The role of systemic diseases and local conditions as risk factors.

Abstract

The integration and long-term success of dental implants exploit the unique biology of the oral cavity, which allows for osseous incorporation of a biomaterial and its long-term health within a bacteria-laden oral milieu.1 The delicate balance of defense and repair mechanisms underlying this unique environment may be challenged by various factors that can act both locally and/or systemically, thereby increasing the risk of implant loss and jeopardizing the long-term success of inserted implants. Local risk factors that are present in the oral cavity and systemic risk factors that have the potential to affect oral health on a systemic level can compromise implant treatment at all stages of treatment delivery by: (a) complicating surgical procedures and other invasive measures required during treatment; (b) compromising the process of tissue healing following implant insertion/increasing the risk of wound infection; and (c) contributing to the deterioration of long-term peri-implant health and tissue stability (Table 1). Reduced bone healing Reduced implant stability Reduced bone remodeling Reduced angiogenesis Reduced bone regeneration Acquired immunosuppression Hypovascularity Iatrogenic immunosuppression Reduced tissue regeneration Hypovascularity hypoxia Leukocyte dysfunction Conditions that interfere with invasive procedures, which include poor general health status (https://www.asahq.org/resources/clinical-information/asa-physical-status-classification-system) as a result of severe systemic disease, may impact upon implant surgery, healing, and maintenance. These are mostly cardiovascular conditions that can place the patient at high risk during surgery, irrespective of the nature of the intervention. Bleeding disorders, which may be innate or acquired, as well as attributable to the use of anticoagulants, may also complicate invasive measures. While the former are considered to be relatively rare, the latter may have a significant impact on daily implant treatment in an aging population. All these conditions can also have a negative impact on long-term peri-implant health and maintenance of peri-implant tissues as a result of compromised vascularity, as well as alterations in the immune defense or repair capacity of peri-implant tissues. The increasing patient demand for implant-based treatments in conjunction with a demographic shift of the patient population has resulted in a growing body of literature dealing with an increasing number of patients presenting with medical conditions. A recent cross-sectional analysis indicated that almost 90% of patients aged > 65 years were taking medication for underlying systemic diseases, which could jeopardize implant success.2 The advent of new treatment modalities, such as antiresorptive drugs or monoclonal antibody therapies, adds to the number of potential risk factors,3 leading to an increasing challenge for the provision of implant-based treatments in the future. The aim of this narrative review was therefore to analyze the importance of systemic and local conditions as risk factors for implant loss by critically evaluating the available evidence. During evaluation of the available literature, it was obvious that the term “implant loss” was used to a much lesser degree than “implant failure.” Very few reports clearly defined implant failure as implant loss, but the context in which this term has historically been used indicates that implant failure was synonymous for implant loss. It is only in the last decade or so that definitions of implant failure have been published, and not until the 2017 World Workshop on Periodontal and Peri-Implant Disease Classification was an international definition agreed upon.4 One of the major reasons for implant loss is the progressive loss of peri-implant bone support. Therefore, marginal bone loss was also included in the analysis. As progressive crestal bone loss around implants in the absence of clinical signs of soft tissue inflammation is rare,5 reported radiographic bone loss was considered in conjunction with clinical peri-implant parameters (where provided) in the individual reports in order to assess the prognostic relevance of the findings. The effect of cardiovascular conditions on implant treatment has been mostly analyzed in cross-sectional cohort studies. In these reports, 15.6%-37%6-8 of patients were affected by cardiovascular diseases. Two recent multivariate analyses of large cohorts consisting of > 6300 and > 22 000 patients did not identify cardiovascular conditions as significant risk factors for implant loss6 or peri-implant pathology.9 This is in line with other cross-sectional studies of smaller cohorts.10-13 Cardiovascular conditions may, however, be associated with the maintenance of long-term peri-implant tissue health. Patients with diseased implants have shown a higher likelihood of cardiovascular comorbidity,8 and a recent prospective study of 44 patients with fixed mandibular prostheses demonstrated an association between cardiovascular disease and increased radiographic peri-implant bone loss.14 The available evidence currently suggests that cardiovascular conditions are not a major risk factor for implant loss. Although the radiographic bone loss reported had not been classified as progressive, cardiovascular disease should be taken into account in maintenance protocols as a potential comorbidity15 that may affect long-term peri-implant tissue health. Bleeding disorders can be innate, such as hemophilia A/B and von Willebrand–Jürgens Syndrome, or acquired during end stage liver disease, with subsequent deterioration of coagulation factors and platelet counts. The placement of implants in patients with hemophilia is rarely documented in case reports.16, 17 In contrast to this, patients with iatrogenic bleeding disorders as a result of anticoagulation therapy have been studied more frequently. Depending on the underlying disease, anticoagulation therapy may encompass antiplatelet drugs, vitamin K antagonists, or direct oral anticoagulants. There is widespread agreement that anticoagulation therapy with antiplatelet drugs or vitamin K antagonists should not be discontinued for dental surgical procedures, as long as a single drug is used and the level of activity is within the therapeutic range (international normalized ratio 2.5-3.0).18, 19 Some uncertainty exists about the management of patients using direct oral anticoagulants, but it is assumed that no interruption of therapy is required; consulting with the hematologist responsible for the patient's care is always advisable.20 Implant surgery in patients undergoing anticoagulation therapy has been reported in a number of controlled clinical studies, albeit consisting of rather small cohorts.21-24 Follow-up included an immediate postoperative period of 8-10 days. All the authors agreed that implants could be safely placed in patients with anticoagulation therapy without interruption of medication of vitamin K antagonists or direct oral anticoagulants. An exception to this may be dual anticoagulation therapy using two antiplatelet drugs (acetylsalicylic acid and clopidogrel), as is commonly employed following stenting of the coronary arteries. In these cases, postoperative morbidity may occur as a result of the increased risk of postoperative bleeding (Figure 1). Implant surgery should therefore be postponed until dual antiplatelet therapy has returned to single antiplatelet drug use. Depending on the type of stent used, this period may vary from 6 weeks to 6 months. To date, no information is available on implant complications arising in anticoagulated patients beyond the immediate period of surgical wound healing. The management of secondary interventions for soft tissue management or peri-implant diseases has not yet been reported on, but may have an impact on the long-term prognosis of implants, and should be taken into consideration when implants are planned for patients with anticoagulation management. Moreover, it should be noted that the necessity for anticoagulation therapy is commonly an underlying cardiovascular condition that needs to be explored and may require additional action. If anticoagulation therapy is used because of a cardiac condition associated with an increased risk for infective endocarditis, antibiotic prophylaxis is required.25 The necessity for antibiotic prophylaxis has been questioned based on a low risk of bacteremia during implant insertion,26 but adherence to current updates of national guidelines is strongly recommended.27, 28 Osteoporosis is characterized by a loss of structural quality of cancellous bone and a reduction in cortical bone thickness resulting in an overall deterioration of bone density. Approximately 48% of women and 15% of men aged ≥ 75 years are known to be affected.29 Primary osteoporosis can arise because of the loss of osteoanabolic effects of sex hormones (type I) in postmenopausal women (and some 10 years later in men), or because of age-related changes in general metabolism (type II). Osteoporosis may also arise secondary to endocrine diseases (eg, Cushing Syndrome, parathyroid hormone excess) or as a result of medication (eg, corticosteroids). Commonly, the diagnosis is derived from dual energy X-ray absorptiometry of the spine and/or the proximal femur. Dual energy X-ray absorptiometry scans provide a T-score that expresses the deviation of bone mineral density of the patient in standard deviations from the average value of healthy young adults. A T-score of < –2.5 is considered to be indicative of osteoporosis. Osteoporosis has been a concern in implant dentistry from an early stage in the development of the field.30-32 A number of papers have addressed the question of whether reduced skeletal bone density is associated with inferior bone quality in the maxilla or mandible. Subjectively, perceived jaw bone quality did not correlate with documented dual energy X-ray absorptiometry scores.33 Moreover, bone next to implants retrieved from osteoporotic patients did not exhibit a reduced number of bone cells or bone-to-implant contact.34 To identify individuals with reduced skeletal bone density, panoramic indices such as the mandibular cortex width,35 panoramic mandibular index,36 and the Klemetti index37 have been developed. A recent review reported these indices as useful in intercepting patients with reduced bone mineral density (T-score < 1), but did not recommend them to intercept patients with osteopenia/osteoporosis.38 Moreover, a systematic review examining the association between objective measures of jaw bone quality and skeletal bone mineral density was unable to clarify whether skeletal osteoporosis is associated with osteoporosis in the jaw bones.39 The role of osteoporosis in the success of implant treatment and the stability of marginal bone has been evaluated in a number of studies. Recent systematic reviews have found no difference in implant survival rates between patients with and without osteoporosis (risk ratio 1.9, 95% confidence interval 0.93-2.08, P = .11),40 or identified a direct but insignificant effect of osteoporosis on dental implant loss (risk ratio 1.09, 95% confidence interval 0.79-1.52).41 Similarly, earlier reviews and case control studies42-45 did not find evidence for an association between skeletal bone mineral density/osteoporosis and increased implant loss. With regard to peri-implant bone loss, the majority of recent studies (two cross-sectional,46, 47 one prospective,48 and one case control study49) reported no difference in radiographic peri-implant bone loss between patients with and without osteoporosis. Only one cross-sectional study reported significantly increased radiographic loss of marginal bone in osteoporotic patients after 1 year.50 All the patients in this study were part of a maintenance program with low periodontal indices and healthy periodontal conditions. Differences in radiographic bone level changes have been attributed to differences in bone remodeling in osteoporotic patients. The relevance of these findings with regard to long-term implant prognosis remains to be determined. While osteoporosis as such may not play a role in implant failure or loss of peri-implant bone, medications used for osteoporosis therapy may interfere with osseointegration and long-term maintenance of peri-implant health. The drugs prescribed are mostly either bisphosphonates51 or denosumab, a monoclonal antibody against the signaling molecule RANKL that is involved in the recruitment of osteoclasts. Bisphosphonates reduce both the resorptive activity of osteoclasts, as well as the activity of osteoblasts in a dose-dependent manner,52, 53 while denosumab directly reduces osteoclast activity.54 The net effect of the antiresorptive therapy is a decrease in bone turnover and remodeling activity of bone tissues. As remodeling is an essential part of bone regeneration and osseointegration, there has been some concern expressed regarding the capacity of peri-implant bone to incorporate implants inserted under bisphosphonate therapy. Controlled clinical trials have reported implant survival rates of 85.7%-100% in patients taking oral bisphosphonates55, 56 and of 100% for those receiving intravenous bisphosphonates.57 Recent meta-analyses of studies assessing the impact of bisphosphonates on implant treatment concluded that there is insufficient evidence for a negative effect of bisphosphonates on implant survival.58, 59 Besides the effect on implant survival, another aspect of the long-term use of antiresorptive agents is the risk of developing a medication-related necrosis of the jaw.60, 61 Medication-related necrosis of the jaw can be triggered by intra-oral surgical interventions and by bacterial invasion from odontogenic infectious lesions,62 as well as through pressure ulcers resulting from poorly fitting removable dentures.63 Triggering of the onset of medication-related necrosis of the jaw during the insertion of dental implants or through the occurrence of peri-implant infections during follow-up under antiresorptive medication is therefore a significant concern,64-66 and most often requires rather invasive measures for management (Figure 2A-G). The prevalence of medication-related necrosis of the jaw has been considered to depend in part on the route and frequency of bisphosphonate administration, with oral bisphosphonates presenting a lower risk for medication-related necrosis of the jaw than intravenous bisphosphonates. More recent reviews suggest that it is not the route of administration but the dosage of antiresorptive medication that affects the prevalence of medication-related necrosis of the jaw.59 The evidence reported for the occurrence of implant-related medication-related necrosis of the jaw under therapy with either bisphosphonates or denosumab is largely based on case reports64, 67-75 or retrospective case series.63, 76-84 In these reports, the number of cases reported for implant-related medication-related necrosis of the jaw in patients taking oral bisphosphonates is almost as high (n = 74) as in patients receiving intravenous bisphosphonates or denosumab (n = 84), suggesting that it is not the route of administration that is critical for the occurrence of implant-related medication-related necrosis of the jaw. Conversely, a number of case reports and case series reporting on implant treatment with concurrent oral bisphosphonate therapy did not find any cases of medication-related necrosis of the jaw in the patients studied.55, 65, 85-95 The existing level of evidence for an association between implant treatment and the occurrence of medication-related necrosis of the jaw under antiresorptive therapy remains low and needs to be substantiated by appropriately designed randomized controlled trials. Nevertheless, the overall number of reported cases of implant-associated medication-related necrosis of the jaw suggests that antiresorptive drugs need to be considered as a risk factor96 and explained to patients97 prior to the start of the treatment, as part of collecting informed consent. Despite the potential hazards of implant-associated medication-related necrosis of the jaw, implants can help to reduce the occurrence of medication-related necrosis of the jaw, for example, in edentulous patients under antiresorptive drugs by avoiding pressure ulcers resulting from poorly fitting dentures. Therefore, multiple factors need to be considered to inform a balanced decision on whether a patient with antiresorptive drugs is eligible for implant therapy (Table 2). If the majority of these factors indicate a low to moderate risk, implant therapy may also be a valid option in patients with antiresorptive medication. When oral surgical procedures are planned in patients with antiresorptive medication, antibiotic prophylaxis is recommended.98, 99 The ideal protocol for administration of antibiotics has not yet been defined. A clear recommendation is given for preoperative antibiotic coverage,100 however, the dosage and duration of postoperative continuation of antibiotic therapy remain to be determined. Adherence to national guidelines (if available) for the perioperative management of patients with antiresorptive medication is strongly advised. Diabetes mellitus is characterized by a lack of insulin secretion as a result of the loss of insulin-producing beta cells in the Langerhans islands of the pancreas (type 1) or by impaired insulin function because of the failure of insulin receptors to appropriately respond to the stimulation by insulin in the periphery (type 2). This results in constantly elevated blood glucose levels in people with diabetes, which leads to nonenzymatic glycation of numerous proteins to produce advanced glycation end products. An elevated level of advanced glycation end products leads to increased expression and activation of receptors for advanced glycation end products. These receptors are present on many cells (eg, endothelial cells, smooth muscle cells, fibroblasts, and mesanglial cells). Their activation mediates inflammatory reactions, which are considered to be responsible for alterations in the microvasculature and thereby can account for diabetic angiopathy.101 Interaction of advanced glycation end products with receptors for advanced glycation end products on macrophages is considered to be associated with macrophage dysfunction, leading to impaired wound healing in patients with diabetes.102 Moreover, bone regeneration is directly impaired on a molecular level in people with diabetes.103 Clinically, poor glycemic control has been shown to negatively affect the balance of bone growth factors in the peri-implant fluid during implant healing.104 Deterioration of vascularity in conjunction with a less efficient immunologic defense and a decreased regenerative capacity of peri-implant bone may compromise the success of implant treatment in patients with diabetes considerably. The effect of diabetes on implant success and the maintenance of peri-implant tissues has therefore been subject to research for more than 20 years. Numerous reviews have analyzed this relationship.105-115 A recent meta-analysis of 14 controlled clinical trials demonstrated that the risk ratio for implant loss between patients with and without diabetes was 1.07 (95% confidence interval 0.08-1.44), without a significant difference between the groups (P = .65).109 Failure to show an association between the existence of diabetes and an increased loss of dental implants is in line with previous reviews.20, 108, 113, 114, 116 The level of glycemic control as assessed by HbA1c appears to have no effect on implant survival rates, although patients with diabetes have demonstrated a compromised process of implant integration.104, 113, 117-119 Moreover, a recent consensus paper reported only inconclusive evidence for diabetes as a risk factor for peri-implantitis.5 While implant loss and peri-implant tissue health are obviously not affected by the presence of diabetes as such, management of the disease may play a role in the maintenance of peri-implant tissue health. A number of reports and systematic reviews have shown that patients with diabetes and poor glycemic control have an increased risk of peri-implantitis and associated peri-implant bone loss.76, 112, 120 This has been reported to become obvious at 2 years of follow-up compared with healthy individuals.107 However, when HbA1c is within the physiological range and oral hygiene is appropriate, the levels of inflammation have been shown to be reduced to those of healthy patients.121 The prophylactic use of antibiotics in oral surgical procedures in patients with diabetes is still controversial. Data from the scarcely available clinical studies favor the use of antibiotics but the evidence for their benefit is still low.122 The immune system is an indispensable part of tissue healing and repair. This holds true also for bone tissue, where pro-inflammatory cytokines are critical, not only for triggering regeneration but also for orchestrating subsequent bone remodeling.123 Moreover, both nonspecific and specific immune responses are crucial for the defense against bacterial invasion following surgery, as well as during the period of restoration and long-term usage. Immune deficiency can thus be critical for integration of dental implants and for the maintenance of peri-implant tissue health. Immune deficiency can result from a large number of conditions. With the exception of very rare innate immune defects, immune deficiencies are mostly acquired in nature. The nonspecific immune response can be affected by medications (immunosuppression/chemotherapy) and metabolic diseases (eg, diabetes mellitus), or because of chronic malnutrition. Specific immunity can also be reduced by immunosuppressive medication, as well as by hematological diseases and lymphotropic viruses (eg, HIV). Iatrogenic immunosuppression as a result of medications is probably the most frequent cause of immune deficiency in dental implant patients. A major indication for deliberate suppression of the immune response is organ transplantation. Organ transplant patients are treated with a combination of drugs that aim to reduce the proliferation of T-cells and to decrease the number of antigen-presenting cells to avoid rejection of the transplanted organ. Commonly, a combination of monoclonal antibody therapy, inhibitors of calcineurin (an enzyme that activates T-cells), corticosteroids, and antiproliferative drugs with different modes of action is employed.124 During the first 3 months, drug doses are high to induce immune tolerance, after which they are reduced for maintenance of immunosuppression. Surgical interventions should not be planned during the induction of immune tolerance. The effect of immunosuppression on the success of implant treatment in organ transplant patients has rarely been reported. Preclinical data indicate that the calcineurin inhibitor cyclosporine inhibits peri-implant bone formation in rabbits.125 At a clinical level, anecdotal information from a case series on 13 patients with liver transplantations reported 100% success after 3 years.126 Moreover, two prospective controlled studies found no significant difference in implant survival rates between organ transplant patients and controls after 1 and 8 years of follow-up.113, 127 Favorable results without significant differences between groups have also been reported for clinical peri-implant soft tissue parameters128 and for the incidence of peri-implant infections.127 The available evidence remains weak129 but suggests that the clinical results of implant treatment are promising and not significantly affected by immunosuppressive drugs used by organ transplant patients. Another important category of diseases in which immunosuppressive medication is used is the group of autoimmune diseases. The most relevant entities for daily clinical work are rheumatic diseases, including rheumatoid arthritis, Sjögren Syndrome, and Crohn's disease, as well as conditions of oral mucosa and skin, such as oral lichen planus, epidermolysis bullosa, and systemic sclerosis. Dermatoses with oral or perioral manifestations represent conditions that may largely cause local problems, while others, such as rheumatoid arthritis or Crohn's disease, may be of greater concern because of the systemic immunosuppressive medications employed. Systemic immunosuppression in rheumatoid arthritis and in Crohn's disease is accomplished by a combination of different drugs, including corticosteroids, biologicals such as monoclonal antibodies against tumor necrosis factor-alpha, and disease-modifying antirheumatic drugs. Disease-modifying antirheumatic drugs are a heterogeneous group of agents that include methotrexate, cyclosporine, and azathioprin, which are also used for immunosuppression in organ transplant patients.130 Autoimmune diseases are characterized by cyclic exacerbations and remissions of clinical symptoms, leading to a variable level of treatment intensity during their course. This should be kept in mind when considering treatment for these patients. Additionally, many patients have continuous steroid medication, therefore, the negative implications of this with regard to bone metabolism, such as steroid-induced osteoporosis and decreased bone regeneration, must also be taken into consideration. Steroid-induced osteoporosis is considered to be present at steroid dosages of ≥ 5 mg prednisolone/d.131 These patients should be carefully explored for receiving antiresorptive medication to avoid the aforementioned problems. There is very little information available regarding patients with rheumatoid arthritis receiving dental implants. A retrospective evaluation of 34 patients with rheumatoid arthritis revealed an implant success rate of 93.8% after 4 years.132 The success rates differed slightly but insignificantly between patients with rheumatoid arthritis only and those with concomitant connective tissue diseases (systemic sclerosis, Sjögren syndrome). The stability of marginal bone appeared unaffected by the basic medication (nonsteroidal anti-inflammatory drugs vs nonsteroidal anti-inflammatory drugs and corticosteroids). The existence of concomitant connective tissue diseases was associated with a significant increase in peri-implant bone loss and higher bleeding indices over time compared with patients with rheumatoid arthritis alone, indicating an increased vulnerability of peri-implant tissues to inflammation. The same group of authors reached similar conclusions133 when examining a smaller cohort of 21 patients with rheumatoid arthritis. Moreover, a retrospective analysis of a larger cohort of 412 patients did not identify isolated rheumatoid arthritis as a significant risk factor for implant loss.134 However, an accumulation of rheumatoid arthritis and systemic sclerosis/Sjögren Syndrome may render these patients more prone to marginal peri-implant infections, thus requiring a strict maintenance protocol. The results available for patients with Crohn's disease are inconclusive. Two cross-sectional analyses and one longitudinal evaluation of three distinct cohorts of different sizes were performed by the same group,10, 135, 136 examining early and late implant loss and the role of different implant surfaces. Neither the longitudinal study nor one of the cross-sectional analyses identified a significant association between Crohn's disease and implant loss,10, 136 whereas the other cross-sectional study did.137 However, the significance of this finding is difficult to interpret as the number of patients in this cohort with Crohn's disease was not provided.108 Autoimmune diseases with oral manifestations (Sjögren Syndrome, systemic sclerosis, epidermolysis bullosa, and oral lichen planus), in conjunction with dental implants, have largely been reported at an anecdotal level for almost 3 decades. In particular, Sjögren Syndrome and systemic sclerosis were subject to early case reports 25 years ago.138, 139 Sjögren Syndrome is considered to be critical for implant survival and success, not only as a result of antirheumatic medication, but even more so because of hyposalivation, leading to increased gingival plaque and bleeding indices, as well as a higher frequency of tooth loss.140 As a result of the oral dryness and unpleasant burning sensations, patients with Sjögren Syndrome are often unable to wear removable mucosa-borne dentures and can benefit significantly from implant treatment. The level of evidence for the effect of Sjögren Syndrome on the success of implant treatment is low. Two case series and six case reports provide insights into 17 patients with a total of 99 implants, with 10 implants being lost after 1.5-13 years of follow-up.138, 141-147 Two recent retrospective cohort studies reported success rates of 95.2% and 97%, respectively.148, 149 Peri-implant soft tissues showed a higher but insignificant increase in the percentage of patients with Sjögren Syndrome (94%) compared with healthy matched controls (64%).149 The existing knowledge thus suggests that implants in patients with Sjögren Syndrome are not significantly compromised by either the underlying disease or antirheumatic medication. The trend for peri-implant mucositis in these patients possibly reflects the elevated gingival scores around natural teeth in patients with Sjögren Syndrome, and needs particular attention during follow-up. Systemic sclerosis is a multisystem autoimmune disease associated with general stiffening of connective tissues resulting in reduced mouth opening, with subsequent problems with food intake, chewing, swallowing, and dental hygiene. Systemic sclerosis has been reported in conjunction with dental implants on an anecdotal level in six individual cases139, 150-155 and for two further cases as