Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 205209

Contents lists available at ScienceDirect

Journal of Oral and Maxillofacial Surgery,

Medicine, and Pathology
journal homepage: www.elsevier.com/locate/jomsmp

Oral and Maxillofacial Surgery/Review article

Simvastatin, dosage and delivery system for supporting bone

regeneration, an update review
Mouetaz Kheirallah a, , Hassan Almeshaly b
a
b

Maxillofacial Surgery Department, College of Dentistry, Alanadalos University for Medical Sciences, Al-Qadmous, Syria
College of Dental Medicine, Majmaah University, Saudi Arabia

a r t i c l e

i n f o

Article history:
Received 19 June 2015
Received in revised form 20 August 2015
Accepted 13 October 2015
Available online 2 December 2015
Keywords:
Simvastatin
Bone regeneration
Topical administration
Controlled-release delivery system

a b s t r a c t
Objective: The purpose of this review is to discuss the dosage, duration and carrier for simvastatin, and
to summarize effects of topical application directly or indirectly for stimulating bone regeneration.
Methods: We have searched in Pubmed using keywords, simvastatin, dose response, bone regeneration,
controlled-release delivery system. This search was complemented with a manual search of the relevant articles cited among the selected papers. The search was among the articles written in English and
published in the last 10 years. The articles were revised in depth, and summarized.
Results: High dose of simvastatin increases bone formation and resorption, while low dose of simvastatin
decreases bone formation and increases bone resorption, furthermore it is reported that high dose of
systemic administration of simvastatin will raise the risk of liver failure, kidney disease, and other side
effects. Local administration can bypass hepatic degradation of statins to achieve therapeutic concentrations in bone and avoid the systemic side effects. The choice of appropriate carrier will depend on the
release kinetics determined to be the best for osteogenesis.
Conclusion: Local delivery of simvastatin from carriers appears to be an attractive solution to the problem
of maintaining therapeutic doses to treat severe bone defects and to minimize the undesired side effects.
Locally delivered simvastatin can increase the bone formation and accelerate healing process of bony
defect. Another advantage of local delivery system is that it can stimulate new bone formation in a
dose-dependent manner. Further evidence-based studies will be required to determine local delivery
concentrations to promote bone regeneration.
2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.

Contents
1.
2.
3.
4.
5.
6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Mechanism of action of simvastatin on bone regeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .206
The effect of statins on osseointegration and periodontitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Dosage and duration of simvastatin for bone regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Controlled-release delivery system of simvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology;
JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants.
Corresponding author at: Maxillofacial Surgery Department, College of Dentistry, Alanadalos University for Medical Sciences, Al-Qadmous, Syria. Tel.: +963 43 657600;
fax: +963 43 656174.
E-mail addresses: m.kheirallah@mu.edu.sa, moutazkheirallah@gmail.com (M. Kheirallah).
http://dx.doi.org/10.1016/j.ajoms.2015.10.005
2212-5558/ 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.

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M. Kheirallah, H. Almeshaly / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 205209

1. Introduction
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase
inhibitors are synthetic statins [1]. Simvastatin is lipophilic statin
derived from fungal metabolites and have elimination half-live of
13 h. Lipophilic statins are more susceptible to metabolism by the
cytochrome P (450) system. Pravastatin and rosuvastatin are relatively hydrophilic and not signicantly metabolized by cytochrome
P (450) enzymes. The chemical structure of simvastatin governs its
water solubility, which in turn inuence its absorption, distribution, metabolism, and excretion. It is not well absorbed, and less
than 5% of an oral dose reaches the systemic circulation [2].
Acquired bone defects from simple tooth extractions to tumor
resections appear daily in our practices and present difcult reconstructive treatment plans. The gold standard in treatment of bone
defect is autogenous bone graft, but it is associated with limited
availability. Osteoinduction is the stimulation of osteoprogenitor cells to differentiate into osteoblasts that then begin new
bone formation. A bone graft material that is osteoconductive and
osteoinductive will not only serve as a scaffold for currently existing
osteoblasts but will also trigger the formation of new osteoblasts,
theoretically promoting faster integration of the graft. However,
many alloplastic reconstructive materials are present but associated with limited osteoinductive and osteoconductive properties.
Osteoconduction occurs when the bone graft material serves as a
scaffold for new bone growth that is perpetuated by the native bone
to guide the tissue regeneration. The material will also partially
be replaced by newly formed cells. Alloplastic bone substitutes
have been combined with several compounds to support osteoconductive and osteoinductive properties. In light of this, different
molecules are used for the efcient induction of bone formation.
Simvastatin is a compound widely prescribed for treatment of
hypercholesterolemia because it prevents the synthesis of cholesterol, it can also elicit some pleiotropic effects, leading to the
modulation of the process of bone regeneration at the molecular
and cellular levels [3]. Simvastatin seems to play an important role
in bone regeneration by participating directly in osteoblast activation (increasing BMP-2 expression) and in osteoclast inhibition
[4], also indirectly, by stimulating neovascularization (increasing
the secretion of vascular endothelial growth factor) [5]. Concentrations of statins in bone marrow have not been well established yet,
but osteoblasts and osteoclasts may be exposed to very low concentrations of simvastatin [6]. The aim of this review is to discuss
the dosage and carrier for simvastatin, and to summarize effects
of topical application directly or indirectly for stimulating bone
regeneration.

2. Mechanism of action of simvastatin on bone

regeneration
Mechanism of action involves reduction in mevalonate pathway
intermediates and inhibition of prenylation by statins is responsible for a large proportion of the pleiotropic effects of these drugs.
Mevalonate, farnesyl pyrophosphate and geranyl pyrophosphate
all inhibited statin stimulated bone formation [7]. Simvastatin,
mevastatin and atorvastatin are activators of bone morphogenetic
protein (BMP2) which accounts for major osteoinductive potential
of bone [8]. Furthermore, because geranyl pyrophosphate inhibited
statin stimulated bone formation, inhibition of prenylation due
to geranyl geranylation must play a major role in the stimulation of bone formation by these drugs [9]. Also, statins inuence
the production of receptor activator of nuclear factor kappa-B
ligand (RANKL) and osteoprotegrin by human gingival broblasts to favor bone catabolism under non-inammatory conditions
[10].

3. The effect of statins on osseointegration and

periodontitis
Topical application of statin affects bone healing around
implants [11]. According to Takeshita et al. a meshlike woven
bone structure was predominantly formed around the implant
5 days after implantation, and then diminished gradually [12].
Also Ayukawa et al. showed that simvastatin promotes osteogenesis around titanium implants. Under the administration of
statin, a similar meshlike structure of bone was seen around the
implant even at 30 days after the implantation which resulted in
an improved implant xation and that the bone network can successfully disperse the stress applied to the implant [13]. Fajardo
et al. applied (20 mg/day) of Atorvastatin for 3 months. The results
of this study suggest that atorvastatin might have benecial effects
in periodontal diseases with bone alveolar loss and tooth mobility
[14].

4. Dosage and duration of simvastatin for bone

regeneration
The conicting results of animal and clinical studies suggest that
orally administered statins may be degraded in the liver, so little
of the drug is available to accumulate in bone [15]. It is reported
that high dose of systemic applied simvastatin will raise the risk
of liver failure, kidney disease, rhabdomyolysis, myalgia and other
side effects [16]. For that, caution should be exercised regarding
the dosing of the simvastatin, since several authors have reported a
dose-dependent inammatory response [17]. Several studies have
shown that the dose of simvastatin modulates the ability of the
drug to increase bone volume [1821]. Dose response of simvastatin, administered orally, for bone formation and resorption are
different. Study of Ho et al. showed that simvastatin (20 mg/kg/day)
enhances bone formation by increasing osteoblast numbers and
osteogenic protein expression in ovariectomized rats [22]. Contradictory results about the effect of simvastatin on bone formation
have also been reported in literature [23,24]. High dose of simvastatin (20 mg/kg/day) increases bone formation and resorption,
while low dose (1 mg/kg/day) of simvastatin decreases bone formation and increases bone resorption [23]. Oxlund et al. reported
that (20 mg/kg/day) of simvastatin orally twice daily for 3 months
reduced loss of cancellous bone caused by ovariectomy [25]. Also
Mousavil et al. reported that a daily dose of 1020 mg/kg/day
for 45 days of Pravastatin orally increases bone formation and
accelerate healing process of bone defect [26]; as well as, Mundy
et al. concluded that simvastatin increased trabecular bone volume among ovariectomized rats when given simvastatin at a daily
dose of 510 mg/kg for 35 days [8], while Maritz et al. reported
that (1 mg/kg/day) for 12 weeks decreased bone mineral density
[23]. In one clinical study, simvastatin (40 mg/day) for one year
signicantly increased bone mineral density at the lumbar spine
and femoral neck [27]. Therewith dose optimization may help in
increasing the bioavailability and distribution of statins to the bone
microenvironment [28]. Wang et al. considered a 10 mg/kg/day
dose to rats about equivalent to 70 mg/day for humans, taking
into account that metabolic process in rodents is 10 times faster
than in humans [29]. So a dose of 10 mg/kg/day is higher than the
routine dose in clinical applications (2040 mg/day) and dosages
tested on rats, when adjusted for humans, were sometimes much
higher than the standard dose in patients. However, it was reported
that even the injection of 1.5 mg/kg/week compares favorably with
7 mg/kg/week in human oral regimens [2]. Pasco et al. also in
casecontrol study reported a 60% reduction in fracture risk in
patients treated with statins [30]. Furthermore no dramatic change
in bone mineral density was found in a one-year prospective

M. Kheirallah, H. Almeshaly / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 205209

clinical study of treatment with simvastatin (20 mg/day) conducted

by Tikiz et al. [31].
The most critical aspect of a local drug delivery system is the
method by which the active ingredient is made available at the
site of action. Local administration can bypass hepatic degradation of statins to achieve therapeutic concentrations in bone and
avoid the side effects caused by its systemic administration. According to Pradeep et al. for humans the topical dose of simvastatin
did not produce any complications or adverse reactions [32,33]. In
animal studies, a (0.10.5 mg) dose of simvastatin would be the
optimal dose for stimulating maximum bone regeneration without inducing inammation [34]. Simvastatin possesses topical and
systemic anti-inammatory properties, but this property alters at
high dose local applications. It has been shown that local application of approximately 70 mg/kg causes inammation and scabbing
of the overlying skin. Thylin et al. and Stein et al. reported that local
application of simvastatin (2.2 mg) caused inammation in soft tissue in a rat calvarial bone defect and in mandible bone [35,36], also
Basarir et al. concluded that 50 mg/kg/day subcutaneous injection
of simvastatin has the potential to enhance osseointegration in a
rabbit arthroplasty model [37], while Wang et al. applied locally
510 mg/kg/day of simvastatin into the fracture region to support
bone healing [38]. Subcutaneous injection of local dose of simvastatin of 0.1 mg/kg/day has no signicant effect on bone formation,
suggesting that circulating simvastatin levels might peak and then
decrease rapidly [39].
Several studies have used local delivery of statins to increase
bone healing and reported that statins have local benecial effects
[40,41] (Table 1). Nyan et al. reported that local administration of
simvastatin (1 mg) in combination with alphatricalcium phosphate
delayed bone union [42]. From this study, it can be concluded that,
delayed bone union was caused by a high dose or burst release of
the locally applied statin. This study shows that daily release of simvastatin in the range of 0.020.53 g/day enhances bone healing
in vivo and does not cause an obvious inammatory response.

5. Controlled-release delivery system of simvastatin

It is known that the absorption of the oral doses of statins is
between 40% and 75% [43], and systemic administration of statins
can result in serious side effects [44,45]. Alternative administration
by local delivery, may bypass the liver, and provide better effects of
simvastatin on bone. Depending on the drug-release mechanism,

207

the delivery system can be categorized into three major classes

[46]: (a) diffusion controlled release. The drug is incorporated into
a degradable matrix and the release kinetics is only dependent
on the physical diffusion through the matrix. (b) Chemical process controlled release. The drug is incorporated into a degradable
matrix and the release kinetics is connected to the degradation of
the matrix. (c) Externally or electronically controlled release. The
drug release is triggered by external factors. Hydrogels (collagen,
gelatin, poly ethylene glycol) are able to swell with water, making it
easier to load with drugs [47,48]. Polymers have an advantage over
calcium phosphate materials because they can chemically bind to
statins and thus provide a slow release [49]. The choice of appropriate carrier will depend on the release kinetics determined to
be the best for osteogenesis. Generally hydrogels release high concentrations of drug for shorter duration, while polymers have a
more tunable release form. Simvastatin loaded into calcium sulfate
cement has shown to increase bone regeneration in a rat calvarial defect at eight weeks compared to non-simvastatin treated rats,
despite the induction of a robust inammatory response [42]. Associated, Simvastatin loaded into calcium phosphate cements has
shown to enhance the osteogenic potential and degradation rates
[50,51]. Stein et al. have combined hydrogel and poly lactic acid,
and investigated dose response by local delivery of simvastatin to
the lateral aspect of the rat mandible; they have reported that a
low dose applied locally could achieve bone growth while avoiding the inammation that occurs with administration of high doses
[36]. Benoit et al. have used hydrogel releasing uvastatin via lactic
acid linkages into a poly ethylene glycol [52]. This delivery system
allowed to control the dose 5500 g of uvastatin/gel.
The choice of appropriate scaffold will depend on the release
kinetics determined to be the best for osteogenesis, with hydrogels
generally releasing high concentrations of drug for shorter duration and polymers having a more tunable release prole. Monjo
et al. investigated the absorbable collagen sponge (ACS) as a carrier
for rosuvastatin to enhance bone formation in critical size cortical
bone defects adjacent to titanium implants with different concentrations [53]. This study reported that the typical burst release
pattern of rosuvastatin (water-soluble) from an absorbable collagen sponge was, with 82% of loaded drug released during 24 h. For
further optimization of dosage and to rene the use of statins for
bone regeneration, Jeon et al. developed a cellulose acetate phthalate/Pluronic F127 sintered-microparticle multi-layered construct
for alternating release of parathyroid hormone (PTH) and simvastatin [54]. Rojbani et al. have evaluated the osteoconductivity of

Table 1
Different studies to explore the benecial effects of simvastatin and doses required.
Delivery system

Dosage

Duration

Results

Author/year

Local delivery of
controlled-release

1 mg in matrix PDLLA-PLGA
microsphere

310 days

Chang et al. [60], 2014

Local delivery of
controlled-release
Local injection
Local delivery of
controlled-release
Local delivery of
controlled-release
Oral (Pravastatin)

0.5 mg in calcium sulfate

scaffold
10 mg/kg/day
13 mg/ml GPT hydrogels

1421 days

Both PDGF and simvastatin

facilitate dentoalveolar
regeneration
Induce osteogenic differentiation

Kocer et al. [62], 2014

Park et al. [61], 2013

0.62.4 mM from titanium

dioxide (TiO2 ) scaffolds
1020 mg/kg/day

19 days

Subcutaneous
Intraperitoneal

50 mg/kg/day
10 mg/kg/day

6 weeks
30 days

Oral

20 mg/kg/day

Oral

1 mg/kg/day

Twice daily
for 3
months
12 weeks

Potential effects on fracture healing

Achievement osteogenic
differentiation
Increased secretion of VEGFA and
OC from osteoblasts
Increase bone formation and
accelerate healing process of bone
defect
Enhanced bone ingrowth
Increased bone density and bone
contact ratio
Reduced loss of cancellous bone
caused by ovariectomy
Decreased bone mineral density

Maritz et al. [23], 2001

1 week
14 days

45 days

Huang et al. [18], 2014

Pullisaar et al. [20], 2013

Mousavil et al. [26], 2013

Basarr et al. [37], 2009

Ayukawa et al. [13], 2004
Oxlund et al. [25], 2004

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M. Kheirallah, H. Almeshaly / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 205209

hydroxyapatite with or without simvastatin, they concluded that

the slow degradation rate limits the bone-forming potential [50].
Poly lactic-co-glycolic acid (PLGA) and poly lactic acid are common synthetic polymer carriers for statins, either as micro particles
or a membrane [15,55,56]. Pauly et al. utilized simvastatin-loaded
poly lactic acid to coat Kirschner wires for stabilization of closed rat
tibial fractures and found comparable healing with application of
simvastatin-coated wires compared to rhBMP-2-coated wires [57].
For load-bearing applications, stronger and slower degrading polymers could potentially be used, such as polypropylene fumarate
(PPF) [58]. These polymers can be made porous to facilitate loading with drug-loaded micro particles so that the construct acts
as a scaffold for bone growth while releasing osteogenic factors
for recruited stem cells. Simvastatin loaded electrospun poly caprolactone has also been investigated for regeneration of cranial
defects [59]. In this study, scaffolds that displayed a burst release
of simvastatin did not increase bone regeneration, but scaffolds
with sustained release had signicantly increased bone regeneration over both untreated controls and burst released statin-loaded
scaffolds.
6. Conclusion
In conclusion, local delivery of simvastatin from carriers appears
to be an attractive solution to the problem of maintaining therapeutic doses to treat severe bone defects and to minimize undesired
side effects. It was evident from this review that simvastatin can
increase the bone formation and accelerate healing process of
defect. As well as that systemic delivery of simvastatin at current
therapeutic doses has shown conicting results. In addition stimulated new bone formation in a dose-dependent manner. Further
studies will be required to determine local delivery concentrations
to promote bone regeneration.
Conict of interest
There were no nancial and personal relationship with other
people or organization that could inappropriately inuence our
work.
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