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12_1a_bornstein.qxp 9/8/09 3:04 PM Page 12 Systemic Conditions and Treatments as Risks for
Implant Therapy
Michael M. Bornstein, Dr Med Dent1/Norbert Cionca, Dr Med Dent2/Andrea Mombelli, Prof Dr Med Dent3 Purpose: To evaluate whether systemic diseases with/without systemic medication increase the risk ofimplant failure and therefore diminish success and survival rates of dental implants. Materials andMethods: A MEDLINE search was undertaken to find human studies reporting implant survival in sub-jects treated with osseointegrated dental implants who were diagnosed with at least one of 12 systemicdiseases. Results: For most conditions, no studies comparing patients with and without the conditionin a controlled setting were found. For most systemic diseases there are only case reports or caseseries demonstrating that implant placement, integration, and function are possible in affectedpatients. For diabetes, heterogeneity of the material and the method of reporting data precluded a for-mal meta-analysis. No unequivocal tendency for subjects with diabetes to have higher failure ratesemerged. The data from papers reporting on osteoporotic patients were also heterogeneous. The evi-dence for an association between osteoporosis and implant failure was low. Nevertheless, somereports now tend to focus on the medication used in osteoporotic patients, with oral bisphosphonatesconsidered a potential risk factor for osteonecrosis of the jaws, rather than osteoporosis as a risk factorfor implant success and survival on its own. Conclusions: The level of evidence indicative of absoluteand relative contraindications for implant therapy due to systemic diseases is low. Studies comparingpatients with and without the condition in a controlled setting are sparse. Especially for patients withmanifest osteoporosis under an oral regime of bisphosphonates, prospective controlled studies areurgently needed. INT J ORAL MAXILLOFAC IMPLANTS 2009;24(SUPPL):12-27 Key words: bisphosphonates, diabetes, implant failure, osseointegration, osteoporosis, systemic disease The replacement of missing teeth with endosseous first described by the two research groups of Bråne- implants for the rehabilitation of edentulous or mark and Schroeder. Fundamental experimental partially edentulous patients has become a standard studies demonstrated that titanium implants regu- of care in the past two decades. This significant larly heal with direct bone-to-implant contact, a progress is based on the concept of osseointegration, process termed osseointegration1 or functional anky-losis.2 To achieve and maintain osseointegration, indi-cations and contraindications must be carefully 1Assistant Professor, Department of Oral Surgery and Stomatology, balanced, and proper patient selection is thus a key School of Dental Medicine, University of Bern, Bern, Switzerland.
issue in treatment planning.3 Contraindications can 2Graduate Student, Department of Periodontology, School of Den- be divided into local and systemic/medical. In a paper tal Medicine, University of Geneva, Geneva, Switzerland.
prepared for the second ITI (International Team of Professor and Chairman, Department of Periodontology, Schoolof Dental Medicine, University of Geneva, Geneva, Switzerland.
Oral Implantology) Consensus Conference, Buser andcoworkers4 (2000) proposed to subdivide the general None of the authors reported a conflict of interest.
medical/systemic risk factors into two groups: Correspondence to: Dr Michael Bornstein, Department of OralSurgery and Stomatology, School of Dental Medicine, University Group 1 (very high risk): Patients with serious sys- of Bern, Freiburgstrasse 7, CH-3010 Bern, Switzerland. Fax: +41 temic disease (rheumatoid arthritis, osteomalacia, 31 632 25 03. Email: Michael.bornstein@zmk.unibe.ch osteogenesis imperfecta); immunocompromisedpatients (HIV, immunosuppressive medications); This review paper is part of the Proceedings of the Fourth ITI Consen- drug abusers (alcohol); noncompliant patients sus Conference, sponsored by the International Team for Implan-tology (ITI) and held August 26-28, 2008, in Stuttgart, Germany. 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 13 Group 2 (significant risk): Patients with irradiated reviews,3,6,7,11-14 a list of systemic diseases suspected bone (radiotherapy), severe diabetes (especially of having a negative impact on the success of type 1), bleeding disorders (hemorrhagic diathe- osseointegration therapy was generated. Severe and sis, drug-induced anticoagulation), heavy smoking acute medical conditions for which implant therapy has always been considered a contraindication (eg,acute infections, severe bronchitis or emphysema, Systemic diseases may affect oral tissues by severe anemia, uncontrolled diabetes, uncontrolled increasing their susceptibility to other diseases or by hypertension, abnormal liver function, nephritis, interfering with healing. In addition, systemic condi- severe psychiatric disease, conditions with severe risk tions may be treated with medications or other thera- of hemorrhage, endocarditis or myocardial infarction) pies that potentially affect implants and the tissues carrying them. Several authors have identified dis- As the present review paper is also an update of eases for which dental implants are not recom- the paper published in 2006 by Mombelli and mended, or are at least questionable,3,5-7 but it often Cionca,15 key word selection was additionally based remains unclear on what type of evidence these on the search terms used in the former publication.
The diseases and conditions retained for further Patients receiving dental implants generally fall analysis were: scleroderma, Sjögren syndrome, neu- into the first two physical status categories of the ropsychiatric disorders/Parkinson disease, lichen Classification System of the American Society of ruber planus/oral lichen planus, HIV infection, ecto- Anesthesiology (ASA): P1, a normal healthy patient; or dermal dysplasia, long-term immunosuppression P2, a patient with mild systemic disease.8,9 For very after organ transplantation, cardiovascular disease, severe and acute medical problems, calculating the Crohn disease, diabetes, osteoporosis, oral bisphos- risk of failure in affected subjects seems impossible, phonate medication, and use of radiotherapy for the simply because patients with such conditions hardly treatment of oral squamous cell carcinoma (OSCC).
ever receive implants. These patients fall into the ASAphysical status categories P3 to P6: patients with severe systemic disease (P3); patients with severe sys- In patients treated with dental implants, to what temic disease that is a constant threat to life (P4); extent does a history of scleroderma, Sjögren syn- moribund patients who are not expected to survive drome, neuropsychiatric disorders/Parkinson disease, without an operation (P5); and subjects declared oral lichen planus, HIV infection, ectodermal dyspla- brain dead whose organs may be removed for donor sia, long-term immunosuppression after organ trans- purposes (P6). A recent publication stated that elec- plantation, cardiovascular disease, Crohn disease, tive dental treatment of patients classified as P4 or diabetes, osteoporosis, medication with oral bisphos- higher should ideally be postponed until the patient's phonates, or irradiated bone due to the treatment of medical condition has stabilized and improved to at OSCC increase the risk for implant failure? Implant failure was selected as the primary study The purpose of this review was to evaluate the parameter, and it was further divided into early and impact of systemic diseases, and/or medications used to treat systemic diseases, on the success of dentalimplant therapy. The analysis was focused on condi- tions that are not generally considered to be an Using EndNote X1, 13 MEDLINE searches were con- absolute contraindication. The role of systemic factors ducted based on the process mentioned previously.
in early failures (ie, during the healing period up to The search was conducted up to and including March initiation of prosthetic treatment) and late failures (ie, 2008 using the following strategy: implant AND (oral after implant loading) was analyzed.
2. Sjögren's syndrome and/or Sjögren3. Neuropsychiatric disorders and/or Parkinson To select the most important key words, a preliminary assessment was made of the potentially relevant lit- erature. This was achieved by "scoping" searches, including searching for existing reviews. Incorporat- ing opinions expressed in seven nonsystematic The International Journal of Oral & Maxillofacial Implants 13 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 14 10. Diabetes or insulin therapy or glucose intolerance 11. Osteoporosis or osteoporotic12. Oral bisphosphonates Scleroderma, Lichen Planus, and Ectodermal 13. Radiotherapy or irradiation or irradiated DysplasiaNo controlled studies were found for scleroderma, This search strategy was designed for high recall oral lichen planus, or ectodermal dysplasia to demon- rather than high precision in the first instance. There strate any positive or negative effects on the out- come of implant therapy. For all three conditions onlycase reports or case series could be identified.
Scleroderma is defined as a multisystem disorder characterized by inflammatory, vascular, and sclerotic The primary study inclusion criteria were: changes of the skin and various internal organs, espe-cially the lungs, heart, and gastrointestinal tract. Typi- Study includes human subjects with the respec- cal clinical features in the facial region are a masklike appearance (patients look younger), thinning of the Subjects have osseointegrated dental implants.
lips, microstomia, radial perioral furrowing, sclerosis of Study reports implant failure, survival, and/or suc- the sublingual ligament, and indurations of the tongue.16 These symptoms cause the skin of the face Case series include at least five subjects with the and lips as well as the intraoral mucosa to become respective diagnosis. If case reports with fewer taut, thereby hindering dental treatment and compli- treated subjects were the only available source of cating or even preventing the insertion of dental prostheses. Only five case reports with up to twopatients treated with dental implants could be found Two independent reviewers screened titles and in the literature.17-21 Therefore, the level of evidence abstracts of the search results (MB, NC). Any disagree- for the efficacy of dental implants in these patients is ment regarding inclusion was resolved by discussion including the third independent reviewer (AM). The full Oral lichen planus (OLP) is a common T-cell-medi- text of all studies of possible relevance was then ated autoimmune disease of unknown cause that obtained by two reviewers (MB, NC) for independent affects stratified squamous epithelium virtually exclu- assessment of the stated inclusion criteria. Additional sively.22 OLP has been considered a contraindication studies were sought by scanning the references cited in for the placement of dental implants possibly because the retained papers and by personal communication.
of the altered capacity of the oral epithelium to The methodological quality was assessed using the adhere to the titanium surface.5 In the literature there levels of evidence proposed by the Oxford Centre for are only case reports with up to three patients treated, Evidence-based Medicine (http://www.cebm.net/ including symptomatic23 and asymptomatic21,24 forms levels_of_evidence.asp), ranging from lowest (level 5, of lichen planus. Nevertheless, OLP is a potentially expert opinion without explicit critical appraisal, or malignant condition, which in rare cases may result in based on physiology, bench research, or first princi- malignant transformation.25 Only one case report ples) to highest (level 1a, systematic reviews with describing an OSCC originating from OLP in associa- homogeneity of randomized clinical trials).
tion with dental implants was identified.26 With the lit-erature available at present (level 4), oral lichen planus as a risk factor for implant surgery and long-term suc- The following data were sought, separately for each condition, for subjects with and without the specific Ectodermal dysplasia (ED) is a hereditary disease diagnosis (if available): implant type, number of sub- characterized by congenital dysplasia of one or more jects, number of implants, number of subjects with ectodermal structures. Common extra- and intraoral early failures, number of early failing implants, years manifestations include defective hair follicles and of follow-up, number of subjects followed up, number eyebrows, frontal bossing, nasal bridge depression, of implants followed up, number of subjects with late protuberant lips, hypo- or anodontia, conical teeth, failures, number of late failing implants. Failures were and generalized spacing.27 Most search results for ED defined as implants lost, and were subdivided into were case reports demonstrating treatment success losses occurring before and those occurring after the with dental implants.21,28-37 A few larger case series functional loading (early and late).
report survival and success rates of implants in suchpatients38-42 (Table 1). However, due to the lack ofcontrols, it cannot be determined how these results 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 15 Table 1 Implant Failures: Case Series of Patients with Ectodermal Dysplasia Treated with Implants %Subj = subject-based rate; %Impl = implant-based rate; Y = years of follow-up after restoration; ND = no data available.
compare to those expected in subjects without the dal diseases characterized by rigidity and tremor,51 condition. All studies reported significantly lower sur- there are some case reports suggesting that successful vival and success rates in the maxilla than in the implant placement is possible.52,53 Therefore, the level of evidence for the efficacy of dental implants in thesepatients is low (level 4). For many neuropsychiatric dis- orders there is no literature available.
Sjögren syndrome (SS) is a chronic autoimmune dis-ease affecting the exocrine glands, primarily the sali- vary and lacrimal glands. At present, the etiology of The introduction of highly active antiretroviral ther- SS is far from being understood.43 The most common apy (HAART) for HIV infection has significantly post- symptoms of SS are extreme tiredness, along with dry poned the outbreak of AIDS-defining diseases, eyes (keratoconjunctivitis sicca) and dry mouth reduced the rates of clinically manifested opportunis- (xerostomia). Xerostomia can eventually lead to diffi- tic infections and oral HIV-associated mucosal lesions, culty in swallowing, severe and progressive tooth and extended life expectancy considerably.54 Several decay, or oral infections. Currently, there is no cure for case reports have demonstrated successful implant- SS, and treatment is mainly palliative.44 prosthetic rehabilitation of these immunocompro- Literature on implant performance in patients with mised but immunologically stable patients.55-58 The SS is scarce. There are no controlled studies available, authors of a recent report conclude that no modifica- and only one case series study with eight patients tion of routine dental treatment is needed in HIV-pos- included was found (level of evidence 4).45 The eight itive patients, provided that their immune status is patients in this study were all women receiving a total stable.59 Optimized oral hygiene, regular recall inter- of 54 implants (18 in the maxilla, 36 in the mandible) vals, screening for HIV-related oral lesions, and detec- with a machined surface. At abutment connection tion of hyposalivation/xerostomia are preventive seven of these implants (12.9%) were found not to be therapies used to treat HAART side effects. Only one osseointegrated at abutment connection. During the study was found that investigated the short-term first year of function, two additional implants in the clinical outcome of implant placement in a group of mandible were lost, resulting in an implant-based fail- HIV-positive patients compared to results with an ure rate of 16.7% (patient-based 50%; four patients HIV-negative control group.60 In this study, 20 HIV- out of eight lost at least one implant).
positive subjects and 9 HIV-negative control patientswere followed for 6 months after loading of the implants. The success rates for both groups were 100%; no differences in clinical outcome were noted There is virtually no literature available on implant per- between the two groups (a level 3b study).
formance in patients with neuropsychiatric disorders.
There are no controlled studies or even case series on defined pathological entities to evaluate implant sur- Crohn disease is an idiopathic chronic inflammatory vival and success in these situations. Only case reports disorder of the gastrointestinal tract that may also on selected psychiatric diseases or neurologic disabili- involve the oral cavity. The disease process is charac- ties-such as Down syndrome, autism, Huntington dis- terized by recurrent exacerbations and remissions.61 ease, and schizophrenia-have been published.46-50 The literature regarding the performance of dental For Parkinson disease, one of a group of extrapyrami- implants in patients with Crohn disease is scarce, with The International Journal of Oral & Maxillofacial Implants 15 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 16 a level of evidence 4.62 In a retrospective study with pathologies-ranging from recent myocardial infarc- observation up to 1 week after second-stage surgery, tion to congestive heart failure to atherosclerosis and two of three patients with Crohn disease had implant hypertension-are referred to as CVD. In a preliminary failures (3 out of 10 inserted implants were lost).63 retrospective study with a total of 246 patients receiv- The authors speculated that the presence of anti- ing dental implants, three different groups were sepa- body-antigen complexes might lead to autoimmune rately analyzed for early implant failures72: group I, CVD inflammatory processes in several parts of the body, (39 patients); group II, healthy subjects (98 patients); including the bone-implant interface. However, in group III, other systemic disease (109 patients). The both of these patients with early implant failures, patient-based failure rates varied between 12.2% and other medical and local risk factors were also present: 13.8% in the three groups, and differences were not claustrophobia, smoking, and poor bone quantity.
statistically significant (evidence level 3b).
In a follow-up study, patients treated from 1982 to One center has published three papers on this 2003 were evaluated to assess the influence of sys- subject. The influence of systemic and local factors on temic and local factors on the occurrence of early implant failure, again only up to 1 week after second- implant failures.64 Crohn disease was significantly stage surgery, was evaluated in a retrospective analy- related to early implant failure, exhibiting an odds sis of patients receiving implants.63 CVD was not ratio of 7.95 (95% CI of 3.47 to18.24)-the highest associated with an increased incidence of early odds ratio of all systemic factors evaluated in the implant failures. In a second retrospective analysis of study. Unfortunately, the authors did not provide the a much larger patient population, hypertension and exact number of patients with Crohn disease treated cardiac problems also were not significantly related or the number of implant failures in these patients.
to early implant failure.64 In a third study, the authors In a recent prospective study from the same prospectively evaluated the occurrence of early fail- group, the influence of various systemic and local fac- ures of implants with a modified, oxidized titanium tors on the occurrence of early failures was once surface, again only up to second-stage surgery.65 more evaluated. This time the implants had a modi- Once more, hypertension and cardiac problems were fied, oxidized titanium surface.65 Between November not factors contributing to early implant failure.
2003 and June 2005, 11 of 12 implants placed in A retrospective cohort study including patients patients with Crohn disease integrated successfully.
consecutively treated with dental implants between Unfortunately, the authors again did not provide the 1982 and 2003 revealed that hypertension and car- exact number of patients with Crohn disease treated.
diac disease were not significant factors associatedwith implant failure.73 Transplantation (Heart/Liver/Renal Transplant) Patients receiving transplanted organs generally undergo long-term immunosuppressive therapy, usu- There are two major types of diabetes: Type 1 (previ- ally consisting of cyclosporine A combined with ously termed "insulin-dependent") is caused by an steroids, which have anti-inflammatory proper- autoimmune reaction destroying the beta cells of the ties.66,67 Several animal studies have demonstrated pancreas, leading to insufficient production of insulin.
that cyclosporine may negatively influence bone Type 2 (previously termed "non-insulin-dependent") healing around dental implants and may even impair is viewed as a resistance to insulin in combination the mechanical retention of dental implants previ- with an incapability to produce additional compen- ously integrated in bone.68-70 With regard to studies satory insulin.74 Type 2 diabetes, often linked to obe- in humans, there is no information available in the lit- sity,75 is the predominant form, notably in the adult erature addressing heart or renal transplantations population in need of implant therapy. Diabetes melli- and the performance of subsequently placed or tus is associated with various systemic complications, already present dental implants (evidence level 5).
including retinopathy, nephropathy, neuropathy, There is one case report describing the placement of micro- and macrovascular disturbances, and impaired two interforaminal implants 6 months after liver wound healing. In the oral cavity, xerostomia, caries, transplantation, providing anecdotal evidence of sta- and periodontitis have been linked to diabetes melli- bility 10 years after insertion71 (evidence level 4).
tus. The increased susceptibility to periodontitis isthought to be due to a negative influence of diabetes on inflammatory mechanisms and apoptosis, resulting The literature addressing dental implants and their in a deregulated host defense, deficits in wound heal- success and failure rates in patients with cardiovascu- ing, and microvascular problems (for review, see Taylor lar diseases (CVD) is scarce. In addition, very different and coworkers [2004],76 Graves et al [2006]77).
12_1a_bornstein.qxp 9/8/09 3:04 PM Page 17 Table 2 Implant Failures: Case Series of Diabetic Patients Treated with Implants %Subj = subject-based rate.;%Impl = implant-based rate; Y = years of follow-up; ND = no data available.
The present authors have analyzed the literature reports, the numbers of subjects and implants avail- published up to October 2005 in a previous paper.15 able to calculate early and late failure rates do not At that time, a search using the terms implant AND always correspond (n indicating the number of (oral OR dental) AND (diabetes OR insulin therapy OR treated subjects). Thus, estimated overall failure rates glucose intolerance) yielded 73 articles. The primary are not identical to the sum of early and late failure screening excluded 60 of these papers because they either did not report results from humans, did not Because the data compiled in Table 2 were hetero- include diabetic subjects, did not deal with osseointe- geneous with regard to the length of time the cases grated implants, or did not quantitatively report fail- were followed, the proportion of implants and sub- ure/success/survival. Scanning the reference lists of jects monitored throughout the entire period varied, the retained studies yielded one additional paper.
and large parts of sought information were unavail- Furthermore, one MSc thesis78 found through per- able, a meta-analysis was not possible. Within the lim- sonal communication was added. A repetition of the itations of the collected material, the following trends same search in April 2008 yielded a limited amount of were recognized: (1) more failures in diabetic patients additional original data published with regard to dia- occurred early, and (2) the percentage of diabetic betes: one case report of successful implants in a dia- patients experiencing failures seemed to be relatively betic patient,79 one prospective cohort study,80 and high, but the percentage of failing implants appeared two papers from the same center presenting retro- spective data of a patient population that included Nine studies reported data on failures in cohorts including some diabetic subjects. Specific attribution Data were extracted from 18 articles.63,64,65,73,78,80-92 of failures to the diabetic status was not reported in Three types of reports were found: (1) case series of one of them.82 The other eight studies are listed in diabetic patients treated with implants; (2) cross-sec- tional, longitudinal, or retrospective evaluations of Again heterogeneity of the material and the groups of subjects treated with implants, including method of data reporting precluded any further some diabetic patients; and (3) one matched control analysis. The diabetic patients in general had well- retrospective chart survey (evidence level 3a).
controlled blood glucose levels, at least before and Table 2 lists eight papers, each reporting results immediately after implant therapy. No unequivocal from multiple diabetic patients treated with implants.
tendency for subjects with diabetes to have higher One paper is a 1-year interim report83 of the same failure rates emerged. However, the largest study patient population presented with a 5-year follow-up reporting early and late failures, the retrospective in another publication.88 From the data in these cohort analysis of Moy and coworkers (2005) already papers, an attempt was made to calculate early, late, mentioned in the context of CVD, included 48 dia- and overall failure rates. However, it was noted that betic and 1,092 nondiabetic patients treated consec- due to incomplete follow-up of subjects in these utively by one surgeon over a period of 21 years.73 The International Journal of Oral & Maxillofacial Implants 17 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 18 Table 3 Implant Failures: Studies Including Diabetic (D) and Nondiabetic (non-D) Subjects %Subj = subject-based rate; %Impl = implant-based rate; Y = years of follow-up; ND = no data available.
*Cumulative (variable time).
This study indicated a statistically significant increase tion, opposing arch, and duration of edentulism.78 In in the relative risk of implant failure with diabetes (RR this study, diabetic patients had no increased risk of 2.75, 95% CI: 1.46 to 5.18, P <.05).
implant failure and a similar number of prosthodon- The most recent publications were limited to tic complications compared to matched nondiabetic reporting the rate of early failures: 50 implants placed in a cohort of 35 subjects, including 25 patients with The present review focused on failure. In the diabetes (10 well controlled, 12 moderately con- recent literature, biological complications not neces- trolled, 3 poorly controlled), showed 100% success at sarily leading to failure, ie, peri-implant mucositis and the 4-month follow-up.80 No apparent influence of peri-implantitis, have become an issue of investiga- diabetes on 252 implant failures in 178 patients was tion as well. A cross-sectional survey of 212 subjects noted in the retrospective assessment of Alsaadi and with 578 implants included 29 diabetics.93 In diabetic coworkers (2007)64 including 2,004 subjects treated patients, peri-implant mucositis was diagnosed in with 6,946 implants (only odds ratios reported; case 59% of the cases and peri-implantitis in 24%. In sub- numbers not known). In the recent report of the same jects with no diabetes, the prevalence of mucositis group, 14 early failing implants in 14 patients out of was similar (66%) but peri-implantitis was signifi- 283 subjects treated with 720 implants are reported.65 This data set includes one subject withdiabetes type 1, who had an early failure, and reports 4% early failures in patients with diabetes type 2, in Osteoporosis has been defined as a decrease in bone comparison to 1.9% in nondiabetic subjects.
mass and bone density and an increased risk and/or At the highest available level of evidence, a group incidence of fracture. However, it has been noted that of 15 diabetics, retrospectively identified in a pool of subjects without fractures may have also lost a signif- 387 consecutively treated patients, were each icant amount of bone, while many patients with frac- matched to two control subjects by age, sex, location tures display levels of bone mass similar to those of of implants (jaw and zone), type of prosthetic restora- control subjects.94,95 Thus, definitions of osteoporosis 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 19 based on reduced bone mass or nonviolent fracture endocrinopathies can cause osteoporosis. These are not perfectly synonymous. In addition, the rela- drugs are used for a variety of conditions, including, tionship between skeletal and mandibular or maxil- but not limited to, Crohn disease, asthma, pemphigus, lary bone mass is limited.96-98 The World Health and polyarthritis. Cases have been reported in which Organization has established diagnostic criteria for dental implants were placed, and successfully main- osteoporosis based on bone density measurements tained, under such circumstances.62,106,107 determined by dual energy X-ray absorptiometry: A In 2005 a number of papers were published evalu- diagnosis of osteoporosis is made if the bone mineral ating implant therapy, including subjects with and density level is 2.5 standard deviations below that in without a diagnosis of osteoporosis. A repetition of the same search in April 2008 yielded two additional In October 2005, a search using the terms implant papers in this category. They have already been men- AND (oral OR dental) AND (osteoporosis OR osteo- tioned previously in the context of CVD and dia- porotic) yielded 66 articles. The primary screening betes64,65 and will be discussed below in the context excluded 54 of these papers because they either did not report results from humans, did not include sub- Van Steenberghe and coworkers63 counted 27 jects with osteoporosis, did not deal with osseointe- early failures among 1,263 consecutively inserted grated implants, or did not quantitatively report implants in 399 patients. Two implants were placed in failure/success/survival rates. Three papers were case patients diagnosed with osteoporosis and both were reports of individual osteoporotic females, all success- a success. In 2007, however, the same center reported fully treated with osseointegrated implants.100-102 One a significant association between osteoporosis and paper reported a case of implant failure after therapy early implant failure.64 In a third paper by the same with an oral bisphosphonate for osteoporosis.103 In group, none of their 29 implants placed in patients this report, the patient lost all five implants, which had with osteoporosis failed early, whereas 2% of the been inserted to retain a fixed hybrid mandibular implants in nonosteoporotic subjects failed.65 prosthesis, approximately 2.5 years after insertion. The Von Wowern and Gotfredsen108 measured changes patient's initial medical history was significant for in mineral content of the mandibular bone in 7 osteo- osteoporosis, hyperparathyroidism, nephrolithiasis, porotic and 11 nonosteoporotic women 5 years after thyroidectomy, cholecystectomy, hysterectomy, an functional loading of their implants. Although no ankle fracture, and a hip fracture with total hip implant failure was observed in any patient, a signifi- replacement. Two years after implant placement, ther- cant difference was noted in the marginal bone loss apy for osteoporosis was commenced with etidronate, between the two groups. One retrospective study an oral bisphosphonate known as Didronel. In the fol- found no difference in failure rates between women lowing routine appointment, all five implants exhib- receiving (n = 25) or not receiving (n = 91) hormone ited massive radiolucency all around the implants. The replacement therapy (HRT).109 In the study by Moy et authors concluded that bisphosphonates should be al,73 already discussed in the context of diabetes, post- avoided in patients who have undergone implant menopausal hormone replacement therapy (or lack placement, and implants should not be placed in thereof ) was also evaluated. Compared to the total of patients who require bisphosphonates. This case 1,140 patients, the relative risk for implant failure was report is the first article to mention bisphosphonates increased by 2.55 (95% CI: 1.72 to 3.77, P <.05) in the as a potential risk factor for oral implantology. In light 161 women on HRT. Implant failure rates of of the current controversy (see next section on bis- postmenopausal women, with or without estrogen phosphonates), it is important to note that etidronate replacement therapy, were compared to those of pre- is one of the least potent bisphosphonates known menopausal women by August and coworkers.110 today and is administered via an oral route only.
Postmenopausal women without HRT (n = 168) had Another paper reported three cases of mandibular the highest maxillary failure rate (13.6%), a rate signifi- fractures following implant placement, two of them cantly greater than that of premenopausal women in elderly women with advanced mandibular (n = 114) (6.3%). The difference in the maxillary failure atrophy.104 Sixteen women, all with a diagnosis of rates of HRT-supplemented postmenopausal women osteoporosis (low bone density or the occurrence of (n = 75) (8.1%) and unsupplemented women did not low-trauma fractures), were assessed in one retro- reach statistical significance. Implants placed in the spective study with regard to the success of implants mandible did not show statistically significant differ- placed between 6 months and 11 years previously.
The reported overall success rate was 97.0% for max- With regard to age, the opposite was found by Dao illary implants and 97.3% for mandibular implants.105 et al111 in an informal review of the Toronto implant The administration of corticosteroids or other study patient series (93 women and 36 men, aged 20 The International Journal of Oral & Maxillofacial Implants 19 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 20 to 76 years): The highest failure rates were noted in The second type are nonmalignant bone diseases, the youngest age group. The heterogeneity and qual- the most common of which are osteoporosis and ity of the data presented in these studies precluded Paget disease.116 Marx first showed a connection between bisphosphonate cancer therapy and Thirty-nine women aged 48 to 70 years, 19 with a osteonecrosis of the jawbones in 2003.117 He densitometric diagnosis of osteoporosis in the lum- described 36 cases of osteonecrosis: 80.5% in the bar spine and femoral neck and 20 controls with a mandible, 14% in the maxilla, 5.5% in both jaws normal densitometric diagnosis, were compared by simultaneously. All affected subjects were being Amorim and coworkers.112 Bone mineral density was treated with intravenous bisphosphonates, either measured in the patients and controls by dual-energy pamidronate (brand name Aredia) or zoledronate x-ray absorptiometry. Eighty-two osseointegrated (Zometa). In 28 of these patients the clinical onset dental implants were placed in the mandible, 39 of was preceded by a tooth extraction. Since then, them in the osteoporosis group and 43 in the control numerous centers have reported similar observa- group. The loss of one implant (1.2%) could not be tions, with incidences of osteonecrosis as high as 12% attributed to systemic osteoporosis.
for patients treated with intravenous bisphospho- Two publications including a collection of cases nates.118,119 Today, intravenous bisphosphonate ther- with failures and a group of control patients with suc- apy is considered a major risk for jaw necrosis cessful implants analyzed factors associated with (bisphosphonate-related osteonecrosis of the jaw implant integration failure.113,114 The analysis by [BRONJ]).120 Elective oral surgery, including the inser- Blomqvist et al113 included 11 patients with severely tion of dental implants, is generally contraindicated atrophied maxillary alveolar processes who had lost for subjects on this type of medication.121-123 43% of implants placed in a one-stage procedure The risk for BRONJ appears to be much lower for together with sinus-floor bone grafts. Mean relative oral than for intravenous drug administration,119 but bone mass density was significantly lower in these appears to increase with the duration of bisphospho- subjects than in 11 control subjects, matched for sex nate therapy.120,123 Especially oral administration of the and age, who had received the same reconstructive potent aminobisphosphonates with N-containing side treatment but no grafts. Becker and coworkers114 groups (alendronate/Fosamax; risedronate/Actonel; compared a case population of 49 individuals who ibandronate/Boniva or Bonvivia) over several years has had experienced implant loss to a control population consisting of 49 successful recall patients. The groups The use of bisphosphonates in the treatment of had the same gender distribution but were osteopenia/osteoporosis requires oral administration unmatched for age. Ten patients in the test group and of much lower dosages than in the context of cancer 7 in the control group had a history of osteoporosis.
therapy. The risk for complications of implant therapy Generalized estimating equations were used to eval- in such patients-implant failure or BRONJ-is cur- uate the likelihood of an individual having at least rently unknown and the subject of controversy.120,125 one implant failure. There was no association The present literature search yielded only three clini- between bone density assessed at the radius and cal studies addressing this issue. As these studies are ulna and the risk of implant failure. The clinical esti- very different in design, they will be discussed indi- mation of local bone quality, however, was related to vidually without a direct comparison.
implant failure, suggesting that a simple visual In a report from 2006 presenting data from two assessment of bone quality at a site considered for controlled studies, oral bisphosphonate usage was implantation may be more informative than bone not associated with osteonecrosis of the jaws.126 In density measures obtained at peripheral bones.
the first study, the effects of alendronate on alveolar Based on the results reported above, the evidence bone loss in patients with moderate or severe perio- for the efficacy of dental implants in patients with dontal disease were explored using a double-blind osteoporosis is on the level of multiple case-control placebo-controlled design. Patients were randomized to either 70 mg alendronate or a placebo once weeklyfor 2 years. No BRONJ was observed in this study. The second study was a parallel-arm controlled study of Bisphosphonates reduce or even suppress osteoclast patients with dental implants receiving oral bisphos- function and can therefore be used in the treatment phonates (alendronate or risedronate) versus control of various disorders causing abnormal bone resorp- dental implant patients over the course of at least 3 tion. The first type of disorders includes malignancies years. After the observation period, 100% of the affecting the bone, such as multiple myeloma and implants in the test group and 99.2% of the implants bone metastases of breast and prostate cancer.115 in the control group (no bisphosphonates) were con- 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 21 sidered successful, thus exhibiting no statistically sig- Radiotherapy or Irradiation or Irradiated nificant difference between the two groups. Also in With regard to cancer, two aspects need to be consid- this study, no evidence of BRONJ was observed (evi- ered: the effect of the disease and the effect of its treat- ment on the tissues containing the implants.The cancer In a retrospective analysis of private practice case may have been treated before the implants were records, patients with a history of oral bisphospho- placed, or treatment may become necessary in subjects nates (alendronate or risedronate; mean time of drug who already have implants. Furthermore, implants may usage 3.3 years) and treatment with implant place- be inserted in residual or grafted bone. Due to the het- ment at the time of tooth removal or in an edentu- erogeneity of disease conditions, combinations of treat- lous area were analyzed for possible side effects.127 ments (radiotherapy and chemotherapy), sequence of The implants were left to heal for 6 weeks before initi- events, time of follow-up, and parameters used for ation of prosthodontic restoration. Patients were fol- assessment, it was decided to analyze the risk factor lowed for 12 to 24 months after implant placement, radiotherapy for dental implant placement in a descrip- and hard and soft tissue complications were noted.
tive manner, with special emphasis on existing system- One patient exhibited exposed bone 1 week after atic reviews. As pointed out in two reviews, several implant insertion. No other postoperative sequelae or factors may potentially influence success rates in irradi- complications were noted in any patients, and all ated patients. They include, but are not limited to: the implants were classified as successful 12 to 24 source, dose, and fractionation of irradiation; concomi- months postinsertion. The authors concluded that tant therapies (ie, chemotherapy, hyperbaric oxygen the incidence of BRONJ after an average of 3.3 years therapy); the anatomic region of implantation; and the of bisphosphonate intake following implant insertion timing of medical and dental therapies.130,131 with or without tooth extraction is minimal, and it is In a recent systematic review, the literature from comparable to complication rates in patients without 1990 to 2006 was searched for implant failure rates to a history of oral bisphosphonate therapy (evidence compare the outcomes of preimplantation radiother- apy and postimplantation radiotherapy.132 The The design of the study mentioned above was crit- authors found similar failure rates for the time points icized in a letter to the editor of the Journal of Peri- (3.2% versus 5.4%, respectively; evidence level 2c), but odontology for the following reasons128: the mean cautioned that it was difficult to compare the studies duration of oral bisphosphonates before implant included because of differences in the exact site of placement was relatively short; the dosage of alen- implant placement in relation to the region of radio- dronate taken by the included patients was low (only therapy, in lengths of follow-up periods, in implant four subjects used 70 mg; the remaining patients systems used, and in the use of prostheses, and used 35 mg); and the sample size, with 61 patients, because there were other confounding variables, such as systemic disease, smoking, and parafunction. When A retrospective questionnaire was mailed to 1,319 implants were inserted after radiotherapy, the implant patients in the United States who received implants in failure rate was lower for the mandible (4.4%) than for the years 1998 to 2006129; 458 of these patients the maxilla (17.5%). The authors could not find evi- returned the questionnaire (34.7%). Anamnestically, dence in the literature to support delaying implant 115 patients receiving 468 implants reported that they placement after radiotherapy for 6 to 12 months to had been taking oral bisphosphonates at the time. Of maximize implant success. No implant failures were these 468 inserted implants, all but 2 integrated. The found to occur below a radiation dose of 45 Gy.
115 patients were asked to come for a clinical visit, and In a study analyzing the long-term survival rates of 72 patients presented. In these 72 patients, no BRONJ 316 dental implants placed in the mandible in 71 could be diagnosed. The implant failure rate for patients after radiotherapy and radical surgery, three patients taking oral bisphosphonates was similar to different groups were evaluated: (1) implants in non- that observed for a healthy control population. The irradiated residual bone, (2) implants in irradiated authors therefore concluded that oral bisphospho- residual bone, and (3) implants in grafted bone.133 In nates represent no risk factor for osteonecrosis in this study, the patients were treated with implants implant surgery. Nevertheless, they limited this conclu- after cancer surgery and after receiving a total sion to a duration of bisphosphonate intake not radiochemotherapy dose of 50 Gy. The survival rates longer than 3 years and also warned against simulta- 2, 3, 5, and 8 years after implant insertion were 95%, neous medication with corticosteroids (evidence level 94%, 91%, and 75%, respectively. Implants placed in irradiated bone showed significantly lower survivalrates than implants in nonirradiated mandibularbone. The survival rates for the three groups com- The International Journal of Oral & Maxillofacial Implants 21 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 22 pared in this study were 95% (group 1), 72% (group implants (71 IMZ and 178 Brånemark implants) in the 2), and 54% (group 3). The authors could not show irradiated maxilla and mandible, osteoradionecrosis that the amount of time between irradiation and occurred in 2 patients in the mandible, and necrosis implantation significantly influenced the results.
of soft tissues in the floor of the mouth occurred in 3 A retrospective study reported the survival rates of patients following implant placement. Osteora- 631 implants inserted in cancer patients over a dionecrosis resulted in continuity defects of the period of 25 years.134 This group of irradiated patients mandible and loss of the implants in the region.
was compared to a control group of nonirradiated Some authors even state that this severe complica- patients receiving 614 implants at the same clinic tion may be underreported in the literature.131 during the same period. The mean time of follow-up To minimize the risk of osteoradionecrosis due to in this study was 6.3 years, with a range of 0.5 to 23 implant placement in irradiated bone and to improve years. During this period, 147 implants in patients survival and success rates of implants inserted in irra- undergoing radiotherapy were lost (23.3%), and 76 diated jawbones, hyperbaric oxygen (HBO) therapy implants (12.4%) failed in the control group. High has been advocated.139-142 The rationale for the use of implant failure rates were especially seen after high- HBO therapy is based on its effect on osteogenesis dose radiotherapy and a long time after irradiation.
through stimulation of capillary ingrowth, fibroblastic Failures occurred in all craniofacial regions, but the proliferation, collagen synthesis, and capillary angio- greatest risk of implant failures was found for the genesis.140,143-145 Therefore, HBO has been recom- frontal bone, zygoma, mandible, and nasal maxilla.
mended for all elective surgery in irradiated tissues, for In another retrospective study, the survival of den- the prevention and treatment of osteoradionecro- tal implants placed in the interforaminal region dur- sis,146,147 and to improve osseointegration of implants ing oral cancer surgery was evaluated in relation to inserted in patients undergoing radiotherapy.131,140-142 postoperative radiotherapy.135 In 48 patients with a Nevertheless, the use of HBO in irradiated patients squamous cell carcinoma of the oral cavity, a total of remains controversial in the literature, with some 139 implants were placed. Of these patients, 21 (with authors considering it ineffective.148,149 In a recent sys- 61 implants) received postoperative radiotherapy tematic review from the Cochrane collaboration, with 10 to 68 Gy on the symphyseal area, while 27 Esposito and coworkers compared the success, mor- patients (78 implants) were treated with surgery bidity, patient satisfaction, and cost effectiveness of alone. The average time interval between surgery and dental implant treatment performed with and with- the commencement of radiotherapy was 6 weeks.
out HBO in irradiated patients150 (evidence level 1b).
The success rate of the dental implants was 97% in After screening of the eligible studies, only one ran- the postoperative irradiated group and 100% in the domized controlled clinical trial was identified.151 In nonirradiated group. The prosthetic success was this study, endosseous implants were placed in the lower, irrespective of radiation administration, anterior part of the mandible either under antibiotic because in 12 patients a denture could not be fabri- prophylaxis alone (13 patients) or under antibiotic cated due to death of the patient (7 patients), psycho- prophylaxis combined with pre- and postsurgery HBO logical reasons (4), and loss of an implant (1). The treatment (13 patients). In the HBO group 85.2% of authors concluded that postoperative radiotherapy implants survived, and in the non-HBO group 93.3% did not negatively affect the osseointegration of survived. Interestingly, osteoradionecrosis developed implants placed during oral cancer surgery.
in one patient in the HBO group only. In their system- Regarding the papers evaluating multiple local atic review, Esposito and coworkers concluded that and systemic risk factors for dental implant failure HBO therapy in irradiated patients requiring dental (already mentioned above in the context of Crohn implants may not offer any evident clinical benefits.150 disease, diabetes, osteoporosis, and cardiovasculardiseases), radiotherapy was identified by two studies as being a statistically significant variable. 63,73 The When discussing the impact of various medical con- calculated relative risk of failure for implants due to ditions on implant failure, it is necessary to keep in radiation therapy was 2.73 (95% CI 1.10 to 3.77). Two mind that recorded data may be interrelated. Poten- papers did not find a significant association between tial risk factors, particularly those found more fre- implant failure and irradiation of the patient due to quently in older adults in general-systemic chronic diseases, medications taken on a long-term basis, Besides the problem of implant failure, the risk of reduced salivary flow-may not be independent of induction of osteoradionecrosis is always pre- each other. On the other hand, one single factor alone sent.136-138 Esser and Wagner137 reported that in their may not influence the risk measurably, whereas a group of 64 patients rehabilitated with a total of 249 combination of multiple independent factors may 12_1a_bornstein.qxp 9/8/09 3:04 PM Page 23 have a significant impact. This is supported by retro- spective investigations showing, for example, that thecombination of specific interleukin-1 gene polymor- On the basis of the data found in the literature, the phisms and smoking could be associated with peri- implant bone loss, whereas only one of these factorsalone is not.152-154 Established risk factors for osteo- porosis include advanced age, smoking, and alcohol The level of evidence indicating absolute and relative consumption, steroid therapy, inadequate calcium contraindications for oral implant therapy due to sys- intake, genetic predisposition, and menopause.
temic conditions and treatments is low. Many condi- There have been attempts in recent years to ana- tions have been listed as potential risk factors, but lyze several factors jointly. Ekfeldt and coworkers155 studies comparing patients with and without the recorded age, gender, smoking habits, alcohol and condition in a controlled setting are sparse. In gen- other drug abuse, as well as medical conditions such eral, the available literature is restricted to case as diabetes, osteoporosis, cytostatic treatment or radiotherapy, impaired immune defense, psychologi- The problem of positive publication bias exists in cal disorders, and bruxism in 27 subjects with multi- case reports and smaller case series.
ple implant failures and 27 matched controls. Patients No data exist for the more severe medical condi- in the failure group had less favorable bone condi- tions, simply because implant therapy has not been tions (bone volume) in general, and bruxism was noted only in this group. But this group also includedmore subjects with signs of addiction to alcohol, nar- cotics, and tobacco. In addition, this group also Based on the published literature it is not possible to included one subject under cortisone treatment, one distinguish between subtypes of systemic diseases with uncontrolled diabetes mellitus, and two psycho- such as diabetes type 1 and 2 or primary and sec- logically stressed individuals. In the retrospective study of Moy and coworkers,73 the database of 1,140 The supposition that subjects with diabetes tend implant patients, including 170 with implant failures, to have higher failure rates is equivocal. The only was subjected to multiple regression analysis to available matched-control retrospective survey indi- explore predictors of the number of failed implants cated no increased risk of failure. The largest study, a per patient. Using this approach, the variables sex, retrospective cohort analysis of patients with type 2 age, implant location, smoking, hypertension, coro- diabetes treated by one clinician, indicated a statisti- nary artery disease, asthma, diabetes, steroids, cally significant increase in the relative risk of implant chemotherapy, head and neck radiation therapy, and postmenopausal HRT were evaluated. The only vari- The density of peripheral bone, as currently used ables identified as having significant predictive value for the diagnosis of osteoporosis, showed only a weak for implant failure were location in the maxillary arch, association with the risk of implant failure in two diabetes, smoking, and head and neck irradiation.
Observations made in case series can reflect For bisphosphonate therapy and implant surgery, cohort effects; for example, results specific to the gen- the duration, route, and the dosage of the medica- eration studied that may not be seen in subsequent tion, as well as the type of bisphosphonate are generations. There may be differences in dental sta- reported to play an important role in potential bis- tus and dental awareness (today's young generation phosphonate-related osteonecrosis of the jaws. There may reach old age with more and better maintained are not enough data to estimate the risk for oral bis- teeth), changes in dietary patterns and in the use and phosphonates in the context of implant therapy, with abuse of substances (based on availability, prefer- only one prospective and two retrospective clinical ences, and the awareness of side effects), and changes in general health conditions (as environ- A systematic review of implants placed before and mental hazards shift and new therapies and pharma- after radiotherapy reported failure rates of between ceutical products become available). These may 0% and 12.6% for a follow-up period up to 12 years.
account for many differences that we ascribe to Osteoradionecrosis following implant placement has aging.156 It remains to be investigated which changes been reported in the literature. A recent systematic observed in older subjects today are truly a conse- review found no beneficial effect of hyperbaric oxy- quence of the physiological aging process (and not due to other extraneous factors), and thus can beexpected to occur in future generations as well.
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