Skip to main content
Top
Published in: BMC Musculoskeletal Disorders 1/2012

Open Access 01-12-2012 | Research article

Influence of Statins locally applied from orthopedic implants on osseous integration

Authors: Stephan Pauly, David A Back, Kathrin Kaeppler, Norbert P Haas, Gerhard Schmidmaier, Britt Wildemann

Published in: BMC Musculoskeletal Disorders | Issue 1/2012

Login to get access

Abstract

Background

Simvastatin increases the expression of bone morphogenetic protein 2 (BMP-2) in osteoblasts, therefore it is important to investigate the influence of statins on bone formation, fracture healing and implant integration. The aim of the present study was to investigate the effect of Simvastatin, locally applied from intramedullary coated and bioactive implants, on bone integration using biomechanical and histomorphometrical analyses.

Methods

Eighty rats received retrograde nailing of the femur with titanium implants: uncoated vs. polymer-only (poly(D,L-lactide)) vs. polymer plus drug coated (either Simvastatin low- or high dosed; “SIM low/ high”). Femurs were harvested after 56 days for radiographic and histomorphometric or biomechanical analysis (push-out).

Results

Radiographic analysis revealed no pathological findings for animals of the control and SIM low dose group. However, n=2/10 animals of the SIM high group showed osteolysis next to the implant without evidence of bacterial infection determined by microbiological analysis. Biomechanical results showed a significant decrease in fixation strength for SIM high coated implants vs. the control groups (uncoated and PDLLA). Histomorphometry revealed a significantly reduced total as well as direct bone/implant contact for SIM high- implants vs. controls (uncoated and PDLLA-groups). Total contact was reduced for SIM low vs. uncoated controls. Significantly reduced new bone formation was measured around SIM high coated implants vs. both control groups.

Conclusions

This animal study suggests impaired implant integration with local application of Simvastatin from intramedullary titanium implants after 8 weeks when compared to uncoated or carrier-only coated controls.
Appendix
Available only for authorised users
Literature
1.
go back to reference Armitage J: The safety of statins in clinical practice. Lancet. 2007, 370 (9601): 1781-1790. 10.1016/S0140-6736(07)60716-8.CrossRefPubMed Armitage J: The safety of statins in clinical practice. Lancet. 2007, 370 (9601): 1781-1790. 10.1016/S0140-6736(07)60716-8.CrossRefPubMed
2.
go back to reference Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature. 1990, 343 (6257): 425-430. 10.1038/343425a0.CrossRefPubMed Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature. 1990, 343 (6257): 425-430. 10.1038/343425a0.CrossRefPubMed
3.
go back to reference LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999, 282 (24): 2340-2346. 10.1001/jama.282.24.2340.CrossRefPubMed LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999, 282 (24): 2340-2346. 10.1001/jama.282.24.2340.CrossRefPubMed
4.
go back to reference Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E: Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999, 100 (3): 230-235. 10.1161/01.CIR.100.3.230.CrossRefPubMed Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E: Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999, 100 (3): 230-235. 10.1161/01.CIR.100.3.230.CrossRefPubMed
5.
go back to reference Weis M, Heeschen C, Glassford AJ, Cooke JP: Statins have biphasic effects on angiogenesis. Circulation. 2002, 105 (6): 739-745. 10.1161/hc0602.103393.CrossRefPubMed Weis M, Heeschen C, Glassford AJ, Cooke JP: Statins have biphasic effects on angiogenesis. Circulation. 2002, 105 (6): 739-745. 10.1161/hc0602.103393.CrossRefPubMed
6.
go back to reference Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G: Stimulation of bone formation in vitro and in rodents by statins. Science. 1999, 286 (5446): 1946-1949. 10.1126/science.286.5446.1946.CrossRefPubMed Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G: Stimulation of bone formation in vitro and in rodents by statins. Science. 1999, 286 (5446): 1946-1949. 10.1126/science.286.5446.1946.CrossRefPubMed
7.
go back to reference Wang EA, Rosen V, D’Alessandro JS, Bauduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, LaPan P: Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA. 1990, 87 (6): 2220-2224. 10.1073/pnas.87.6.2220.CrossRefPubMedPubMedCentral Wang EA, Rosen V, D’Alessandro JS, Bauduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, LaPan P: Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA. 1990, 87 (6): 2220-2224. 10.1073/pnas.87.6.2220.CrossRefPubMedPubMedCentral
8.
go back to reference Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA: Novel regulators of bone formation: molecular clones and activities. Science. 1988, 242 (4885): 1528-1534. 10.1126/science.3201241.CrossRefPubMed Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA: Novel regulators of bone formation: molecular clones and activities. Science. 1988, 242 (4885): 1528-1534. 10.1126/science.3201241.CrossRefPubMed
9.
go back to reference Wang EA, Israel DI, Kelly S, Luxenberg DP: Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors. 1993, 9 (1): 57-71. 10.3109/08977199308991582.CrossRefPubMed Wang EA, Israel DI, Kelly S, Luxenberg DP: Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors. 1993, 9 (1): 57-71. 10.3109/08977199308991582.CrossRefPubMed
10.
go back to reference Maeda T, Matsunuma A, Kawane T, Horiuchi N: Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun. 2001, 280 (3): 874-877. 10.1006/bbrc.2000.4232.CrossRefPubMed Maeda T, Matsunuma A, Kawane T, Horiuchi N: Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun. 2001, 280 (3): 874-877. 10.1006/bbrc.2000.4232.CrossRefPubMed
11.
go back to reference Ayukawa Y, Okamura A, Koyano K: Simvastatin promotes osteogenesis around titanium implants. Clin Oral Implants Res. 2004, 15 (3): 346-350. 10.1046/j.1600-0501.2003.01015.x.CrossRefPubMed Ayukawa Y, Okamura A, Koyano K: Simvastatin promotes osteogenesis around titanium implants. Clin Oral Implants Res. 2004, 15 (3): 346-350. 10.1046/j.1600-0501.2003.01015.x.CrossRefPubMed
12.
go back to reference Gutierrez GE, Lalka D, Garrett IR, Rossini G, Mundy GR: Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporos Int. 2006, 17 (7): 1033-1042. 10.1007/s00198-006-0079-0.CrossRefPubMed Gutierrez GE, Lalka D, Garrett IR, Rossini G, Mundy GR: Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporos Int. 2006, 17 (7): 1033-1042. 10.1007/s00198-006-0079-0.CrossRefPubMed
13.
go back to reference Skoglund B, Forslund C, Aspenberg P: Simvastatin improves fracture healing in mice. J Bone Miner Res. 2002, 17 (11): 2004-2008. 10.1359/jbmr.2002.17.11.2004.CrossRefPubMed Skoglund B, Forslund C, Aspenberg P: Simvastatin improves fracture healing in mice. J Bone Miner Res. 2002, 17 (11): 2004-2008. 10.1359/jbmr.2002.17.11.2004.CrossRefPubMed
14.
go back to reference Gutierrez GE, Edwards JR, Garrett IR, Nyman JS, McCluskey B, Rossini G, Flores A, Neidre DB, Mundy GR: Transdermal lovastatin enhances fracture repair in rats. J Bone Miner Res. 2008, 23 (11): 1722-1730. 10.1359/jbmr.080603.CrossRefPubMedPubMedCentral Gutierrez GE, Edwards JR, Garrett IR, Nyman JS, McCluskey B, Rossini G, Flores A, Neidre DB, Mundy GR: Transdermal lovastatin enhances fracture repair in rats. J Bone Miner Res. 2008, 23 (11): 1722-1730. 10.1359/jbmr.080603.CrossRefPubMedPubMedCentral
15.
go back to reference Wong RW, Rabie AB: Statin collagen grafts used to repair defects in the parietal bone of rabbits. Br J Oral Maxillofac Surg. 2003, 41 (4): 244-248. 10.1016/S0266-4356(03)00081-0.CrossRefPubMed Wong RW, Rabie AB: Statin collagen grafts used to repair defects in the parietal bone of rabbits. Br J Oral Maxillofac Surg. 2003, 41 (4): 244-248. 10.1016/S0266-4356(03)00081-0.CrossRefPubMed
16.
go back to reference Ozec I, Kilic E, Gumus C, Goze F: Effect of local simvastatin application on mandibular defects. J Craniofac Surg. 2007, 18 (3): 546-550. 10.1097/scs.0b013e318052ff05.CrossRefPubMed Ozec I, Kilic E, Gumus C, Goze F: Effect of local simvastatin application on mandibular defects. J Craniofac Surg. 2007, 18 (3): 546-550. 10.1097/scs.0b013e318052ff05.CrossRefPubMed
17.
go back to reference Lee Y, Schmid MJ, Marx DB, Beatty MW, Cullen DM, Collins ME, Reinhardt RA: The effect of local simvastatin delivery strategies on mandibular bone formation in vivo. Biomaterials. 2008, 29 (12): 1940-1949. 10.1016/j.biomaterials.2007.12.045.CrossRefPubMedPubMedCentral Lee Y, Schmid MJ, Marx DB, Beatty MW, Cullen DM, Collins ME, Reinhardt RA: The effect of local simvastatin delivery strategies on mandibular bone formation in vivo. Biomaterials. 2008, 29 (12): 1940-1949. 10.1016/j.biomaterials.2007.12.045.CrossRefPubMedPubMedCentral
18.
19.
go back to reference Garrett IR, Gutierrez GE, Rossini G, Nyman J, McCluskey B, Flores A, Mundy GR: Locally delivered lovastatin nanoparticles enhance fracture healing in rats. J Orthop Res. 2007, 25 (10): 1351-1357. 10.1002/jor.20391.CrossRefPubMed Garrett IR, Gutierrez GE, Rossini G, Nyman J, McCluskey B, Flores A, Mundy GR: Locally delivered lovastatin nanoparticles enhance fracture healing in rats. J Orthop Res. 2007, 25 (10): 1351-1357. 10.1002/jor.20391.CrossRefPubMed
20.
go back to reference Pauly S, Luttosch F, Morawski M, Haas NP, Schmidmaier G, Wildemann B: Simvastatin locally applied from a biodegradable coating of osteosynthetic implants improves fracture healing comparable to BMP-2 application. Bone. 2009, 45 (3): 505-511. 10.1016/j.bone.2009.05.010.CrossRefPubMed Pauly S, Luttosch F, Morawski M, Haas NP, Schmidmaier G, Wildemann B: Simvastatin locally applied from a biodegradable coating of osteosynthetic implants improves fracture healing comparable to BMP-2 application. Bone. 2009, 45 (3): 505-511. 10.1016/j.bone.2009.05.010.CrossRefPubMed
21.
go back to reference Wang JW, Xu SW, Yang DS, Lv RK: Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int. 2007, 18 (12): 1641-1650. 10.1007/s00198-007-0412-2.CrossRefPubMed Wang JW, Xu SW, Yang DS, Lv RK: Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int. 2007, 18 (12): 1641-1650. 10.1007/s00198-007-0412-2.CrossRefPubMed
22.
go back to reference Serin-Kilicoglu S, Erdemli E: New addition to the statin’s effect. J Trauma. 2007, 63 (1): 187-191. 10.1097/01.TA.0000240974.07999.bc.CrossRefPubMed Serin-Kilicoglu S, Erdemli E: New addition to the statin’s effect. J Trauma. 2007, 63 (1): 187-191. 10.1097/01.TA.0000240974.07999.bc.CrossRefPubMed
23.
go back to reference Du Z, Chen J, Yan F, Xiao Y: Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats. Clin Oral Implants Res. 2009, 20 (2): 145-150. 10.1111/j.1600-0501.2008.01630.x.CrossRefPubMed Du Z, Chen J, Yan F, Xiao Y: Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats. Clin Oral Implants Res. 2009, 20 (2): 145-150. 10.1111/j.1600-0501.2008.01630.x.CrossRefPubMed
24.
go back to reference Basarir K, Erdemli B, Can A, Erdemli E, Zeyrek T: Osseointegration in arthroplasty: can simvastatin promote bone response to implants?. Int Orthop. 2009, 33 (3): 855-859. 10.1007/s00264-007-0490-y.CrossRefPubMed Basarir K, Erdemli B, Can A, Erdemli E, Zeyrek T: Osseointegration in arthroplasty: can simvastatin promote bone response to implants?. Int Orthop. 2009, 33 (3): 855-859. 10.1007/s00264-007-0490-y.CrossRefPubMed
25.
go back to reference Ayukawa Y, Ogino Y, Moriyama Y, Atsuta I, Jinno Y, Kihara M, Tsukiyama Y, Koyano K: Simvastatin enhances bone formation around titanium implants in rat tibiae. J Oral Rehabil. 2010, 37 (2): 123-130. 10.1111/j.1365-2842.2009.02011.x.CrossRefPubMed Ayukawa Y, Ogino Y, Moriyama Y, Atsuta I, Jinno Y, Kihara M, Tsukiyama Y, Koyano K: Simvastatin enhances bone formation around titanium implants in rat tibiae. J Oral Rehabil. 2010, 37 (2): 123-130. 10.1111/j.1365-2842.2009.02011.x.CrossRefPubMed
26.
go back to reference Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Koyano K: Topical application of statin affects bone healing around implants. Clin Oral Implants Res. 2008, 19 (6): 600-605. 10.1111/j.1600-0501.2007.01508.x.CrossRefPubMed Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Koyano K: Topical application of statin affects bone healing around implants. Clin Oral Implants Res. 2008, 19 (6): 600-605. 10.1111/j.1600-0501.2007.01508.x.CrossRefPubMed
27.
go back to reference Masuzaki T, Ayukawa Y, Moriyama Y, Jinno Y, Atsuta I, Ogino Y, Koyano K: The effect of a single remote injection of statin-impregnated poly (lactic-co-glycolic acid) microspheres on osteogenesis around titanium implants in rat tibia. Biomaterials. 2010, 31 (12): 3327-3334. 10.1016/j.biomaterials.2010.01.016.CrossRefPubMed Masuzaki T, Ayukawa Y, Moriyama Y, Jinno Y, Atsuta I, Ogino Y, Koyano K: The effect of a single remote injection of statin-impregnated poly (lactic-co-glycolic acid) microspheres on osteogenesis around titanium implants in rat tibia. Biomaterials. 2010, 31 (12): 3327-3334. 10.1016/j.biomaterials.2010.01.016.CrossRefPubMed
28.
go back to reference Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Todo M, Takao Y, Koyano K: Local application of fluvastatin improves peri-implant bone quantity and mechanical properties: a rodent study. Acta Biomater. 2010, 6 (4): 1610-1618. 10.1016/j.actbio.2009.10.045.CrossRefPubMed Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Todo M, Takao Y, Koyano K: Local application of fluvastatin improves peri-implant bone quantity and mechanical properties: a rodent study. Acta Biomater. 2010, 6 (4): 1610-1618. 10.1016/j.actbio.2009.10.045.CrossRefPubMed
29.
go back to reference Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A: Non-lipid-related effects of statins. Ann Med. 2000, 32 (3): 164-176. 10.3109/07853890008998823.CrossRefPubMed Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A: Non-lipid-related effects of statins. Ann Med. 2000, 32 (3): 164-176. 10.3109/07853890008998823.CrossRefPubMed
30.
go back to reference Schmidmaier G, Wildemann B, Stemberger A, Haas NP, Raschke M: Biodegradable poly(D, L-lactide) coating of implants for continuous release of growth factors. J Biomed Mater Res. 2001, 58 (4): 449-455. 10.1002/jbm.1040.CrossRefPubMed Schmidmaier G, Wildemann B, Stemberger A, Haas NP, Raschke M: Biodegradable poly(D, L-lactide) coating of implants for continuous release of growth factors. J Biomed Mater Res. 2001, 58 (4): 449-455. 10.1002/jbm.1040.CrossRefPubMed
31.
go back to reference Schmidmaier G, Wildemann B, Cromme F, Kandziora F, Haas NP, Raschke M: Bone morphogenetic protein-2 coating of titanium implants increases biomechanical strength and accelerates bone remodeling in fracture treatment: a biomechanical and histological study in rats. Bone. 2002, 30 (6): 816-822. 10.1016/S8756-3282(02)00740-8.CrossRefPubMed Schmidmaier G, Wildemann B, Cromme F, Kandziora F, Haas NP, Raschke M: Bone morphogenetic protein-2 coating of titanium implants increases biomechanical strength and accelerates bone remodeling in fracture treatment: a biomechanical and histological study in rats. Bone. 2002, 30 (6): 816-822. 10.1016/S8756-3282(02)00740-8.CrossRefPubMed
32.
go back to reference Schmidmaier G, Wildemann B, Schwabe P, Stange R, Hoffmann J, Sudkamp NP, Haas NP, Raschke M: A new electrochemically graded hydroxyapatite coating for osteosynthetic implants promotes implant osteointegration in a rat model. J Biomed Mater Res. 2002, 63 (2): 168-172. 10.1002/jbm.10130.CrossRefPubMed Schmidmaier G, Wildemann B, Schwabe P, Stange R, Hoffmann J, Sudkamp NP, Haas NP, Raschke M: A new electrochemically graded hydroxyapatite coating for osteosynthetic implants promotes implant osteointegration in a rat model. J Biomed Mater Res. 2002, 63 (2): 168-172. 10.1002/jbm.10130.CrossRefPubMed
33.
go back to reference Wildemann B, Bamdad P, Holmer C, Haas NP, Raschke M, Schmidmaier G: Local delivery of growth factors from coated titanium plates increases osteotomy healing in rats. Bone. 2004, 34 (5): 862-868. 10.1016/j.bone.2004.01.015.CrossRefPubMed Wildemann B, Bamdad P, Holmer C, Haas NP, Raschke M, Schmidmaier G: Local delivery of growth factors from coated titanium plates increases osteotomy healing in rats. Bone. 2004, 34 (5): 862-868. 10.1016/j.bone.2004.01.015.CrossRefPubMed
34.
go back to reference Greiner SH, Wildemann B, Back DA, Alidoust M, Schwabe P, Haas NP, Schmidmaier G: Local application of zoledronic acid incorporated in a poly(D, L-lactide)-coated implant accelerates fracture healing in rats. Acta Orthop. 2008, 79 (5): 717-725. 10.1080/17453670810016768.CrossRefPubMed Greiner SH, Wildemann B, Back DA, Alidoust M, Schwabe P, Haas NP, Schmidmaier G: Local application of zoledronic acid incorporated in a poly(D, L-lactide)-coated implant accelerates fracture healing in rats. Acta Orthop. 2008, 79 (5): 717-725. 10.1080/17453670810016768.CrossRefPubMed
35.
go back to reference Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S: Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol. 2001, 21 (10): 1636-1641. 10.1161/hq1001.097781.CrossRefPubMed Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S: Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol. 2001, 21 (10): 1636-1641. 10.1161/hq1001.097781.CrossRefPubMed
36.
go back to reference Mukozawa A, Ueki K, Marukawa K, Okabe K, Moroi A, Nakagawa K: Bone healing of critical-sized nasal defects in rabbits by statins in two different carriers. Clin Oral Implants Res. 2011, 22 (11): 1327-1335. 10.1111/j.1600-0501.2010.02135.x.CrossRefPubMed Mukozawa A, Ueki K, Marukawa K, Okabe K, Moroi A, Nakagawa K: Bone healing of critical-sized nasal defects in rabbits by statins in two different carriers. Clin Oral Implants Res. 2011, 22 (11): 1327-1335. 10.1111/j.1600-0501.2010.02135.x.CrossRefPubMed
37.
go back to reference Cottrell JA, Vales FM, Schachter D, Wadsworth S, Gundlapalli R, Kapadia R, O’Connor JP: Osteogenic activity of locally applied small molecule drugs in a rat femur defect model. J Biomed Biotechnol. 2010, 2010: 597641-CrossRefPubMedPubMedCentral Cottrell JA, Vales FM, Schachter D, Wadsworth S, Gundlapalli R, Kapadia R, O’Connor JP: Osteogenic activity of locally applied small molecule drugs in a rat femur defect model. J Biomed Biotechnol. 2010, 2010: 597641-CrossRefPubMedPubMedCentral
38.
go back to reference Piskin E, Isoglu IA, Bolgen N, Vargel I, Griffiths S, Cavusoglu T, Korkusuz P, Guzel E, Cartmell S: In vivo performance of simvastatin-loaded electrospun spiral-wound polycaprolactone scaffolds in reconstruction of cranial bone defects in the rat model. J Biomed Mater Res A. 2009, 90 (4): 1137-1151.CrossRefPubMed Piskin E, Isoglu IA, Bolgen N, Vargel I, Griffiths S, Cavusoglu T, Korkusuz P, Guzel E, Cartmell S: In vivo performance of simvastatin-loaded electrospun spiral-wound polycaprolactone scaffolds in reconstruction of cranial bone defects in the rat model. J Biomed Mater Res A. 2009, 90 (4): 1137-1151.CrossRefPubMed
39.
go back to reference Thillemann TM, Pedersen AB, Mehnert F, Johnsen SP, Soballe K: The risk of revision after primary total hip arthroplasty among statin users: a nationwide population-based nested case–control study. J Bone Joint Surg Am. 2010, 92 (5): 1063-1072. 10.2106/JBJS.H.01805.CrossRefPubMed Thillemann TM, Pedersen AB, Mehnert F, Johnsen SP, Soballe K: The risk of revision after primary total hip arthroplasty among statin users: a nationwide population-based nested case–control study. J Bone Joint Surg Am. 2010, 92 (5): 1063-1072. 10.2106/JBJS.H.01805.CrossRefPubMed
40.
go back to reference Patil S, Holt G, Raby N, McLellan AR, Smith K, O’Kane S, Beastall G, Crossan JF: Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing. J Orthop Res. 2009, 27 (3): 281-285. 10.1002/jor.20572.CrossRefPubMed Patil S, Holt G, Raby N, McLellan AR, Smith K, O’Kane S, Beastall G, Crossan JF: Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing. J Orthop Res. 2009, 27 (3): 281-285. 10.1002/jor.20572.CrossRefPubMed
41.
go back to reference Hendriksen CF: Refinement, reduction, and replacement of animal use for regulatory testing: current best scientific practices for the evaluation of safety and potency of biologicals. ILAR J. 2002, 43 (Suppl): S43-48.PubMed Hendriksen CF: Refinement, reduction, and replacement of animal use for regulatory testing: current best scientific practices for the evaluation of safety and potency of biologicals. ILAR J. 2002, 43 (Suppl): S43-48.PubMed
42.
go back to reference Back DA, Pauly S, Rommel L, Haas NP, Schmidmaier G, Wildemann B, Greiner SH: Effect of local zoledronate on implant osseointegration in a rat model. BMC Musculoskelet Disord. 2011, 13: 42-CrossRef Back DA, Pauly S, Rommel L, Haas NP, Schmidmaier G, Wildemann B, Greiner SH: Effect of local zoledronate on implant osseointegration in a rat model. BMC Musculoskelet Disord. 2011, 13: 42-CrossRef
Metadata
Title
Influence of Statins locally applied from orthopedic implants on osseous integration
Authors
Stephan Pauly
David A Back
Kathrin Kaeppler
Norbert P Haas
Gerhard Schmidmaier
Britt Wildemann
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2012
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-13-208

Other articles of this Issue 1/2012

BMC Musculoskeletal Disorders 1/2012 Go to the issue