Table 2 The effect of statins on dental and oral diseases based on clinical and preclinical studies

Madi M et al. 2017 [116]

Randomized controlled trial (RCT)

Palatal donor site following free gingival graft (FGG)

40

Group I: Simvastatin suspension (S) group II: simvastatin/chitosan gel (SC) group III: chitosan gel (C) group IV: petroleum gel (P)

1 mL of the gel or the suspension (final concentration of simvastatin is 10 mg/ml) three times/day.

7 days post-operatively.

Local

Topical application of S/C gel could be used as a novel therapeutic modality that improved healing and reduced pain in the palatal donor site following FGG procedure

Noronha Oliveira M et al. 2017 [66]

RCT

Maxillary third molars postextraction sockets

13 patients(26 sockets)

1. Poly (d, l-Lactide-co-glycolide)/hydroxyapatite/b-TCP (PLGA/HA/b-TCP) with 2.0% simvas-tatin scaffold(PLGA/HA/S)

2. Deproteinized bovine bone min-eral with 10% collagen at the bone crest level (DBBM-C)

3. Poly (d, l-Lactide-co-glycolide)/hydroxyapatite/b-TCP (PLGA/HA/b-TCP)

4.No treatment group

–

3 months

Local

Poly (d, l-lactide-co-glycolide) with hydroxyapatite/b-TCP (PLGA/HA/b-TCP) scaffolds, with and without simvastatin, failed to obtain the initial expected results and presented more complications. Scaf- folds with simvastatin showed to be superior, with less clinical complications than scaffolds without simvastatin

Lin HP et al. 2017 [35]

In vitro + in vivo animal study

Target tissue (in vitro):Human dental pulp cells. In vivo animal study:The left and right first maxillary molars of male Wistar rats

36 Rats

PLGA–lovastatin nanoparticles on human dental pulp

Animal study:

1. PLGA–lovastatin nanoparticles

2. ProRoot MTA

3. no treatment

100 µg/mL for dental pulp capping

2 to 4 weeks

Local

PLGA–lovastatin nanoparticles showed an effective controlled release to the 44th day. The nanoparticles exhibited good biocompatibility and superior osteogenic and odontogenic potential to dental pulp cells. They also promoted the fo mation of tubular reparative dentin and a complete dentinal bridge at the pulp exposure site in rat teeth. Therefore, this local delivery device could be used as an adjunctive treatment in direct pulp capping

Dolci GS et al. 2016 [109]

Animal study

Maxillary right molar of male wistar rats

36 Rats

1. Atorvastatin

2. Saline solution

15 mg/kg

For 7, 14, or 21 days

Systemic

Statin-induced OPG overexpression reduces relapse after orthodontic tooth movement, in a phenomenon correlated with decreased osteoclast counts. This phenomenon sheds light on OPG as a molecular target that modulates maxillary bone metabolism and orthodontic relapse

Türer A et al. 2016 [118]

Animal study

Right side of rat’s mandibular

22 rats

1. absorbable collogen sponge with saline solution containing 1 mg RSV (14 and 28 days)

2. Sterile saline treated absorbable collogen sponge(14 and 28 days)

–

2 to 4 weeks

Local

Group R-14 had significantly more new bone at 2 weeks compared with group C-14. Connective tissue volumes were also significantly higher in R-14. New bone and connective tissue volume differences were not statistically significant between groups C-28 and R-28. Locally administered RSV enhances early bone regeneration on mandibular fracture in rats

Pokhrel NK et al. 2017 [76]

In vitro and in vivo animal study

Mouse bone marrow macrophages (BMMs) animal study: male ICR mice

28 mice

Fluvastatin

3 mg/kg

On 1,4 and 7 days

Systemic

Fluvastatin significantly inhibited both RANKL- and LPS-induced osteoclast differentiation in mouse BMMs. Fluvastatin also markedly reduced the expression of osteoclast differentiation marker genes as well as fusion markers. Fluvastatin reduced the generation of reactive oxygen species (ROS) upon the addition of RANKL and LPS, suggesting an anti-oxidant role. Finally, the administration of fluvastatin in mice conspicuously reduced P. gingivalis LPS-induced osteoclastogenesis and alveolar bone erosion in vivo

Xu L et al. 2016 [122]

Animal study

Saliva and submandibular gland tissues of mice

96 Mice

Solvent +sham irradiation (IR) (Group I), Simvastatin +sham IR (Group II), R +solvent (Group III), and IR + Simvastatin (Group IV).

10 mg/kg three times per week

1 week prior to IR through to the end of the experiment

Systemic

IR caused a significant reduction of salivary secretion and amylase activity but elevation of malondialdehyde. SMV remitted the reduction of saliva secretion and restored salivary amylase activity. The protective benefits of SMV may be attributed to scavenging malondialde-hyde, remitting collagen deposition, and reducing and delaying the elevation of transforming growth factor 1 expression induced by radiation

Goes P et al. 2016 [73]

Animal study

Maxillary second molar of wistar rats

36 Rats

0.9% saline, Atorvastatin

(0.3, 3 or 27 mg/kg)

11 days

Systemic

ATV 27 mg/kg prevented alveolar bone loss and cemental resorption, and inflammatory cell infiltration induced by ligature. ATV showed a protecting effect in the ligature-induced periodontitis, without affecting system parameters, by inhibition of inflammatory process and by its anabolic activity on the alveolar bone

Jia W et al.2016 [34]

Animal study

The pulp tissues of the canine upper incisors immature premolars of male beagle dogs

2 beagle dogs 18 immature premolars

MTA, Absorbable gelatin sponge, cDPSCs + absorbable gelatin sponge, SMV + cDPSCs + absorbable gelatin sponge

1 mmol/L SIM for dental pulp capping

10 weeks

Local

Simvastatin stimulates cDPSCs mineralization both in vivo and in vitro. It also promotes DPSC-induced pulp and dentin regeneration after pulpotomy

Jahanbin A et al. 2016 [111]

RCT

Six anterior teeth of female orthodontic patients

16 Patients

1.2% Simvastatin gel, 0.9% sodium chloride as a placebo

0.1 ml of 1.2% SMV gel

1 day

Local

Space re-opening was reduced in patients receiving Simvastatin Moreover, GI reduction was significantly greater in Sim- vastatin group compared to the control group. Simvastatin may decrease space re-opening after orthodontic space closure in human anterior teeth

Vieira GM et al. 2015 [113]

Animal study

Maxillary first molars of wistar rats

25 adult male Wistar rats

Simvastatin solution with 0.5% carboxymethyl cellulose 0.5% carboxymethyl cellulose

5 mg/kg dose

From the 19th day until the 38th day (20 days)

Systemic

Simvastatin did not inhibit the relapse of tooth movement in rats, and there was no correlation between bone density and orthodontic relapse

Assaggaf MA et al. 2015 [135]

Animal study

Human gingival samples of patients with severe gingival overgrowth who were treated with phenytoin. Anterior maxillary and mandibular gingiva of rats

28 Rats

Control groups: physiological saline, vehicle (50% water, 41% propylene glycol, and 9% ethanol) treatment groups: Phenytoin, Phenytoin plus Lovastatin

0.65 mg/kg

12 weeks

Systemic

Phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that lovastatin normalizes the tissue morphology and the expression of the molecular markers. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required

MirHashemi AH et al. 2013 [112]

Animal study

First maxillary left molars of rats

Thirty-six adult male Sprague–Dawley rats

No medication, carboxymethyl cellulose (CMC), Atorvastatin in CMC

5 mg/kg

21 days

Systemic

According to the results obtained in the current study, atorvastatin appears to reduce tooth movement in rats; however its effect on osteoclasts, especially osteoclastic function, requires further investigation

Pettiette MT et al. 2013 [36]

Retrospective case–control study

Mandibular molars

90

Statin, no treatment

–

–

Systemic

The significant increase of calcification and loss of vertical height of the pulp chamber observed in mandib- ular molars in patients on statin medication indicated a possible increased odontoblastic activity. Therefore, systemic statins could be a contributing factor for pulp chamber calcification

Alghofaily M et al. 2018 [104]

Cohort study

Nonsurgical root canal treatment- Apical periodontitis

30: Statins 30: No Statins

Simvastatin, Atorvastatin, Pravastatin, Rosuvastati, Lovastatin

Regular dose (10, 20, 40, and 80 mg daily)

2 to 5 years

Systemic

A significant higher healing was observed in patients who used Statins (93%) for 2 years or greater in comparison to the patients who never took statins (70%)

Wang C et al. 2018 [125]

In vitro

Human salivary adenoid cystic carcinoma (SACC)

–

Simvastatin

1) 10, 20, 30, 40, 50 and 60 μmol/l

2) microRNA-21 inhibitor (miR-21i) + 25.37 μM simvastatin

48 h

Local

In a dose-dependent manner, simvastatin dramatically inhibited the salivary adenoid cystic carcinoma (SACC-LM) cell proliferation. Resistance of SACC-LM to simvastatin was reduced by miR-21i, which lead to SACC-LM acquisition of epithelial traits, reduction in cell migration and invasion, inhibition of growth and stimulation of apoptosis

Cai WY et al. 2018 [123]

In vitro

Human salivary adenoid cystic carcinoma cell line (SACC)

–

Simvastatin

10, 20, 30, 40 and 50 μmol/l

24 to 48 h

Local

Simvastatin therapy significantly inhibited the proliferation of SACC‑83 cells, increased the percentage of cells in early and late apoptosis, inhibited the invasiveness of SACC-83 cells and downregulated the expression of survivin in SACC‑83 cells compared with untreated cells

Dolci GS et al. 2018 [108]

Animal study

Maxilla and femur bone

24 rats

Atorvastatin

15 mg/kg

14 days

Systemic

Atorvastatin significantly reduced OTM and osteoclast counts while it did not effect on the overall bone-volume ratio compared with saline (control group). Long-term statin administration had no effect on femoral endochondral ossification

AlSwafeeri H et al. 2018 [107]

Animal study

Mandibular quadrant

10 Rabbits

Simvastatin

0.5 mg per 480 μl of solution

21 days

Local

There were no significant differences in relapse magnitude and the relapse percentage between quadrant received Simvastatin and the other quadrants. A significant reduction in the area of active bone-resorptive lacunae and a significant increase in newly formed bone area were found in respond to the local Simvastatin administration

Sezavar M et al. 2018 [68]

Clinical trail

Dental sockets

20 dental sockets

Simvastatin

20 mg

2 months

Local

A non-significant higher percentages of vital bone, amorphous, trabecular bone and lower percentages of dead bone and nonosteoblastic was observed in Simvastatin group compared with control group

Rakhmatia YD et al. 2018 [67]

Animal study

The right mandibular incisors of rats

48 male rats

Fluvastatin hydroxyapatit, hydroxyapatite plus Fluvastatin, carbonate apatite, or carbonate apatite plus Fluvastatin

0.5 mg

4 weeks

Local

Highest bone volume, trabecular thickness, trabecular separation, and bone mineral density was observed in the Carbonate apatite plus Fluvastatin group, compared with the other intervention and control groups

Medeiros C.A et al. 2010 [136]

Animal study

Atorvastatin (ATV)

ATV 1, 5 or 10 mg/kg or vehicle (saline and 5% (vol/vol) ethanol)

Rutledge J et al. 2011 [117]

Animal study (split-mouth design)

4 dog

Simvastatin

hydroxyapatite–collagen grafts +10-mg SMV (0.5 mg/kg) was placed. One week later, three weekly

2 month (1 + 3 injection) euthanized 2 months after the final injections.

Locally injected

Locally injected SMV has the ability to induce modest amounts of new bone formation in closed injection sites over a periosteal surface. buccal bone in the dehiscence defects lacking periosteum was not augmented in the SMV group

Islam M et al.2013 [37]

In vitro and in vivo

RhoC function and HNSCC metastasis

Different concentrations of Atorvastatin

The width of the scratch was measured at 0 h and after 24 h to calculate the percentage of the gap covered by the cells in this time period

RhoC [GTP] expression is greatly reduced in Atorvastatin treated head and neck squamous cell carcinoma cell lines

Varalakshmi PR et al.2013 [106]

In vitro Extracted third molar pulp tissue

Cell proliferation, cell adherence on a dent in disc, alkaline phosphatase (ALP) activity, expression of osteogenic/odontoblastic markers, and mineralization of the human dental pulp cells on experimental cement and MTA were assesed.

Simvastatin and Atorvastatin

7 and 14 day

The results suggest that a-TCP can be used for local delivery of statin as a pulp capping material to accelerate reparative dentin formation

Goes P,et al. 2014 [74]

In vivo

78 Wistar rats: Saline group— ALD groups— ATV groups- ALD +ATV groups (low doses (ALD 0.01 mg/kg + ATV 0.3 mg/kg); high/low or low/high doses (ALD 0.25 mg/kg + ATV 0.3 mg/kg and ALD 0.01 mg/kg + ATV 27 mg/kg, respectively); or high doses (ALD 0.25 mg/kg + ATV 27 mg/kg).)

Atorvastatin (ATV) Alendronate (ALD)

The rats were killed on day 11 after ligature placement

In summary, rats subjected to periodontitis and treated with the lower-dose combination of ALD and ATV (0.01 mg/kg + 0.3 mg/kg, respectively) administered prophylactically or therapeutically, showed a reduction of periodontal inflammation and alveolar bone loss without important systemic changes

Asl Aminabadi N et al. 2012 [105]

RCT

120 Primary molar teeth:

Simvastatin

Group Ι as a control, underwent DPC with calcium hydroxide. The dental pulp in group II, III and IV were directly capped with Simvastatin-based materials at concentrations of 1, 5 and 10 μM, respectively

7.41 month

Local

Statins are not recommended as an alternative for calcium hydroxide as a DPC agent

Goes P et al. 2010 [72]

Animal study

24 male Wistar rats (± 200 g)

Atorvastatin (ATV

Oral gavage either saline or ATV (1, 3 and 9 mg/kg)

11 days

Systemic oral gavage

ATV was able to prevent alveolar bone loss seen on a ligature-induced periodontitis model

Han G et al. 2010 [110]

Animal study

Thirty-two adult male Wistar rats

Simvastatin

Simvastatin at a dose of 2.5 mg per kilogram per day for 4 weeks, and animals in the control group received 0.9% sodium chloride.

4 weeks

Systemi injections

Results indicate that simvastatin inhibits the bone-resorbing activity of osteoclasts while stimulating bone formation, probably by controlling the ratio of local osteoprotegerin to RANKL in the periodontal tissues. Therefore, it might be useful for retention

Seto H et al. 2008 [77]

In vitro & Animal study

15 rats

Simvastatin

In vitro: Different concentrations of simvastatins (1.0, 3.0 and 5.0 µM; were added to the medium and the cells were cultured for 28 d. Experiments were repeated at least three times using triplicate rat calvaria cell cultures. In vivo: Fifty microlitres of phosphate-buffered saline, alone, or containing 0.2 mg of simvastatin, was injected into the subperiosteum at the buccal area of the maxillary second molar twice a week for 70 d.

Seto H et al. 2008

In vitro & Animal study

Moriyama et al. 2008 [93]

Animal study

60 Ten-week-old female rats

Fluvastatin. Propylene glycol alginate (PGA) was used as a carrier

Implant-only group, implant with PGA group, low-dose roup [implant‏PGA containing 3 mg of fluvastatin (FS)], medium-dose group (15 mg of FS), and high-dose group (75 mg of FS).

1 and 2 weeks

Topical

Histomorphometrical and mechanical evaluations revealed the positive effect of topically applied fluvastatin on the bone around the implant

Nassar et al. 2009 [75]

Animal study

Eighty male Holtzman rats

Simvastatin

Cyclosporine A (10 mg/kg/day), Simvastatin (20 mg/kg/day), Cyclosporine A and Simvastatin concurrently (Cyclosporine A/Simvastatin) or vehicle for 30 days.

30 days

Oral daily doses (once a day) Simvastatin

The result shows that simvastatin therapy leads to a reversal of the cyclosporine A-induced bone loss, which may be mediated by downregulation of interleukin-1b and prostaglandin E2 production

Ayukawa et al. 2004 [95]

Animal study

Ten rats

Simvastatin

10 mg/kg of simvastatin daily.

30 days

Intra peritoneally

Simvastatin increases the value of both bone contact ratio to the implant and bone density around the implant