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

From: The effects of statins on dental and oral health: a review of preclinical and clinical studies

Author, yearType of the studyTarget tissue/cellsSample sizeStatins/interventionDose per dayDuration of treatmentLocal or systemic delivery of statinsMain outcomes
Madi M et al. 2017 [116]Randomized controlled trial (RCT)Palatal donor site following free gingival graft (FGG)40Group 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.LocalTopical 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]RCTMaxillary third molars postextraction sockets13 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 monthsLocalPoly (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 studyTarget tissue (in vitro):Human dental pulp cells. In vivo animal study:The left and right first maxillary molars of male Wistar rats36 RatsPLGA–lovastatin nanoparticles on human dental pulp
Animal study:
1. PLGA–lovastatin nanoparticles
2. ProRoot MTA
3. no treatment
100 µg/mL for dental pulp capping2 to 4 weeksLocalPLGA–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 studyMaxillary right molar of male wistar rats36 Rats1. Atorvastatin
2. Saline solution
15 mg/kgFor 7, 14, or 21 daysSystemicStatin-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 studyRight side of rat’s mandibular22 rats1. 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 weeksLocalGroup 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 studyMouse bone marrow macrophages (BMMs) animal study: male ICR mice28 miceFluvastatin3 mg/kgOn 1,4 and 7 daysSystemicFluvastatin 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 studySaliva and submandibular gland tissues of mice96 MiceSolvent +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 week1 week prior to IR through to the end of the experimentSystemicIR 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 studyMaxillary second molar of wistar rats36 Rats0.9% saline, Atorvastatin(0.3, 3 or 27 mg/kg)11 daysSystemicATV 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 studyThe pulp tissues of the canine upper incisors immature premolars of male beagle dogs2 beagle dogs 18 immature premolarsMTA, Absorbable gelatin sponge, cDPSCs + absorbable gelatin sponge, SMV + cDPSCs + absorbable gelatin sponge1 mmol/L SIM for dental pulp capping10 weeksLocalSimvastatin 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]RCTSix anterior teeth of female orthodontic patients16 Patients1.2% Simvastatin gel, 0.9% sodium chloride as a placebo0.1 ml of 1.2% SMV gel1 dayLocalSpace 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 studyMaxillary first molars of wistar rats25 adult male Wistar ratsSimvastatin solution with 0.5% carboxymethyl cellulose 0.5% carboxymethyl cellulose5 mg/kg doseFrom the 19th day until the 38th day (20 days)SystemicSimvastatin 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 studyHuman gingival samples of patients with severe gingival overgrowth who were treated with phenytoin. Anterior maxillary and mandibular gingiva of rats28 RatsControl groups: physiological saline, vehicle (50% water, 41% propylene glycol, and 9% ethanol) treatment groups: Phenytoin, Phenytoin plus Lovastatin0.65 mg/kg12 weeksSystemicPhenytoin-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 studyFirst maxillary left molars of ratsThirty-six adult male Sprague–Dawley ratsNo medication, carboxymethyl cellulose (CMC), Atorvastatin in CMC5 mg/kg21 daysSystemicAccording 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 studyMandibular molars90Statin, no treatmentSystemicThe 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 studyNonsurgical root canal treatment- Apical periodontitis30: Statins 30: No StatinsSimvastatin, Atorvastatin, Pravastatin, Rosuvastati, LovastatinRegular dose (10, 20, 40, and 80 mg daily)2 to 5 yearsSystemicA 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 vitroHuman salivary adenoid cystic carcinoma (SACC)Simvastatin1) 10, 20, 30, 40, 50 and 60 μmol/l
2) microRNA-21 inhibitor (miR-21i) + 25.37 μM simvastatin
48 hLocalIn 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 vitroHuman salivary adenoid cystic carcinoma cell line (SACC)Simvastatin10, 20, 30, 40 and 50 μmol/l24 to 48 hLocalSimvastatin 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 studyMaxilla and femur bone24 ratsAtorvastatin15 mg/kg14 daysSystemicAtorvastatin 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 studyMandibular quadrant10 RabbitsSimvastatin0.5 mg per 480 μl of solution21 daysLocalThere 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 trailDental sockets20 dental socketsSimvastatin20 mg2 monthsLocalA 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 studyThe right mandibular incisors of rats48 male ratsFluvastatin hydroxyapatit, hydroxyapatite plus Fluvastatin, carbonate apatite, or carbonate apatite plus Fluvastatin0.5 mg4 weeksLocalHighest 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 dogSimvastatinhydroxyapatite–collagen grafts +10-mg SMV (0.5 mg/kg) was placed. One week later, three weekly2 month (1 + 3 injection) euthanized 2 months after the final injections.Locally injectedLocally 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 vivoRhoC 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 tissueCell 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:SimvastatinGroup 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, respectively7.41 monthLocalStatins 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 (ATVOral gavage either saline or ATV (1, 3 and 9 mg/kg)11 daysSystemic oral gavageATV 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 ratsSimvastatinSimvastatin 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 weeksSystemi injectionsResults 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 ratsSimvastatinIn 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. 2008In vitro & Animal study 
Moriyama et al. 2008 [93] Animal study60 Ten-week-old female ratsFluvastatin. Propylene glycol alginate (PGA) was used as a carrierImplant-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 weeksTopicalHistomorphometrical 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 ratsSimvastatinCyclosporine A (10 mg/kg/day), Simvastatin (20 mg/kg/day), Cyclosporine A and Simvastatin concurrently (Cyclosporine A/Simvastatin) or vehicle for 30 days.30 daysOral daily doses (once a day) SimvastatinThe 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 ratsSimvastatin10 mg/kg of simvastatin daily.30 daysIntra peritoneallySimvastatin increases the value of both bone contact ratio to the implant and bone density around the implant