Dental Implants in the Medically Compromised Patient Population Dental Implants in the Medically Compromised Patient Population

As a result of the increase of the life expectancy, elder people live with diverse diseases or conditions like systemic disorders, immune-related disorders, and psychiatric issues. Consecutively, practicing clinicians are faced with serving dental implant treatments in such a population comprised of medical and demographic characteristics. Most commonly, implant therapy is performed among patients above middle ages; therefore, clinicians often encounter medically compromised patients. The patients are usually with adverse conditions like bleeding disorders, bone diseases, cardiovascular disease (CVD), and/or immunologic conditions like cancer therapy, steroid or immunosuppressive or antiresorptive medication, alcoholism, smoking, and many others. Nevertheless, only few conditions could be stated for contraindication to dental implant therapy. Besides the broad range of the mentioned dental implant comorbidities smoking seems less prevalent compared to the general population. Dental implants in smoking patients are certainly affected in relation to the failure rate, marginal bone loss, and some other risks of postoperative complications. Hence, smoking or other similar conditions could be accounted as a chronic systemic disorder just like diabetes mellitus or drug usage. Briefly, it seems that establishing the medical and demographic conditions prior to implant therapy along with controlling the systemic diseases or disorders may be more important than the presence of compromise.


Introduction
Dental implant (DI) is broadly considered to be the ideal treatment of the tooth loss, which is mostly required in the aged population [1,2]. The prevalent age-range for implant therapy has been reported above 40 years [2] or between 51 and 60 years [1], thus the patients who required Author, year, study design Followup  Regarding the MBL, smoking seems to have a destroying effect by increasing the annual rate of MBL by 0.164 mm/year [14], and MBL is about 1.4 mm after 3 years with a statistically significant difference from people who do not smoke tobacco [15,16].
As a result, tobacco smoking alone is not contraindicated for DI, and DI survival is about 90% for a long time period. On the other hand, smokers are under a higher risk of implant failure compared to the nonsmokers. Thus, clinicians should take into account other concomitant systemic factors which could increase the risk of failures.

Alcohol consumption
There is no evidence to suggest that alcoholism is a contraindication for DIs. SR of DI is similar to healthy population with a reasonable alcohol consumption. Nevertheless, alcoholism is claimed to increase the risk of complications for DI because it may cause many systemic disorders like liver disease, bleeding disorders and osteoporosis (OP), and it may impair immune response and some nutritional elements like folate and B vitamins, and it is often associated with tobacco smoking [28].
It is reported that consumption of >10 g of alcohol increases the MBL and decreases DI survival in humans [15]. Despite there are few studies available ( Table 3) concerning the DI outcomes in patients who consumed high level of alcohol, further clinical studies with well-defined subjects are required for clarifying the relation.

Cardiovascular diseases
Cardiovascular disease (CVD) compromises the blood flow which may restrict oxygen or nutrients in the osseous tissue, thus is hypothesized to have higher risk of osseointegration failure [29][30][31]. Clinical studies and reviews demonstrate no evidence of contraindication related to DI success in patients with CVD (Table 4), and this disease is registered as a relative complication due to the risk of infective endocarditis. Antibiotic prophylaxis is necessary prior to the surgery [31] according to the guidelines of the American Heart Association's last publish [32,33].
Author, year, study design DI surgery is suggested as a legitimate procedure for the patients at high risk for IE (such as aortic or mitral valve replacement or cyanotic congenital malformation) which under prophylactic antibiotic regime of 2 g amoxicillin orally at 1 hour preoperatively [34]. There is also evidence suggesting that this regimen significantly reduces failures of DIs though it is still unknown whether postoperative antibiotics are more beneficial, and which antibiotic is the most effective [33]. Reviewers stated the importance of concomitant bleeding or cardiac ischemia which could develop during DI insertion, therefore, procuring medical advice is recommended prior to the implant surgery [28]. As a matter of fact, recent myocardial infarction, stroke, and cardiovascular surgery are well-known contraindications for performing DI surgery [35].
According to the current literature, CVD does not hinder the osseointegration of DI [36,37] and is not associated with higher risk of implant failure ( Table 4). SR is about 89% up to 20 years (Table 4). However, the number of the studies that reports peri-implant health condition is insufficient. Unlike the other studies available, one study revealed that CVD has risk factors for peri-implant bone loss with the mean value of 1.38 mm after 3 years [16]. Further studies are needed in this respect.

Diabetes
As being the most prevalent endocrine disease, diabetes mellitus is a metabolic disorder that is generally diagnosed by the characteristic symptoms of polydipsia, polyuria, and polyphagia in correlation with exceeded blood glucose levels more than 200 mg/dL. It causes hyperglycemia due to a defect of insulin secretion [39], that insulin has an effect on the regeneration of bone matrix. In a diabetic patient, hyperglycemia reduces clot quality, number of osteoclasts, and collagen production, which are the keys of bone regeneration [30].  A decreased bone density is observed around the titanium implants in animal subjects, and implant survival is slightly reduced in poor metabolic control [28] with an average rate of 89% ( Table 5). Yet no clinical evidence exists to establish an association of glycemic control with implant failure because of the insufficient identification and reporting of glycemic control in most of the published studies [40].
Though diabetes is not a contraindication for DI therapy, evaluating the HbA1c level of the patient and chlorhexidine mouth wash and antibiotic prophylaxis are recommended in order to reduce the relative risk of infection associated with diabetes [28,30].

Bleeding disorders
There is no evidence to suggest that bleeding disorders (BDs) are contraindication for placement of DIs [28] or a contraindication for implant survival/success [31]. Since the risk of thromboembolism of interrupting or changing the antiplatelet therapy is higher than the risk of hemorrhage caused by dental implant surgery, invasive dental procedures including dental implant surgery are suggested to perform normally [42].
Considering the oral anticoagulant therapy (OAT), DI is not contraindicated in patients under an OAT [28,31]. Minor DI surgery (that does not involve autogenous bone grafts, extensive flaps, or osteotomy preparations extending outside the bony envelope) is asserted to be safe regarding the risk of hemorrhage in patients who have an INR value of 2-4, and local hemostatic agents are suggested enough for these patients [43,44]. On the other hand, it should be noted that some medications that are commonly used in dental practice (like metronidazole, erythromycin, and clarithromycin) may increase the anticoagulant effect of warfarin [31].
There are some additional precautions for the patients with inherited BDs such as taking medical advice previously, the replacement of deficient coagulation factor to reach a minimum level of 50% before surgery, slow injection of local anesthesia with vasoconstrictor, the use of antifibrinolytic agents (oral tranexamic acid and/or 5% tranexamic mouthwash) up to 7 days postsurgically, and the use of topical antiseptics (chlorhexidine or povidone iodine) in order to reduce the risk of local infection. Sinus lifting and bone graft procedures are recommended to be avoided, and consulting for the use of nonsteroidal anti-inflammatory drugs is advised as they may increase the risk of a dangerous hemorrhage [31].
Studies that analyze the bleeding risk and DI success after invasive DI surgeries are lacking ( Tables 6 and 7). Studies are also required for evaluating whether anticoagulants have an effect on DI therapy negatively or which is the optimum drug or regimen.

Thyroid disorders
Thyroid hormones of triiodothyronine (T3) and thyroxine (T4) have been demonstrated to have influence on cortical bone healing than cancellous bone around titanium implants [47]. Thus, thyroid hormones-related disorders could be regarded as the considerable issues for evaluating the success of dental implants.  Concerning the peri-implant pathology, thyroid disorders are reported to have the lowest potential risk compared to the other systemic disorders, in a recent clinical study [2] ( Table 8).
Due to the limited number of clinical studies that report DI outcomes in patients with thyroid disorders, it is hard to deduce a suggestion. Therefore, there is a certain need for further studies about the thyroid disorders.

Hepatitis
Concerning the dental implantology, hepatitis is one other disease which has not been studied widely yet. These infectious diseases impair immune system, increase oxidative stresses induced by the viral proteins, and cause virus-associated organ damage including liver fibrosis, steatosis, or hepatocellular carcinoma [48].  [45] Postoperative bleeding risk of patients continuing their anticoagulation therapy (antiaggregant, vit-K inhibitors, vitamin-K inhibitor withdrawal bridged with heparin, direct oral anticoagulants) and undergoing implant surgery and advanced bone grafting procedures 564 patients
The postoperative bleeding risk after implant surgery and/or bone grafting procedures is very low in patients continuing the anticoagulant therapy 3.
The invasiveness of the surgical procedure had no statistically significant effect on bleeding frequencies 4.
Patients taking vit-K inhibitors had a significantly higher risk of a postoperative bleeding compared to patients without any anticoagulant 5.
Most of the postoperative bleedings are easily controllable via local hemostatic measures Table 6. Hemorrhagic risks in patients undergoing advanced implant surgery and bone grafting procedures.
Author, year, study design  Being one of the most spread and dangerous human pathogens, hepatitis C is shown to affect the oral conditions by increasing decays, gingival bleeding, and pocket depth due to the evident change in salivary flow [49].
Though hepatitis was indicated only as a possible risk factor previously [50], a present report is registered that hepatitis is the only risk factor for peri-implant pathology among the other systemic compromising factors such as cardiac diseases, thyroid disorders, diabetes, rheumatologic disorders, HIV infection, and smoking [2] ( Table 9).

Bone diseases
Being the most frequent bone disorder, osteoporosis (OP) affects both bone mass and density. The effect is also more prominent in cancellous bone and in women [30].
Clinical studies have demonstrated that a SR of DIs in the patients with the diagnosis of OP is about 94% (Table 10). Despite a small number of studies that report peri-implant conditions, one study has presented a high rate of peri-implantitis in patients with OP (76.1%), but this rate does not differ from the healthy population or the patients with osteopenia [51]. Regarding the peri-implant MBL, one recent study has reported a mean value of 0.11 mm at first   year [52], and one other has reported a mean of 0.65 mm at fifth year [53]. Additionally, bone status does not seem to be a predisposition for DI failures.

Rheumatologic disorders
Rheumatologic disorders encompass a large number of diseases and syndromes such as rheumatoid arthritis, osteoarthritis, and osteoporosis, which are the most common rheumatologic diseases (RDs) [2]. Different RDs could affect DI success in different ways [28]. For instance, rheumatoid arthritis (RA) has not stated a predominant player for late implant loss in one study [21]. However, together with the connective tissue disease, RA increases bone resorption when compared to the connective tissue disease alone [55].
Today, there are only a few number of clinical studies with limited amount of participants that evaluate the success of DIs in patients with RD. Although RD was shown as risk factor for periimplant MBL in a recent prospective study [16], no relationship was found with the implant failure risk or peri-implant pathology in another study [2]. Therefore it can be concluded that any relation of RD in DI success is unclear, and there is a certain need for further studies with sufficient number of participants (Table 11).

Bisphosphonate therapy
Bisphosphonates (BFs) suppress the osteoclast function and therefore are used for the treatment of disorders causing abnormal bone resorption such as OP, malignancies (multiple myeloma, bone metastases of breast, or prostate cancer), or nonmalignant bone diseases (the most prevalent of osteoporosis and Paget disease) [30,37].
According to the recent meta-analyses, the consumption of oral BF in patients with OP could only be assumed to be a relative contraindication for DI. Further, there is no evidence that any BFs have a negative impact upon implant survival. In this context, patients should be informed about the related risks and DI could be placed under optimum oral care conditions. On the contrary, in patients who are under BF treatment intravenously together with RT doses of above 50 Gy, DI placement was reported to be a contraindication [30,56].  In conclusion, BFs do not seem to have an adverse effect on DI survival under optimum oral care conditions, and OBFs are not associated with occurrence of osteonecrosis of jaws (ONJ) ( Table 12).

Head and neck cancer
Squamous cell carcinoma, adenocarcinoma, and ameloblastoma are the most common malignancies that are encountered in the head and neck regions. These patients with malignancies frequently go under challenging adjuvant therapeutic procedures such as radiotherapy (RT) or chemotherapy (CT) in addition to the tumor surgery. Due to the aggressive nature of the cancer and challenging cancer therapies, it is difficult to manage the DI surgery and prosthetic procedures.
Furthermore, studies that evaluate the DI success in cancer patients are limited because most of the studies had a control group of patients who are under another cancer treatment (instead of a healthy control group) or have no control subjects to compare the success of dental implants. Therefore, the results are sufficient to achieve a conclusion regarding DI success (Tables 13 and 14). According to these clinical studies, CT does not seem to be associated with the higher DI failure when compared with the surgical treatment only. RT seems to be impairing the osseointegration process. Regardless of the cancer-treatment procedure, smoking and alcohol consumption in patients diagnosed with head and neck cancer yield higher implant failures. Additionally, there are no studies about implant therapy in patients with malignant diseases that are treated with BFs [64], and no study determined peri-implant conditions of DI in such patient population.
For improving the DI success in cancer patients, implant surgery is recommended to be performed at least 21 days prior to the initiation or following after 9 months of radiotherapy under a strict surgical asepsis and antimicrobial prophylaxis. Premature loading of the implants should be avoided [28,31].    Studies that indicate dental implant outcomes in patients who underwent radiation therapy.

Radiotherapy and hyperbaric oxygen therapy
RT reduces the cellular and vascular processes of healing, therefore it is assumed to impair the osseointegration and increase the risk of DI-related complications [31]. RT doses higher than 50 Gy are known to hinder osseointegration of DIs [30]. On the other hand, DI placement becomes contraindicated in patients who have received additional therapy of BFs intravenously or hormonal therapy, corticosteroids or immunosuppressive medication [30]. According to the data retrieved from the recent studies, it can be concluded that implant loss is clearly higher in irradiated patients ( Table 14). The failures are more prominent in mandible or in grafted bone [68].
In the past, adjuvant hyperbaric oxygen therapy (HBO) treatment was shown to lead lower DI failure rates in cancer patients who underwent RT than those nonirradiated and irradiated patients [73]. Whereas, according to the recent clinical studies and reviews (
Since a good immune response is necessary for wound healing, immunocompromised conditions have been commonly assumed as a contraindication for DI placement [31]. In animal studies, it is showed that immunosuppressive drugs reduce osteoblast's proliferation and impair implant osseointegration [79,80]. Furthermore, immunocompromised condition may present additional risks for blood borne infections [28]. Therefore, installation of DIs in patients under long-term immunosuppressive treatment should be elucidated with additional measures [81].

Organ transplantation
Bone healing is negatively affected by immunosuppressive medications. There are reports of case series and clinical studies that show successful treatments of DIs in patients who underwent organ transplants ( Table 16). Reviewers stated that DIs could be a valid treatment providing that the appropriate surgical procedures and hygienic conditions are ensured [28,78]. Modification of the immunosuppressive medication could lead a significantly lower toxicity [78].
As a conclusion, it is apparent that DI is not contraindicated for the patients who had organ transplants. However, it is suggested that the patients' medical condition should be investigated with the relevant physician before DI surgery, and the surgery should also be conducted under prophylactic medication in order to reduce the risk of blood-borne infections [28,31].

HIV-positive patients
Acquired immune deficiency syndrome (AIDS) is a condition that is caused by the infection of the human immunodeficiency virus (HIV). HIV-infected individuals may have compromised oral health because of having HIV-associated gingivitis and periodontitis etc. [85] that yield an additional impairment of the general health.
Recently, HIV-infection is regarded as a chronic disease rather than a terminal disease owing to the therapeutic regimen of highly active antiretroviral therapy (HAART) that includes combinations of diverse antiretroviral medications. This regimen, however, is associated with many adverse effects including bone disorders, osteopenia, osteonecrosis, and osteoporosis [86,87]. Hence, there is a need for identifying the predictability of dental implant therapy in patients with HIV-infection.
According to the clinical studies available (Table 17), clinical outcomes regarding the periimplant pathology are conflicting. There may be a tendency for peri-implant infections due to the immunocompromised condition. However, HIV infection does not seem to increase the failure in the short or long term. So DI could be regarded as an eligible treatment for improving quality of life in the HIV-positive patients.

Psychiatric disorders
Patients with neurologic disorders or other disabilities such as cerebral palsy, mental retardation, epilepsy, Down syndrome, Rett's syndrome, Asperger syndrome, Prader-Willi syndrome, fragile X chromosome, dystrophia myotonica, autism, and schizophrenia cause many problems during implant treatment and prosthetic maintenance [93]. Epilepsy impairs the oral condition of patients due to nausea-induced vomiting, mechanical trauma caused by seizures, and antiepileptic drugs-associated oral complications such as gingival overgrowth, xerostomia, and yeast infections [94,95]. Likewise, most widely used antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), affect not only the nervous system but also peripheral tissues  50% of peri-implant pathology rate for mean follow-up of 7 years SR is acceptable. Mean MBL outcomes are scarce and conflicting. Peri-implant pathology incidences seem higher as compared to the healthy population HAART, highly active anti-retroviral therapy; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; MBL, marginal bone loss; BoP, bleeding on probing; SR, survival rate; resp, respectively. Table 17.
Studies that indicate dental implant outcomes in HIV-infected patients.
including bones because of having serotonin receptors [96]. Therefore, SSRI blocks on bone cells have been reported to affect bone formation negatively [97].
Since bone metabolism and oral conditions have an influence on the osseointegration of DI, neuropsychiatric disabilities and the drugs used are considerable issues for DI treatment. Clinical research related to the effect of psychiatric disorders on DI success is limited. It seems that this kind of disorders do not cause higher failures or peri-implant pathology ( Table 18).
On the other hand, SSRIs might increase DI failure rate as presented in a cohort study with a large number of subjects. Further studies are required to ascertain the association between antidepressant drugs and DI failure.

Conclusion
Implant survival in the elderly population, osteoporosis (OP) and HIV infection seem to be similar with the healthy population. CVDs or diabetes may present a small risk. RT seems to have the worst effect on DI success with an average SR of 83%. Some of the other compromised conditions such as alcoholism, bleeding disorders, thyroid disorders, hepatitis, RDs, organ transplantation, and HBO therapy should be investigated with additional clinical data to reveal objective conclusions regarding DIs.  Results with regard to peri-implantitis or peri-implant conditions are insufficient and even conflicting for majority of the compromising systemic aspects. Future studies should be designed for indicating peri-implant tissue health and maintenance in compromised patients.
It must be taken into account that follow-up of the patients in a professional oral maintenance regimen after implant placement reduces the implant failure rate by 80% [12]. Thus, it can be stated that controlling the systemic diseases before the implant therapy and proper establishment of the medical conditions are more important than the presence of a compromise alone.