91220799 The effects of etidronate on trabecular bone remodeling in postmenopausal spinal osteoporosis: A randomized study comparing intermittent treatment and an ADFR regime

Since phosphorus is a component of hydroxyapatite, its prolonged deprivation affects bone mineralization. Fibroblast growth factor 23 (FGF23) is essential for maintaining phosphate homeostasis and is mainly produced by osteocytes. FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys. Osteocytes are cells of osteoblastic lineage that have undergone terminal differentiation and become embedded in mineralized bone matrix. Osteocytes express FGF23 and other multiple genes responsible for hereditary hypophosphatemic rickets, which include phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C (FAM20C). Since inactivating mutations in PHEX, DMP1, and FAM20C boost the production of FGF23, these molecules might be considered as local negative regulators of FGF23. Mouse studies have suggested that enhanced FGF receptor (FGFR) signaling is involved in the overproduction of FGF23 in PHEX-deficient X-linked hypophosphatemic rickets (XLH) and DMP1-deficient autosomal recessive hypophosphatemic rickets type 1. Since FGFR is involved in the transduction of signals evoked by extracellular Pi, Pi sensing in osteocytes may be abnormal in these diseases. Serum levels of sclerostin, an inhibitor Wnt/β-catenin signaling secreted by osteocytes, are increased in XLH patients, and mouse studies have suggested the potential of inhibiting sclerostin as a new therapeutic option for the disease. The elucidation of complex abnormalities in the osteocytes of FGF23-related hypophosphatemic diseases will provide a more detailed understanding of their pathogenesis and more effective treatments.

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Osteocytes and the pathogenesis of hypophosphatemic rickets

Bone tumors are a group of histologically diverse diseases that occur across all ages. Two of the commonest, osteosarcoma (OS) and Ewing sarcoma (ES), are regarded as characteristic adolescent and young adult (AYA) cancers with an incidence peak in AYAs. They are curable for some but associated with unacceptably high rates of treatment failure and morbidity. The introduction of effective new therapeutics for bone sarcomas is slow, and to date, complex biology has been insufficiently characterized to allow more rapid therapeutic exploitation. This review focuses on current standards of care, recent advances that have or may soon change that standard of care and challenges to the expert clinical research community that we suggest must be met.

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Current approaches to management of bone sarcoma in adolescent and young adult patients.

BACKGROUND. CT is the imaging modality of choice to identify lung metastasis. OBJECTIVE. The purpose of this study was to evaluate the performance of reduced-dose CT for the detection of lung nodules in children and young adults with cancer. METHODS. This prospective study enrolled patients 4-21 years old with known or suspected malignancy who were undergoing clinically indicated chest CT. Study participants underwent an additional investigational reduced-dose chest CT examination in the same imaging encounter. Separated deidentified CT examinations were reviewed in blinded fashion by three independent radiologists. One reviewer performed a subsequent secondary review to match nodules between the standard- and reduced-dose examinations. Diagnostic performance was computed for the reduced-dose examinations using the clinical examinations as the reference standard. Intraobserver agreement and interobserver agreement were calculated using Cohen kappa. RESULTS. A total of 78 patients (44 male patients and 34 female patients; mean age, 15.2 ± 3.8 [SD] years) were enrolled. The mean estimated effective dose was 1.8 ± 1.1 mSv for clinical CT and 0.3 ± 0.1 mSv for reduced-dose CT, which is an 83% dose reduction. Forty-five of the 78 (58%) patients had 162 total lung nodules (mean size, 3.4 ± 3.3 mm) detected on the clinical CT examinations. A total of 92% of nodules were visible on reduced-dose CT. The sensitivity and specificity of reduced-dose CT for nodules ranged from 63% to 77% and from 80% to 90%, respectively, across the three reviewers. Intraob-server agreement between clinical CT and reduced-dose CT was moderate to substantial for the presence of nodules (κ = 0.45-0.67) and was good to excellent for the number of nodules (κ = 0.68-0.84) and nodule size (κ = 0.69-0.86). Interobserver agreement for the presence of nodules was moderate for both reduced-dose (κ = 0.53) and clinical (κ = 0.54) CT. A median of one nodule was present on clinical CT in patients with a falsely negative reduced-dose CT examination. CONCLUSION. Reduced-dose CT depicts more than 90% of lung nodules in children and young adults with cancer. Reviewers identified the presence of nodules with moderate sensitivity and high specificity. CLINICAL IMPACT. CT performed at a 0.3-mSv mean effective dose has acceptable diagnostic performance for lung nodule detection in children and young adults and has the potential to reduce patient dose or expand CT utilization (e.g., to replace radiography in screening or monitoring protocols). TRIAL REGISTRATION. ClinicalTrials.gov NCT03681873.

Comparison of 0.3-mSv CT to Standard-Dose CT for Detection of Lung Nodules in Children and Young Adults With Cancer.

Early research has suggested a rather straightforward relation between phosphate exposure, increased serum FGF23 (Fibroblast Growth Factor 23) concentrations and clinical endpoints. Unsurprisingly, however, subsequent studies have revealed a much more complex interplay between autocrine and paracrine factors locally in bone like PHEX and DMP1, concentrations of minerals in particular calcium and phosphate, calciprotein particles, and endocrine systems like parathyroid hormone PTH and the vitamin D system. In addition to these physiological regulators, an expanding list of disease states are shown to influence FGF23 levels, usually increasing it, and as such increase the burden of disease. While some of these physiological or pathological factors, like inflammatory cytokines, may partially confound the association of FGF23 and clinical endpoints, others are in the same causal path, are targetable and hence hold the promise of future treatment options to alleviate FGF23-driven toxicity, for instance in chronic kidney disease, the FGF23-associated disease with the highest prevalence by far. These factors will be reviewed here and their relative importance described, thereby possibly opening potential means for future therapeutic strategies.

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Shedding Light on the Complex Regulation of FGF23

Sclerostin antibody improves phosphate metabolism hormones, bone formation rates, and bone mass in adult Hyp mice.

For osteosarcoma, staging criteria, prognosis estimates, and surgical recommendations have not yet changed to reflect increasingly sensitive computed tomography (CT) imaging. However, the frequent identification of micronodules ( 10 mm or pulmonary surgical intervention. Kaplan-Meier curves showed there was no difference in 5-year overall survival in patients with any size nodule <5 mm compared to patients with no nodules. Additionally, our study showed a survival advantage for those who presented with 0 or 1 nodule (90%) compared to ≥2 nodules (53%). Our data suggest surgery may not be necessary for singular nodules <5 mm identified on presentation, and that these patients behave more like "localized" patients than metastatic patients.

https://www.mdpi.com/2077-0383/10/6/1213/pdf

What Effect Do Pulmonary Micronodules Detected at Presentation in Patients with Osteosarcoma Have on 5-Year Overall Survival?

To test how osteoporosis drugs affect bone matrix maturation during cortical bone remodeling, 72 pregnant rats were switched from a 0.4% to a 0.01% calcium diet at parturition for a 23-day lactation period. At weaning, eight dams were sacrificed to establish baseline values, while the remaining dams were returned to 0.4% calcium and treated with vehicle (saline), sodium fluoride (NaF), zoledronic acid (ZA), or sclerostin antibody (Scl-Ab) for either 7 or 28 days (eight animals per group per time point). Femora were examined by μCT, dynamic histomorphometry, Fourier transform infrared imaging, and three-point bending of notched specimens. Cortical porosity decreased in all groups from baseline to day 28. Intracortical mineralizing surface (MS/BS) and mineral apposition rate (MAR), as well as the mineral-to-matrix ratio were unaffected by treatment, but intracortical crystallinity was increased in the ZA group at day 10 compared with vehicle. Cortical area increased in all groups over 28 days mainly because of an addition of bone at the endocortical surface. Endocortical MS/BS did not vary among the groups, but endocortical MAR was suppressed in the NaF group at day 2 and elevated in the Scl-Ab group at day 4 compared with vehicle. Endocortical mineral-to-matrix ratio was increased at days 5 and 10 following NaF treatment and endocortical crystallinity was increased at day 5 following ZA treatment compared with vehicle. Fracture toughness did not differ among the groups. Thus, the treatments affected matrix maturation more strongly at the endocortical then intracortical envelope. In this model of induced remodeling, the bone formation phase is synchronized at multiple sites, facilitating study of the effects of drugs or other bone-targeting agents on matrix maturation independent of their effects on the initiation of remodeling. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1002/jbm4.10344

Osteoporosis Treatments Affect Bone Matrix Maturation in a Rat Model of Induced Cortical Remodeling.

Background:The sudden and debilitating nature of lower extremity injuries can trigger mood disturbances, including major depressive disorder.Methods:This prospective study enrolled patients undergo...

Reid Davison

Papers

Sclerostin antibody improves phosphate metabolism hormones, bone formation rates, and bone mass in adult Hyp mice.

What Effect Do Pulmonary Micronodules Detected at Presentation in Patients with Osteosarcoma Have on 5-Year Overall Survival?

Osteoporosis Treatments Affect Bone Matrix Maturation in a Rat Model of Induced Cortical Remodeling.

Depression Following Operative Treatments for Achilles Ruptures and Ankle Fractures