immunogenic load of the graft or lowering the host immune response, would result in improved bone incorporation. Take home message: It is essential that the complex biological processes related to bone immunogenicity are understood, since this may allow the development of safer and more successful ways of controlling the outcome of bone allografting.

Bone metabolism in anorexia nervosa: molecular pathways and current treatment modalities

Eating disorders are associated with a multitude of metabolic abnormalities which are known to adversely affect bone metabolism and structure. We aimed to comprehensively review the literature on the effects of eating disorders, particularly anorexia nervosa (AN), on bone metabolism, bone mineral density (BMD), and fracture incidence. Furthermore, we aimed to highlight the risk factors and potential management strategies for patients with eating disorders and low BMD. We searched the MEDLINE/OVID (1950–July 2011) and EMBASE (1980–July 2011) databases, focussing on in vitro and in vivo studies of the effects of eating disorders on bone metabolism, bone mineral density, and fracture incidence. Low levels of estrogen, testosterone, dehydroepiandrosterone, insulin-like growth factor-1 (IGF-1), and leptin, and high levels of cortisol, ghrelin, and peptide YY (PYY) are thought to contribute to the ‘uncoupling’ of bone turnover in patients with active AN, leading to increased bone resorption in comparison to bone formation. Over time, this results in a high prevalence and profound degree of site-specific BMD loss in women with AN, thereby increasing fracture risk. Weight recovery and increasing BMI positively correlate with levels of IGF-1 and leptin, normalisation in the levels of cortisol, as well as markers of bone formation and resorption in both adolescent and adult patients with AN. The only treatments which have shown promise in reversing the BMD loss associated with AN include: physiologic dose transdermal and oral estrogen, recombinant human IGF-1 alone or in combination with the oral contraceptive pill, and bisphosphonate therapy.

Disease-modifying osteoarthritis drugs: in vitro and in vivo data on the development of DMOADs under investigation

Introduction: Osteoarthritis is a disabling affliction, and disease-modifying osteoarthritis drugs (DMOADs) would be highly desirable adjuncts to symptomatic relief as they may delay the disease process. Areas covered: This study is a comprehensive review of the recent literature on the efficacy of DMOADs in the treatment of OA. In vitro and in vivo evidence was collected using MEDLINE® (1950 to November 2012) and EMBASE (1980 to November 2012) databases. Several drugs have demonstrated DMOAD effects in OA. They can be divided into three groups based on their predominant mode of action: those targeting cartilage, inflammatory pathways and subchondral bone. OARSI guidelines recommend glucosamine and chondroitin sulphates and diacerein as DMOADS, and NICE will recommend glucosamine sulphate in the next update of guidelines. Exploration of improved outcome measures and identification of subgroups of patients most likely to benefit from different DMOADs are likely to be the most important areas of development over the coming years. Expert opinion: It is expected that a wider range of prospective clinical studies will be embarked upon in the coming years. Trials including MRI as well as joint space narrowing (JSN) should be designed in a systematic manner, powered with sufficient numbers to demonstrate clinical benefit at different stages of disease.

Rigid versus flexible plate fixation for periprosthetic femoral fracture—Computer modelling of a clinical case

A variety of plate designs have been implemented for treatment of periprosthetic femoral fracture (PFF) fixation. Controversy, however, exists with regard to optimum fixation methods using these plates. A clinical case of a PFF fixation (Vancouver type C) was studied where a rigid locking plate fixation was compared with a more flexible non-locking approach. A parametric computational model was developed in order to understand the underlying biomechanics between these two fixations. The model was used to estimate the overall stiffness and fracture movement of the two implemented methods. Further, the differing aspects of plate design and application were incrementally changed in four different models. The clinical case showed that a rigid fixation using a 4.5 mm titanium locking plate with a short bridging length did not promote healing and ultimately failed. In contrast, a flexible fixation using 5.6 mm stainless steel non-locking plate with a larger bridging length promoted healing. The computational results highlighted that changing the bridging length made a more substantial difference to the stiffness and fracture movement than varying other parameters. Further the computational model predicted the failure zone on the locking plate. In summary, rigid fracture fixation in the case of PFF can suppress the fracture movement to a degree that prevents healing and may ultimately fail. The computational approach demonstrated the potential of this technique to compare the stiffness and fracture movement of different fixation constructs in order to determine the optimum fixation method for PFF.

Sclerostin monoclonal antibodies on bone metabolism and fracture healing

Introduction: The biological enhancement of fracture healing may prevent complications such as non-union and revision surgery. Sclerostin is produced by osteocytes and binds to the LRP5/6 receptor. This inhibits the Wnt signalling pathway and thereby reduces bone formation. Areas covered: Targeted deletion of the sclerostin gene has been found to enhance bone formation and fracture healing in rodent models. A number of in vivo studies have investigated the effect of sclerostin antibody on bone density with promising results. It also has an ability to promote fracture healing, screw fixation and metaphyseal bone healing in vivo. Early clinical studies have also demonstrated that it can increase bone mineral density, whilst being safe and well tolerated by patients. Expert opinion: The data support the further investigation of this agent for the promotion of fracture healing. We aim to review the current literature and present an update on the use of this agent to promote bone formation and healing.

Nerve injuries in total hip arthroplasty with a mini invasive anterior approach

Purpose Minimal invasive techniques in total hip arthroplasty (THA) have become increasingly popular during recent years. Despite much debate over the outcome of several minimal invasive techniques, complications arising from the use of anterior minimally invasive surgery (AMIS) for THA on a traction table are not well documented. Our study aims to focus on nerve damage during the AMIS procedure and the possible explanations of these injuries. Methods We reviewed all primary THAs performed with the AMIS technique using a traction table, over 5 years and recorded all intraoperative and postoperative complications up to the latest follow-up. We focused on nerve injuries and nerve function impairment following the aforementioned technique. Results Our study included 1,512 THAs performed with the AMIS technique in 2 major hip reconstruction centres (KAT General Hospital, Athens, Greece and University Hospital of Geneva, Switzerland), on 1,238 patients (985 women, 253 men; mean age 65.24 years). Mean follow-up was 29.4 months. We observed 51 cases of transient lateral femoral cutaneous nerve neuropraxia (3.37%), 4 cases of femoral nerve paralysis (3 permanent, 1 transient [0.26%]) and 1 case of permanent sciatic nerve paralysis (0.06%). No case of obturator or pudendal nerve injury was noticed. Mean age of these cases was 68.97 years. Sciatic and femoral nerve injuries were confirmed by electromyography, showing axonotmesis of the damaged nerve. Conclusions Neurological injuries are a rare but distinct complication of THAs using the AMIS technique. Possible explanations for such referred nerve injuries are direct nerve injury, extreme traction, hyperextension, extreme external rotation of the leg, use of retractors and coexisting spinal deformities. Controlled use of traction in hip extension, cautious use of retractors and potential use of dynamometers may be useful, so that neurological damage can be avoided. Further studies are needed to fully elucidate the role of the above factors in AMIS neurological complications.

Evaluation of fracture topography and bone quality in periprosthetic femoral fractures: A preliminary radiographic study of consecutive clinical data

The unique configuration of periprosthetic femoral fractures (PFFs) is a major determinant of the subsequent management. The aim of this preliminary study was to investigate potential relationships between fracture angle (FA), fracture level (FL) and bone quality of Vancouver type B PFF. The FA, FL and the canal thickness ratio (CTR) were quantified for 27 patient X-rays. The CTR is an indicator of the underlying bone quality. Relationships between these factors were studied for the whole X-ray set, for a subgroup involving fracture above the tip of the stem and for subgroups with stable and unstable implants. When considering all cases, no significant correlation was found between the FA and any other measurement. Considering only cases with unstable implants, a statistically significant correlation was found between the FA and the FL (R(2)=0.489, p=0.002). No correlation was found between FA and any other measurement for stable implants suggesting that FA could be considered as an independent factor when classifying B1 fractures. Considering all cases, a weak correlation was found between CTR and FL (R(2)=0.152, p=0.044) suggesting that fractures below the tip of the stem may indicate a lower bone quality. This preliminary study suggests that the effect of FA on the optimal management of Vancouver type B1 fractures could be considered, independent of the quality of the bone or fracture position. Furthermore, fractures around or below the tip of the stem may suggest a poor bone quality. Larger number of patients is required to confirm these initial findings.

Pediatric Monteggia fractures: a single-center study of the management of 40 patients.

Introduction: Early identification and conservative management of pediatric Monteggia fractures has been shown to correlate with good results. Nevertheless, several authors advocate more aggressive management with open reduction and internal fixation (ORIF) for unstable fractures. We herein present the experience of a tertiary pediatric hospital in the management of Monteggia fractures. Methods: Forty patients with Monteggia fractures (26 male and 14 female) were admitted and treated over a period of 20 years (1989 to 2009). The age of the patients ranged between 3 and 14 years (mean 7.5 y). On the basis of the Bado classification, 28 fractures were type I, 3 were type II, 8 type III, and 1 fracture was classified as type IV. Out of the 40 patients, 32 were managed with manipulation under anesthesia (MUA) and above-elbow plaster, whereas 8 underwent ORIF of the ulna. Results: To assess outcomes, the Bruce, Harvey, and Wilson scoring system was used. Range of movement, pain, and deformity were evaluated to class an outcome as excellent, good, fair, or poor. Patients were followed up for an average of 4.6 years (range, 1 to 7 y). All patients in the MUA group had excellent results. In the ORIF group, 8 out of 9 patients had good results. Discussion and Conclusions: According to our recorded experience, conservative management of Monteggia fractures, when indicated, results in excellent outcomes. In cases where emergency MUA fails to achieve or maintain reduction, the choice of ORIF has also demonstrated good results. Early diagnosis and management are of paramount importance as mismanaged cases demonstrate less satisfactory results. Level of Evidence: Level IV. Case series.