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Item Bone Quality in Chronic Kidney Disease: Definitions and Diagnostics(Springer, 2017-06) McNerny, Erin M.B.; Nickolas, Thomas L.; Medicine, School of MedicinePURPOSE OF REVIEW: In this paper, we review the epidemiology, diagnosis, and pathogenesis of fractures and renal osteodystrophy. RECENT FINDINGS: The role of bone quality in the pathogenesis of fracture susceptibility in chronic kidney disease (CKD) is beginning to be elucidated. Bone quality refers to bone material properties, such as cortical and trabecular microarchitecture, mineralization, turnover, microdamage, and collagen content and structure. Recent data has added to our understanding of the effects of CKD on alterations to bone quality, emerging data on the role of abnormal collagen structure on bone strength, the potential of non-invasive methods to inform our knowledge of bone quality, and how we can use these methods to inform strategies that protect against bone loss and fractures. However, more prospective data is required. CKD is associated with abnormal bone quality and strength which results in high fracture incidence.Item Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis(American Society of Nephrology, 2017-07-07) Moe, Sharon M.; Wetherill, Leah; Decker, Brian Scott; Lai, Dongbing; Abdalla, Safa; Long, Jin; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.; Medicine, School of MedicineBACKGROUND AND OBJECTIVES: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. RESULTS: There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). CONCLUSIONS: These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.Item Common Dietary Modifications in Preclinical Models to Study Skeletal Health(Frontiers Media, 2022-07-14) Rendina-Ruedy, Elizabeth; Smith, Brenda J.; Obstetrics and Gynecology, School of MedicineBone is a highly dynamic tissue that undergoes continuous remodeling by bone resorbing osteoclasts and bone forming osteoblasts, a process regulated in large part by osteocytes. Dysregulation of these coupled catabolic and anabolic processes as in the case of menopause, type 2 diabetes mellitus, anorexia nervosa, and chronic kidney disease is known to increase fracture risk. Recent advances in the field of bone cell metabolism and bioenergetics have revealed that maintenance of the skeleton places a high energy demand on these cells involved in bone remodeling. These new insights highlight the reason that bone tissue is the beneficiary of a substantial proportion of cardiac output and post-prandial chylomicron remnants and requires a rich supply of nutrients. Studies designed for the specific purpose of investigating the impact of dietary modifications on bone homeostasis or that alter diet composition and food intake to produce the model can be found throughout the literature; however, confounding dietary factors are often overlooked in some of the preclinical models. This review will examine some of the common pre-clinical models used to study skeletal biology and its pathologies and the subsequent impact of various dietary factors on these model systems. Furthermore, the review will include how inadvertent effects of some of these dietary components can influence bone cell function and study outcomes.Item A Comprehensive Review of Mouse Diaphyseal Femur Fracture Models(Elsevier, 2020-07) Gunderson, Zachary J.; Campbell, Zachery R.; McKinley, Todd O.; Natoli, Roman M.; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineComplications related to treatment of long bone fractures still stand as a major challenge for orthopaedic surgeons. Elucidation of the mechanisms of bone healing and development, and the subsequent alteration of these mechanisms to improve outcomes, typically requires animal models as an intermediary between in vitro and human clinical studies. Murine models are some of the most commonly used in translational research, and mouse fracture models are particularly diverse, offering a wide variety of customization with distinct benefits and limitations depending on the study. This review critically examines three common femur fracture models in the mouse, namely cortical hole, 3-point fracture (Einhorn), and segmental bone defect. We lay out the general procedure for execution of each model, evaluate the practical implications and important advantages/disadvantages of each and describe recent innovations. Furthermore, we explore the applications that each model is best adapted for in the context of the current state of murine orthopaedic research.Item Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing(Springer, 2024) Nazzal, Murad K.; Morris, Ashlyn J.; Parker, Reginald S.; White, Fletcher A.; Natoli, Roman M.; Kacena, Melissa A.; Fehrenbacher, Jill C.; Orthopaedic Surgery, School of MedicinePurpose of review: Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing. Recent findings: Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.Item Effects of diet, BMP-2 treatment, and femoral skeletal injury on endothelial cells derived from the ipsilateral and contralateral limbs(Wiley, 2022) Dadwal, Ushashi C.; Staut, Caio de Andrade; Tewari, Nikhil P.; Awosanya, Olatundun D.; Mendenhall, Stephen K.; Valuch, Conner R.; Nagaraj, Rohit U.; Blosser, Rachel J.; Li, Jiliang; Kacena, Melissa Ann; Orthopaedic Surgery, School of MedicineType 2 diabetes (T2D) results in physiological and structural changes in bone, contributing to poor fracture healing. T2D compromises microvascular performance, which can negatively impact bone regeneration as angiogenesis is required for new bone formation. We examined the effects of bone morphogenetic protein-2 (BMP-2) administered locally at the time of femoral segmental bone defect (SBD) surgery, and its angiogenic impacts on endothelial cells (ECs) isolated from the ipsilateral or contralateral tibia in T2D mice. Male C57BL/6 mice were fed either a low fat diet (LFD) or high fat diet (HFD) starting at 8 weeks. After 12 weeks, the T2D phenotype in HFD mice was confirmed via glucose and insulin tolerance testing and echoMRI, and all mice underwent SBD surgery. Mice were treated with BMP-2 (5μg) or saline at the time of surgery. Three weeks post-surgery, bone marrow ECs were isolated from ipsilateral and contralateral tibias, and proliferation, angiogenic potential, and gene expression of the cells was analyzed. BMP-2 treatment increased EC proliferation by 2 fold compared to saline in LFD contralateral tibia ECs, but no changes were seen in surgical tibia EC proliferation. BMP-2 treatment enhanced vessel-like structure formation in HFD mice whereas, the opposite was observed in LFD mice. Still, in BMP-2 treated LFD mice, ipsilateral tibia ECs increased expression of CD31, FLT-1, ANGPT1, and ANGPT2. These data suggest that the modulating effects of T2D and BMP-2 on the microenvironment of bone marrow ECs may differentially influence angiogenic properties at the fractured limb versus the contralateral limb.Item Events Due to Snowblower Use Seen in US Emergency Departments From 2003 Through 2018(Cureus, 2020-12-01) Loder, Randall T.; Solanki, Dhruv; Orthopaedic Surgery, School of MedicineObjective To comprehensively analyze emergency department (ED) visits associated with snowblower use in the United States. Methods Data on National Electronic Injury Surveillance System ED visits due to snow blowers from 2003 through 2018 were analyzed by age, sex, diagnosis, anatomic location of the injury, and year, month, or weekday. The mechanism of injury and alcohol use were noted. Statistical analyses were performed, accounting for the weighted, stratified nature of the data. Results There were an estimated 91,451 patients with an average age of 51 years; 91.2% were male. Amputation, fracture, or laceration accounted for 43,524 (47.6%) of the ED visits. The mechanism of injury was placing the hand into the chute (44.5%), a fall/slip (13.3%), medical events (6.1%), and miscellaneous (33.8%). Most (68.9%) occurred at home. Alcohol was rarely involved (0.4%). There were 648 deaths; 647 were due to cardiac events. The five major injury diagnoses were fracture (25.9%), laceration (20.2%), strain/sprain (15.0%), amputation (11.2%), and contusion/abrasion (10.2%); 99.8% of the amputations involved fingers. The incidence of ED snowblower visits was 1.845 per 100,000 US population with no change over time. There was a general correlation between the number of visits and the annual snow cover. Conclusions Ample opportunity for injury prevention exists, as there was no change in the incidence over time. Cardiac events accounted for essentially all of the deaths.Item Fractures in children and adolescents living with perinatally acquired HIV(Elsevier, 2020-10) Jacobson, Denise L.; Yu, Wendy; Hazra, Rohan; Brummel, Sean; Geffner, Mitchell E.; Patel, Kunjal; Borkowsky, William; Wang, Jiajia; Chen, Janet S.; Mirza, Ayesha; DiMeglio, Linda A.; Pediatrics, School of MedicineBackground: Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS). Methodology: Lifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr). Results: PHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis. Conclusions: Among children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood. Summary: Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents.Item Fractures in Children Due to Firearm Activity(MDPI, 2023-03-30) Loder, Randall T.; Luster, Taylor; Orthopaedic Surgery, School of MedicineThe purpose of this study was to investigate fracture patterns due to pediatric firearm injuries. The data used was from the US Firearm Injury Surveillance Study 1993-2019. Over these 27 years, there were 19,033 children with fractures due to firearm activity with an average age of 12.2 years; 85.2% were boys and the firearm was a powder type in 64.7%. The finger was the most common fracture location, while the tibia/fibula was the most common location for those admitted to the hospital. Children ≤ 5 years of age sustained more skull/face fractures; most spine fractures occurred in the 11-15-year age group. The injury was self-inflicted in 65.2% of the non-powder and 30.6% of the powder group. The injury intent was an assault in 50.0% of the powder and 3.7% of the non-powder firearm group. Powder firearms accounted for the majority of the fractures in the ≤5 and 11-15 year-olds, non-powder firearms accounted for the majority of the fractures in the 6-10 year-olds. Injuries occurring at home decreased with increasing age; there was an increase in hospital admissions over time. In conclusion, our findings support the need for safe storage of firearms in the home away from children. This data will be helpful to assess any changes in prevalence or demographics with future firearm legislation or other prevention programs. The increasing acuity of firearm-associated injuries seen in this study is detrimental to the child, impacts familial wellbeing, and results in significant financial costs to society.Item From the Mind to the Spine: The Intersecting World of Alzheimer's and Osteoporosis(Springer, 2024) Margetts, Tyler J.; Wang, Hannah S.; Karnik, Sonali J.; Plotkin, Lilian I.; Movila, Alexandru; Oblak, Adrian L.; Fehrenbacher, Jill C.; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicinePurpose of review: This comprehensive review delves into the intricate interplay between Alzheimer's disease (AD) and osteoporosis, two prevalent conditions with significant implications for individuals' quality of life. The purpose is to explore their bidirectional association, underpinned by common pathological processes such as aging, genetic factors, inflammation, and estrogen deficiency. Recent findings: Recent advances have shown promise in treating both Alzheimer's disease (AD) and osteoporosis by targeting disease-specific proteins and bone metabolism regulators. Monoclonal antibodies against beta-amyloid and tau for AD, as well as RANKL and sclerostin for osteoporosis, have displayed therapeutic potential. Additionally, ongoing research has identified neuroinflammatory genes shared between AD and osteoporosis, offering insight into the interconnected inflammatory mechanisms. This knowledge opens avenues for innovative dual-purpose therapies that could address both conditions, potentially revolutionizing treatment approaches for AD and osteoporosis simultaneously. This review underscores the potential for groundbreaking advancements in early diagnosis and treatment by unraveling the intricate connection between AD and bone health. It advocates for a holistic, patient-centered approach to medical care that considers both cognitive and bone health, ultimately aiming to enhance the overall well-being of individuals affected by these conditions. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.