Early Effect of Simvastatin Gel on Bone Formation of Orthopaedically Expanded Sagittal Suture of Rabbits

Alaa Dawood Mahmood, Khudhair Adday Salman Al-Jumaili, Hafidh I. Al-Sadi


OBJECTIVES: To evaluate early bone-healing effects of local simvastatin application to orthopaedically expanded sagittal suture of
MATERIALS AND METHODS:A total of 30 male Rabbits of an average weight of 0 .75-1.0 kg and aged 2-3 months were used in
this study. The animals were divided into three groups of ten animals each: simvastatin (group I), active control (group II), and
passive control (group III). The sagittal suture was expanded with an expansion spring for one week, after that, the expander was
removed and replaced with wire retainer for two weeks .At the time of wire retainer placement: Group I received an injection of
0.5mg simvastatin /0.5ml methylcellulose gel over the suture; group II received 0.5 ml of methylcellulose gel subcutaneously over
the expanded suture; group III received no treatment. Half of the animals (five animals in each group) were sacrificed after two
weeks of retention, and the sutures were prepared for radiological and histological assessment of regenerated bone. In the other
half, the wire retainer was removed after two weeks of retention and the relapsed ratio of the expanded suture was calculated
one week later.
RESULTS: Local application of simvastatin has been found to have a positive influence on bone regeneration of orthopaedically
expanded sagittal suture in comparison to control group. The density of the suture in the simvastatin group was significantly higher
than control group. The relapse ratio in simvastatin gel treated group was nearly half that of methyl cellulose carrier gel and control
groups, the difference was highly significant.
CONCLUSION:0.5 mg simvastatin greatly promote early bone formation of orthopaedically expanded sagittal suture.


Bone, Early, Effect, Simvastatin, Expanded, Sagittal, Suture, Rabbits.


Sari Z, Uysal T, Usumez S, Basciftci F (2003). Rapid maxillary

expansion. Is it better in the mixed or in the permanent

dentition?.Angle Orthod ;73(6):654-661.

Tang GH, Xu J, Chen RJ, Qian YF, Shen G (2011). Lithium

delivery enhances bone growth during midpalatal expansion. J

Dent Res; 90(3):336-340.

Gurel HG, Memili B, Erkan M, Sukurica Y (2010). Longterm

effects of rapid maxillary expansion followed by fixed

appliances. Angle Orthod 80(1): 5–9.

Garrett BJ, Caruso JM, Rungcharassaeng K, Farrage JR, Kim

JS, Taylor GD (2008). Skeletal effects to the maxilla after

rapid maxillary expansion assessed with cone-beam computed

tomography. Am J Orthod Dentofacial Orthop; 134(1): 8–9.

Capezolla Filho L, Silva Filho OG (1997). Rapid maxillary

exapansion: a general approach and clinical applications. Part

I. Rev Dent Press Ortod Ortop Maxillofac 2:88-102.

McNamara JA (2002). Treatment of children in mixed dentition

phase. In: Graber TM, Vanarsdall RL (eds) Current principles

and techniques, 3rd edn. Guanabara Koogan, Rio de Janeiro,

Pp 467-496.

Iseri H, Ozsoy S (2004).Semirapid maxillary expansion—a

study of long-term transverse effects in older adolescents and

adults. Angle Orthod; 74(1):71–8.

Halazonetis DJ, Katsavrias E, Spyropoulos MN (1994).Changes

in cheek pressure following rapid maxillary expansion. Eur J

Orthod; 16(40):295–300.

Koudstaal MJ, Smeets JB, Kleinrensink GJ, Schulten AJ, van

der Wal KG (2009). Relapse and stability of surgically assisted

rapid maxillary expansion: an anatomic biomechanical study.

J Oral Maxillofac Surg; 67(1):10–4.

Saito S, Shimizu N (1997). Stimulatory effects of low-power

laser irradiation on bone regeneration in midpalatal suture

during expansion in the rat. Am J Orthod Dentofacial Orthop;


Lai RF, Zhou ZY, and Chen T (2013). Accelerating bone

generation and bone mineralization in the interparietal sutures

of rats using rhBMP-2/ACS composite after rapid expansion.

Exp Anim; 62 (3):189-196.

Jiang Y, Liu HX, Guo JJ, Tang GH, and QianYF (2013).

Stimulation of bone formation in the expanding premaxillary

suture with a GSk-3β inhibitor. Oral Dis; 19(1):73-79.

Uysal T, Amasyali M, Olmez H, Enhos S, Karslioglu Y,

Gunhan O (2011). Effect of vitamin C on bone formation in

the expanded interpremaxillary suture. Early bone changes. J

Orofac Orthop;72 (4):290-300.

Uysal T, Amasyali M, Olmez H, Karslioglu Y, Gunhan O

(2009). Stimulation of bone formation in the expanding interpremaxillary

suture by vitamin E, in rat. Korean J Orthod;


Uysal T, Amasyali M, Enhos S, Sonmez MF, Sagdic D (2009).

Effect of ED-71, a new active vitamin D analog, on bone

formation in an orthopaedically expanded suture in rats. A

histomorphometric study. Eur J Dent; 3(3):165-172.

Öztürk F, Babacan H, and Gümüş (2012). Effects of zoledronic

acid on sutural bone formation: a computed tomography study.

Eur J Orthod; 34(2): 141–146.

Zhong WJ, Zhang WB, Ma JQ, Wang H, Pan YC, Wang

L.(2011). Periostin-like-factor-induced bone formation within

orthopedic maxillary expansion. Orthod Craniofac Res;


Uysal T, Amasyali M, Olmez H, Karslioglu Y, Gunhan O

(2010). Stimulation of bone formation by direct electrical

current in an orthopedically expanded suture in the rat. Korean

J Orthod; 40(2):106-114.

Ana P R, da Silva B, Petri AD, Crippa GE, Stuani AS, Stuani

AS , Rosa AL and Stuani MB(2012). Effect of low-level

laser therapy after rapid maxillary expansion on proliferation

and differentiation of osteoblastic cells. Lasers Med Sci; 27


Altan BA, Karab IM, Nalcacic R, Ozand F, Erdogane SM,

Ozkutf MM, Inan S (2013). Systemic propolis stimulates new

bone formation at the expanded suture :A histomorphometric

study. Angle Orthod; 83(2):286–291.

Kara MI, Altan AB, Zeser U, Erdogan MS, Inan S, Ozkut M,

Nalcaci R (2012).Effects of Ginko Biloba on experimental

rapid maxillary expansion model: a histomorphometric study.

Oral Surg Oral Med Oral Pathol Oral Radiol; 114(6):712-718.

Tang GH, Xu J, Chen RJ, Qian YF, Shen G (2011). Lithium

delivery enhances bone growth during midpalatal expansion. J

Dent Res; 90(3):336-340.

Uysal T, Ustdal A, Sonmez MF, Öztürk F (2009). Stimulation

of bone formation by dietary boron in an orthopedically

expanded suture in rabbits. Angle Orthod; 79(5):984-990.

Uysal T, Gorgulu S, Yagci A, Karslioglu Y, Gunhan O,

Sagdic D (2011). Effect of resveratrol on bone formation in

the expanded interpremaxillary suture: early bone changes.

Orthod Craniofac Res; 14(2):80-87.

Kara MI, Erciyas K, Altan AB, Ozkut M, Ay S, Inan S (2012).

Thymoquinone accelerates new bone formation in the rapid

maxillary expansion procedure. Arch Oral Biol; 57:357-363.

Mukozawa A, Ueki K, Okabe K, Moroi A, Nakagawa K (2011).

Bone healing of critical sized defects in rabbits by statins in

two different carriers.Clin Oral implants Res; 22(11):1327-1335.

Mundy G, Garret R, Harris S, Chan J, Chen D, Rossini

G, Boyce B, Zhao M, Gutierrez G. (1999). Stimulation of

bone formation in vitro and in rodents by statins. Science;


Liao JK (2006). Isoprenoids as mediators of the biologic effects

of statins. J Clin Invest; 110(3):285-288.

Nyan M, Sato D, Oda M, Machida T, Kobayashi H, Nakanura

T, Kasugai S (2007). Bone formation with the combination of

simvastatin and calcium sulfate in critical –sized rat calvarial

defects. J Pharmacol Sci; 104(4):384-385.

Ozeç I, Kiliç E, Gümüş C, Göze F (2007). Effect of local

simvastatin application on mandibular defects. J Craniofac

Surg; 18(3):546-550.

Wong RW, Rabie AB (2005). Histologic and ultrastructural

study on statin graft in rabbit skulls. J Oral Maxillofac Surg;


Wu Z, Liu C, Zang G, Sun H (2008). The effect of simvastatin

on remodeling of the alveolar bone following tooth extraction.

Int J Oral Maxillofac Surg; 37(2):170-176.

Chen S, Yang JY, Zhang SY, Feng L, Ren J (2011). Effects of

simvastatin gel on bone regeneration in alveolar defects in

miniature pigs Chinese Med J; 124(23):3953-3958.

Lee K, Sugiyama H, Imoto SH, Tanne K. Effects of

Bisphosphonate on the Remodeling of Rat Sagittal Suture

After Rapid Expansion. Angle Orthod 2001; 71(4):265–273.

Stossel TP (2008). The discovery of statins.Cell;134(6):903-

Schmidt-Lucke C, Fichtlscherer S, Rossig L, Kamper U,

Dimmeler S (2010).Improvement of endothelial damage and

regeneration indexes in patients with coronary artery disease

after 4 weeks of statin therapy. Atherosclerosis;211(1):249–54.

Ankur R, Seema R, Gurfateh S,Ashok K, khan MU (2011).

Cardioprotection with simvastatin: an appraisal. Int Res J

Pharm ;2(6):23–7.

West B, Williams CM, Jilbert E, James AM, Haines TP (2013).

Statin use and peripheral sensory perception: A pilot study.

Somatosens Mot Res. Nov 12. [Epub ahead of print]

Millar PJ, Floras JS (2014). Statins and the autonomic nervous

syetem.Clin Sci (Lond).;126(6):401-15.

Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM (2013).

Statins and musculoskeletal conditions,arthropathies, and

injuries.JAMA Intern Med;173(14):1-10.

De Jong HJ, Damoiseaux JG, Vandebriel RJ, Souverein

PC, Gremmer ER, Wolfs M, Klungel OH, Van Loveren

H, Cohen Tervaert JW,Verschuren WM (2013).Statin use and

markers of immunity in the doetinchem cohort study. PLoS

One. ;8(10):e77587.

Nam DH, Lee H, Park JC, Shin SK, Lee SK, Hyung WJ, Lee

YC, Kang MW, Noh SH (2014). Long-term statin therapy

improves oncological outcome after radical gastrectomy for

stage II and III gastric cancer. Anticancer Res. 34(1):355-361.

Vallianou NG, Kostantinou A, Kougias M, Kazazis C (2013).

Statins and Cancer. Anticancer Agents Med Chem. [Epub

ahead of print]

Tsartsalis AN, Dokos C, Kaiafa GD, Tsartsalis

DN, Kattamis A, Hatzitolios AI, Savopoulos CG (2012).

Statins, bone formation and osteoporosis: hope or hype?

Hormones (Athens). ;11(2):126-139.

Ruan F, Zheng Q, Wang J (2012). Mechanisms

of bone anabolism regulated by statins.Biosci Rep.;32(6):511-

Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini

G, Boyce B, Zhao M, Gutierrez G (1999). Stimulation of bone

formation in vitro and in rodents by statins. Science


Liu C, Wu Z, Sun HC (2009). The effect of simvastatin on

mRNA expression of transforming growth factor-beta1, bone

morphogenetic protein-2 and vascular endothelial growth

factor in tooth extraction socket. Int J Oral Sci;1(2):90-98.

Wu z, Liu c, Zang G, Sun H (2008).The effect of simvastatin on

remodeling of the alveolar bone following tooth extraction. Int

J Oral Maxillofac Surg;37(2):170-176.

Nayan M, Sato D, Kihara H, Machida T, Ohya K, Kasugai

S (2009). Effects of the combination with alpha-tricalcium

phosphate and simvastatin on bone regeneration. Clin Oral

Implants Res ;20(3)280-7.

Maciel-Oliveira N, Bradaschia-Correa V, Arana-Chavez VE

(2011). Early alveolar bone regeneration in rats after topical

administration of simvastatin. Oral Surg Oral Med Oral Pathol

Oral Radiol Endod;112(2):170-179.

Ma B, Clarke SA, Brooks RA, Rushton N (2008). The effect

of simvastatin on bone formation and ceramic resorption in a

peri-implant defect model. Acta Biomater;4(1):149-155.

Calixto JC, Lima CE, Frederico L, Lima RP, Anbinder AL

(2011). The influence of local administration of simvastatin

in calvarial bone healing in rats. J Craniomaxillofac

Surg ;39(3):215-20.

Benoit DS, Nuttelman CR, Collins SD, Anseth KS (2006).

Synthesis and characterization of a fluvastatin -releasing

hydrogel delivery system to modulate hMSC differentiation and

function for bone regeneration. Biomaterials;27(36):6102-10.

Stein D, Lee Y, Schmid MJ, Killpack B, Genrich MA, Narayana

N, Marx DB, Cullen DM, Reinhardt RA (2005).Local

simvastatin effects on mandibular growth and inflammation. J

Periodontol ;76:1861e1870.

Özeç I, Kiliç E, Gümüs¸ C, Göze F (2007): Effect of local

simvastatin application on mandibular defects. J Craniofac

Surg ;18(3): 546-550.

Mansour G, Koura AS, ElAshwah A (2006).Evaluation of the

regenerative potential of simvastatin around immediate dental

implants in freshly extracted sockets:An experimental study.

Egypt Dent J; 52(1313): 1324.

Ezirganlı S, Kazancıoğlu HO, Mihmanlı A, Aydın MS, Sharifov

R, Alkan A (2013).The effect of local simvastatin application

on critical size defects in the diabetic rats. Clin Oral Implants

Res. Apr 21. doi: 10.1111/clr.12177. [Epub ahead of print]

Ishihara Y, Ueki K, Sotobori M, Marukawa K, Moroi A

(2013).Bone regeneration by statin and low-intensity pulsed

ultrasound (LIPUS) in rabbit nasal bone. J Craniomaxillofac

Surg. Aug 27. pii: S1010-5182(13)00121-2. doi: 10.1016/j.

jcms.2013.05.002. [Epub ahead of print]

Morris MS, Lee Y, Lavin MT, Giannini PJ, Schmid MJ, Marx

DB, Reinhardt RA (2008). Injectable simvastatin in

periodontal defects and alveolar ridges: pilot studies. J

Periodontol ;79(8):1465-73.

Nath SD, Son S, Sadiasa A, Min YK, Lee BT (2013).

Preparation and characterization of PLGA microspheres by

the electrospraying method for delivering simvastatin for

bone regeneration. Int J Pharm ;443(1-2):87-94.

Jiang L, Sun H, Yuan A, Zhang K, Li D, Li C, Shi C, Li

X, Gao K, Zheng C, Yang B, Sun H (2013). Enhancement

of osteoinduction by continual simvastatin release

from poly(lactic-co-glycolic acid)-hydroxyapatitesimvastatin

nanofibrous scaffold. J Biomed Nanotechnol


Xu LY, Sun XJ, Zhang XL, Jin YQ, Wu YQ, Jiang XQ (2013).

Repair of calvarial defect using a tissue-engineered bone

with simvastatin-loaded β-tricalcium phosphate scaffold and

adipose derived stem cells in rabbits. Shanghai Kou Qiang Yi

Xue ;22(4):361-7.

DOI: http://dx.doi.org/10.26477/idj.v36i2.14


  • There are currently no refbacks.