H vessels are an essential link in angiogenic-osteogenic coupling and orchestrate the process of bone healing. H vessels are critically deficient in the setting of radiation-induced fractures, which have been reported to occur in up to 25% of patients undergoing radiotherapy. By increasing H-vessel proliferation, Deferoxamine (DFO) revitalizes the physiologic response to skeletal injury and accelerates irradiated fracture repair. H-vessel quantification is therefore an important outcome measure in histologic analysis of bone healing. However, an optimized protocol for staining H vessels in formalin-fixed paraffin-embedded (FFPE) tissue sections has not been reported. With this protocol, we describe a method of staining FFPE bone samples with minimal background fluorescence and high signal-to-noise ratio. We examined mandibular specimens in a rat model of bone healing from a range of fracture conditions, including healthy bone (Fx), irradiated bone (XFx), and irradiated bone with DFO treatment (XFx-DFO). Quantitative analysis revealed a significant increase of H vessels in the XFxDFO group compared to both the Fx and XFx groups. By optimizing immunofluorescent staining of H vessels in FFPE samples across a range of fracture conditions, we offer investigators an efficacious means of producing reliable imaging for quantitative analysis of H vessels in an irradiated fracture callus.

UNASSIGNED: Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival.
UNASSIGNED: A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs.
UNASSIGNED: A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01).
UNASSIGNED: Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents-particularly maltoses-of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue.

Over a span of more than two years, a collaborative expert group consisting of 9 professional societies has meticulously crafted the S2e guideline on fracture sonography. This publication encapsulates the essential insights pertaining to specific indications. A thorough and systematic literature search, covering the period from 2000 to March 2021, was conducted across PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews, complemented by an evaluation of bibliographies. Inclusion criteria encompassed randomized controlled clinical trials, observational clinical trials, meta-analyses, and systematic reviews, while guidelines, conferences, reviews, case reports, and expert opinions were excluded. The SIGN grading system (1999-2012) was applied to assess evidence, and resultant SIGN tables were presented to the expert group. Specific recommendations for the application of fracture sonography were then derived through unanimous consensus after detailed discussions. Out of the initial pool of 520 literature sources, a meticulous screening and content assessment process yielded 182 sources (146 clinical studies and 36 meta-analyses and systematic reviews) for evaluation. The comprehensive analysis identified twenty-one indications that substantiate the judicious use of fracture sonography. Ultrasound emerges as a pragmatic and user-friendly diagnostic method, showcasing feasibility across a diverse range of indications.

UNASSIGNED: The aim of this study was to investigate the efficacy of calcitonin (CT) in animal models of experimental osteoarthritis (OA) and rheumatoid arthritis (RA), as new stabilized CT formulations are currently being introduced.
UNASSIGNED: A comprehensive and systemic literature search was conducted in PubMed/MEDLINE and Embase databases to identify articles with original data on CT treatment of preclinical OA and RA. Methodological quality was assessed using the Systematic Review Centre for Laboratory Animal Experimentation\'s risk of bias tool for animal intervention studies. To provide summary estimates of efficacy, a meta-analysis was conducted for outcomes reported in four or more studies, using a random-effects model. Subgroup analyses were employed to correct for study specifics.
UNASSIGNED: Twenty-six studies were ultimately evaluated and data from 16 studies could be analyzed in the meta-analysis, which included the following outcomes: bone mineral density, bone volume, levels of cross-linked C-telopeptide of type I collagen, histopathological arthritis score, and mechanical allodynia. For all considered outcome parameters, CT-treated groups were significantly superior to control groups (P = 0.002; P = 0.01; P < 0.00001; P < 0.00001; P = 0.04). For most outcomes, effect sizes were significantly greater in OA than in RA (P ≤ 0.025). High in-between study heterogeneity was detected.
UNASSIGNED: There is preclinical evidence for an antioxidant, anti-inflammatory, antinociceptive, cartilage- and bone-protective effect of CT in RA and OA. Given these effects, CT presents a promising agent for the treatment of both diseases, although the potential seems to be greater in OA.

BACKGROUND: Delayed union, malunion, and nonunion are serious complications in the healing of fractures. Predicting the risk of nonunion before or after surgery is challenging.
OBJECTIVE: To compare the most prevalent predictive scores of nonunion used in clinical practice to determine the most accurate score for predicting nonunion.
METHODS: We collected data from patients with tibial shaft fractures undergoing surgery from January 2016 to December 2020 in three different trauma hospitals. In this retrospective multicenter study, we considered only fractures treated with intramedullary nailing. We calculated the tibia FRACTure prediction healING days (FRACTING) score, Nonunion Risk Determination score, and Leeds-Genoa Nonunion Index (LEG-NUI) score at the time of definitive fixation.
RESULTS: Of the 130 patients enrolled, 89 (68.4%) healed within 9 months and were classified as union. The remaining patients (n = 41, 31.5%) healed after more than 9 months or underwent other surgical procedures and were classified as nonunion. After calculation of the three scores, LEG-NUI and FRACTING were the most accurate at predicting healing.
CONCLUSIONS: LEG-NUI and FRACTING showed the best performances by accurately predicting union and nonunion.

OBJECTIVE: This systematic review aims to evaluate existing evidence to investigate the therapeutic efficacy of M2 macrophage-derived exosomes in bone regeneration.
METHODS: A comprehensive search between 2020 and 2024 across PubMed, Web of Science, and Scopus was conducted using a defined search strategy to identify relevant studies regarding the following question: \"What is the impact of M2 macrophage-derived exosomes on bone regeneration?\". Controlled in vitro and in vivo studies were included in this study. The SYRCLE tool was used to evaluate the risk of bias in the included animal studies.
RESULTS: This review included 20 studies published. Seven studies were selected for only in vitro analysis, whereas 13 studies underwent both in vitro and in vivo analyses. The in vivo studies employed animal models, including 163 C57BL6 mice and 73 Sprague-Dawley rats. Exosomes derived from M2 macrophages were discovered to be efficacious in promoting bone regeneration and vascularization in animal models of bone defects. These effects were primarily confirmed through morphological and histological assessments. This remarkable outcome is attributed to the regulation of multiple signaling pathways, as evidenced by the findings of 11 studies investigating the involvement of miRNAs in this intricate process. In addition, in vitro studies observed positive effects on cell proliferation, migration, osteogenesis, and angiogenesis. Heterogeneity in study methods hinders direct comparison of results across studies.
CONCLUSIONS: M2 macrophage-derived exosomes demonstrate remarkable potential for promoting bone regeneration. Further research optimizing their application and elucidating the underlying mechanisms can pave the way for clinical translation.

In 2023 following extensive consultation with key stakeholders, the expert Nosology Working Group of the International Skeletal Dysplasia Society (ISDS) published the new Dyadic Nosology for Genetic Disorders of the Skeleton. Some 770 entities were delineated associated with 552 genes. From these entities, over 40 genes resulting in distinct forms of Osteogenesis Imperfecta (OI) and Bone Fragility and/or Familial Osteoporosis were identified. To assist clinicians and lay stake holders and bring the considerable body of knowledge of the matrix biology and genomics to people with OI as well as to clinicians and scientists, a dyadic nosology has been recommended. This combines a genomic co-descriptor with a phenotypic naming based on the widely used Sillence nosology for the OI syndromes and the many other syndromes characterized in part by bone fragility.This review recapitulates and explains the evolution from the simple Congenita and Tarda subclassification of OI in the 1970 nosology, which was replaced by the Sillence types I-IV nosology which was again replaced in 2009 with 5 clinical groups, type 1 to 5. Qualitative and quantitative defects in type I collagen polypeptides were postulated to account for the genetic heterogeneity in OI for nearly 30 years, when OI type 5, a non-collagen disorder was recognized. Advances in matrix biology and genomics since that time have confirmed a surprising complexity both in transcriptional as well as post-translational mechanisms of collagens as well as in the many mechanisms of calcified tissue homeostasis and integrity.

OBJECTIVE: To evaluate the effect of osteotomy preparation technique and implant diameter on primary stability and bone-implant interface of short implants (6mm), when placed in bone with high degree of cancellous content.
METHODS: 90 short (S) implants (6 mm) divided in nine groups based on width (Narrow 4.2 mm, Regular 4.8 mm, Wide 5.4 mm) (N,R,W) and osteotomy preparation (Standard, Osteotome, Osseodensification) (ST, OT, OD) and placed in porcine tibia plateau bone samples: Group SN-ST; Group SN-OT; Group SN-OD; Group SRST; Group SR-OT; Group SR-OD; Group SW-ST; Group SW-OT and Group SW-OD. Insertion torque and Implant Stability Quotient (ISQ) were measured. Four implants from each group SNST, SN-OT, SN-OD were evaluated histomorphometrically.
RESULTS: Insertion torque was significantly higher for implants of Group SW-OD compared to Group SW-ST (50.00 ±14.14 Ncm vs 28.00 ±10.85 Ncm, p= 0.005) and Group SW-OT compared to Group SW-ST (46.87 ±17.10 Ncm vs 28.00 ±10.85 Ncm, p=0.026). Insertion torque was significantly higher for implants of Group SW-OD compared to Group SN-OD (50.00 ±14.14 Ncm vs 31.5 ±15.82 Ncm, p=0.04). No significant differences were observed for the percentage of bone, marrow space and connective tissue in contact to the implant surface between studied groups.
CONCLUSIONS: Osteotomy preparation technique at sites with high degree of cancellous content can influence the implant insertion torque for short and wide implants (5.4x6mm). Implant width can influence the insertion torque of short implants placed with the osseodensification technique.

Myoepithelioma is a benign salivary gland tumor. Central myoepitheliomas are very rare. The aim of this report was to describe a case of maxillary myoepithelioma. A 14-year-old female patient presented with an multilocular lesion in the anterior maxilla, with nearly 8 months of duration. The lesion was asymptomatic, and the patient\'s dental history was unremarkable. The diagnostic hypothesis was an odontogenic tumor. Biopsy specimen consisted of nests of plasmacytoid cells in a myxoid stroma without duct formation. No cellular atypia or bone and cartilage formation were noted. The neoplastic cells were positive for Pan-cytokeratin, S100, CK7, and CK8. The final diagnosis was myoepithelioma. The patient was treated by surgical excision followed by bone curettage, and no signs of recurrence were found after 8 years of treatment.