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JBMR Plus Jul 2024Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new...
Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 μg/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume ( = .0028), Trabecular Number ( = .0076), Trabecular Fractal Dimension ( = .0044), and increasing Trabecular Separation ( = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot.
PubMed: 38855797
DOI: 10.1093/jbmrpl/ziae066 -
Theranostics 2024Current pharmacological therapeutic approaches targeting chronic inflammation exhibit transient efficacy, often with adverse effects, limiting their widespread use -... (Review)
Review
Current pharmacological therapeutic approaches targeting chronic inflammation exhibit transient efficacy, often with adverse effects, limiting their widespread use - especially in the context of neuroinflammation. Effective interventions require the consideration of homeostatic function, pathway dysregulation, and pleiotropic effects when evaluating therapeutic targets. Signalling molecules have multiple functions dependent on the immune context, and this complexity results in therapeutics targeting a single signalling molecule often failing in clinical translation. Additionally, the administration of non-physiologic levels of neurotrophic or anti-inflammatory factors can alter endogenous signalling, resulting in unanticipated effects. Exacerbating these challenges, the central nervous system (CNS) is isolated by the blood brain barrier (BBB), restricting the infiltration of many pharmaceutical compounds into the brain tissue. Consequently, there has been marked interest in therapeutic techniques capable of modulating the immune response in a pleiotropic manner; ultrasound remains on this frontier. While ultrasound has been used therapeutically in peripheral tissues - accelerating healing in wounds, bone fractures, and reducing inflammation - it is only recently that it has been applied to the CNS. The transcranial application of low intensity pulsed ultrasound (LIPUS) has successfully mitigated neuroinflammation , in models of neurodegenerative disease across a broad spectrum of ultrasound parameters. To date, the underlying biological effects and signalling pathways modulated by ultrasound are poorly understood, with a diverse array of reported molecules implicated. The distributed nature of the beneficial response to LIPUS implies the involvement of an, as yet, undetermined upstream signalling pathway, homologous to the protective effect of febrile range hyperthermia in chronic inflammation. As such, we review the heat shock response (HSR), a protective signalling pathway activated by thermal and mechanical stress, as the possible upstream regulator of the anti-inflammatory effects of ultrasound.
Topics: Humans; Animals; Heat-Shock Response; Neuroinflammatory Diseases; Ultrasonic Therapy; Inflammation; Blood-Brain Barrier
PubMed: 38855178
DOI: 10.7150/thno.96270 -
BMC Oral Health Jun 2024To investigate the fracture resistance and failure modalities of anterior endocrown restorations fabricated employing diverse ceramic materials, and bonded using various...
OBJECTIVE
To investigate the fracture resistance and failure modalities of anterior endocrown restorations fabricated employing diverse ceramic materials, and bonded using various cementation methodologies.
MATERIALS AND METHODS
Forty maxillary central incisors were divided into two main groups based on the ceramic materials used; GroupI (Zir): zirconia endocrwons (Zolid HT, Ceramill, Amanngirrbach) and GroupII (E-Max): e-max endocrowns (IPS e.max CAD, Ivoclar Vivadent). Both groups were further split into two subgroups depending on the cementation protocols; subgroup IA "ZirMDP": endocowns cemented with MDP primer + MDP resin cement, subgroup IB (ZirNon-MDP): cemented with MDP primer + non-MDP resin cement, subgroup IIA (E-maxMDP): cemented with MDP primer + MDP resin cement, subgroup IIB (E-maxNon-MDP): cemented with MDP primer + non-MDP resin cement. (n = 10/subgroup). Endocrowns were manufactured using CAD/ CAM. Teeth were subjected to 10,000 thermal cycles. The fracture test was performed at 45 with a palatal force direction until the fracture occurred. Test results were recorded in Newton. The failure mode was examined using a stereomicroscope. A One-way ANOVA test was utilized to compare different groups regarding fracture strength values. Tukey`s Post Hoc was utilized for multiple comparisons.
RESULTS
The comparative analysis of fracture strength across the diverse groups yielded non-significant differences, as indicated by a p-value exceeding 0.05. Nonetheless, an observable trend emerged regarding the mode of failure. Specifically, a statistically significant prevalence was noted in fractures localized within the endocrown/tooth complex below the cementoenamel junction (CEJ) across all groups, except for Group IIB, "E-max Non-MDP," where fractures within the endocrown/tooth complex occurred above the CEJ.
CONCLUSIONS
Combining an MDP-based primer with an MDP-based resin cement did not result in a significant effect on the anterior endocrown fracture strength.
CLINICAL RELEVANCE
Regardless of the presence of the MDP monomer in its composition, adhesive resin cement achieved highly successful fracture strength when used with MDP-based ceramic primers. Additionally, ceramic materials exhibiting elastic moduli surpassing those of dentin are discouraged due to their propensity to induce catastrophic fractures within the tooth structure.
Topics: Humans; Cementation; Incisor; In Vitro Techniques; Dental Stress Analysis; Resin Cements; Zirconium; Materials Testing; Crowns; Dental Restoration Failure; Ceramics; Dental Materials; Computer-Aided Design; Dental Porcelain
PubMed: 38851731
DOI: 10.1186/s12903-024-04381-9 -
Advances in Orthopedics 2024Olecranon fractures are common injuries that require surgical intervention for optimal outcomes. Various fixation methods have been described in the literature,...
INTRODUCTION
Olecranon fractures are common injuries that require surgical intervention for optimal outcomes. Various fixation methods have been described in the literature, including the use of intramedullary proximal ulna screws in combination with tension band augmentation. Limited research has compared this hybrid technique to other established methods of fixation. This study compared complication and reoperation rates between multiple groups.
METHODS
A retrospective review was conducted on patients with olecranon fractures who underwent internal fixation at a level 1 trauma center between January 1st, 2013, and April 22nd, 2023. Data was collected using CPT codes, and patients were categorized into five groups based on the method of fixation received: no implant, tension band only, locking olecranon plate, intramedullary screw and tension band hybrid, and others. Variables such as patient demographics, Mayo fracture classification, open vs. closed injury, implant type, reoperation rates, and postoperative complications were recorded.
RESULTS
A total of 217 patients were included in the study. No difference was found with implant choice and reoperation rate ( = 0.461). There was a significant difference found with reoperation and fracture type ( = 0.027) and open fracture ( = 0.002).
CONCLUSION
The primary findings of this study indicate no significant difference in implant choice and reoperation rates among the various fixation methods used for olecranon fractures. These findings suggest that the hybrid fixation technique, utilizing intramedullary proximal ulna screws in combination with tension band augmentation, is a viable and comparable treatment option when evaluated against other well-documented methods of fixation. This study also reiterates that severity of initial injury is often the most important factor related to poorer outcomes. Further discussion and analysis of the data will provide a comprehensive understanding of implications and recommendations for olecranon fracture fixation.
PubMed: 38845777
DOI: 10.1155/2024/6471544 -
BMJ Open Jun 2024The main objective of this study was to investigate the characteristics of patients receiving private community physiotherapy (PT) the first year after a hip fracture.... (Observational Study)
Observational Study
Impact of physiotherapy access on health-related quality of life following hip fracture: an observational study on 30 752 hip fractures from the Norwegian Hip Fracture Register 2014-2018.
OBJECTIVES
The main objective of this study was to investigate the characteristics of patients receiving private community physiotherapy (PT) the first year after a hip fracture. Second, to determine whether utilisation of PT could improve health-related quality of life (HRQoL).
METHODS
In an observational cohort study, 30 752 hip fractures from the Norwegian Hip Fracture Register were linked with data from Statistics Norway and the Norwegian Control and Payment of Health Reimbursements Database. Association between covariates and utilisation of PT in the first year after fracture, the association between covariates and EQ-5D index score and the probability of experiencing 'no problems' in the five dimensions of the EQ-5D were assessed with multiple logistic regression models.
RESULTS
Median age was 81 years, and 68.4% were females. Most patients with hip fracture (57.7%) were classified as American Society of Anesthesiologists classes 3-5, lived alone (52.4%), and had a low or medium level of education (85.7%). In the first year after injury, 10 838 of 30 752 patients with hip fracture (35.2%) received PT. Lower socioeconomic status (measured by income and level of education), male sex, increasing comorbidity, presence of cognitive impairment and increasing age led to a lower probability of receiving postoperative PT. Among those who used PT, EQ-5D index score was 0.061 points (p<0.001) higher than those who did not. Correspondingly, the probability of having 'no problems' in three of the five dimensions of EQ-5D was greater.
CONCLUSIONS
A minority of the patients with hip fracture had access to private PT the first year after injury. This may indicate a shortcoming in the provision of beneficial post-surgery rehabilitative care reducing post-treatment HRQoL. The findings underscore the need for healthcare policies that address disparities in PT access, particularly for elderly patients, those with comorbidities and reduced health, and those with lower socioeconomic status.
Topics: Humans; Female; Male; Hip Fractures; Quality of Life; Norway; Aged, 80 and over; Aged; Physical Therapy Modalities; Registries; Health Services Accessibility
PubMed: 38844395
DOI: 10.1136/bmjopen-2024-086428 -
Orthopaedic Surgery Jun 2024Distal femur fractures remain a significant cause of morbidity and mortality for elderly patients. There is a lack of large population studies investigating short-term...
OBJECTIVE
Distal femur fractures remain a significant cause of morbidity and mortality for elderly patients. There is a lack of large population studies investigating short-term outcomes after distal femur c in elderly patients. The purpose of this study is to assess the incidence of and risk factors for various short-term outcomes after distal femur open reduction internal fixation (ORIF) in the geriatric population.
METHODS
The American College of Surgeons' National Surgical Quality Improvement Program (NSQIP) database was used to identify all primary distal femur ORIF cases in patients 60+ years old between January 1, 2015 and December 31, 2020 using Current Procedural Terminology (CPT) codes 27511, 27513, and 27514. Demographic, medical, and surgical variables were extracted for all patients. Propensity score matching was used to match cases in the two age groups based on various demographic and medical comorbidity variables. Several 30-day outcome measures were compared between the 60-79-year-old and 80+-year-old groups both before and after matching. Subsequent multivariate logistic regression was used to identify independent risk factors for 30-day outcome measures in the matched cohort.
RESULTS
A total of 2913 patients were included in the final cohort: 1711 patients in the 60-79-year-old group and 1202 patients in the 80+-year-old group. Most patients were female (n = 2385; 81.9%). Prior to matching, the older group had a higher incidence of 30-day mortality (1.9% vs. 6.2%), readmission (3.7% vs. 9.7%, p = 0.024), and non-home discharge (74.3% vs. 89.5%, p < 0.001). Additionally, the older group had a higher rate of blood loss requiring transfusion (30.9% vs. 42.3%, p < 0.001) and medical complications (10.4% vs. 16.4%, p < 0.001), including myocardial infarction (0.7% vs. 2.7%, p < 0.001), pneumonia (2.7% vs. 4.6%, p = 0.008), and urinary tract infection (4.1% vs. 6.1%, p = 0.0188). After matching, the older group consistently had a higher incidence of mortality, non-home-discharge, blood loss requiring transfusion, and myocardial infarction. Various independent risk factors were identified for 30-day morbidity and mortality, including American Society of Anesthesiologists (ASA) classification, body mass index (BMI) status, operative duration, and certain medical comorbidities.
CONCLUSION
Geriatric patients undergoing distal femur ORIF are at significant risk for 30-day morbidity and mortality. After matching, octogenarians and older patients specifically are at increased risk for mortality, non-home discharge, and surgical complications compared to patients aged 60-79 years old. Multiple factors, such as BMI status, ASA classification, operative time, and certain medical comorbidities, are independently associated with poor 30-day outcomes.
PubMed: 38837679
DOI: 10.1111/os.14124 -
Scientific Reports Jun 2024The prevalence of thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) is high. Previous studies have indicated a potential association between TDFDs and OP, yet...
The prevalence of thyroid dysfunction diseases (TDFDs) and osteoporosis (OP) is high. Previous studies have indicated a potential association between TDFDs and OP, yet the causal direction remains unclear. This study aimed to investigate the potential causal relationship between TDFDs and the risk of developing OP and related fractures. We obtained pooled data from genome-wide association studies (GWASs) conducted on TDFDs and OP in European populations and identified single-nucleotide polymorphisms (SNPs) with genome-wide significance levels associated with exposure to TDFDs as instrumental variables. Inverse variance weighted (IVW) was employed as the primary method for Mendelian randomization (MR) analysis, supplemented by MR‒Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were conducted to evaluate the robustness of the findings. The IVW method demonstrated an increased risk of OP in patients with TDFDs, including hyperthyroidism and hypothyroidism (TDFDs: OR = 1.11; 95% CI 1.09, 1.13; hypothyroidism: OR = 1.14; 95% CI 1.10, 1.17; hyperthyroidism: OR = 1.09; 95% CI 1.06, 1.12). These findings were supported by supplementary analysis, which revealed a positive correlation between TDFDs and the risk of OP. Multiple sensitivity analyses confirmed the absence of horizontal pleiotropy in the study, thus indicating the robustness of our results. The causal relationship between TDFDs and increased risk of OP implies the need for early bone mineral density (BMD) screening and proactive prevention and treatment strategies for individuals with TDFDs.
Topics: Humans; Mendelian Randomization Analysis; Osteoporosis; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Thyroid Diseases; Hyperthyroidism; Risk Factors; Hypothyroidism
PubMed: 38834708
DOI: 10.1038/s41598-024-62854-x -
BMJ Open Jun 2024Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile,...
An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.
INTRODUCTION
Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4.
METHODS AND ANALYSIS
BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in or can be included in the trial.Each subject receives four intravenous doses of 3×10/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover.
ETHICS AND DISSEMINATION
The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals.
TRIAL REGISTRATION NUMBERS
EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.
Topics: Humans; Osteogenesis Imperfecta; Female; Pregnancy; Mesenchymal Stem Cell Transplantation; Infant; Clinical Trials, Phase I as Topic; Multicenter Studies as Topic; Infant, Newborn; Clinical Trials, Phase II as Topic; Mesenchymal Stem Cells; Treatment Outcome; Male; Fetal Stem Cells
PubMed: 38834319
DOI: 10.1136/bmjopen-2023-079767 -
Bioactive Materials Sep 2024Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to...
Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to develop an osteoanabolic therapy which activates the Wnt/β-catenin pathway, a molecular driver of endochondral ossification. We hypothesize that using an mRNA-based therapeutic encoding β-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes. To optimize a delivery platform built on recent advancements in liposomal technologies, two FDA-approved ionizable phospholipids, DLin-MC3-DMA (MC3) and SM-102, were used to fabricate unique ionizable lipid nanoparticle (LNP) formulations and then tested for transfection efficacy both and in a murine tibia fracture model. Using firefly luciferase mRNA as a reporter gene to track and quantify transfection, SM-102 LNPs showed enhanced transfection efficacy and prolonged transfection, minimal fracture interference and no localized inflammatory response over MC3 LNPs. The generated β-catenin mRNA encapsulated in SM-102 LNPs (SM-102-β-catenin mRNA) showed bioactivity through upregulation of downstream canonical Wnt genes, and . When testing SM-102-β-catenin mRNA therapeutic in a murine tibia fracture model, histomorphometric analysis showed increased bone and decreased cartilage composition with the 45 μg concentration at 2 weeks post-fracture. μCT testing confirmed that SM-102-β-catenin mRNA promoted bone formation , revealing significantly more bone volume over total volume in the 45 μg group. Thus, we generated a novel mRNA-based therapeutic encoding a β-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.
PubMed: 38832305
DOI: 10.1016/j.bioactmat.2024.05.020 -
Journal of Children's Orthopaedics Jun 2024The purpose of this study is to assess clinical and functional outcomes in separate cohorts of operatively and nonoperatively managed pediatric patella fractures.
PURPOSE
The purpose of this study is to assess clinical and functional outcomes in separate cohorts of operatively and nonoperatively managed pediatric patella fractures.
METHODS
A retrospective review was completed for patients aged 5-19 years treated for a unilateral patella fracture at a single pediatric level-1 trauma center. Patients were excluded for osteochondral fracture associated with patellar dislocation, polytrauma presentation with additional fractures, or <3 months of clinical follow-up. Functional outcomes were assessed via the Pediatric International Knee Documentation Committee form and the Marx Knee Activity Scale.
RESULTS
A total of 53 patients met inclusion criteria; 30 patients were treated operatively and 23 patients were treated nonoperatively. Patients with patellar sleeve/pole fractures were significantly younger by 5.2 years (p < 0.01) and presented with greater variability in mechanism of injury (p < 0.01). The nonoperative cohort achieved bony healing and returned to sports at a median (interquartile range) of 1.7 (1.2-2.3) months and 2.8 (2.3-3.3) months, respectively, post-injury. The operative group achieved bony healing and returned to sports at 2.8 (2.1-3.5) months and 5.9 (4.0-7.1) months, respectively, following surgery. Median (interquartile range) Pediatric International Knee Documentation Committee and Marx scores were 98 (89-100) and 14 (10-16), respectively, for the nonoperative group, and 92 (84-99) and 13 (12-16), respectively, for the operative group. No significant differences in patient-reported outcomes were observed between fracture patterns or treatment cohorts.
CONCLUSION
Pediatric and adolescent patients sustaining patella fractures reported long-term functional outcomes comparable to normative values, across multiple fracture patterns and with appropriate operative and nonoperative treatment. Fractures requiring surgery were expectedly associated with slower healing and return to sport timelines.
LEVEL OF EVIDENCE
Therapeutic Level III.
PubMed: 38831855
DOI: 10.1177/18632521241232301