Entire Skeletal System Research Articles

Parathyroid Hormone and Osteocalcin as Criteria for Osteoporosis in Patients with Celiac Disease

Background: Osteoporosis is a disease that affects the entire skeletal system. It is characterized by the deterioration of the fine structural structure of the bone and the decline in bone mass, which ultimately leads to an increase in the bone's susceptibility to fracture. Celiac disease, often known as wheat allergy, is a single condition with numerous names. Celiac disease is a chronic autoimmune disorder that mostly affects the small intestine. It occurs when patients develop an intolerance to gluten, a protein found in foods including wheat, rye, and barley. Aim of the study: The objective of our study is to track the levels of osteocalcin and parathyroid hormone in the blood serum of patients diagnosed with celiac disease in Wasit Governorate, Iraq. We will be using Human Anti-Deamidated Gliadin Peptide IgG and IgA to diagnose celiac disease and evaluate the progress of bone health. Materials and methods: This study examined a total of 80 samples, consisting of 50 samples from individuals with celiac disease. The sample group included 19 males and 31 women. There are 30 control samples, with an equal number of samples for each sexes. Utilized an Enzyme-linked immunosorbent assay (ELISA) kit to quantify the levels of osteocalcin, parathyroid hormone, and Human Anti-Deamidated Gliadin Peptide IgG and IgA. Results: The study revealed that individuals with celiac disease had significantly higher levels of osteocalcin, parathyroid hormone, and Human Anti-Deamidated Gliadin Peptide IgG and IgA compared to the control group, with a statistical significance of p≤(0.05). Conclusion: The examined parameters serve as indicators of the development of health risks to the body and bone health in individuals with celiac disease.

Developmental changes in tibia and humerus of goose: morphometric, densitometric, and mechanical analysis.

The skeletal system of young animals undergoes a series of intensive and rapid changes. In this study, we aimed to verify the hypothesis that geese exhibit a distinct pattern of bone growth compared to gallinaceous species. Specifically, we hypothesised that geese would experience an accelerated growth rate in the humerus bone, which can be attributed to the increased wing mobility facilitated by their rearing in free-range systems. This need for access to both ground and water environments contributes to the unique demands placed on their skeletal development. We focused on evaluating the mechanical properties and geometry of the humerus as the forelimb bone, and the tibia as the hindlimb bone. The 320 geese used in this study were divided into 12 groups according to sex (females and males) and age (0-,1-,3-,6-,8-,12-,14-week-old). To assess bone mechanical properties, a three-point bending test was performed, along with densitometry and morphological measurements. The tibiae of the geese showed the most intensive growth until 6weeks of age and then stabilised. The wing bones (humerus) showed only slight changes in the first weeks after hatching, and then a rapid growth between the third and sixth week, both in terms of mechanical and morphological properties. This is most likely due to a change in the geese's living environment during this period, i.e., allowing them to leave their enclosures and enter open space, which gives them the opportunity to use their wings, resulting in the rapid growth of the wing bones to support increasing muscle mass in this area. This study increases our understanding of bone growth and development in domesticated birds, specifically waterfowl species, and highlights the importance of rearing methods on the proper bone development and functionality of the entire skeletal system, and thus, on their welfare.

Why Animal Experiments Are Still Indispensable in Bone Research: A Statement by the European Calcified Tissue Society.

Major achievements in bone research have always relied on animal models and in vitro systems derived from patient and animal material. However, the use of animals in research has drawn intense ethical debate and the complete abolition of animal experimentation is demanded by fractions of the population. This phenomenon is enhanced by the reproducibility crisis in science and the advance of in vitro and in silico techniques. 3D culture, organ-on-a-chip, and computer models have improved enormously over the last few years. Nevertheless, the overall complexity of bone tissue cross-talk and the systemic and local regulation of bone physiology can often only be addressed in entire vertebrates. Powerful genetic methods such as conditional mutagenesis, lineage tracing, and modeling of the diseases enhanced the understanding of the entire skeletal system. In this review endorsed by the European Calcified Tissue Society (ECTS), a working group of investigators from Europe and the US provides an overview of the strengths and limitations of experimental animal models, including rodents, fish, and large animals, as well the potential and shortcomings of in vitro and in silico technologies in skeletal research. We propose that the proper combination of the right animal model for a specific hypothesis and state-of-the-art in vitro and/or in silico technology is essential to solving remaining important questions in bone research. This is crucial for executing most efficiently the 3R principles to reduce, refine, and replace animal experimentation, for enhancing our knowledge of skeletal biology, and for the treatment of bone diseases that affect a large part of society. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Transfer Learning-Based Osteoporosis Classification Using Simple Radiographs

Osteoporosis is a condition that affects the entire skeletal system, resulting in decreased density of bone mass and the weakening of bone tissue's micro-architecture. This leads to weaker bones that are more susceptible to fractures. Detecting and measuring bone mineral density has always been a critical area of focus for researchers in the diagnosis of bone diseases such as osteoporosis. However, existing algorithms used for osteoporosis diagnosis encounter challenges in obtaining accurate results due to X-ray image noise and variations in bone shapes, especially in low contrast conditions. Therefore, the development of efficient algorithms that can mitigate these challenges and improve the accuracy of osteoporosis diagnosis is essential. In this research paper, a comparative analysis was conducted Assessing the accuracy and efficiency of the latest deep learning CNN model, such as VGG16, VGG19, DenseNet121, Resnet50 and InceptionV3 in detecting to Classify Normal and Osteoporosis cases. The study employed 830 X-ray images of Spine, Hand, Leg, Knee, and Hip, comprising of Normal (420) and Osteoporosis (410) cases. Various performance metrics were utilized to evaluate each model, and the findings indicate that DenseNet121 exhibited superior performance with an accuracy rate of 93.4% with Achieving an error rate of 0.07 and a validation loss of only 0.57 in comparison with other models considered in this study.

Genetics implicates overactive osteogenesis in the development of diffuse idiopathic skeletal hyperostosis

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition where adjacent vertebrae become fused through formation of osteophytes. The genetic and epidemiological etiology of this condition is not well understood. Here, we implemented a machine learning algorithm to assess the prevalence and severity of the pathology in ~40,000 lateral DXA scans in the UK Biobank Imaging cohort. We find that DISH is highly prevalent, above the age of 45, ~20% of men and ~8% of women having multiple osteophytes. Surprisingly, we find strong phenotypic and genetic association of DISH with increased bone mineral density and content throughout the entire skeletal system. Genetic association analysis identified ten loci associated with DISH, including multiple genes involved in bone remodeling (RUNX2, IL11, GDF5, CCDC91, NOG, and ROR2). Overall, this study describes genetics of DISH and implicates the role of overactive osteogenesis as a key driver of the pathology.

A Dynamic Optimization Approach for Solving Spine Kinematics While Calibrating Subject-Specific Mechanical Properties.

This study aims to propose a new optimization framework for solving spine kinematics based on skin-mounted markers and estimate subject-specific mechanical properties of the intervertebral joints. The approach enforces dynamic consistency in the entire skeletal system over the entire time-trajectory while personalizing spinal stiffness. 3D reflective markers mounted on ten vertebrae during spine motions were measured in ten healthy volunteers. Biplanar X-rays were taken during neutral stance of the subjects wearing the markers. Calculated spine kinematics were compared to those calculated using inverse kinematics (IK) and IK with imposed generic kinematic constraints. Calculated spine kinematics compared well with standing X-rays, with average root mean square differences of the vertebral body center positions below 10.1 mm and below [Formula: see text] for joint orientation angles. For flexion/extension and lateral bending, the lumbar rotation distribution patterns, as well as the ranges of rotations matched in vivo literature data. The approach outperforms state-of-art IK and IK with constraints methods. Calculated ratios reflect reduced spinal stiffness in low-resistance zone and increased stiffness in high-resistance zone. The patterns of calibrated stiffness were consistent with previously reported experimentally determined patterns. This approach will further our insight into spinal mechanics by increasing the physiological representativeness of spinal motion simulations.

Bone-Specific Drug Delivery for Osteoporosis and Rare Skeletal Disorders.

The skeletal system provides an important role to support body structure and protect organs. The complexity of its architecture and components makes it challenging to deliver the right amount of the drug into bone regions, particularly avascular cartilage lesions. In this review, we describe the recent advance of bone-targeting methods using bisphosphonates, polymeric oligopeptides, and nanoparticles on osteoporosis and rare skeletal diseases. Hydroxyapatite (HA), a calcium phosphate with the formula Ca10(PO4)6(OH)2, is a primary matrix of bone mineral that includes a high concentration of positively charged calcium ion and is found only in the bone. This unique feature makes HA a general targeting moiety to the entire skeletal system. We have applied bone-targeting strategy using acidic amino acid oligopeptides into lysosomal enzymes, demonstrating the effects of bone-targeting enzyme replacement therapy and gene therapy on bone and cartilage lesions in inherited skeletal disorders. Virus or no-virus gene therapy using techniques of engineered capsid or nanomedicine has been studied preclinically for skeletal diseases. Efficient drug delivery into bone lesions remains an unmet challenge in clinical practice. Bone-targeting therapies based on gene transfer can be potential as new candidates for skeletal diseases.

Physical Activity in Women with Breast Cancer and Those After Mastectomy

Mammary gland cancer, commonly known as breast cancer, is the most common malignancy in women in Poland. The occurrence of the disease and its treatment are associated with a decrease in physical fitness and endurance of the body, and also make it difficult to meet basic life needs and result in a deterioration in the quality of life. The aim of the study is to present physical activity in women with breast cancer and after mastectomy. Analysis of professional literature and available research results in patients undergoing oncological therapy in the treatment of breast cancer indicates the need for them to undertake physical activity and physiotherapy in order to minimize the effects of chemotherapy, radiotherapy, and mastectomy. Analysis of studies in terms of the impact of physical activity on the rehabilitation and recovery of patients with breast cancer showed a significant impact of physical fitness on bone mineral density as the most important factor in the development and maintenance of normal bone metabolism. Physical exercises have also been shown to have a positive effect on patients during and after treatment. Regular physical exercise in women treated for cancer is essential and has a significant impact on reducing muscle deficits and the entire skeletal system.

Targeted Marrow Radiation (TMI) Improves Therapeutic Efficacy of STAT3 Decoy Molecules By Augmenting Its Delivery and Immune Modulation in an AML Mouse Model

Introduction Acute myeloid leukemia (AML) is a highly aggressive form of leukemia with poor long-term survival. Our clinical development of a targeted radiation treatment for relapsed/refractory AML disease led to an impressive two-year overall survival (OS) rate of 41% (Stein et al., 2019) in contrast to <10% reported for similar patients (Duval et al., 2019). Unfortunately, a lack of a preclinical model for TMI has impaired further scientific advancement. Ionizing radiation therapy (RT) has been shown to have immune modulatory functions; however, previous studies demonstrated that its efficacy is limited by activation of the radiation-induced tolerogenic TLR9/IL-6/STAT3 signaling axis in myeloid immune cells (Gao et al., 2013; Won et al., 2017). TLR9+ myeloid cells (macrophages, AML, etc) can be efficiently targeted using TLR9 agonists (CpG) conjugated with oligonucleotide (ODN) drugs (e.g., siRNA) to eliminate STAT3 signaling. Such a strategy has been shown to synergize with local tumor RT to prevent tumor recurrence (Gao et al., 2013). A CPG-STAT3-dODN inhibitor (CSI) has been previously reported as an effective immunotherapy for AML (Zhang et al., 2016), but the efficacy of immunotherapeutic agents is drastically reduced at high disease burden (Pai et al., 2019). Therefore, we hypothesized that the immunomodulatory effects of low dose RT can be augmented by blocking the STAT3 signaling in AML cells, enhancing the efficacy of CSI in a high-disease burden model. Methods We first developed a TMI treatment methodology using a Precision X-RAD small animal irradiator. A whole body CT image was acquired, and three-dimensional (3D) dose calculations were performed using a Monte Carlo dose engine-based SmART-Plan treatment system (van Hoof et al, 2013; Downes et al., 2009; Faddegon et al., 2009). Before treatment, mice were further imaged to verify target anatomy prior to delivering precise radiation doses to the entire skeletal system and spleen while sparing vital organs (lungs, liver, gut). We used a Cbfb-MYH11/Mpl (CMM)-induced mice leukemia model. At 5-10% CMM-GFP cells in peripheral blood (~20-30% in bone marrow; high disease burden), the mice were treated with three doses of CSI (2.5mg/kg) on alternate days with or without 4 Gy radiation (TMI or total body irradiation [TBI]). Cy3 labeled CSI uptake studies were carried out 48h post RT by flow cytometry, and immune cell trafficking and activation studies were conducted by harvesting bone marrow and spleen cells on day 8 post RT. Results Dose volume histogram (DVH) and radiation dose painting show that the TMI treatment plan significantly reduced doses to critical organs (lungs, liver, gut) while maintianing the same dose to the skeleton and spleen, unlike TBI (same dose to entire body) (Figure 1A-D). In TMI-treated mice, the CSI-Cy3 uptake was significantly higher in CMM cells than in the CMM cells of mice treated with CSI alone, indicating improved delivery post RT (Figure 1E, F). The trafficking of T helper cells (CD4+) and cytotoxic T lymphocytes (CD8+; CTLs) as well as effector (CD62L-CD44+) and effector memory T cells (CD62L+CD44+) is significantly augmented in the bone marrow of TMI+CSI treated mice compared to levels in mice treated with TBI+CSI or CSI alone (Figure 1G, H). An increased total number of IFNγ secreting CTLs, and a higher CD8:Treg (CD4+CD25+FOXP3+) ratio indicate enhanced anti-tumerogenic activity in TMI+CSI treated mice over that of mice treated with TBI+CSI or CSI alone (Figure 1I, J). Similarly, myeloid cell trafficking and activation was augmented in TMI-treated bone marrow (data not shown). The benefit of augmented immune modulation in TMI+CSI combinatorial therapy is reflected in a significantly increased survival (~39 median survival days) over untreated mice and those treated with CSI or TMI alone ( ~8-9 days median survival) (Figure 1K). Conclusion This is the first report of a novel radio-immunotherapy using a systemic targeted precise RT (TMI) in combination with STAT3 down-regulation (CSI) in AML. As hypothesized, low-dose targeted RT in combination with blocking of STAT3 signaling improved immune cell trafficking and activation, thereby enhancing the efficacy of this combinatorial therapy in high-disease burden. Further, newly developed low-dose TMI shows enhanced immune modulation over conventional TBI, suggesting the benefits of localized targeted RT in hematological malignancies. Disclosures Hui: Janssen Research & Development, LLC: Consultancy, Honoraria.

Transitioning to whole-body SPECT/CT in prostate cancer staging: anew concept for a better imaging workflow.

Whole-body bone scan (BS) is the clinical standard in detecting bone metastases in prostate cancer patients. Additional SPECT/CT has allowed to significantly increase its diagnostic accuracy. However, performing both planar and additional SPECT/CT prolongs the total examination time and lowers patient throughput. In this study we aim to assess the diagnostic performance of a SPECT/CT-only protocol compared to the traditional procedure that is BS with a facultative SPECT/CT in case of unclear findings. 50 patients with high-risk prostate cancer and suspected bone metastases were enrolled in this retrospective study. All patients received a whole-body Tc-99m-DPD BS followed by a 3 field-of-view (FOV) SPECT/CT (GE Discovery 670 Pro®) covering an area from the vertex to the mid-femur. Metastatic lesions were evaluated visually on BS and SPECT/CT and correlated to PSA-levels. Detection rate was up to 50 % higher in SPECT/CT than in BS (n = 2829 vs. n = 1942; p < 0.001), but 31/1942 (1.5 %) lesions detected on BS were located out of the SPECT/CT field-of-view. In our analysis a PSA-level of > 80 µg/l could be defined as a cut-off-value for metastatic spread beyond mid-thigh, as no patient with PSA< 80 µg/l had localizations outside the SPECT/CT field-of-view (AUCPSA = 0.95, p < 0.001 sensitivity: 100 %, specificity: 77 %, NPV: 100 %, PPV: 67 %). The SPECT/CT-only protocol did not prolong acquisition time significantly as compared to BS. In patients with high-risk prostate cancer presenting with PSA < 80 µg/l and absent clinical symptoms, vertex to mid-thighs 3-FOV-SPECT/CT was representative for the entire skeletal system and was able to detect more lesions than planar acquisition. This procedure did not prolong patient handling time significantly.

Morphological and mechanical properties of bone tissues

Introduction: Adult human skeletal system consists of 206 bones and this system gives the human body its shape, supports it, and helps in movements. These bones are made of living bones tissues which replenish throughout the lifetime of an individual. There are different bone diseases associated to these bone tissues like osteoporosis, low bone density, osteogenesis imperfecta, and Paget’s disease of bones which happen when these bone tissues synthesis is not normal, and can cause fracture. The most common bone disease is osteoporosis which causes bones to become less dense and more fragile. It affects the entire skeletal system and causes fracture in hips, wrists, ankles, and spine commonly.Methodology: CT ScanningThree calcaneus bone samples were scanned using micro CT (SkyScan 1172, Aarteslaar, Belgium) at the voxel size of 17.41 µm, rotating at increments of 0.7˚ for 180˚, and the data was stored in numbered 16bit high resolution grayscale images. Results: The analysis of bone properties has not been limited to mechanical testing only. With the development of computer tomography techniques and finite element modelling software, the researchers have started using simulations to study bone morphology and properties. The previous studies indicate that not much has been done to study the fracture mechanism of calcaneal trabeculae. So, this study was designed to conduct compression test on sections of calcaneal trabeculae and compare it with the available results.Conclusion: The study focuses on the mechanical properties of trabecular bone incompression. The main purpose of the study is investigating the factors which could influence the mechanical properties of the trabecular bone.Summary: The human skeletal system suffers from number of diseases like osteoporosis, osteoarthritis, and Paget’s disease which impair its function and cause discomfort and fracture to patients. The study of bone properties have helped in treating a variety of bone diseases. This study involved non-destructive finite element analysis of calcaneal trabecular bone specimens under compressive loading. Three calcaneal trabecular bone specimens were scanned using micro CT and 3D models were reconstructed using the image data. The reconstructed models were assigned material heterogeneous properties based on grayscale values from the images. These models were converted to FE models with a variety of mesh coarseness and analysed, and the best models were used for further finite element analysis. The results were compared with previous studies and matched subject to certain errors. It was concluded that mesh parameters affect the quality of finite element simulation and the heterogeneous bone material properties caused non-uniform deformation in the trabeculae structure.

64cu-DOTA-Anti-CD33 PET-CT Imaging for Acute Myeloid Leukemia and Image-Guided Treatment

Introduction:Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that results a poor survival outcome. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). Although non-invasive positron emission tomography (PET) imaging has been developed for almost all solid tumors and some hematological malignancies, there is currently no non-invasive imaging specific to AML available, representing an unmet clinical need. About 85% of AML cells express CD33, and expression levels of CD33 has been correlated with poor survival outcomes (Pollard et al., Blood (2012)), making it an ideal candidate for immuno-PET. Therefore, our primary goal is to develop anti-CD33 immuno-PET for detecting CD33+ AML. The secondary goal is to assess the feasibility of CD33 PET image-guided external beam targeted radiation delivery in combination with chemotherapy (AraC).Methods:Murine anti-human CD33 monoclonal antibody clone p67.6 was conjugated to DOTA and radiolabeled with Cu-64 for imaging studies. In vivo PET-CT imaging and bio distribution of 64Cu-DOTA-anti-CD33 in vivo was carried out in NSG mice bearing CD33+ (MV4-11, HL60) AML cells. CD33-negative MM1s cells (multiple myeloma) were used as negative control. The AML and MM bearing mice were injected with 64Cu-DOTA-anti-CD33 (100 µCi/10 µg) and serial PET imaged at 24-48 h.We developed a functional total marrow irradiation (fTMI) treatment, where mice received total marrow irradiation (TMI) (2 Gy) and boost radiation (2 Gy) to regions with increased CD33 activity, followed by 2 days of AraC (40 mg/kg) and 24h later a bone marrow transplant. Furthermore, a humanized anti-human CD33 monoclonal antibody was generated and tested for immunogenicity against CD33 in AML cell lines and patient samples for future clinical studies.Results:PET-CT imaging and biodistribution studies of 64Cu-DOTA-anti-CD33 clearly indicates a CD33+ PET signal in the femur, tibia, humerus joints, L spine and spleen in AML-bearing mice, but not in multiple myeloma-bearing mice or in cold anti-CD33-DOTA treated leukemic mice (Figure 1A and B). Our new imaging method was able to detect CD33+ AML with a favorable sensitivity (71.4%) and specificity (100%). Based on detailed whole-body 3D imaging and validated with biodistribution studies, we discovered preferential regions in the skeletal system with differential CD33 activity, indicating the spatial heterogeneity of AML. CD33+ PET intensity was observed in the following descending order: femur≥lspine>humerus>tibia (Figure 1C).Next, using the PET-CT images, we targeted these CD33-active regions using the fTMI treatment plan. We have developed a unique irradiation system which allows targeting only skeletal tissues while sparing major organs like gut, lung and liver, unlike conventional total body irradiation (TBI). This approach will also provide an opportunity to escalate doses to specific regions in the body without damaging other unintended targets. The fTMI (2 Gy TMI and 2 Gy boost) treatment plan increased the medial survival of the mice to 43 days versus that of untreated control mice (26 days) or AraC treated mice (33 days) Figure(1D).Since the preclinical study was carried out using murine anti-CD33 antibody clone p67.6, we further tested the newly generated humanized anti-human-CD33 monoclonal antibody. This humanized antibody detects CD33 in both AML cell lines and human patient sample (Fig 1E).Conclusion:This study is the first to use an anti-CD33 monoclonal antibody for non-invasive immuno-PET-based imaging for AML detection, showing high sensitivity and specificity. This whole body imaging may be useful for AML diagnosis not only in the entire skeletal system, but also in the extramedullary organs, and for longitudinal monitoring of treatment response. Unlike conventional TBI, Image-guided fTMI along with conventional chemotherapy may result in an improved prognosis, as unintended major organs are spared from radiation. [Display omitted] DisclosuresVallera:GT Biopharma: Consultancy, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.

Eficácia da reeducação postural global na dor de indivíduos com disfunção temporomandibular: uma revisão sistemática

INTRODUÇÃO: Disfunção temporomandibular (DTM) é caracterizada por um conjunto de alterações funcionais, que envolvem fatores predisponentes, iniciantes e perpetuantes. Considerando que os desvios posturais desorganizam a harmonia corporal entre a postura da mandíbula e todo o sistema esquelético, várias modalidades fisioterapêuticas foram propostas no tratamento da DTM, incluindo a Reeducação Postura Global (RPG). OBJETIVO: Avaliar sistematicamente as evidências sobre a eficácia da RPG no tratamento da dor em indivíduos com DTM. MÉTODOS: Revisão sistemática realizada pesquisa nas bases de dados, maio a setembro 2017, Pubmed, Biblioteca Virtual em Saúde (Lilacs, Scielo e Medline), PEDro e Cochrane Library. Os critérios de inclusão: Ensaios clínicos randomizados (ECR) e Ensaios clínicos controlados (ECC); artigos publicados em língua inglesa, portuguesa e espanhola; que abordavam sobre o tratamento com RPG; com indivíduos adultos &gt; 18 e ?60 anos; diagnosticados com DTM; que continham avaliação da dor. Excluídos: estudos duplicados; que utilizaram exercícios para pacientes pós-cirúrgico e que apresentassem doenças sistêmicas ou qualquer afecção que afetasse o sistema osteomioarticular; que avaliaram pacientes com histórico de trauma facial ou cervical e em uso de medicamentos. RESULTADOS: Um total de 349 artigos foram encontrados, que após a eliminação de duplicatas, filtragem de títulos, resumos e leitura de texto completo foram incluídos na pesquisa três estudos, o que evidenciou a eficácia da RPG na redução da dor. CONCLUSÃO: Considerando os resultados obtidos neste estudo, foi possível concluir que a RPG demonstra ser eficaz na redução da dor presente na DTM. Porém, faz-se necessários mais ensaios clínicos randomizados com maior rigor metodológico, protocolos mais bem definidos, que possam auxiliar na tomada de decisão clínica e que contemplem também a comparação do tratamento entre homens e mulheres.

Development of Bone Targeting Drugs.

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments.

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography

To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition. Whole-body dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF=RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatment planning was simulated to target irradiation differentially at a higher dose (18Gy) to either RM or YM and a lower dose (12Gy) to the rest of the skeleton. A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI). Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.

A NOVEL METHOD TO EVALUATE HUMAN LOCOMOTION ABILITY BASED ON THE FINITE ELEMENT MODELING AND SIMULATION OF MUSCULOSKELETAL SYSTEM

A novel method based on the finite element modeling and simulation of human musculoskeletal system was proposed to evaluate the human locomotion ability in this paper. Biomechanical models that compute muscle forces and human joint forces are broadly applicable to the study of factors that promote human musculoskeletal injury and optimize musculoskeletal motion planning. However, it is still difficult to acquire the biomechanical characteristics of human skeletal system in vivo. Especially, there is little research about the biomechanical modeling and simulation of the entire human skeletal system. The finite element method was broadly used various mechanical analyses. It has been used to model and simulate biomechanical behavior of segments of human skeletal system, such as arthrosis, organs and so on. A novel finite element model of the entire human skeletal system was proposed in this paper. As far as we know, there is no similar reports yet. First, the anatomical detailed three-dimension models of human musculoskeletal system were reconstructed from the cross-sectional images of China Visible Human Project. Second, the sectional finite element models of musculoskeletal system was built. And, the finite element model of the entire human musculoskeletal system was integrated. In the end, a weightlifting motor task simulation was implemented as a case study using the proposed method on supercomputer platform Dawning4000A in Shanghai Supercomputer Center. The muscle forces and the skeleton stresses of subject during weightlifting locomotion were obtained. Based on these parameters, the locomotion ability of subject was evaluated. It was validated that the proposed method could provide the inbeing biomechanical information of musculoskeletal system in vivo. Furthermore, it could evaluate human locomotion ability based on these information from a novel viewpoint.

Whole body MRI in type I Gaucher patients: Evaluation of skeletal involvement

Background Bone disease is a serious complication of type 1 Gaucher disease, which if untreated can result in pain, disability and reduced quality of life. MRI is the method of choice for assessing and monitoring bone involvement in Gaucher patients. MRI bone evaluation has been predominantly carried out on the lumbar spine and/or lower extremities using quantitative or semi-quantitative methods. We describe evaluation of skeletal involvement in Gaucher patients using whole body MRI scanning. Methods Whole body MRI was performed in 39 adult type I Gaucher patients using a 1.5 T superconducting magnet with total imaging matrix technology. A standard MRI protocol was performed in all patients using coronal T1-, T2-weighted (thighs) and STIR-sequences of the whole body, sagittal T1-, T2- (lumbar spine) and STIR-sequences of the entire axial skeleton. Bone marrow involvement was analysed using the Düsseldorf Gaucher score (DGS), bone marrow burden score (BMB), and vertebra-disc-ratio (VDR). Pelvis, humerus, legs and spine were also analysed using the pattern of marrow involvement described by homogeneous type A or non-homogeneous type B morphology. Avascular necrosis (AVN) of the humeral head was determined. Results Whole body MRI was well tolerated and of diagnostic value in all patients. Thirty one out of 39 patients (79%) showed bone involvement. In fifteen of these 31 patients (48%) humeral bone involvement was observed. The morphological appearance of bone involvement (type A or B) was consistent across the humerus, legs and pelvis. The infiltration pattern was also similar across cervical, thoracic and lumbar vertebral bodies. Humeral bone involvement was present in 89% of patients with type B morphology compared with 32% of patients with type A morphology (p < 0.005). Humeral involvement was detected more frequently in patients with severe bone involvement as determined by higher DGS and BMB scores, than in patients with lower DGS and BMB scores (p < 0.0001 and p = 0.0016). AVN of the humeral head was detected in 6 patients (19%). Conclusions In this group of patients, severe bone involvement in the lumbar spine and lower extremities and type B morphology was also associated with humeral involvement. The morphological infiltration pattern was consistent in the entire skeleton indicating the systemic character of bone disease. Whole body MRI presents a feasible means of assessing the entire skeletal system and could be a valuable diagnostic and monitoring tool in the management of patients with type 1 Gaucher disease.

Polyostotic Fibrous Dysplasia on F-18 FDG PET/CT Imaging

A 13-year-old girl diagnosed as polyostotic fibrous dysplasia on plain radiography and histopathology presented with diffuse bone pain. F-18 FDG PET/CT scan was performed to establish the extent of bone involvement, which revealed increased radiotracer uptake at multiple sites. The CT images clearly depicted the extent of each individual lesion along with associated complications. The volume rendered images provided an excellent 3-dimensional representation of the entire skeletal system. Bone scintigraphy, plain radiography, and CT scans are the traditionally employed imaging modalities for evaluation of this rare entity. F-18 FDG PET/CT with its superior spatial resolution and added advantage of lesion characterization could serve as a 1-stop shop for evaluation of this unusual disease.

Whole‐body magnetic resonance imaging in the detection of skeletal metastases in patients with prostate cancer

Whole-body MRI is an effective method for evaluating the entire skeletal system in patients with metastatic disease. This study aimed to compare whole-body MRI and radionuclide bone scintigraph in the detection of skeletal metastases in patients with prostate cancer. Patients with prostate cancer at high risk of skeletal metastasis with (i) prostate-specific antigen of > or =50 ng/mL; (ii) composite Gleason score of > or =8 with prostate-specific antigen of >20 ng/mL; or (iii) node-positive disease were enrolled in this prospective study before systemic treatment was initiated. Whole-body MR images and bone scans of 39 patients were analysed. Seven patients had bone metastases on bone scans, while seven patients had skeletal metastases by whole-body MRI, with concordant findings only in four patients. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivity for both bone scans and MRI was 70%, and the specificity for both was 100%. Magnetic resonance imaging detected 26 individual lesions compared with 18 lesions on bone scans. Only eight lesions were positive on both. Bone scans detected more rib metastases, while MRI identified more metastatic lesions in the spine. Whole-body MRI and radionuclide bone scintigraphy have similar specificity and sensitivity and may be used as complementary investigations to detect skeletal metastases from prostate cancer.

Total Marrow Irradiation with Helical Tomotherapy for Bone Marrow Transplantation of Multiple Myeloma: First Experience in Asia

Three Asian patients with plasma cell myeloma stage IIIa with IgG predominant were selected for autologous hematopoietic cell transplantation (HSCT). Total marrow irradiation (TMI) tomotherapy planned with melphalan 140 mg/m2 as a preconditioning regimen of HSCT. Two image sets of computed tomography (CT) were scanned with 2.5 mm and 5 mm for the upper and lower part of the plan, respectively. The junction was determined and marked at 15 cm above knee on both thighs for upper and lower part of the plan. The clinical target volume (CTV) included the entire skeletal system. The planning target volume (PTV) was generated with with 0.8 cm for CTV(extremities) and with 0.5 cm margin for all other bones of CTV. A total dose of 800 cGy (200 cGy/fraction) was delivered to the PTV. Update to presentation, all of three patients post transplant without evidence of active disease were noted. During TMI treatment, one with grade 1 vomiting, two with grade 1 nausea, one with grade 1 mucositis, and three with grade 1 anorexia were noted. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0). The average for upper part versus lower part of PTV (Bone marrow) of CI and H-index were 1.5 and 1.4 versus 1.2 and 1.2, respectively. The dose reduction of TMI tomotherapy to various OARs of head, chest, and abdomen relative to TBI varied from 31% to 74%, 21% to 51%, and 46% to 63%, respectively. The maximum average value of registration for upper torso versus lower extremities in different translation directions were 5.1 mm versus 4.1 mm for pretreatment and 1.5 mm versus 0.7 mm for post-treatment, respectively. The average treatment time for the upper versus lower part in beam-on time, setup time, and MVCT registration time took roughly 49.9, 23.3, and 11.7 min versus 11.5, 10.0, and 7.3 min, respectively. The margin of PTV could be less than 1 cm under good fixation and close position confirmation with MVCT. Antiemetics should be prescribed in the whole course of TMI for emesis prevention. TMI technique replaced TBI technique with 8 Gy as conditioning regiment for multiple myeloma could be acceptable for the Asian and the outcomes were feasible for the Asian.