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      Discontinuation of simvastatin leads to a rebound phenomenon and results in immediate peri‐implant bone loss


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          Although administration of simvastatin has been reported to promote bone formation, the effect of short‐term simvastatin administration is not well known. Following implant installation, 10‐week‐old male Wistar rats ( n = 24) were divided into two groups randomly. The experimental group received 10 mg/kg of simvastatin daily for seven days. Then simvastatin administration was discontinued, and the animals were observed up to 28 days. Animals in the control group underwent the same procedure but received saline instead of simvastatin. All animals were analyzed by micro‐computed tomography. Samples at days 14 and 21 were subjected to histological analyses. After seven days of simvastatin administration, more new bone formation around the implant was observed in the simvastatin group compared with the control group. Seven days after simvastatin discontinuation, however, the amount of peri‐implant trabecular bone began to decrease. Results from morphometric analysis also showed a reduction in new bone area after day 7, which was lowest at day 14. These results were confirmed by histological analyses. In contrast, both the peri‐implant trabecular bone and new bone area were maintained in the control group. Short‐term administration of simvastatin may affect implant stability owing to a rebound phenomenon and an immediate loss of peri‐implant bone.

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          Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism.

          HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
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            A method for the study of undecalcified bones and teeth with attached soft tissues. The Säge-Schliff (sawing and grinding) technique.

            A new sawing-grinding method is described for the histological evaluation of jaw bones with teeth or bones containing implants (ceramic or metallic). The undecalcified bone is embedded in acrylic resin and sawed at 100 to 150 micrometers. The slices are ground automatically by a special machine to a thickness of 5-10 micrometers. The usually employed staining procedures for hard plastic embedded-tissues may be used. Plaque, fillings, crowns, bridges, implants and soft tissues are preserved in situ. Macroscopic and microscopic detail of good quality is preserved for histological and morphometrical evaluation.
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              Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells.

              Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. The present study was undertaken to understand the events of osteoblast differentiation induced by statins. Simvastatin at 10(-7) M markedly increased mRNA expression for bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (OCN) in nontransformed osteoblastic cells (MC3T3-E1), while suppressing gene expression for collagenase-1, and collagenase-3. Extracellular accumulation of proteins such as VEGF, OCN, collagenase-digestive proteins, and noncollagenous proteins was increased in the cells treated with 10(-7) M simvastatin, or 10(-8) M cerivastatin. In the culture of MC3T3-E1 cells, statins stimulated mineralization; pretreating MC3T3-E1 cells with mevalonate, or geranylgeranyl pyrophosphate (a mevalonate metabolite) abolished statin-induced mineralization. Statins stimulate osteoblast differentiation in vitro, and may hold promise drugs for the treatment of osteoporosis in the future. Copyright 2004 Wiley-Liss, Inc.

                Author and article information

                Clin Exp Dent Res
                Clin Exp Dent Res
                Clinical and Experimental Dental Research
                John Wiley and Sons Inc. (Hoboken )
                18 March 2016
                June 2016
                : 2
                : 1 ( doiID: 10.1002/cre2.v2.1 )
                : 65-72
                [ 1 ] Department of Hard Tissue Research, Institute for Oral Science Matsumoto Dental University Shiojiri Japan
                [ 2 ] School of Dentistry Shanxi Medical University Taiyuan China
                [ 3 ] Center of Health‐Care in Stomatology Tenth People's Hospital of Tongji University Shanghai China
                [ 4 ] Department of Oral Health Promotion, Institute for Oral Science Matsumoto Dental University Shiojiri Japan
                [ 5 ] Department of Oral and Maxillofacial Surgery, School of Dentistry Matsumoto Dental University Shiojiri Japan
                Author notes
                [*] [* ] Correspondence

                Xianqi Li and Hideaki Kagami, Department of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399‐0781, Japan.

                Tel and Fax: +81 263 51 2066;

                E‐mail: li@ 123456po.mdu.ac.jp (Xianqi Li);

                kagami@ 123456po.mdu.ac.jp (Hideaki Kagami)

                CRE223 CRE2.20150056.R1
                © 2016 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 01 December 2015
                : 14 January 2016
                : 26 January 2016
                Page count
                Pages: 8
                Funded by: Japan Society for the Promotion of Science (JSPS)
                Award ID: 24592972
                Award ID: 24592972
                Funded by: Specially Promoted Research Grant of Matsumoto Dental University
                Funded by: Japan Society for the Promotion of Science (JSPS)
                Funded by: Specially Promoted Research Grant of Matsumoto Dental University
                Original Article
                Original Articles
                Custom metadata
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version= mode:remove_FC converted:05.03.2018

                bone loss,implant,micro‐ct,osteogenesis,rebound phenomenon,simvastatin


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