Periodontology 2000, Vol. 17, 1998, 55-62 Printed in Denmark.

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Copvrinht 0 Munksnaard 1998

PERIODONTOLOGY 2 0 0 0
ISSN 0906-6713

Risk factors for osseodisintegration

MAURIZIO S. TONETTI
The documented high survival rate of osseointegrated root form dental implants has led to their acceptance as a realistic treatment alternative in modern dentistry. In spite of these successes, however, it is becoming increasingly clear that successfully integrated implants are susceptible to disease conditions that may eventually lead to the loss of the implant. The purposes of this chapter are: i) to present a brief update regarding the emerging evidence on the nature of these disease conditions; and ii) to discuss the attributes and types of exposure that seem to increase the risk of loss of osseointegration. radiographic and histological picture. In this group of implants a discrepancy was noted between the magnitude of attachment loss and bone loss, with greater amounts of bone loss being observed. Furthermore, 75% of the implants displayed clinically detectable mobility associated with sharp decreases in the percentages of direct implant to bone contact. This eventually led to loss of two of the implants. The histopathological appearance of some of these lesions showed complete replacement of the boneto-implant contact with nonmineralized soft tissue. Of interest, however, was the observation that the epithelium did not migrate apically past the implant shoulder. This has suggested that it may be possible to lose osseointegration without losing clinical attachment.

Peri-implant disease
This section considers only recently published evidence. A review of older literature can be found in previous reviews by this author (45, 47). It has been suggested that disease processes leading to late implant failures may be due to marginal infection (peri-implantitis), biomechanical overload, or a combination of the two (47). In a seminal investigation, Isidor (19, 20) has experimentally shown that both ligature-induced infection and biomechanical overload caused by a supraocclusal contact leading to nonaxial forces may lead to clinical and histopathological alterations of the tissue integration of dental implants. As expected, this investigation indicated that ligature-induced infection resulted in clinically detectable attachment level loss and marginal bone loss that were comparable in magnitude. Implants exposed to infection remained clinically immobile (191, and such lack of clinically appreciable mobility correlated with a high percentage of residual direct bone-to-implant contact in the more apical portion of the implant (20). The histological analysis of these lesions revealed evidence of an obvious supracrestal inflammatory infiltrate (20). Implants subjected to biomechanical overload, however, presented a somewhat different clinical,

Distribution of implant failures in the population

Recent experimental evidence has indicated that implant failures do not seem to be randomly distributed in the population, but seem to cluster in a small subset of individuals. Weyant & Burt (52) have studied the survival of dental implants in a group of 598 consecutive patients with a total of 2098 implants from the U.S. Veterans Administration dental implant registry. Their results indicated that a total of 81 implants in 45 subjects were removed over 5.5 years. Such clustering of failures in a small subpopulation was highly significant (the estimated withinpatient correlation coefficient @ was 0.114, a value that is close to the theoretical maximum for that data set). Another striking observation of that study was a 30% increase in the probability of removal of a second implant in patients with multiple implants presenting with one failure. This observation was confirmed by an independent investigation showing that subjects with one implant failure are likely to

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have more than one implant failure (18). These data are consistent with the current notions on the distribution of severe periodontal disease and are generally interpreted as an indication of the existence of high-risk groups for implant failure. It also implies that patient factors are important determinants of implant survival. No direct evidence, however, is available with regard to within-patient clustering of peri-implant disease. Limited data are also available on the chronological distribution of failures. The hazard rate for implant failures seems to follow an exponential function over a 6-year period. In particular, the highest incidence rate was observed in the early post-implantation period (0 to 120 days). This observation supports the reports indicating a higher rate of implant loss in the earlier healing and/or loading periods. These data, however, model implant failure rather than incidence of disease conditions such as peri-implantitis or biomechanical overload that may eventually lead to the loss of the implanted device. These diseases may require a certain time to reach clinical expression and an even longer period to lead to implant loss. It may therefore be anticipated that the hazard rate for implant failure may be bimodal, with increasing hazard rates as longer observation times will occur. Estimating the prevalence and incidence of attachment loss and radiographic bone loss around successfully osseointegrated implants has received relatively little attention. Cross-sectional investigations have reported wide variation in the prevalence of peri-implantitis lesions. It is currently unclear whether these variations result from variability in disease definition or represent true differences across various populations. The prospective longitudinal investigations reporting the incidence of attachment loss and radiographic bone loss are few. Van Steenberghe et al. (48) reported, in a prospective longitudinal study, an incidence of marginal bone loss rl mm at 2.5% of implants per year of observation in a carefully maintained partially edentulous population. This estimate relates to the incidence between year 1 and year 3 after insertion of the suprastructure. Ellegaard et al. (12) in a retrospective study reported a similar incidence of marginal bone loss during the initial 24 months after insertion of the suprastructure in periodontal patients requiring additional tooth support. In this material, however, the incidence of bone loss increased during the following 3 years, with 45% of all implants displaying marginal bone loss of 1.5 mm or more. This investigation also showed a time-de-

pendent increase in the incidence of probable pockets around implants (12). These data seem to suggest that, at least in periodontal patients, marginal bone loss and periodontal pockets seem to increase with time. Taken together, this initial evidence suggests that hazard rates for implant loss decrease with time, while the incidence of peri-implant disease seems to increase with time, possibly leading to a later increase in implant loss.

Risk assessment and management

The "risk" revolution, that is, the probabilistic assessment and management of the likelihood of a health event or outcome, is one of the most significant advances occurring in medicine over the past decades (17). In the current state of incomplete knowledge of most human diseases, including periimplantitis and dental implant biomechanical overload, health care professionals are generally unable to make accurate predictions concerning the health outcomes of a single patient or implant; the probabilistic approach, which is the epidemiological basis of risk assessment and management, however, allows accurate predictions for a group of individuals or implants presenting with specific attributes or exposures associated with greater probability of disease. This possibility to make accurate predictions for a group of individuals improves the chances of making the right prediction and thus of choosing the appropriate intervention at the individual level as well. Many areas of modern medicine have been engaged in the evidence-building process to perform accurate risk assessment and management for decades. In the field of periodontology, however, the concepts of universal susceptibility to severe forms of periodontal disease and universal response to treatment prevailed until the second half of the 1980s. At that time, pivotal experimental evidence indicated that: i) only a minority of the population is affected with severe forms of periodontitis; and ii) the risk of developing destructive periodontitis does not seem to be homogeneously distributed in the population. This recognition has fostered a major effort towards the identification of the attributes and exposures that are associated with increased risks of developing periodontitis, disease progression and incomplete treatment outcomes. Evidence of these attributes and exposures has recently been reviewed
(14, 37).

In implantology, the recent recognition of the

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Risk factors for osseodisintegration

existence of high-risk groups (52) offers the opportunity to rapidly apply to implantology the concepts that have been developed in medicine and only recently have been applied in periodontology. Of key importance for the clinical application of a risk approach to the diagnosis, prevention and treatment of implant disease is understanding the nature of the association between the recognized factors and the disease of interest. In essence, the link can be causal in nature (risk factor) or a simple association (risk indicator). If there were no causal link, a risk indicator would be useful to identify highrisk groups or individuals but its elimination would be of little therapeutic and preventive significance. On the other hand, if the relationship were causal in nature, elimination, reduction in dose or prevention of the exposure would result in a decrease in the incidence of the disease and possibly better treatment outcomes. At present there is insufficient data to support a causal link between some of the identified factors and peri-implantitis, biomechanical overload or loss of the implanted device. The criteria to differentiate the nature of the association have been extensively discussed in periodontology and should be applied in implantology as well (5, 14, 37).

Subject risk
Among attributes and exposures, cigarette smoking, the cause of tooth loss, poor oral hygiene, osteopenia and osteoporosis, and the assumption of specific medications have been tentatively associated with loss of a dental implant or the presence of disease in the soft and hard tissues that surround the implant. Substantial differences, however, exist in the level of available experimental evidence supporting the significance of each factor. The reported factors will be discussed in more detail. Cigarette smoking Cigarette smoking is a major preventable cause of human disease; it results in increased mortality and morbidity, and it has been estimated that 50% of smokers will eventually die of a smoking-related illness (11). Cigarette smoking has also been known to be associated with impaired healing of surgical wounds (38, 42, 43). The deleterious effects of cigarette smoking on periodontal status have also been well documented (46). In this respect, the current evidence indicates that: i) smokers have a three to sevenfold increase in the risk of developing periodontitis; ii) smoking has been shown to explain up to 51% of the total attributable risk for periodontitis; iii) smokers respond less well to periodontal therapy; and iv) the treatment-associated decrease in the risk of periodontal disease progression seem to be more limited in time. The adverse effect of smoking in implant dentistry has been recently described: in a retrospective analysis of the outcome of 2194 implants placed in 540 subjects, Bain & Moy (3)observed that a significantly greater percentage of implant failures occurred in smokers than in nonsmokers. In facts, smokers had an overall implant failure rate of 11.3%,whereas only 4.8%of the implants that were placed in nonsmokers failed. The difference was highly significant for implants placed in all regions of the jaws, with the exception of the posterior mandible. Furthermore, while failure rates decreased with increasing implant length, the failure rate for each implant length was consistently higher in smokers than in nonsmokers (3). These results were confirmed in several retrospective short-term studies in different populations and using different implant systems (10, 15). Other investigations have assessed the effect of smoking status on the hard and the soft peri-implant tissues. Cigarette smoking was associated with significantly higher levels of marginal bone loss (16, 27)

Risk of osseodisintegration
After obtaining the initial evidence of the existence of high risk groups for implant failures, a series of studies has attempted to identify specific characteristics associated with an elevated probability of implant loss or peri-implant tissue disease. These studies have been performed to identify both patient- and implant-specific characteristics. Most of the investigations, however, have been retrospective or cross-sectional studies whose results need confirmation in prospective studies and in different populations. Furthermore, most investigations did not differentiate between risk factors or indicators for early implant failures, that is, the ones arising during the healing period leading to osseointegration, and risk factors for late implant failures, that is, the onset of disease(s) or the loss of a previously integrated implant. As recently suggested for periodontitis (26), risk estimation and management should be performed at multiple levels: at the subject, implant and individual implant site level. Furthermore, since implants are frequently joined to support a prosthetic device, risk assessment should also be performed using the prosthetic reconstruction as the unit of analysis.

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and soft tissue inflammation (16, 51). The extent of marginal bone loss around successfully osseointegrated implants has been recently associated with the number of cigarettes smoked (28). This investigation has also reported that both smoking status and oral hygiene level are associated with marginal bone loss. A recent prospective investigation has evaluated the effect of a peri-operative smoking cessation protocol on short-term implant survival (2). The protocol involved patient information of the increased risks of implant failure among smokers and involved complete smoking cessation for 1 week before and 8 weeks after surgery. The results indicated that the smokers who complied with the cessation protocol displayed short-term implant failure rates similar to those who had never smoked, and significantly lower than among the smokers who did not follow the protocol. This initial indication of the short-term benefits of a smoking cessation protocol is highly suggestive of a possible causal relationship between smoking and implant failure. Osteopenia and osteoporosis Low bone density at the site of implant placement (type 4 bone) has been associated with increased risk of implant failure in retrospective (21) and prospective (18) investigations. The latter investigation also indicated that patients with low quantity and low density of bone were at highest risk for implant loss. Of particular interest is also the preliminary report of a possible relationship between smoking and low bone density at implant sites (4). The results of this investigation indicated that the prevalence of implant sites with type 4 bone was twice as high among heavy smokers as among people who had never smoked or light smokers. Smoking might therefore produce its negative effects on implant survival both directly and via a possible effect on jaw bone density. Systemic osteoporosis has also been mentioned as a possible risk factor for lack of success with osseointegration. Local rather than systemic bone density, however, seem to be the predominant factor (9, 39). The effect of osteopenia on the survival of dental implants has been directly evaluated in a prospective investigation (18). This demonstrated that implants placed in lower quantities of bone were at higher risk of failure. Indirect evidence to support this notion also comes from the recognition that shorter implants present higher failure rates than longer ones in a given time period.

Diabetes Uncontrolled diabetes has been shown to be a risk factor for periodontal disease (13, 31). So far, evidence related to disease-free implant survival in diabetics is still initial. A l-year report of implant survival in non-insulin-dependent diabetics indicated a 7.3% failure rate (41).This seems to indicate that 0sseointegration can be obtained in the majority of diabetic patients. Nevertheless, the medium- to long-term prognosis of implants placed in these subjects is currently unknown. Medications
A positive medical and medication history has been associated with an increased risk of implant loss (51). Few, isolated reports have associated implant failure with the assumption of anti-osteoporosis drugs and diphosphonate, in particular (44). These reports, though preliminary in nature, should caution clinicians with regards to the potential impact of medication whose mode of action might interfere with the physiology of the bone-remodeling process.

Cause of tooth loss and persistent periodontal infection

A case report showing loss of the endosteal osseo-

integrated implants placed in the dentition of a subject affected with a rapidly progressive, early-onset form of periodontal disease has suggested a possible relationship between the cause of tooth loss and an increased risk of implant disease leading to implant failure (29). Nevins & Langer (32) reported a case series of partially edentulous patients with a clinical diagnosis of recalcitrant periodontitis who were treated with osseointegrated dental implants. In all subjects, implants were present in the oral cavity of patients who had residual periodontal lesions that had not responded to treatment. All subjects received meticulous supportive periodontal care. The authors reported that implants remained stable over the medium-term observation period. Ellegaard et al. (12) have recently evaluated the periodontal parameters and the marginal bone loss of a cohort of implants inserted in periodontal patients requiring additional tooth support up to 7 years previously. At 5 years, authors observed that 45% of the implants displayed marginal bone loss of 1.5 mm or more and 30% of the implants displayed pockets of 6 mm or more even though all patients participated in a periodontal supportive care program. The comparison

Risk factors for osseodisintegration

of these results with the ones obtained in populations at low risk for periodontitis using the same implant system (see Bragger in this volume) suggests that implants inserted in periodontal patients may pose an increased risk for marginal soft and hard tissue problems. Further investigations are urgently needed in this area. Support for the concept that implants may be affected by the periodontal conditions comes from two indirect lines of evidence: i) the similarity in the microflora colonizing teeth and implants in partially edentulous patients (30, 36); and ii) the identification of an hyperinflammatory phenotype in partially edentulous patients with peri-implantitis lesions (40). Inadequate oral hygiene
An increased incidence of implant failure (48) and an increased prevalence of soft tissue problems (51) have been reported in subjects with suboptimal levels of oral hygiene. These observations are consistent with the ones reporting an increased prevalence of complications following oral and periodontal surgery procedures in plaque-infected dentitions. A recent investigation (28) has also suggested a possible synergistic effect of inadequate oral hygiene and cigarette smoking in the determination of marginal bone loss around successfully integrated implants.

with increased production of interleukin 1, has recently been associated with severe forms of periodontal disease (23). It is currently unclear whether or not such a factor is also associated with the development of peri-implantitis. Further knowledge being gathered in this area will enable the open questions to be answered regarding the existence of common risk factors or underlying susceptibility traits for periodontitis and peri-implantitis.

Implant risk
A variety of implant-associated attributes have been reported to be important for implant survival and the absence of peri-implant tissue disease. These relate to the implant site, to the implanted device proper or the interrelation of the two. Given the lack of direct controlled comparisons in clinical trials, however, most of these concepts arise from the interpretation of biological principles and/or indirect scientific evidence. Discussion of implant design factors is beyond the scope of this chapter.

Implant site Substantial experimental evidence has indicated that different intraoral sites are associated with different rates of implant survival. It is currently unclear whether the observed differences can be explained, at least in part, by the insertion of shorter devices in the posterior regions of the jaws and/or by lower bone density in these regions. Implant device Several investigation have indicated that shorter devices seem to be lost more frequently than longer ones (1, 8). This observation is generally interpreted in two ways: i) the shorter implants offer a smaller surface for implant-bone contact and may therefore be more prone to biomechanical overload of the implanted device; and/or ii) a marginal peri-implant infection spreading apically along a shorter implant may require less time to cause resorption of a critical portion of the established osseointegration to lead to loss of the device. Differences in implant surface have also been associated with increased risk of implant loss: hydroxyapatite-coated implants have been found to be at higher risk for failure in a large independent medium-term investigation (51).

Hyperinflammatory phenotype Recent experimental evidence has associated severe forms of periodontal disease with patients who seem to respond to the bacterial challenge represented by the periodontal pathogenic microflora with increased production of inflammatory mediators such as prostaglandin E2 and interleukin 1 (33-35). Such a hyperinflammatory phenotype is considered to be the result of both genetic characteristics and environmental factors (6); it leads to increased production of the inflammatory mediators that represent the major pathway of activation of endogenous matrix metalloproteinases, which are considered to be the principal actors in periodontal breakdown (7). A recent report (40) has indicated that patients presenting with periimplantitis release significantly more prostaglandin E2 and interleukin 1 in response to the bacterial inflammatory stimuli than do implant patients without such disease. A genetic trait, a polymorphism of the interleukin 1 gene complex associated

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Site-specificrisk
At present no direct evidence seem to indicate that peri-implantitis is a site-specific disease: the disease process leading to peri-implant tissue breakdown may be limited to a specific surface of the implant-tissue interface. Rather, most radiographic reports of peri-implantitis show a cup-shaped defect apparently involving the whole surface of the implant. This apparent lack of site specificity explains the fact that, in spite of the long-term emphasis of periodontal research on the recognition of site-specific factors associated with progression of attachment loss, few and only initial investigations have assessed the potential significance of site-specific periodontal parameters as risk indicators for the continuous progression of peri-implantitis. Pocket depth, gingival inflammation, bleeding on probing or the involvement of specific plaque-retentive elements of implant design (such as exposure of threads, retention holes and osteophilic rough surfaces) have not been specifically evaluated as risk factors for the apical spread of marginal infections. Such research, however, is essential to making rational treatment decisions. An initial longitudinal investigation on the progression of untreated peri-implantitis (22) has recently addressed the significance (or lack thereof) of sitespecific clinical parameters on the progression of peri-implantitis. This study will be briefly discussed with emphasis on bleeding on probing. Bleeding on probing
A recent prospective investigation on the progression of peri-implantitis assessed the risk associated with bleeding on controlled force probing of peri-implant pockets (22). The results indicated that absence of bleeding on probing had a 97% negative predictive value for continuing attachment loss over the 6-month experimental observation period. The positive predictive value, however, was much lower. This initial observation seems to indicate that absence of bleeding on probing may be a clinically useful predictor for stability of peri-implant attachment loss. It is also consistent with current data on periodontitis, which show a 99% negative predictive value of bleeding on probing for progressing periodontitis but limited positive predictive value (24, 25). This initial information should be confirmed in largerscale experiments involving a larger number of subjects, implant designs and surfaces.

Attached keratinized mucosa An animal investigation (49) has suggested that implants inserted in movable nonkeratinized mucosa may be more susceptible to progression of peri-implantitis induced by ligatures. A clinical investigation on the influence of masticatory mucosa on the periimplant soft tissue condition, however, failed to support the concept that the lack of an attached portion of keratinized mucosa might jeopardize the maintenance of soft tissue health around dental implants in totally edentulous or partially edentulous patients (50). The data of this clinical investigation failed to demonstrate a significant association between either the width of masticatory mucosa or its marginal mobility on the standard of plaque control and the tested periodontal parameters.

Clinical significance
Clinical application of the improving knowledge about the risk factors and indicators associated with implant loss andlor disease is urgently needed to improve and maintain over time the high success rate of dental implants. Knowledge of subject risk should assist the clinician with determining the prognosis for the individual case and thus with patient selection. Improved understanding of subjectbased risk for peri-implantitis and biomechanical overload combined with a careful preoperative assessment of implant-based risk could be useful in determining number, location and type of implants as well as the design of the reconstruction. Site-specific monitoring of periodontal parameters around implants will help with early diagnosis of marginal infection and in effective monitoring of soft tissue health around these devices during the necessary recall appointments.

References
1. Bahat 0. Treatment planning placement of implants in the posterior maxillae: report of 732 consecutive Nobelpharma implants. Int J Oral Maxillofac Implants 1993: 8: 151-161. 2. Bain C. Smoking and implant failure - benefits of a smoking cessation protocol. Int J Oral Maxillofac Implants 1996: 11: 756759. 3. Bain C, Moy l? The association between the failure of dental implants and cigarette smoking. Int J Oral Maxillofac Implants 1993: 8: 609-615. 4. Bain C, Moy E The influence of smoking on bone quality

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and implant failures. Int J Oral Maxillofac Implants 1994: 9: 123 (abstr). 5. Beck J. Methods of assessing risk of periodontitis and developing multifactorial models. J Periodontol 1994: 65: 468478. 6. Beck J, Garcia R, Heiss G, Vokonas P, Offenbacher S. Peri24. Lang NP, Adler R, Joss A, Nyman S. Absence of bleeding on probing. An indicator of periodontal stability. J Clin Periodontol 1990: 17: 714-721. 25. Lang NP, Joss A, Orsanic T, Gusberti FA, Siegrist BE. Bleed-

odontal disease and cardiovascular disease. J Periodontol

1996: 67: 1123-1137. 7. Birkedal-Hansen H. Role of cytokines and inflammatory mediators in tissue destruction. J Periodont Res 1993: 22: 500-51 1. 8. Buser D, Mericske-Stern R, Bernard J, Behneke A, Behneke N, Hirt H, Belser U, Lang N. Long term evaluation of nonsubmerged IT1 implants. Part 1. 8 year life table analysis of a prospective multicenter study with 2359 implants. Clin Oral Implants Res 1997: 8: 161-172. 9. Dao T, Anderson J, Zarb G. Is osteoporosis a risk factor for osseointegration of dental implants? Int J Oral Maxillofac Implants 1993: 8: 137-144. 10. De Bruyn H, Collaert B. The effect of smoking on early implant failure. Clin Oral Implants Res 1994: 5: 260-264. 11. Doll R, Pet0 R, Hall E, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking. Br Med J 1994: 309: 901911. 12. Ellegaard B, Baelum V Karring T. Implant therapy in peri-

ing on probing. A predictor for the progression of periodontal disease? J Clin Periodontol 1986: 13: 590-596. 26. Lang NP, Tonetti MS. Periodontal diagnosis in treated periodontitis. Why, when and how to use clinical parameters. J Clin Periodontol 1996: 23: 240-50. 27. Lindquist L, Carlsson G, Jemt T. A prospective 15 year follow-up study of mandibular fixed prostheses supported by osseointegrated implants. Clinical results and marginal bone loss. Clin Oral Implants Res 1996: 7: 329-336. 28. Lindquist L, Carlsson G, Jemt T. Association between marginal bone loss around osseointegrated mandibular implants and smoking habits: a 10 year follow-up study. J Dent Res 1997: 76: 1667-1674. 29. Malmstrom HS, Fritz ME, Timmis DP, Van Dyke TE. Osseointegrated implant treatment of a patient with rapidly progressive periodontitis. J Periodontol 1990: 61: 300-304. 30. Mombelli A, Marxer M, Gaberthiiel T, Grunder U, Lang N. The microbiota of osseointegrated implants in patients with a history of periodontal disease. J Clin Periodontol
1995: 2 2 124-130. 31. Nelson R, Shlossman M, Budding L, Saad M, Genco R,

odontally compromised patients. Clin Oral Implants Res

1997: 8: 180-188. 13. Emrich L, Schlossman M, Genco R. Periodontal disease in

non-insulin dependent diabetes mellitus. J Periodontol

1991: 62 123-130. 14. Genco R. Current view of risk factors for periodontal diseases. J Periodontol 1996: 67: 1041-1049. 15. Gorman L, Lambert P, Morris H, Ochi S, Winkler S. The

effect of smoking on implant survival at second stage surgery: DICRG interim report No. 5. Dental Implant Clinical Research Group. Implant Dent 1994: 3: 165-168. 16. Haas R, Haimbock W, Mailath G, Watzek G. The relationship of smoking o n peri-implant tissue: a retrospective study. J Prosthet Dent 1996: 76: 592-596. 17. Hayes M. On the epistemology of risk language, logic and social science. SOC Sci Med 1992: 35:401-421. 18. Hutton J, Heath M, Chai J, Harnett J, Jemt T, Johns R, McKenna S, McNamara D, van Steenberghe D. Factors related to the success and failure rates at 3-year follow-up in a multicenter study of overdentures supported by Brbnemark implants. Int J Oral Maxillofac Implants 1995: 10: 3342. 19. Isidor E Loss of osseointegration caused by occlusal load of oral implants. A clinical and radiographic study in monkeys. Clin Oral Implants Res 1996: 7: 143-152. 20. Isidor E Histologic evaluation of peri-implant bone at im-

plants subjected to occlusal overload or plaque accumulation. Clin Oral Implants Res 1997: 8: 1-9. 21. Jaffin R, Berman C. The excessive loss of Branemark implants in type N bone. A five year analysis. J Periodontol
1991: 62: 2-4. 22. Jepsen S, Riihling A, Jepsen K, Ohlenbusch B, Albers H. Pro-

gressive peri-implantitis. Incidence and prediction of attachment loss. Clin Oral Implants Res 1996: 7: 133-142. 23. Kornman K, Crane A, Wang H, di-Giovine F, Newman M, Pirk E Wilson T, Higginbottom E Duff G. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997: 24: 72-77.

Knowler W. Periodontal disease and NIDDM in Pima Indians. Diabetes Care 1990: 13: 836-840. 32. Nevins M, Langer B. The successful use of osseointegrated implants for the treatment of the recalcitrant periodontal patient. J Periodontol 1995: 66: 150-157. 33. Offenbacher S, Heasman P, Collins J. Modulation of host PGE2 secretion as a determinant of periodontal disease. J Periodontol 1993: 64: 432-444. 34. Offenbacher S, Odle BM, Gray RC, Van Dyke TE. Crevicular fluid prostaglandin E levels as a measure of the periodontal disease status of adult and juvenile periodontitis patients. J Periodont Res 1984: 19: 1-13. 35. Offenbacher S, Odle BM, Van Dyke TE. The use of crevicular fluid prostaglandin E2 levels as a predictor of periodontal attachment loss. J Periodont Res 1986: 21: 101-112. 36. Papaioannou W, Quirynen M, Van Steenberghe D. The influence of periodontitis on the subgingival flora around implants in partially edentulous patients. Clin Oral Implants Res 1996: 7: 405-409. 37. Papapanou El Periodontal diseases: epidemiology. Ann Periodontol 1997: 1: 1-36. 38. Rees T, Liverett D, Guy C. The effect of cigarette smoking on skin flap survival in the face lift patient. Plast Reconstruct Surg 1984: 73: 911-915. 39. Roberts W, Simmons K, Garetto L, De-Castro R. Bone physiology and metabolism in dental implantology: risk factors for osteoporosis and other metabolic diseases. Implant Dent 1992: 1: 11-22. 40. Salcetti J, Moriartry J, Cooper L, Smith E Collins 1, Socransky S, Offenbacher S. The clinical microbial and host response characteristics of the failing implant. Int J Oral Maxillofac Implants 1997: 12: 3 2 4 2 . 41. ShernoffA, Colwell J, Bingham S. Implants for type I1 diabetic patients: interim report. V A implants in diabetes study group. Implant Dent 1994: 3: 183-185. 42. Siana J, Rex S, Gottrup E The effect of cigarette smoking on wound healing. Scand J Plast Reconstr Surg Hand Surg
1989: 23: 207-209.

61

Tonetti
43. Silverstein I? Smoking and wound healing. Am J Med 1992: 9 3 ( ~ ~ p1A): p l 22s-24s. 44. Stark W, Epker B. Failure of osseointegrated dental implants after disphosphonate therapy for osteoporosis: a case report. Int J Oral Maxillofac Implants 1995: 10: 74-78. 45. Tonetti M. Peri-implantitis: biological considerations. J Parodontol Implant01 Oral 1996: 15: 269-284. 46. Tonetti M. The role of smoking and periodontal disease: etiology and management of disease. Ann Periodontol (in press). 47. Tonetti MS, Schmid J. Pathogenesis of implant failures. Periodonto12000 1994: 3: 127-138. 48. van Steenberghe D, Hinge B, Linden U, Quirynen M, Herrmann I, Garpland C. Periodontal indices around natural and titanium abutments: a longitudinal multicenter study. J Periodontol 1993: 64: 538-541.

.Plaque induced peri49. Warrer K, Buser D, Lang N, Karring T implantitis in the presence or absence of keratinized mucosa. An experimental study in monkeys. Clin Oral Implants Res 1995: 6: 131-138. 50. Wennstrom J, Bengazi Lekholm U. The influence of masticatory mucosa on the peri-implant soft tissue condition. Clin Oral Implants Res 1994: 5: 1-8. 51. Weyant R. Characteristics associated with the loss and periimplant tissue health of endosseous dental implants. Int J Oral Maxillofac Implants 1994: 9: 95-102. 52. Weyant R, Burt B. An assessment of survival rates and within patient clustering of failures for endosseous oral implants. J Dent Res 1993: 71: 2-8.

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