Abstract
The aim of this study was to systematically review the influence of the local delivery of bisphosphonates on the osseointegration of titanium implants in humans. A search of health sciences databases was performed (The Cochrane Library, Embase, PubMed MEDLINE, ISI Web of Knowledge, Scopus, and SIGLE OpenGrey), including articles published until October 2016. A total of 679 articles were identified. Following the removal of duplicates, 278 were screened by title and abstract. The complete texts of seven studies were read, and of these, three met the inclusion criteria. Each article included in the analysis was submitted to a quality and level of evidence evaluation, and relevant data were extracted and tabulated. Despite methodological differences, all articles presented positive results for osseointegration when a local bisphosphonate was used: the authors reported greater implant stability, better implant survival rates, and reduced peri-implant bone loss when compared with the control groups. On the basis of the results of this systematic review, it is concluded that the local use of a bisphosphonate appears to favour the osseointegration of titanium implants in humans. Nonetheless, a higher level of standardization and the control of methodological bias is required in future research so that stronger evidence might be produced.
Scientific developments in areas such as orthopaedics, medical traumatology, and implant dentistry have facilitated and extended the use of osseointegrated metal implants as a therapeutic option in the endeavour to re-establish functions lost due to trauma, amputation, physical disability , tooth loss and agenesis . In spite of the dissemination of preventive methods in medicine and dentistry and the advancements in rehabilitative specialties, sequelae arising from these problems continue to be a prevalent reality, particularly in the elderly . Because older persons present pathologies such as osteoporosis and diabetes, and as these are factors that have a direct influence on osseointegration , these patients are expected to show lower success rates in rehabilitative therapy. Moreover, due to the aging process, their physiological response to healing is reduced . In this context, new technologies and materials to promote, facilitate, and/or accelerate osseointegration have been investigated, particularly with the objective of immediate dental prosthesis insertion .
The bisphosphonate class of drugs represents one such material that is under investigation. These are substances that biomodulate the bone response and act by inhibiting osteoclast activity, such that they may have a positive influence on bone remodeling . In orthopaedics and traumatology, they appear to diminish bone resorption . In implant dentistry, there are reports that they promote a positive effect on peri-implant bone formation , by improving the bone turnover rate , in addition to acting on improving the fixation of osseointegrated implants in humans .
With a view to diminishing the side effects caused by the systemic use of bisphosphonates , such as oesophagitis and osteonecrosis of the jaw , recent studies have sought alternative systems for local delivery of the drug , either by means of immobilizing the bisphosphonate on the implant surface or by applying the drug directly to the surgical site before implant insertion .
The present systematic review was focused on the following question: Does the local delivery of bisphosphonates influence the osseointegration of titanium implants? Thus, the aim of the present study was to conduct a systematic review of previous studies that have investigated the influence of the local delivery of bisphosphonates (via surface coating and/or direct application to the surgical site) on the osseointegration of titanium implants in humans.
Materials and methods
This study was reported according to the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and has been registered in the PROSPERO database (International Prospective Register of Systematic Reviews, CRD 42016038246).
Inclusion criteria
The following types of study were included in the analysis: randomized controlled clinical trials, prospective and retrospective studies, case–control studies, and case series studies, in which the test group received implants with the local delivery of bisphosphonates and the control group received implants without this delivery system or any other intervention. The population studied in this review was restricted to human beings. There was no restriction on the language of publication.
Exclusion criteria
Clinical case reports, reviews of the literature, studies involving patients with metabolic bone diseases in which the subjects used systemic medications for bone biomodulation or immunosuppression, and studies involving patients with pathologies that could interfere with healing were excluded from the analysis.
Search strategy
The search process was performed by two examiners (MB, TA) in a duplicate and independent manner. The following databases were searched: The Cochrane Library, PubMed MEDLINE, Embase, ISI Web of Knowledge, Scopus, and SIGLE OpenGrey.
The key words used were organized as shown in Table 1 ; the key words were categorized according to the order of the focused question in the ‘PICO’ format (population; intervention; comparison; outcome). Appropriate changes to the key words were made to follow the syntax rules of each database. There was no restriction as regards the year of publication. The search was concluded in October 2016.
| Database | Search strategy |
|---|---|
| Cochrane Library | (“Prostheses and Implants” OR “Dental Implants” OR “Orthopedic Fixation Devices” OR “Bone Screws” OR implant OR “mini-implant” OR miniscrew OR screw OR titanium) AND (local* OR topic* OR coat* OR surface OR immobil* OR “Coated Materials, Biocompatible”) AND (Diphosphonates OR bisphosphonates OR zoledron* OR pamidron* OR alendron* OR ibandron* OR risedron* OR etidron* OR clodron* OR tiludron*) AND (“Bone-Implant Interface” OR Osseointegration OR “Prosthesis Implantation” OR “Dental Implantation, Endosseous” OR fixation OR integration OR stability OR success OR “ISQ” OR “implant stability quotient” OR “RFA” OR “Osstell” OR “Periotest value” OR “PTV” OR “Periotest”) |
| Embase https://www.embase.com/ |
(“Prostheses and Implants” OR “Dental Implants” OR “Orthopedic Fixation Devices” OR “Bone Screws” OR implant OR “mini-implant” OR miniscrew OR screw OR titanium) AND (local* OR topic* OR coat* OR surface OR immobil* OR “Coated Materials, Biocompatible”) AND (Diphosphonates OR bisphosphonates OR zoledron* OR pamidron* OR alendron* OR ibandron* OR risedron* OR etidron* OR clodron* OR tiludron*) AND (“Bone-Implant Interface” OR Osseointegration OR “Prosthesis Implantation” OR “Dental Implantation, Endosseous” OR fixation OR integration OR stability OR success OR “ISQ” OR “implant stability quotient” OR “RFA” OR “Osstell” OR “Periotest value” OR “PTV” OR “Periotest”) |
| PubMed MEDLINE | (Prostheses and Implants [MeSH Terms] OR Dental Implants [MeSH Terms] OR Orthopedic Fixation Devices [MeSH Terms] OR Bone Screws [MeSH Terms] OR implant OR “mini-implant” OR miniscrew OR screw OR titanium) AND (local* OR topic* OR coat* OR surface OR immobil* OR Coated Materials, Biocompatible [MeSH Terms]) AND (Diphosphonates [MeSH Terms] OR bisphosphonates OR zoledron* OR pamidron* OR alendron* OR ibandron* OR risedron* OR etidron* OR clodron* OR tiludron*) AND (Bone-Implant Interface [MeSH Terms] OR Osseointegration [MeSH Terms] OR Prosthesis Implantation [MeSH Terms] OR Dental Implantation, Endosseous [MeSH Terms] OR fixation OR integration OR stability OR success OR “ISQ” OR “implant stability quotient” OR “RFA” OR “Osstell” OR “Periotest value” OR “PTV” OR “Periotest”) |
| Web of Knowledge | ((Prostheses and Implants) OR (Dental Implants) OR (Orthopedic Fixation Devices) OR (Bone Screws) OR implant OR (mini-implant) OR miniscrew OR screw OR titanium) AND (local* OR topic* OR coat* OR surface OR immobil* OR (Coated Materials, Biocompatible)) AND (Diphosphonates OR bisphosphonates OR zoledron* OR pamidron* OR alendron* OR ibandron* OR risedron* OR etidron* OR clodron* OR tiludron*) AND ((Bone-Implant Interface) OR Osseointegration OR (Prosthesis Implantation) OR (Dental Implantation, Endosseous) OR fixation OR integration OR stability OR success OR (ISQ) OR (implant stability quotient) OR (RFA) OR Osstell OR (Periotest value) OR (PTV) OR Periotest) |
| Scopus | (“Prostheses and Implants” OR “Dental Implants” OR “Orthopedic Fixation Devices” OR “Bone Screws” OR implant OR “mini-implant” OR miniscrew OR screw OR titanium) AND (local* OR topic* OR coat* OR surface OR immobil* OR “Coated Materials, Biocompatible”) AND (Diphosphonates OR bisphosphonates OR zoledron* OR pamidron* OR alendron* OR ibandron* OR risedron* OR etidron* OR clodron* OR tiludron*) AND (“Bone-Implant Interface” OR Osseointegration OR “Prosthesis Implantation” OR “Dental Implantation, Endosseous” OR fixation OR integration OR stability OR success OR “ISQ” OR “implant stability quotient” OR “RFA” OR “Osstell” OR “Periotest value” OR “PTV” OR “Periotest”) |
| Grey literature (SIGLE) http://www.opengrey.eu/ |
(“Prostheses and Implants” OR “Dental Implants” OR “Orthopedic Fixation Devices” OR “Bone Screws” OR implant OR “mini-implant” OR miniscrew OR screw OR titanium) AND (local* OR topic* OR coat* OR surface OR immobil* OR “Coated Materials, Biocompatible”) AND (Diphosphonates OR bisphosphonates OR zoledron* OR pamidron* OR alendron* OR ibandron* OR risedron* OR etidron* OR clodron* OR tiludron*) AND (“Bone-Implant Interface” OR Osseointegration OR “Prosthesis Implantation” OR “Dental Implantation, Endosseous” OR fixation OR integration OR stability OR success OR “ISQ” OR “implant stability quotient” OR “RFA” OR “Osstell” OR “Periotest value” OR “PTV” OR “Periotest”) |
Selection of studies
The studies were first assessed by title and abstract. A third reviewer (MG) was consulted to resolve any doubt about whether an article should be included or not. In the event that doubt remained, the article was included in the full-text analysis. Finally, the complete texts were analyzed.
Evaluation of the quality of studies and presentation of the data
The quality and strength of evidence of the studies was evaluated by two examiners after the qualitative evaluation, by means of previously published guidelines , in which a concept based on the characteristics evaluated was attributed to each article individually. The most important data in each article included were summarized and transferred to a table for later presentation and comparison of the results.
Results
A flow chart of this systematic review, as recommended in the PRISMA statement , is given in Fig. 1 . The database search resulted in the identification of a total of 679 records. After the exclusion of duplicate articles, a total of 278 remained; the title and abstract of each of these were read. The inclusion and exclusion criteria were applied, resulting in the selection of seven articles for full-text reading.
Following the full-text reading stage, four studies were excluded and three remained in the systematic review. Two articles were excluded due to the fact that knee implants with no titanium in their composition were used in the research . The third study was excluded because it had not used locally applied bisphosphonate , and the fourth study was excluded because it was a clinical case report . Thus, the remaining articles that fulfilled all of the criteria established for inclusion in the systematic review remained for analysis .
Every article included in the analysis was submitted to an evaluation of quality and level of evidence ( Table 2 ). Furthermore, all were carefully assessed and the relevant data were extracted and tabulated ( Table 3 ). Information were lacking for two studies of the same authors, which appeared to present duplicate samples. So, the authors were contacted by e-mail and the information was clarified: they reported that the studies represented separate samples with no duplication of patients, which allowed both articles to be included.
| Study | Level of evidence | Strength of evidence | Degree of recommendation |
|---|---|---|---|
| Abtahi et al., 2010 | 4 | Limited/weak | C |
| Abtahi et al., 2012 | 1 | Strong | A |
| Zuffetti et al., 2013 | 1 | Strong | A |
| Zuffetti et al., 2013 | Abtahi et al., 2012 | Abtahi et al., 2010 | |
|---|---|---|---|
| Type of study | Double-blind RCT | Double-blind RCT | Case series study |
| Number of patients | 39 | 16 | 5 |
| Mean age (years) | 52.6 | 65 | 66 |
| Sex, male/female | 22/17 | 5/11 | 4/1 |
| Number of implants, case/control | 75/80 | 16/16 | 5/30 |
| Insertion site (bone) | Maxilla and mandible | Maxilla | Maxilla |
| Implant characteristics | Use: dental implants | Use: dental implants | Use: dental implants |
| Shape: screw | Shape: screw | Shape: screw | |
| Specifications: | Specifications: | Specifications: | |
| Osseotite NT, Biomet 3i | Brånemark Mk III TiUnite | Brånemark Mk III TiUnite | |
| 4 × 8.5 to 13 mm, 5 × 8.5 to 13 mm | 3.75 × 11.5 mm | Control: 3.75 × 11.5 mm, 3.75 × 13 mm; Test: 3.75 × 10 mm | |
| Bisphosphonate tested | Aqueous solution of clodronate 3% | Pamidronate disodium 60% (1 mg/ml) | Pamidronate disodium 60% (1 mg/ml) |
| Ibandronate 40% (50 μg/ml) | Ibandronate 40% (50 μg/ml) | ||
| Local delivery system | Implant immersion in the solution containing bisphosphonate for 5 min | Immobilization on implant surface: fibrinogen layer containing the combination of bisphosphonates bound to titanium | Immobilization on implant surface: fibrinogen layer containing the combination of bisphosphonates bound to titanium |
| Solution containing bisphosphonate applied directly at the surgical site | |||
| Analysis performed and period of follow-up | Radiographic analysis at 3 months (baseline), 6 months, 12 months, and 5 years | Radiographic analysis at baseline, 2 months, and 6 months | Radiographic analysis at baseline, 2 months, and 6 months |
| Implant survival rate | Resonance frequency (ISQ) at baseline and 6 months | Resonance frequency (ISQ) at baseline and 6 months | |
| Histological analysis at 6 months | |||
| Implant survival/success rate | At the 5-year follow-up: | Not analyzed | Not analyzed |
| Control group: 91.3% | |||
| Test group: 100% | |||
| ( P = 0.001) | |||
| Marginal bone loss | At the 1-year follow-up (mean ± SD): | Marginal bone loss at the 2-month follow-up was less in the test group than in the control group ( P = 0.017) | Descriptive analysis: |
| Control group: 1.12 ± 0.85 mm | For control implants, one patient showed 1 mm of bone loss on one side of one implant, and one patient showed 1 mm of bone loss on one side of each of three implants | ||
| Test group: 0.85 ± 0.71 mm | For test implants, two patients showed 1 mm of bone loss on both the mesial and distal sides, and one showed 1 mm of loss only on one side | ||
| ( P = 0.15) | |||
| At the 5-year follow-up (mean ± SD): | Marginal bone loss at the 6-month follow-up was less in the test group than in the control group ( P = 0.012) | ||
| Control group: 1.26 ± 0.88 mm | |||
| Test group: 0.98 ± 0.76 mm | |||
| ( P = 0.18) | |||
| ISQ | Not analyzed | Baseline (mean ± SD): | Descriptive analysis: |
| Control group: 61.8 ± 5.7 | For all implants, the values ranged from 47 to 82, with a mean of 62 at insertion and 64 at abutment connection | ||
| Test group: 62.5 ± 5.7 | For the test group, the values ranged from 51 to 76, with a mean of 58 at insertion and 69 at abutment connection | ||
| 6-month follow-up (mean ± SD): | |||
| Control group: 65 ± 6.1 | |||
| Test group: 72.6 ± 5.4 | |||
| Difference of 6.9 units ( P = 0.0001) | |||
| Histological analysis | Not analyzed | Not analyzed | Descriptive analysis: |
| Two test implants were removed en bloc at abutment connection (6 month follow-up); histology showed that both screws were fully osseointegrated; mature lamellar bone trabeculae had formed in intimate contact with the implant | |||
| Important notes | In total 10 patients were excluded because their radiographs were either not available or were of too low quality for evaluation | 2 control implants showed ISQ values lower than 57 at the 6-month follow-up, suggesting questionable or insufficient fixation | The control implants were placed in the anterior region of the maxilla (between the positions of canines), while the test implants were placed in the posterior region of the maxilla (premolar and molar regions) |
| 1 control implant was lost |
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