Int. J. Oral Maxillofac. Surg.

2017; 46: 1429–1436

http://dx.doi.org/10.1016/j.ijom.2017.04.014, available online at http://www.sciencedirect.com

Systematic Review
Dental Implants

Does local delivery of M. B. Guimarães, T. H. Antes,

M. B. Dolacio, D. D. Pereira,
M. Marquezan

bisphosphonates influence the Department of Restorative Dentistry, Faculty

of Dentistry, Universidade Federal de Santa
Maria, Santa Maria, RS, Brazil

osseointegration of titanium
implants? A systematic review
M. B. Guimarães, T. H. Antes, M. B. Dolacio, D. D. Pereira, M. Marquezan: Does
local delivery of bisphosphonates influence the osseointegration of titanium implants?
A systematic review. Int. J. Oral Maxillofac. Surg. 2017; 46: 1429–1436. ã 2017
International Association of Oral and Maxillofacial Surgeons. Published by Elsevier
Ltd. All rights reserved.

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
Key words: bisphosphonates; osseointegra-
review, it is concluded that the local use of a bisphosphonate appears to favour the tion; dental implants.
osseointegration of titanium implants in humans. Nonetheless, a higher level of
standardization and the control of methodological bias is required in future research Accepted for publication 18 April 2017
so that stronger evidence might be produced. Available online 15 May 2017

Scientific developments in areas such as
orthopaedics, medical traumatology, and
implant dentistry have facilitated and ex-
tended the use of osseointegrated metal
implants as a therapeutic option in the
endeavour to re-establish functions lost
due to trauma, amputation, physical dis-
ability1, tooth loss and agenesis2. In spite
of the dissemination of preventive meth-
ods in medicine and dentistry and the
advancements in rehabilitative specialties,
sequelae arising from these problems con-
tinue to be a prevalent reality, particularly
in the elderly3. Because older persons
present pathologies such as osteoporosis
and diabetes, and as these are factors that
have a direct influence on osseointegra-
tion4,5, these patients are expected to show

0901-5027/01101429 + 08 ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
1430 Guimarães et al.

lower success rates in rehabilitative thera-
py. Moreover, due to the aging process,
their physiological response to healing is
reduced6. In this context, new technolo-
gies and materials to promote, facilitate,
and/or accelerate osseointegration have
been investigated, particularly with the
objective of immediate dental prosthesis
insertion7,8.
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 remodeling9,10. In orthopaedics and
traumatology, they appear to diminish
bone resorption7. In implant dentistry,
there are reports that they promote a posi-
tive effect on peri-implant bone forma-
tion11, by improving the bone turnover
rate12, in addition to acting on improving
the fixation of osseointegrated implants in
humans9,10,13.
With a view to diminishing the side
effects caused by the systemic use of
bisphosphonates14, such as oesophagitis15
and osteonecrosis of the jaw16–19, recent
studies have sought alternative systems for
local delivery of the drug7,9,10,13,20, either
by means of immobilizing the bisphospho-
nate on the implant surface13,20,21 or by
applying the drug directly to the surgical
site before implant insertion7,12,22,23.
The present systematic review was fo-
cused on the following question: Does the
local delivery of bisphosphonates influ-
ence 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

Table 1. Search strategy through key words, by database.

Database
Cochrane Library
http://www.cochranelibrary.com/
Embase
https://www.embase.com/
PubMed MEDLINE
http://www.ncbi.nlm.nih.gov/pubmed
Web of Knowledge
http://apps.webofknowledge.com
Scopus
http://www.scopus.com
Grey literature (SIGLE)
http://www.opengrey.eu/
Search strategy
(‘‘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’’)
(‘‘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’’)
(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’’)
((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)
(‘‘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’’)
(‘‘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’’)
 Local bisphosphonates and implant osseointegration 1431

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)24 and has been registered in the
PROSPERO database (International Pro-
spective Register of Systematic Reviews,
CRD 42016038246).
Inclusion criteria
The following types of study were includ-
ed in the analysis: randomized controlled
clinical trials, prospective and retrospec-
tive 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 re-
stricted to human beings. There was no
restriction on the language of publication.
Exclusion criteria
Clinical case reports, reviews of the liter-
ature, studies involving patients with met-
abolic bone diseases in which the subjects
used systemic medications for bone bio-
modulation or immunosuppression, and
studies involving patients with patholo-
gies 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 data-
bases were searched: The Cochrane Li-
brary, 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 publica-
tion. The search was concluded in October
2016.

Records Records Records Records Records Records

Identification

identified identified identified identified identified identified

through through through ISI through through through grey
Cochrane PubMed Web of Scopus Embase literature
Library MEDLINE Knowledge (n = 213) (n = 70) (SIGLE)
(n = 7) (n = 195) (n = 194) (n = 0)

Records after duplicates removed

Screening

(n = 278)

Records screened Records excluded

(n = 278) (n = 271)

Full-text articles assessed for

eligibility (n = 7) Full-text articles excluded, with
reasons (n = 4)
Wilkinson et al., 200126
Bambini et al., 200327 Hilding and Aspenberg, 20077; Toksvig-
Eligibility

Hilding and Aspenberg, 20077 Larsen and Aspenberg, 201320 – did not
Abtahi et al., 20109 use titanium implants
Abtahi, et al., 201210 Wilkinson et al., 200126 – did not use
Toksvig-Larsen and Aspenberg, 201320 local delivery of bisphosphonate
Zuffetti et al, 201313 Bambini et al., 200327 – case report

Studies included in qualitative

synthesis (n = 3)
Included

Abtahi et al., 20109

Abtahi, et al., 201210
Zuffetti et al, 201313

Fig. 1. Flow diagram of the different stages of the systematic review.

1432 Guimarães et al.
Selection of studies
The studies were first assessed by title and
abstract. A third reviewer (MG) was con-
sulted 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 guidelines25, in
which a concept based on the character-
istics evaluated was attributed to each
article individually. The most important
data in each article included were summa-
rized 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 state-
ment24, 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 research7,20.
The third study was excluded because it
had not used locally applied bisphospho-
nate26, and the fourth study was excluded
because it was a clinical case report27.
Thus, the remaining articles that fulfilled
all of the criteria established for inclusion
in the systematic review remained for
analysis9,10,13.
Every article included in the analysis
was submitted to an evaluation of quality
and level of evidence (Table 2). Further-
more, all were carefully assessed and the
Table 2. Level of evidence and evaluation of the quality of studies included in the analysis.
Level of
Study evidence
Abtahi et al., 20109 4 Limited/weak
Abtahi et al., 201210 1 Strong
Zuffetti et al., 201313 1 Strong
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 sepa-
rate samples with no duplication of
patients, which allowed both articles to
be included.
The studies selected were performed
between 2010 and 2013. All of the patients
included in the studies received titanium
dental implants for oral rehabilitation. The
number of patients included in the sample
ranged from five9 to 3913; their mean age
ranged from 52.613 to 66 years9.
Two different brands of implants were
used in the studies: Brånemark Mk III
TiUnite (Nobel Biocare, Zurich,
Switzerland)9,10 and Osseotite NT (Bio-
met 3i, Palm Beach Gardens, FL, USA)13.
The length and diameter of the implants
inserted was not standardized across the
studies. Moreover, the active principle,
concentration, and system of bispho-
sphonate delivery also varied among
the studies.
The types of analysis performed to eval-
uate the results and the time-points at
which these analyses were done were also
assessed. Radiographs were taken in all of
the studies, and this was complemented by
an analysis of the implant survival rate in
one study13, determination of the implant
stability quotient (ISQ) in two studies9,10,
and a histological analysis in one study9.
The time intervals of the evaluations were
not standardized.
In spite of the methodological differ-
ences, all of the articles presented positive
results for osseointegration when a local
bisphosphonate was used (test implants).
Implant survival at the 5-year follow-up in
the control group was significantly lower
than that in the test group, with survival
rates of 91.3% and 100%, respectively
(P = 0.001)13. Marginal bone loss values
were significantly lower in the test group
than in the control group at the 2-month
and 6-month follow-ups in one study10,
and at the 1-year and 5-year follow-ups in
another13. The test implants showed a
higher increase in ISQ value from baseline
to 6 months than did the controls
Strength of Degree of
evidence recommendation
C parison among the studies selected
A statistical terms
A
(P = 0.0001)10. Histological analysis of
two test implants removed en bloc at the
6-month follow-up showed mature lamel-
lar bone trabeculae in intimate contact
with the implants9.
Discussion
The articles analyzed in this systematic
review demonstrated that the local use of a
bisphosphonate appeared to favour the
osseointegration of titanium implants:
the authors reported greater stability10, a
lower level of peri-implant bone loss10,13,
and a higher survival rate13. In addition,
the qualitative analysis of implants
inserted with the local delivery of bispho-
sphonates showed full osseointegration,
with no signs of toxic effects9.
The use of bisphosphonates as an adju-
vant for osseointegration was initially con-
sidered due to the characteristics of this
class of drugs: they act as biomodulators
of bone remodelling, with the main action
occurring through the inhibition of osteo-
clasts28. The positive effect of the local
delivery of a bisphosphonate on osseoin-
tegration has been investigated widely in
different animal models23,29–34. One of the
inclusion criteria of this systematic review
was studies in human beings, with the
intention of approximating the scientific
question to clinical reality. Only three
articles were obtained as a result of the
search all of them in the field of den-
tistry showing early evidence of the
need for further studies on this topic, in
clinical scenarios.
Not only has there been little research,
but the authors of this systematic review
perceived poor standardization in the
choice of the type of bisphosphonate used;
there were variations in the chemical com-
position and classification in general, in-
dicating notable differences among the
studies. The literature has highlighted that
first-generation non-nitrogen-containing
bisphosphonates, such as clodronate13,
bind weakly to hydroxyapatite crystals
when compared with ibandronate9,10 or
pamidronate9,10 (classified as second-gen-
eration), which are more potent because
there is binding to the nitrogen ion35.
While the anti-resorptive power of clodro-
nate is 10, that of pamidronate reaches 100
and that of ibandronate ranges between
1000 and 10,000. Moreover, because of
this difference in power, the clinical doses
used also end up differing markedly36. As
a result of the information above, a com-
in
did not appear to be
indicated.
Table 3. Summary of the data collected from the selected articles.
Zuffetti et al., 201313
Type of study Double-blind RCT
Number of patients 39
Mean age (years) 52.6
Sex, male/female 22/17
Number of implants, case/control 75/80
Insertion site (bone) Maxilla and mandible
Implant characteristics Use: dental implants
Shape: screw
Specifications:
Osseotite NT, Biomet 3i
4  8.5 to 13 mm, 5  8.5 to 13 mm
Bisphosphonate tested Aqueous solution of clodronate 3%
Local delivery system Implant immersion in the solution
containing bisphosphonate for 5 min
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
Implant survival rate
Implant survival/success rate At the 5-year follow-up:
Control group: 91.3%
Test group: 100%
(P = 0.001)
Marginal bone loss At the 1-year follow-up (mean  SD):
Control group: 1.12  0.85 mm
Test group: 0.85  0.71 mm
(P = 0.15)
At the 5-year follow-up (mean  SD):
Control group: 1.26  0.88 mm
Test group: 0.98  0.76 mm
(P = 0.18)
Abtahi et al., 201210 Abtahi et al., 20109
Double-blind RCT Case series study
16 5
65 66
5/11 4/1
16/16 5/30
Maxilla Maxilla
Use: dental implants Use: dental implants
Shape: screw Shape: screw
Specifications: Specifications:
Brånemark Mk III TiUnite Brånemark Mk III TiUnite
3.75  11.5 mm Control: 3.75  11.5 mm,
3.75  13 mm; Test: 3.75  10 mm
Pamidronate disodium 60% (1 mg/ml) Pamidronate disodium 60% (1 mg/ml)
Ibandronate 40% (50 mg/ml) Ibandronate 40% (50 mg/ml)
Immobilization on implant surface: Immobilization on implant surface:
fibrinogen layer containing the fibrinogen layer containing the
combination of bisphosphonates bound to combination of bisphosphonates bound to
titanium titanium
Radiographic analysis at baseline, 2 Radiographic analysis at baseline, 2
months, and 6 months months, and 6 months
Resonance frequency (ISQ) at baseline Resonance frequency (ISQ) at baseline
Local bisphosphonates and implant osseointegration
and 6 months and 6 months
Histological analysis at 6 months
Not analyzed Not analyzed
Marginal bone loss at the 2-month follow- Descriptive analysis:
up was less in the test group than in the
control group (P = 0.017)
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
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
Marginal bone loss at the 6-month follow-
up was less in the test group than in the
control group (P = 0.012)
1433
 1434 Guimarães et al.

Two test implants were removed en bloc

at abutment connection (6 month follow-
For the test group, the values ranged from

region of the maxilla (premolar and molar

For all implants, the values ranged from
47 to 82, with a mean of 62 at insertion

51 to 76, with a mean of 58 at insertion

The control implants were placed in the

The system used for local delivery of

lamellar bone trabeculae had formed in

the positions of canines), while the test

anterior region of the maxilla (between
up); histology showed that both screws

implants were placed in the posterior

the drug also varied among the studies:

were fully osseointegrated; mature

immobilization of the drug on the implant

intimate contact with the implant

and 64 at abutment connection surface9,10 and the direct application of a

and 69 at abutment connection

Abtahi et al., 20109

pharmacologically active compound at the

1 control implant was lost

surgical site13 were used. Another local
delivery system cited in the literature is the
Descriptive analysis:

Descriptive analysis:
application of bisphosphonate in the form
of a gel directly at the surgical site, with
the aim of having greater control of
extravasation in comparison with the so-

regions)
lution form; the drug is contained in the
surgical recess and is kept in contact with
the bone walls23. Unfortunately, there
were no articles in the literature that com-
pared these differences in delivery sys-
tems in a satisfactory manner.

lower than 57 at the 6-month follow-up,

suggesting questionable or insufficient
2 control implants showed ISQ values When researching the use of bispho-
Difference of 6.9 units (P = 0.0001)

sphonates in dentistry, many studies on

6-month follow-up (mean  SD):

osteonecrosis of the jaw are found

Abtahi et al., 201210

(BRONJ bisphosphonate-related osteo-

Control group: 61.8  5.7

Control group: 65  6.1

necrosis of the jaw), because this repre-

Test group: 62.5  5.7

Test group: 72.6  5.4

Baseline (mean  SD):

sents a potential adverse effect of therapy

with drugs of this class37. All of the arti-
cles analyzed in this review reported that
this condition did not develop in any of the
Not analyzed

study patients. Zuffetti et al. argued that a

large proportion of patients affected by
fixation

this disease are on long-term intravenous

treatment with second- and third-genera-
tion bisphosphonates13. Their hypothesis
was that first-generation bisphosphonates
used on a single occasion and at a low dose
their radiographs were either not available
In total 10 patients were excluded because

or were of too low quality for evaluation

would not be sufficient to lead to the

development of BRONJ. In the 2010 study
by Abtahi et al.9, it was reported that the
RCT, randomized clinical trial; ISQ, implant stability quotient; SD, standard deviation.
Zuffetti et al., 201313

concentrations of bisphosphonates used

would not be sufficient to lead to this
condition; moreover, as the presence of
the drug slowed down bone resorption, the
authors believed that any infection could
be easily controlled. In the 2012 study by
Not analyzed

Not analyzed

Abtahi et al.10, it was stated that in the case

of the development of BRONJ, the prob-
lem would easily be resolved by removing
the bone tissue in the region neighbouring
the implant.
With regard to the evaluation of the
results, a point in common among the
studies was the use of radiographic anal-
yses to evaluate peri-implant bone loss;
however, the periods of follow-up dif-
fered. In the studies of Abtahi et al.10
and Zuffetti et al.13, a lower level of
peri-implant bone loss was demonstrated
for the test group after 6 and 12 months of
follow-up. However, in the earlier study
by Abtahi et al.9, no difference was found
Table 3 (Continued )

Histological analysis

for this outcome. This discrepancy in the

Important notes

results between the studies could be

explained by the small sample size in
the earlier study (pilot study) and by the
fact that the control implants were inserted
ISQ

in an area of greater bone density (anterior


maxilla) in comparison with the test
implants (posterior maxilla), which repre-
sents a methodological bias that was not
adequately controlled.
Moreover, the tendency for higher suc-
cess rates with longer implants of a larger
diameter is well known, which possibly
results from the larger area of contact
between the implant and bone tissue, in-
creasing their anchorage38–40. Therefore,
it is inadvisable to compare success rates
between inserted implants of different
lengths and diameters, a bias found in
the studies of Zuffetti et al.13 and Abtahi
et al.9. Furthermore, two different brands
of implants were used Brånemark Mk
III TiUnite and Osseotite NT whose
manufacturers indicated different surface
treatments. This is another important fac-
tor known to influence osseointegration41
and represents a point of methodological
divergence between the studies.
Although two articles demonstrated ex-
cellent strength of evidence10,13, one of the
studies presented a level of evidence clas-
sified as limited or weak9. This latter study
was a case series study a study type that
is known to be inferior to the randomized
clinical trial with regard to the level of
evidence. However, it was a pilot study
conducted before the randomized clinical
trial performed by the same authors, em-
phasizing their commitment to methodo-
logical quality and ethics in relation to the
sample involved.
As is the case with any type of study,
systematic reviews also have their limita-
tions. One of the most relevant observed in
this research was the methodological het-
erogeneity of the articles selected. This
heterogeneity in association with the lim-
ited number of research studies performed
in humans impeded a statistical analysis of
the results (meta-analysis). Thus, the
results offered to the reader are qualitative
and not quantitative, allowing a certain
degree of subjectivity in the conclusions.
Publication bias may also be present and
represents an important limitation of sys-
tematic reviews: articles reporting positive
results have a greater chance of being
published when compared to those that
do not demonstrate beneficial effects42.
In order to control for publication bias,
a ‘grey literature’ (SIGLE) database was
included in the search strategy. However,
this search did not identify any additional
information.
On the basis of the results of this sys-
tematic review, it is concluded that the
local use of a bisphosphonate appears to
favour the osseointegration of titanium
implants in human beings. In spite of this,
the authors suggest a higher level of meth-
Local bisphosphonates and implant osseointegration
odological standardization and the control
of biases in future research so that a
stronger body of evidence can be pro-
duced.
Funding
There was no funding source for this
research.
Competing interests
No conflicts of interest.
Ethical approval
Not applicable.
Patient consent
Not applicable.
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Address:
Magáli Beck Guimarães
Curso de Odontologia
Universidade Federal de Santa Maria
Rua Marechal Floriano Peixoto 1184
sala 309
Centro
Cep 97010-032
Santa Maria
RS
Brazil
Tel: +55 55 3220 9276
E-mail: magaliguimaraes@gmail.com