Unraveling the Link of Altered TGFß Signaling with Scoliotic Vertebral Malformations in Osteogenesis Imperfecta: A Comprehensive Review.

Osteogenesis Imperfecta (OI) is a genetic disorder caused by mutations in genes responsible for collagen synthesis or polypeptides involved in the formation of collagen fibers. Its predominant skeletal complication is scoliosis, impacting 25 to 80% of OI patients. Vertebral deformities of the scoliotic curves in OI include a variety of malformations such as codfish, wedged-shaped vertebrae or platyspondyly, craniocervical junction abnormalities, and lumbosacral spondylolysis and spondylolisthesis. Although the precise pathophysiology of these spinal deformities remains unclear, anomalies in bone metabolism have been implicated in the progression of scoliotic curves. Bone Mineral Density (BMD) measurements have demonstrated a significant reduction in the Z-score, indicating osteoporosis and a correlation with the advancement of scoliosis. Factors such as increased mechanical strains, joint hypermobility, lower leg length discrepancy, pelvic obliquity, spinal ligament hypermobility, or vertebrae microfractures may also contribute to the severity of scoliosis. Histological vertebral analysis has confirmed that changes in trabecular microarchitecture, associated with inadequate bone turnover, indicate generalized bone metabolic defects in OI. At the molecular level, the upregulation of Transforming Growth factor-ß (TGFß) signaling in OI can lead to disturbed bone turnover and changes in muscle mass and strength. Understanding the relationship between spinal clinical features and molecular pathways could unveil TGFß -related molecular targets, paving the way for novel therapeutic approaches in OI.

Complications Following Intraosseous Injections of Calcium Phosphate Bone Cement in Subchondroplasty.

An alternative approach to the major problem of osteoarthritis that has begun to pique the interest of researchers focuses on the pathology of the subchondral bone, its constant cross-talk with the articular cartilage, and its interaction with the joint. The presence of bone marrow lesions, detectable on MRI scans, has proven to be a cause of pain as well as a predictor of the progression of degenerative changes. Subchondroplasty is a relatively new surgical procedure for the treatment of these lesions, in which injectable calcium phosphate bone cement is infused into the affected area percutaneously, under fluoroscopic guidance. In its use as a synthetic scaffold, calcium phosphate bone cement exhibits considerable osteoconductivity, bioabsorbability, and low toxicity, thus showing great potential for restoring subchondral biomechanical properties through structural remodeling. Although published results appear quite promising, there are certain complications that the surgeon should be aware of. We reviewed the published data regarding complications of the procedure, highlighting possible causes according to these data, and suggesting safety measures. Avascular necrosis of the talus is the most reported concern. Postsurgical pain, infection, and continuous wound drainage due to bone substitute material extravasation to the joint or soft tissue are also mentioned, necessitating further standardization of the procedure. There are no reports of permanent postoperative disability or fatal outcomes.

Current Progress and Future Perspectives in Contact and Releasing-Type Antimicrobial Coatings of Orthopaedic Implants: A Systematic Review Analysis Emanated from In Vitro and In Vivo Models.

Background: Despite the expanding use of orthopedic devices and the application of strict pre- and postoperative protocols, the elimination of postoperative implant-related infections remains a challenge. Objectives: To identify and assess the in vitro and in vivo properties of antimicrobial-, silver- and iodine-based implants, as well as to present novel approaches to surface modifications of orthopedic implants. Methods: A systematic computer-based review on the development of these implants, on PubMed and Web of Science databases, was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Overall, 31 in vitro and 40 in vivo entries were evaluated. Regarding the in vitro studies, antimicrobial-based coatings were assessed in 12 entries, silver-based coatings in 10, iodine-based in 1, and novel-applied coating technologies in 8 entries. Regarding the in vivo studies, antimicrobial coatings were evaluated in 23 entries, silver-coated implants in 12, and iodine-coated in 1 entry, respectively. The application of novel coatings was studied in the rest of the cases (4). Antimicrobial efficacy was examined using different bacterial strains, and osseointegration ability and biocompatibility were examined in eukaryotic cells and different animal models, including rats, rabbits, and sheep. Conclusions: Assessment of both in vivo and in vitro studies revealed a wide antimicrobial spectrum of the coated implants, related to reduced bacterial growth, inhibition of biofilm formation, and unaffected or enhanced osseointegration, emphasizing the importance of the application of surface modification techniques as an alternative for the treatment of orthopedic implant infections in the clinical settings.

A 3D-printed load sharing implant achieved union of a 9-cm femoral segmental bone defect within three months using a hybrid Masquelet induction membrane technique. A case-report.

Case: A 30-year-old male was admitted in our hospital having an open left distal femoral fracture with 9-cm segmental bone defect and a closed proximal left tibial fracture. He was treated successfully using a Hybrid (Titanium Cage and Bone Graft) Masquelet Induction Membrane Technique (MIMT). His femoral fracture united 3-months post - operatively. The left tibia was treated initially with two locking plates. Following infection, a 3-cm tibial bone gap was treated with external fixation and conventional MIMT. The tibial fracture united 12-months post- operatively. Conclusion: The Hybrid MIMT achieved a successful healing outcome in this challenging case.

3D-printed glenoid implant reconstruction, after partial scapulectomy for malignant tumors: a case series.

PURPOSE: Glenoid tumors are extremely rare, and reconstruction remains very challenging. The aim of this study is to present the clinical and functional outcomes, of a new glenoid reconstruction method using 3-dimensional-printed implant. METHODS: Four patients with primary glenoid tumors underwent reconstruction using 3-dimensional-printed glenoid implant linked with reverse shoulder arthroplasty. We retrospectively reviewed the clinical and functional outcome, using MSTS and DASH score, as well as complications' rate. RESULTS: Wide excision was achieved in all patients. No local recurrence or distant metastasis was diagnosed at the follow-up period. The mean MSTS score was 80.5%, and DASH score was 15.2%. According to Hendersons' classification, there were no postoperative complications. CONCLUSION: The use of 3-dimensional-printed implants, can be a very reliable solution with satisfying clinical and functional outcomes for reconstruction, in patients with musculoskeletal malignancies of the glenoid. Level of evidence IV Treatment Study.

Bone mineral density, vitamin D and osseous metabolism indices in neurofibromatosis type 1: A systematic review and meta-analysis.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic autosomal neurocutaneous syndrome correlated with skeletal dysplasia and defects in the osseous microarchitecture. The physiological mechanism for the development of NF1-related bone abnormal turnover is still unclear. OBJECTIVES: A meta-analysis was performed to investigate the effects of NF1 on bone mineral density (BMD) and osseous metabolic indices in order to provide clinical evidence for the pathogenesis of the associated skeletal deformities. METHODS: A systematic literature review search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed/Medline and Web of Science databases from the date of inception of each database through to 10 September 2023. Specific inclusion and exclusion criteria were applied for the identification of studies examining the effects of NF1 on bone strength and metabolism. The Newcastle-Ottawa and Jadad scales were applied to assess the quality of the included studies. RevMan 5.3 software was used for the analysis of the data, and MedCalc was applied to examine publication bias. RESULTS: Overall, 13 studies met the inclusion criteria comprised of 5 cross-sectional, 6 case-control and 2 retrospective studies. 703 patients and 973 healthy subjects formed the NF1 and control group, respectively. The results of the meta-analysis displayed that lumbar (SMD = -3.85, 95%CI = -7.53 to -0.18, Z = 2.05, p = 0.04) and femoral (SMD = -4.78, 95%CI = -8.86 to -0.69, Z = 2.29, p = 0.02) BMD was reduced in the NF1 group. Both in children and adults the serum levels of 25 hydroxyvitamin D3 were also decreased in NF1 group, but without any statistical significance (SMD = -0.62, 95%CI = -1.34 to -0.11, Z = 1.66, p = 0.10). Serum Parathyroid hormone (PTH) (SMD = 0.73, 95%CI = 0.31 to 1.15, Z = 3.43, p = 0.0006) and C-telopeptide of type 1 collagen (CTX) (SMD = 0.82, 95%CI = 0.33 to 1.30, Z = 3.29, p = 0.001) were elevated in NF1 patients, while serum calcium (SMD = -0.10, 95%CI = -0.74 to 0.53, Z = 0.32, p = 0.75) phosphorous (SMD = 0.33, 95%CI = -0.38 to 1.05, Z = 0.92, p = 0.36), alkaline phosphatase (ALP) (SMD = -0.36, 95%CI = -0.77 to 0.05, Z = 1.71, p = 0.09), osteocalcin (SMD = 1.81, 95%CI = -0.37 to -3.98, Z = 1.63, p = 0.10) and bone formation markers (SMD = 0.28, 95%CI = -0.37 to -0.94, Z = 0.85, p = 0.39) were not. CONCLUSION: NF1 is associated with decreased BMD at the lumbar spine and femur. Taking into account that the serum levels of PTH, CTX were increased whereas the concentrations of vitamin D, calcium, phosphorous, ALP, osteocalcin and bone formation markers were not altered significantly in the NF1 patients compared with the healthy subjects, a vitamin D independent dysregulated bone cellular activity could be considered. STUDY REGISTRATION: Registered on PROSPERO (CRD42023424751).

Knee Arthrodesis with a Modular Silver-Coated Endoprosthesis for Infected Total Knee Arthroplasty with Extensive Bone Loss: A Retrospective Case-Series Study.

INTRODUCTION: Knee arthrodesis is a limb salvage intervention for persistent periprosthetic joint infection (PJI) when revision total knee arthroplasty fails. Conventional arthrodesis techniques are associated with the increased rate of complications, especially in patients with extensive bone loss and extensor tendon deficiency. METHODS: Eight patients with a modular silver-coated arthrodesis implant after failed exchange arthroplasty for infection, were retrospectively reviewed. All patients had significant bone loss, while 5 displayed extensor tendon deficiency. Survivorship, complications, leg length discrepancy, median Visual Analogue Scale (VAS) and Oxford Knee score (OKS) were evaluated. RESULTS: The median follow up was 32 months (range 24-59 months). The survivorship rate of the prosthesis was 86% during the minimum time of follow up of 24 months. In one patient recurrence of the infection was observed and above-knee amputation was performed. The median postoperative leg length discrepancy was 2.07 ± 0.67 cm. Patients were able to ambulate with mild or no pain. The median VAS and OKS was 2.14 ± 0.9 and 34.7 ± 9.3, respectively. CONCLUSIONS: The results of our study demonstrated that knee arthrodesis with a silver coated arthrodesis implant, performed for persistent PJI in patients with significant bone loss and extensor tendon deficit, provided a stable construct, allowed eradication of infection and was associated with good functional outcome.

Neuromuscular activity of the lower-extremities during running, landing and changing-of-direction movements in individuals with anterior cruciate ligament reconstruction: a review of electromyographic studies.

PURPOSE: Running, jumping/landing and cutting/change of direction (CoD) are critical components of return to sport (RTS) following anterior cruciate ligament reconstruction (ACLR), however the electromyographic (EMG) activity patterns of the operated leg during the execution of these tasks are not clear. METHODS: A systematic review was conducted to retrieve EMG studies during running, jumping/landing and cutting/(CoD) in ACLR patients. MEDLINE, PubMed, SPORTDiscus and Web of Science databases were searched from 2000 to May, 2022 using a combination of keywords and their variations: "anterior cruciate ligament reconstruction" OR "ACLR", "electromyography" OR "EMG", "running", "jumping" OR "landing", "cutting" OR "change-of-direction" OR "CoD". The search identified studies comparing EMG data during running, landing and cutting/(CoD) between the involved limb and contralateral or control limbs. Risk of bias was assessed and quantitative analyses using effect sizes were performed. RESULTS: Thirty two studies met the inclusion criteria. Seventy five percent (24/32) of the studies reported altered EMG activity pattern of the ACLR leg during running, jumping/landing and cutting/(CoD) when compared with either the healthy control leg or the contra-lateral leg. Twelve studies showed decreased, delayed or earlier onset and delayed peak in quadriceps EMG activity with small to large effect sizes and 9 studies showed increased, delayed or earlier onset and delayed peak in hamstrings EMG activity with small to large effect sizes. Four studies showed a "hamstrings-dominant" strategy i.e. decreased quadriceps coupled with increased hamstrings EMG activity in both running and jumping/landing irrespective of graft type. One study reported that on the grounds of decreased quadriceps activity, lower hamstrings EMG activity was predictive of ipsilateral re-injury in ACLR patients. CONCLUSION: This systematic review of Level III evidence showed that the ACLR leg displays decreased quadriceps or increased hamstrings EMG activity or both despite RTS. Simultaneous decreased quadriceps and increased hamstrings EMG activity was shown for both running and jumping/landing. From a clinical perspective this "hamstrings dominant" strategy can serve as a protective mechanism against graft re-injury. LEVEL OF EVIDENCE: III.

Impact of Preoperative Quality of Life and Related Factors on the Development of Surgical Site Infections Following Primary Total Joint Arthroplasty: A Prospective Case-Control Study with a Five-Year Follow-Up.

Introduction: As surgical site infections (SSIs) after joint arthroplasty contribute to increased morbidity and mortality, they require further surgical intervention, prolonged hospitalisation, and antimicrobial treatment. The aim of our study is to examine the association between preoperative quality of life (QoL) and other predictive factors on the development of SSIs after primary arthroplasty. Methods: This is a prospective study that enrolled 56 patients with hip and knee primary osteoarthritis who underwent joint replacement. Data were collected from January to March 2017, including patient demographic characteristics, comorbidities, laboratory results, and perioperative clinical data. The patients' QoL was evaluated preoperatively by applying the knee injury and osteoarthritis outcome score (KOOS) and the hip disability and osteoarthritis outcome score (HOOS) for total knee replacement (TKR) and total hip replacement (THR), respectively. A 5-year follow-up was conducted to assess the clinical status of the patients. Results: 66.1% of patients underwent TKR, with 4.9 ± 1.2 days of hospitalisation, 16% of them required autologous blood transfusion, while 33.9% of patients were treated with THR, with 5.7 ± 1 days hospitalisation and 36.8 of them required this type of transfusion. 16 patients were diagnosed with SSIs, with the older of them (>65 years old) presenting lower probability (odds ratio: 0.13, 95% CI: 0.03-0.62) requiring treatment with additional antibiotics, while revision surgery was performed in 3 of these cases, following periprosthetic joint infection (PJI). Overall preoperative QoL was not statistically associated with SSIs, but low QoL scores were associated with higher rates of SSIs and increased levels of postoperative pain (p = 0.009 < 0.05). Conclusions: The duration of each operation (>90 min), the length of hospitalisation (>4 days), and the presence of comorbidities including hypothyroidism and recurrent urinary tract infections were associated with a high risk for SSIs following arthroplasties. On the contrary, this study revealed no association between other comorbidities, including heart coronary disease, hypertension, and diabetes mellitus, with close monitoring of plasma glucose and SSIs. Moreover, the younger the patients, the more likely they were to require treatment with antibiotics. Overall, high QoL index scores were mainly accompanied by low rates of postoperative SSIs and pain.

Subchondral Bone Cyst Development in Osteoarthritis: From Pathophysiology to Bone Microarchitecture Changes and Clinical Implementations.

Osteoarthritis is a degenerative joint disease affecting middle-aged and elderly patients. It mainly involves weight-bearing joints such as the hip, knee and spine as well as the basilar joint of the thumb, causing dysfunction and painful symptoms. Often, joint arthritis is accompanied by cartilage defects, joint space narrowing, osteophytes, bone sclerosis and subchondral bone cysts (SBC). The aim of the present study was to explore the pathophysiology responsible for the development of SBCs as well as the association between SBCs and disease progress, the level of clinical symptoms and their impact on postoperative outcomes and risk of possible complications following joint replacements if left untreated. A literature review on PubMed articles was conducted to retrieve and evaluate all available evidence related to the main objective mentioned above. A few theories have been put forth to explain the formation process of SBCs. These involve MMPs secretion, angiogenesis, and enhanced bone turnover as a biological response to abnormal mechanical loads causing repeated injuries on cartilage and subchondral tissue during the development of arthritis. However, the application of novel therapeutics, celecoxib-coated microspheres, local administration of IGF-1 and activated chondrocytes following surgical debridement of SBCs hinders the expansion of SBCs and prevents the progression of osteoarthritis.

Milder impact of the COVID-19 pandemic on the practice of orthopaedic surgery in Greece and Cyprus than other European countries.

PURPOSE: The aim of this study was to highlight the impact of the COVID-19 pandemic on the practice of orthopaedics in Greece and Cyprus. METHODS: The survey used the online questionnaire from AGA (Gesellschaft für Arthroskopie und Gelenkchirurgie; Society for Arthroscopy and Joint Surgery) to facilitate the comparison between different European countries. The questionnaire was distributed online to members of the HAOST (Hellenic Association of Orthopaedic Surgery and Trauma), the ΟΤΑΜΑΤ (Orthopaedic and Trauma Association of Macedonia and Thrace) and the CAOST (Cypriot Association of Orthopaedic Surgery and Trauma). The questionnaire consisted of 29 questions, which included demographic data, questions on the impact of the pandemic on the practice of orthopaedic surgery and questions on the impact on the personal and family life of orthopaedic surgeons. RESULTS: The questionnaire was sent to 1350 orthopaedic surgeons in Greece and Cyprus, 303 of whom responded (response rate 22.44%). 11.2% of the participants reported cancellation of overall orthopaedic procedures. According to 35.6-49.8% of the participants, arthroscopic procedures were continued. As regards elective primary arthroplasties, 35.3% of the participants reported that these continued to be performed at their hospitals. Post-operative follow-ups as well as physiotherapy were affected by the pandemic, and changes were also observed in the habits of orthopaedic surgeons in their personal and family lives. CONCLUSION: The orthopaedic service in Greece and Cyprus decreased during the first wave of the COVID-19 pandemic. Arthroscopic procedures and total joint replacements decreased significantly, but not to the same extent as in other countries. Health systems were not fully prepared for the first wave of the pandemic and the various countries took social measures at different times and to different extents. Thus, studying the impact of the pandemic on the practice of orthopaedic surgery in different countries can help health systems to better prepare for future pandemics; public health can then be shielded and hospitals can continue to provide high-quality orthopaedic care. LEVEL OF EVIDENCE: Level V.

Point-of-Care Orthopedic Oncology Device Development.

BACKGROUND: The triad of 3D design, 3D printing, and xReality technologies is explored and exploited to collaboratively realize patient-specific products in a timely manner with an emphasis on designs with meta-(bio)materials. METHODS: A case study on pelvic reconstruction after oncological resection (osteosarcoma) was selected and conducted to evaluate the applicability and performance of an inter-epistemic workflow and the feasibility and potential of 3D technologies for modeling, optimizing, and materializing individualized orthopedic devices at the point of care (PoC). RESULTS: Image-based diagnosis and treatment at the PoC can be readily deployed to develop orthopedic devices for pre-operative planning, training, intra-operative navigation, and bone substitution. CONCLUSIONS: Inter-epistemic symbiosis between orthopedic surgeons and (bio)mechanical engineers at the PoC, fostered by appropriate quality management systems and end-to-end workflows under suitable scientifically amalgamated synergies, could maximize the potential benefits. However, increased awareness is recommended to explore and exploit the full potential of 3D technologies at the PoC to deliver medical devices with greater customization, innovation in design, cost-effectiveness, and high quality.

Hypophosphatemic osteomalacia in neurofibromatosis 1 associated with intracranial gliomas and congenital renal agenesis: A rare case report and review of the literature.

Introduction: Neurofibromatosis Type 1 (Nf1), also termed von Recklinghausen disease, is a rare autosomal dominant genetic disorder accompanied by several osseous and skeletal manifestations. In NF, hypophosphatemia linked to secondary hyperparathyroidism due to Vitamin D deficiency and low calcium intake has been reported as a risk factor for low bone mass density (BMD), but reports of NF1 associated oncogenic hypophosphatemic osteomalacia (HO) are extremely rare. Case Report: We report a patient with NF1 associated with intracranial low-grade gliomas and congenital renal agenesis suffering from HO. Bone defects and deformities such as generalized bone pains located in feet, ankles and lower limbs, thoracic scoliosis, mild bowing of long bones of lower limbs, stress fractures, and old fractures as well as with altered bone metabolic serum markers were present. After 8 weeks of follow-up, it was observed that the combination of oral administration of phosphate and Vitamin D improved her medical symptoms without significant changes in phosphate levels or BMD. Conclusion: Although renal agenesis is not correlated with hypophosphatemia, the coexistence of NF1, renal congenital deformities, and low-grade gliomas may contribute to disease severity. Conventional treatment with high doses of oral calcitriol associated with phosphate is efficient to improve the clinical and laboratory symptoms of the disease.

Prosthetic Reconstruction of the Shoulder After Resection of Proximal Humerus Bone Tumor.

Prosthetic reconstruction after wide resection of tumors of the proximal humerus presents a unique challenge. The shoulder is a complex articulation, and patients have high expectations for postoperative function. The goal of this study is to compare functional outcomes, oncologic outcomes, and complication rates for 2 reconstructive methods. Forty patients with proximal humeral tumors were reviewed retrospectively. Proximal humeral endoprosthesis (PHE) was used for 21 patients, and reverse shoulder arthroplasty (RSA) was used for 19 patients. Clinical results, oncologic outcomes, and complication rates were assessed. The functional outcomes of the patients were assessed with the Musculoskeletal Tumor Society scoring system (MSTS), the shortened version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, and shoulder range of motion. The mean follow-up was 62±15 months. Shoulder dislocations occurred among 8 patients with PHE and 1 patient with RSA (P=.021). The other complication rates were similar for the 2 groups (P<.05). At the latest follow-up, the mean MSTS score was 68±10.3 for those with PHE and 76±7.7 for the patients with RSA (P=.72). However, the QuickDASH score was significantly better (P=.031) for those with RSA (mean, 19±6.3) compared with patients with PHE (mean, 30±4.8). Additionally, shoulder active abduction and forward flexion were significantly greater for the RSA group (P=.04 and P=.03, respectively). Five patients had local recurrence. Prosthetic reconstruction after oncologic re-section of the proximal humerus is associated with significant limitation of shoulder range of motion and a high rate of revision surgery. However, in this study, RSA was associated with fewer dislocations, improved Quick-DASH score, and greater abduction and forward flexion compared with PHE. [Orthopedics. 2022;45(6):e335-e341.].

Sonication of revised hip and knee prostheses detects occult infections, improves clinical outcomes and prevents re - revisions. A case series study.

Introduction: Periprosthetic joint infection (PJI) is a devastating complication occurring in 1-2% of primary and up to 10% of revised total hip and knee arthroplasties (THA and TKA) impairing patient's quality of life. Occult infections are underdiagnosed, sub-treated and sub-clinically experienced by patients. This study aimed to correlate patients' clinical outcomes with early antibiotic treatment based on use or non-use of a sonication technique on explanted prostheses. Methods: 33 patients with revised THA or TKA were retrospectively evaluated. Clinical outcomes were assessed via Oxford hip or knee scores, and correlated with administration or not of antibiotic treatment based on sonication results. Results: According to laboratory findings the patients were divided in the following three groups: 1. Septic loosening (conventional cultures and/or sonication positive), 2. Aseptic loosening (conventional cultures and sonication negative) and 3. Occult loosening (conventional cultures negative, sonication not performed). The average Oxford score was poor (27.9/60) for the septic, excellent (43.8/60) for the aseptic and intermediate (37.7/60) for the occult group. Additionally, conventional cultures were negative, but sonication-positive, in 6 individuals with patient-related risk factors (male gender, BMI > 30 kg/m2, diabetes, hypertension, steroids and rheumatoid arthritis). Conclusions: Sonication represents a valuable diagnostic technique to guide administration of effective antibiotic treatment for patients, especially for detection of persistent post-revision occult infections. We recommend the systematic investigation of revised prostheses with a sonication technique, but especially in cases with risk factors for infection who it is suspected may have occult loosening.

Doxycycline inhibits the progression of metastases in early-stage osteosarcoma by downregulating the expression of MMPs, VEGF and ezrin at primary sites.

INTRODUCTION: Osteosarcoma (OS) is the most common primary osseous malignant tumour, with high propensity to metastasise in lungs. Pulmonary micro-metastases are present in up to 80% of patients at initial diagnosis and they are associated with significantly worse prognosis. Doxycycline (Dox) is a synthetic tetracycline that has been shown to have anti-cancer properties in vitro and in vivo, and inhibit angiogenesis - effects that may prove beneficial for several types of cancer. The aim of the present work was to study how Dox affects OS cell growth in vitro and in vivo and OS-driven pulmonary metastasis in vivo. METHODS: In vitro, the effect of Dox was measured in MG-63 and 143B human OS cell viability, apoptosis, invasion and migration. In vivo, highly metastatic 143B cells were orthotopically implanted into the tibia of SCID mice. The tumour growth and pulmonary metastases between Dox treated and untreated, non-amputated and early amputated xenografts were examined. RESULTS: In vitro, Dox decreased viability, inhibited invasion, migration, and induced the apoptosis of OS cells. In vivo, Dox significantly enhanced tumour necrosis at primary OS sites, similarly to its in vitro effect, and downregulated the expression of Ki67, MMP2, MMP9, VEGFA and ezrin. It also decreased circulating VEGFA and MMP9 protein levels, in line with the decreased metastatic burden in Dox-treated mice (non-amputated and early-amputated). CONCLUSIONS: Reprofiling of Dox can prevent the evolvement of pulmonary micro-metastases to clinically detectable macro-metastases and suppress the lethal progress of OS by inhibiting the expression of MMPs, VEGFA and ezrin at primary sites.

Three-dimensional Printed Endoprosthesis for Reconstruction of the Distal Tibia and Ankle Joint After Tumor Resection.

Below-knee amputation is the treatment of choice for distal tibia malignancies, considering the specific anatomic features of the distal leg and ankle. However, advances in imaging modalities and adjuvant therapies and improved surgical techniques have made limb salvage surgery increasingly possible. The distal tibia is an uncommon location for malignant bone tumors, and there is limited information about limb salvage and reconstruction. Currently, 3-dimensional printed implants may successfully address reconstruction challenges after tumor resection. We present a patient with high-grade osteosarcoma of the distal tibia who underwent limb salvage and distal tibia and ankle joint replacement with a 3-dimensional printed endoprosthesis. [Orthopedics. 2022;45(6):e348-e352.].

Oncological and Functional Outcomes after Hemicortical Resection and Biological Reconstruction Using Allograft for Parosteal Osteosarcoma of the Distal Femur.

Background: Parosteal osteosarcoma (PAOS) is a surface osteosarcoma. Treatment options include wide excision and endoprosthetic or allograft. However, due to the low local recurrence and metastasis rate, when it appears in the posterior surface of the distal femur, the lesion can be managed with hemicortical wide resection and biological reconstruction with hemicortical allograft. The purpose of this study is to evaluate the oncological and functional outcomes of patients with parosteal osteosarcoma (PAOS) of the posterior cortex of the distal femur who underwent biological reconstruction after hemicortical resection. Methods: Eleven patients who underwent wide tumor resection and defect reconstruction of the posterior surface of the distal femur using hemicortical allograft were retrospectively studied. Local recurrence, metastasis, complications, and the functional outcome using the Musculoskeletal Tumor Society (MSTS) scoring system were evaluated. Results: The average postoperative follow-up period was 53.64 months (range, 30 to 84 months). At the latest follow-up, all patients had no evidence of disease without metastases. One patient with local recurrence underwent revision surgery with fibula autograft reconstruction. The mean MSTS score was 93.45 ± 3.56. Conclusions: Treatment of patients with PAOS of the posterior aspect of the distal femur with hemicortical resection and allograft reconstruction has satisfactory oncological and functional outcome and low complication rates.

Sex, but not age and bone mass index positively impact on the development of osteochondral micro-defects and the accompanying cellular alterations during osteoarthritis progression.

Background: Osteoarthritis (ΟΑ) is characterized by cartilage breakdown and subchondral sclerosis. Micro-fractures of the calcified tissues have been, also, detected, but their exact role has not been elucidated yet. This study was to examine the frequency of cracks during OA progression and to correlate them with the underlying cellular modifications and matrix metalloproteinase-2 (MMP-2) expression using histological/immunohistological methods. Methods: Overall, 20 patients and 3 controls (9 specimens per patient), aged 60-89 years, diagnosed with hip/knee OA were included. The development of cracks was examined in 138 sections, whereas the expression of MMP-2 was examined in 69 additional sections. Results: Based on Mankin score, three groups of OA severity were analyzed: Group I (mild) was constituted of sections with score 1-5 while Groups II (moderate) and III (severe) with score 6-7 and greater or equal to 8, respectively. Demographic characteristics did not reveal any association between the number of microdefects and age or body mass index (BMI). Cartilage micro-cracks were increased during moderate and severe OA, while bone cracks were increased during mild and severe OA. In knee OA, cartilage cracks were not correlated with Mankin score, whereas in hip OA they appeared association with severity score. Bone cracks were positively correlated with matrix apoptotic osteocytes and osteoblastic cells, but not with osteoclasts. MMP-2 immunostaining was increasing by OA severity in the osteochondral unit. Similarly, MMP-2 was expressed on the microcracks' wall mainly in Group III. Conclusion: Our data displayed that bone cracks during primary OA stages, represent an early adaptative mechanism aiming to maintain cartilage integrity. Accumulation of bone defects and concomitant increase of apoptotic osteocytes activated an abnormal remodeling due to osteoblastic activity, in which MMP-2 played a pivotal role, leading to subchondral sclerosis promoting further osteochondral deformities.

Current Aspects on the Pathophysiology of Bone Metabolic Defects during Progression of Scoliosis in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1), which is the most common phacomatoses, is an autosomal dominant disorder characterized by clinical presentations in various tissues and organs, such as the skin, eyes and nervous and skeletal systems. The musculoskeletal implications of NF1 include a variety of deformities, including scoliosis, kyphoscoliosis, spondylolistheses, congenital bony bowing, pseudarthrosis and bone dysplasia. Scoliosis is the most common skeletal problem, affecting 10-30% of NF1 patients. Although the pathophysiology of spinal deformities has not been elucidated yet, defects in bone metabolism have been implicated in the progression of scoliotic curves. Measurements of Bone Mineral Density (BMD) in the lumbar spine by using dual energy absorptiometry (DXA) and quantitative computer tomography (QCT) have demonstrated a marked reduction in Z-score and osteoporosis. Additionally, serum bone metabolic markers, such as vitamin D, calcium, phosphorus, osteocalcin and alkaline phosphatase, have been found to be abnormal. Intraoperative and histological vertebral analysis confirmed that alterations of the trabecular microarchitecture are associated with inadequate bone turnover, indicating generalized bone metabolic defects. At the molecular level, loss of function of neurofibromin dysregulates Ras and Transforming Growth factor-ß1 (TGF-ß1) signaling and leads to altered osteoclastic proliferation, osteoblastic activity and collagen production. Correlation between clinical characteristics and molecular pathways may provide targets for novel therapeutic approaches in NF1.