The impact of simvastatin intervention on the healing of bone, soft tissue, and TMJ cartilage in dentistry: a systematic review and meta-analysis

Swati Gupta, Massimo Del Fabbro, Jia Chang, Swati Gupta, Massimo Del Fabbro, Jia Chang

Abstract

The review aimed at assessing the osteopromotive potential as well as soft tissue and temporomandibular joint (TMJ) cartilage healing properties of simvastatin by summarizing its efficacy on the current dental treatment of periodontal bone and soft tissue defects, and temporomandibular joint (TMJ) arthritis from the available animals and human studies. An electronic search was performed on MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) using a combination of keywords. A hand search was undertaken on seven oral surgery journals. No limitation of publication year in the English language was placed. Controlled randomized animal and human clinical trials, as well as prospective comparative studies, were included. Data on the comparison of topical/systemic simvastatin on bone healing in intrabony and furcation defects, extraction sockets, distraction osteogenesis, as well as soft tissue healing in mucogingival grafting procedures and cartilage protection in TMJ arthritis were extracted from all the eligible studies. Studies with a minimum of ten participants and follow up at least 6 months were included. Ten animal studies and six clinical studies were included in this study. All the animal studies included a minimum of eight sites per group assessed clinically, histologically, and radiographically. All human studies included clinical and radiological evaluation. The results of the review show that simvastatin administration displays positive treatment outcomes in the full range of therapies investigated in the oral regions such as periodontal infection control, periodontal and alveolar bone regeneration, soft tissue grafting, TMJ inflammation reduction, and cartilage repair. Its mechanism includes stimulating bone formation, promoting soft tissue healing, increasing articular and condylar cartilage thickness, as well as reducing inflammation at surgical sites in TMJ disorders. Simvastatin administration is beneficial to the healing of oral bone and cartilage. More studies are desired to determine its potential in soft tissue healing.

Keywords: Implants; Periodontal tissues; Regeneration; Simvastatin; Soft tissue healing; Statins.

Conflict of interest statement

Ethics approval and consent to participate

This review was executed by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), and no approval by an ethics committee was required.

Consent for publication

Not applicable.

Competing interests

Swati Gupta, Massimo Del Fabbro, and Jia Chang declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
PRISMA flowchart of literature search and screening process
Fig. 2
Fig. 2
Meta-analysis using a random effect model for assessing bone height changes in various types of defects in human studies. a Clinical attachment level (CAL) changes at 6 months. b Probing depth (PD) reduction. Significant positive effect of simvastatin was found in both cases. Heterogeneity was found for PD (I2 = 87%, p = 0.0004), but not for CAL (I2 = 43%, p = 0.17). Mean differences and 95% confidence intervals are expressed in mm
Fig. 3
Fig. 3
Meta-analysis using a random effect model for assessing bone fill in various types of defects in human studies. Overall analysis showed a significant positive effect of simvastatin in enhancing bone defect fill (p < 0.0001). Slight heterogeneity among studies was found (I2 = 70%, p = 0.03). Mean differences and 95% confidence intervals are expressed in mm

References

    1. Johner R. Dependence of bone healing on defect size. Helv Chir Acta. 1972;39:409–411.
    1. Hughes FJ, Ghuman M, Talal A. Periodontal regeneration: a challenge for the tissue engineer? Proc Inst Mech Eng H. 2010;224:1345–1358. doi: 10.1243/09544119JEIM820.
    1. Hämmerle CH, Karring T. Guided bone regeneration at oral implant sites. Periodontol 2000. 1998;17:151–175. doi: 10.1111/j.1600-0757.1998.tb00132.x.
    1. Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. J Pharm Pharmacol. 2006;58:3–18. doi: 10.1211/jpp.58.1.0002.
    1. 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;286:1946–1949. doi: 10.1126/science.286.5446.1946.
    1. Yamashita M, Otsuka F, Mukai T, Yamanaka R, Otani H, Matsumoto Y, Nakamura E, Takano M, Sada KE, Makino H. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept. 2010;162(1-3):99-108.
    1. Sonobe M, Hattori K, Tomita N, Yoshikawa T, Aoki H, Takakura Y, et al. Stimulatory effects of statins on bone marrow-derived mesenchymal stem cells. Study of a new therapeutic agent for fracture. Biomed Mater Eng. 2005;15:261–267.
    1. Maeda T, Matsunuma A, Kurahashi I, Yanagawa T, Yoshida H, Horiuchi N. Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. J Cell Biochem. 2004;92(3):458-71.
    1. Grasser WA, Baumann AP, Petras SF, Harwood HJ, Jr, Devalaraja R, Renkiewicz R, et al. Regulation of osteoclast differentiation by statins. J Musculoskelet Neuronal Interact. 2003;3:53–62.
    1. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche Peter C, Ioannidis John PA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151:W65–W94. doi: 10.7326/0003-4819-151-4-200908180-00136.
    1. Vaziri H, Naserhojjati-Roodsari R, Tahsili-Fahadan N, Khojasteh A, Mashhadi-Abbas F, Eslami B, et al. Effect of simvastatin administration on periodontitis-associated bone loss in ovariectomized rats. J Periodontol. 2007;78:1561–1567. doi: 10.1902/jop.2007.060480.
    1. Anbinder AL, Prado Fde A, Prado Mde A, Balducci I, Rocha RF. The influence of ovariectomy, simvastatin and sodium alendronate on alveolar bone in rats. Braz Oral Res. 2007;21:247–252. doi: 10.1590/S1806-83242007000300010.
    1. Wu Z, Liu C, Zang G. The effect of simvastatin on remodelling of the alveolar bone following tooth extraction. Int J Oral Maxillofac Surg. 2008;37:170–177. doi: 10.1016/j.ijom.2007.06.018.
    1. Sherif YM, Masry NE, Karam SS, Nasra MA. Evaluation of local administration of simvastatin on height and width of the healing extraction socket in rat mandible. Alex Dent J. 2016;41:283–286.
    1. Killeen AC, et al. Impact of local and systemic alendronate on simvastatin-induced new bone around periodontal defects. J Periodontol. 2012;83:1463–1471. doi: 10.1902/jop.2012.110683.
    1. Rutledge J, Schieber MD, Chamberlain JM, Byarlay M, Killeen AC, Giannini PJ. Simvastatin application to augment facial jaw bone in a dog model: pilot study. J Periodontol. 2011;82:597–605. doi: 10.1902/jop.2010.100214.
    1. Ozec I, Kilic E, Gumus C, Goze F. Effect of local simvastatin application on mandibular defects. J Craniofac Surg. 2007;18:546–550. doi: 10.1097/scs.0b013e318052ff05.
    1. Kilic E, Ozeç I, Yeler H, Korkmaz A, Ayas B, Gumuş C. Effects of simvastatin on mandibular distraction osteogenesis. J Oral Maxillofac Surg. 2008;66:2233–2238. doi: 10.1016/j.joms.2008.05.362.
    1. Kinra P, Gupta H, Mohammad KS, Ahmad S. Evaluation of the relative efficacy of an allograft used alone and that in combination with simvastatin in the treatment of human periodontal infrabony defects—a clinical and radiological study. J Taibah Univ Med Sci. 5:75–88.
    1. Ranjan R, Patil SR, H R V. Effect of in-situ application of simvastatin gel in surgical management of osseous defects in chronic periodontitis—a randomized clinical trial. J Oral Biol Craniofac Res. 2017; 7:113–118.
    1. Pradeep AR, Priyanka N, Kalra N, Naik SB, Singh SP, Martande S. Clinical efficacy of subgingivally delivered 1.2-mg simvastatin in the treatment of individuals with class II furcation defects: a randomized controlled clinical trial. J Periodontol. 2012;83:1472–1479. doi: 10.1902/jop.2012.110716.
    1. Chauhan AS, Maria A, Managutti A. Efficacy of simvastatin in bone regeneration after surgical removal of mandibular third molars: a clinical pilot study. J Maxillofac Oral Surg. 2015;14:578–585. doi: 10.1007/s12663-014-0697-6.
    1. Gouda A, Helal E, Ali S, Bakry S, Yassin S. Maxillary sinus lift using osteoinductive simvastatin combined with β-TCP versus β-TCP—a comparative pilot study to evaluate simvastatin enhanced and accelerated bone formation. Acta Odontol Scand. 2017;76:39–47. doi: 10.1080/00016357.2017.1381345.
    1. Alam S, Ueki K, Nakagawa K, Marukawa K, Hashiba Y, Yamamoto E, et al. Statin-induced bone morphogenetic protein (BMP) 2 expression during bone regeneration: an immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:22–29. doi: 10.1016/j.tripleo.2008.06.025.
    1. Maeda T, Kawane T, Horiuchi N. Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology. 2003;144:681–692. doi: 10.1210/en.2002-220682.
    1. Leung BP, Sattar N, Crilly A, Prach M, Carey M, Payne DW, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003;170:1524–1530. doi: 10.4049/jimmunol.170.3.1524.
    1. Bertl K, Pietschmann P, Stavropoulos A. Chapter 12: Osteoimmunological aspects of periodontal diseases. In: Pietschmann PP, ed. Principles of Osteoimmunology: Molecular Mechanisms and Clinical Applications. Cham, Switzerland: Springer; 2016. p. 289-321.
    1. Wang SP, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. J Am Med Assoc. 2000;283:3211–3216. doi: 10.1001/jama.283.24.3211.
    1. 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;21:1636–1641. doi: 10.1161/hq1001.097781.
    1. 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;17:1033–1042. doi: 10.1007/s00198-006-0079-0.
    1. Ho ML, Chen YH, Liao HJ, Chen CH, Hung SH, Lee MJ, et al. Simvastatin increases osteoblasts and osteogenic proteins in ovariectomized rats. Eur J Clin Investig. 2009;39:296–303. doi: 10.1111/j.1365-2362.2009.02092.x.
    1. Junqueira JC, Mancini MN, Carvalho Y, Anbinder AL, Balducci I, Rocha RF. Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol level. J Oral Sci. 2002;44:117–124. doi: 10.2334/josnusd.44.117.
    1. Nyan M, Sato D, Kihara H, Machida T, Ohya K, Kasugai S. Effects of the combination with alpha-tricalcium phosphate and simvastatin on bone regeneration. Clin Oral Implants Res. 2009;20:280–287. doi: 10.1111/j.1600-0501.2008.01639.x.
    1. Rojbani H, Nyan M, Ohya K, Kasugai S. Evaluation of the osteoconductivity of a-tricalcium phosphate, b-tricalcium phosphate, and hydroxyapatite combined with or without simvastatin in rat calvarial defect. J Biomed Mater Res A. 2011;98:488–498. doi: 10.1002/jbm.a.33117.
    1. Zerbo IR, Zijderveld SA, de Boer A, et al. Histomorphometry of human sinus floor augmentation using a porous beta-tricalcium phosphate: a prospective study. Clin Oral Implants Res. 2004;15:724–732. doi: 10.1111/j.1600-0501.2004.01055.x.
    1. Zijderveld SA, Zerbo IR, van den Bergh JP, Schulten EA, ten Bruggenkate CM. Maxillary sinus floor augmentation using a beta-tricalcium phosphate (Cerasorb) alone compared to autogenous bone grafts. Int J Oral Maxillofac Implants. 2005;20:432–440.
    1. George MD, Owen CM, Reinhardt AL, Giannini PJ, Marx DB, Reinhardt RA. Effect of simvastatin injections on temporomandibular joint inflammation in growing rats. J Oral Maxillofac Surg. 2013;71:846–853. doi: 10.1016/j.joms.2012.12.020.
    1. Holwegner C, Reinhardt AL, Schmid MJ, Marx DB, Reinhardt RA. Impact of local steroid or statin treatment of experimental temporomandibular joint arthritis on bone growth in young rats. Am J Orthod Dentofac Orthop. 2015;147:80–88. doi: 10.1016/j.ajodo.2014.09.016.
    1. Stein D, Lee Y, Schmid MJ. Local simvastatin effects on mandibular bone growth and inflammation. J Periodontol. 2005;76:1861–1870. doi: 10.1902/jop.2005.76.11.1861.
    1. Madi M, Kassem A. Topical simvastatin gel as a novel therapeutic modality for palatal donor site wound healing following free gingival graft procedure. Acta Odontol Scand. 2018;76:212–219. doi: 10.1080/00016357.2017.1403648.

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