Clinical Efcacy of Subgingivally

Delivered 1.2-mg Simvastatin

in the Treatment of Individuals
With Class II Furcation Defects:
A Randomized Controlled Clinical Trial
A.R. Pradeep,* N. Priyanka,* Nitish Kalra,* Savitha B. Naik,

Sonender P. Singh,*
and Santosh Martande*
Background: Simvastatin (SMV) assists in bone regenera-
tion and has an anti-inammatory effect when delivered or
applied locally. The present clinical trial is designed to
investigate the effectiveness of 1.2-mg SMV as a local drug
delivery system as an adjunct to scaling and root planing
(SRP) for the treatment of Class II furcation defects.
Methods: Seventy-two patients with mandibular buccal
Class II furcation defects were randomized and categorized
into two treatment groups: SRP plus placebo (group 1) and
SRP plus 1.2-mg SMV (group 2). Clinical parameters were
recorded at baseline before SRP and at 3 and 6 months; they
included modied sulcus bleeding index (mSBI), probing depth
(PD), and relative vertical (RVAL) and horizontal (RHAL) at-
tachment levels. At baseline and after 6 months, radiologic as-
sessment of bone defect ll was performed.
Results: Both therapies resulted in signicant improve-
ments. The decrease in mSBI score at 6 months was greater
in group 2 (2.02 0.23) compared with group 1 (1.80
0.22). The mean decrease in PD at 6 months was 1.30 1.0
and 4.05 1.31 mm in groups 1 and 2, respectively. A signif-
icantly greater gain in mean RVAL and RHAL was found in
group 2 than in group 1 (P <0.05). Furthermore, signicantly
greater mean percentage of bone ll was found in group 2
(25.16%) compared with group 1 (1.54%).
Conclusion: Locally delivered SMV provides a comfortable
and exible method to improve clinical parameters and also
to enhance bone formation. J Periodontol 2012;83:1472-1479.
KEY WORDS
Bone regeneration; chronic periodontitis; dental scaling; root
planing; simvastatin.
P
eriodontitis is considered as sub-
gingival inammation caused by
bacterial infection.
1
It affects the
periodontal supporting tissues, includ-
ing periodontal ligament, cementum,
and alveolar bone. Periodontitis affects
the junction of multi-rooted teeth, ini-
tially with tissue destruction and then
gradually as additional furcation involve-
ment bone loss occurs. Treatment of
furcation lesions is one of the most chal-
lenging tasks in periodontal therapy
today. The reduced rate of success ex-
perienced in the treatment of furcation
involvements seems to result from the
incomplete removal of subgingival pla-
que and calculus in the interradicular
area as a result of the peculiar anatomy
of the furcation space.
2,3
Attempts to treat furcation lesions
have led to therapies ranging from non-
surgical periodontal therapy, such as
scaling and root planing (SRP) alone or
SRP plus systemic or local antimicrobial
or anti-inammatory agents, to surgical
ap debridement, root resection, hemi-
section, and, more recently, regenerative
therapy. Surgical access signicantly en-
hances removal of calculus from molars
with furcation invasion; however, in
most cases, residual calculus has been
* Department of Periodontics, Government Dental College and Research Institute, Bangalore,
Karnataka, India.
Department of Conservative Dentistry and Endodontics, Government Dental College and
Research Institute.
doi: 10.1902/jop.2012.110716
Volume 83 Number 12
1472
detected even after open-ap surgery,
4
and there is
clinically signicant loss of attachment within the
furcation area during at least the rst 2 years of
maintenance care.
5
Bone deciencies are of major
concern and affect therapies in all dental and medical
elds. Because of the limitations of current bone
grafting methods, alternative methods for repairing
bone defects are needed.
Statins are specic inhibitors of 3-hydroxy-3-
methylglutaryl coenzyme A reductase, a rate-limit-
ing enzyme of the cholesterol synthesis pathway.
6
Statins are widely used to lower blood cholesterol
levels. A recent study suggests that statins can
stimulate bone formation by stimulating the pro-
duction of bone morphogenetic protein-2 (BMP-2).
7
Simvastatin (SMV) is a chemical modication of
lovastatin, which is obtained by the replacement
of 2-methyl-butyryl side chain of lovastatin with
a 2,2-dimethyl-butyryl group. Various animal studies
showed that SMV assists in bone regeneration as well
as the anti-inammatory effect when delivered or ap-
plied locally.
8-10
SMV enhances alkaline phosphatase
activity andmineralizationandincreases the expression
of bone sialoprotein, osteocalcin, and type I collagen,
and it is shown to have an anti-inammatory effect
by decreasing the production of interleukin-6 and
interleukin-8.
11
SMV is reported to stimulate vascular
endothelial growth factor (VEGF) release in a dose-
dependent manner, and the authors of a previous
study
12
suggested that statins may promote osteo-
blast differentiation and bone nodule formation by
stimulating VEGF expression in bone tissue.
Recently, a study by the authors of the present
study
13
showed that locally delivered 1.2-mg SMV
stimulated signicant increase in probing depth (PD)
reduction, clinical attachment level (CAL) gain, and
improved bone ll compared with placebo gel as an
adjunct to SRP in the treatment of intrabony defects
(IBDs) in patients with chronic periodontitis (CP).
Various vehicles have been used for local drug
delivery (LDD) in patients with periodontitis. Vehicles
used are biocompatible, have predictable biodeg-
radation kinetics and ease of fabrication, and have
regulatoryapproval; thus, theyhavewideapplications
in controlled drug delivery systems.
14
Methylcellulose
is widely used in a variety of oral and topical phar-
maceutical formulations, such as ophthalmic con-
trolled-release in situ gelling systems for ciprooxacin
andnimesulide-loaded methylcellulose nanoparticles
and microparticles for oral delivery.
15,16
It is used
extensively in cosmetic and food products. Methyl-
cellulose is generally regarded as a non-toxic, non-
allergic, and non-irritating material and is used as
a sustained-release vehicle for therapeutic drugs.
17
To the best of our knowledge, there are no pub-
lished data on the use of in situ gel using SMV with
methylcellulose (as a vehicle) for direct placement
in patients with Class II furcation defects. Keeping
the above facts in mind, the present study was per-
formed as a single-center, randomized controlled
clinical trial to investigate the clinical and radiologic
(bone ll) efcacy of 1.2-mg SMV as an adjunct to
SRP in the treatment of mandibular buccal Class II
furcation defects.
MATERIALS AND METHODS
Source of Data
The participants for this study were selected from the
outpatient section of the Department of Periodontics,
Government Dental College and Research Institute,
Bangalore, India, from March 2011 to August 2011.
Seventy-two patients (38 males and 34 females, aged
30 to 50 years), diagnosed with CP with mandibular
buccal Class II furcation defects,
18
were enrolled in this
study. It wasmadeclear tothepotential participantsthat
participation was voluntary. Written informed consent
was obtainedfromall patients, andethical clearance for
the study was received from the Institutional Ethical
Committee and Review Board, Government Dental
College and Research Institute of Bangalore, India.
Selection Criteria
The inclusion criteria for the study was: 1) the pres-
ence of buccal Class II furcation defects in end-
odontically vital, asymptomatic mandibular rst and
second molars with a radiolucency in the furcation
area on an intraoral periapical radiograph with PD
5 mmand horizontal PD 3 mmafter Phase I therapy
(SRP) and 2) no history of antibiotic or periodontal
therapy in the preceding 6 months. Exclusion criteria
were: 1) known systemic disease; 2) known or sus-
pected allergy to the SMV group; 3) systemic statin
therapy; 4) aggressive periodontitis; 5) use of to-
bacco in any form; 6) alcoholism; 7) diabetes; 8)
immunocompromised patients; and 9) pregnant
or lactating females. In addition, teeth with gingival
recession, endodontic (pulpal) involvement, Class III
furcation involvement,
18
and/or tooth mobility of at
least grade II
19
were also excluded.
Eighty individuals were initially analyzed for
the study. Eight individuals were excluded because
they did not meet the inclusion criteria. After par-
ticipant selection (by ARP), 36 participants were
randomly assigned to each treatment group (using
a computer-generated system), and one site per
participant was treated with SRP plus placebo gel
(group 1) or SRP plus SMV (1.2 mg/0.1 mL) in situ
gel (group 2). SRP was performed at baseline until
the root surface was considered smooth and clean
by the operator (NP). No antibiotics or antiplaque
and anti-inammatory agents were prescribed after
treatment.
J Periodontol December 2012 Pradeep, Priyanka, Karla, Naik, Singh, Martande
1473
Clinical parameters, including modied sulcus
bleeding index (mSBI)
20
and full-mouth and site-
specic plaque index (PI) score,
21
were considered
before SRP, and PD, relative vertical attachment
level (RVAL), and relative horizontal attachment level
(RHAL) were recorded at baseline (after SRP) and at
3 and 6 months. A custom-made acrylic stent and a
color-coded periodontal probe

were used to stan-

dardize the measurement of PD and RVAL. RVAL was
calculated by measuring the distance from the stent
(apical extent) to the base of the pocket minus
the distance from the stent to the cemento-enamel
junction. RHAL was measured using a periodontal
probe

from the stent to the deepest horizontal point

of the periodontal pocket.
Asingle clinician (NP) provided treatment to both
groups, and all pretreatment and post-treatment
clinical parameters were recorded by another exam-
iner (NK) who was masked to the type of treatment
received by the participants.
Radiographic Evaluation of Furcation Defects
Bone ll was evaluated at baseline and after 6 months
using an image analyzer.
i
The radiographic bone ll
was measured with a computer-aided program ac-
cording to the method used by Francetti et al.
22
In-
dividually customized bite blocks and a parallel-angle
technique were used to obtain lms that were as re-
producible as possible. All radiographs were reviewed
in a single reference center by a masked evaluator
(ARP). For evaluation, radiographs were scanned at
800 dots per inch with a scanner,

and the bone defect

was evaluated using computer-aided software. The
bone defect was measured on the radiograph by
measuring the distance from the furcation fornix to
the base of the defect (Figs. 1 and 2).
Intra-Examiner Calibration
Intra-examiner calibration was achieved by exami-
nationof 20patients twotimes (24hours apart) before
beginning the study. Calibration was accepted if
measurements at baseline and 24 hours were similar
within 1 mm at the 95% level.
Primary and Secondary Outcome Measures
The primary outcome of the study was bone ll. The
secondary outcomes included RVAL, RHAL, PD, PI,
and mSBI.
Formulation of 1.2-mg SMV In Situ Gel
The SMV gel (1.2 mg) was prepared as described in
a previous study.
13
The release prole of SMVfromgel
has been studied previously using high-performance
liquid chromatography.
13
Based on its sufciently
prolonged release in gingival crevicular uid after
LDD,
13
1.2 mg SMV was delivered locally in furcation
areas. Briey, methylcellulose insitugel was prepared
by adding the required amount of biocompatible
solvent to an accurately weighed amount of methyl-
cellulose. The vial was heated to 50C to 60C and
agitated using a mechanical shaker to obtain a clear
solution.
23
A weighed amount of SMV was added to
the above solution and dissolved completely to ob-
tain a homogeneous phase of polymer, solvent, and
drug. Thus, the SMV in situ gel was prepared with a
concentration of 1.2 mg.
LDD
For standardization, 0.1 mL prepared SMV gel
(1.2 mg/0.1 mL) was injected into the furcation
defect using a syringe with a blunt cannula. After
placement of the in situ gel, patients were instructed
to refrain fromchewing hard or sticky foods, brushing
near the treated areas, or using any interdental aids
for 1 week. Adverse effects were noted at recall visits,
and any supragingival deposits were removed.
Statistical Analyses
Power analysiscalculationswereperformedbeforethe
study was initiated. To achieve 90% power and detect
mean differences of the clinical parameters between
Figure 1.
Furcation defect was measured on the baseline radiograph by measuring
the distance from the furcation fornix to the base of the defect (3.8 mm).
UNC-15 periodontal probe, Hu-Friedy, Chicago, IL.
Nabers periodontal probe, Hu-Friedy.
i Scion Image Analyzer, Scion Corporation, Frederick, MD.
HP Scanjet 3c/I, Hewlett-Packard, Singapore.
Simvastatin As Local Drug Delivery for Treatment of Class II Furcation Defects Volume 83 Number 12
1474
groups, 30 sites in each group were required. Cate-
gorical variable (site-specic PI) was expressed as
percentage and continuous variable (full-mouth PI,
mSBI, PD, RVAL, RHAL, and bone ll) as mean SD.
Site-specic PI was compared by using the
x
2
test
or a Fisher exact test when the expected frequency
was <5. Normality assumption was tested using
the Shapiro-Wilk W test. Between-treatment-group
comparison was performed using the Mann-Whitney
U test. The adjusted mean at each visit is shown in
Table 1. Decreases in each period were calculated
from baseline (Table 2). Wilcoxon signed-rank test
was used for comparison within the SMV and control
groups, respectively. Statistical signicance was de-
ned as P <0.05. Statistical analysis was performed
with statistical software.
#
RESULTS
The consort owchart exhibiting the number of par-
ticipants analyzed and those dropping out is shown in
Fig. 3. Sixty-six of 72individuals completed the study.
Three individuals did not follow up after the baseline
examination, and three individuals refused to partic-
ipate because of reasons unrelatedto the study. Sixty-
six treatment sites (one site per participant) were
evaluated for clinical parameters at baseline (before
SRP) and at 3 and 6 months; radiographic parameters
were recorded at baseline and at 6 months in 66
treatment sites.
Clinical Evaluation
No adverse reaction was observed in any participant
from the test group, and no patient reported any dis-
comfort. Healing was uneventful. All participants
tolerated the drug, without any post-application
complications.
Evaluation of Oral Hygiene
No statistically signicant difference was found be-
tween group 1 and group 2 at any time for full-mouth
plaque score or for PI at the test site (Tables 3 and 4).
This indicates that both groups maintained compa-
rable levels of oral hygiene throughout the study.
Figure 2.
Furcation defect was measured on the radiograph of the same area
after 6 months by measuring the distance from the furcation fornix to
the base of the defect (2.6 mm).
Table 1.
PD, RVAL, and RHAL for Groups 1 and 2
(mean SD) at Different Time Intervals
Group PD (mm) RVAL (mm) RHAL (mm)
1
Baseline 6.80 1.32 7.43 1.53 7.86 1.46
3 months 5.13 1.22 5.07 0.99 5.56 1.27
6 months 5.50 1.28 4.97 0.89 5.43 1.15
2
Baseline 7.33 1.49 7.92 1.50 8.43 1.28
3 months 4.27 0.91 4.22 1.31 4.93 0.94
6 months 3.28 0.83 3.28 1.40 4.10 1.19
Table 2.
Decrease in PD and Gain in RVAL and
RHAL From Baseline (mean SD) at
Different Time Intervals for Groups 1 and 2
Parameter Group 1 Group 2 P value
PD (mm)
3 months 1.66 1.19 3.06 1.09 0.001*
6 months 1.30 1.01 4.05 1.31 0.001*
RVAL (mm)
3 months 2.36 1.25 3.70 1.21 0.001*
6 months 2.46 1.49 4.63 1.01 0.001*
RHAL (mm)
3 months 2.30 1.75 3.50 1.28 0.001*
6 months 2.43 1.66 4.33 1.42 0.001*
* Statistically signicant at 5% level of signicance (P <0.05).
# SPSS v.10.5, IBM, Chicago, IL.
J Periodontol December 2012 Pradeep, Priyanka, Karla, Naik, Singh, Martande
1475
mSBI
A statistically signicant decrease in mSBI scores
frombaseline was found in both groups. The decrease
in mSBI score was greater in group 2 (2.02 0.23)
compared with group 1 (1.80 0.22) at 6 months; it
was signicant in both groups at the 5% level of sig-
nicance (P <0.05) (Table 4).
PD
The decrease in PD was statistically signicant within
both groups compared with baseline at all time in-
tervals (Tables 1 and 2). When the groups were
compared, the difference in the decrease in PD at
each time period was statistically signicant.
RVAL and RHAL
The difference in RVAL and RHAL from baseline was
statistically signicant in both groups, RVAL and
RHAL gain were greater in group 2 compared with
group 1 at all periods, and the
difference reached the level of
signicance (Tables 1 and 2).
Bone Fill
There was a greater bone ll in
group 2 (1.15 0.61 mm or
25.16%) compared to group 1
(0.06 0.25mmor 1.54%), and
it was statistically signicant
(P <0.001) (Table 5).
DISCUSSION
The LDD system has a thera-
peutic advantage of preventing
systemic side effects and fo-
cusing the drug dose. Other
advantages include achieving
high intrasulcular drug con-
centrations and better patient
compliance.
24,25
Therefore, this
studyhas evaluatedtheefcacy
of 1.2-mgSMVgel as anadjunct
to SRP in treating mandibular
buccal Class II furcation defects
and showed signicant radio-
graphic bone ll and improve-
ment in clinical parameters
compared with placebo gel.
Statins are a group of lipid-
lowering drugs that are widely
used to prevent cardiovas-
cular events. Statins have
pleiotropic effects, and there
is some evidence of health
benets beyond cardiovascular
diseases.
26
Anti-inammatory
and bone-stimulating proper-
ties are among the actions of statins that could posi-
tively affect CP.
7,27
Since locally delivered statins
28
were discovered to
be potent stimulators of bone formation,
7
the possi-
bility of using these compounds as practical bone
anabolic agents has been postulated. There is evi-
dence that statins promote osteoblast differentiation
and enhance BMPs in mouse bone marrow stromal
cells,
29
and SMV increased alkaline phosphatase
activity and osteocalcin expression levels in human
bone marrow stem cells.
30
In the ovariectomized rat
model, more new bone formation in mandibular de-
fects and skeletal bone was seen when statins were
given orally,
31,32
and systemic statin-treated humans
showed an increase in bone mineral density, bone-
specic alkaline phosphatase activity, and osteo-
calcin after 3 months.
33
However, the effect of statins
when administered systemically appears to be
Figure 3.
Study owchart.
Simvastatin As Local Drug Delivery for Treatment of Class II Furcation Defects Volume 83 Number 12
1476
minimized by clearance by the liver,
34
and systemic
side effects of high doses are signicant.
A signicant mean bone ll in Class II furcation
involvement from baseline (1.54%) to 6 months
(25.16%) in group 2 suggests a role for SMV in
bone formation. This may be because of increased
BMP-2 expression during bone regeneration,
35
anti-
inammatory effects,
36
and angiogenesis during
wound healing.
Local delivery of statins in healing sites or defects
has been shown effective in new bone formation.
Morris et al.
9
studied the effect of injectable SMV
Table 4.
Full-Mouth Plaque Scores and Gingival Index (GI) for SMV and Placebo Groups
at Different Time Intervals
PI GI
Group Mean SD Mean Difference P value Mean SD Mean Difference P value
1
Baseline 1.90 0.20 2.51 0.42
3 months 0.83 0.15 1.07 0.16 NS 1.42 0.44 1.09 0.17 0.001*
6 months 0.66 0.18 1.24 0.13 NS 1.61 0.43 0.89 0.27 0.001*
2
Baseline 1.88 0.22 2.83 0.27
3 months 0.97 0.18 0.91 0.14 NS 1.03 0.18 1.80 0.22 0.001*
6 months 0.68 0.18 1.20 0.13 NS 0.80 0.18 2.02 0.23 0.001*
NS = not signicant.
* Statistically signicant at 5% level of signicance (P <0.05).
Table 5.
Comparison of Furcation Defect Values From Baseline to 6 Months
Group
Furcation Defect
(mm; mean SD)
Furcation Defect Decrease
(mm; mean SD) Furcation Defect Decrease (%) P value
1
Baseline 4.33 0.99
6 months 4.27 0.94 0.06 0.25 1.54 0.453
2
Baseline 4.57 1.14
6 months 3.42 0.98 1.15 0.61 25.16 0.001*
* Statistically signicant at P <0.001.
Table 3.
Site-Specic PI Score for Groups 1 and 2 at Baseline and at 3 and 6 Months
Baseline 3 Months 6 Months
PI Score Group 1 (%) Group 2 (%) Group 1 (%) Group 2 (%) Group 1 (%) Group 2 (%)
0 0 0 22 (66.6) 24 (72.7) 28 (84.8) 30 (90.9)
1 13 (39.3) 11 (33.3) 11 (33.3) 9 (27.2) 5 (15.1) 3 (9.09)
2 12 (36.3) 10 (30.3) 0 0 0 0
3 10 (30.3) 12 (36.3) 0 0 0 0
P value* NS NS NS NS NS NS
NS = not signicant.
* Not statistically signicant at 5% level of signicance (P <0.05).
J Periodontol December 2012 Pradeep, Priyanka, Karla, Naik, Singh, Martande
1477
in three-wall periodontal IBDs, Class II furcations de-
fects, and edentulous alveolar ridges in beagle dogs
by histomorphometric analysis; 29% greater ridge
thickness was found with SMV, but bone height loss
was detected in the interproximal IBDs and furcation
defects. The greater degree of bone loss in the IBDs
and furcation defects found in this study was the result
of ap surgeries involving manipulation of bone with
rotary instruments. However, the present study, in
which only a non-surgical approach (SRP) was used
in conjunction with locally delivered 1.2-mg SMV,
effective bone ll and a greater decrease in PD and
RVAL and RHAL gain was found in the treatment of
mandibular buccal Class II furcation involvement.
Therefore, this study conrms that locally delivered
SMV enhances bone growth in furcation areas when
used as an adjunct to SRP.
In the present study, there is decreased gingival
bleeding index frombaseline to 6 months, suggesting
an anti-inammatory effect of SMV. A similar anti-
inammatory effect of SMV was observed in our pre-
vious study
13
in patients with periodontal IBD. With
regard to the dose of SMV used, 1.2 mg/0.1 mL per
site is injected in the present study. It has been
shown that local application of 70 mg/kg causes
inammation.
23
Stein et al.
8
demonstrated that, by
reducing the SMVdose from2.2 to 0.5 mg, there was
a decrease in the inammation to a more clinically
acceptable level without sacricing bone growth po-
tential. A 45% increase in bone area was reported
with 0.5-mg SMV versus the gel control (similar to
a 2.2-mg dose), and clinical swelling was signicantly
reduced compared with the high SMV dose. Because
it was difcult to achieve proper viscosity with a low-
er concentration, a 1.2%SMV concentration was used
to prepare a owable gel that could easily pass
through the syringe. Adecrease in the viscosity of gel
was also studied in vitro when exposed to 37C
(mouth temperature). The use of smaller (25-gauge)
needles with little extrusion of drug solution and better
dispersion of the drug at the site of injection made
it easier to inject the SMV gel at the diseased site.
A decrease in PD and gain in CAL are the major
clinical outcomes measured to determine the suc-
cess of any periodontal treatment. A signicant
decrease in PD and gain in RVAL and RHAL were
found within both groups compared with baseline at
all time intervals. When comparing the two groups,
the decrease in PD and RVAL and RHAL gain were
statistically signicant at each period, even after 6
months (P <0.05).
The percentage of bone ll in the present study
is found to be statistically signicant in group 2
(25.16%) compared with group 1 (1.54%) at 6 months.
Thus, LDD of 1.2-mg SMV gel as an adjunct to SRP
showed effective bone ll compared with SRP alone
inClass II furcationdefects. The percentage of bone ll
in the present study is less comparable to the bone ll
(32.54%) in IBDs in CP patients in a previous study.
13
The lesser bone ll is probably attributable to the
complex furcation morphology and, hence, the limi-
tation for accessibility.
The possible errors in measuring the bone ll on
radiographs, such as those attributable to exposure
settings, geometric error (e.g., radiographic tech-
niques), and the development of lms, were mini-
mized. Another factor that may have caused an error
was the use of conventional lm rather than digital
images. However, Borg et al.
36
assessed the marginal
bone level around implants placed in dogs and found
no difference in accuracy and precision between
digital and conventional lms.
CONCLUSIONS
It canbeconcludedfromthecurrent studythat therewas
a greater decrease in gingival index and PD and more
RVAL and RHAL gain with signicant bone ll with
locally delivered SMV in patients with Class II furca-
tion defects. These observations may give a new
direction in the therapeutic management of furcation
defects, without any invasive procedures, thereby
causing less discomfort to the patients. However,
long-term, multicenter, longitudinal studies, using
different vehicles and concentrations of SMV, should
be performed to afrm the observations of our study.
ACKNOWLEDGMENTS
The authors thank Biocon Pharmaceutical, Bangalore,
India, for providinga gift sample of SMV. We also thank
Dr. B. G. Shivananda (Principal) and Mr. M. Nagraju
Patro (PhD student), Department of Pharmaceutics,
Al-Ameen College of Pharmacy, Bangalore, India, for
helping us in the preparation of SMV and placebo
gel. The authors report no conicts of interest related
to this study.
REFERENCES
1. Shimizu H, Nakagami H, Morita S, et al. New treatment
of periodontal diseases by using NF-kappaB decoy
oligodeoxynucleotides via prevention of bone resorp-
tion and promotion of wound healing. Antioxid Redox
Signal 2009;11:2065-2075.
2. Porciu ncula HF, da Porciu ncula MM, Zuza EP, de
Toledo BE. Biometric analysis of the maxillary perma-
nent molar teeth and its relation to furcation involve-
ment. Braz Oral Res 2004;18:187-191.
3. de los Rios CM, Pustiglioni FE, Romito GA. Biometric
study of the width, length and depth of the root trunk
groove of human lower second molars. Pesqui Odontol
Bras 2002;16:26-30.
4. Fleischer HC, Mellonig JT, Brayer WK, Gray JL, Barnett
JD. Scaling and root planing efcacy in multirooted
teeth. J Periodontol 1989;60:402-409.
5. Kalkwarf KL, Kaldahl WB, Patil KD. Evaluation of
furcation region response to periodontal therapy.
J Periodontol 1988;59:794-804.
Simvastatin As Local Drug Delivery for Treatment of Class II Furcation Defects Volume 83 Number 12
1478
6. Jadhav SB, Jain GK. Statins and osteoporosis: New
role for old drugs. J Pharm Pharmacol 2006;58:3-18.
7. Mundy G, Garrett R, Harris S, et al. Stimulation of bone
formation in vitro and in rodents by statins. Science
1999;286:1946-1949.
8. Stein D, Lee Y, Schmid MJ, et al. Local simvastatin
effects on mandibular bone growth and inamma-
tion. J Periodontol 2005;76:1861-1870.
9. Morris MS, Lee Y, Lavin MT, et al. Injectable simvastatin
in periodontal defects and alveolar ridges: Pilot studies.
J Periodontol 2008;79:1465-1473.
10. Nyan M, Sato D, Oda M, et al. Bone formation with the
combination of simvastatin and calcium sulfate in
critical-sized rat calvarial defect. J Pharmacol Sci
2007;104:384-386.
11. Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K,
Izumi Y. Simvastatin decreases IL-6 and IL-8 produc-
tion in epithelial cells. J Dent Res 2006;85:520-523.
12. Takenaka M, Hirade K, Tanabe K, et al. Simvastatin
stimulates VEGF release via p44/p42 MAP kinase in
vascular smooth muscle cells. Biochem Biophys Res
Commun 2003;301:198-203.
13. Pradeep AR, Thorat MS. Clinical effect of subgingivally
delivered simvastatin in the treatment of patients
with chronic periodontitis: a randomized clinical trial.
J Periodontol 2010;81:214-222.
14. Gilding DK, Reed AM. Biodegradable polymers for use
in surgery polyglycolic/polylactic acid homo- and co-
polymers 1. Polymer 1979;2:1459-1484.
15. Al-Kassas RS, El-Khatib MM. Ophthalmic controlled
release in situ gelling systems for ciprooxacin based
on polymeric carriers. Drug Deliv 2009;16:145-152.
16. Ravikumara NR, Madhusudhan B, Nagaraj TS, Hiremat
SR, Raina G. Preparation and evaluation of nimesulide-
loaded ethylcellulose and methylcellulose nanopar-
ticles and microparticles for oral delivery. J Biomater
Appl 2009;24:47-64.
17. Final report on the safety assessment of hydroxye-
thylcellulose, hydroxypropylcellulose, methylcellu-
lose, hydroxypropyl methylcellulose and cellulose
gum. Int J Toxicol 1986;5:1-59.
18. Hamp SE, Nyman S, Lindhe J. Periodontal treatment of
multirooted teeth. Results after 5 years. J Clin Perio-
dontol 1975;2:126-135.
19. Miller SC. Textbook of Periodontia. Philadelphia: Bla-
kiston Company; 1938:91.
20. Mombelli A, van Oosten MA, Schurch E, Lang NP. The
microbiota associated with successful or failing os-
seointegrated titanium implants. Oral Microbiol Immu-
nol 1987;2:145-151.
21. Silness J, Loe H. Periodontal disease in pregnancy. II.
Correlation between oral hygiene and periodontal
condition. Acta Odontol Scand 1964;22:121-135.
22. Francetti L, Trombelli L, Lombardo G, et al. Eval-
uation of efcacy of enamel matrix derivative in
the treatment of intrabony defects: A 24-month mul-
ticenter study. Int J Periodontics Restorative Dent
2005;25:461-473.
23. Thylin MR, McConnell JC, Schmid MJ, et al. Effects of
simvastatin gels on murine calvarial bone. J Periodon-
tol 2002;73:1141-1148.
24. Goodson JM, Hogan PE, Dunham SL. Clinical re-
sponses following periodontal treatment by local drug
delivery. J Periodontol 1985;56(Suppl. 11):81-87.
25. Needleman IG, Pandya NV, Smith SR, Foyle DM. The
role of antibiotics in the treatment of periodontitis (Part
2 Controlled drug delivery). Eur J Prosthodont Restor
Dent 1995;3:111-117.
26. Sotiriou CG, Cheng JW. Benecial effects of statins in
coronary artery disease Beyond lowering choles-
terol. Ann Pharmacother 2000;34:1432-1439.
27. Garlet GP, Martins WJr, Fonseca BA, Ferreira BR, Silva
JS. Matrix metalloproteinases, their physiological in-
hibitors and osteoclast factors are differentially regu-
lated by the cytokine prole in human periodontal
disease. J Clin Periodontol 2004;31:671-679.
28. Tobert JA. New developments in lipid-lowering ther-
apy: The role of inhibitors of hydroxymethylglutaryl-
coenzyme A reductase. Circulation 1987;76:534-538.
29. Song C, Guo Z, Ma Q, et al. Simvastatin induces
osteoblastic differentiation and inhibits adipocytic
differentiation in mouse bone marrow stromal
cells. Biochem Biophys Res Commun 2003;308:
458-462.
30. Baek KH, Lee WY, Oh KW, et al. The effect of
simvastatin on the proliferation and differentiation of
human bone marrow stromal cells. J Korean Med Sci
2005;20:438-444.
31. Junqueira JC, Mancini MN, Carvalho YR, Anbinder AL,
Balducci I, Rocha RF. Effects of simvastatin on bone
regeneration in the mandibles of ovariectomized rats
and on blood cholesterol levels. J Oral Sci 2002;44:
117-124.
32. Pytlik M, Janiec W, Misiarz-Myrta M, Guba1a I. Effects of
simvastatin on the development of osteopenia caused
by ovariectomy in rats. Pol J Pharmacol 2003;55:63-
71.
33. Tikiz C, Tikiz H, Taneli F, Gumusxer G, Tuzun C. Effects
of simvastatin on bone mineral density and remodeling
parameters in postmenopausal osteopenic subjects: 1-
year follow-up study. Clin Rheumatol 2005;24:447-
452.
34. Todd PA, Goa KL. Simvastatin. A review of its phar-
macological properties and therapeutic potential in
hypercholesterolaemia. Drugs 1990;40:583-607.
35. Alam S, Ueki K, Nakagawa K, et al. Statin-induced
bone morphogenetic protein (BMP) 2 expression dur-
ing bone regeneration: An immunohistochemical
study. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2009;107:22-29.
36. Borg E, Grondahl K, Persson LG, Grondahl HG.
Marginal bone level around implants assessed in
digital and lm radiographs: In vivo study in the dog.
Clin Implant Dent Relat Res 2000;2:10-17.
Correspondence: Dr. A. R. Pradeep, Department of Peri-
odontics, Government Dental College and Research In-
stitute, Bangalore 560002, Karnataka, India. E-mail:
periodonticsgdcri@gmail.com.
Submitted December 05, 2011; accepted for publication
January 26, 2012.
J Periodontol December 2012 Pradeep, Priyanka, Karla, Naik, Singh, Martande
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