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Following the mevalonate pathway to bone heal alley
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)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 [en]
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: urn:nbn:se:liu:diva-11282ISBN: 978-91-85895-30-4 (print)OAI: oai:DiVA.org:liu-11282DiVA: diva2:17708
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
List of papers
1. Simvastatin Improves Fracture Healing in Mice
Open this publication in new window or tab >>Simvastatin Improves Fracture Healing in Mice
2002 (English)In: Journal of bone and mineral research, ISSN 0884-0431, Vol. 17, no 111, 2004-2008 p.Article in journal (Refereed) Published
Abstract [en]

Recently, several articles have been published dealing with the anabolic effects on bone by statins. Mundy and associates discovered that several statins were able to activate the promotor of bone morphogenetic protein (BMP) 2. Additionally, oral simvastatin and lovastatin increased the cancellous bone volume in rats, presumably an effect of the increase of BMP-2. Other studies have followed, with conflicting results; some have found a positive bone metabolic effect of statins and others have not. Studies published so far have focused on osteoporosis. In this study, femur fractures were produced in 81 mature male BALB/c mice and stabilized with marrow-nailing. Forty-one mice were given a diet prepared with simvastatin, so that each mouse received an approximate dose of 120 mg/kg of body weight per day. The remaining mice received the same diet with the exception of the simvastatin. Bilateral femurs were harvested at 8, 14, and 21 days postoperatively (po), the marrow-nail was extracted, and diameters were measured. Biomechanical tests were performed on 42 mice, by way of three-point bending. Histological specimens were prepared using standard techniques. For statistical analysis, ANOVA with Scheffé’s post hoc test was used. At 8 days, the fracture callus was too soft for meaningful biomechanical testing. At 14 days, the callus of the simvastatin-treated mice had a 53% larger transverse area than controls (p = 0.001), the force required to break the bone was 63% greater (p = 0.001), and the energy uptake was increased by 150% (p = 0.0008). Stiffness and modulus of elasticity were not significantly affected. At 21 days, the fractures were histologically healed and the mechanical differences had disappeared. The contralateral unbroken bone showed a slight increase in transverse area because of the simvastatin treatment, but there was no significant effect on the force required to break the bone or on energy uptake. These results point to a new possibility in the treatment of fractures.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13037 (URN)10.1359/jbmr.2002.17.11.2004 (DOI)
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2009-06-04
2. Locally applied Simvastatin Improves Fracture Healing in Mice
Open this publication in new window or tab >>Locally applied Simvastatin Improves Fracture Healing in Mice
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13038 (URN)10.1186/1471-2474-8-98 (DOI)
Available from: 2009-02-22 Created: 2009-02-22 Last updated: 2017-12-13Bibliographically approved
3. Systemic and Local Ibandronate Enhance Screw Fixation
Open this publication in new window or tab >>Systemic and Local Ibandronate Enhance Screw Fixation
2004 (English)In: Journal of Orthopaedic Reserach, ISSN 0736-0266, Vol. 22, no 5, 1108-1113 p.Article in journal (Refereed) Published
Abstract [en]

The trauma involved with inserting implants into bone leads to an activation of the inflammatory response and an activation of osteoclasts. In addition, apoptosis of osteocytes in the surrounding area has been implicated in further activation of osteoclasts. If the balance between resorption and bone formation shortly after implantation favours resorption, an impairment of early fixation might ensue.Because bisphosphonates inhibit resorption, this study analyses whether they can improve early fixation. Stainless steel screws (M 1.7) were inserted into the tibiae of 76 male Sprague-Dawley rats. Daily subcutaneous injections of ibandronate (3 μg) or saline were given to 20 rats. The remaining rats received ibandronate or saline directly applied into the drill hole before the screw was inserted. Tibiae were harvested at 14 days. Mechanical tests were performed on 50 tibiae. Systemically treated tibiae were tested for pull-out strength alone. Locally treated tibiae were tested for either pull-out or torque resistance. The remaining 18 tibiae were prepared for histology.Systemic ibandronate increased the pull-out force at failure by 30% (p=0.04). Local treatment increased the force at failure by 15% (p=0.02) and stiffness by 28% (p=0.01). In the removal torque measurements, local ibandronate increased the torque-moment at failure by 60% (p=0.04), and the maximum friction moment by 51% (p=0.04). Energy for turning the screw 1/4 revolution was increased by 68% (p=0.02).These results demonstrate that early remodeling events plays an important role in screw fixation, and that systemic or local bisphosphonate treatment could be an effective pharmacological path to improve early implant fixation.

Keyword
Bisphosphonates, Implant, Fixation, Resorption
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13039 (URN)10.1016/j.orthres.2003.12.015 (DOI)
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2009-08-21
4. Surface Immobilized Bisphosphonate Improves Stainless-Steel Screw Fixation in Rats
Open this publication in new window or tab >>Surface Immobilized Bisphosphonate Improves Stainless-Steel Screw Fixation in Rats
2004 (English)In: Biomaterials, ISSN 0142-9612, Vol. 25, no 11, 2133-2138 p.Article in journal (Refereed) Published
Abstract [en]

An increase in the mechanical fixation in bone of metallic biomaterials is considered advantageous in joint replacement and fracture surgery. Different approaches to improve fixation may be e.g. surface roughening, Ca-mineral coating or surface immobilization of growth factors or drugs. In the present work, bisphosphonate, a class of drugs that inhibit bone resorption, was immobilized onto stainless-steel screws.

The screws were first roughened and coated with immobilized and cross-linked fibrinogen. Subsequently, an N-bisphosphonate, pamidronate, was immobilized onto fibrinogen, and another N-bisphosphonate, ibandronate, adsorbed on top of this. The so coated screws were inserted into the tibiae of eight male Sprague-Dawley rats. Another eight rats received screws prepared in the same way, but without the bisphosphonate coating. Pullout strength tests were performed after 2 weeks of implantation.

The results showed a 28% (p=0.0009) higher pullout force and 90% increased pullout energy for the bisphosphonate coated screws, and support the idea that surface immobilized bisphosphonates can be used to improve biomaterials fixation in bone.

Keyword
Bisphosphonate, Immobilize, Bone, Pullout, Implant, Biomaterial
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13040 (URN)10.1016/j.biomaterials.2003.08.049 (DOI)
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2009-08-21

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