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      Do Nonsteroidal Anti-Inflammatory Drugs Affect Bone Healing? A Critical Analysis

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          Abstract

          Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients.

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          Most cited references196

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          The cell and molecular biology of fracture healing.

          Fracture healing is a complex physiologic process that involves the coordinated participation of several cell types. By using a reproducible model of experimental fracture healing in the rat, it is possible to elucidate the integrated cellular responses that signal the pathways and the role of the extracellular matrix components in orchestrating the events of fracture healing. Histologic characterization of fracture healing shows that intramembranous ossification occurs under the periosteum within a few days after an injury. Events of endochondral ossification occur adjacent to the fracture site and span a period of up to 28 days. Remodeling of the woven bone formed by intramembranous and endochondral ossification proceeds for several weeks. Spatial and temporal expression of genes for major collagens (Types I and II), minor fibrillar collagens (Types IV and XI), and several extracellular matrix components (osteocalcin, osteonectin, osteopontin, fibronectin and CD44) are detected by in situ hybridization. Immunohistochemical studies show that expression of proliferating cell nuclear antigen is both time and space dependent and differentially expressed in the callus tissues formed by the intramembranous and endochondral processes. Chondrocytes involved in endochondral ossification undergo apoptosis (programmed cell death), and early events in fracture healing may be initiated by the expression of early response genes such as c-fos. Additional characterization and elucidation of fracture healing will lay the foundation for subsequent studies aimed at identifying mechanisms for enhancing skeletal repair.
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            Current concepts of molecular aspects of bone healing.

            Fracture healing is a complex physiological process. It involves the coordinated participation of haematopoietic and immune cells within the bone marrow in conjunction with vascular and skeletal cell precursors, including mesenchymal stem cells (MSCs) that are recruited from the surrounding tissues and the circulation. Multiple factors regulate this cascade of molecular events by affecting different sites in the osteoblast and chondroblast lineage through various processes such as migration, proliferation, chemotaxis, differentiation, inhibition, and extracellular protein synthesis. An understanding of the fracture healing cellular and molecular pathways is not only critical for the future advancement of fracture treatment, but it may also be informative to our further understanding of the mechanisms of skeletal growth and repair as well as the mechanisms of aging.
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              Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research.

              This study compares bone composition, density, and quality in bone samples derived from seven vertebrates that are commonly used in bone research: human, dog, pig, cow, sheep, chicken, and rat. Cortical femoral bone samples were analyzed for their content of ash, collagen, extractable proteins, and insulin-like growth factor-I. These parameters were also measured in bone powder fractions that were obtained after separation of bone particles according to their density. Large interspecies differences were observed in all analyses. Of all species included in the biochemical analyses, rat bone was most different, whereas canine bone best resembled human bone. In addition, bone density and mechanical testing analyses were performed on cylindrical trabecular bone cores. Both analyses demonstrated large interspecies variations. The lowest bone density and fracture stress values were found in the human samples; porcine and canine bone best resembled these samples. The relative contribution of bone density to bone mechanical competence was largely species-dependent. Together, the data reported here suggest that interspecies differences are likely to be found in other clinical and experimental bone parameters and should therefore be considered when choosing an appropriate animal model for bone research.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                The Scientific World Journal
                1537-744X
                2012
                4 January 2012
                : 2012
                : 606404
                Affiliations
                1Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds LS1 3EX, UK
                2Academic Department of Trauma & Orthopaedics, School of Medicine, University of Milan, 20122 Milano, Italy
                3Academic Unit, Department of Trauma and Orthopaedics, Clarendon Wing, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK
                Author notes
                *Peter V. Giannoudis: pgiannoudi@ 123456aol.com

                Academic Editors: A. Ndreu and A. Sihoe

                Article
                10.1100/2012/606404
                3259713
                22272177
                6860bd2d-79fc-4912-9bdc-8e90f1494e82
                Copyright © 2012 Ippokratis Pountos et al.

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

                History
                : 18 September 2011
                : 18 October 2011
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