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Purpose: The purpose of this case report was to provide a detailed description of the ocular manifestations, in a patient with multicentric carpotarsal osteolysis (MCTO), with particular emphasis on bilateral corneal opacities., Methods: A 43-year-old woman with a history of MCTO was followed with visual acuity assessment and slit-lamp examination at the Department of Ophthalmology in the University Hospitals of Leuven., Results: The patient was found to have bilateral subepithelial haze, along with anterior stromal corneal opacities, and small central lens opacities upon examination. There was a slight corneal thickening. A progression of the corneal opacities was observed, without a further drop in visual acuity., Conclusions: This case report shows a rare association between MCTO and corneal opacities in adulthood. Interdisciplinary care involving an ophthalmologist is beneficiary for patients with MCTO., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This systematic review aimed to assess the different treatments of benign maxillo-mandibular radiolucent bone lesions over 4 cm to propose a management algorithm., Study Design: A literature search was conducted using MEDLINE/PubMed, Scopus, Google Scholar, Virtual Health Library databases, and gray literature. Randomized or non-randomized clinical trials and case series with 10 or more patients with a minimum follow up of 1 year, published in French or English until August 2023, were included. The risk of bias was assessed for all papers included., Results: Of 1433 records identified, 22 were included in this review, reporting data from 1364 lesions. Ameloblastoma was the most common lesion (51.22%) and mandible was the most common site (81.21%). Initial conservative treatment was prevalent (71.04%). Recurrence was higher after conservative (13.8%) than after radical treatments (6.5%). Multilocularity, cortical perforation, dental element preservation were linked to a higher recurrence risk., Conclusion: This study has shown importance of understanding specific characteristics and recurrence risk in benign maxillomandibular osteolytic lesions. Multidisciplinary team approval, personalized approach based on lesion type and patient are crucial. The presence of at least one risk factor could lead to therapeutic decision. Despite limitations, the study informed lesion management and provided precise recommendations., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The use of highly crosslinked ultra-high molecular weight polyethylene (XLPE) has significantly reduced the volumetric wear of acetabular liners, thereby reducing the incidence of osteolysis. However, contemporary components tend to generate smaller wear particles, which can no longer be identified using conventional histology. This technical limitation can result in imprecise diagnosis. Here, we report on two uncemented total hip arthroplasty cases (~7 years in situ) revised for periprosthetic fracture of the femur and femoral loosening, respectively. Both liners exhibited prominent wear. The retrieved pseudocapsular tissue exhibited a strong macrophage infiltration without microscopically identifiable polyethylene particles. Yet, using Fourier-transform infrared micro-spectroscopic imaging (FTIR-I), we demonstrated the prominent intracellular accumulation of polyethylene debris in both cases. This study shows that particle induced osteolysis can still occur with XLPE liners, even under 10 years in situ. Furthermore, we demonstrate the difficulty of determining the presence of polyethylene debris within periprosthetic tissue. Considering the potentially increased bioactivity of finer particles from XLPE compared to conventional liners, an accurate detection method is required, and new histopathological hallmarks of particle induced osteolysis are needed. FTIR-I is a great tool to that end and can help the accurate determination of foreign body tissue responses., (© 2024 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

We report a rarely occurring hematologic neoplasm in a young adult. Hematologic neoplasms were first described in 2008 and are now included in both accepted tumor classification systems, i.e., International Consensus Classification and World Health Organization. This hematologic neoplasm shows a characteristic ALK positivity in immunohistochemical examination and correspondingly, ALK fusion genes in the molecular analysis. Pathologists should be aware of this entity, particularly as it is challenging to differentiate from other more frequent neoplasms of the same disease group or mesenchymal neoplasm with ALK aberration., (© 2024. The Author(s).)

Background: Multicentric Carpo-Tarsal Osteolysis Syndrome (MCTO) is an autosomal dominant disease with increased bone reabsorption in the carpus and tarsus and the elbows, knees and spine. The disease is extremely heterogeneous and secondary and tertiary injuries vary widely and can lead to progressive disability and severe functional limitations. In addition to the available and upcoming drug therapies, physical medicine and rehabilitation are important treatment options. Currently, the indication and plan are overlooked, nonspecific and reported only for one patient., Methods: We describe a case series of MCTO patients diagnosed and followed by a centre to identify functional deficit as a potential clinical marker of disease progression for future etiological therapies. In addition, we define a symptomatic treatment approach and specific clinical management, including a patient-centred rehabilitation approach. Functional assessments are performed independently by a multidisciplinary group to establish the functional abilities of patients and the relationship between residual motor skills and their degree of autonomy and participation. We suggest a way to identify a rehabilitation plan based on a specific disease using the International Classification of Functioning, Disability and Health Children and Youth (ICF-CY)., Results: To define a reliable and reproducible "Function Profile", through age and over time, we used to value the disease status according to the ICF-CY domains. It could be used to determine the complexity of the illness, its overall impact on the complexity of the person and the burden on the caregiver, and an eventual short- and long-term rehabilitation plan for MCTO and other ultra-rare diseases., Conclusion: Based on the MCTO experience, we suggest a way to determine a rehabilitation plan based on a specific disease and patient needs, keeping in mind that often the final point is not recovering the full function but improving or maintaining the starting point. In all cases, each patient at the time of diagnosis requires a functional assessment that must be repeated over time to adjust the course of rehabilitation. The evaluations revealed the importance of early rehabilitation management in enhancing independence, participation and control of stress deconditioning, shrinking of muscle tendons and loss of movement to immobility., (© 2023. The Author(s).)

Abstract: Weightlifting associated shoulder injuries have seen a dramatic rise in the last 20 years. Distal clavicular osteolysis, coined weightlifter's shoulder, is one such condition caused by repetitive microtrauma to the distal clavicle with subsequent, painful development of bony erosions and resorption of the distal clavicle. Diagnosis, treatment, and prevention of this condition can be challenging. In this article, we highlight evidence-based clinical recommendations for the diagnosis and management of distal clavicular osteolysis, including specific considerations for atraumatic and posttraumatic etiologies, to help clinicians better care for their patients. Activity modification and rehabilitation are the mainstays of the initial treatment. Adjuvant treatments, such as injections or surgery, may be required in refractory cases or in certain patient populations. Early recognition and treatment of weightlifter's shoulder is essential to prevent progression to acromioclavicular joint pathology or instability and to allow for continued participation in sport-specific activities., (Copyright © 2023 by the American College of Sports Medicine.)

Gorham-Stout disease (GSD) is thought to be due to uncontrolled proliferation of vascular and lymphatic structures within bone tissue causing destruction and osteolysis of bone. We present a patient in her mid-40s who reported chronic shoulder pain, a pleural effusion and irregular periods. Investigations showed osteolysis of her ribs, pleural effusions, an ovarian mass and a raised carbohydrate antigen 125 (Ca-125). She was subsequently diagnosed with GSD, and referred to gynaecology-oncology in consideration of potential ovarian malignancy. GSD is a diagnosis of exclusion that requires a high degree of clinical suspicion, as well as multiple investigations to achieve diagnosis. Clinicians rely on a small number of case reports to provide guidance for this. Therefore, this report provides an overview of a rare pathology, considers the differentials of a raised Ca-125 and describes how a pleural effusion, which links them both, alarmed us regarding an incidental finding of an ovarian cyst., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflict of Interest The authors declare that there are no conflict of interest.

Background: While recent reports have suggested that hip corticosteroid injections can hasten joint degeneration, there are few published data on the topic. The purpose of the present study was to evaluate for an association between corticosteroid injection and rapidly destructive hip disease (RDHD) and to determine the rate of, and risk factors for, occurrence., Methods: This study was conducted in 2 parts. First, to assess for a potential association between hip corticosteroid injection and RDHD, a case-control analysis was performed. Patients who developed RDHD between 2013 and 2016 served as cases, whereas those who underwent total hip arthroplasty for diagnoses other than RDHD during the same period served as controls, and the exposure of interest was prior intra-articular hip corticosteroid injection. Second, in a retrospective cohort analysis, we analyzed all patients who received a fluoroscopically guided intra-articular hip corticosteroid injection at our institution from 2013 to 2016. The rate of post-injection RDHD was determined, and logistic regression was used to identify risk factors for occurrence., Results: In the case-control analysis, hip corticosteroid injection was associated with the development of RDHD (adjusted odds ratio, 8.56 [95% confidence interval, 3.29 to 22.3], p < 0.0001). There was evidence of a dose-response curve, with the risk of RDHD increasing with injection dosage as well as with the number of injections received. In the retrospective cohort analysis, the rate of post-injection RDHD was 5.4% (37 of 688). Cases of post-injection RDHD were diagnosed at an average of 5.1 months following injection and were characterized by rapidly progressive joint-space narrowing, osteolysis, and collapse of the femoral head., Conclusions: This study documents an association between hip corticosteroid injection and RDHD. While the risk of RDHD following a single low-dose (≤40 mg) triamcinolone injection is low, the risk is higher following high-dose (≥80 mg) injection and multiple injections. These findings provide information that can be used to counsel patients about the risks associated with this common procedure. In addition, caution should be taken with intra-articular hip injections utilizing ≥80 mg of corticosteroid and multiple injections., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G684)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Osteolytic bone metastasis leads to skeletal‑related events, resulting in a decline in the patient activities and survival; therefore, it is important to understand the mechanism underlying bone metastasis. Recent studies have suggested that microRNAs (miRNAs or miRs) are involved in osteoclast differentiation and/or osteolytic bone metastasis; however, the roles of miRNAs have not been elucidated. In the present study, the roles of miRNAs in bone destruction caused by breast cancer metastasis were investigated in vitro and in vivo . miR‑16, miR‑133a and miR‑223 were transfected into a human breast cancer cell line, MDA‑MB‑231. The expression of osteolytic factors in conditioned medium (miR‑CM) collected from the culture of transfected cells was assessed. To evaluate the effects of miRNAs on osteoclast differentiation and activities, tartrate‑resistant acid phosphatase (TRAP) staining and bone resorptive assays were performed in osteoclasts following miR‑CM treatment. To create in vivo bone metastasis models for histological and morphometric evaluation, miRNA‑transfected MDA‑MB‑231 cells were transplanted into the proximal tibia of nude mice. Expression of osteolytic factors, including receptor activator for nuclear factor‑κB ligand (RANKL), interleukin (IL)‑1β, IL‑6, parathyroid hormone‑related protein (PTHrP), and tumor necrosis factor (TNF), was increased in miR‑16‑CM, whereas it was decreased in both miR‑133a‑CM and miR‑223‑CM. TRAP staining and bone resorptive assays revealed that osteoclast function and activities were promoted by miR‑16‑CM treatment, whereas they were suppressed by miR‑133a‑CM and miR‑223‑CM. Consistent with in vitro findings, in vivo experiments revealed that the overexpression of miR‑16 increased osteoclast activities and bone destruction in MDA‑MB‑231 cells, whereas the opposite results were observed in both miR‑133a‑ and miR‑223‑transfected MDA‑MB‑231 cells. Our results indicated that miR‑16 promoted osteoclast activities and bone destruction caused by breast cancer metastasis in the bone microenvironment, whereas miR‑133a and miR‑223 suppressed them. These miRNAs could be potential biomarkers and therapeutic targets for breast cancer bone metastasis.

Background: The purpose of this study was to evaluate glenoid component position and radiolucency following anatomic total shoulder arthroplasty (TSA) using sequential 3-dimensional computed tomography (3D CT) analysis., Methods: In a series of 152 patients (42 Walch A1, 16 A2, 7 B1, 49 B2, 29 B3, 3 C1, 3 C2, and 3 D glenoids) undergoing anatomic TSA with a polyethylene glenoid component, sequential 3D CT analysis was performed preoperatively (CT1), early postoperatively (CT2), and at a minimum 2-year follow-up (CT3). Glenoid component shift was defined as a change in component version or inclination of ≥3° from CT2 to CT3. Glenoid component central anchor peg osteolysis (CPO) was assessed at CT3. Factors associated with glenoid component shift and CPO were evaluated., Results: Glenoid component shift occurred from CT2 to CT3 in 78 (51%) of the 152 patients. CPO was seen at CT3 in 19 (13%) of the 152 patients, including 15 (19%) of the 78 with component shift. Walch B2 glenoids with a standard component and glenoids with higher preoperative retroversion were associated with a higher rate of shift, but not of CPO. B3 glenoids with an augmented component and glenoids with greater preoperative joint-line medialization were associated with CPO, but not with shift. More glenoid component joint-line medialization from CT2 to CT3 was associated with higher rates of shift and CPO. A greater absolute change in glenoid component inclination from CT2 to CT3 and a combined absolute glenoid component version and inclination change from CT2 to CT3 were associated with CPO. Neither glenoid component shift nor CPO was associated with worse clinical outcomes., Conclusions: Postoperative 3D CT analysis demonstrated that glenoid component shift commonly occurs following anatomic TSA, with increased inclination the most common direction. Most (81%) of the patients with glenoid component shift did not develop CPO. Longer follow-up is needed to determine the relationships of glenoid component shift and CPO with loosening over time., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This study was funded by a State of Ohio grant (TIOSO), an Orthopaedic Research and Education Foundation (OREF)/American Shoulder and Elbow Surgeons (ASES) Rockwood Clinical Research Grant (OREF1403ER), and an NIH/NIAMS Research Grant (R01AR075286). On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (http://links.lww.com/JBJS/G459)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Wear particle-induced periprosthetic osteolysis is mainly responsible for joint replacement failure and revision surgery. Curculigoside is reported to have bone-protective potential, but whether curculigoside attenuates wear particle-induced osteolysis remains unclear. In this study, titanium particles (Ti) were used to stimulate osteoblastic MC3T3-E1 cells in the presence or absence of curculigoside, to determine their effect on osteoblast differentiation. Rat osteoclastic bone marrow stromal cells (BMSCs) were cocultured with Ti in the presence or absence of curculigoside, to evaluate its effect on osteoclast formation in vitro . Ti was also used to stimulate mouse calvaria to induce an osteolysis model, and curculigoside was administrated to evaluate its effect in the osteolysis model by micro-CT imaging and histopathological analyses. As the results indicated, in MC3T3-E1 cells, curculigoside treatment attenuated the Ti-induced inhibition on cell differentiation and apoptosis, increased alkaline phosphatase activity (ALP) and cell mineralization, and inhibited TNF- α , IL-1 β , and IL-6 production and ROS generation. In BMSCs, curculigoside treatment suppressed the Ti-induced cell formation and suppressed the TNF- α , IL-1 β , and IL-6 production and F-actin ring formation. In vivo , curculigoside attenuated Ti-induced bone loss and histological damage in murine calvaria. Curculigoside treatment also reversed the RANK/RANKL/OPG and NF- κ B signaling pathways, by suppressing the RANKL and NF- κ B expression, while activating the OPG expression. Our study demonstrated that curculigoside treatment was able to attenuate wear particle-induced periprosthetic osteolysis in in vivo and in vitro experiments, promoted osteoblastic MC3T3-E1 cell differentiation, and inhibited osteoclast BMSC formation. It suggests that curculigoside may be a potential pharmaceutical agent for wear particle-stimulated osteolysis therapy., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Fangbing Zhu et al.)

Peri-prosthetic osteolysis (PPO) and following aseptic loosening are regarded as the prime reasons for implant failure after joint replacement. Increasing evidence indicated that wear-debris-irritated inflammatory response and macrophage polarization state play essential roles in this osteolytic process. Harmine, a β-carboline alkaloid primitively extracted from the Peganum harmala seeds, has been reported to have various pharmacological effects on monoamine oxidase action, insulin intake, vasodilatation and central nervous systems. However, the impact of harmine on debris-induced osteolysis has not been demonstrated, and whether harmine participates in regulating macrophage polarization and subsequent osteogenic differentiation in particle-irritated osteolysis remains unknown. In the present study, we investigated the effect of harmine on titanium (Ti) particle-induced osteolysis in vivo and in vitro . The results suggested harmine notably alleviated Ti particle-induced bone resorption in a murine PPO model. Harmine was also found to suppress the particle-induced inflammatory response and shift the polarization of macrophages from M1 phenotypes to M2 phenotypes in vivo and in vitro , which improved anti-inflammatory and bone-related cytokines levels. In the conditioned medium from Ti particle-stimulated murine macrophage RAW264.7 cells treated with harmine, the osteoblast differentiation ability of mouse pre-osteoblastic MC3T3-E1 cells was greatly increased. And we also provided evidences that the immunomodulatory capacity of harmine might be attributed to the inhibition of the c-Jun N-terminal kinase (JNK) in wear particle-treated macrophages. All the results strongly show that harmine might be a promising therapeutic agent to treat PPO., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Wang, Wang, Ge, Xu, Zheng, Jiang, Zhao, Xu, Wang, Zhu and Geng.)

Gorham-Stout Disease (GSD), also named vanishing bone disease, is an ultrarare condition characterized by progressive osteolysis with intraosseous lymphatic vessel proliferation and bone cortical loss. So far, about 300 cases have been reported. It may occur at any age but more commonly affects children and young adults. The aim of this study is to retrospectively review our internal patient series and to hypothesize a diagnostic-therapeutic protocol for earlier diagnosis and treatment. Clinical datasets from our center were examined to identify all GSD patients for collection and analysis. We identified 9 pediatric cases and performed a retrospective case-series review to examine and document both diagnosis and treatment. We found that delay in diagnosis after first symptoms played a critical role in determining morbidity and that multidisciplinary care is key for proper diagnosis and treatment. Our study provides additional insight to improve the critical challenge of early diagnosis and highlights a multidisciplinary treatment approach for the most appropriate management of patients with rare GSD disease. Although GSD is an ultrarare disease, physicians should keep in mind the main clinical features since neglected cases may result in potentially fatal complications., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Introduction: Sarcoidosis is a multi-systemic disease characterized by non-caseating granulomas. Bone involvement initially considered as rare and described as a peripheral osteitis of the hands and feet, has recently been reported on the axial skeleton., Case Reports: We report 4 clinical observations of sarcoidosis (3 women, 1 man) with axial bone involvement located to the spine (n = 4), pelvic bone (n = 2), scapular bone (n = 2), sternum (n = 1), mandible (n = 1). Sarcoidosis was already diagnosed in 3 cases. Bone pain was the main symptom, related in 3 cases. Magnetic resonance imaging appeared to be the best imaging test Histological bone analysis revealed typical granulomatous lesions (n = 2). Treatment included corticosteroids (n = 4), hydroxychloroquine (n = 2), and methotrexate (n = 2), with a good efficacy on bone pain in symptomatic patients., Conclusion: These 4 cases, as well as recent literature, illustrate bone involvement of sarcoidosis on the axial skeleton. It is symptomatic in around 50% of cases but may be a source of significant disability. Differential diagnosis with neoplasm may require bone histological analysis. This condition appears to be responsive to usual treatments for sarcoidosis., (Copyright © 2020. Published by Elsevier Masson SAS.)

Skeletal involvement is a rare complication of hairy cell leukemia (HCL) with an incidence of approximately 3%. Bone lesions are commonly lytic, and the most common sites of involvement are the femoral head and neck. Skeletal involvement is typically associated with high tumor burden and bone marrow infiltration. However, isolated cases of skeletal disease without splenomegaly or bone marrow involvement are occasionally reported. This review focuses on skeletal lesions in HCL, particularly the pathogenesis, clinical symptoms, diagnostic methods, and treatment approach. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skeletal symptoms, bone involvement was conducted via PubMed. Publications from January 1970 to May 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and purpose - Survivorship of total hip arthroplasty (THA) with the ultra-high molecular weight polyethylene (UHMWPE) monoblock cup has been limited due to periprosthetic osteolysis and aseptic loosening, secondary to wear of the UHMWPE. In response, a vitamin E blended highly cross-linked polyethylene (HXLPE) cup was developed. This study set out to compare the wear and clinical 6-year outcomes of vitamin E blended HXLPE with UHMWPE in an isoelastic monoblock cup in patients with hip osteoarthritis who underwent uncemented THA. The 2-year results have been reported previously. Patients and methods - For this randomized controlled trial 199 patients were included. 102 patients received the vitamin E blended HXLPE uncemented acetabular cup and 97 patients the uncemented UHMWPE monoblock cup. Clinical and radiographic parameters were obtained preoperatively, directly postoperatively, and at 3, 12, 24, and 72 months. Wear rates were compared using the femoral head penetration (FHP) rate. Results - 173 patients (87%) completed the 6-year follow-up. The mean NRS scores for rest pain, load pain, and patient satisfaction were 0.3 (SD 1), 0.6 (SD 1), and 8.6 (SD 1) respectively. The mean Harris Hip Score was 93 (SD 12). The FHP rate was lower in the vitamin E blended HXLPE cup (0.028 mm/year) compared with the UHMWPE cup (0.035 mm/year) (p = 0.002). No adverse reactions associated with the clinical application of vitamin E blended HXLPE were observed. 15 complications occurred, equally distributed between the two cups. The 6-year survival to revision rate was 98% for both cups. There was no aseptic loosening. Interpretation - This study shows the superior performance of the HXLPE blended with vitamin E acetabular cup with clinical and radiographic results similar to the UHMWPE acetabular cup.

Background: Hypercalcemia of malignancy (HCM) is a serious metabolic complication, and the highest rates are in multiple myeloma (MM). The cause of hypercalcemia in newly diagnosed multiple myeloma (NDMM) remains unknown. We sought to evaluate the prognostic impact and mechanism of hypercalcemia in patients with symptomatic NDMM., Methods: We studied all consecutive MM patients who were initially diagnosed and followed up at Beijing Jishuitan Hospital between February 2013 and December 2019; 357 patients were included in the retrospective analysis., Results: A total of 16.8% of MM patients presented with hypercalcemia at the time of MM diagnosis. The presence of hypercalcemia was associated with higher serum levels of β2 microglobulin, creatinine, phosphorus, uric acid, procollagen I N-terminal peptide, β-carboxy-terminal cross-linking telopeptide of type I collagen and osteocalcin, lower serum levels of hemoglobin, parathyroid hormone (PTH), and advanced ISS and R-ISS stages. Multivariate analysis showed that serum PTH, hemoglobin, creatinine, and uric acid levels were the main factors affecting hypercalcemia. The presence of hypercalcemia was associated with significantly inferior survival (40 months vs 57 months, p < 0.05) based on univariate analysis, and it remained an independent poor prognostic factor (HR: 1.854, 95% CI: 1.006-3.415, adjusted p = 0.048) in a multivariate model that included age and R-ISS stage., Conclusion: This study shows that hypercalcemia is associated with poor survival and is caused by manifold factors with humoral effects and local bone destruction., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Opinion Statement: Denosumab is a RANK ligand inhibitor approved for the treatment of giant cell tumor of bone. While the role of denosumab in the setting of advanced and unresectable disease is well established, its role in surgically resectable disease is currently under discussion. Several prospective and retrospective series on neoadjuvant therapy in potentially resectable tumor with high morbidity surgery reported a relapse rate of 10-20% after resection and 30-40% after curettage. At the same time, less morbid surgery has obvious clinical advantages for the patient, and several studies have shown the efficacy of denosumab in downgrading of the surgical procedure. Currently, the role of neoadjuvant denosumab in operable GCTB is limited to selected cases in which a diffuse reactive bone formation and peripheral ossification can make an easier surgical procedure, for example, in tumors with a large soft tissue component. A planned resection may become less morbid when preoperative denosumab is administered. Whenever a segmental resection is thought to be indicated at diagnosis, denosumab may be considered in the neoadjuvant setting. A preoperative course of 6 months is considered safe and effective. Two case scenarios are presented and critically discussed. Because of the high recurrence rates after denosumab treatment followed by curettage, we discourage the use of denosumab when curettage is considered feasible. In this setting, a short course of preoperative denosumab (2-6 months) may be considered for highly selected cases, for example in pathological fractures. The role of adjuvant denosumab needs further investigation. Long-term disease control has been reported in case of non-surgical lesions, even after treatment interruption, but there is no consensus on ideal treatment duration and dosage for these scenarios. In all cases, multidisciplinary discussion with oncology, pathologist, radiologist, and surgeons is mandatory. Patient's comorbidities, dental conditions, and preferences, including family planning, should always be taken into account.

Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis in vitro and prevented inflammatory osteolysis in vivo. Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.

Not required for Clinical Vignette.

Chromoblastomycosis (CBM) is a chronic cutaneous and subcutaneous fungal infection caused by certain dematiaceous fungi (usually Fonsecaea, Phialophora, or Cladophialophora). Histologically, CBM is characterized by the presence of medlar bodies. However, the diagnosis is difficult because of the rarity of these pathognomonic presentations and the wide variety of presentations. Treatment of these infections is challenging as it lacks standardization. Herein, we report a case of chromoblastomycosis caused by Phialophora, in a 42-year-old immunocompetent male agriculturist from the humid and subtropical region of southern China. He had a 3-month history of pneumonia with intermittent fever, coughing, and expectoration. The infection subsequently spread to the bone and lymph nodes forming deep lesions and eventually resulting in osteolysis and lymphadenectasis. These subcutaneous nodules were observed after 9 months. Antifungal treatment was administered for 20 months leading to clinical improvement before the patient was lost to follow-up. This case is unique because such deep lesions are rare in immunocompetent individuals and because the initial onset was associated with pneumonia., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: None declared.

Objectives: The objective of this study was to evaluate the incidence of osteolysis around the bioabsorbable and nonabsorbable anchors using serial magnetic resonance imaging (MRI) and to determine the relationship between osteolysis and the retear rate after arthroscopic rotator cuff repair., Methods: From July 2012 to July 2014, 50 patients [28 men and 22 women; mean age, 56.4 (range: 45-56) years] underwent arthroscopic rotator cuff repair for a medium-to large-size tear with double-row suture-bridge technique. The bioabsorbable anchors used in the medial row comprised hydroxyapatite-polylactic acid enantiomer, and the nonabsorbable anchors in the lateral row were polyetheretherketone (PEEK)-type anchors. All patients underwent MRI evaluation at 3, 6, and 12 months postoperatively to determine osteolysis and identify any retear., Results: The incidences of osteolysis at 3, 6, and 12 months postoperatively were 1%, 4%, and 6% with nonabsorbable anchors and 13%, 29%, and 39% with bioabsorbable anchors, respectively. The incidences of osteolysis were significantly higher with the bioabsorbable anchors than with the nonabsorbable anchors (P < 0.005 for all three follow-ups). There was no significant difference between osteolysis and non-osteolysis groups regarding the retear rate or retear size (P = 0.189 and 0.069, respectively)., Conclusions: Osteolysis was common around bioabsorbable anchors used for arthroscopic rotator cuff repair, and it also occurred around the PEEK-type nonabsorbable anchors. The incidence of osteolysis of nonabsorbable anchors was significantly lower than that of bioabsorbable anchors. Osteolysis did not significantly affect rotator cuff retear after arthroscopic repair with either bioabsorbable or nonabsorbable anchors., Level of Evidence: Level III, Therapeutic Study., (Copyright © 2019 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: Parathyroid carcinoma (PC) is a rare neoplasm with a high rate of recurrence and an indolent course. It is frequently functional, causing nearly 1% of the cases of primary hyperparathyroidism (HPT), and in some cases, it may be complicated by brown tumors, mimicking bone metastases. Synchronous parathyroid and papillary thyroid carcinomas are rare., Case Report: We present a patient with HPT due to PC, misdiagnosed at first evaluation, which exhibited multiple hypermetabolic lytic lesions in the skeleton, suggesting bone metastases. Their regression after PTH reduction suggested the diagnosis of brown tumors due to severe HPT. Given the persistence of HPT, the patient underwent a number of neck surgeries, and a papillary thyroid microcarcinoma with a nodal metastasis was diagnosed. A genetic test discovered a previously unreported mutation of the CDC73 (HRPT2) gene, codifying for parafibromin and resulting in a premature stop codon (c.580A>Tp.Arg194). Because of the persistence of HPT, cinacalcet therapy was started in order to control hypercalcemia., Conclusion: This is a very unusual patient with a newly discovered variant of the CDC73 gene and a phenotype characterized by recurrent PC, brown tumors, and N1a metastasized thyroid carcinoma. The present case confirms that PC may not exhibit clear malignant properties at first assessment, contributing to inadequate initial surgical treatment. Although infrequently, PC can be associated with papillary thyroid cancer. The diagnosis of brown tumor should be considered in patients with severe HPT and multiple destructive bone lesions mimicking metastases on PET/CT imaging.

As the demand for total hip arthroplasty (THA) continues to increase, the burden of revision THA is also expected to increase. Although the quality of polyethylene has improved markedly, osteolysis continues to be a risk for older designs and younger, active patients. Although progressive but typically asymptomatic in early stages, osteolysis can result in component failure and complicate revision surgery. Serial radiographs are paramount for monitoring progression. Although select cases may be treated with observation, surgery should be considered based on age, activity level, and projected life span. Well-fixed, noncemented modular acetabular components may be treated with curettage and bone grafting, as well as having to bear liner exchange with retention of the acetabular shell. However, in the setting of osteolysis, it is controversial whether bone grafting and component retention is superior to cup revision. This review explores the pathophysiology of osteolysis after THA and provides a comprehensive analysis of the evaluation and treatment of patients with osteolysis.

Pubic osteolysis is a rare pathology characterized by a painful radiographic destructive changes in the pubic rami, pubis or pubic symphysis that often follows a post-traumatic event. The etiology is unclear but it is a benign lesion, frequently misinterpreted as malignant. We report a case of a 54-year-old woman with pubic osteolysis mimicking a malignant lesion, diagnosed after open bone biopsy, conservatively treated without any sequelae and followed-up 10 years after the end of treatment. Although in the majority of the reported cases, a previous trauma has been commonly referred, in our case the patient did not refer to any cause before the onset of clinical symptoms. Knowledge of this entity is important to avoid invasive diagnostic procedures, costly investigations or overtreatment.

This article discusses developments in total hip arthroplasty related to the use of highly cross-linked polyethylene (HXLPE) liner material as the new standard of care for acetabular cup articulation surfaces. The pathologic implications of metal-on-metal hip prostheses in asymptomatic patients also are discussed.

Background: Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown., Questions/purposes: We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis., Methods: The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken., Results: Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ≤ 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ≤ 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ≤ 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ≤ 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10)., Conclusions: We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease., Clinical Relevance: The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.

Purpose: The purpose of this systematic review was to (1) identify the optimal diagnostic modality for tunnel widening in skeletally mature patients; (2) identify potentially modifiable risk factors for tunnel widening, such as graft type, and (3) determine what elements of a post-operative rehabilitation program exert the most influence on TW., Methods: The electronic databases MEDLINE, EMBASE, PubMed, and Cochrane Library were searched from database inception to January 2018. Studies that discussed tunnel widening following anterior cruciate ligament reconstruction (ACLR) of skeletally mature patients and written in English were included. Descriptive statistics, such as means, ranges, and measures of variance (e.g. standard deviations, 95% confidence intervals (CI)) are presented where applicable., Results: 103 studies (6,383 patients) were included. Plain radiographs were the most commonly used diagnostic modality, but radiographs on average required 10 months longer than CT and 2 months longer on average than MRI to diagnose tunnel widening after ACLR. Although CT was the least commonly used modality, it was the shortest time to diagnose tunnel widening at 9.5 months after ACLR. Bone-patellar tendon-bone (BPTB) allograft had the largest average tunnel widening overall. BPTB autograft had the lowest average tunnel widening overall. Double-bundle hamstring graft configuration had a lower average tunnel widening than single-bundle configuration. Rehabilitation protocols after ACLR that used a full weight-bearing prescription in rehabilitation showed a greater average femoral tunnel widening than partial weight-bearing, and partial weight-bearing showed a greater average tibial tunnel widening than full weight-bearing., Conclusions: Based on this systematic review and the descriptive data evaluated, CT demonstrated a time of 9.5 months on average from ACLR to diagnosing tunnel osteolysis post-ACLR. With respect to graft types, double-bundle hamstring autografts reported lower average femoral and tibial TW than single-bundle hamstring autografts. BPTB autografts reported the lowest average TW and BPTB allograft the largest average TW of all the grafts. Furthermore, extension-locked bracing had the lowest TW of all the brace protocols. Lastly, several other surgical technical parameters influencing tunnel osteolysis remain to be determined. No definitive recommendations can be made at this time due to the high heterogeneity of data and the lack of comparative studies analysed in this systematic review., Level of Evidence: IV.

Background: Tibial osseous defects can present a serious challenge in primary total knee arthroplasty. We describe a technique of using porous tantalum cones along with primary arthroplasty implants to address large tibial osseous defects in primary total knee arthroplasty and present the short-term results., Methods: We present 17 cases (15 patients) in which primary total knee implants and porous tantalum cones were used to address large tibial bony defects. Clinical results were evaluated using Knee Society Scores, pre- and postoperative knee range of motion, and serial radiographs., Results: At an average of 3.5 years of follow-up, all 17 knees had functioning implants with stable metaphyseal cones demonstrating radiographic evidence of osteointegration. At a minimum follow-up of two years, no patient had signs of osteolysis, instability, infection, or systemic complications. All 15 patients had excellent results with an average post-operative Knee Society Score of 94.6. Knee flexion improved by an average of 12.0° and knee extension improved to neutral in all patients., Conclusion: Primary total knee arthroplasty with porous tantalum cone augmentation produced excellent short-term results and should be considered an effective method for addressing large tibial osseous defects in primary total knee arthroplasty., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To summarize the biological effects of metal debris from hip arthroplasties which characterize a polymorphic clinical spectrum of local and remote manifestation., Methods: Retrospective study. Patient, implant, and surgical characteristics were collected, including implant survival, clinical manifestations, cause of arthroplasty revision or implant failure, and peri- and intra-operative complications. The primary endpoint was implant survivorship. Hip revision arthroplasty was decided considering clinical signs and symptoms, abnormal imaging (XR, MR, TC, echotomography, scintigraphy), and blood metal ion level. An ad hoc electronic form was used to collect demographic, epidemiological, and clinical variables. In-between group comparisons of quantitative variables were performed with the Student t test and the Mann-Whitney for parametric and non-parametric variables, respectively. Logistic regression analyses were carried out to assess the relationship between clinical and radiographic characteristics and stem and cup revision. Radiographic measurements of implant positioning validity and reliability were assessed using Krippendorff's alpha reliability coefficient. The statistical software STATA version 15 (StatsCorp, TX) was used to perform statistical computations., Results: In this MoM THA series, the most incident cause of implant failure was ARMD in 11 out of 14 (78.6%) patients. All clinical failure manifestations, revision surgery highlights, and intra-operative findings are reported., Conclusions: The local adverse reactions include lesions of different clinical relevance from small asymptomatic soft tissue lesions to dramatic osteolysis, necrosis, effusion, and growing masses which can cause secondary pathological effects. Symptoms of systemic toxicity are rarely described but may have been largely unreported in literature. Despite the extensive literature on the topic, the patient's management is still uncertain and challenging. Every metallic implant (e.g., screws, plates, spinal instrumentations) has a potential local or systemic adverse effect. Organizing a national registry of arthroplasty should be mandatory, in order to collect data about the patients, the surgery, the implanted device (with a careful post-marketing tracking), and the follow-up for all the procedures performed at a national level. The data collected in the registry will allow to analyze the implant survival and to better recognize the undesirable and sometimes unexpected effects of different biomaterials on the whole body.

A brown tumor is a rare complication of hyperparathyroidism. Its circumstances of discovery are multiple and its symptoms are nonspecific. We report here two cases with deceptive forms of multiple brown tumors discovered in patients with bone pain. It was a parathyroid adenoma in both cases. So, measurement of parathyroid hormone (even in absence of hypercalcemia) should be systematic in every patient with lytic skeletal images.

A 36-year-old man was diagnosed with Langerhans cell histiocytosis (LCH) of the cervical spine with a unifocal expansive osteolytic lesion of C4. The surgical management with a 2-year follow-up and a review of the literature on LCH of the cervical spine are presented. Although a rare condition, LCH is an important differential diagnosis of any osteolytic lesion in the cervical spine with localized pain in a young adult patient. Review of the literature suggests a higher prevalence of LCH lesions affecting the cervical spine as compared with the thoracic or lumbar spine than historically reported., Competing Interests: The patient consented to submission of this case report to the journal., (Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Competing interests: None declared.

Knee dislocation following total knee replacement arthroplasty is a rare but serious complication. The incidence of dislocation following primary total knee arthroplasty with posterior stabilized implants ranges from 0.15 to 0.5%, and posterior dislocation after revision total knee arthroplasty is even rarer. Here, we report the case of a 76-year-old male who presented with posterior dislocation after posterior stabilized revision total knee arthroplasty.

Clear cell chondrosarcoma (CCCS) is a rare variant of conventional chondrosarcoma with low-grade malignant features that may be confused radiographically and histologically with chondroblastoma. We report a case of a 50-year-old female who presented with 6 months of left hip pain. Initial radiographs demonstrated an osteolytic lesion with adjacent area of sclerosis in the proximal left femur. Magnetic resonance imaging demonstrated a marrow-infiltrative lesion with periosteal reaction and thickened enhancing periosteum. Biopsy of the sclerotic area demonstrated chondroblastoma-like findings, whereas biopsy of the lytic area showed features suggestive of CCCS. The patient eventually underwent en bloc resection and reconstruction with a proximal femoral megaprosthesis. The final diagnosis was CCCS. We present this unusual case with review of the radiographic and histologic features of CCCS with attention to its ability to mimic chondroblastomas. This case highlights the importance of sampling radiographically heterogeneous areas within a bone lesion to facilitate accurate diagnosis and appropriate management.

Periostin is an extracellular matrix protein that actively contributes to tumor progression and metastasis. Here, we hypothesized that it could be a marker of bone metastasis formation. To address this question, we used two polyclonal antibodies directed against the whole molecule or its C-terminal domain to explore the expression of intact and truncated forms of periostin in the serum and tissues (lung, heart, bone) of wild-type and periostin-deficient mice. In normal bones, periostin was expressed in the periosteum and specific periostin proteolytic fragments were found in bones, but not in soft tissues. In animals bearing osteolytic lesions caused by 4T1 cells, C-terminal intact periostin (iPTN) expression disappeared at the invasive front of skeletal tumors where bone-resorbing osteoclasts were present. In vitro, we found that periostin was a substrate for osteoclast-derived cathepsin K, generating proteolytic fragments that were not recognized by anti-periostin antibodies directed against iPTN. In vivo, using an in-house sandwich immunoassay aimed at detecting iPTN only, we observed a noticeable reduction of serum periostin levels (- 26%; P < 0.002) in animals bearing osteolytic lesions caused by 4T1 cells. On the contrary, this decrease was not observed in women with breast cancer and bone metastases when periostin was measured with a human assay detecting total periostin. Collectively, these data showed that mouse periostin was degraded at the bone metastatic sites, potentially by cathepsin K, and that the specific measurement of iPTN in serum should assist in detecting bone metastasis formation in breast cancer.

Neurofibromatosis type (NF1) is an autosomal dominant inherited tumor-suppressor gene syndrome of significant phenotypic variability with probable complete penetrance of the disease. Skeletal malformations of the skull belong to the phenotype of NF1. In the skull, defects of the calvaria and the sphenoid bone are diagnostically groundbreaking findings in NF1. Malformations of the facial skull are usually diagnosed in patients with NF1 in a topographical context with a plexiform neurofibroma (PNF). This report describes the rare occurrence of slowly advancing, unilateral destruction of proportions of the mandible in NF1, with the affected bone segment completely surrounded by a PNF. A malignant process was ruled out as a cause of partial organ loss. Various hypotheses on the pathogenesis of the rare finding are presented., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Multiple myeloma (MM) is characterized by bone destruction due to increased bone resorption and decreased bone formation. Semaphorin 4D (CD100, Sema4D) is expressed by osteoclasts, binds to its receptor Plexin-B1, and acts as a mediator of osteoclast-osteoblast interaction that ultimately inhibits osteoblastic bone formation. Preclinical data suggest that Sema4D/Plexin-B1 pathway is implicated in MM-induced bone disease. However, there is no information on the role of Sema4D in MM patients. Thus, we evaluated Sema4D and Plexin-B1 in six myeloma cells lines in vitro; in the bone marrow plasma (BMP) and serum of 72 newly diagnosed symptomatic MM (NDMM) patients and in 25 healthy controls. Only one myeloma cell line produced high Sema4D. BMP and circulating Sema4D and Plexin-B1 levels were significantly higher in MM patients compared to controls (p < 0.01). Sema4D correlated with serum calcium levels (p < 0.001), increased bone resorption (as assessed by CTX; p < 0.01), and ISS (p < 0.001). There was a trend for higher Sema4D levels in patients with osteolysis (p = 0.07), while patients with diffuse MRI pattern had higher BMP Sema4D levels (p = 0.02). Our data suggest that Sema4D is elevated in MM patients and correlate with adverse myeloma features and increased bone resorption, providing a possible target for novel therapeutic approaches in MM.