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Locally applied Simvastatin Improves Fracture Healing in Mice
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
2007 (English)In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 8, no 98Article in journal (Refereed) Published
Abstract [en]

Background: HMG-CoA reductase inhibitors, statins, are widely prescribed to lower cholesterol. High doses of orally administered simvastatin has previously been shown to improve fracture healing in a mouse femur fracture model. In this study, simvastatin was administered either subcutaneously or directly to the fracture area, with the goal of stimulating fracture repair at acceptable doses.

Methods: Femur fractures were produced in 70 mature male Balb-C mice and stabilized with marrow-nailing. Three experiments were performed. Firstly, 20 mice received subcutaneous injections of either simvastatin (20 mg) or vehicle. Secondly, 30 mice were divided into three groups of 10 mice receiving continuous subcutaneous delivery of the vehicle substance, the vehicle with 5 mg or with 10 mg of simvastatin per kg bodyweight per day. Finally, in 20 mice, a silicone tube was led from an osmotic mini-pump to the fracture area. In this way, 10 mice received an approximate local dose of simvastatin of 0.1 mg per kg per day for the duration of the experiment and 10 mice received the vehicle compound. All treatments lasted until the end of the experiment. Bilateral femurs were harvested 14 days post-operative. Biomechanical tests were performed by way of three-point bending. Data was analysed with ANOVA, Scheffé's post-hoc test and Student's unpaired t-test.

Results: With daily simvastatin injections, no effects could be demonstrated for any of the parameters examined. Continuous systemic delivery resulted in a 160% larger force at failure. Continuous local delivery of simvastatin resulted in a 170% larger force at failure as well as a twofold larger energy uptake.

Conclusion: This study found a dramatic positive effect on biomechanical parameters of fracture healing by simvastatin treatment directly applied to the fracture area.

Place, publisher, year, edition, pages
2007. Vol. 8, no 98
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13038DOI: 10.1186/1471-2474-8-98OAI: oai:DiVA.org:liu-13038DiVA: diva2:17705
Available from: 2009-02-22 Created: 2009-02-22 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Following the mevalonate pathway to bone heal alley
Open this publication in new window or tab >>Following the mevalonate pathway to bone heal alley
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mevalonate pathway is an important biosynthetic pathway, found in all cells of virtually all known pro- as well as eukaryotic organisms. This thesis is an investigation into the use of two drugs, originally developed for different applications, but both affecting the mevalonate pathway, in to models of fracture repair.

Using two different rodent models of fracture repair, a commonly used cholesterol lowering drug (statin) and two drugs used to treat osteoporosis (bisphosphonate) were applied both systemically as well as locally in order to enhance fracture repair.

Papers I and II investigate the potential of simvastatin to improve the healing of femoral fractures in mice. Papers III and IV explore the use of two bisphosphonates to improve early fixation of stainless steel screws into rat bone.

The statin simvastatin lead to an increased strength of the healing cellus. The application of bisphosphonates increased early screw fixation.

It seems clear that both drugs have uses in orthopaedic applications. One interesting avenue of further research would be to combine the two classes of drugs and see if we can get the benefits while at the same time diminishing the drawbacks.

Place, publisher, year, edition, pages
Acta Orthopaedica, Volume 78, No. 328, 2007
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1033
Keyword
Bone screws, coated materials, biocompatible, chemistry, diphosphonates, pharmacology, Equipment failure analysis methods, Femoral fractures, drug therapy, fracture fixation, instrumentation, Fracture fixation, fracture healing, drug effects, simvastatin, tibial fractures, physiopathologyial fractures, surgery
National Category
Medicinal Chemistry Other Veterinary Science
Identifiers
urn:nbn:se:liu:diva-11282 (URN)978-91-85895-30-4 (ISBN)
Public defence
2007-12-12, Linden, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2009-08-21

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Skoglund, BjörnAspenberg, Per

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