Objectives: To evaluate the impact of systemic diseases and their treatment on the success of osseointegration therapy.
Material and methods: A search was made to find human studies including subjects treated with osseointegrated oral implants, with a diagnosis of 11 systemic diseases, and reporting at least implant survival.
Results: For most conditions, no studies comparing patients with and without the condition in a controlled setting were found. The evidence to recommend implant therapy was low and consisted in presentations of some successfully treated cases. With regard to diabetes, three types of reports were found: eight case series of diabetic patients treated with implants, six cross-sectional, longitudinal or retrospective evaluations of groups of subjects treated with implants, including some diabetic patients, and one matched control retrospective chart survey. The heterogeneity of the material and the method of data reporting precluded a formal meta-analysis. No unequivocal tendency for subjects with diabetes to have higher failure rates emerged, but the largest of these studies indicated a significant increase in the relative risk of implant failure with diabetes. The data obtained from 17 papers reporting data from osteoporotic patients were also heterogeneous. The evidence for an association of osteoporosis and implant failure was low.
Conclusions: The level of evidence indicative of absolute and relative contraindications for implant therapy due to systemic diseases is low. Many conditions have been listed as potentially critical, but studies comparing patients with and without the condition in a controlled setting are sparse.
Since the beginning of oral implant surgery, it has been recommended to exclude certain patients with systemic health problems from implant therapy. Systemic diseases may affect oral tissues, may increase their susceptibility to other diseases, or interfere with healing. In addition, systemic conditions may be treated with medications or other therapy potentially affecting implants and the tissues carrying them. Implant failures may be classified as ‘early,’ if they occur before, and ‘late,’ if they arise subsequent to the functional loading of the implant.
Detailed lists of diseases for which oral implants are not recommended have been published (e.g. Sugerman & Barber 2002) but it is often questionable on what type of evidence these recommendations are based. For very severe and acute medical problems, calculating the risk for failure in affected subjects seems impossible, simply because patients with such conditions hardly ever receive implants. Chronic medical problems that are not generally considered an absolute contraindication may be evaluated more accurately with regard to their risk to affect osseointegration therapy.
The purpose of this review was to evaluate the impact of systemic diseases and their treatment on the success of osseointegration therapy. The analysis was focused on conditions that are not generally considered an absolute contraindication.
Material and methods
This protocol was based on a preliminary assessment of potentially relevant literature and its size. This was achieved by scoping searches, including searching for existing reviews. Incorporating opinions expressed in four non-systematic reviews (Sugerman & Barber 2002; Beikler & Flemmig 2003; van Steenberghe et al. 2003; Wood & Vermilyea 2004), a list of systemic diseases suspected of having a negative impact on the success of osseointegration therapy was generated. Severe and acute medical conditions for which implant therapy has always been considered a contraindication (e.g. acute infections, severe bronchitis or emphysema, severe anemia, uncontrolled diabetes, uncontrolled hypertension, abnormal liver function, nephritis, severe psychiatric disease, conditions with severe risk of hemorrhage, endocarditis or myocardial infarction) were excluded. With regard to cancer, two aspects needed to be considered: the effect of the disease, and the effect of its treatment on the tissues carrying implants. The treatment of cancer may have occurred before implants are placed or may become necessary in subjects already carrying implants. Furthermore, implants may be inserted in residual or grafted bone. Owing to the heterogeneity of disease conditions, combinations of treatments, sequence of events, time of follow-up, and parameters used for assessment, noted in the preliminary assessment, it was decided not to analyze the issue of cancer further. Implants placed in grafted and/or irradiated tissue have been discussed by others (Chiapasco 1999; Granström 2003). As pointed out by these authors, several factors may potentially influence success rates in irradiated patients; they include, but are not limited to the source, dose and fractionation of irradiation, concomitant therapies (i.e. chemotherapy, hyperbaric oxygen therapy), the anatomic region of implantation, and the timing of medical and dental therapies.
The diseases and conditions retained for further analysis were as follows: scleroderma, Parkinson's disease, Sjögren's syndrome, HIV infection, pemphigus vulgaris, ectodermal dysplasia, long-term immunosupression after organ transplantation, cardiovascular disease, Crohn's disease, controlled diabetes Type 2, and osteoporosis.
Review question and study parameters
In patients treated with dental implants, to what extent does a history of scleroderma, Parkinson's disease, Sjögren's syndrome, HIV infection, pemphigus vulgaris, ectodermal dysplasia, long-term immunosupression after organ transplantation, cardiovascular disease, Crohn's disease, controlled diabetes Type 2, or osteoporosis predict implant failure?
Implant failure was selected as the primary study parameter.
Using EndNote 9 for Macintosh, we conducted 11 Medline searches up to and including October 2005 using the following strategy:
‘implant,’ and ‘oral’ or ‘dental,’ and
Search 1: ‘scleroderma’
Search 2: ‘Parkinson’
Search 3: ‘Sjögren’
Search 4: ‘AIDS’ or ‘HIV’
Search 5: ‘pemphigus’
Search 6: ‘ectodermal dysplasia’
Search 7: ‘Crohn’
Search 8: ‘transplantation’
Search 9: ‘cardiovascular’
Search 10: ‘diabetes’ or ‘insulin therapy’ or ‘glucose intolerance’
Search 11: ‘osteoporosis’ or ‘osteoporotic.’
This search strategy was designed for high recall, rather than high precision in the first instance. There were no language restrictions.
Study selection and quality assessment procedures
The primary study inclusion criteria were:
- •includes human subjects with the respective diagnosis;
- •subjects carry osteointegrated dental implants; and
- •study reports implant survival.
Two independent reviewers screened titles and abstracts of the search results. Any disagreement regarding inclusion was resolved by discussion. The full text of all studies of possible relevance was then obtained for independent assessment by two reviewers against the stated inclusion criteria. Additional studies were sought by scanning the references cited in the retained papers and by personal communication.
The methodological quality was assessed by evaluating the levels of evidence proposed by the Oxford Centre for Evidence-based Medicine (http://www.cebm.net/levels_of_evidence.asp), ranging from the lowest (Level 5, expert opinion without explicit critical appraisal, or based on physiology, bench research, or ‘first principles’), to the highest (Level 1a, systematic reviews with homogeneity of randomized clinical trials).
Data extraction strategy
The following data were sought, separately for each condition, for subjects with and without the specific diagnosis (if available): implant type, number of subjects, number of implants, number of subjects with early failures, number of early failing implants, years of follow-up, number of subjects followed up, number of implants followed up, number of subjects with late failures, and number of late failing implants. Failures were defined as implants lost and were subdivided into those occurring before and those occurring after the functional loading (early and late). Estimated survival rates were also recorded, if reported by the authors.
Results and discussion
For most conditions viewed as potentially critical for implant therapy, no studies comparing patients with and without the condition in a controlled setting were found. For the following diseases, the evidence to recommend implant therapy was low and consisted in presentations of some successfully treated cases: scleroderma (Jensen & Sindet-Pedersen 1990; Patel et al. 1998; Haas 2002; Oczakir et al. 2005), Parkinson's disease (Heckmann et al. 2000; Chu et al. 2004), Sjogren's syndrome (Payne et al. 1997; Isidor et al. 1999; Binon 2005; Oczakir et al. 2005), HIV infection (Rajnay & Hochstetter 1998; Baron et al. 2004; Shetty & Achong 2005), pemphigus vulgaris (Cranin 1991), and ectodermal dysplasia (Smith et al. 1993; Davarpanah et al. 1997; Guckes et al. 1997; Escobar & Epker 1998; Kearns et al. 1999; Bergendal 2001; Oczakir et al. 2005). Successful implant maintenance under long-term immunosupression after organ transplantation was demonstrated in one case (Heckmann et al. 2004). One preliminary retrospective study examined implant treatment outcomes of 39 patients with cardiovascular diseases (Khadivi et al. 1999). Failure rates were not different from those of 98 systemically healthy subjects and 109 patients with a history of other systemic disease. With regard to Crohn's disease, one center reported that out of three treated cases two experienced early implant failures (van Steenberghe et al. 2002).
For two frequently mentioned medical problems potentially affecting osseointegration therapy, and for which implant therapy is not generally considered an absolute contraindication – diabetes mellitus, osteoporosis – a more detailed analysis was possible.
There are two major types of diabetes: Type 1 (previously termed ‘insulin-dependent’) is caused by an autoimmune reaction destroying the β cells of the pancreas, leading to an insufficient production of insulin. Type 2 (previously termed ‘non-insulin dependent’) is viewed as a resistance to insulin in combination with an incapacity to produce additional compensatory insulin. Type 2 diabetes, often linked to obesity (Kahn & Flier 2000), is the predominant form, notably in the adult population in need for implant therapy. Diabetes mellitus is associated with various systemic complications, including retinopathy, nephropathy, neuropathy, micro- and macrovascular disturbances, and impaired wound healing. In the oral cavity, xerostomia, caries, and periodontitis have been linked to diabetes mellitus. The increased susceptibility to periodontitis is thought to be due to a negative influence of diabetes on inflammatory mechanisms and apoptosis, resulting in a deregulated host defense, deficits in wound healing, and microvascular problems (for a review, see Taylor et al. 2004; Graves et al. 2006).
A search using the terms ‘implant,’ and ‘oral’ or ‘dental,’ and ‘diabetes’ or ‘insulin therapy’ or ‘glucose intolerance’ yielded 73 articles. The primary screening excluded 60 of these papers because they were either not reporting results from humans, did not include diabetic subjects, did not deal with osteointegrated implants, or did not quantitatively report failure/success/survival. Scanning the reference lists of the retained studies yielded one additional paper. Furthermore, one MSc thesis (Accursi 2000), found through personal communication, was added.
Data were extracted from 15 articles (Smith et al. 1992; Mericske-Stern & Zarb 1993; Shernoff et al. 1994; Kapur et al. 1998; Balshi & Wolfinger 1999; Accursi 2000; Fiorellini et al. 2000; Morris et al. 2000; Olson et al. 2000; Rutar et al. 2001; Abdulwassie & Dhanrajani 2002; Farzad et al. 2002; van Steenberghe et al. 2002; Peled et al. 2003; Moy et al. 2005). Three types of reports were found: (1) case series of diabetic patients treated with implants, (2) cross-sectional, longitudinal, or retrospective evaluations of groups of subjects treated with implants, including some diabetic patients, and (3) one matched control retrospective chart survey. Table 1 lists eight papers reporting the results from cases with diabetes treated with implants.
One paper (Shernoff et al. 1994) represents a 1-year interim report of the same cases presented with a 5-year follow-up in another publication (Olson et al. 2000). An attempt was made to calculate early, late, and overall failure rates. These values are presented if the data available allowed the calculation. One should note that due to incomplete follow-up of subjects, in these reports the number of subjects and implants available to calculate early and late failure rates does not necessarily correspond (n indicating the number of treated subjects). Thus, estimated overall failure rates are not identical to the sum of early and late failure rates.
Because the data compiled in Table 1 were heterogeneous with regard to the time the cases were followed, the proportion of implants and subjects monitored throughout the entire period varied, and large parts of sought information were unavailable, further meta-analysis was not possible. Within the limitations of the collected material, the following trends were recognized: (1) more failures in diabetic patients occurred early, and (2) the percentage of diabetic patients experiencing failures seemed to be relatively high, but the percentage of failing implants appeared to lie within the normal range.
Seven studies reported data on failures in cohorts including some diabetic subjects. Specific attribution of failures to the diabetic status was not reported in one of them (Mericske-Stern & Zarb 1993). The other six studies are listed in Table 2.
Again, heterogeneity of the material and the method of data reporting precluded any further analysis. Based on the indications of the authors, diabetic patients in general had well-controlled blood glucose levels, at least before and immediately after active implant therapy. No unequivocal tendency for subjects with diabetes to have higher failure rates emerged. The largest of these studies (Moy et al. 2005), a retrospective cohort analysis including 48 diabetic and 1092 non-diabetic patients, treated consecutively by one surgeon over a period of 21 years, using various implant types, however, indicated a statistically significant increase in the relative risk of implant failure with diabetes (RR=2.75%, 95% CI: 1.46–5.18, P<0.05).
At the highest available level of evidence, a group of 15 diabetics, retrospectively identified in a pool of 387 consecutively treated patients, were each matched to two control subjects by age, gender, location of implants (jaw and zone), type of prosthetic restoration, opposing arch, and duration of edentulism (Accursi 2000). In this study, diabetic patients had no increased risk of implant failure and a similar number of prosthodontic complications compared with matched non-diabetic controls.
Osteoporosis has been defined as a decrease in bone mass and bone density and an increased risk and/or incidence of fracture. However, it has been noted that subjects without fractures may have lost a significant amount of bone, while many patients with fractures display levels of bone mass similar to those of control subjects (Cummings 1985; Melton & Wahner 1989). Thus, definitions of osteoporosis based on reduced bone mass or nonviolent fracture are not perfectly synonymous. In addition, the relationship between skeletal and mandibular or maxillary bone mass is limited (von Wowern & Melsen 1979; von Wowern et al. 1988; Jacobs et al. 1996). The World Health Organization has established diagnostic criteria for osteoporosis based on bone density measurements determined by dual-energy X-ray absorptiometry: a diagnosis of osteoporosis is attributed if the bone mineral density level is 2.5 standard deviations below that of a mean young population (Glaser & Kaplan 1997).
A search using the terms ‘implant,’ and ‘oral’ or ‘dental,’ and ‘osteoporosis’ or ‘osteoporotic’ yielded 66 articles. The primary screening excluded 54 of these papers because they were either not reporting results from humans, did not include subjects with osteoporosis, did not deal with osteointegrated implants, or did not report failure/success/survival rates. Three papers were case reports of individual osteoporotic females, all successfully treated with osteointegrated implants (Fujimoto et al. 1996; Eder & Watzek 1999; Degidi & Piattelli 2003). One paper reported a case of implant failure after diphosphonate therapy for osteoporosis (Starck & Epker 1995). Another paper reported three cases of mandibular fractures following implant placement, two of which were in elderly women with advanced mandibular atrophy (Mason et al. 1990). Sixteen women, all with a diagnosis of osteoporosis (low bone density or the occurrence of low-trauma fractures), were assessed in one retrospective study with regard to the success of implants placed between 6 months and 11 years previously. The reported overall success rate was 97% for maxillary, and 97.3% for mandibular implants (Friberg et al. 2001).
The administration of corticosteroids or other endocrinopathies can cause osteoporosis. These drugs are used for a variety of reasons, including, but not limited to, Crohn's disease, asthma, pemphigus, and polyarthritis. Cases have been shown where dental implants were placed, and successfully maintained, under such circumstances (Steiner & Ramp 1990; Cranin 1991; Friberg 1994).
The following publications evaluated implant therapy, including subjects with and without a diagnosis of osteoporosis: van Steenberghe et al. (2002) counted 27 early failures among 1263 consecutively installed implants in 399 patients. Two implants were placed in the presence of a diagnosis of osteoporosis and both were a success. Von Wowern & Gotfredsen (2001) measured changes in the mineral content of the mandibular bone in seven osteoporotic and 11 non-osteoporotic women 5 years after functional loading. Although no implant failure was observed in any patient, a significant difference was noted in the marginal bone loss between the two groups. One retrospective study (Minsk & Polson 1998) found no difference in failure rates between women receiving (n=25) or not receiving (n=91) hormone replacement therapy (HRT). In the study by Moy et al. (2005), already discussed in the context of diabetes, postmenopausal hormone replacement therapy (or lack thereof) was also evaluated. Compared with the total of 1140 patients, the 161 women on HRT had a relative risk for implant failure increased by 2.55 (95% CI: 1.72–3.77, P<0.05). Implant failure rates of postmenopausal women, with or without estrogen replacement therapy, were compared with those of premenopausal women by August et al. (2001). Postmenopausal women without HRT (n=168) had the highest maxillary failure rate (13.6%), which was significantly greater than for premenopausal women (n=114, 6.3%). The difference in maxillary failure rate of unsupplemented and HRT supplemented postmenopausal women (n=75, 8.1%) did not reach statistical significance. Implants placed in the mandible did not show statistically significant differences of failures. With regard to age, the opposite was found by Dao et al. (1993) in an informal review of the Toronto implant study patient series (93 women and 36 men, aged 20–76 years): the highest failure rates were noted in the youngest age group. The heterogeneity and quality of the data presented in these studies precluded any formal meta-analysis.
Including a collection of cases with failures and a group of control patients with successful implants, two publications (Blomqvist et al. 1996; Becker et al. 2000) analyzed factors associated with implant integration failure. The analysis by Blomqvist et al. included 11 patients with severely atrophied maxillary alveolar processes, who had lost 43% of implants placed in a one-stage procedure together with sinus-floor bone grafts. The mean relative bone mass density was significantly lower in these subjects than in 11 control subjects, matched for sex and age, who had received the same reconstructive treatment but no grafts. Becker et al. compared a case population of 49 individuals who had experienced implant loss with a control population consisting of 49 successful recall patients. The groups had the same gender distribution but were unmatched for age. Ten patients in the test group and seven in the control group gave a history of osteoporosis. Generalized estimating equations were used to relate the likelihood of having at least one implant failure in an individual to osteoporosis measures. There was no association between bone density assessed at the radius and ulna and the risk for implant failure. The clinical estimation of local bone quality, however, was related to implant failure, suggesting that a simple visual assessment of bone quality at a site considered for implantation may be more informative than bone density measures obtained at peripheral bones.
Combined risk factors
When discussing the impact of various medical conditions on implant failure, one needs to consider the fact that recorded data may be interrelated. Potential risk factors, particularly those found more frequently in older adults in general – systemic chronic diseases, medications taken on a long-term basis, reduced salivary flow – may not be independent of each other. On the other hand, one single factor alone may not influence the risk measurably, while a combination of multiple, independent factors may have a significant impact. This is supported by retrospective investigations showing, for example, that the combination of specific interleukin-1 gene polymorphisms and smoking could be associated with peri-implant bone loss, whereas only one of these factors alone could not (Feloutzis et al. 2003; Gruica et al. 2004). Established risk factors for osteoporosis include advanced age, smoking and alcohol consumption, steroid therapy, inadequate calcium intake, genetic predisposition, and menopause. Attempts have been made in recent years to analyze several factors jointly. Ekfeldt et al. (2001) recorded age, gender, smoking habits, alcohol and other drug abuse as well as medical conditions such as diabetes, osteoporosis, cytostatic treatment or radiotherapy, impaired immune defense, psychological disorders, and bruxsism in 27 subjects with multiple implant failures and 27 matched control subjects. Patients in the failure group had less favorable bone conditions (bone volume) in general, and bruxsism was noted only in this group. But this group also included more subjects with signs of addiction to alcohol, narcotics, and tobacco. In addition, this group also included one case under cortisone treatment, one case with uncontrolled diabetes mellitus, and two psychologically stressed individuals. In the retrospective study of Moy et al. (2005), the database of 1140 implant patients, including 170 with implant failures, was subject to multiple regression analysis to explore predictors of the number of failed implants per patient. Using this approach, of the variables gender, age, implant location, smoking, hypertension, coronary artery disease, asthma, diabetes, steroids, chemotherapy, head and neck radiation therapy, and postmenopausal HRT, only the following variables were identified as having significant predictive value for implant failure: location in the maxillary arch, diabetes, smoking, and head and neck irradiation.
Observations made in case series can reflect cohort effects, for example results specific to the generation studied and that may not be seen in subsequent generations. Differences in dental status and dental awareness (the current generation of young may reach old age with more and better maintained teeth than the current older generation), changes in dietary patterns and habits in the use and abuse of substances (as availability, preferences, and the awareness of side effects change), and general health conditions (as environmental hazards shift and new therapies and pharmaceutical products become available) may account for many differences that we ascribe to ‘getting old’ (Mombelli 1998). It remains to be investigated which changes observed in older subjects today are a consequence of the physiological aging process (and not due to other extraneous factors), and can thus be expected to occur similarly in future generations.
On the basis of the data found in the literature, the following can be concluded:
- •As a general comment, the level of evidence indicating absolute and relative contraindications for oral implant therapy due to systemic diseases is low. Many conditions have been listed as potentially critical, but studies comparing patients with and without the condition in a controlled setting are sparse.
- •No data exist for the most severe medical conditions, simply because implant therapy has not been performed and documented.
- •The tendency for subjects with diabetes to have higher failure rates is equivocal. The largest study, a retrospective cohort analysis of one clinician, indicated a statistically significant increase in the relative risk of implant failure with diabetes. The only available matched-control retrospective survey, however, indicated no increased risk for failure.
- •Unlike local bone quality, the density of peripheral bone shows only a weak association with the risk for implant failures.