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Osteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong invasiveness, rapid disease progression, and extremely high mortality rate; it is considered as a serious threat to the human health globally. The incidence of OS is common in the metaphysis of long tubular bones, but rare in the spine, pelvis, and sacrum areas; moreover, majority of the OS patients present with only a single lesion. OS has a bimodal distribution pattern, that is, its incidence peaks in the second decade of life and in late adulthood. We examine historical and current literature to present a succinct review of OS. In this review, we have discussed the types, clinical diagnosis, and modern and future treatment methods of OS. The purpose of this article is to inspire new ideas to develop more effective therapeutic options.

Osteosarcoma, one of the common malignant tumors in the skeletal system, originates in mesenchymal tissue, and the most susceptible area of occurrence is the metaphysis with its abundant blood supply. Tumors are characterized by highly malignant spindle stromal cells that can produce bone-like tissue. Most of the osteosarcoma are primary, and a few are secondary. Osteosarcoma occurs primarily in children and adolescents undergoing vigorous bone growth and development. Most cases involve rapid tumor development and early blood metastasis. In recent years, research has grown in the areas of molecular biology, imaging medicine, biological materials, applied anatomy, surgical techniques, biomechanics, and comprehensive treatment of tumors. With developments in molecular biology and tissue bioengineering, treatment methods have also made great progress, especially in comprehensive limb salvage treatment, which significantly enhances the quality of life after surgery and improves the 5-year survival rate of patients with malignant tumors. This article provides a review of limb salvage, immunotherapy, gene therapy, and targeted therapy from traditional amputation to neoadjuvant chemotherapy, providing a reference for current clinical treatments for osteosarcoma.

Synthetic glucocorticoids (GCs), one of the most effective treatments for chronic inflammatory and autoimmune conditions in children, have adverse effects on the growing skeleton. GCs inhibit angiogenesis in growing bone, but the underlying mechanisms remain unclear. Here, we show that GC treatment in young mice induces vascular endothelial cell senescence in metaphysis of long bone, and that inhibition of endothelial cell senescence improves GC-impaired bone angiogenesis with coupled osteogenesis. We identify angiogenin (ANG), a ribonuclease with pro-angiogenic activity, secreted by osteoclasts as a key factor for protecting the neighboring vascular cells against senescence. ANG maintains the proliferative activity of endothelial cells through plexin-B2 (PLXNB2)-mediated transcription of ribosomal RNA (rRNA). GC treatment inhibits ANG production by suppressing osteoclast formation in metaphysis, resulting in impaired endothelial cell rRNA transcription and subsequent cellular senescence. These findings reveal the role of metaphyseal blood vessel senescence in mediating the action of GCs on growing skeleton and establish the ANG/PLXNB2 axis as a molecular basis for the osteoclast-vascular interplay in skeletal angiogenesis. Glucocorticoids (GCs) inhibit bone angiogenesis and affect bone development, but the underlying mechanisms remain unclear. Here, the authors show that GCs induce vascular cell senescence during bone development by inhibiting angiogenin secretion from osteoclasts, impairing angiogenesis via endothelial Plexin B2, resulting in unpaired bone growth.

Coupling between angiogenesis and osteogenesis has an important role in both normal bone injury repair and successful application of tissue‐engineered bone for bone defect repair. Type H blood vessels are specialized microvascular components that are closely related to the speed of bone healing. Interactions between type H endothelial cells and osteoblasts, and high expression of CD31 and EMCN render the environment surrounding these blood vessels rich in factors conducive to osteogenesis and promote the coupling of angiogenesis and osteogenesis. Type H vessels are mainly distributed in the metaphysis of bone and densely surrounded by Runx2+ and Osterix+ osteoprogenitors. Several other factors, including hypoxia‐inducible factor‐1α, Notch, platelet‐derived growth factor type BB, and slit guidance ligand 3 are involved in the coupling of type H vessel formation and osteogenesis. In this review, we summarize the identification and distribution of type H vessels and describe the mechanism for type H vessel‐mediated modulation of osteogenesis. Type H vessels provide new insights for detection of the molecular and cellular mechanisms that underlie the crosstalk between angiogenesis and osteogenesis. As a result, more feasible therapeutic approaches for treatment of bone defects by targeting type H vessels may be applied in the future. Type H vessels are mainly distributed in the metaphyseal region and sub‐periosteum and show strong positive staining for CD31 and EMCN. They are specialized microvascular components and closely related to bone healing speed through the crosstalk between angiogenesis and osteogenesis.

Background Long-lasting reconstruction after extensive resection involving peri-knee metaphysis is a challenging problem in orthopedic oncology. Various reconstruction methods have been proposed, but they are characterized by a high complication rate. The purposes of this study were to (1) assess osseointegration at the bone implant interface and correlated incidence of aseptic loosening; (2) identify complications including infection, endoprosthesis fracture, periprosthetic fracture, leg length discrepancy, and wound healing problem in this case series; and (3) evaluate the short-term function of the patient who received this personalized reconstruction system. Methods Between September 2016 and June 2018, our center treated 15 patients with malignancies arising in the femur or tibia shaft using endoprosthesis with a 3D-printed custom-made stem. Osseointegration and aseptic loosening were assessed with digital tomosynthesis. Complications were recorded by reviewing the patients’ records. The function was evaluated with the 1993 version of the Musculoskeletal Tumor Society (MSTS-93) score at a median of 42 (range, 34 to 54) months after reconstruction. Results One patient who experienced early aseptic loosening was managed with immobilization and bisphosphonates infusion. All implants were well osseointegrated at the final follow-up examination. There are two periprosthetic fractures intraoperatively. The wire was applied to assist fixation, and the fracture healed at the latest follow-up. Two patients experienced significant leg length discrepancies. The median MSTS-93 score was 26 (range, 23 to 30). Conclusions A 3D-printed custom-made ultra-short stem with a porous structure provides acceptable early outcomes in patients who received peri-knee metaphyseal reconstruction. With detailed preoperative design and precise intraoperative techniques, the reasonable initial stability benefits osseointegration to osteoconductive porous titanium, and therefore ensures short- and possibly long-term durability. Personalized adaptive endoprosthesis, careful intraoperative operation, and strict follow-up management enable effective prevention and treatment of complications. The functional results in our series were acceptable thanks to reliable fixation in the bone-endoprosthesis interface and an individualized rehabilitation program. These positive results indicate this device series can be a feasible alternative for critical bone defect reconstruction. Nevertheless, longer follow-up is required to determine whether this technique is superior to other forms of fixation.

Chronic recurrent and multifocal osteomyelitis (CRMO) is a nonsporadic autoinflammatory disorder. Currently, it is diagnosed based on clinical, radiologic, pathological, and longitudinal data. Numerous aspects should be highlighted due to increased knowledge in imaging and immunology. We emphasize the use of whole-body MRI, which is a non-invasive diagnostic strategy. A literature review was carried out on longitudinal studies. Commonly, the mean age at diagnosis is 11 years, ranging between 3 and 17. The most common sites are the long bone metaphysis, particularly femoral and tibial metaphysis. In addition, the pelvis, spine, clavicle, and mandible may be involved. In long bones, the radiologic appearance can show typical structure, mixed lytic and sclerotic, sclerotic or lytic. It is frequently metaphyseal or juxta-physeal, with hyperostosis or periosteal thickening. The involvement of the vertebral skeleton is often multifocal. Therefore, whole-body MRI is essential in identifying subclinical lesions. CRMO is a polymorphic disorder in which whole-body MRI is beneficial to demonstrate subclinical edema. Vertebral collapse requires long-term monitoring.

The multi-disciplinary approach involving imaging, multi-agent chemotherapy, meticulous surgical procedures, and careful postoperative care has facilitated an increase in the use of limb-sparing surgery for pediatric osteosarcoma. Osteosarcoma usually occurs around the metaphysis of the distal femur or proximal tibia and needs wide excision with the adjacent joint and replacement by a megaprosthesis. The recent advancement in imaging modalities and surgical techniques supports joint-preservation surgery (JPS), involving the preservation of the adjacent epiphysis, for select patients following careful assessment of the tumor margins and precise tumor excision. An advantage of this surgery is that it maintains the adjacent joint and preserves the growth of the residual epiphysis, which provides excellent limb function. Various reconstruction options are available, including allograft, tumor-devitalized autograft, vascularized fibula graft, distraction osteogenesis, and custom-made implants. However, several complications are inevitable with these options, such as loosening, non-union at the host-graft junction, infection, fracture, implant loosening, breakage, deformity, limb-length discrepancy related to the reconstruction methods, or patient growth in pediatric osteosarcoma. Surgeons should fully understand the advantages and disadvantages of this procedure. In this review, we discuss the concept of JPS, types of reconstruction methods, and current treatment outcomes. It is our opinion that the further analysis by multi-institutional setting is necessary to clarify long-term outcomes and establish global guidelines on the indications and surgical procedure for JPS.

Blood vessels are essential for bone development and metabolism. Type H vessels in bone, named after their high expression of CD31 and Endomucin (Emcn), have recently been reported to locate mainly in the metaphysis, exhibit different molecular properties and couple osteogenesis and angiogenesis. A strong correlation between type H vessels and bone metabolism is now well‐recognized. The crosstalk between type H vessels and osteoprogenitor cells is also involved in bone metabolism‐related diseases such as osteoporosis, osteoarthritis, fracture healing and bone defects. Targeting the type H vessel formation may become a new approach for managing a variety of bone diseases. This review highlighted the roles of type H vessels in bone‐related diseases and summarized the research attempts to develop targeted intervention, which will help us gain a better understanding of their potential value in clinical application.

Background:Several case series have recently described Methotrexate associated insufficiency fractures, so called Methotrexate osteopathy (MTXO)[1].Objectives:Our aim was to assess whether the continuation of Methotrexate after an insufficiency fracture impacts on future fracture risk.Methods:Retrospective single-centre case note review of patients who sustained MTXO insufficiency fractures. Cases were identified through a search of radiology reports for the term ‘insufficiency fracture’ and through direct referral to a tertiary centre of Rheumatology and Metabolic Bone Disease. Patient demographics, clinical and radiological features of fractures and bone health assessment data including DXA scans were collected. In patients who sustained a typical MTXO insufficiency fracture, we recorded all subsequent fractures and whether MTX was continued after the first insufficiency fracture or not. The impact of MTX continuation on subsequent fracture time and incidence was investigated by Kaplan–Meier analysis.Results:We identified 33 patients with characteristic MTXO lower limb insufficiency fractures. Similar to the cases described in a recent systematic review[1], the mean age at presentation with MTXO was 67 ± 9 years, most patients (97%) were women and had rheumatoid arthritis (79%). Mean MTX dose was 20 ± 5.9 mg weekly with an average treatment duration of 10.7 ± 6.2 years. Three quarter (75.8%) of patients had osteoporosis as assessed by DEXA and the mean spine T-score was -2.3 ± 1.0 and femoral neck T-score was -2.6 ± 0.9. A quarter of patients (24%) were treated with OP treatment prior to the first MTXO insufficiency fractures and the vast majority (28/31) of patients were started or continued on osteoporosis treatment after the first insufficiency fracture. Only 3 of the patients received glucocorticoids at the time of diagnosis. The described fracture sites are in line with previous reports with the metaphysis of the distal tibia (71%) and calcaneus (71%) most commonly affected. Typical radiographic features of MTXO insufficiency fractures are shown in Figure 1. After the first insufficiency fracture 21/32 patients continued MTX initially and of those who continued almost all patients (95.2%) sustained either further insufficiency (67%) or major osteoporotic (33%) fractures. Of those patients who stopped Methotrexate only 3/11 (27.3%) sustained further fractures. A Kaplan-Meier analysis (Figure 2) showed that significant more patients who continued Methotrexate after the initial insufficiency fracture sustained a further fracture over time when compared to patients who stopped Methotrexate (Log Rank test, p=0.042).Figure 1.MRI images of left ankle, sagittal view, proton density fat suppressed. Insufficiency fractures with band-like fracture line along the metaphysis of the distal tibia and a calcaneal fracture with surrounding bone marrow oedemaFigure 2.Kaplan Meier curve of subsequent fractures in patients who continued or stopped methotrexate after sustaining MTXO insufficiency fractureConclusion:Most patients who sustained MTX associated insufficiency fractures have underlying poor bone health and elevated fracture risk which seems to be significantly worsened by ongoing MTX treatment. It is important to recognise such insufficiency fractures and stop MTX to minimize future fracture risk.REFERENCES:[1] Ruffer, N., et al., Clinical features of methotrexate osteopathy in rheumatic musculoskeletal disease: A systematic review. Semin Arthritis Rheum, 2022. 52: p. 151952.Acknowledgements:NIL.Disclosure of Interests:Barbara Hauser reports personal fees from UCB, Amgen, Thornton & Ross and Gedeon-Richter and Fresenius Kabi outside the submitted work, reports grants from UCB Eli Lilly outside the submitted work, Andrew Merriman: None declared, Jon Foley: None declared, Janardhana Golla: None declared, Euan McRorie: None declared.