Periodontology 2000 – Willey

2.1 | Biological mechanism

Although the biomolecular mechanisms are still not well understood, it seems that the local and systemic effects of nicotine and other tobacco components may compromise bone metabolism at the bone/implant interface and jeopardize the maintenance of stable osseointegration. Several animal and in-vitro studies indicated that nicotine can inhibit the proliferation of fibroblasts and their production of fibronectin and collagen.5–9 Other studies reported that tobacco products can modulate bone turnover by increasing the production of MMP-1,2,3 in osteoblasts and, consequently, favoring the bone resorption processes.10,11 Based on current experimental evidence, an amplification of oxidative stress in periodontal and peri-implant tissues, an increase in the production of IL-6, IL-8, PGE2, and AGEs by gingival fibroblasts, and an impairment of the function of polymorphonuclear neutrophils could justify the mechanisms underlying the onset of biological complications around implants.12

2.2 | Clinical evidence

The effects of smoking constantly seem to be dose-dependent. Conversely, they might not be influenced linearly by the exposure over time.13 Indeed, two studies have shown that heavy smokers (>20 cigarettes/day) have a threefold higher risk than moderate or light smokers of experiencing implant loss, while for marginal bone loss (MBL) greater effects (especially in the maxilla) have been reported for heavy smokers compared with nonor moderate smokers.14,15 A systematic review and meta-analysis by Manzano et al.,16 in which factors that could jeopardize the establishment of an intimate bone-to-implant contact in the early stages of bone healing were evaluated, concluded that tobacco consumption is an important risk factor capable of significantly increasing the risk of early implant failure from 1.3to 2.3-fold. Furthermore, in a review by Moraschini and Barboza17 after a follow-up ranging from 8 to 240 months, a statistically significant difference in MBL in favor of the non-smoking group (standardized mean difference = 0.49, p < 0.00001) was detected. Similarly, Nazeer et al.18 found significantly higher MBL at 3, 6, and 9 months after implant loading in smoking patients compared to non-smokers. At the same time, several authors have suggested that bone loss is greater in the maxilla than in the mandible.17,19,20 When smokers were compared to non-smokers, the implantrelated odds ratio (OR) for a late failure rate of osseointegrated implants was significantly elevated, as demonstrated by Moraschini et al. (OR = 1.96), Strietzel et al. (OR = 2.25), and Hinode et al. (OR = 2.17).17,21,22 Similarly, a more recent review reported a significantly greater relative risk (RR = 2.45) for implant failure in smokers of >20 cigarettes per day compared with non-smokers.23 Finally, some authors have reported that tobacco consumption can negatively influence the survival rate of the implant after ridge augmentation procedures.22,24,25 Notably, a review by Chambrone et al.24 found a significantly higher risk of implant loss (RR = 1.87) after sinus lift in the smoking group than in the control group. A retrospective study by Kan et al.25 over a mean follow-up period of 41.6 months, found a significantly different cumulative implant success rate (p = 0.027) in grafted maxillary sinuses between non-smokers and smokers, with values, respectively, of 82.7% and 65.3%.Unlike periodontitis, the correlation between smoking and peri-implantitis seems to be controversial. A multilevel cross-sectional study by Pimentel et al.26 conducted on 147 patients observed athree times higher probability of developing peri-implantitis (prevalence ratio = 3.49) in smokers compared to non-smokers. A study by Roos-Jansåker et al.27 carried out on 218 implant patients followed up for 9–14 years concluded that smoking was a variable significantly associated with the risk of peri-implantitis in both univariate and multivariate analyses. A recent cross-sectional study by Costa et al.28 on 350 subjects reported an adjusted OR for the occurrence of periimplantitis of 2.63 for current smokers compared with non-smokers. A review by Sgolastra et al.29 revealed, with little evidence and a limited number of studies, that smoking was a significant risk factor for peri-implantitis when an implant-based meta-analysis was conducted (OR = 2.1), unlike the patient-based analysis which did not obtain the same significance (OR = 1.17). A meta-analysis by Stacchi et al.30 found no evidence justifying the role of smoking in the pathogenesis of peri-implantitis, reporting no statistically significant differences in the rate of implant loss and peri-implantitis between smokers and non-smokers. Finally, the 2017 World Workshop on the classification of periodontal and peri-implant diseases and conditions stated that the available evidence supporting tobacco consumption to be a risk factor/indicator for peri-implantitis is still inconsistent and inconclusive.31

2.3 | Clinical recommendations

Although there are no contraindications to implant placement in smoking patients, the clinician should consider the above observations. There are currently no clear guidelines indicating the daily cut-off of cigarettes that the implant patient can smoke. However, patients should be informed that the hazardous effects of tobacco maybe directly proportional to the dose and frequency of smoking habit, and therefore it should be recommended that they quit before any implant procedure. The most common reasons given to support patient obedience with perioperative smoking cessation are the potentially high costs of implant failure and understanding that implants are “an investment worth of smoking cessation”. Besides, smoking patients who are candidates for implant therapy should be advised to follow cessation programs that incorporate multidisciplinary approaches, both medical and psychological.

Some of the deleterious effects of smoking on periodontal tissues are reversible after cessation and therefore the possibility of quitting smoking can represent, a prerequisite for maintaining and preserving long-term implant health.32

3.1 | Biological mechanism

Diabetes represents a group of metabolic disorders characterized by hyperglycemia and caused by partial or total insulin deficiency or resistance. Epidemiological studies have predicted an increase in the worldwide prevalence of diabetes from 2.8% in the 2000s to 4.4% in 2030.33 The increasing prevalence of this disorder and its potential biological implications underline the importance of making some considerations before and during implant therapy for this type of patient. Several Histomorphometric and animal studies have highlighted some mechanisms that would justify an alteration of surgical wound healing and osseointegration. First, studies in pigs with streptozocin-induced diabetes reported a significant delay in wound re-epithelialization associated with a significant decrease in wound fluids of concentration of growth factors such as IGF-1 and TGF- β.34 Secondly, studies in diabetic mice have found overexpression of MMP-9 metalloproteinases in the wound microenvironment impairing granulation tissue formation and producing the inactivation of various growth factors.35 In fact, the increased amount of MMP-9 would favor a shift toward a pro-degradative activity of the fibroblasts determining the production of a lesser and texture-altered extracellular collagen matrix.36 The hyperglycemia-induced chronic inflammatory state could also have unfavorable repercussions on osseointegration. In fact, the production of advanced glycation endproducts (AGEs) and the increase in the levels of reactive oxygen species (ROS) would seem to be the basis of the mechanisms that could justify the increase in bone resorption and a decrease in its formation. First, the interaction of AGEs with their RAGE receptors (receptors for AGEs) would lead to the release of proinflammatory cytokines and the inactivation of osteoblasts. Second, systemically produced ROS would induce apoptosis of bone marrow stromal cells, osteocytes, and osteoblasts altering their differentiation processes and their ability to modulate mineralization.37 Finally, immunohistochemical studies on rats injected with AGEs found less bone-to- implant contact and a slower rate of osseointegration, which would lead to compromised implant stability.38

3.2 | Clinical evidence

Similar to smoking, findings on the implant failure and the onset of peri-implantitis rate in diabetic and non-diabetic patients appear to be controversial and not as strong as in periodontitis where diabetes is considered as a grade modifier. The biological mechanisms could explain the results of some studies that reported an increase in the failure rate and peri-implantitis in diabetic subjects. A retrospective study by Fiorellini et al. conducted on 40 (wellcontrolled) diabetic patients with 215 implants followed for an average follow-up of 8.9 ± 14.3 years, revealed a lower cumulative success rate (85.7%) than the criteria established in the literature. Notably, 24 of the 31 total implants lost in the study were found to have occurred between the first 6 and 18 months, resulting in a first-year cumulative success rate of 88.9%.39 Similarly, a review by Annibali et al., while not finding a statistically significant difference in the overall implant survival rate between diabetic and nondiabetic patients, a higher tendency for implant failure was observed in diabetic patients during the period of osseointegration and the first year after loading reporting an implant loss rate of 4% ± 1% and 3% ± 1%, respectively. After the first year, these values remained constant throughout the 6 years of follow-up. Finally, an analysis of the implant survival rate did not allow to show a statistically significant difference between diabetic (type 1 and 2) and non-diabetic patients in a review by Moraschini et al.41 (RR = 1.43, p = 0.47; RR = 3.65, p = 0.29). A difference in the implant failure rate was also not appreciated in a comparison between patients with type 1 and type 2 diabetes (RR = 1.56, p = 0.34). Also, a review by Chrcanovic et al.,42 including 14 publications, demonstrated that diabetes is unable to significantly influence the implant failure rate with a risk ratio of 1.07. Finally, by evaluating the implant failure rate over a longer time frame, a 21-year retrospective cohort study was able to conclude that a diabetic condition is significantly correlated with an increased risk of implant loss (OR = 2.75).43 A review by Al Ansari, including 89 studies with a mean follow-up of 3.2 + 2.9 years, also found a slightly higher but statistically significant relative risk of implant failure when diabetic patients were compared with healthy subjects (OR = 1.777, p < 0.001). In addition, patients with type 1 diabetes experienced failure more frequently than type 2 diabetics (OR = 4.477, p = 0.03). Conversely, some authors have not observed a significant effect of diabetes on early implant failure. An observational study by Eskow et al.45 demonstrated that diabetic patients with poor glycemic control (8.0% ≤ HbA1c ≤ 12.0%) had very high 1-year survival rates (98.6%), without the onset of any complications. Another review reported a significant association between diabetes with poor glycemic control and implant failure, with a 50% higher probability for implant failure compared to healthy patients (OR = 1.89, p < 0.001). Last but not least, the healing time is another consideration that should be kept in mind when placing implants in diabetic patients. A study by Oates et al. evaluated the effects of controlled glycemic levels on implant stability quality (ISQ) over a 1-year time. Although delayed implant integration was observed in the group with HbA1c >8.1% compared with the group with wellor moderately controlled glucose levels, no association between ISQ and HbA1c was appreci- ated in the 1-year post-loading period. Concerning the mean difference (MD) of MBL around implants, a review by Al Ansari et al.44 reported a significant difference (MD = 0.776 mm, p = 0.027) between diabetic and non-diabetic patients in favor of the latter. A meta-analysis by Chrcanovic et al.42 detected an MD (0.20 mm, p < 0.001) for MBL which, although significantly greater in the diabetic group, was almost clinically irrelevant. Also in a review by Moraschini et al.,41 in which 5 included studies reported outcomes for MBL, they found a minimal but statistically significant MD (0.18, p < 0.00001) favoring the non-diabetic group.

Regarding the incidence of peri-implantitis, a review by Dreyer et al.48 noted that patients with type 2 diabetes mellitus have more than double the risk than non-diabetic patients for developing peri-implant disease (OR = 2.5). However, most of the studies included in that review were cross-sectional compromising the quality of the evidence which was rated as medium level.48 Conversely, several studies have failed to find a correlation with diabetes. A retrospective study by Alberti et al.49 conducted on 204 patients followed up for 5.7 ± 3.82 years after loading, found an adjusted OR (0.47) for diabetes as a nonsignificant risk factor for peri-implantitis. A retrospective analysis by Renvert et al.50 performed on 240 patients also failed to demonstrate a correlation between type 2 diabetes and the development of periimplantitis. Finally, the 2017 World Workshop also stated that it is not yet possible to establish with conclusiveness and consistency whether diabetes represents an effective risk factor for the onset of peri-implantitis.31

3.3 | Clinical recommendations

Diabetes is not an absolute contraindication to implant therapy. Generally, it can be concluded that the survival rate for implants in diabetic patients maybe slightly lower than that of healthy patients, and failure is appreciable, especially in the long term.51 Though the literature regarding survival rates and the need for glycemic control is quite inconsistent due to a lack of standardization of collected data and results, it is desirable and recommended to have well-controlled glycemic control in patients undergoing implant therapy. Diabetes is defined as ‘well-controlled’ when HbA1C values are < 7%. In addition to this parameter, which evaluates the glycemic levels in the previous 2–3 months, a measurement of the pre-prandial glucose levels and the post-prandial peak could also give us a broader view of the current state.3 A good peri-operative glycemic control would guarantee better and faster osseointegration of the implants and better healing of the surgical wound. Conversely, poor metabolic control (≥8.1%) associated with diabetic microangiopathy would cause an alteration of the immune response, an impairment of the flap vas- cularization and would favor the onset of infectious complications. Based on the same rationale, prophylactic antibiotic therapy is also recommendable in diabetic patients.52 Amoxicillin is the antibiotic of choice to prevent any infections caused by streptococci, gramnegative and gram-positive anaerobes. The use of topical antiseptics (chlorhexidine digluconate 0.12%) has also proved to be useful in reducing the risk of implant failure.3

4.1 | Biological mechanism

In 80% of cases, this condition is diagnosed in women, as post- menopausal estrogen decline causes an acceleration of bone resorp- tion. At the same time, the chronic use of some medications (such as glucocorticoids, antiepileptics, immunosuppressive drugs, proton pump inhibitors, Selective Serotonin Reuptake Inhibitors), and some systemic conditions (diabetes mellitus, severe hyperthyroidism, Cushing’s syndrome, severe hepatic disease, multiple myeloma, leu- kemia, lymphoma, hemophilia, rheumatoid arthritis) may be associ- ated with the development of osteoporosis.54

The success of implant therapy and osseointegration are strictly conditioned by the bone quality of the jaws and it is for this reason that osteoporosis could represent a condition of important clinical relevance. Type IV bone with poorly represented cortical and tra- becular bone was shown to be more frequently associated with im- plant failure; due to difficulty obtaining primary stability.55

However, the relationship between skeletal and mandibular or maxillary bone density is limited and inconsistent.56,57

Indeed, some authors have found a weak evidence to establish that regional bone density could be a useful parameter in predicting primary implant stability and at the same time a useful indicator of skeletal BMD.56,58

4.2 | Clinical evidence

In response to these issues, Merheb et al., in fact, evaluated the quality of implant stability (ISQ) at the time of implant and abutment placement using a resonance frequency analysis in osteoporotic and non-osteoporotic patients. Although a statistically significant difference in quality scores at abutment placement was found between osteoporotic patients (66.4 ± 9.5 ISQ) and healthy patients (72.2 ± 7.2 ISQ), in favor of the latter, an overall survival rate of 100% was reported.59

On the other hand, a retrospective analysis by Alsaadi et al.,60 using multivariate logistic regression, found a significant association between early implant failure and osteoporosis (OR = 2.88, p < 0.001); however, a causal relationship could not be established. Interestingly, the same research group in another study using a 61 Therefore, despite the micro and macroscopic anatomical modifications linked to osteoporosis which could undermine the primary stability of the implant, the literature, albeit very lacking, does not seem to place emphasis on this issue and does not outline osteoporotic conditions as a contraindication to implant therapy.

Regarding MBL, some studies reported a significantly greater increase in osteoporotic patients than in healthy ones.62–64Notably, de Medeiros et al.62 found a statistically significant difference in MBL around implants between patients with and without osteoporosis (0.18 mm, 95% CI 0.05–0.30, p = 63 observed a mean MBL of 1.20 ± 0.29 mm in the osteoporosis group and 0.87 ± 0.15 in the control group, with a significant difference between the two groups (p = 65 which analyzed 148 implants in 48 women over an observation period of 5 years, concluded that no statistically significant differences in MBL values were obtained between the osteoporosis group and the group of healthy women at both patient level (p = 0.54) and implant level (p = 0.31).

Regarding the incidence of peri-implantitis, a 2017 World Seminar 31 A cross-sectional study by Dvorak of 203 women with 967 implants failed to identify an association between systemic bone loss and peri-implantitis (OR = 2.1, p = 66 48 62,67,68 62 considering 15 publications involving 8859 patients and 29 798 implants, found no differences in the implant survival rate between patients with and without osteoporosis, nor at the implant level (RR 1.39, p = 0.11) nor at the patient level (RR 0.98, p = 0.94). Similarly, a meta-analysis by Lu et al. and Chen et al. could not demonstrate a significant detrimental effect of osteoporosis on implant survival (RR = 1.19, p = 0.067; RR = 1.09, , p = 0.14, respectively). 67,68

4.3 | Clinical recommendations

There are no reported contraindication for implant placement in patients with osteoporosis. However, the healing process of bone tissue might take longer and the low quality of bone could affect primary stability and consequently osseointegration.69 There are no studies that provide indications on the exact healing time in these 70 In many respects, this condition would not seem to represent a limitation per se for implant therapy, but rather the necessary therapy usually made up of bone resorption inhibitors could expose the patient to serious post-surgical complications.

5.1 | Biological mechanism

5.2 | Clinical evidence

5.3 | Clinical recommendations

6.1 | Biological mechanism

6.2 | Clinical evidence

6.3 | Clinical recommendations

• < 50 Gy: indicate a low risk of implant failure and recommend the adoption of standard precautions.
• 50–65 Gy associate moderate risk and recommend caution.
• 65–74 Gy indicate a relatively high risk and advise against the placement of implants unless hyperbaric oxygen therapy is also used.
• 75–120 Gy implant therapy is not recommended due to the high associated risks.121

7.1 | General considerations

A cross-sectional analysis in the North American population reported a 2.8% prevalence of temporary or chronic immunosuppressive conditions.123

A state of immunosuppression can be associated with a wide variety of circumstances, ranging from pathological conditions to physiological states (i.e., pregnancy). Most cases of short-term or long-term non-HIV-related changes in the immune system that the oral or maxillofacial surgeon may face in the treatment of implant patients could derive from the intake of drugs.124

Steroid derivatives (i.e., corticosteroids) are medications used for a wide range of pathologies, including asthma and especially autoimmune diseases (i.e., rheumatoid arthritis, pemphigus vulgaris, lupus erythematosus, Sjogren’s syndrome, polymyalgia rheumatica). Immunomodulatory drugs are also used in patients with transplanted organs, for whom in addition to the use of corticosteroids (CS), other drugs such as cyclosporine, tacrolimus, sirolimus, and mycophenolate are also used.124

One of the side effects mainly related to the prolonged use of corticosteroids is an alteration of bone metabolism, so much so that it represents one of the three leading causes of osteoporosis. In fact, CSs induce apoptosis of most osteoblastic cells and osteocytes and inhibit the differentiation of stem cells into osteoblasts and prolong the lifespan of osteoclasts.125 CSs also cause a reduction in the production of insulin-like growth factor (IGF-I) by the osteoblastic cell population, compromising its anabolic and proliferative activity and the formation of new bone. At the same time, it causes an increased release of RANK ligand from osteoblastic cells, which in turn has a potentiating action on osteoclastic activity.126 The result is an imbalance between the osteoblastic-mediated activity of bone neoapposition and that of osteoclastic-mediated resorption, in favor of the latter, causing a reduction in the volume and density of the bone tissue.

The same effect was found among the side events of cyclo-sporine, as observed in a rat Histomorphometric study by Shen et al.127 Another animal study demonstrated that cyclosporin, thanks to its ability to induce the production of TGF-beta, can determine suppression of MMP 2 and −9 in rats. As a consequence, there is an impairment of the processes of angiogenesis and bone remodeling, and healing.128

7.2 | Clinical evidence

Although the mechanisms described above justify the intentions of some studies to investigate the plausible correlation between the administration of these drugs and implant failure, the scarce literature available to date seems to have failed to out 129 A review by Duttenhoefer et al., in which 19 studies (11 case reports, 6 retrospective, and 3 prospective) were included, investigated the influence of autoimmune diseases and their treatment with steroid derivatives on implant loss over a period ranging from 6to 156 months of follow-up. In none of the studies did the comorbidity associated with these conditions influence implant failure, reporting a survival rate of 88.8%.124 A retrospective study by Petsinis et al., in which 31 patients (105 implants) receiving glucocorticoid therapy for various systemic diseases were followed up for 3 years, observed an implant survival rate of 99% and did not find any signs clinically or radiographically relevant evidence of impaired osseointegration.130

Similarly, in the review by Duttenhoefer et al., in which 6 studies of patients with organ transplants and immunosuppressive therapy were included (2 prospective and 4 case reports), an implant survival rate of 100% was reported at a mean follow-up of 58 months and no clinically appreciable effect on osseointegration was found. A recent systematic review and meta-analysis by Burtscher et al., however including only case–control studies and case series/case reports, found a 100% implant survival rate in transplant patients receiving various drugs for immunosuppressive therapy at an average follow-up of 60 months. At the same time, no studies described early implant loss, and no statistically significant differences were reported for MBL between transplant recipients and healthy control patients.

7.3 | Clinical recommendations

Although the quality of the available evidence is very low, above all due to the prevalent presence of non-controlled and nonrandomized studies, the results we have available today seem to find no contraindication to implant therapy in patients with drug-induced immunosuppression and organ transplants.124 New investigations are certainly necessary to increase the data at our disposal and to highlight the aspects of such a vast and articulated research field.

Generally, to avoid peri-operative complications in patients on prolonged corticosteroid therapy, some considerations must be made. Indeed, steroid-derived drugs could cause some level of suppression of the hypothalamic–pituitary–adrenal axis, rendering the patient unable to produce cortisol in stressful occasions such as surgical procedures. This could trigger an adrenocortical crisis manifesting in hypotension and collapse.131 To prevent this event, an administration of a supplemental dose of corticosteroids to the patient 30 min before surgery has been suggested. However, the available evidence has shown that the risk of adrenocortical crisis is very low in patients on prolonged steroid therapy undergoing minor surgery and, therefore, supplemental steroid therapy is unnecessary.132

Finally, since immune-suppressed patients are a category to be considered at high risk for postoperative infections, prophylactic antibiotic therapy should always be contemplated. A 5–6 day protocol depending on the type of drug (first choice amoxicillin + clavulanic acid or clindamycin or moxifloxacin in case of allergy), to be started 12–24 h before implant placement, is considered adequate.133

New investigations are certainly necessary to increase the data at our disposal and to highlight the aspects of such a vast and articulated research field.

8.1 | Biological mechanism

8.2 | Clinical evidence

8.3 | Clinical recommendations

9.1 | General mechanisms

The term cardiovascular disease (CVD) indicates a broad spectrum of diseases affecting the heart and blood vessels of the entire body and represents the main cause of death in the USA, Europe, and Asia. Among the main CVDs, we can include ischemic heart disease, angina pectoris, heart failure, aortic aneurysm, and cerebrovascular diseases, including ischemic and hemorrhagic stroke. CVDs include sex, age, and family history among non-modifiable risk factors. Among the modifiable risk factors, we mainly include hypertension, atherosclerosis, hypercholesterolemia/dyslipidemia, diabetes, obesity/sedentary lifestyle, and smoking habits. In most of its forms, CVDs occur following an obstruction, a reduction of the lumen, or a rupture of medium and large arterial vvessels consequently compromising the perfusion of downstream tissues which go against necrosis from hypoxia and lack of nutrients.156 Hypoxia manifests itself with an alteration of the homeostatic mechanisms of tissue oxygenation which results in an impairment of the healing processes, with a reduction in fibroblast proliferation, collagen synthesis, capillary growth, and macrophage activity.157 Due to the nature of these mechanisms, it has been hypothesized that CVD may alter bone healing mechanisms around implants. Therefore, it was considered plausible to investigate a possible correlation between CVD and impaired osseointegration.

9.2 | Clinical evidence

Several retrospective studies with follow-up from 7.3 up to 21 years, did not find a significant increase in the implant failure rate in cardiovascular patients.43,60,157–159 No influence (p = 0.359) of coexisting CVD was appreciated on the implant survival rate of diabetic patients in a retrospective study by Araujo Nobre.160

Surprisingly, a review by Wu et al. reported the positive effect of antihypertensive drugs on implant survival. An analysis of survival adjusted for confounders obtained favorable results in favor of users of antihypertensive drugs (HR = 0.12, p = 0.01). Beta-blockers, thiazine diuretics, and ACE inhibitors, in fact, would seem to positively influence bone metabolism, stimulating its formation and reducing its reabsorption.161 Conversely, a review by Schimmel et al. and several retrospective studies unanimously demonstrated that there is no evidence regarding hypertension as a risk factor for implant failure.162–165

Regarding the incidence of peri-implantitis, a retrospective study by Renvert et al.50 found a history of CVD in 27.3% of patients with peri-implantitis and only 3% of patients in the healthy implant/ mucositis group reporting an OR (adjusted for age, gender, and smoking) of 8.7. Saabi et al.158 through a retrospective assessment found the presence of CVD in 26% of patients with peri-implantitis. Conversely, Neves et al. failed to establish a significant correlation between cardiac disease and peri-implantitis (OR = 1.14, p = 0.61). Froum et al.,166 in a systematic review of the literature, concluded that inconsistency of data in the literature and the heterogeneity of the evaluated populations make further investigations necessary to establish the existence of a link between CVD and peri-implant disease. Similarly, there is currently no evidence demonstrating that CVD was or is not an actual risk factor for implant loss.

9.3 | Clinical recommendations

However, the clinician should take into consideration a few other issues before undertaking any surgical treatment in this category of patients. In fact, an increased risk of bleeding, a rise in blood pressure, and the appearance of ischemic attacks during surgery could occur. Comprehensive informed consent, in which the aforementioned risks are explained, continuous monitoring during surgery, and periodic updating of the medications taken by these patients are highly recommended.167

First, there is an absolute contraindication to proceeding with implant placement in patients with recent myocardial infarction or cardiovascular attack up to 6 months after preliminary care; in fact, harmful complications can probably occur in this time window. Similarly, patients undergoing heart valve replacement surgery should not undertake implant therapy before 6 months.3 In any case, adequate antibiotic prophylaxis must be performed to prevent the development of endocarditis.

Another aspect to carefully evaluate is the possible intake of anticoagulants or antiplatelet drugs. When we are going to treat patients treated with vitamin K or direct oral anticoagulants (DAOs), an assessment of the INR is always recommended. INR values necessarily established between 2 and 4 do not contraindicate implant placement associated with minor surgical procedures.168 Obviously, a weighing of the type of surgery that is planned is always necessary, considering that less invasive procedures are associated with a lower risk of bleeding while more complex interventions such as the insertion of bimaxillary or zygomatic implants and the use of bone grafts correlate at a higher risk.

In patients on antiplatelet therapy (AT) (i.e., acetylsalicylic acid, clopidogrel, ticlopidine, prasugrel, and ticagrelor) an adequate evaluation of hemorrhagic risk should be done by assessment of platelet count and hematocrit. Platelet counts < 50 000 cells/mm3 are associated with a higher risk of postoperative bleeding, while values < 20 000 cells/mm3 also predispose to spontaneous mucosal bleeding. On the other hand, hematocrit levels < 60% of normal values should be carefully evaluated.169

Several systematic reviews do not recommend discontinuing DAO or AT therapy before undertaking oral surgical procedures. Kämmerer et al.170 concluded that in patients with INR < 4 treated with vitamin K antagonists dental surgery procedures can be performed safely without suspending therapy, implementing local hemostatic measures. Similarly recent reviews found a clinically insignificant risk of periand post-operative bleeding in patients who have not stopped anticoagulant therapy.171,172 Analogous results have been achieved in studies of patients on AT.173 Iwabuchi et al., in a cross-sectional multicenter observational study, carried out on 2817 patients, reported a low absolute incidence of bleeding events in the anticoagulated group, but slightly higher than in untreated patients. In particular, age < 65 years, high INR values, and the presence of acute inflammation before extraction surgery could significantly increase the risk of bleeding.174

Furthermore, some authors also report a greater risk of thromboembolic events or myocardial infarction which may derive from the interruption of therapy with DAO or with antiplatelets, respectively.175,176 At the same time, other studies showed that the implementation of bridging therapies (i.e. heparin) can increase bleeding events compared to patients who continued the canonical anticoagulant therapy; no differences, however, have been.177,178

Finally, among the local measures to ensure hemostasis in these patients, the use of compressive sutures, the application of hemostatic dressings (collagen, absorbable sponges, oxidized cellulose, bone wax, and L-PRF) or topical tranexamic acid (5%, three to four times/day) can reduce periand post-operative bleeding complications and make the procedure safer.104,179

10.1 | Biological mechanisms

10.2 | Clinical evidence

10.3 | Clinical recommendations

11.1 | Biological mechanism

Many oral problems are related to an imbalance of antioxidants and ROS in the body. Recently, free radicals are related to the occurrence and development of dental diseases, and antioxidants have also been used in dental treatment.193

Oxidative stress is an imbalance in the production of free radicals and in the antioxidant system (2), so it could be measured by monitoring some useful parameters: ROS, Malondialdehyde (MDA), Superoxide Dismutase and Total Antioxidant Capacity (TAC).193–195 All these parameters are present also in peri-implant crevicular fluid (PICF).195

On one side, ROS are required for cell signaling and normal metabolism. On the other hand, excessive oxidative stress may lead to damage to DNA, RNA, and proteins.196 Short-term oxidative stress may occur in tissue loss such as trauma, heat damage, and infection. In these damaged tissues, the production of enzymes (rich of free radicals) is increased by phagocytic cells with the release of free metal ions, epoxidation, and production of excessive ROS.197,198

When ROS production increases or antioxidant capacity decreases there’s oxidative damage to cellular components as in proteins, lipids, and nucleic acids.199

It has already been proven that oxidative stress is related to many diseases, including CVD, diabetes, rheumatoid arthritis, cancer, and various kinds of inflammation.200

Oxidative stress and oxidative damage are in the contest of dental procedures and it has been shown that periodontal inflammation is a direct result of increased ROS and oxidative damage products in the oral cavity.201

Alcohol consumption and nicotine exposure can increase ROS and are related to periodontal disease. A lot of dental procedures such as implants, bleaching, and fillings are related to oxidative stress.202–204

11.2 | Clinical evidence

The process of dental implant implantation inevitably generates ROS. Tsarik et al.205 reported that the oxide layer generated on the surface of titanium alloy implant may reduce the potential corrosion. Friction during implantation would lead to the metal surface rupture and the titanium dioxide layer corrosion and an electrochemical reaction with free radicals and hydrogen peroxide were generated as intermediate products. When titanium dioxide is corroded, hydrogen peroxide generated by electrochemical reaction will continue to react with titanium dioxide to form hydroxyl radicals.206 Bressan et al. analyzed the effects of titanium (Ti) particles on mesenchymal stem cells (MSCs) and fibroblasts (FU); they evaluate cell proliferation and generation of ROS and it was found that titanium particles reduced the survival time of the cells and increased the generation of ROS. Concurred by oxidative stress, bone regeneration imbalance was induced.207

The implant placement process may lead Ti particles to enter the tissue and cause inflammation. Therefore, tetracycline, doxycycline, chlorhexidine, hydrogen peroxide, and citric acid can be used to remove excess Ti particles, among which hydrogen peroxide, citric acid, and chlorhexidine are more effective.208

Also, Abdulhameed et al.209 reported that titanium dioxide nanoparticles (TiO2NPs) can induce oxidative stress, reduce osteogenesis, and damage the antioxidant defense system.

After a dental implant placement, friction and twisting could damage the oxide layer on the surface, leading to an increase of ROS and an inflammatory, such as peri-implantitis (PI).210,211

Antioxidants are choices for treatment. PI and periodontal disease are manifested by soft tissue and bone damage, in which ROS plays an important role in cell transmission, maintenance, and proliferation.212

A certain amount of ROS is already present before the dental implant is implanted 213 and the somministration of antioxidants have a protective effect on periodontal tissue and can neutralize ROS to prevent tissue damage.214 A lot of antioxidants can be obtained from diets and supplements, and supplements can be taken in addition to a diet rich in berries and vegetables.193 Some useful antioxidants are tannic acid macromolecules consisting of a central glucose molecule linked to 10 surrounding gallic acid units.215–218 Green tea and quercetin have both anti-inflammatory and antioxidant properties.219–222 Polyphenols are natural compounds with antioxidant and antimicrobial properties.223,224 The antioxidant activity of polyphenols cleans free radicals by supplying hydrogen atoms from hydroxyl groups in the phenolic ring,224 and chelating iron and other metal ions, thereby preventing the catalytic oxidation of hydrogen peroxide and superoxide to hydroxyl radicals.225

Curcumin, a polyphenolic compound can also lead to an in-crease in the level of the antioxidant enzyme glutathione peroxidase, which reduces the ROS level in cells.222 Vitamin E is a common antioxidant with the highest concentration in human mitochondria. The main action of vitamin E is to interact with superoxide in mitochondria, limiting its formation, stabilizing the mitochondrial membrane, and removing antioxidants that have been generated.226 A study indicated that adding low concentrations of vitamin E (less than 0.1%) did not affect the physical and mechanical properties and can prevent oxidation for up to 24 months post-implantation.227

At present, antioxidants in the treatment of local inflammatory reactions, such as periodontitis, and PI usually quickly disappear with ROS and other free radicals. Some studies reported the effects of new materials in which hydrogels can reduce the presence of ROS, and inhibit hydrogen peroxide and lipid peroxidation.195,228

11.3 | Clinical recommendations

There are no reported contraindication for implant placement in patients with elevated oxidative stress. However, there’s evidence that lowering the level of ROS could help the healing process of periimplant bone tissue.195,229

Studies that evaluate peri-implantitis found significant correlations between probing pocket depth, level of MDA and TAC.195

Moreover, the level of oxidative stress markers (MDA, SOD, and TAC) in PICF does not significantly change in peri-implantitis compared to healthy implants.195,212

Therefore, the prevention of possible peri-implantitis could be suppoterted by antioxidant supplementation and delivery by new gel encapsulation that is worth of studying.209,229

While the clinical relevance of Oxidative Stress is growing, we need to focus attention to how it affects the possible outcome of patient with dental implants.230 Like inflammation, it is likely to play a major role in both healing and harm. As diagnostic biomarker techniques become more, reliable and sophisticated, we need to interlace this information into new protocols of peri-operative evaluation in dentistry. The pre-operative and postoperative evaluation of oxidative stress is used in other surgical fields like colon-rectal oncology, a desirable outcome would be the application in dental implant surgery.231–234

Systemic conditions and/or an unhealthy lifestyle may directly lead to surgical complications, compromise implant/bone healing, or influence the long-term peri-implant health and its response to biologic nuisances. Similar risks may pertain to the medications taken by implant patients rather than the disease itself.

The present review shows that there are very few absolute contraindications and a full evaluation of each individual patient is of the utmost importance to avoid implant-related complications in medically compromised patients with or without unhealthy lifestyle/elevated oxidative stress.

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