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The Journal of Steroid Biochemistry and... Jul 2014In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone... (Review)
Review
In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two lines of therapy. First OPG was used as a therapy to block RANKL was initially successful but later antibodies against OPG developed and this line of treatment had to be discontinued. The next step was to develop a monoclonal antibody against RANKL and this proved to be highly effective in blocking bone resorption. It led to development of a drug Denosumab that successfully reduces fractures and is now one of the therapeutic options for osteoporosis treatment. On the anabolic side bone biology research showed that osteocytes produces sclerostin an inhibitor of the anabolic WNT signaling pathway. Recent development of a monoclonal antibody against sclerostin has shown remarkable anabolic activity in bone showing large increases in bone density and fracture trials are now underway. The newer treatments for osteoporosis are likely to be based on our understanding of bone biology and the design of new highly specific compounds with fewer side effects. This review summarizes the diagnosis of postmenopausal osteoporosis and various available non-pharmacological and pharmacological therapies available for its management. This article is part of a Special Issue entitled 'Menopause'.
Topics: Aged; Aged, 80 and over; Alendronate; Antibodies, Monoclonal, Humanized; Bone Density; Bone Remodeling; Calcitonin; Denosumab; Diphosphonates; Estrogen Replacement Therapy; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Risk Factors; Selective Estrogen Receptor Modulators; Teriparatide
PubMed: 24176761
DOI: 10.1016/j.jsbmb.2013.09.008 -
Cells Dec 2021Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such... (Review)
Review
Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA). RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity. However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis. TNFα can induce OC differentiation that is independent of the RANKL/RANK system. In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation. Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation. However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j. TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB. However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions. Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.
Topics: Animals; Arthritis, Rheumatoid; Cell Differentiation; Humans; Osteoclasts; Osteoporosis; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 35011694
DOI: 10.3390/cells11010132 -
BMC Oral Health Jun 2021The present study aimed to investigate the effects of low-level laser therapy (LLLT) on orthodontic tooth movement and its correlation with the levels of interleukin-1β... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The present study aimed to investigate the effects of low-level laser therapy (LLLT) on orthodontic tooth movement and its correlation with the levels of interleukin-1β (IL-1β), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in gingival crevicular fluid (GCF).
METHODS
This split-mouth design study included 12 patients scheduled for the extraction of both upper first premolars. Patients were randomly selected for experimental group that received left- or right-side radiation with a diode laser (810 nm wavelength, 100 mW power output, 6.29 J/cm energy density). Laser treatment was applied on days 0, 7, 14, and 21, after loading the canine retraction forces. GCF concentrations of IL-1β, RANKL, and OPG were analyzed. The upper arch of each patient was scanned with an intraoral scanner to assess tooth movement.
RESULTS
The cumulative tooth movement over 28 days was significantly higher in the laser group than in the control group. We observed significant reductions in OPG levels and increases in IL-1β and RANKL levels in GCF samples on the experimental sides.
CONCLUSION
With the parameter settings used in this study, LLLT could, to some extent, lead to changes in bone metabolism, which could accelerate orthodontic tooth movement.
TRIAL REGISTRATION
Chinese Clinical Trial Registry, ChiCTR2000039594. Registered 2 November 2020-Retrospectively registered, www.chictr.org.cn/edit.aspx?pid=62465&htm=4 .
Topics: Bicuspid; Gingival Crevicular Fluid; Humans; Lasers, Semiconductor; Low-Level Light Therapy; Tooth Movement Techniques
PubMed: 34182967
DOI: 10.1186/s12903-021-01684-z -
Clinical Microbiology and Infection :... Jun 2021Coronavirus disease 2019 (COVID-19) survivors are reporting residual abnormalities after discharge from hospital. Limited information is available about this stage of...
OBJECTIVES
Coronavirus disease 2019 (COVID-19) survivors are reporting residual abnormalities after discharge from hospital. Limited information is available about this stage of recovery or the lingering effects of the virus on pulmonary function and inflammation. This study aimed to describe lung function in patients recovering from COVID-19 hospitalization and to identify biomarkers in serum and induced sputum samples from these patients.
METHODS
Patients admitted to Spanish hospitals with laboratory-confirmed COVID-19 infection by a real-time PCR (RT-PCR) assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited for this study. Each hospital screened their lists of discharged patients at least 45 days after symptom onset. SARS-CoV-2-infected patients were divided into mild/moderate and severe disease groups according to the severity of their symptoms during hospitalization. Patients' epidemiological and medical histories, comorbidities, chronic treatments, and laboratory parameters were evaluated. Pulmonary function tests, the standardized 6-minute walk test (6MWT) and chest computed tomography (CT) were also performed. The levels of proteases, their inhibitors, and shed receptors were measured in serum and induced sputum samples.
RESULTS
A total of 100 patients with respiratory function tests were included in this study. The median number of days after the onset of symptoms was 104 (IQR 89.25, 126.75). COVID-19 was severe in 47% of patients (47/100). CT was normal in 48% of patients (48/100). Lung function was normal forced expiratory volume in one second (FEV1) ≥80%, forced vital capacity (FVC) ≥80%, FEV1/FVC ≥0.7, and diffusing capacity for carbon monoxide (DLCO) ≥80% in 92% (92/100), 94% (94/100), 100% (100/100) and 48% (48/100) of patients, respectively. Multivariate analysis showed that a DLCO <80% (OR 5.92; 95%CI 2.28-15.37; p < 0.0001) and a lower serum lactate dehydrogenase level (OR 0.98; 95%CI 0.97-0.99) were associated with the severe disease group of SARS-CoV-2 cases during hospital stay.
CONCLUSIONS
A diffusion deficit (DLCO <80%) was still present after hospital discharge and was associated with the most severe SARS-CoV-2 cases.
Topics: Adult; Aged; Biomarkers; COVID-19; COVID-19 Nucleic Acid Testing; Comorbidity; Female; Follow-Up Studies; Humans; Lung; Male; Middle Aged; Patient Discharge; Prospective Studies; Respiratory Function Tests; SARS-CoV-2; Spain; Survivors; Tomography, X-Ray Computed
PubMed: 33662544
DOI: 10.1016/j.cmi.2021.02.019 -
Journal of Orthopaedic Translation Nov 2022Osteogenesis and angiogenesis are important for bone fracture healing. Irisin is a muscle-derived monokine that is associated with bone formation.
BACKGROUND
Osteogenesis and angiogenesis are important for bone fracture healing. Irisin is a muscle-derived monokine that is associated with bone formation.
METHODS
To demonstrate the effect of irisin on bone fracture healing, closed mid-diaphyseal femur fractures were produced in 8-week-old C57BL/6 mice. Irisin was administrated intraperitoneally every other day after surgery, fracture healing was assessed by using X-rays. Bone morphometry of the fracture callus were assessed by using micro-computed tomography. Femurs of mice from each group were assessed by the three-point bending testing. Effect of irisin on osteogenic differentiation in mesenchymal stem cells was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), alkaline phosphatase staining and alizarin red staining. Angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by qRT-PCR, migration tests, and tube formation assays.
RESULTS
Increased callus formation, mineralization and tougher fracture healing were observed in the irisin-treated group than in the control group, indicating the better fracture callus healing due to Irisin treatment. The vessel surface and vessel volume fraction of the callus also increased in the irisin-treated group. The expression of BMP2, CD31, and VEGF in callus were enhanced in the irisin-treated group. In mouse bone mesenchymal stem cells, irisin promoted ALP expression and mineralization, and increased the expression of osteogenic genes, including , , , , and . Irisin also promoted HUVEC migration and tube formation. Expression of angiogenic genes, including , , , , , and in HUVECs were increased by irisin.
CONCLUSION
All the results indicate irisin can promote fracture healing through osteogenesis and angiogenesis. These findings help in the understanding of muscle-bone interactions during fracture healing.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
Irisin was one of the most important monokine secreted by skeletal muscle. Studies have found that irisin have anabolic effect one bone remodeling through affecting osteocyte and osteoblast. Based on our study, irisin could promote bone fracture healing by increasing bone mass and vascularization, which provide a potential usage of irisin to promote fracture healing and improve clinical outcomes.
PubMed: 36196152
DOI: 10.1016/j.jot.2022.07.006 -
Bioactive Materials Apr 2023Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the...
Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C CCR2 monocytes, and S100a8 macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant. The enrichment of mature neutrophils, FcgR1 and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response. Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration. Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis. These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of 'osteoimmune-smart' biomaterials in the bone regeneration field.
PubMed: 36311047
DOI: 10.1016/j.bioactmat.2022.10.009 -
Journal of the American College of... Mar 2020Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).
BACKGROUND
Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).
OBJECTIVES
The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.
METHODS
In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).
RESULTS
Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.
CONCLUSIONS
Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.
Topics: Aged; Biomarkers; Female; Heart Failure; Humans; Machine Learning; Male; Middle Aged; Risk Assessment; United States
PubMed: 32192654
DOI: 10.1016/j.jacc.2019.12.069 -
Journal of Orthopaedic Surgery and... Nov 2023The OPG/RANKL signal pathway was important regulation mechanism of bone remodeling cycle, but the effect of osteoprotegerin (OPG) and RANKL in osteoporosis was... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The OPG/RANKL signal pathway was important regulation mechanism of bone remodeling cycle, but the effect of osteoprotegerin (OPG) and RANKL in osteoporosis was uncertain. We did a systematic review with meta-analysis to assess the association between serum OPG/RANKL and osteoporosis.
METHODS
The systematic search, data extraction, critical appraisal, and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Randomized controlled studies were searched in PubMed, OvidMedline, Embase (1946 to present). Standard mean difference (SMD), and associated credible interval (CI) were calculated using RevMan statistical software to assess the continuous data. Heterogeneity in studies was measured by I values. Subgroup analysis was performed based on different bone turnover.
RESULTS
A total of 5 randomized controlled studies met the inclusion criteria. Both OPG and RANKL had no significant differences between the osteoporosis and control group, and the statistical heterogeneity was high in meta-analysis. However, RANKL had significant differences between the osteoporosis group with low bone turnover and control group (SMD = - 1.17; 95% CI - 1.77 to 0.57; P value < 0.01) in subanalysis. Furthermore, the OPG/RANKL ratio was significant lower in the osteoporosis group than in the control group (SMD = - 0.29; 95% CI - 0.57 to - 0.02; P value < 0.05), and the statistical heterogeneity was very low (Chi = 0.20, P = 0.66, I = 0%).
CONCLUSIONS
Our meta-analysis study supported OPG and RANKL were important modulatory factors of bone formation and resorption in bone turnover, respectively. Although the serum level of both OPG and RANKL were not associated with osteoporosis, but the OPG/RANKL ratio was associated with osteoporosis. In future, standardizing the test method and unit was good to clinical application.
Topics: Humans; Osteoprotegerin; Osteoporosis; Bone Remodeling; Osteogenesis; RANK Ligand; Bone Density
PubMed: 37932757
DOI: 10.1186/s13018-023-04179-5 -
Brain : a Journal of Neurology Jun 2022The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in... (Randomized Controlled Trial)
Randomized Controlled Trial
The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.
Topics: Adolescent; Adult; Alzheimer Disease; Amyloid beta-Peptides; Antigens, Neoplasm; Atomoxetine Hydrochloride; Biomarkers; Cell Adhesion Molecules; Cognitive Dysfunction; Cross-Over Studies; Double-Blind Method; Drug Repositioning; Humans; Inflammation; Middle Aged; Neuroprotection; Norepinephrine; tau Proteins
PubMed: 34919634
DOI: 10.1093/brain/awab452 -
Journal of the American Heart... Apr 2022Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular...
Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (<0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality (<0.001 by log-rank test), the incidence of fatal aortic rupture (=0.08), and aortic dissection (<0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.
Topics: Aortic Dissection; Angiotensin II; Animals; Aortic Rupture; Disease Models, Animal; Elastin; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoprotegerin; RANK Ligand
PubMed: 35411794
DOI: 10.1161/JAHA.122.025336