Osteolytic Bone Research Articles

Mechanobiological cues to bone cells during early metastasis drive later osteolysis: a computational mechanoregulation framework prediction

Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation, but also by resorbing bone matrix (osteolysis) that releases further stimulatory factors for tumour growth in a vicious cycle. Changes in the local mechanical environment of bone tissue occur during early metastasis, which might activate mechanobiological responses by resident bone cells (osteocytes) to activate resorption (osteoclasts) and thereby contribute to tumour invasion. The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by (a) implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis (3-weeks after tumour inoculation) and then (b) applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis. We implemented a global resorption rate derived from an experimental model, but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region, the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model. Moreover, the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks. Thus, we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.

Computational Shape Design Optimization of Femoral Implants: Towards Efficient Forging Manufacturing

Total hip replacement is one of the most successful orthopedic operations in modern times. Osteolysis of the femur bone results in implant loosening and failure due to improper loading. To reduce induced stress, enhance load transfer, and minimize stress, the use of Ti-6Al-4V alloy in bone implants was investigated. The objective of this study was to perform a three-dimensional finite element analysis (FEA) of the femoral stem to optimize its shape and analyze the developed deformations and stresses under operational loads. In addition, the challenges associated with the manufacturing optimization of the femoral stem using large strain-based finite element modeling were addressed. The numerical findings showed that the optimized femoral stem using Ti-6Al-4V alloy under the normal daily activities of a person presented a strains distribution that promote uniform load transfer from the proximal to the distal area, and provided a mass reduction of 26%. The stress distribution was found to range from 700 to 0.2 MPa in the critical neck area of the implant. The developed computational tool allows for improved customized designs that lower the risk of prosthesis loss due to stress shielding.

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50 % cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20–900 μm3 range compared to control samples. In the larger lacunae 900–3000 μm3 range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes, and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.

Cutibacterium acnes invades submicron osteocyte lacuno-canalicular networks following implant-associated osteomyelitis.

Cutibacterium acnes, part of normal skin flora, is increasingly recognized as an opportunistic pathogen capable of causing chronic prosthetic joint infections (PJI) associated with total hip and knee arthroplasty. However, there is a paucity of literature examining the pathogenesis of C. acnes during PJI. To study this, we developed an implant-associated osteomyelitis murine model in which 8-10-week-old C57BL6 mice were subjected to transtibial implantation of titanium or stainless-steel L-shaped pins contaminated with C. acnes. Postsurgery, mice were killed on Days 14 and 28 for terminal assessments of (1) bacterial load in bone, implant, and internal organs (heart, spleen, kidney, and liver), (2) bone osteolysis (micro-CT), (3) abscess formation (histology), and (4) systematic electron microscopy (EM). In vitro scanning EM (SEM) confirmed that C. acnes can form biofilms on stainless-steel and titanium implants. In mice, C. acnes could persist for 28 days in the tibia. Also, we observed C. acnes dissemination to internal organs. C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation compared to Staphylococcus aureus infections. Importantly, transmission EM (TEM) investigation revealed the presence of C. acnes within canaliculi, demonstrating that C. acnes can invade the osteocyte lacuno-canalicular networks (OLCN) within bone. Our preliminary pilot study, for the first time, revealed that the OLCN in bone can be a reservoir for C. acnes and potentially provides a novel mechanism of why C. acnes chronic implant-associated bone infections are difficult to treat.

Scleroderma: oral, maxillofacial and radiographic manifestations for dental practitioners.

Scleroderma is an autoimmune condition of unknown aetiology with a range of manifestations, which can be limited to the skin or can extend to be multisystemic. It is characterised by fibrosis, microangiopathy and dysregulation of the immune system and commonly affects the oral cavity. Frequent oral and maxillofacial features include fibrosis of the face, circumoral furrows and reduced oral aperture. Radiographic findings are often incidental, including uniform, asymptomatic periodontal ligament space widening of teeth and osteolysis of bone at muscular attachments. The oral and maxillofacial manifestations significantly contribute to its disease burden and are often overlooked and undertreated as their treatment can be limited due to their challenging rheumatological care. Given the complexity of the condition and its multisystemic impacts, better co-operation between dentists and rheumatologists may help improve this patient cohort's quality of life. This clinical article aims to better equip dentists to identify features of scleroderma and manage the day-to-day oro-facial manifestations.

Clinical results and computed tomography analysis of intuitive shoulder arthroplasty (ISA) stemless at a minimum follow-up of 2 years

IntroductionThe utilization of stemless anatomic total shoulder arthroplasty is on the rise. Epiphyseal fixation leads to radiological bone remodeling, which has been reported to exceed 40% in certain studies series. The aim of this study was to present the clinical and radiological outcomes of a stemless implant with asymmetric central epiphyseal fixation at an average follow-up of 31 months. MaterialsThis retrospective multicenter study examined prospective data of patients undergoing total anatomic arthroplasty with ISA Stemless implant and followed up at least 2 years. Clinical assessment included preoperative and final follow-up measurements of active range of motion (ROM), Constant score, and Subjective Shoulder Value (SSV). Anatomical epiphyseal reconstruction and bone remodeling at the 2-year follow-up were assessed by standardized Computed Tomography Scanner (CT scan). Statistical analysis employed unpaired Student's t-test or chi-squared test depending on the variable type, conducted using EasyMedStat software (version 3.22; www.easymedstat.com). ResultsFifty patients (mean age 68 years, 62% females) were enrolled, with an average follow-up of 31 months (24-44). Primary osteoarthritis (68%) with type A glenoid (78%) was the prevailing indication. The mean Constant score and SSV improved significantly from 38 ± 11 to 76 ± 11 (p<0.001) and from 31% ± 16 to 88% ± 15 (p<0.001) respectively at the last follow-up. Forward elevation, external rotation and internal rotation ROM increased by 39° ± 42, 28° ± 21 and 3,2 ± 2,5 points respectively, surpassing the Minimally Clinically Important Difference (MCID) after total shoulder arthroplasty. No revisions were necessary. CT scans identified 30% osteolysis in the posterior-medial calcar region, devoid of clinical repercussions. No risk factors were associated with bone osteolysis. ConclusionAt an average follow-up of 31 months, ISA Stemless implant provided favorable clinical results. CT analysis revealed osteolysis-like remodeling in the posterior-medial zone of the calcar (30%), without decline in clinical outcomes and revisions. Long-term follow-up studies are mandated to evaluate whether osteolysis is associated with negative consequences.

#1496 High levels of sclerostin promote bone resorption and changes and mineral metabolism

Abstract Background and Aims The physiological function of sclerostin (SOST) remains unknown. It is known that SOST is produced in osteocytes and functions as an inhibitor of the Wnt/β-catenin pathway. Similarly, it is well-established that low levels of SOST lead to bone alterations affecting cortical bone, resulting in osteopetrosis and reduced calciuria. High levels of SOST are associated with osteoporosis. In this study, we aimed to investigate the impact of three elevated doses of SOST on cortical, trabecular, and subchondral bone, as well as its relationship with other parameters of mineral metabolism. Method Bone histomorphometry, mCT, immunohistochemistry, and analysis of mineral metabolism parameters revealed that high doses of SOST over a 14-day period led to a reduction in trabecular bone volume due to a significant increase in bone resorption through the direct activation of osteoclastogenesis. Results Bone resorption, as measured by TRAP activity, was higher in trabecular, cortical, and subchondral bone. Similarly, high doses of SOST increased the number of hypertrophic chondrocytes, consequently expanding the growth plate area. Cortically, positive TRAP staining was observed, suggesting osteocytic osteolysis and trabecularization of cortical bone. The increased bone resorption resulted in a substantial rise in urinary excretion of phosphorus and calcium, accompanied by elevated levels of FGF23 and a significant decrease in PTH. Conclusion The findings suggest that elevated levels of SOST promote bone resorption through the activation of osteoclasts and the generation of osteocytic osteolysis. The increase in calcium and phosphorus levels led to changes in mineral metabolism, indicating a close relationship between SOST and other mineral metabolism parameters.

Estradiol induces bone osteolysis in triple-negative breast cancer via its membrane-associated receptor ERα36.

Triple-negative breast cancer (TNBC) is thought to be an estradiol-independent, hormone therapy-resistant cancer because of lack of estrogen receptor alpha 66 (ERα66). We identified a membrane-bound splice variant, ERα36, in TNBC cells that responds to estrogen (E2) and may contribute to bone osteolysis. We demonstrated that the MDA-MB-231 TNBC cell line, which expresses ERα36 similarly to MCF7 cells, is responsive to E2, forming osteolytic tumors in vivo. MDA-MB-231 cells activate osteoclasts in a paracrine manner. Conditioned media (CM) from MDA-MB-231 cells treated with bovine serum albumin-bound E2 (E2-BSA) increased activation of human osteoclast precursor cells; this was blocked by addition of anti-ERα36 antibody to the MDA-MB-231 cultures. Osteoclast activation and bone resorption genes were elevated in RAW 264.7 murine macrophages following treatment with E2-BSA-stimulated MDA-MB-231 CM. E2 and E2-BSA increased phospholipase C (PLC) and protein kinase C (PKC) activity in MDA-MB-231 cells. To examine the role of ERα36 signaling in bone osteolysis in TNBC, we used our bone-cancer interface mouse model in female athymic homozygous Foxn1nu mice. Mice with MDA-MB-231 tumors and treated with tamoxifen (TAM), E2, or TAM/E2 exhibited increased osteolysis, cortical bone breakdown, pathologic fracture, and tumor volume; the combined E2/TAM group also had reduced bone volume. These results suggest that E2 increased osteolytic lesions in TNBC through a membrane-mediated PLC/PKC pathway involving ERα36, which was enhanced by TAM, demonstrating the role of ERα36 and its membrane-associated signaling pathway in bone tumors. This work suggests that ERα36 may be a potential therapeutic target in patients with TNBC.

Imaging in psoriatic arthritis: established methods and emerging techniques.

Psoriatic arthritis (PsA) is a heterogeneous, chronic, inflammatory musculoskeletal disease that can lead to peripheral and axial damage and loss of function. A clear difference between PsA and other forms of inflammatory arthritis is the different forms of bone remodeling seen in PSA which incorporates not only increased bone resorption with bone erosions, osteolysis, and loss of bone mineral density but also increased bone formation with periostitis, syndesmophytes, enthesiophytes, and ankylosis. PsA, if diagnosed late, will lead to significant structural damage, the most severe form of which is known as arthritis mutilans, and loss of physical function. Imaging plays a crucial role in diagnosing and monitoring both peripheral and axial conditions associated with PsA. Radiography is currently the main modality used to monitor structural damage in PsA though commonly used scoring systems do not include bony proliferation as a criterion. Besides, radiography is limited in determining the presence and cause of periarticular soft tissue thickening, which may arise from tendinosis, tenosynovitis, synovial proliferation, bursitis, or enthesitis. Recently, much more attention has been paid to determining the imaging characteristics of PsA, which enables more precise identification of disease and severity assessment. Newer imaging technologies also enable variations in normal bone microstructure to be distinguished from disease-related abnormality. This review discusses the current state of innovative imaging modalities in PsA, specifically concentrating on their roles in PsA diagnosis and treatment, improving the early detection of PsA, and identifying patients with skin psoriasis at risk of developing psoriatic arthritis.

Epistaxis and Facial Swelling Due to Nasal Blastomycosis in a Cat.

A 5 yr old castrated male domestic longhair was examined because of left-sided facial swelling and epistaxis. Head computed tomography with contrast identified a mass within the left nasal cavity and multifocal regions of nasal bone osteolysis. Histopathology of nasal mass biopsies and cytology of the facial swelling revealed pyogranulomatous inflammation due to Blastomyces dermatitidis. The cat experienced resolution of clinical signs following 8 mo of treatment with itraconazole. Although rare, clinicians should include blastomycosis on the differential diagnoses list of infectious causes for feline nasal disease if within an endemic area.

Application of photocured hydrogels in the treatment of bone defect diseases

Photocured hydrogels are materials with great potential, offering a novel approach in the treatment of bone defects. They exhibit excellent biocompatibility, tunable degradation characteristics, and the ability to incorporate cells and growth factors. This paper explores the mechanisms and advantages of photocured hydrogel applications in the treatment of bone defects, focusing on bone formation promotion, drug-loading and antimicrobial properties, and enhancement of vascularization in the surrounding tissues. Research indicates that photocured hydrogels can serve as scaffolds, drug delivery systems, and tissue engineering materials, promoting bone cell proliferation, osteogenic differentiation, inhibiting bone resorption and osteolysis, fostering vascularization, and providing drug-loading antimicrobial effects. Nevertheless, the application of photocured hydrogels in the treatment of bone defect diseases faces challenges, such as long-term stability and interface adaptability. Further research and development are required to overcome these challenges, facilitating the widespread clinical use of photocured hydrogels and improving the treatment outcomes and quality of life for patients with bone defects.

Aminooxyacetic acid hemihydrochloride leads to decreased intracellular ATP levels and altered cell cycle of prostate cancer cells by suppressing energy metabolism

The second most common cancer among men is prostate cancer, which is also the fifth leading reason for male cancer deaths worldwide. Bone metastases are the main factor affecting the prognosis of prostate cancer. Consequently, antitumor and anti-prostate cancer-induced bone destruction medicines are urgently needed. We previously discovered that aminooxyacetic acid hemihydrochloride (AOAA) suppressed bone resorption and osteoclast growth by decreasing adenosine triphosphate (ATP) production and limiting oxidative phosphorylation (OXPHOS). Here, we evaluated the impacts of AOAA on prostate cancer RM-1 cells in vitro. It’s found that AOAA significantly inhibited cell proliferation, migration, and invasiveness, decreased ATP levels, increased ROS, halted the cell cycle phase, and triggered apoptosis. AOAA also decreased mitochondrial membrane potential and the ability to uptake glucose, suggesting that the antitumor effects of AOAA were expressed through the inhibition of OXPHOS and glycolysis. Furthermore, we assessed the effects of AOAA in vivo using a prostate cancer-induced bone osteolysis mice model. AOAA also delayed tumor growth and bone destruction in vivo. On the whole, our findings imply that AOAA may potentially have therapeutic effects on prostate cancer and prostate cancer-induced osteolysis.

A new osteogenic protein isolated from Dioscorea opposita Thunb accelerates bone defect healing through the mTOR signaling axis.

Delayed bone defect repairs lead to severe health and socioeconomic impacts on patients. Hence, there are increasing demands for medical interventions to promote bone defect healing. Recombinant proteins such as BMP-2 have been recognized as one of the powerful osteogenic substances that promote mesenchymal stem cells (MSCs) to osteoblast differentiation and are widely applied clinically for bone defect repairs. However, recent reports show that BMP-2 treatment has been associated with clinical adverse side effects such as ectopic bone formation, osteolysis and stimulation of inflammation. Here, we have identified one new osteogenic protein, named 'HKUOT-S2' protein, from Dioscorea opposita Thunb. Using the bone defect model, we have shown that the HKUOT-S2 protein can accelerate bone defect repair by activating the mTOR signaling axis of MSCs-derived osteoblasts and increasing osteoblastic biomineralization. The HKUOT-S2 protein can also modulate the transcriptomic changes of macrophages, stem cells, and osteoblasts, thereby enhancing the crosstalk between the polarized macrophages and MSCs-osteoblast differentiation to facilitate osteogenesis. Furthermore, this protein had no toxic effects in vivo. We have also identified HKUOT-S2 peptide sequence TKSSLPGQTK as a functional osteogenic unit that can promote osteoblast differentiation in vitro. The HKUOT-S2 protein with robust osteogenic activity could be a potential alternative osteoanabolic agent for promoting osteogenesis and bone defect repairs. We believe that the HKUOT-S2 protein may potentially be applied clinically as a new class of osteogenic agent for bone defect healing.

Compressed Sensing SEMAC MRI of Hip, Knee, and Ankle Arthroplasty Implants: A 1.5-T and 3-T Intrapatient Performance Comparison for Diagnosing Periprosthetic Abnormalities.

Background. The utility of 3-T MRI for diagnosing joint disorders is established, but its performance for diagnosing abnormalities around arthroplasty implants is unclear. Objective. This study compared 1.5-T and 3-T compressed sensing slice encoding for metal artifact correction (CS-SEMAC) MRI for diagnosing periprosthetic abnormalities around hip, knee, and ankle arthroplasty implants. Methods. Forty-five participants (mean age ± SD, 71 ± 14 years; 26 women, 19 men) with symptomatic lower extremity arthroplasty (hip, knee, and ankle, 15 each) prospectively underwent consecutive 1.5- and 3-T MRI with intermediate-weighted (IW) and STIR CS-SEMAC sequences. Using a Likert scale, three radiologists evaluated presence or absence of periprosthetic abnormalities, including bone marrow edema-like signal, osteolysis, stress reaction/fracture, synovitis, tendon abnormalities and collections, image quality, and visibility of anatomic structures. Statistical analysis included nonparametric comparison and interchangeability testing. Results. For diagnosing periprosthetic abnormalities, 1.5-T and 3-T CS-SEMAC MRI were interchangeable. Across all three joints, 3 T produced lower noise than 1.5 T (median IW/STIR score at 3 T vs 1.5 T, 4/4 [range, 2-5/3-5] vs 3/3 [2-5/2-4]; p < .01 for both), sharper edges (4/4 [both 2-5] vs 3/3 [2-4/2-5]; p < .02/p < .05), and more effective metal artifact reduction (4/4 [3-5/2-5] vs 4/4 [both 3-5]; p < .02/p = .72). Agreement was moderate to substantial for image contrast (IW/STIR, 0.66/0.54 [95% CI, 0.41-0.91/0.29-0.80]; p = .58/p = .16) and joint capsule visualization (0.57/0.70 [0.32-0.81/0.51-0.89]; p = .16/p = .19). The bone-implant interface was more visible at 1.5 T (median IW/STIR score, 4/4 [range, both 2-5] at 1.5 T vs 3/3 [both 2-5] at 3 T; p = .08/p = .58), but periprosthetic tissues had superior visibility at 3 T (4/4 [both 3-5] at 3 T vs 4/4 [2-5/3-5] at 1.5 T; p = .07/p = .19). Conclusion. Optimized 1.5-T and 3-T CS-SEMAC MRI are interchangeable for diagnosing periprosthetic abnormalities, although metallic artifacts are larger at 3 T. Clinical Impact. With CS-SEMAC MRI, lower extremity arthroplasty implants can be scanned at 3 T rather than 1.5 T.

Biochemical, clinical manifestation of vitamin D deficiency in calves

Today, one of the priority tasks in animal husbandry and veterinary medicine is the creation of a highly productive, stable herd with a stable level of metabolism. A large load on the animal's body reveals high milk productivity; in connection with this, metabolic processes slow down, directly reducing milk productivity and requiring a balanced diet and high-quality feed. An increase in milk productivity is often directly related to metabolic disorders and the appearance of diseases, including the intensity of physiological and biochemical metabolic processes associated with converting a significant amount of energy and nutrients from feed into milk. Metabolic pathologies in animals can be caused by hereditary defects in the metabolism of nucleic acids, congenital insufficiency of enzymes responsible for the synthesis and breakdown of amino acids, disorders of organic acid metabolism, fatty acid deficiency, etc. Timely diagnosis of rickets and rapid therapy in the initial period is essential in treatment because the earlier the diagnosis is made, the easier it is to treat the disease. This will lead to the termination of the further destructive process, the occurrence of bone deformations, and changes in internal organs. The article deals with the issue of vitamin D deficiency in young cattle from a modern perspective. Materials on the classification, etiology, and pathogenesis of vitamin D-deficient rickets in calves are covered. The role of vitamin D in the prevention of rickets and its importance for general animal health and welfare are summarized. It is noted that this disease's characteristic feature is mainly the course's hidden stages. Clinical symptoms of D-hypovitaminosis appear in the late stages of the disease when restoring the animal's health is impossible. The essence of the pathology is a violation of mineralization of the organic matrix of bone tissues (D-hypovitaminosis) or osteolysis of already formed structures. The work aimed to find out the distribution, etiology, biochemical and clinical manifestation of D-hypovitaminosis in calves in one of the farms of the northern districts of Zhytomyr region, which belongs to the natural-geographical zone of Zhytomyr Polissia. The material for the study was clinically healthy calves and calves with rickets aged 1–3 months. The conditions of keeping and feeding animals on the farm were studied. Diagnosis and spread of D-hypovitaminosis among calves 1–3 months old were carried out with the help of clinical and unique methods; first, preference was given to laboratory studies. Clinical manifestations are described, and laboratory features of the course of vitamin D deficiency in animals are presented. It has been established that vitamin D deficiency in calves is quite widespread on the farm. Thus, the subclinical (hidden) course was registered in 45.8 % of animals and the clinical – in 24.1 %. The disease was more often registered in the winter-spring period. The leading cause of the disease in calves is insufficient motor activity (hypodynamia) in the absence of insolation, as well as a low level of feeding: reduced provision of cholecalciferol (25.8 %), violation of the calcium-phosphorus ratio (2.7–4.2:1 versus 1.5–2.0:1), deficiency of microelements – cobalt, zinc, copper, the provision of which was, respectively, 57.6, 85.6 and 96.2 % of the need. Pathognomotic manifestations of the disease in calves are licking, allotriophagia, thickening of carpal joints, partial resorption of the last ribs and tail vertebrae, and loose teeth. Vitamin D deficiency prevents the efficient absorption of calcium and phosphorus in feed. With vitamin D deficiency, only 10–15 % of feed calcium and 50–60 % of phosphorus are absorbed. The most informative laboratory markers for diagnosing pathology are determining cholecalciferol content, total calcium, inorganic phosphorus, alkaline phosphatase activity, and its bone isoenzyme in blood serum.

A biomechanical analysis of double screw, double button and screw button fixation constructs in PSI guided Latarjet procedure.

The Latarjet coracoid transfer procedure reliably stabilizes the glenohumeral joint for shoulder instability. However, complications such as graft osteolysis, non-union and fracture continue to affect patient clinical outcomes. The double screw (SS) construct is regarded as the gold standard method of fixation. SS constructs are associated with graft osteolysis. More recently, a double button technique (BB) has been suggested to minimize graft related complications. However, BB constructs are associated with fibrous non-union. To mitigate this risk, a single screw combined with a single button (SB) construct has been proposed. It is thought that this technique incorporates the strength of the SS construct and allows micromotion superiorly to mitigate stress shielding related graft osteolysis. The primary aim of this study was to compare the failure load of SS, BB and SB constructs under a standardized biomechanical loading protocol. The secondary aim was to characterize the displacement of each construct throughout testing. Computed tomography scans of twenty matched-pair cadaveric scapulae were performed. Specimens were harvested and dissected free of soft tissue. SS and BB techniques were randomly assigned to specimens for matched-pair comparison with SB trials. A patient specific instrument (PSI) guided Latarjet procedure was performed on each scapula. Specimens were tested using a uniaxial mechanical testing device under cyclic loading (100 cycles, 1Hz, 200N/s) followed by a load-to-failure protocol (0.5mm/s). Construct failure was defined by graft fracture, screw avulsion and/or graft displacement of more than 5mm. Forty scapulae from twenty fresh frozen cadavers with a mean age of 69.3 years underwent testing. On average, SS constructs failed at 537.8N (SD 296.8), while BB constructs failed at 135.1N (SD 71.4). SB constructs required a significantly greater load to fail compared to BB constructs (283.5N, SD 162.8, p=0.039). Additionally, SS (1.9mm, IQR 0.87) had a significantly lower maximum total graft displacement during the cyclical loading protocol compared to SB (3.8mm, IQR 2.4, p=0.007) and BB (7.4mm, IQR 3.1, p<0.001) constructs. These findings support the potential of the SB fixation technique as a viable alternative to SS and BB constructs. Clinically, the SB technique could reduce the incidence of loading-related graft complications seen in the first three months of BB Latarjet cases. The study is limited to time-specific results and does not account for bone union or osteolysis.

Inhibiting Osteolytic Breast Cancer Bone Metastasis by Bone-Targeted Nanoagent via Remodeling the Bone Tumor Microenvironment Combined with NIR-II Photothermal Therapy.

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.

Is it possible to stop the osteolysis of the periprosthetic bone during re-endoprosthetics of the hip joint against the background of osteoporosis?

Revision interventions due to aseptic instability show a marked upward trend, and one of the reasons is an increase in the number of people with osteoporosis in the population. The impaired bone metabolism in these cases persist even after re-endoprosthetics. The authors aim to draw attention of trauma orthopaedists to the need to treat osteoporosis either before or immediately after the re-endoprosthetic surgery. A clinical case is presented. A 65-year-old patient T., 5 months after surgery, complained of persistent pain in the left hip joint radiating to the left knee joint, which intensified when walking, lameness, inability to move without additional support (two crutches), limited range of motion within the left hip joint that had undergone surgery (endoprosthesis). The patient had a history of femoral neck fracture associated with a low energy fall. The left hip joint re-endoprosthetics was performed due to aseptic instability of the femoral and acetabular components of the prosthetic implant. The diagnosed diseases included secondary osteoporosis, D-deficiency, hypocalcemia, and periprosthetic osteolysis. Given the increased intensity of resorption and the fact that the femoral neck fracture occurred with underlying secondary osteoporosis, it was decided to prescribe antiresorptive therapy with denosumab 60 mg once every 6 months combined with alfacalcidol and calcium supplement. Despite an objective 3-month delay in antiresorptive therapy initiation, the treatment result was achieved in the observed patient. In summary, denosumab 60 mg increases the effectiveness of re-endoprosthetics with underlying osteoporosis by reducing activity of the periprosthetic bone osteolysis.

Can We Reliably Compare Outcomes of Ream-and-Run and Anatomic Total Shoulder Arthroplasty?: Commentary on an article by James Levins, MD, et al.: "Comparison of Humeral-Head Replacement with Glenoid-Reaming Arthroplasty (Ream and Run) Versus Anatomic Total Shoulder Arthroplasty. A Matched-Cohort Study".

Commentary Ream-and-run arthroplasty represents one of many options for the challenging problem of glenohumeral arthritis in the young active patient. Proponents of this procedure may contend that, despite higher revision rates in the short term compared with anatomic total shoulder arthroplasty (aTSA), ream-and-run arthroplasty may obviate potential longer-term complications related to polyethylene loosening and wear, such as glenoid bone loss and osteolysis leading to reverse baseplate fixation failure and humeral osteolysis and loosening1,2. It may also allow patients to avoid activity restrictions related to concern over polyethylene-related complications and to potentially avoid another surgery in their lifetime. However, these theoretical long-term advantages must be balanced against the fact that patients undergoing ream and run are at higher risk for early revision surgery. Data on ream-and-run arthroplasty outside of the originating institution are sparse, so this study by Levins et al. comparing aTSA and ream and run is useful to consider. Comparing these 2 procedures is no easy task; at baseline, patients choosing to undergo ream-and-run arthroplasty are different in many ways (age, sex, psychosocial factors, and glenoid morphology and retroversion) compared with patients choosing to undergo aTSA3. This usually results in a demographics table full of significant differences4, and therefore, non-comparable patient-reported outcomes and revision rates. Levins et al. attempted to address this in 2 ways. First, they included 2 distinct time periods: an earlier period in which no ream-and-run procedures were performed, and a later period in which both ream and run and aTSA were offered. Such an approach may reduce any surgical decision-making bias that leads to different baseline patient characteristics. Second, they utilized propensity-score matching (PSM). Short of a randomized controlled trial comparing ream and run and aTSA, which would be nearly impossible to undertake, this study provides the most comparable cohorts in the literature since the initial matched-cohort study reported by Dr. Matsen 15 years ago5. This PSM approach used is not perfect, and it is important to understand 2 major limitations of the methodology. First, one must consider the prototypical patient undergoing ream and run: a motivated, resilient male patient with glenoid biconcavity and retroversion who wants to participate in heavy lifting and impact sports. Many of these characteristics are addressed in the PSM algorithm, but notably, activity level and psychosocial attributes like resilience and motivation, thought to be very important in selecting a patient for a ream-and-run procedure, were absent. These characteristics are more difficult to objectively assess, but without taking them into account, the study cannot convince the reader that these cohorts truly comprised similar patients. The second major limitation of the PSM in this study pertains to matching on the basis of duration of follow-up. By doing so, the authors reduce the benefit of including a time period in which ream and run was not offered to patients. While the alternative of not matching on follow-up leads to other issues, such as imbalanced follow-up durations and differences in patient management, this study’s approach of matching length of follow-up increases the probability that the total shoulder cohort contains more patients from the latter time period in which more motivated, resilient, and active patients were likely offered ream-and-run arthroplasty. It should also be noted that the senior author, similar to Dr. Matsen, has substantial experience with the ream-and-run procedure. The technical nuances in addressing glenoid deformity and soft-tissue balancing during the procedure are different from those considered during aTSA. As with any other surgical procedure, higher volume produces better results, and this surgeon’s thoughtful approach to the operative technique and rehabilitation after ream and run likely were adapted over time to optimize patient outcomes. The generalizability of these results may not be assured. Despite these limitations, the authors should be commended for providing us with the largest report on the ream-and-run procedure outside of Dr. Matsen’s cohort. They demonstrate that acceptable results, similar to those of aTSA, can be achieved in this challenging population. Further studies objectively assessing activity level and the psychosocial aspects of patient selection will help us further elucidate who the “optimal” ream-and-run candidate is. Continued follow-up of the cohorts in this study will be essential to determining whether the perceived long-term value of avoiding glenoid polyethylene in the young patient with glenohumeral arthritis is worth it.

Osteoimmune Interactions and Therapeutic Potential of Macrophage-Derived Small Extracellular Vesicles in Bone-Related Diseases.

Due to the aging of the global population, the burden of bone-related diseases has increased sharply. Macrophage, as indispensable components of both innate immune responses and adaptive immunity, plays a considerable role in maintaining bone homeostasis and promoting bone establishment. Small extracellular vesicles (sEVs) have attracted increasing attention because they participate in cell cross-talk in pathological environments and can serve as drug delivery systems. In recent years, an increasing number of studies have expanded our knowledge about the effects of macrophage-derived sEVs (M-sEVs) in bone diseases via different forms of polarization and their biological functions. In this review, we comprehensively describe on the application and mechanisms of M-sEVs in various bone diseases and drug delivery, which may provide new perspectives for treating and diagnosing human bone disorders, especially osteoporosis, arthritis, osteolysis, and bone defects.