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Objectives: To investigate the effect of tranexamic acid (TXA) through in vitro culture of primary human osteoblasts (HOB) and in vivo using an operative rat femur fracture model. It was hypothesized that there would not be any effect on fracture healing in both studies., Methods: Primary HOBs were exposed to varying concentrations of TXA over different time periods. Cells were assessed for viability, metabolism, and mineralization. For the in vivo model, fractures were created in the femora of adult rats, exposed to either TXA or saline, and then assessed for healing at different time points. A modified radiographic union score for tibia was used to evaluate radiographs, callus mineralization was assessed with microcomputed tomography, and biomechanical tests were performed., Results: Overall, HOB viability and metabolism decreased as TXA concentration and exposure time increased. However, at concentrations below 56.44 mg/mL, HOB viability was not affected. Similarly, mineralization also decreased as TXA concentration and exposure time increased. In both groups, in vivo results demonstrated increasing radiographic healing, callus mineralization, and biomechanical strength as a function of time. There was a trend for increased healing in the TXA group at 6 weeks after fracture; however, the difference compared with untreated animals was not statistically significant., Conclusions: Although a degradation of HOB viability and metabolism occurred with increased TXA concentrations and exposure times, clinically relevant concentrations do not adversely affect HOB viability, metabolism, or mineralization. In addition, there were no noticeable adverse effects of TXA administration in the in vivo model., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin immunoprecipitation enrichment and mechanistic studies show that p38 MAPK-mediated CCAAT enhancer binding protein delta (CEBPD) upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in mesenchymal stem cells exerts a negative regulatory effect on osteogenesis through a similar mechanism. Chromatin immunoprecipitation-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.

Background: The study aims to develop a data-driven methodology to assess bone drilling in preparation for future clinical trials in residency training. The existing assessment methods are either subjective or do not consider the interdependence among individual skill factors, such as time and accuracy. This study uses quantitative data and radar plots to visualize the balance of the selected skill factors., Methods: In the experiment, straight vertical drilling was assessed across 3 skill levels: expert surgeons (N = 10), intermediate residents (postgraduate year-2-5, N = 5), and novice residents (postgraduate year-1, N = 10). Motion and force were measured for each drilling trial, and data from multiple trials were then converted into 5 performance indicators, including overshoot, drilling time, overshoot consistency, time consistency, and force fluctuation. Each indicator was then scored between 0 and 10, with 10 being the best, and plotted into a radar plot., Results: Statistical difference (p < 0.05) was confirmed among 3 skill levels in force, time, and overshoot data. The radar plots revealed that the novice group exhibited the most distorted pentagons compared with the well-formed pentagons observed in the case of expert participants. The intermediate group showed slight distortion that was between the expert and novice groups., Conclusion/clinical Relevance: This research shows the utility of radar plots in drilling assessment in a comprehensive manner and lays the groundwork for a data-driven training scheme to prepare novice residents for clinical practice., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A583)., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

In this study, we sought to synthesize chitosan nanoparticles (CS-NPs) and characterize their morphology, efficacy in inhibiting bacterial attachment, and efficacy in eradicating bacteria established on implantable hardware. CS-NPs possess desirable properties, including antibacterial properties in biofilm-mediated infections. CS-NPs were produced using ionic gelation and characterized via scanning electron microscope imaging. Staphylococcus aureus was incubated with CS-NPs at various concentrations and compared to a 1% povidone-iodine with 1% H 2 O 2 control in 24-well plates. Stainless steel bone screws were placed in six-well plates and inoculated with S. aureus. After 24 h, the screws were transferred to one of three solutions (saline, 40 mg/mL CS-NP, or 1% povidone-iodine with 1% H 2 O 2 ). Four screws from each group were vortexed in saline and plated. The remaining screw from each group was prepped and imaged to map the location of persistent bacteria. Synthesized CS-NPs had a mean diameter of 0.39 ± 0.13 μm and circularity of 0.87 ± 0.05. The percent inhibition of bacterial attachment was 73% at 20 mg/mL, 73% at 30 mg/mL, 75% at 40 mg/mL, 79% at 50 mg/mL, and 78% at 60 mg/mL. When compared to saline, the 40 mg/mL CS-NP solution reduced bacteria on the screws by 76%. No bacteria were retrieved from the 1% povidone-iodine with 1% H 2 O 2 group. This study demonstrated that CS-NP solution effectively inhibited S. aureus bacterial attachment and was more effective than saline in eradicating bacteria from orthopedic hardware, suggesting that CS-NPs have the potential for prevention and treatment of musculoskeletal infections as a component of an intraoperative surgical irrigation solution., (© 2023 Orthopaedic Research Society.)

Background: Proper vascular injury risk stratification (VIRS) methods for L4-L5 lateral lumbar interbody fusion (LLIF) surgery have not been well-described. The objective of this study was to propose a novel VIRS method for L4-L5 LLIF surgery via the transpsoas approach., Methods: Axial magnetic resonance imaging (MRI) of adult patients were obtained and analyzed. The VIRS scores were assessed using anterior disc line to posterior vessel wall distance, the disc vessel angle (DVA), and the disc edge to vessel distance at the level of L4-L5 disc space., Results: Ninety-one consecutive adult patients were included in the study. The right common iliac vein (CIV) had a high risk of injury with both right- and left-sided approaches. The left CIV had a moderate risk with a left-sided approach when the iliocaval confluence was above the L4-L5 disc space but had a high risk when the confluence was at the L4-L5 disc space. The left CIV had a high risk with a right-sided approach when the confluence was above the L4-L5 disc space but had a moderate risk when the confluence was at the L4-L5 disc space. The inferior vena cava (IVC) had a high risk with both right- and left-sided approaches. The aorta had a moderate risk regardless of the right or left-sided approaches. The left common iliac artery (CIA) had a moderate risk with a right-sided approach and a low risk with a left-sided approach. The right CIA had a low risk with both right- and left-sided approaches., Conclusions: There are significant vascular anatomic variations at the L4-L5 disc level and a proper VIRS can be performed utilizing a combination of anterior disc line to posterior vessel wall distance, DVA, and disc edge to vessel distance, on the axial MRI., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-23-94/coif). A.J.G. has the following disclosures that are unrelated to this article: Partner of Premier Brain & Spine. R.A.W.M. has the following disclosures that are unrelated to this paper: Royalties from Globus Medical. The other authors have no conflicts of interest to declare., (2023 Journal of Spine Surgery. All rights reserved.)

Tooth enamel is generated by ameloblasts. Any failure in amelogenesis results in defects in the enamel, a condition known as amelogenesis imperfecta. Here, we report that mice with deficient autophagy in epithelial-derived tissues ( K14-Cre;Atg7 F/F and K14-Cre;Atg3 F/F conditional knockout mice) exhibit amelogenesis imperfecta. Micro-computed tomography imaging confirmed that enamel density and thickness were significantly reduced in the teeth of these mice. At the molecular level, ameloblast differentiation was compromised through ectopic accumulation and activation of NRF2, a specific substrate of autophagy. Through bioinformatic analyses, we identified Bcl11b , Dlx3 , Klk4 , Ltbp3 , Nectin1 , and Pax9 as candidate genes related to amelogenesis imperfecta and the NRF2-mediated pathway. To investigate the effects of the ectopic NRF2 pathway activation caused by the autophagy deficiency, we analyzed target gene expression and NRF2 binding to the promoter region of candidate target genes and found suppressed gene expression of Bcl11b , Dlx3 , Klk4 , and Nectin1 but not of Ltbp3 and Pax9 . Taken together, our findings indicate that autophagy plays a crucial role in ameloblast differentiation and that its failure results in amelogenesis imperfecta through ectopic NRF2 activation.

The purpose of this study is to propose a quantitative assessment scheme to help with surgical bone drilling training. This pilot study gathered and compared motion and force data from expert surgeons (n = 3) and novice residents (n = 6). The experiment used three-dimensional printed bone simulants of young bone (YB) and osteoporotic bone (OB), and drilling overshoot, time, and force were measured. There was no statistically significant difference in overshoot between the two groups (p = 0.217 for YB and 0.215 for OB). The results, however, show that the experts took less time (mean = 4.01 s) than the novices (mean = 9.98 s), with a statistical difference (p = 0.003 for YB and 0.0001 for OB). In addition, the expert group performed more consistently than the novices. The force analysis further revealed that experts used a higher force to drill the first cortical section and a noticeably lower force in the second cortex to control the overshoot (approximate reduction of 5.5 N). Finally, when drilling time and overshoot distance were combined, the motion data distinguished the skill gap between expert and novice drilling; the force data provided insight into the drilling mechanism and performance outcomes. This study lays the groundwork for a data-driven training scheme to prepare novice residents for clinical practice., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

High-resolution computed tomography (CT) is widely used to assess bone structure under physiological and pathological conditions. Although the analytic protocols and parameters for micro-CT (μCT) analyses in mice are standardized for long bones, vertebrae, and the palms in aging mice, they have not yet been established for craniofacial bones. In this study, we conducted a morphometric assessment of craniofacial bones, in comparison with long bones, in aging mice. Although age-related changes were observed in the microarchitecture of the femur, tibia, vertebra, and basisphenoid bone, and were more pronounced in females than in males, the microarchitecture of both the interparietal bone and body of the mandible, which develop by intramembranous ossification, was less affected by age and sex. By contrast, the condyle of the mandible was more affected by aging in males compared to females. Taken together, our results indicate that mouse craniofacial bones are uniquely affected by age and sex., (© 2022. The Author(s).)

Osteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long-bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4-phenylbutiric acid (4-PBA), an established chemical chaperone, to determine if treatment of Aga2 +/- mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2 +/- osteoblasts show increased protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4-PBA. The in vivo data demonstrate that a postweaning 5-week 4-PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone-derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/-enhancer-binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2 +/- mice resulted in increased severity of the Aga2 +/- phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Type I collagen (Col1) is the most abundant protein in mammals. Col1 contributes to 90% of the total organic component of bone matrix. However, the precise cellular origin and functional contribution of Col1 in embryogenesis and bone formation remain unknown. Single-cell RNA-sequencing analysis identifies Fap + cells and Fsp1 + cells as the major contributors of Col1 in the bone. We generate transgenic mouse models to genetically delete Col1 in various cell lineages. Complete, whole-body Col1 deletion leads to failed gastrulation and early embryonic lethality. Specific Col1 deletion in Fap + cells causes severe skeletal defects, with hemorrhage, edema, and prenatal lethality. Specific Col1 deletion in Fsp1 + cells results in Osteogenesis Imperfecta-like phenotypes in adult mice, with spontaneous fractures and compromised bone healing. This study demonstrates specific contributions of mesenchymal cell lineages to Col1 production in organogenesis, skeletal development, and bone formation/repair, with potential insights into cell-based therapy for patients with Osteogenesis Imperfecta., (© 2021. The Author(s).)

Osteogenesis imperfecta (OI) is characterized by short stature, skeletal deformities, low bone mass, and motor deficits. A subset of OI patients also present with joint hypermobility; however, the role of tendon dysfunction in OI pathogenesis is largely unknown. Using the Crtap -/- mouse model of severe, recessive OI, we found that mutant Achilles and patellar tendons were thinner and weaker with increased collagen cross-links and reduced collagen fibril size at 1- and 4-months compared to wildtype. Patellar tendons from Crtap -/- mice also had altered numbers of CD146 + CD200 + and CD146 - CD200 + progenitor-like cells at skeletal maturity. RNA-seq analysis of Achilles and patellar tendons from 1-month Crtap -/- mice revealed dysregulation in matrix and tendon marker gene expression concomitant with predicted alterations in TGF-β, inflammatory, and metabolic signaling. At 4-months, Crtap -/- mice showed increased αSMA, MMP2, and phospho-NFκB staining in the patellar tendon consistent with excess matrix remodeling and tissue inflammation. Finally, a series of behavioral tests showed severe motor impairments and reduced grip strength in 4-month Crtap -/- mice - a phenotype that correlates with the tendon pathology., Competing Interests: MG, NH, JL, EM, MA, DH, ST, DK, KL, DP, CK, CA, DE, BL No competing interests declared, (© 2021, Grol et al.)

Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by bone deformities and fractures caused by low bone mass and impaired bone quality. OI is a genetically heterogeneous disorder that most commonly arises from dominant mutations in genes encoding type I collagen (COL1A1 and COL1A2). In addition, OI is recessively inherited with the majority of cases resulting from mutations in prolyl-3-hydroxylation complex members, which includes cartilage-associated protein (CRTAP). OI patients are at an increased risk of fracture throughout their lifetimes. However, non-union or delayed healing has been reported in 24% of fractures and 52% of osteotomies. Additionally, refractures typically go unreported, making the frequency of refractures in OI patients unknown. Thus, there is an unmet need to better understand the mechanisms by which OI affects fracture healing. Using an open tibial fracture model, our study demonstrates delayed healing in both Col1a2 G610c/+ and Crtap -/- OI mouse models (dominant and recessive OI, respectively) that is associated with reduced callus size and predicted strength. Callus cartilage distribution and chondrocyte maturation were altered in OI, suggesting accelerated cartilage differentiation. Importantly, we determined that healed fractured tibia in female OI mice are biomechanically weaker when compared with the contralateral unfractured bone, suggesting that abnormal OI fracture healing OI may prime future refracture at the same location. We have previously shown upregulated TGF-β signaling in OI and we confirm this in the context of fracture healing. Interestingly, treatment of Crtap -/- mice with the anti-TGF-β antibody 1D11 resulted in further reduced callus size and predicted strength, highlighting the importance of investigating dose response in treatment strategies. These data provide valuable insight into the effect of the extracellular matrix (ECM) on fracture healing, a poorly understood mechanism, and support the need for prevention of primary fractures to decrease incidence of refracture and deformity in OI patients. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Coronary artery disease (CAD) and osteoporosis, the two most frequently occurring chronic diseases of aging populations, share many risk factors including lack of estrogen, smoking, and low physical activity. CAD and low bone mineral density (BMD) are strongly associated. Statins, (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors), are used to prevent and treat CAD and have been associated with high BMD. This cross-sectional study examined associations of BMD with statin use and nonuse in elderly women with or without CAD. Multivariate regression analyses were conducted on 185 women aged ≥60 years who were referred between October 2010 and March 2015 to a geriatric osteoporosis clinic in Houston, Texas, for compromised skeletal health. Compared to the control group (without CAD and without statin use), patients with CAD and no statin use were more likely to have lower femoral neck BMD (β: -0.46, 95% confidence interval: -0.75 to -0.18). The BMD of patients taking statins, regardless of presence of CAD, was similar to that of the control group. Statins may be protective in preventing bone loss in elderly women suffering from CAD. Prospective trials are warranted to determine if continued use of statins in them would help prevent both CAD and bone loss.

Objectives: Patients with dementia are at high risk for hip fractures and often have poor outcomes when a fracture is sustained. Despite this poor prognosis, little data are available on what factors should be prioritized to guide surgical decision making in these cases. We aimed to understand the decision-making process for older dementia patients hospitalized after hip fractures., Design: We performed a qualitative analysis of in-depth elite interviews conducted with a clinical care team involved in management of patients with dementia after hospitalization for hip fractures., Setting: Interviews were conducted with an interprofessional team involved in the care of patients with dementia after being hospitalized for hip fractures., Participants: Interviewees included nine orthopaedic surgeons, three hospitalists, three geriatricians, five nurses, three occupational therapists, three physical therapists, and two clinical ethicists., Measurements: Verbatim transcripts of the interviews were analyzed and coded using QSR International's NVivo 10 qualitative database management software., Results: The three main themes that most interviewees discussed were pain control, functional status, and medical comorbidities. Interviewees brought up many factors related to restoring functional status including baseline functional status, rehabilitation potential, social support, and the importance of mobility. Dementia and its impact on rehabilitation potential were mentioned by all geriatricians., Conclusion: Although frailty, prognosis, and life expectancy were largely absent from the responses, the emphasis on dementia, advanced directives, and involving family or caregivers by the three geriatricians indicates the importance of including geriatricians in the decision-making team for these patients., (© 2019 The American Geriatrics Society.)

Although an understanding of bone material properties is crucial for interpreting and predicting fracture patterns due to injury or defining the effects of disease on bone strength, information about infant bone properties is scant in the literature. In this study we present the mechanical testing results from 47 tibia and 52 rib specimens taken from 53 infant decedents in order to further our understanding of infant bone strength. Bone specimens were imaged using microCT and tested in three-point bending until failure. Extrinsic and intrinsic properties demonstrated an increase in strength and stiffness over the first year of life, while ductility measures remained largely unchanged. Donor race had no effect on the material properties, but tibia bone specimens showed significant sex differences, with the elastic modulus from females being larger than males. When compared to properties from adolescent and adult donors, infant bone is less strong, less stiff, and more ductile., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Altered bone quality due to the underlying metabolic changes of type 2 diabetes (T2D) has been hypothesized to affect bone strength, leading to increased fracture risk in patients with T2D. Lumbar spine trabecular bone score (LS-TBS), an indirect measure of trabecular microarchitecture, provides information on bone quality and has been associated with T2D. However, trabecular bone score (TBS) is also affected by demographic patterns and body size, and is expected to be different in people from various ethnic or racial backgrounds. Therefore, it is important to understand associations between T2D and TBS for each ethnic or racial group separately. Although the relationship between TBS and age has been reported to be similar between non-Hispanic Caucasians and Mexican Americans (MAs), data on associations of LS-TBS with T2D in older MAs are lacking. Here, we report associations between TBS and T2D in 149 older MA men and women. Participants are part of a cohort known as the Cameron County Hispanic Cohort in Texas who have high prevalence of obesity and poor glycemic control. Bone mineral density was not altered for MA women with T2D, but was significantly higher in MA men with T2D compared with MA men without diabetes. Low LS-TBS was associated with T2D in women in our study. Although low TBS was associated with older age in men, TBS did not show any significant association with T2D for men. These results are similar to those found in other studies of non-Hispanic whites with diabetes. LS-TBS may add value in diagnosing poor bone quality in older MA women with T2D regardless of bone mineral density scoring., (Copyright © 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Polymerase chain reaction (PCR) has been proposed as a method to identify bacteria in clinical samples because it is more sensitive than culture techniques and can produce results rapidly. However, PCR can detect DNA from dead cells and thus cannot distinguish between live and dead cells in a tissue sample. Killed Staphylococcus aureus cells were implanted into the femurs and knee joints of rats to determine the length of time that DNA from dead cells is detectable in a living animal under conditions similar to common orthopedic infections. In the joint infection model studied here, the DNA from the dead planktonic bacteria was detected using PCR immediately after injection or 24 h later, but was undetectable 48 and 72 h after injection. In the biofilm implanted-device model studied, the DNA from these dead biofilm cells was detected by PCR immediately after implantation and at 24 h, but not at 48 or 72 h. Thus, our results indicate that DNA from dead cells does not persist in these animal model systems for more than 2 days, which should reduce concerns about possible false positive results using molecular DNA-based techniques for the detection of pathogens., (Copyright © 2018. Published by Elsevier Inc.)

Altered bone quality, caused by underlying metabolic changes of type 2 diabetes (T2D), has been hypothesized to cause altered bone strength and turnover leading to increased fracture risk in T2D patients. Current understanding about changes in bone turnover markers in T2D patients is mainly based on studies focused on Caucasian men and women. However, Hispanic populations have the highest prevalence of both T2D and osteoporosis in the US. We investigated associations of glycemic control (in terms of glycated hemoglobin [HbA1c]) and bone turnover rate in 69 older (≥50 years) Mexican American Cameron County Hispanic Cohort (CCHC) participants with T2D. Multivariable analyses were conducted to assess the associations between HbA1c (%), serum osteocalcin (OC), and serum sclerostin. In agreement with published reports from other racial/ethnic populations, our study found that lower bone turnover (indicated by lower serum OC) occurred in Mexican American men with T2D who had poorer glycemic control. For the women in our study, we found no significant association between glycemic control and OC. In contrast, HbA1c was positively associated with sclerostin for women, with near significance ( p = 0.07), while no association was found in men. We recommend screening Mexican American individuals with T2D, specifically those with poor glycemic control, for bone loss and fracture risk.

Depression and osteoporosis are 2 common comorbidities in geriatric patients. There are concerns about the deleterious effects of selective serotonin reuptake inhibitor (SSRI) antidepressant use on bone mineral density (BMD). We examined the association between SSRI use and BMD in elderly women (≥65 yr) referred to a geriatric osteoporosis clinic for bone health evaluation. Cross-sectional analyses using the general linear model were performed on data collected retrospectively from August 2010 to April 2015. A total of 250 women were seen during the study period. Of these, 140 women had complete data on BMD measurements: 22 (15.7%) used an SSRI and 118 (84.3%) did not. The 2 groups, SSRI users and SSRI nonusers, did not differ significantly across any of the covariates tested (age, ethnicity, body mass index, and past and present osteoporosis treatment medications). After adjusting for covariates, there was no difference in the BMDs at the femoral neck (p = 0.887) or the spine (p = 0.275) between the 2 groups. Similarly, no difference was seen in the T-scores between SSRI users and nonusers at the femoral neck (p = 0.924) or at the spine level (p = 0.393). Our study did not show an association between SSRI use and BMD among elderly women referred for bone health evaluation. Other studies in the literature have been inconclusive, and therefore, robust longitudinal studies are needed to further assess the interaction between SSRI use and predictors of fracture such as BMD, bone turnover markers, and genes involved in bone turnover. Until then, clinicians should closely monitor the bone health of long-term SSRI users., (Copyright © 2017 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Trabecular bone score (TBS) is a texture parameter that measures the grayscale variation within dual-energy X-ray absorptiometry (DXA) images, and has been shown to significantly correlate with the 3-dimensional bone microarchitecture. The objective of this study was to determine whether TBS is a better clinical tool than traditionally used bone mineral density (BMD) to detect the skeletal deterioration seen in patients with diabetes (DM), patients undergoing oral glucocorticoid (GC) therapy, and patients who are both diabetic and taking steroids (GC + DM). We performed retrospective, cross-sectional study using DXA images of patients who visited UTHealth Department of Internal Medicine DXA clinic in Houston, TX, from May 30, 2014 to May 30, 2016. A total of 477 men and women, who were 55 years or older, were included in the study. Lumbar spine (LS) BMD and TBS were collected. Electronic medical records were reviewed to collect clinical information for each patient. When both men and women were analyzed as a single group, LS-BMD was significantly higher in the diabetic group than in the control group (1.14 vs 1.10, p = 0.038), whereas mean TBS of L1-L4 was significantly lower in the diabetic group (1.21 vs 1.26, p = 0.004). LS-TBS was also significantly lower in diabetic women than in nondiabetic women (1.20 vs 1.26, p = 0.002). Receiver operating characteristic curves and areas under the curve indicated that LS-TBS provided better ability than LS-BMD to discriminate between control subjects and those in the DM, GC, or GC + DM groups (areas under the curve between 0.645 and 0.697, p < 0.010 for all). LS-TBS is a BMD-independent parameter that is capable of capturing a larger portion of bone quality deterioration undetected by BMD alone in patients with DM and undergoing oral GC therapy., (Copyright © 2017 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Mutations in COMP (cartilage oligomeric matrix protein) cause severe long bone shortening in mice and humans. Previously, we showed that massive accumulation of misfolded COMP in the ER of growth plate chondrocytes in our MT-COMP mouse model of pseudoachondroplasia (PSACH) causes premature chondrocyte death and loss of linear growth. Premature chondrocyte death results from activation of oxidative stress and inflammation through the CHOP-ER pathway and is reduced by removing CHOP or by anti-inflammatory or antioxidant therapies. Although the mutant COMP chondrocyte pathologic mechanism is now recognized, the effect of mutant COMP on bone quality and joint health (laxity) is largely unknown. Applying multiple analytic approaches, we describe a novel mechanism by which the deleterious consequences of mutant COMP retention results in upregulation of miR-223 disturbing the adipogenesis - osteogenesis balance. This results in reduction in bone mineral density, bone quality, mechanical strength and subchondral bone thickness. These, in addition to abnormal patterns of ossification at the ends of the femoral bones likely contribute to precocious osteoarthritis (OA) of the hips and knees in the MT-COMP mouse and PSACH. Moreover, joint laxity is compromised by abnormally thin ligaments. Altogether, these novel findings align with the PSACH phenotype of delayed ossification and bone age, extreme joint laxity and joint erosion, and extend our understanding of the underlying processes that affect bone in PSACH. These results introduce a novel finding that miR-223 is involved in the ossification defect in MT-COMP mice making it a therapeutic target., (Published by Elsevier B.V.)

The growing field of osteoimmunology seeks to unravel the complex interdependence of the skeletal and immune systems. Notably, we and others have demonstrated that complement signaling influences the differentiation of osteoblasts and osteoclasts, the two primary cell types responsible for maintaining bone homeostasis. However, the net effect of complement on bone homeostasis in vivo was unknown. Our published in vitro mechanistic work led us to hypothesize that absence of complement component 3 (C3), a central protein in the complement activation cascade, protects against bone loss in the ovariectomy-based model of postmenopausal osteoporosis. Indeed, we report here that, when compared to their C57BL/6J (WT) counterparts, ovariectomized C3 deficient mice experienced reduced bone loss at multiple sites and increased stiffness at the femoral neck, the latter potentially improving mechanical function. WT and B6;129S4-C3 tm 1 Crr /J (C3 -/- ) mice were either ovariectomized or sham-operated at 6 weeks of age and euthanized at 12 weeks. MicroCT on harvested bones revealed that the trabecular bone volume fraction in the metaphyses of both the proximal tibiae and distal femora of ovariectomized C3 -/- mice is significantly greater than that of their WT counterparts. Lumbar vertebrae showed significantly greater osteoid content and mineral apposition rates. Mechanical testing demonstrated significantly greater stiffness in the femoral necks of ovariectomized C3 -/- mice. These results demonstrate that C3 deficiency reduces bone loss at ovariectomy and may improve mechanical properties. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:118-128, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Greater bone mineral density was observed after treating hypertension using angiotensin-converting enzyme inhibitor (ACEi). We report decreased rate of bone loss in hypertensive black men using ACEi for 9 years. There may be a gender- and race-specific effect of ACEi in the prevention of age-associated bone loss., Purpose: There is evidence of bone mass preservation in patients receiving ACEis, commonly used to treat hypertension. However, limitations of previous studies include being cross-sectional or only including a short-term follow-up of patients using ACEi and including patients with diabetes, which affects bone metabolism. None of the previous studies described effects of ACEi stratified by race. The objective of this study was to investigate differences in changes in bone mineral density (BMD) in older adults who suffer from hypertension and had reported ACEi use during each study visit for at least 9 years during the study, stratified by gender and race., Methods: We used data from the Dynamics of Health, Aging and Body Composition (HABC) study, which enrolled 3075 community-dwelling older white and black individuals. We compared changes in femoral neck, total hip, and whole-body BMD after either no use of ACEi (n = 580) or long-term use (at least 9 years) of ACEi (n = 239) in HABC participants with hypertension and no known diagnosis of diabetes mellitus., Results: Overall, BMD values significantly decreased for all subgroups over time. In the stratified multivariate analysis, long-term use of ACEi was associated with a reduced rate of decline for all three BMD measures among black men, but no significant effect was observed in the other subgroups., Conclusion: Our findings show a gender- and race-specific effect of ACEi in the prevention of age-associated bone loss that warrants further evaluation.

Purpose: Autologous chondrocyte implantation (ACI) is a treatment option even in early osteoarthritis (OA). Surgical preparation for ACI should avoid penetration of the subchondral bone plate to prevent hemorrhage, fibrin clot formation, and subsequent activation of the inflammatory response., Hypothesis: Current surgical procedures with ring curettes preserve the integrity of the subchondral bone plate, even in patients with OA., Methods: Subchondral femoral bone plates ( n = 40) of OA knees undergoing total knee arthroplasty were prepared in vivo using standard, non-brute-force debridement for ACI. To approach regular wear/early OA, only cartilage with maximally grade 3A International Cartilage Repair Society score was prepared. Effects were analyzed by light microscopy., Results: In 87.5% of the specimens (35/40), standard debridement did not violate the tide mark, except for occasional minor openings with a smooth edge (diameter approximately 20 µm). In contrast, 5/40 samples (12.5%) showed one large area with a missing bone plate and an open bone marrow space. Twenty-eight specimens (70%) showed at least remnants of uncalcified cartilage., Conclusion: On the basis of size/fine structure, the occasional minor openings are likely due to increased vascular penetration through the tide mark in the pathologically altered bone-cartilage interface in OA. The consequences of limited hemorrhage through minor openings or selected large defects following in vivo debridement are still unknown. Thus, standard debridement appears suitable for cartilage regeneration even in OA defects.

Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65-kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10 fl/fl mice (Mus musculus; C57BL/6) using the osteoblast-specific Col1a1 2.3-kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small-angle X-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild-type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-β signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-β treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-β treatment from both recessive (Crtap -/- ) and dominant (Col1a2 +/P.G610C ) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-β treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2 +/P.G610C femurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-β treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Background: Sepsis from bacteremia occurs in 250,000 cases annually in the United States, has a mortality rate as high as 60%, and is associated with a poorer prognosis than localized infection. Because of these high figures, empiric antibiotic administration for patients with systemic inflammatory response syndrome (SIRS) and suspected infection is the second most common indication for antibiotic administration in intensive care units (ICU)s. However, overuse of empiric antibiotics contributes to the development of opportunistic infections, antibiotic resistance, and the increase in multi-drug-resistant bacterial strains. The current method of diagnosing and ruling out bacteremia is via blood culture (BC) and Gram stain (GS) analysis., Methods: Conventional and molecular methods for diagnosing bacteremia were reviewed and compared. The clinical implications, use, and current clinical trials of polymerase chain reaction (PCR)-based methods to detect bacterial pathogens in the blood stream were detailed., Results: BC/GS has several disadvantages. These include: some bacteria do not grow in culture media; others do not GS appropriately; and cultures can require up to 5 d to guide or discontinue antibiotic treatment. PCR-based methods can be potentially applied to detect rapidly, accurately, and directly microbes in human blood samples., Conclusions: Compared with the conventional BC/GS, particular advantages to molecular methods (specifically, PCR-based methods) include faster results, leading to possible improved antibiotic stewardship when bacteremia is not present., Competing Interests: Author Disclosure Statement The authors have no financial disclosures to report. Funding: None. The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the Department of Defense or the Departments of the United States Army. Mention of trade names, commercial products, or organization does not imply endorsement by the United States Government.

Background: Patients with pelvic ring displacement and instability can benefit from surgical reduction and instrumentation to stabilize the pelvis and improve functional outcomes. Current treatments include iliosacral screw or transsacral-transiliac screw, which provides greater biomechanical stability. However, controversy exists regarding the effects of placement of a screw across an uninjured sacroiliac joint for pelvis stabilization after trauma., Questions/purposes: Does transsacral-transiliac screw fixation of an uninjured sacroiliac joint increase pain and worsen functional outcomes at minimum 1-year followup compared with patients undergoing standard iliosacral screw fixation across the injured sacroiliac joint in patients who have sustained pelvic trauma?, Methods: All patients between ages 18 and 84 years who sustained injuries to the pelvic ring (AO/OTA 61 A, B, C) who were surgically treated between 2011 and 2013 at an academic Level I trauma center were identified for selection. We included patients with unilateral sacroiliac disruption or sacral fractures treated with standard iliosacral screws across an injured hemipelvis and/or transsacral-transiliac screws placed in the posterior ring. Transsacral-transiliac screws were generally more likely to be used in patients with vertically unstable sacral injuries of the posterior ring as a result of previous reports of failures or in osteopenic patients. We excluded patients with bilateral posterior pelvic ring injuries, fixation with a device other than a screw, previous pelvic or acetabular fractures, associated acetabular fractures, and ankylosing spondylitis. Of the 110 patients who met study criteria, 53 (44%) were available for followup at least 12 months postinjury. Sixty patients were unable to be contacted by phone or mail and seven declined to participate in the study. Outcomes were obtained by members of the research team using the visual analog scale (VAS) pain score for both posterior sacroiliac joints, Short Musculoskeletal Functional Assessment (SMFA), and Majeed scores. Patients completed the forms by themselves when able to return to the clinic. A phone interview was performed for others after they received the outcome forms by mail or email., Results: There were no differences between iliosacral and transsacral-transiliac in terms of VAS injured (2.9 ± 2.9 versus 3.0 ± 2.8, mean difference = 0.1 [95% confidence interval, -1.6 to 1.7], p = 0.91), VAS uninjured (1.8 ± 2.4 versus 2.0 ± 2.6, mean difference = 0.2 [-1.3 to 1.6], p = 0.82), Majeed (80.3 ± 19.9, 79.3 ± 17.5, mean difference = 1.0 [-11.6 to 9.6], p = 0.92), SMFA Function (22.8 ± 22.2, 21.0 ± 17.6, mean difference = 1.8 [-13.2 to 9.6], p = 0.29, and SMFA Bother (24.3 ± 23.8, 29.7 ± 23.4, mean difference = 5.4 [-7.8 to 18.6], p = 0.42)., Conclusions: Placement of fixation across a contralateral, uninjured sacroiliac joint resulted in no differences in pain and function when compared with standard iliosacral screw placement across an injured hemipelvis at least 1 year after instrumentation. When needed for biomechanical stability, transsacral-transiliac fixation across an uninjured sacroiliac joint can be used without expectation of positive or negative effects on pain or functional outcomes at minimum 1-year followup., Level of Evidence: Level III, therapeutic study.

Objectives: Iliosacral screw pathways in the first (S1) and second (S2) sacral segments are commonly used for adult pelvic ring stabilization. We hypothesize that radiographically "safe" pathways exist in pediatric patients., Setting: Academic level I Trauma Center., Patients: All patients between ages 2 and 16 years with a computed tomography scan including the pelvis obtained over a 6-week period (174 children, mean age 10.8 ± 3.9 years; 90 boys, 84 girls)., Intervention: The width and height at the "constriction point" in 3 safe screw pathways were measured bilaterally by 3 orthopaedists (resident, trauma fellow, trauma attending). Pathways corresponding to: (1) an "iliosacral" screw at S1, a "trans-sacral trans-iliac" (TSTI) screw at S1, and a TSTI screw at S2., Main Outcome Measurements: (1) Mean width and height of pathways, (2) interrater reliability coefficient, (3) availability of pathways greater than 7 mm, (4) growth of pathways with age, (5) sacral morphology., Results: The interrater reliability coefficient was above 0.917 for all measurements. Radiographically safe pathways were available for 99%, 51%, and 89% of children for iliosacral screws at S1 (width 16.4 ± 2.8 mm, height 15.1 ± 3.3 mm), TSTI screws at S1 (width 7.2 ± 4.9 mm, height 8.3 ± 5.6 mm), and TSTI at S2 (width 9.3 ± 2.2 mm, height 11.5 ± 2.7 mm), respectively., Conclusions: Contrary to our hypothesis, almost all children aged 2-16 had a radiographically safe screw pathway for an iliosacral screw at S1, and most of the children had an available pathway for a TSTI screw at S2. However, only 51% had a pathway for a TSTI screw at S1.

Metabolic bone disorders are associated with several types of human cancers. Pancreatic cancer patients usually suffer from severe nutrition deficiency, muscle wasting, and loss of bone mass. We have previously found that silencing of a zinc transporter ZIP4 prolongs the survival and reduces the severity of the cachexia in vivo. However, the role of ZIP4 in the pancreatic cancer related bone loss remains unknown. In this study we investigated the effect of ZIP4 knockdown on the bone structure, composition and mechanical properties of femurs in an orthotopic xenograft mouse model. Our data showed that silencing of ZIP4 resulted in increased bone tissue mineral density, decreased bone crystallinity and restoration of bone strength through the RANK/RANKL pathway. The results further support the impact of ZIP4 on the progression of pancreatic cancer, and suggest its potential significance as a therapeutic target for treating patients with such devastating disease and cancer related disorders.

Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1(sw/sw)) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1(sw/sw) mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1(sw/sw) mouse is a murine model of OI caused by WNT1 mutations., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Prevention of infection associated with uncemented orthopaedic implants could lead to improved implant stability and better patient outcomes. We hypothesized that coating porous metal implants with antibiotic-containing microspheres would prevent infections in grossly contaminated wounds., Methods: Bioresorbable polymer microspheres containing tobramycin were manufactured and pressed into porous metal cylinders that were then implanted into radial defects in rabbits. Control implants that did not contain antibiotic microspheres were also implanted into the contralateral limbs. Each implant was then contaminated with Staphylococcus aureus prior to closure of the wound. The animal was euthanized after clinical signs of infection appeared, or at two weeks after surgery. Periprosthetic tissue was cultured for the presence of S. aureus, and integration of the implant with the surrounding bone was measured., Results: The antibiotic microspheres successfully prevented infection in 100% of the eleven limbs with treated implants, which represented a significant improvement (p = 0.004) compared with the infection rate of 64% (seven of eleven) for the limbs with control implants. Implant integration averaged 38.87% ± 12.69% in the fifteen uninfected limbs, which was significantly better (p = 0.012) than the average of 19.46% ± 14.49% in the seven infected limbs., Conclusions: The antibiotic delivery system successfully prevented infection in 100% of the cases studied, resulting in an increase in implant integration., Clinical Relevance: Antibiotic delivery utilizing the system described here may be effective in preventing implant-associated infections after orthopaedic surgery and increasing the longevity of orthopaedic implants.

Objectives: The purpose of this study is to compare open reduction and internal fixation of the patella with a locking plate and tension-band construct (PF) versus cannulated screws and tension-band fixation (SF). The hypothesis is that both constructs will have similar failure loads with simulated extension loading., Methods: Transverse patellar fractures were created in 10 cadaveric pairs of legs and were fixed with either PF or SF. Dual-energy X-ray Absorptiometry (DXA) scans of all calcanei measured bone mineral density (BMD). Using an MTS 810 servohydraulic testing machine, each leg cycled to full extension 10 times before loading to failure. A differential variable reluctance transducer measured the distraction of the patella. Data were analyzed using paired t test analysis and bivariate analysis for Pearson correlation coefficients., Results: There was no difference in the BMD between the PF and the SF groups (P = 0.367). No measurable differences occurred during the 10 cycles, and load at clinical failure was not significantly different between the 2 fixation groups (P = 0.38). Stiffness during the final loading cycle was significantly higher for the SF group (P = 0.008). Ultimate strength of fixation was significantly higher in PF group (P = 0.048). BMD was not correlated to the ultimate strength of SF (P = 0.112), but was correlated for PF (P = 0.025)., Conclusions: Based on our results, PF provides comparable strength to SF, and it seems to be a safe and effective alternative to the current gold standard.

TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro-TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1(-/-) mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1(-/-) osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1(-/-) osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1(-/-) calvaria exhibit an elevated mature TGF-β/pro-TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-β antibody, significantly improved the low bone mass of Esl-1(-/-) mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1(-/-) mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.

Background: Disruption of the distal tibia and fibula articulation or syndesmosis can occur without fracture, and isolated syndesmotic disruption is often treated operatively. Following syndesmotic screw removal, a period of protected weight-bearing usually follows to allow the screw holes to heal. Our hypothesis was that supplementing transsyndesmotic fixation with a one-third tubular plate would potentially increase the torsional stiffness about the ankle, thus reducing the risk of fracture after screw removal and potentially allowing a faster return to weight-bearing and sport., Methods: Ten pairs of fresh frozen cadaveric specimens were divided into 2 groups. In group 1 (7 pairs), each left extremity underwent the placement, and subsequent removal, of a 4.5-mm transsyndesmotic screw in a tricortical fashion. The matching right extremity underwent the same procedure but with the addition of a one-third tubular plate, which remained in situ after screw removal. In group 2 (3 pairs), the left specimens had a screw placed and removed while the right limbs remained intact. All specimens were tested under an axial preload and a torsional load until failure., Results: In group 1, the results demonstrated an increase in torsional stiffness in 5 of 7 specimens with supplemental fixation of a one-third tubular plate. In group 2, the presence of the screw hole alone reduced the torsional stiffness in all specimens tested when compared with intact specimens. However, neither of these differences were statistically significant., Conclusion: From this study, we can conclude that the use of supplementary one-third tubular plate fixation demonstrated a trend toward increasing the torsional stiffness following transsyndesmotic screw removal., Clinical Relevance: We believe the trend toward improved stiffness justifies the continued use of our technique, although further studies are necessary to confirm it.

Background: To prevent hemorrhage, fibrin clot formation, and subsequent activation of the inflammatory response, surgical preparation for articular cartilage regeneration should avoid penetration of the subchondral bone plate., Hypothesis: Current surgical procedures with ring curettes do not violate the subchondral bone plate., Study Design: Controlled laboratory study., Methods: The subchondral bone plates of normal human (n = 5) or sheep (n = 12) cadaver femoral condyles were prepared in vitro using either traditional debridement for autologous chondrocyte implantation/transplantation (ACI/ACT) or a modified approach aimed at deliberately violating the subchondral bone plate (ie, brute force). Effects were analyzed by light microscopy. In addition, subchondral bone plates of osteoarthritic (OA) human knees undergoing total knee arthroplasty (n = 5) or normal sheep knees (n = 5) were prepared in vivo. To approximate normal/regular wear, in humans, only OA samples with maximally grade 3A (International Cartilage Repair Society score) were used., Results: In both human and sheep (in vitro), no penetration of the subchondral bone plate was observed by either standard preparation or brute force. In vivo, standard preparation of human or sheep knees also did not violate the tidemark line. Human and sheep specimens prepared by brute force, however, occasionally showed areas with an open bone marrow space., Conclusion: Traditional debridement techniques for ACI/ACT using a ring curette do not violate the normal subchondral bone plate in vitro or in vivo. Even in OA knee joints, the bone plate is only violated by brute force. Therefore, the standard technique appears suitable for studies on cartilage regeneration in cases of traumatic and possibly even osteoarthritic defects., Clinical Relevance: The described surgical preparation technique is the traditional debridement technique for the ACI/ACT. The classic indication for the ACI/ACT is an articular cartilage injury, common in athletes.

Purpose: To compare the biomechanical characteristics of screw versus plate versus both screw and plate fixation for large, type 3 O'Driscoll coronoid fractures., Methods: Synthetic ulnas had 70% of their coronoids cut. Fixation was performed with either a cannulated screw, a plate, or both a screw and a plate. Energy to failure, force at failure, first cycle stiffness, and stiffness at failure were measured on a servohydraulic testing machine under cyclic posterior axial loading., Results: The combination of a plate and screw had significantly greater energy to failure (83 Nm), force required to cause failure (634 N), and stiffness at failure (387 N/mm) compared to either an isolated plate (38 Nm, 474 N, 237 N/mm, respectively) or a screw (10 Nm, 279 N, 149 N/mm, respectively). For energy to failure and force required to cause failure, the plate group significantly outperformed the screw group. There was no significant difference in stiffness at the time of failure between the plate and screw groups., Conclusions: For type 3 O'Driscoll coronoid fractures or nonunions when both a screw and a plate can be placed, the combination of these 2 fixation devices appears to produce significantly greater biomechanical stability than either fixation device alone., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: The treatment of osteogenesis imperfecta has been directed at improvement of bone mineral density, yet the importance of bone mineral density in predicting functional and clinical outcome in this patient population has not been demonstrated. We used a validated functional outcome measure to identify the relationship between bone mineral density and physical function in children with osteogenesis imperfecta, and we also evaluated the relationship of bone mineral density to the rate of surgery and fracture in patients with osteogenesis imperfecta., Methods: Twenty patients (age range, four to seventeen years) with osteogenesis imperfecta who had undergone bone mineral densitometry as measured by dual x-ray absorptiometry of the lumbar spine, wrist, and proximal aspect of the femur between November 1999 and April 2001 were retrospectively analyzed. Functional outcome was measured with use of the Pediatric Outcomes Data Collection Instrument. These questionnaires were completed by the parents of all twenty patients and, in addition, by fifteen patients in the study who were between the ages of eleven and eighteen years. Fracture and surgery rates were calculated on the basis of the number of documented fractures and surgical procedures that the patient had had from the time of the initial presentation until the time of the latest follow-up visit., Results: There were significant relationships between the bone mineral density of the lumbar spine and the scores obtained on the parent-completed questionnaires with regard to upper-extremity functioning (r = 0.57, p < 0.01), transfers and basic mobility (r = 0.55, p = 0.01), sports and physical functioning (r = 0.55, p = 0.01), and global functioning (r = 0.60, p < 0.004). There were also significant relationships between the bone mineral density of the wrist and the scores obtained on the child-completed questionnaires with regard to upper-extremity functioning (r = 0.82, p < 0.01), sports and physical functioning (r = 0.76, p < 0.01), and global functioning (r = 0.83, p = 0.001). There were significant negative relationships between the bone mineral density of the lumbar spine and the rate of fractures (r = -0.69, p < 0.001) and the bone mineral density of the lumbar spine and the rate of surgery (r = -0.60, p < 0.01)., Conclusions: There is a relationship between bone mineral density and the functional outcome, rate of fracture, and rate of surgery in patients with osteogenesis imperfecta. Bone mineral density appears to be an indicator of disease severity and may be predictive of long-term functional outcome. To establish specific guidelines for treatment, more data on normative bone-mineral density in children with osteogenesis imperfecta will be needed.

Undissolved calcium (Ca) tablets in the gastrointestinal tract at the time of a dual-energy X-ray absorptiometry (DXA) scan could conceivably affect the accuracy of the lumbar spine bone mineral density (BMD) determination. We studied phantoms and volunteers to determine the effect of Ca tablets overlying bone, Ca tablets in the soft-tissue field, and Ca tablets overlapping both bone and soft tissue. For L1-4, a 500-mg Ca tablet taped to the phantom surface or the skin of volunteers resulted in

Inexpensive, commercially produced devices that directly measure bone strength in vivo are not currently available. Mechanical response tissue analysis (MRTA), a unique prototype device, is an in vivo vibrational test that measures transverse bending stiffness (a measure of whole bone strength expressed as the product of estimated Young's modulus of elasticity and cross-sectional moment of inertia, EI, Nm2) at ulna midshaft. We compared speed of sound (SOS; [m/s]) in ulna cortical bone using a commercially available axial transmission quantitative ultrasound (QUS) device with EI using MRTA. Dual-energy X-ray absorptiometry (DXA) was used to provide an estimate of ulna size (cm2), bone mineral content (BMC; [g/cm]) and areal bone mineral density (BMD; [g/cm2]). The objective of the study was to determine if ulna SOS--alone or in combination with BMD from DXA--was correlated with ulna EI, thus becoming a surrogate measure of transverse bending stiffness, and thus whole bone strength. Data were collected from 138 female volunteers (18-86 yr). EI and SOS were significantly correlated, r = +0.218, p = 0.01, but r2 was very low, 4.8%. SOS and total ulna BMD were combined to estimate elastic modulus, which correlated with EI, r = +0.377, p < 0.0001; however, the correlation was not significantly better than with SOS alone. We conclude that axial transmission QUS is not a strong surrogate in vivo technique for estimating transverse bending stiffness.

Calcium phosphate ceramics have been widely used for filling bone defects to aid in the regeneration of new bone tissue. Addition of osteogenic cells to porous ceramic scaffolds may accelerate the bone repair process. This study demonstrates the feasibility of culturing marrow stromal cells (MSCs) on porous biphasic calcium phosphate ceramic scaffolds in a flow perfusion bioreactor. The flow of medium through the scaffold porosity benefits cell differentiation by enhancing nutrient transport to the scaffold interior and by providing mechanical stimulation to cells in the form of fluid shear. Primary rat MSCs were seeded onto porous ceramic (60% hydroxyapatite, 40% beta-tricalcium phosphate) scaffolds, cultured for up to 16 days in static or flow perfusion conditions, and assessed for osteoblastic differentiation. Cells were distributed throughout the entire scaffold by 16 days of flow perfusion culture whereas they were located only along the scaffold perimeter in static culture. At all culture times, flow perfused constructs demonstrated greater osteoblastic differentiation than statically cultured constructs as evidenced by alkaline phosphatase activity, osteopontin secretion into the culture medium, and histological evaluation. These results demonstrate the feasibility and benefit of culturing cell/ceramic constructs in a flow perfusion bioreactor for bone tissue engineering applications.

Background: Medial opening wedge distal tibial osteotomy, a relatively new technique for treatment of intermediate ankle joint arthritis, is a technically demanding procedure that requires preoperative planning to determine the size of the wedge that will restore anatomic alignment of the joint surface. The purpose of this study was to facilitate the preoperative planning process for distal tibial osteotomy by determining angular correction obtained with various wedge heights., Methods: Measurements of the distal tibia were taken from cadaver specimens to develop a database of average distal tibial widths. A distal tibial osteotomy was then done on the cadaver specimens with the placement of wooden block wedges of various heights at the osteotomy site. Preoperative and postoperative radiographic measurements of the joint surface angle were obtained on all specimens. The measured amount of angular change was compared to the mathematically predicted angular change using the formula tan theta = H/W., Results: The mathematical model accurately predicted the amount of measured angular correction of the distal tibial articular surface. There was an approximate 2-degree angular change of the articular surface per millimeter of wedge height. As the tibial width increased, a smaller amount of angular correction per millimeter of wedge height was noted, and as wedge height increased with the same tibial width, less angular correction was obtained per millimeter of wedge height., Conclusion: With appropriate preoperative planning, an accurate prediction can be made as to the amount of ankle joint correction that should be obtained with surgery. The size of the wedge that will provide the desired amount of correction can be accurately determined preoperatively.

Novel hydrogel materials based on oligo(poly(ethylene glycol) fumarate) (OPF) crosslinked with a redox radical initiation system were recently developed in our laboratory as injectable cell carriers for orthopedic tissue engineering applications. The effect of OPF hydrogel material properties on in vitro osteogenic differentiation of encapsulated rat marrow stromal cells (MSCs) with and without the presence of osteogenic supplements (dexamethasone) was investigated. Two OPF formulations that resulted in hydrogels with different swelling properties were used to encapsulate rat MSCs (seeding density approximately 13 million cells/mL, samples 6 mm diameter x 0.5 mm thick before swelling) and osteogenic differentiation in these constructs over 28 days in vitro was determined via histology and biochemical assays for alkaline phosphatase, osteopontin and calcium. Evidence of MSC differentiation was apparent over the culture period for samples without dexamethasone, but there was large variability in calcium production between constructs using cells of the same source. Differentiation was also seen in samples cultured with osteogenic supplements, but calcium deposition varied depending on the source pool of MSCs. By day 28, osteopontin and calcium results suggested that, in the presence of dexamethasone, OPF hydrogels with greater swelling promoted embedded MSC differentiation over those that swelled less (43.7 +/- 16.5 microg calcium/sample and 16.4 +/- 2.8 microg calcium/sample, respectively). In histological sections, mineralized areas were apparent in all sample types many microns away from the cells. These experiments indicate that OPF hydrogels are promising materials for use as injectable MSC carriers and that hydrogel swelling properties can influence osteogenic differentiation of encapsulated progenitor cells., (Copyright 2004 Wiley Periodicals, Inc. J Biomed Mater Res 70A: 235-244, 2004)

Biodegradable microspheres were manufactured from a high molecular weight copolymer of 50% lactic and 50% glycolic acid and the antibiotic tobramycin. It was hypothesized that the microspheres would be more effective than polymethylmethacrylate beads in the local delivery of tobramycin and that the microspheres would not inhibit bone healing. Osteomyelitis was established in 40 New Zealand White rabbits using Staphylococcus aureus. All animals had irrigation and debridement of the infected radii four weeks after inoculation and were divided into five treatment groups: debridement alone, microspheres alone, microspheres containing tobramycin plus parenteral treatment with cefazolin, polymethylmethacrylate beads containing tobramycin plus parenteral cefazolin, and parenteral cefazolin. All animals were sacrificed after 4 weeks of treatment. The group treated with microspheres plus parenteral antibiotics was the only group to have a significantly higher percentage of animals without bacteria after 4 weeks of treatment when compared with the control group. Additionally, the animals treated with microspheres had a higher degree of bone healing in the defect than the animals treated with bone cement. The most effective treatment was biodegradable microspheres combined with parenteral antibiotic in this rabbit osteomyelitis model.

A novel polymer, oligo(poly(ethylene glycol) fumarate) (OPF), cross-linked with a thermal radical initiation system has recently been developed in our laboratory as an injectable, biodegradable cell carrier for regeneration of orthopaedic tissues. The cross-linking, swelling, and degradative properties of hydrogels prepared from OPF with poly(ethylene glycol) of two different chain lengths were assessed. The two OPF types had similar gelation onset times ( approximately 3.6 min) but, when cross-linked for 8 min at 37 degrees C, exhibited significantly different swelling characteristics (fold swelling: 17.5 +/- 0.2 vs 13.4 +/- 0.4). Rat marrow stromal cells (MSCs) were then directly combined with the hydrogel precursors and encapsulated in a model OPF formulation at approximately 14 million cells/mL, cultured in vitro in the presence of osteogenic supplements (dexamethasone), and monitored over 28 days via histology. MSC differentiation in these samples (6 mm diameter x 0.5 mm thick before swelling), as determined by Von Kossa staining for calcified matrix, was apparent by day 21. At day 28, mineralized matrix could be seen throughout the samples, many microns away from the cells. These experiments strongly support the usefulness of thermally cross-linked OPF hydrogels as injectable cell carriers for bone regeneration.

Bioabsorbable implants are widely used in orthopedic surgery today and the worldwide market is expanding rapidly. Despite the popularity of these implants, reports of complications continue to appear in the literature. Although the complications rarely have an adverse affect on long-term outcomes, the reports are too numerous to be mere isolated incidents related to one specific implant. Complications have been reported with most of the commercially available implant materials with varying incidence rates and severities of reactions to the implants. The purpose of this review is to summarize the adverse events that have been reported in clinical trials of bioabsorbable implants in orthopedic surgery.

This work presents a new molding process for photo-crosslinked, degradable polymeric networks of poly(propylene fumarate) (PPF) and the crosslinking agent poly(propylene fumarate)-diacrylate (PPF-DA). Transparent room temperature vulcanizing silicone molds were fabricated for parts ranging from simple test coupons to orthopaedic implants. The PPF/PPF-DA resin blend was injected into the cavity and photo-crosslinked as light was transmitted through the mold wall. The volumetric shrinkage, mechanical properties, and the effects of gamma sterilization were reported for molded PPF/PPF-DA networks prepared with varying compositions of the two polymer components. The shrinkage decreased while the mechanical properties displayed a general increasing trend when more of the crosslinking agent was incorporated into the network. Gamma irradiation resulted in an improvement of the mechanical properties. In addition, PPF/PPF-DA replicates of a 70:30 poly(L/DL-lactide) biodegradable fixation plate and a bone allograft interbody fusion spacer were produced to evaluate the performance of PPF/PPF-DA as an orthopaedic implant and allow for a comparison to be made with materials that have been established for clinical use.

Introduction: Small fracture screws are among the most commonly used implants in the field of orthopedic surgery. The goal of this study was to compare the insertion and failure torques of three screw types: cortical, partially threaded cancellous, and fully threaded cancellous from three manufacturers: Zimmer, Richards, and Synthes., Materials and Methods: Each type of screw was subjected to biomechanical tests to determine the insertion ( n=6/group) and failure ( n=10/group) torques., Results: Two-factor ANOVA tests were run to determine whether the insertion or failure torques were different for the different screw types and manufacturers. In the case of insertion torques, neither the screw nor the manufacturer had any significant effect. In the case of failure torque, significant differences were found based on both the screw type and the manufacturer, with the cortical screws manufactured by Zimmer being the strongest. Although there were strength differences, the most important comparison clinically is between the failure torque and the insertion torque of each screw. In all cases, the failure torques were approximately 20 times larger than the insertion torques, and therefore no failures should occur if only torsional loads are applied during insertion. This comparison shows that factors other than screw strength and manufacturing processes may be involved in cases of screw failure during insertion., Conclusion: All three screw types from all three manufacturers appear to be mechanically reliable, with the proper insertion to failure torque ratio. The surgeon's choice of implant should be based on other considerations.