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      Cardiovascular Outcomes of Romosozumab and Protective Role of Alendronate : A Conundrum or Clarification

      1 , 2
      Arteriosclerosis, Thrombosis, and Vascular Biology
      Ovid Technologies (Wolters Kluwer Health)

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          Abstract

          <p class="first" id="d3972361e67">Osteoporosis and cardiovascular diseases are major public health issues. Bone and cardiovascular remodeling share multiple biological markers and pathways. Medical intervention, such as using romosozumab, an antisclerostin antibody, improves the clinical outcome of osteoporosis. However, blocking sclerostin leads to Wnt (wingless/integrated) activation and participation in the cardiovascular remodeling process, which could potentially lead to adverse events. Based on the opposing roles of bisphosphonates and the Wnt pathway on endothelial dysfunction, lipid accumulation and calcification of the vessel walls, the combination of romosozumab and bisphosphonates could be a new therapeutic approach to reducing the risks of adverse cardiovascular events in romosozumab receivers. Visual Overview- An online visual overview is available for this article. </p>

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          Is Open Access

          Bisphosphonates and Risk of Cardiovascular Events: A Meta-Analysis

          Background and Objectives Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of bisphosphonates on total adverse cardiovascular (CV) events, atrial fibrillation, myocardial infarction (MI), stroke, and CV death in adults with or at risk for low bone mass. Methods A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs) and 95% confidence intervals (CIs) of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed. Results Absolute risks over 25–36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs [95% CI]: 0.98 [0.84–1.14]; I2 = 0.0%), atrial fibrillation (41 trials; 1.08 [0.92–1.25]; I2 = 0.0%), MI (10 trials; 0.96 [0.69–1.34]; I2 = 0.0%), stroke (10 trials; 0.99 [0.82–1.19]; I2 = 5.8%), and CV death (14 trials; 0.88 [0.72–1.07]; I2 = 0.0%) with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 [0.96–1.61]; I2 = 0.0%), not for oral bisphosphonates (26 trials; 1.02 [0.83–1.24]; I2 = 0.0%). The CV effects did not vary by subgroups or study quality. Conclusions Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified.
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            The role of Wnt signaling pathway in atherosclerosis and its relationship with angiogenesis

            Expression and function of Wnt signaling pathway in rats with atherosclerosis (AS) were investegated. The AS model of rats was established after 8-week continuous feeding of a high-fat diet, with normal rats as the control. Blood was taken from the carotid artery to detect the level of blood lipid. Aortic slices were made to observe the pathological changes of the aorta after the rats were sacrificed. Enzyme-linked immunosorbent assay kits were used to detect the contents of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Western blot analysis and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) were performed to detect the expression levels of related proteins and mRNA in rat Wnt signaling pathway. Correlation analysis between the protein expression level of vascular endothelial growth factor (VEGF) and that of Wnt1 was conducted. Aortic slices showed that the ratio of intima thickness to media thickness of the rats in the model group was higher than that of in the control group (P<0.01). Blood lipid and the contents of IL-6 and TNF-α of the rats in the model group were higher than those of the rats in the control group (P<0.01). Semi-quantitative RT-PCR indicated that mRNA expression levels of Wnt1, β-catenin and dickkopf1 in the aorta of rats in the model group were increased compared with those of control group (P<0.01). The results of western blot analysis revealed that the protein expression levels of Wnt1, β-catenin, DKK1 and VEGF of the rats in the model group were remarkably higher than those of the control group (P<0.01). The level of VEGF protein was positively correlated with that of Wnt1 (P<0.05, r=0.7810). The activation of Wnt signaling pathway in the aorta of the rats with AS can induce the expression of relevant inflammatory cytokines. It has the effects of promoting the progression of AS and accelerating angiogenesis.
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              Author and article information

              Journal
              Arteriosclerosis, Thrombosis, and Vascular Biology
              ATVB
              Ovid Technologies (Wolters Kluwer Health)
              1079-5642
              1524-4636
              July 2019
              July 2019
              : 39
              : 7
              : 1343-1350
              Affiliations
              [1 ]From the Division of Endocrinology and Molecular Medicine, Department of Medicine, University of Kentucky, Lexington (K.A.)
              [2 ]Departments of Medicine (Cardiology) and Cell Biology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York (A.W.).
              Article
              10.1161/ATVBAHA.119.312371
              31242037
              56ec77dd-aa78-4557-90bd-b58d7eb83d06
              © 2019
              History

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