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Objective: To provide an evidence-based resource for paleopathologists to consider multiple skeletal indicators of pathology associated with early tooth loss in children to aid in diagnosis., Materials: Three databases (Cochrane Library, MedLine, and Scopus) were used for a review., Methods: According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, a systematic review guideline, 85 articles were selected., Results: A total of 189 children had a syndrome or disease associated with early tooth loss. Our review, based on 25 diseases, lists the bone and dental lesions observable in archeological remains., Conclusions: Based on a review of the literature, a synthesis of 25 diseases and syndromes that may be associated with premature loss of permanent or deciduous teeth in children was developed for paleopathologists. It highlights the importance of a thorough dental examination by paleopathologists to further assess past health conditions., Significance: This paper provides an extensive resource addressing early tooth loss in childhood to assist researchers with differential diagnosis., Limitations: The articles included in this review are case reports based on living populations., Suggestions for Further Research: Further studies into diseases and their association with early tooth loss would complement this work, as would utilizing the differential diagnoses on archeological individuals to clarify its value and limitations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the intricate landscape of multiple myeloma, a hematologic malignancy of plasma cells, bone disease presents a pivotal and often debilitating complication. The emergence of Chimeric Antigen Receptor T-cell (CAR-T) therapy has marked a pivotal shift in the therapeutic landscape, offering novel avenues for the management of MM, particularly for those with relapsed or refractory disease. This innovative treatment modality not only targets malignant cells with precision but also influences the bone microenvironment, presenting both challenges and opportunities in patient care. In this comprehensive review, we aim to examine the multifaceted aspects of bone disease in patients with multiple myeloma and concurrent CAR-T therapy, highlighting its clinical ramifications and the latest advancements in diagnostic modalities and therapeutic interventions. The article aims to synthesize current understanding of the interplay between myeloma cells, CAR-T cells, and the bone microenvironment in the context of current treatment strategies in this challenging and unique patient population., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Type 1 Gaucher disease (GD1) is a rare, autosomal recessive disorder caused by glucocerebrosidase deficiency. Skeletal manifestations represent one of the most debilitating and potentially irreversible complications of GD1. Although imaging studies are the gold standard, early diagnostic/prognostic tools, such as molecular biomarkers, are needed for the rapid management of skeletal complications. This study aimed to identify potential protein biomarkers capable of predicting the early diagnosis of bone skeletal complications in GD1 patients using artificial intelligence. An in silico study was performed using the novel Therapeutic Performance Mapping System methodology to construct mathematical models of GD1-associated complications at the protein level. Pathophysiological characterization was performed before modeling, and a data science strategy was applied to the predicted protein activity for each protein in the models to identify classifiers. Statistical criteria were used to prioritize the most promising candidates, and 18 candidates were identified. Among them, PDGFB, IL1R2, PTH and CCL3 (MIP-1α) were highlighted due to their ease of measurement in blood. This study proposes a validated novel tool to discover new protein biomarkers to support clinician decision-making in an area where medical needs have not yet been met. However, confirming the results using in vitro and/or in vivo studies is necessary.

Background: Growth hormone (GH) positive pituitary neuroendocrine tumors do not always cause acromegaly. Approximately one-third of GH-positive pituitary tumors are classified as non-functioning pituitary tumors in clinical practice. They typically have GH and serum insulin-like growth factor 1 (IGF-1) levels in the reference range and no acromegaly-like symptoms. However, normal hormone levels might not exclude the underlying hypersecretion of GH. This is a rare and paradoxical case of pituitary tumor causing acromegaly-associated symptoms despite normal GH and IGF-1 levels., Case Presentation: We report a case of a 35-year-old woman with suspicious acromegaly-associated presentations, including facial changes, headache, oligomenorrhea, and new-onset diabetes mellitus and dyslipidemia. Imaging found a 19 × 12 × 8 mm pituitary tumor, but her serum IGF-1 was within the reference, and nadir GH was 0.7ng/ml after glucose load at diagnosis. A thickened skull base, increased uptake in cranial bones in bone scan, and elevated bone turnover markers indicated abnormal bone metabolism. We considered the pituitary tumor, possibly a rare subtype in subtle or clinically silent GH pituitary tumor, likely contributed to her discomforts. After the transsphenoidal surgery, the IGF-1 and nadir GH decreased immediately. A GH and prolactin-positive pituitary neuroendocrine tumor was confirmed in the histopathologic study. No tumor remnant was observed three months after the operation, and her discomforts, glucose, and bone metabolism were partially relieved., Conclusions: GH-positive pituitary neuroendocrine tumors with hormonal tests that do not meet the diagnostic criteria for acromegaly may also cause GH hypersecretion presentations. Patients with pituitary tumors and suspicious acromegaly symptoms may require more proactive treatment than non-functioning tumors of similar size and invasiveness., (© 2024. The Author(s).)

Bone health is crucial at all stages of life. Several medical conditions and changes in lifestyle affect the growth, structure, and functions of bones. This may lead to the development of bone degenerative disorders, such as osteoporosis, osteoarthritis, rheumatoid arthritis, etc., which are major public health concerns worldwide. Accurate and reliable measurement and monitoring of bone health are important aspects for early diagnosis and interventions to prevent such disorders. Significant progress has recently been made in developing new sensing technologies that offer non-invasive, low-cost, and accurate measurements of bone health. In this review, we have described bone remodeling processes and common bone disorders. We have also compiled information on the bone turnover markers for their use as biomarkers in biosensing devices to monitor bone health. Second, this review details biosensing technology for bone health assessment, including the latest developments in various non-invasive techniques, including dual-energy X-ray absorptiometry, magnetic resonance imaging, computed tomography, and biosensors. Further, we have also discussed the potential of emerging technologies, such as biosensors based on nano- and micro-electromechanical systems and application of artificial intelligence in non-invasive techniques for improving bone health assessment. Finally, we have summarized the advantages and limitations of each technology and described clinical applications for detecting bone disorders and monitoring treatment outcomes. Overall, this review highlights the potential of emerging technologies for improving bone health assessment with the potential to revolutionize clinical practice and improve patient outcomes. The review highlights key challenges and future directions for biosensor research that pave the way for continued innovations to improve diagnosis, monitoring, and treatment of bone-related diseases., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Fibrous dysplasia (FD) is a benign developmental disorder of the bone that causes normal skeletal tissue to be replaced by excess fibrous tissue and poorly differentiated osteoblasts. Intraosseous xanthomas are benign intraosseous tumor growths characterized microscopically by the presence of lipid-laden foamy histiocytes, often with cortical expansion or disruption. Although FD commonly occurs in craniofacial bones, primary intraosseous xanthomas of the skull or facial skeleton are extremely rare. Although 2 distinct conditions, each may be difficult to differentiate on CT imaging when occurring in the facial skeleton., Methods: We report a case of an incidental finding on craniofacial CT of a frontal bone lesion originally thought to be FD. The finding was in a 55-year-old transgender woman who was assigned male at birth before receiving multiprocedural facial feminization surgery., Results: The clinical features, radiological findings, and treatment are discussed. Postoperatively, the patient had no sequelae secondary to facial feminization surgery or to the orbital lesion biopsy procedure. Bone graft appeared stable on CT imaging, although FD did not appear to resolve completely., Conclusions: Diagnosis of such lesions is challenging and may require both radiographic and histopathologic assessment. As in the case of this patient, intraosseous xanthomas may also be misdiagnosed as other benign lesions such as FD. In most known cases, surgical intervention leads to complete resolution without recurrence of the lesion., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Constitutional diseases of bone form a heterogeneous group of rare diseases of varied phenotypic presentations with a vast genetic heterogeneity. Detected mostly in childhood, they may also be diagnosed in adulthood. Medical history, clinical examination as well as biological and radiological investigations may lead to the diagnosis, which should be confirmed genetically. Joint limitations, early osteoarthritis, hip dysplasia, bone deformity, enthesopathies, bone fragility or a small height can be warning signs of a constitutional disease of bone. Establishing the diagnosis is crucial to enable optimal medical management with a specialized multidisciplinary team., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Osteoporosis is a highly prevalent bone disease worldwide and the most studied bone-associated pathological condition. Although its diagnosis makes use of advanced and clinically relevant imaging and biochemical tools, the information suffers from several limitations and has little or no prognostic value. In this context, circulating micro-RNAs represent a potentially attractive alternative or a useful addition to the diagnostic arsenal and offer a greater prognostic potential than the conventional approaches. These short non-coding RNA molecules act as inhibitors of gene expression by targeting messenger RNAs with different degrees of complementarity, establishing a complex multilevel network, the basis for the fine modulation of gene expression that finally regulates every single activity of a cell. Micro-RNAs may passively and/or actively be released in the circulation by source cells, and being measurable in biological fluids, their concentrations may be associated to specific pathophysiological conditions. Mounting, despite debatable, evidence supports the use of micro-RNAs as markers of bone cell metabolic activity and bone diseases. Indeed, several micro-RNAs have been associated with bone mineral density, fractures and osteoporosis. However, concerns such as absence of comparability between studies and, the lack of standardization and harmonization of the methods, limit their application. In this review, we describe the pathophysiological bases of the association between micro-RNAs and the deregulation of bone cells activity and the processes that led to the identification of potential micro-RNA-based markers associated with metabolic bone diseases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aptamers are single-stranded nucleic acids (DNA, short RNA, or other artificial molecules) produced by the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology, which can be tightly and specifically combined with desired targets. As a comparable alternative to antibodies, aptamers have many advantages over traditional antibodies such as a strong chemical stability and rapid bulk production. In addition, aptamers can bind targets in various ways, and are not limited like the antigen-antibody combination. Studies have shown that aptamers have tremendous potential to diagnose and treat clinical diseases. However, only a few aptamer-based drugs have been used because of limitations of the aptamers and SELEX technology. To promote the development and applications of aptamers, we present a review of the methods optimizing the SELEX technology and modifying aptamers to boost the selection success rate and improve aptamer characteristics. In addition, we review the application of aptamers to treat bone diseases.

C-X-C motif chemokine receptor 4 (CXCR4), stromal cell-derived factor-1 (SDF-1), monocyte chemoattractant protein-1 (MCP-1), extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) affect bone cells and play an important role in bone and joint diseases, but the data on CXCR4, SDF-1, MCP-1, ERK1/2 and NF-κB in the serum of skeletal fluorosis (SF) patients are inconclusive. Thus, according to the "Diagnostic Criteria for Endemic Skeletal Fluorosis" (WS 192-2008), we enrolled patients with SF ( n = 60) as the SF group and those without SF as the controls ( n = 60). Serum levels of CXCR4, SDF-1, MCP-1, ERK1/2 and NF-κB were detected by enzyme-linked immunosorbent assays (ELISAs). Serum SDF-1, CXCR4, MCP-1 and NF-κB levels were significantly higher in the SF group than in the control group. Within the serum of SF patients, CXCR4 and SDF-1 levels were positively correlated with NF-κB levels. There was no correlation between MCP-1 levels and those of ERK1/2 or NF-κB. SDF-1 and CXCR4 may activate the NF-κB pathway, and MCP-1 affects the occurrence and development of SF by regulating osteocytes through other pathways. The SDF-1/CXCR4 axis and MCP-1 signalling pathway provide a new theoretical basis for the occurrence and development of SF.

Chronic Kidney Disease (CKD) is associated with a strong impact on phosphocalcic homeostasis, due to the chronic reduction in glomerular filtration rate (GFR) (phosphate excretion decrease), the inhibition of calcitriol synthesis and dietary restrictions. CKD-Mineral and Bone Disorders (CKD-MBD) must be monitored in CKD patients with biological work-up associated with bone markers and bone density dual X-ray absorptiometry. Adapted diet (phosphate restriction, normalization of calcium intake) and medications (vitamin D, phosphate binders, calcimimetics) help to correct CKD-MBD. Serum parathormone must be kept between 2 to 9 times the usual values, to limit renal osteodystrophy and avoid tertiary hyperparathyroidism. CKD patients are also at risk of artery calcifications, which can significantly increase the morbidity and mortality of the affection. Bisphosphonates may be used after correction of biological abnormalities, in patients with estimated GFR above 30ml/min/1,73m 2 . Even if transplantation aims to normalize kidney function, kidney transplant recipients remain at risk of CKD-MBD. Biology and bone density dual X-ray absorptiometry must be regularly assessed, especially in the few months following the transplantation. More studies are needed to know if treatments of CKD-MBD are well tolerated in severe CKD and if they are associated with a decrease of bone fracture and vascular calcifications., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Fluoride is a natural element widely distributed in the environment and plays an important role in the growth of humans and animals. However, in many species, high concentrations of fluoride induce several problems, such as dental, skeletal, and non-skeletal fluorosis. Sheep living in endemic areas are sensitive to the chronic toxicity of fluoride, and they have been found to suffer not only from teeth and bone problems but also from other organs. Studies indicating the chronic harmful effects of fluoride on teeth, bones, blood biochemical parameters, kidney, liver, heart, reproductive system and growth in sheep have been clearly summarized in this review. Besides, this work also includes updated progress in terms of prevention or reduction of fluoride toxicity in this species., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Bone lesions of Langerhans cell histiocytosis (LCH) may be triggered by trauma., Methods: The characteristics of pediatric patients in the JLSG-02 study cohort who developed a bone lesion at the trauma site at diagnosis of LCH were analyzed retrospectively., Results: Of the 261 pediatric patients with LCH, 12 (4.6%), of median age 4.9 years, had trauma-triggered bone LCH lesions at diagnosis, making them significantly older than the remaining patients (P = 0.006). Trauma sites included the craniofacial regions in 10 patients and the lumbar spine and pelvis in one patient each. At the time of trauma, six patients had a bump at the site, whereas none had extradural hematomas or bone fractures. The median time from trauma to onset was 4 weeks. Of these 12 patients, three had isolated bone (IB) disease; four had multifocal bone (MFB) disease, including the bone lesion at the trauma site; and five had multisystem disease, including four with lesions in neighboring tissue and one with polyuria (posterior pituitary lesion) more than 1 year before the trauma-triggered bone lesion. Treatment responses were good in all 12 patients and none died, but relapses were observed in two patients, one each with IB and MFB disease., Conclusions: About 5% of pediatric patients with LCH developed new trauma-triggered bone lesions at a relatively old age. These lesions can manifest as IB, or, in patients with underlying LCH diseases, as MFB or multisystem. Good clinical outcomes were observed in these patients., (© 2022 Japan Pediatric Society.)

Background: In the Korean medical system, the severity classification for a specific disease depends primarily on its nationwide admission rate in tertiary hospitals. Inversely, one of the important designation criteria for a tertiary hospital is the hospital's treatment ratio of patients classified as having a specific severe disease. Most diseases requiring pediatric orthopaedic surgery (POS) are not currently classified as high severity in terms of disease severity. We investigated the admission rates for the representative POS diseases in tertiary hospitals and compared these rates with those for adult orthopaedic surgery (AOS) diseases., Methods: Seven POS diagnoses and three AOS diagnoses were selected based on frequency of admission. Nationwide sample data were used to investigate the admission rates for these representative diagnoses from 2008 to 2017., Results: Six of the seven frequent POS diagnoses presented high admission rates in tertiary hospitals (62.5-92.3%). In contrast, all frequent AOS diagnoses presented low admission rates in tertiary hospitals., Conclusion: The admission rates of frequent POS diagnoses in tertiary hospitals are high. Considering that these rates are the most important factors for the classification of disease severity, POS diseases seem to be underestimated in terms of severity. This may lead to a tendency for tertiary hospitals to intentionally reduce the admission of children with POS diseases. As a result, these children may not receive appropriate professional care. Therefore, for the disease severity, POS diseases should be classified differently from general AOS diseases by using different criteria reflecting the patient's age., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Monocyte chemoattractant protein-1, also called chemokine (C-C motif) ligand 2 (CCL2) or small inducible cytokine A2, is an inflammatory mediator capable of recruiting monocytes, memory T cells, and dendritic cells. CCL2 is a member of the CC chemokine superfamily, which binds to its receptor, C-C motif chemokine receptor-2 (CCR2), for the induction of chemotactic activity and an increase of calcium influx. It exerts multiple effects on a variety of cells, including monocytes, macrophages, osteoclasts, basophils, and endothelial cells, and is involved in a diverse range of diseases. This review discusses the molecular structure and role of CCL2 and CCR2 in skeletal biology and disease. Molecular structure analyses reveal that CCL2 shares a conserved C-C motif; however, it has only limited sequence homology with other CCL family members. Likewise, CCR2, as a member of the G-protein-coupled seven-transmembrane receptor superfamily, shares conserved cysteine residues, but exhibits very limited sequence homology with other CCR family members. In the skeletal system, the expression of CCL2 is regulated by a variety of factors, such as parathyroid hormone/parathyroid hormone-related peptide, interleukin 1b, tumor necrosis factor-α and transforming growth factor-beta, RANKL, and mechanical forces. The interaction of CCL2 and CCR2 activates several signaling cascades, including PI3K/Akt/ERK/NF-κB, PI3K/MAPKs, and JAK/STAT-1/STAT-3. Understanding the role of CCL2 and CCR2 will facilitate the development of novel therapies for skeletal disorders, including rheumatoid arthritis, osteolysis and other inflammatory diseases related to abnormal chemotaxis., (© 2021 Wiley Periodicals LLC.)

Zygomatic root abscess is a rare extracranial extratemporal complication of otitis media. To the best of our knowledge, there are only a few scattered cases of zygomatic root abscesses reported in the literature. We present an unusual case of a zygomatic root abscess in a 24 years old adult. He presented with one month duration of right zygomatic swelling. Otoscopic examination revealed superior and posterior external auditory canal wall sagging with an intact tympanic membrane. High Resolution Computed Tomography (HRCT) temporal bone revealed a rim enhancing lesion lateral to the zygomatic process with fluid filled mastoid air cells. He was managed with antibiotics and staged surgical interventions. He recovered well. Our case serves to shed light on the pathways of infection, clinical manifestations and timely staged surgical intervention in this rare pathology., Competing Interests: Declaration of Competing Interest No potential conflict of interest relevant to this article was reported., (Copyright © 2020. Published by Elsevier B.V.)

Cystic echinococcosis (CE) may be encountered in almost every site of the body, but bone involvement is relatively rare. The vertebral column and pelvis are the most affected areas. The combined medical and surgical approach is the main treatment option in current literature. Although percutaneous treatment of CE cysts located in the liver, spleen, kidney, and soft tissues has become a serious alternative to surgery, there is no bone CE cyst treated percutaneously in the literature. This case report aims to point out that percutaneous treatment can be an effective treatment choice and alternative to surgery.

In a healthy body, homeostatic actions of osteoclasts and osteoblasts maintain the integrity of the skeletal system. When cellular activities of osteoclasts and osteoblasts become abnormal, pathological bone conditions, such as osteoporosis, can occur. Traditional imaging modalities, such as radiographs, are insensitive to the early cellular changes that precede gross pathological findings, often leading to delayed disease diagnoses and suboptimal therapeutic strategies. 18 F-sodium fluoride ( 18 F-NaF)-positron emission tomography (PET) is an emerging imaging modality with the potential for early diagnosis and monitoring of bone diseases through the detection of subtle metabolic changes. Specifically, the dissociated 18 F - is incorporated into hydroxyapatite, and its uptake reflects osteoblastic activity and bone perfusion, allowing for the quantification of bone turnover. While 18 F-NaF-PET has traditionally been used to detect metastatic bone disease, recent literature corroborates the use of 18 F-NaF-PET in benign osseous conditions as well. In this review, we discuss the cellular mechanisms of 18 F-NaF-PET and examine recent findings on its clinical application in diverse metabolic, autoimmune, and osteogenic bone disorders.

Bone diseases constitute a major issue for modern societies as a consequence of progressive aging. Advantages such as open mesoporous channel, high specific surface area, ease of surface modification, and multifunctional integration are the driving forces for the application of mesoporous nanoparticles (MNs) in bone disease diagnosis and treatment. To achieve better therapeutic effects, it is necessary to understand the properties of MNs and cargo delivery mechanisms, which are the foundation and key in the design of MNs. The main types and characteristics of MNs for bone regeneration, such as mesoporous silica (mSiO 2 ), mesoporous hydroxyapatite (mHAP), mesoporous calcium phosphates (mCaPs) are introduced. Additionally, the relationship between the cargo release mechanisms and bone regeneration of MNs-based nanocarriers is elucidated in detail. Particularly, MNs-based smart cargo transport strategies such as sustained cargo release, stimuli-responsive (e.g., pH, photo, ultrasound, and multi-stimuli) controllable delivery, and specific bone-targeted therapy for bone disease diagnosis and treatment are analyzed and discussed in depth. Lastly, the conclusions and outlook about the design and development of MNs-based cargo delivery systems in diagnosis and treatment for bone tissue engineering are provided to inspire new ideas and attract researchers' attention from multidisciplinary areas spanning chemistry, materials science, and biomedicine., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

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.)

Background: Bone sporotrichosis is rare. The metropolitan region of Rio de Janeiro is hyperendemic for zoonotic sporotrichosis and the bone presentations are increasing., Methods: We studied a retrospective cohort of 41 cases of bone sporotrichosis, diagnosed from 1999-2016. The inclusion criteria was fungal culture isolation from any clinical specimen associated to bone involvement (radiography and/or computed tomography) compatible with fungal osteomyelitis or histopathological findings of bone material compatible with sporotrichosis. Molecular identification was performed when possible., Results: Male patients represented 58.5% of the cases, with a cohort median age of 43 years. Immunosuppressive conditions were present in 68.3% of the patients, mostly HIV coinfection (51.2%). Multifocal bone involvement (more than one anatomical segment) was diagnosed in 61% of the patients, while 39% presented unifocal involvement. The bones of the hands were the most affected (58.5%), followed by the feet (41.5%) and tibia (26.8%). Multifocal group was characterized by a higher proportion of males (p = 0.0045) with immunosuppressive conditions (p = 0.0014). Amphotericin B followed by oral itraconazole was the main treatment, with a median time of 16.7 months (1.5 to 99.2 months), and cure of 53.7% of the patients (84.6% of immunocompetent and 39.3% of immunocompromised patients). Sequelae occurred in 12.2% of the patients-amputations (7.3%) and ankylosis (4.9%), while 22% died in the course of the disease. Sporothrix brasiliensis was the causative agent in all the 9 (22%) performed cases., Conclusions: Bone sporotrichosis is a chronic, challenging condition with prolonged treatment, often with poor results and sequelae., Competing Interests: The authors have declared that no competing interests exist.

Cystic angiomatosis (CA) is a rare disease characterized by the proliferation of vascular and lymphatic channels lined by a single layer of endothelial cells. CA may present with isolated skeletal or visceral disease. There is no consensus for the standard of care in these patients, and diverse regimens for CA have been reported, including observation, surgery, radiation, and a variety of medical therapies. We present a case of multifocal, isolated skeletal CA, treated with close observation alone and review the literature. We suggest that these cases may be safely followed without intervention and may be stable for prolonged periods of time., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pseudocarcinomatous squamous hyperplasia (PSH) within the bone is uncommon and closely mimics well-differentiated squamous cell carcinoma (SCC). It arises from cutaneous or mucosal surfaces and grows directly into the bone. This study analyzes a large series of PSH and discusses the clinicopathologic features that facilitate its distinction from SCC., Design: Cases were identified from the surgical pathology files between 1985 and 2020., Results: The 31 cases included 21 males, 9 females, 1 unknown sex; who were 20 to 87 years old (average: 59 y). Sites included mandible-17, maxilla-5, toes-4, and 1 case from finger, femur, tibia, ischium, and unknown. Fourteen patients had a history of SCC, 13 treated with resection and chemoradiation and developed infected osteoradionecrosis, 4-medication-related osteonecrosis, 3-peripheral vascular disease, and diabetes mellitus, 3-trauma, 3-osteomyelitis, 3-unknown, and 1-hematologic malignancy. All cases exhibited severe osteomyelitis and nests of reactive keratinizing squamous epithelium that matured towards the bone surface, lacked significant atypia, or mitotic activity but permeated the medullary cavity. Patients with previous SCC developed PSH after 2 months to 8 years (average: 4 y). Nineteen of 30 patients had follow-up (2 to 48 mo, average: 17 mo); 6 patients experienced repeated debridements over 2 months to 1 year; no patient developed SCC., Conclusions: PSH involving bone is infrequent, complicates severe osteomyelitis, and is often therapy related. The clinical findings are usually not concerning for malignancy, however, the histologic findings are an important diagnostic pitfall because they mimic SCC., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.

We present a rare case of sarcoidosis with extensive bony destruction of the maxillofacial and skull base bones. A 65-year-old woman was referred with an asymptomatic, non-healing dental socket. Examination revealed an oroantral fistula that was biopsied and repaired under general anaesthesia. Investigations included plain and cross-sectional imaging. Serological tests, in particular ACE, were normal. Histology showed benign florid granulomatous inflammation. At 6 months, the patient remained asymptomatic. She was re-referred 3 years later with further bony destruction of her maxilla and mandible. Repeat imaging showed intrathoracic lymphadenopathy and skull base involvement. Repeat biopsy confirmed granulomatous inflammation. Given the pulmonary, histological and radiological findings, a sarcoidosis diagnosis was made. Following multidisciplinary team meetings, the patient was treated with methotrexate and arrangements made for close monitoring. This case highlights the need for a consensus in identifying, treating and developing a follow-up protocol in such patients., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years, Raman spectroscopy has undergone major advancements in its ability to probe deeply through turbid media such as biological tissues. This progress has been facilitated by the advent of a range of specialist techniques based around spatially offset Raman spectroscopy (SORS) to enable non-invasive probing of living tissue through depths of up to 5 cm. This represents an improvement in depth penetration of up to two orders of magnitude compared to what can be achieved with conventional Raman methods. In combination with the inherently high molecular specificity of Raman spectroscopy, this has therefore opened up entirely new prospects for a range of new analytical applications across multiple fields including medical diagnosis and disease monitoring. This article discusses SORS and related variants of deep Raman spectroscopy such as transmission Raman spectroscopy (TRS), micro-SORS and surface enhanced spatially offset Raman spectroscopy (SESORS), and reviews the progress made in this field during the past 5 years including advances in non-invasive cancer diagnosis, monitoring of neurotransmitters, and assessment of bone disease.

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.)

Objectives: This paper aims to provide an explicit theoretical model for the cognitive processes involved in paleopathological diagnosis., Methods: The approach adopted is a dual process model (DPM). DPMs recognize that cognition is a result of both Type 1 (intuitive) and Type 2 (analytical) processes. DPMs have been influential for understanding decision-making in a range of fields, including diagnosis in clinical medicine. Analogies are drawn between diagnosis in a clinical and a paleopathological setting., Results: In clinical medicine, both Type 1 and Type 2 processes play a part in diagnosis. In paleopathology the role of Type 1 processes has been unacknowledged. However, like clinical diagnosis, paleopathological diagnosis is inherently a result of a combination of both Type 1 and Type 2 processes. A model is presented by which Type 1 processes can be explicitly incorporated into a scientific approach to diagnosis from skeletal remains, and in which diagnosis is formalized as a process of hypothesis testing., Significance: Accurately modelling our diagnostic processes allows us to understand the biases and limitations in our work and potentially helps us to improve our procedures, including how we impart diagnostic skills in pedagogical settings., Limitations: This work provides a theoretical model for paleopathological diagnosis. However, such models are by their nature dynamic and developing rather than static entities; it is hoped that this work stimulates further debate and discussion in this important area., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The last 2 decades have seen tremendous growth in understanding the clinical characteristics of various childhood bone disorders, their mechanisms and natural histories, and their responses to treatment. In this review, the authors describe advances in bone assessment techniques for children. In addition, they provide their skeletal site-specific applications, underscore the principles that are relevant to the biology of the growing child, show how these methods assist in the diagnosis and management of pediatric bone diseases, and highlight how these techniques have shed light on bone development and underlying disease mechanisms., Competing Interests: Disclosure L.M. Ward has participated in clinical trials with ReveraGen BioPharma, PTC Therapeutics, Catabasis Pharmaceuticals, Novartis, Ultragenyx, and Amgen. Dr L.M. Ward has also received unrestricted educational grants from Alexion and Ultragenyx, and consulting fees from Ipsen, Ultragenyx, PTC Therapeutics, Novartis, and Amgen, with funds to Dr L.M. Ward’s institution. V.N. Konji has no conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A lobular capillary hemangioma, previously known as a pyogenic granuloma, is a benign vascular lesion of the skin or mucous membrane. We report a case of capillary hemangioma of lobular subtype in the calvarium of a 28-year-old pregnant woman which presented as a sore and rapidly growing bulge over the left fronto-parietal region. Magnetic resonance imaging of the brain and skull showed an expansive tumor with brain displacement, skull erosion, and scalp infiltration. The tumor was surgically removed, and histopathological examination showed a capillary hemangioma of lobular subtype. To the best of our knowledge, this is the first report of a lobular capillary hemangioma in the calvarium, and it represents a rarity to be considered among the many other differential diagnoses for neurosurgical lesions involving the skull, especially in pregnant women.

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.)

Many children with chronic disease are now surviving into adulthood. As a result, there is a growing interest in optimizing bone health early in the disease course with the dual goals of improving quality of life during childhood and reducing life-long fracture risk. Risk factors for impaired bone health in these children include immobility, nutritional deficiency, exposure to bone toxic therapies, hormonal deficiencies affecting growth and pubertal development, and chronic inflammation. This review focuses on the chronic diseases of childhood most commonly associated with impaired bone health. Recent research findings and clinical practice recommendations, when available, for specific disorders are summarized., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: The diagnosis of osteoporosis and assessment of fracture risk prior to a sentinel fracture was transformed by the widespread clinical use of dual-energy X-ray absorptiometry (DXA) for the assessment of bone mineral density (BMD)., Evidence Acquisition: This review is based on a collection of primary and review literature gathered from a PubMed search of "dual energy X-ray absorptiometry," "trabecular bone score," and "atypical femur fracture" among other keywords. PubMed searches were supplemented by the authors' prior knowledge of the subject., Evidence Synthesis: While uncertainty exists for some aspects of osteoporosis care, patient and clinician familiarity with BMD assessment for screening and monitoring is firmly established. Beyond BMD, lateral spine images obtained with DXA can diagnose osteoporosis and refine fracture risk through the detection of unrecognized vertebral fractures. In addition, analysis of DXA lumbar spine images can reflect changes in trabecular bone microarchitecture, a component of bone "quality" that predicts risk of fracture independent of BMD. Finally, monitoring of bone health by DXA may be extended to include assessment of the femoral cortices for rare but serious adverse effects associated with antiresorptive therapies., Conclusions: Increasing technologic sophistication requires additional consideration for how DXA imaging is performed, interpreted and applied to patient care. As with any test, clinicians must be familiar with DXA performance, pitfalls in analysis, and interpretation within each clinical context in which DXA is applied. With this perspective, care providers will be well positioned to contribute to continuous improvement of DXA performance and, in turn, quality of osteoporosis care., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Sclerostin and osteoprotegerin (OPG) are new markers of chronic kidney disease (CKD) mediated mineral bone disease (CKD-MBD) which were extensively evaluated in adult population. We aimed to evaluate the associations between serum levels of sclerostin/OPG and parameters of bone turnover and compare the serum levels of sclerostin/OPG in different stages of CKD in children. Methods 70 children with CKD stage 1-5, aged 2-21 years were examined. Serum levels of alkaline phosphatase (ALP), creatinine, total calcium, phosphorus , intact parathyroid hormone (iPTH) and vitamin D were measured. Serum sclerostin and OPG levels were measured in children with different levels of CKD stage and their association with bone turnover parameters were noted. Results We did not observe any significant correlation between serum levels of sclerostin and OPG and stages of CKD. A negative relationship was present between serum sclerostin and 25-OH vitamin D levels. Osteoprotegerin was positively and significantly correlated with ALP but serum sclerostin was negatively correlated with ALP. Conclusion Our study, which includes only children and adolescents with a growing skeleton under uremic conditions and excluding diabetes and atherosclerosis interference, is very valuable. We couldn't find any significant relationship between either sclerostin or OPG levels among different stages of CKD. Also our study demonstared a strong negative relationship between ALP and sclerostin levels and a strong positive relationship between ALP and OPG levels, reminding the importance of ALP levels to predict the bone-mineral status of the children with CKD.

Competing Interests: AUTHOR DISCLOSUREDrs Kamat and Leingang have disclosed no financial relationships or conflicts of interest relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

Hamamy syndrome (HS) is an autosomal recessive syndrome with a genetic origin that is very rarely observed. The syndrome with craniofacial dysmorphisms, including midface prominence, severe telecanthus, sparse lateral eyebrows, protruding ears, fronto-nasal abnormalities, lacrimal-salivary apparatus agenesis, thin upper vermillion border, myopia, mental retardation, sensorineural hearing impairment, congenital heart anomalies with intraventricular conduction delay, hypochromic microcytic anaemia and skeletal abnormalities of the long bones with recurrent fractures. In this paper, we report a case of two brothers diagnosed with HS at the ages of 25 and 18 years, visited out clinic at different times due to dental reasons. In the radiological examinations, it was observed that both brothers have sphenoid sinuses agenesia, and their sella turcica were smaller than normal. HS may be observed very rarely, and it should be kept in mind that, in addition to various symptoms, it may also cause sphenoid sinus agenesis and sella turcica hypoplasia as shown for the first time in this case report.

Bone and joint infections (BJI) of the lower limb can cause functional sequelae and in some cases have an impact on patient's life prognostic. One of the main objectives of multidisciplinary consultation team meetings (MTM) in the treatment of bone and joint infections is to provide an appropriate medical-surgical care, pooling skills of different organ specialists: infectious disease physicians, microbiologists, orthopedic surgeons and plastic surgeons. Treatment is based on aggressive debridement, bone stabilization, adequate antibiotic therapy, long-term coverage of the loss of skin substance and close clinical monitoring. The authors present their multidisciplinary diagnostic and therapeutic approaches to BJI complicating an open fracture at a referent center in the management of complex bone and joint infections., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Bone tissue engineering employs acellular scaffolds or scaffolds, along with cells and growth factors, to provide the mechanical support needed, as well as serve as a delivery vehicle for bioactive molecules to the injury sites. As tissue engineering continues to evolve, it has integrated two emerging fields: stem cells and nanotechnology. A paracrine factor that is found to be responsible for the major regenerative effect in stem cell transplantation is an extracellular vesicle called an 'exosome'. Recent advances in nanotechnology have allowed the 'exosome' to be distinguished from other extracellular vesicles and be polymerized into a well-defined concept. Scientists are now investigating exosome uses in clinical applications. For bone-related diseases, exosomes are being explored as biomarkers for different bone pathologies. They are also being explored as a therapeutic agent where progenitor cell-derived exosomes are used to regenerate damaged bone tissue. In addition, exosomes are being tested as immune modulators for bone tissue inflammation, and finally as a delivery vehicle for therapeutic agents. This review discusses recently published literature on the clinical utilization of exosomes in bone-related applications and the correlated advantages. A particular focus will be placed on the potential utilization of regenerative cell-derived exosomes as a natural biomaterial for tissue regeneration.

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

Background: Chronic pancreatitis (CP) patients have a high prevalence of osteoporotic fractures. In addition to prevalence of osteoporotic fractures, we evaluated how often bone health is assessed by dual-energy x-ray absorptiometry (DXA) in clinical practice, and the performance of Fracture Risk Assessment Tool (FRAX®) in predicting fracture risk in CP patients., Methods: Medical records of CP patients age ≥40 years prospectively enrolled in the North American Pancreatitis Study 2 (NAPS2) from the University of Pittsburgh Medical Center from 2000 to 2014 were retrospectively reviewed to gather additional relevant data before, at, and after enrollment until December 2016. We determined if patients underwent DXA, compared their observed prevalence of fractures with published data from two large US studies based on administrative data, and their predicted fracture risk with US population based on FRAX®., Results: Only 21% (49/239) patients were evaluated by DXA during their care. The observed cumulative prevalence of fragility fractures in NAPS2 CP patients (9.2%, 95% confidence interval 5.9-13.6) was significantly greater than in controls (1.46% and 2.16%, p ≤ 0.001 for each comparison) and CP patients (4.66%, and 5.13%, p < 0.005 for each comparison) in the two US administrative data studies. The FRAX® 10-year probability of major osteoporotic fracture of ≥20% (5.1% vs. 8.3%, p > 0.05) and for hip fracture of ≥3% (19.6% vs. 18.9%, p > 0.05) in NAPS2 CP patients did not differ from the US population., Conclusions: Despite their high risk of fragility fractures, bone health is infrequently assessed in CP patients. FRAX® may not adequately predict fracture risk in CP patients., (Copyright © 2020. Published by Elsevier B.V.)

This approach to the work-up and diagnosis will help you to ensure prompt treatment while maximizing your patient's quality of life.

Competing Interests: Competing interests: None declared.