Effect of Local Simvastatin on the Healing of Surgically Created Critical-Sized Bone Defects: An experimental Study on sheep.

Authors

  • Rebin Azad Abdulsamad Department of Oral and Maxillofacial Surgery, College of Dentistry, Hawler Medical University, Erbil, Iraq.
  • Luqman Fawzi Omar Department of Oral and Maxillofacial Surgery, College of Dentistry, Hawler Medical University, Erbil, Iraq.

DOI:

https://doi.org/10.15218/edj.2024.5

Keywords:

Bone formation, Bone graft, Bone healing, Simvastatin, Statin

Abstract

Background and objective: the role of simvastatin in lowering serum cholesterol levels is well described. However, recent findings suggest they have a role in bone formation as well. The study aims to determine the effect of local simvastatin application on bone defect healing and compare the amount of new bone produced by a simvastatin-treated defect with that produced by a bone graft (biphasic calcium phosphate) and non-treated defects (left empty) histologically.

Methods: Forty-five critical-size defects were created (8mm in diameter and depth) in the iliac bone of 6 sheep. For the first three sheep (5 defects/ilium), the five defects on the right ilium were left empty as a Control group, while the five defects on the left ilium were filled with biphasic calcium phosphate as Test 1 group. For the other three sheep, 5 defects were created on the right ilium, the defects were filled with 10mg crushed simvastatin tablet with gelfoam (as a carrier) as Test 2 group. The animals were sacrificed over periods of 1, 2, and 3 months. Histopathological studies were done for all the samples. SPSS version 28 was used to analyze the results. The numerical variables were checked for normality using Smirnov – Kolmogorov test, then analyzed using ANOVA and unpaired t-test (p–values ≤ 0.05 were considered statistically significant).

Results: All 6 adult male sheep passed the scheduled periods uneventfully. During the wound healing period, there was no complication such as infection, excessive hematoma, or wound dehiscence. All 45 standardized iliac bone defects were included in the final analysis (n= 45). The histologic results showed that Test 2 group (defect filled with simvastatin) in the 1st, 2nd, and 3rd months had significantly higher bone formation at the surface and depth of the defects than Test 1 and Control group with P values (<0.0001) at all period intervals.

Conclusion: Simvastatin enhances bone formation and accelerates the healing process of the bony defect.

References

De Oliveira E Silva M, Pelegrine AA, Alves Pinheiro da Silva A, Manhães Júnior LR, De Mello E Oliveira R, Gaiba França S, et al. Xenograft enriched with autologous bone marrow in inlay reconstructions: a tomographic and histomorphometric study in rabbit calvaria. International Journal of Biomaterials. 2012;2012.

Ihghaf NON, Tawfik MAM, El–Hawary YM, Mansour NA. Osteon Ii Versus Biogen In Healing Of Jaw Bone Defects. Dental Journal. 2015;61(4045):4053.

Monaco AP. The beginning of clinical tolerance in solid organ allografts. Experimental and clinical transplantation: official journal of the Middle East Society for Organ Transplantation. 2004;2(1):153–61.

Araújo M, Linder E, Lindhe J. Effect of a xenograft on early bone formation in extraction sockets: an experimental study in dog. Clinical oral implants research. 2009;20(1):1–6.

Maus U, Andereya S, Gravius S, Ohnsorge JA, Niedhart C, Siebert CH. BMP-2 incorporated in a tricalcium phosphate bone substitute enhances bone remodeling in sheep. Journal of biomaterials applications. 2008;22(6):559–76.

Kim JW, Shin YC, Lee JJ, Bae EB, Jeon YC, Jeong CM, et al. The effect of reduced graphene oxide-coated biphasic calcium phosphate bone graft material on osteogenesis. International Journal of Molecular Sciences. 2017;18(8):1725.

Mahmoud HM, Zaki HF, El Sherbiny GA, Abd El-Latif HA. Effects of Simvastatin and Vitamin E on Diet-induced Hypercholesterolemia in Rats. British Journal of Pharmacology and Toxicology. 2014;5(1):16–25.

Mathur M, Kusum Devi V. Potential of novel drug delivery strategies for the treatment of hyperlipidemia. Journal of Drug Targeting. 2016;24(10):916–26.

Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286(5446):1946–9.

Liu C, Wu Z, Sun H. The effect of simvastatin on mRNA expression of transforming growth factor‐β1, bone morphogenetic protein‐2 and vascular endothelial growth factor in tooth extraction socket. International journal of oral science. 2009;1(2):90–8.

Gutierrez G, Lalka D, Garrett I, Rossini G, Mundy G. Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporosis international. 2006;17(7):1033–42.

Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundamental & clinical pharmacology. 2005;19(1):117–25.

Chauhan AS, Maria A, Managutti A. Efficacy of simvastatin in bone regeneration after surgical removal of mandibular third molars: A clinical pilot study. Journal of maxillofacial and oral surgery. 2015;14(3):578–85.

Aktas İ, Yarsan E. Pharmacokinetics of Conventional and Long-Acting Oxytetracycline Preparations in Kilis Goat. Front Vet Sci. 2017 Dec 22; 4:229.

Wong R, Rabie A. Statin collagen grafts used to repair defects in the parietal bone of rabbits. British Journal of Oral and Maxillofacial Surgery. 2003;41(4):244–8.

Ismail FA. Design and in vitro evaluation of polymeric formulae of simvastatin for local bone induction. Drug development and industrial pharmacy. 2006;32(10):1199–206.

Garrett IR, Mundy GR. The role of statins as potential targets for bone formation. Arthritis research & therapy. 2002;4(4):1–4.

Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochemical and biophysical research communications. 2001;280(3):874–7.

Saifi AM, Giraddi GB, Ahmed N. Healing of extraction socket following local application of simvastatin: A split-mouth prospective study. Journal of oral biology and craniofacial research. 2017;7(2):106–12.

Ayukawa Y, Yasukawa E, Moriyama Y, Ogino Y, Wada H, Atsuta I, et al. Local application of statin promotes bone repair through the suppression of osteoclasts and the enhancement of osteoblasts at bone-healing sites in rats. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2009;107(3):336–42.

Özeç I, Kiliç E, Gümüs C, Göze F. Effect of local simvastatin application on mandibular defects. Journal of Craniofacial Surgery. 2007;18(3):546–50.

Nishimura K. Local application of simvastatin to rat incisor sockets augments bone. Kokubyo Gakkai zasshi The Journal of the Stomatological Society, Japan. 2008;75(1):49–54.

Wong RW, Rabie ABM. Early healing pattern of statin-induced osteogenesis. British Journal of Oral and Maxillofacial Surgery. 2005;43(1):46–50.

Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, et al. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation. 2005;111(14):1841–6.

Pauly S, Luttosch F, Morawski M, Haas N, 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):505–11.

Lee Y, Schmid MJ, Marx DB, Beatty MW, Cullen DM, Collins ME, et al. The effect of local simvastatin delivery strategies on mandibular bone formation in vivo. Biomaterials. 2008 Apr;29(12):1940–9.

Tanigo T, Takaoka R, Tabata Y. Sustained release of water-insoluble simvastatin from biodegradable hydrogel augments bone regeneration. Journal of Controlled Release. 2010;143(2):201–6.

Gupta S, Verma P, Tikku AP, Chandra A, Yadav RK, Bharti R, et al. “Effect of local application of simvastatin in bone regeneration of peri-apical defects-a clinical-radiographic study. Journal of Oral Biology and Craniofacial Research. 2020;10(4):583–91.

Ferguson JC, Tangl S, Barnewitz D, Genzel A, Heimel P, Hruschka V, et al. A large animal model for standardized testing of bone regeneration strategies. BMC veterinary research. 2018;14(1):1–10.

Malhotra A, Pelletier MH, Yu Y, Christou C, Walsh WR. A sheep model for cancellous bone healing. Frontiers in surgery. 2014; 1:37.

Sartoretto SC, Uzeda MJ, Miguel FB, Nascimento JR, Ascoli F, Calasans-Maia MD. Sheep as an experimental model for biomaterial implant evaluation. Acta ortopedica brasileira. 2016; 24:262–6.

von Rechenberg B. Experiences with sheep models in musculoskeletal research at the MSRU. European Cells and Materials. 2008;16(Suppl. 4):31.

Gibson AJ, Coffey TJ, Werling D. Of creatures great and small: the advantages of farm animal models in immunology research. Frontiers in Immunology. 2013; 4:124.

Harding J, Roberts RM, Mirochnitchenko O. Large animal models for stem cell therapy. Stem cell research & therapy. 2013;4(2):1–9.

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. Clinical oral implants research. 2011;22(11):1327–35.

Mouhamed A, Mouhamed AI, Sadek H. Evaluation of the outcome of adding a biological modifier (simvastatin) to bone grafting material. International Journal of Oral and Maxillofacial Surgery. 2009;38(5):455.

Hassan S, Sadek H, Tantawi E. Bone graft remodeling after ridge reconstruction with autogenous bone and statin. International Journal of Oral and Maxillofacial Surgery. 2011;40(10):1047.

Rosselli JEGC, Martins DMFS, Martins JL, Oliveira CRGCM de, Fagundes DJ, Taha MO. The effect of simvastatin on the regeneration of surgical cavities in the femurs of rabbits. Acta cirurgica brasileira. 2014; 29:87–92.

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Published

2024-06-06

How to Cite

1.
Abdulsamad RA, Omar LF. Effect of Local Simvastatin on the Healing of Surgically Created Critical-Sized Bone Defects: An experimental Study on sheep. EDJ [Internet]. 2024 Jun. 6 [cited 2024 Jun. 30];7(1):37-49. Available from: https://edj.hmu.edu.krd/index.php/journal/article/view/269

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