Javier Ata-Ali What is the impact of bisphosphonate

Fadi Ata-Ali
David Pen~ arrocha-Oltra
therapy upon dental implant survival?
Pablo Galindo-Moreno A systematic review and meta-analysis

Authors’ affiliations:
Javier Ata-Ali, Public Dental Health Service, Arnau
de Vilanova Hospital, Valencia University Medical
and Dental School, Valencia, Spain
Fadi Ata-Ali, David Pe~ narrocha-Oltra, Valencia
University Medical and Dental School, Valencia,
Spain
Pablo Galindo-Moreno, Department of Oral Surgery
and Implant Dentistry, University of Granada,
Granada, Spain
Corresponding author:
Dr Javier Ata-Ali, DDS, MS, MPH, PhD
Public Dental Health Service, Arnau de Vilanova
Hospital, San Clemente Street 12, 46015 Valencia,
Spain
Tel.: +0034963868501
Fax: +0034963868197
e-mail: javiataali@hotmail.com
Key words: bisphosphonate-related osteonecrosis of the jaws, dental implant, failure,
risk factor, success rate, survival rate
Abstract
Objective: A systematic review and meta-analysis are carried out to assess the scientific evidence
that bisphosphonate therapy can decrease the success rate of dental implants.
Material and methods: The PubMed (Medline) database was used to search for articles published
up until February 22, 2014. The meta-analysis was conducted based on the Preferred Reporting
Items for Systematic Reviews and Meta-analysis (PRISMA). The Newcastle–Ottawa scale (NOS) was
used to assess study quality.
Results: The combinations of search terms resulted in a list of 256 titles. Fourteen finally met the
inclusion criteria and were thus selected for inclusion in the systematic review. Eight studies (six
retrospective and two prospective) were included in the meta-analysis, with a total of 1288
patients (386 cases and 902 controls) and 4562 dental implants (1090 dental implants in cases and
3472 in controls). The summary odds ratio (OR = 1.43, P = 0.156) indicates that there is not enough
evidence that bisphosphonates have a negative impact upon implant survival. According to the
number need to harm (NNH), over 500 dental implants are required in patients receiving
bisphosphonate treatment to produce a single implant failure.
Conclusion: Our results show that dental implant placement in patients receiving bisphosphonates
does not reduce the dental implant success rate. On the other hand, such patients are not without
complications, and risk evaluation therefore must be established on an individualized basis, as one
of the most serious though infrequent complications of bisphosphonate therapy is bisphosphonate-
related osteonecrosis of the jaws. Given the few studies included in our meta-analysis, further
prospective studies involving larger sample sizes and longer durations of follow-up are required to
confirm the results obtained.

Many studies have analyzed the local and
systemic factors that affect dental implant
osseointegration (van Steenberghe et al. 2002;
Renouard & Nisand 2006; Alsaadi et al.
2007; Candel-Marti et al. 2011; Stoker et al.
2012). A series of systemic factors such as
smoking (Alsaadi et al. 2007; Stoker et al.
2012), osteoporosis (Alsaadi et al. 2007), Cro-
hn’s disease (van Steenberghe et al. 2002; Al-
saadi et al. 2007), epidermolysis bullosa, and
lichen planus (Candel-Marti et al. 2011) are
related to dental implant failure. In turn, the
local factors associated to implant failure
include the type and location of the edentu-
Date: lous zone, the length and diameter of the
Accepted 22 October 2014
implant (Renouard & Nisand 2006; Alsaadi
To cite this article: et al. 2007), and the type of bone (Alsaadi
Ata-Ali J, Ata-Ali F, Pe~
narrocha-Oltra D, Galindo-Moreno P.
What is the impact of bisphosphonate therapy upon dental et al. 2007). Other local contributing factors
implant survival? A systematic review and meta-analysis are immediate implant placement, periapical
Clin. Oral Impl. Res. 00, 2014, 1–9
doi: 10.1111/clr.12526 lesions, cortical layer rupture, the absence of
keratinized gingival tissue, and poor oral
hygiene.
Osteoporosis is a progressive systemic skel-
etal disease characterized by low bone mass
and micro-architectural deterioration of bone
tissue, with a consequent increase in bone
fragility and susceptibility to fracture (Kanis
1994). The most common medical treatment
for osteoporosis involves the use of bis-
phosphonates (BPs) (Kunchur et al. 2009),
which inhibit osteoclast activity, prevent the
resorption of bone, and reduce its turnover
(Rodan & Reszka 2002). Traditionally, BPs
are divided into nitrogen-containing (N) and
non-nitrogen-containing (non-N) drugs (Wang
et al. 2007). The most commonly prescribed
BP is alendronate. Other BPs include etidro-
nate, risedronate, ibandronate, and zoledro-
nate (Burch et al. 2014). Alendronate is an
oral nitrogen-containing BP and is the most

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1
Ata-Ali et al
Bisphosphonates and dental implants
commonly used drug to treat osteoporosis
and osteopenia (Marx 2003), while intrave-
nous BPs are used in patients with cancer
and bone metastases for the prevention of
bone complications (pathological fractures,
spinal cord compression, and problems
related to bone irradiation and/or surgery)
and for the treatment of tumor-induced
hypercalcemia (Borromeo et al. 2011).
One of the most serious though infrequent
complications of BP therapy is bisphospho-
nate-related osteonecrosis of the jaws
(BRONJ). The American Dental Association
warns that the placement of dental implants
or guided bone regeneration procedures
involve an increased risk of osteonecrosis in
patients receiving oral BP treatment (Ameri-
can Dental Association Council on Scientific
Affairs 2006). Many authors have reported
the appearance of osteonecrosis in patients
subjected to dental implant placement (Jacob-
sen et al. 2013; L opez-Cedrun et al. 2013;
Tam et al. 2014). According to the American
Association of Oral and Maxillofacial Sur-
geons (Advisory Task Force on Bisphospho-
nate-Related Osteonecrosis of the Jaws,
American Association of Oral & Maxillofa-
cial Surgeons 2007), the frequency of osteone-
crosis of the jaws in patients receiving
intravenous BPs is 0.8–12%. The incidence of
osteonecrosis of the jaws related to oral BP
use is estimated to be 0.7 per 100,000 person
years of exposure (American Dental Associa-
tion Council on Scientific Affairs 2006). The
reason why BPs exclusively affect maxillary
bone is not clear. Many factors could be
implicated, including the anatomical charac-
teristics of alveolar bone, its fine overlying
epithelial layer, mechanical stress caused by
chewing, inflammatory processes (periodonti-
tis), and a complex oral microbiota involving
the presence of certain bacteria (Hoefert &
Eufinger 2011; Landesberg et al. 2011).
Another purported factor is the important
vascularization and bone remodeling found at
periodontal ligament level (Marx et al. 2005).
Although the condition is typically confined
to the maxillofacial region, there have been
reports of cases in the hip, tibia, and femur
(Gupta et al. 2009).
Jeffcoat (2006), Fugazzotto et al. (2007), and
Grant et al. (2008) reported a dental implant
success rate of 99% in patients treated with
oral BPs. However, other authors (Kasai et al.
2009; Yip et al. 2012) have reported a rela-
tionship between BP use and dental implant
failure. It is reasonable to assume that if
these drugs significantly reduce bone turn-
over, they could influence dental implant
osseointegration.
2 | Clin. Oral Impl. Res. 0, 2014 / 1–9
The purpose of this study was to systemat-
ically review the current literature and con-
duct a comprehensive meta-analysis of the
published data to answer the question: What
is the impact of bisphosphonate therapy upon
dental implant survival?
Material and methods
The Preferred Reporting Items for Systematic
Reviews and Meta-analysis (PRISMA) state-
ment was used in this study (Moher et al.
2009).
Search strategy for the identification of studies
The PubMed (Medline) database of the Uni-
ted States National Library of Medicine was
used for the literature search of articles pub-
lished up until February 22, 2014. The fol-
lowing search terms were used in different
combinations: “dental implants,” “bis-
phosphonate(s),” “etidronate,” “clodronate,”
“risedronate,” “alendronate,” “ibandronate,”
“pamidronate,” and “zoledronic acid.” Two
examiners (JAA and FAA) read the titles and
abstracts of all studies, and no blinding was
carried out regarding names of authors,
names of journals, or publication date. The
search was completed with a review of the
references of the selected articles to identify
additional studies not found in the initial lit-
erature search.
In addition, a manual search (likewise up
until February 22, 2014) was made of the fol-
lowing journals: Clinical Implant Dentistry
and Related Research, Clinical Oral Investi-
gations, Clinical Oral Implants Research,
European Journal of Oral Implantology,
Implant Dentistry, The International Journal
of Oral and Maxillofacial Implants, Journal
of Clinical Periodontology, Journal of Oral
Implantology, Journal of Periodontology,
Medicina Oral, Patologıa Oral y Cirugıa Bu-
cal, and Oral Surgery and Oral Medicine,
Oral Pathology, Oral Radiology, and Endod-
ontology.
Study selection criteria
Before starting the study, a series of inclusion
and exclusion criteria were established. Cho-
sen full-text articles were required to meet
the following criteria: (i) studies including
patients with a history of systemic BP ther-
apy (via the oral and/or intravenous route)
and receiving at least one dental implant
before or after BP administration; (ii) prospec-
tive or retrospective studies and cases series;
and (iii) studies specifying implant success
rate (osseointegration). The following articles
were excluded: (i) studies failing to specify
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
the implant success rate; (ii) in vitro or ani-
mal studies; (iii) case reports and short case
series; and (iv) studies lacking a control
group. The cases were defined as those
patients subjected to dental implant place-
ment and who received bisphosphonate ther-
apy, while the controls were patients
subjected to dental implant placement but
who did not receive bisphosphonate therapy.
Authors were contacted for clarification of
missing information when necessary. In cases
of more than one publication on the same
patient group involving the same follow-up,
only the study nearest to the objectives of
this review or with the largest sample was
included. No restrictions were placed on the
year or language of publication. All articles
selected from the electronic and manual
searches were independently assessed by the
first and second authors of this study, accord-
ing to the established inclusion criteria. Any
disagreements between the reviewing authors
were resolved by consensus among all the
authors of the study.
Quality assessment
The quality of the studies was evaluated
using the Newcastle–Ottawa scale (NOS)
(Wells et al. 2001). The scale consists of 8
items that cover three dimensions: (i) patient
selection (adequate definition of cases, repre-
sentativeness of cases, selection of controls,
and definition of control); (ii) comparability
of the two study arms (control for the most
important factor or the second most impor-
tant factor); and (iii) assessment of outcome
(exposure assessment, same method of ascer-
tainment for all subjects, and non-response
rate). A point is awarded for each item that is
satisfied by the study, with the exception of
the second section of the scale (comparability
based on design or analysis), which is
assigned a maximum of two points. A full
score is 9 points, and a score ≥6 is considered
to indicate high quality, while a score <6
indicates low quality. The NOS score was
assessed independently by two reviewers.
Discrepancies in the score were resolved
through discussion by the reviewers.
Inter-study heterogeneity and publication bias
The Qh heterogeneity statistic and corre-
sponding P-value for the chi-squared test
were recorded. As the number of studies
included in the meta-analysis is small, the
heterogeneity study was complemented with
the Galbraith plot.
Potential publication bias was assessed
using the funnel plot and rank correlation of
Begg’s test (Begg & Mazumdar 1994) and
Egger’s test (Egger et al. 1997).

Statistical analysis
The meta-analysis was based on the inverse
variance calculation method of DerSimonian
and Laird, taking the odds ratio (OR) as
measure of effect. Results were obtained for
a random effects model. The OR estima-
tions are accompanied by the corresponding
95% confidence interval (95% CI), standard
error, and P-value of the factor null effect
contrast (OR = 1) for solution of the meta-
analysis. The Forest plot shows the OR
value and corresponding confidence interval
for the studies and the global cluster value.
The relative size of each symbol reflects
the weight attributed to each study, on the
basis of sample size. The number needed to
harm (NNH) represents the number of den-
tal implants that must be exposed to a risk
factor (the administration of BPs) to cause a
single implant failure which otherwise
would not have occurred. A significance
level of 5% was established in the analyses
Identification
Records identified through
database searching
Screening
Eligibility
Included
Fig. 1. Prismaâ flow diagram of the searching processes and results.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
(a = 0.05). All statistical analyses were per-
formed using the SPSS version 15.0 statisti-
cal package for Microsoft Windows (SPSS,
Chicago, IL, USA) and R version 3.0.2 (R
Foundation for Statistical Computing,
Vienna, Austria). R can be downloaded from
the Web site (The R Project for Statistical
Computing).
Results
Study selection and description
The combinations of search terms resulted in
a list of 256 titles. Of these, 26 were found to
be duplicated; as a result, 230 references were
reviewed. In turn, 215 articles were excluded
on the basis of the evaluation of the title and
abstract, leaving 15 articles to be assessed for
eligibility. Fourteen finally met the inclusion
criteria and were thus selected for inclusion
in the systematic review (Fig. 1). Of the men-
tioned 14 publications, 10 (Fugazzotto et al.
Additional records identified
through other sources
(n = 256)
Records after removal of duplicates
(n = 26)
Records screened
(n = 230)
Full-text articles assessed
for eligibility
(n = 15)
Studies included in
qualitative synthesis
(n = 14)
Studies included in
quantitative synthesis
(meta-analysis)
(n = 8)
n=6 retrospective
studies
n=2 prospective
studies
Ata-Ali et al
Bisphosphonates and dental implants
2007; Bell & Bell 2008; Grant et al. 2008; Ka-
sai et al. 2009; Koka et al. 2010; Shabestari
et al. 2010; Famili et al. 2011; Zahid et al.
2011; Memon et al. 2012; Yip et al. 2012)
were retrospective studies, two (Jeffcoat 2006;
Siebert et al. 2013) were prospective studies,
and two (Goss et al. 2010; Martin et al. 2010)
were case series. The characteristics of the
studies meeting the inclusion criteria are
summarized in Table 1. Regarding the way in
which the patients were selected in each
study included in the meta-analysis, two
enrolled the patients on a prospective basis
(Jeffcoat 2006; Siebert et al. 2013), 5 used a
retrospective chart review (Bell & Bell 2008;
Kasai et al. 2009; Koka et al. 2010; Zahid
et al. 2011; Memon et al. 2012), and one
study (Grant et al. 2008) included the
patients from among the responders of a sur-
vey reporting a history of bisphosphonate
use. The study published by Zuffetti et al.
(2013) was excluded from the systematic
(n = 0)
Records excluded
(n = 215)
Full-text articles excluded,
with reasons
(n = 1)
Zuffetti et al.2013: topical
administration of
bisphosphonates
3 | Clin. Oral Impl. Res. 0, 2014 / 1–9
 4 |
Table 1. Studies meeting the inclusion criteria
Type Mean age No. of No. of implants cases/ Success rate Duration of BP No. of
of or range Type of BP/administration cases/ controls (no. of implants cases/ Implant follow- treatment cases of Location of failed
Article study (years) route controls lost cases/controls) controls (%) up (months) (months) BRONJ implants
Jeffcoat P 30–79 70 mg alendronate/oral 25/25 102/108 (0/1) 100/99.2 36 12–48 (mean 0 NA
(2006) 36)
Fugazzotto R 51–83 Alendronate or risedronate 61/no 169/no controls 100/no 12–24 39.6 1 No dental implant
et al. (70 mg or 35 mg)/oral controls controls failures
(2007)
Bell & Bell R 67.4 Alendronate (34), risedronate 42/NA 100/734 (5/26) 95/96.5 4–89 6–60 0 40% ant

Clin. Oral Impl. Res. 0, 2014 / 1–9

(2008) (6), and ibandronate (2)/oral 100% max
60% post
Grant et al. R 67.4/– Alendronate, risedronate, 115/343 468/1450 (2/14) 99.5/99 48 38 0 100% max
(2008) and ibandronate/oral 100% post
Kasai et al. R >36 Alendronate/oral 11/40 35/161 (5/7) 85.7/95.7 84.3 (64–146) >36 0 40% mandib
Ata-Ali et al
Bisphosphonates and dental implants

(2009 60% max

60% ant
40% post
Koka et al. R 71/66 70 mg alendronate/oral 55/82 121/166 (1/3) 99.17/98.19 18 >60 0 NA
(2010)
Martin CS 70.2 Alendronate/oral 16/no 44/ no controls NA/no 1–132 3–69 (mean 38) 0 54% mandib
et al. controls controls 46% max
(2010) 30% ant
70% post
Goss et al. CS 65.7 Alendronate and risedronate/ 7/no 28,000/no controls (9/no 99.9/no NA 3–120 5 77.7% mandib
(2010) oral controls controls) controls 22.3% max
44.5% ant
55.5% post
Shabestari R 53 (42–79) Alendronate (35–70 mg)/oral 21/no 46/no controls NA/no 50 (7–97) Mean 20.5 0 37% mandib ant
et al. controls controls 32% max ant 20%
(2010) mandib post
11% max post
Zahid et al. R 56 70 mg alendronate, 150 mg 26/300 51/661 (3/19) 94.1*/97.1 26 (2–72) 6–192 0 Cases: 66.6% mandib,
(2011) ibandronate/oral 33.3% max, 66.6% post,
33.3% ant
Control: 89.5% post,
10.5% ant
Famili et al. R NA Alendronate, ibandronate, 28/183 82/510 98.7/NA NA 6–>60 0 NA
(2011) and risedronate/oral
Memon R 66/63 Alendronate (72), 100/100 153/132 (10/6) 93.5/95.5 Implants placed 12–>36 NA NA
et al. ibandronate (5), and between 1999
(2012) risedronate (23)/oral and 2008
Yip et al. R 57 Alendronate, ibandronate, 114/223 490/691 66.7/NA 72 NA NA 41.1% mandib 58.9%
(2012) risedronate, etidronate, (163/NA) max 33.7% ant 66.2%
tiludronate/oral post
Siebert P 54 Zoledronic acid/IV 12/12 60/60 100/100 12 24–36 0 No dental implant
et al. (0/0) failures
(2013)

NA, Not available; Ant, anterior; R, retrospective; P, prospective; CS, case series; BP, bisphosphonate; Post, posterior; Max, maxillary; IV, intravenous; Mandib, mandibular; BRONJ, bisphosphonate-related
osteonecrosis of the jaws.
*
94.1% for the implant-based analyses and 88.4% for the subject-based analyses.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Ata-Ali et al
Bisphosphonates and dental implants

review, as it involved topical BP use, not

Total (9)
systemic administration.
The eight studies included in the meta-
4
3
7
4
8
6
3
3
3
4
7
8
7
7
analysis summed a total of 386 cases and 902
controls, with the placement of 1090 and
Non-response

3472 dental implants, respectively. Twenty-

rate (1)

six of the 1090 implants among the cases

failed vs. 76 of the 3472 implants in the
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control group.
Same method of ascertainment

Quality assessment of studies

for cases and controls (1)

Assessment of the methodological quality of

each article is summarized in Table 2. Of the
14 studies that met the inclusion criteria, 7
Fig. 3. Funnel plot for assessing possible publication
(Jeffcoat 2006; Fugazzotto et al. 2007; Bell &
bias.
Bell 2008; Goss et al. 2010; Martin et al.
2010; Shabestari et al. 2010; Zahid et al.
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2011) were considered to be of low quality, Meta-analysis

with NOS scores < 6. In turn, seven studies The results of the meta-analysis are shown
Ascertainment of

(Grant et al. 2008; Kasai et al. 2009; Koka in Fig. 4 (Forest plot). The eight studies com-
Exposure (3)

exposure (1)

et al. 2010; Famili et al. 2011; Memon et al. prised a total of 4562 dental implants: 1090
2012; Yip et al. 2012; Siebert et al. 2013) in the BP group and 3472 in the control
were of relatively high quality, with NOS group. With these data, two-tailed chi-
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scores ≥ 6. squared testing yielded a power of 99.8% in

defining proportions of 0.99 and 1 in the
Inter-study heterogeneity and publication bias groups as being significantly different, with a
Comparability based on
design or analysis (2)

The homogeneity test confirmed that the 95% confidence level. Table 3 shows the
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Comparability (2)

eight studies were suitable for obtaining a individual effect measures, as well as the
combined effect measure (Qh = 6.97, summary odds ratio for the 8 studies, result-
P = 0.432). The Galbraith plot (Fig. 2) shows ing from the meta-analysis for a random
the studies to be distributed around the effects model. The estimated summary odds
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adjusted regression line – all within the cor- ratio (OR = 1.43, P = 0.156) indicates that
responding 95% confidence limits. Conse- there is not enough evidence that BPs have a
Definition of
controls (1)

quently, there is not enough evidence to negative impact upon implant survival. The
reject the homogeneity of the studies number need to harm (NNH) was found to
included in the meta-analysis. be 509 dental implants (Table 4).
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Table 2. Quality assessment of the studies included in the systematic review

A funnel plot (Fig. 3) served as a visual

means for assessing any disproportionate rep- Discussion
Selection of
controls (1)

resentation of study results according to

strength and precision. The results of Begg’s The present systematic review and meta-
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test with continuity correction and Egger’s analysis examined the scientific evidence
test confirmed that there was no evidence of that bisphosphonate (BP) therapy can
Representativeness

publication bias. The results of Begg’s test decrease the success rate of dental implants.
of the cases (1)

was P = 0.216, and the results of Egger’s test Eight publications (six retrospective and two
was P = 0.113. prospective studies) were included in our
meta-analysis comprising 1288 patients (386
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cases and 902 controls) and 4562 dental

implants (1090 dental implants in cases and
Case definition

3472 in controls). The results indicate that

adequate (1)
Selection (4)

there is not enough evidence that BPs have a

negative impact upon implant survival.
Although information has been collected on
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a prospective basis from each of the articles

Fugazzotto et al. (2007)

included in the systematic review, 10 retro-

Shabestari et al. (2010)

Memon et al. (2012)

Siebert et al. (2013)

Martin et al. (2010)

spective studies, two prospective studies, and

Famili et al. (2011)
Grant et al. (2008)

Zahid et al. (2011)

Kasai et al. (2009)
Koka et al. (2010)

Goss et al. (2010)

Bell & Bell (2008)

Yip et al. (2012)

two case series were included. We must

Quality criteria

Jeffcoat (2006)

assume the results as reported by the authors

of the studies included in the systematic
review. The problem of retrospective studies
Fig. 2. Galbraith plot. is the possible selection bias involved.

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 5 | Clin. Oral Impl. Res. 0, 2014 / 1–9
Ata-Ali et al
Bisphosphonates and dental implants

AUTHOR OR Lower Upper 2010; Gupta 2012; Yuan et al. 2012).

95%CI 95%CI
0.35 0.01 8.68 Table 5 describes the case series (reporting
Jeffcoat 2006
1.43 0.54 3.82
at least two patients) with osteonecrosis of
Bell & Bell 2008
the jaws due to the administration of BPs
Grant et al. 2008 0.44 0.10 1.94
after dental implant placement. A recent
Kasai et al. 2009 3.67 1.09 12.32
prospective study (Siebert et al. 2013) has
Koka et al. 2010 0.45 0.05 4.41
examined the risk of developing BRONJ in
Zahid et al. 2011 2.11 0.60 7.39 patients with osteoporosis receiving annual
Memon et al. 2012 1.47 0.52 4.16 intravenous infusions of 5 mg of zoledronic
Siebert et al. 2013 1.00 0.02 51.21 acid. After placing 60 dental implants in
1.43 0.87 2.34 two groups of 12 patients each (intravenous
GLOBAL EFFECT
zoledronic acid and controls), the implant
success rate was found to be 100% in both
Fig. 4. Meta-analysis with Forest plot for dental implant failure rate. The vertical axis is located at OR = 1; the groups, and BRONJ was not seen in any
geometric symbol represents the OR value, with its confidence interval. In the individual studies, the size of the patient. In any case, this potential compli-
symbol is proportional to the study sample size. cation should be explained to the patient
by both the prescribing physician and the
dental surgeon in charge of oral treatment,
Table 3. Studies included in the meta-analysis, with odds ratio (OR) and 95% confidence interval with the obtainment of informed consent in
(95% CI)
all cases (Ata-Ali et al. 2012).
95% CI 95% CI
Study OR lower limit upper limit P-value
A longitudinal, single-masked, controlled
study by Jeffcoat (2006) assessed the inci-
Jeffcoat (2006) 0.35 0.01 8.68
Bell & Bell (2008) 1.43 0.54 3.82 dence of complications following implant
Grant et al. (2008) 0.44 0.10 1.94 placement in 25 patients receiving oral BPs
Kasai et al. (2009) 3.67 1.09 12.32 and a control group of 25 patients. The
Koka et al. (2010) 0.45 0.05 4.41
authors reported that 100% of the implants
Zahid et al. (2011) 2.11 0.60 7.39
Memon et al. (2012) 1.47 0.52 4.16 placed in patients receiving oral BPs and
Siebert et al. (2013) 1.00 0.02 51.21 99.2% of the implants in the control group
Total 1.43 0.87 2.34 0.156 were functioning successfully. No statisti-
OR, Odds ratio. cally significant differences were observed
between the two groups. A retrospective
study carried out by Bell & Bell (2008)
Table 4. Representation of the number need to harm (NNH) according to the different studies recorded the loss of five dental implants of a
95% CI 95% CI total of 100 implants in 42 patients adminis-
Study NNH lower limit upper limit tered BPs via the oral route. The implant
Jeffcoat (2006) 108.0 28.6 – success rate was 95% in the patients receiv-
Bell & Bell (2008) 68.6 16.9 –
ing BPs vs. 96.5% of the patients who did
Grant et al. (2008) 185.8 76.1 –
Kasai et al. (2009) 10.1 4.6 – not receive BPs. In that same year, another
Koka et al. (2010) 102.0 28.0 – retrospective analysis by Grant et al. (2008)
Zahid et al. (2011) 33.2 10.4 – recorded the loss of two implants in 115
Memon et al. (2012) 50.2 13.7 –
Siebert et al. (2013) – – –
patients administered BPs and of 14
Total 509.2 81.6 – implants in the control group composed of
1450 patients. The implant success rate for
both groups was 99%. Kasai et al. (2009) in
However, we must assume that the subjects implants in individuals with and without turn compared 35 dental implants placed in
without implant failure are included in the exposure to oral BPs. Although cases of 11 patients receiving BPs for more than
different samples with the same probability, spontaneous BRONJ have been described, it 3 years vs. 161 dental implants in 40
regardless of whether they received is typically triggered by local trauma, patients not receiving BP. The implant suc-
bisphosphonates or not. almost always in the context of oral proce- cess rate in the oral BP treatment group was
Bisphosphonates are potent inhibitors of dures, particularly dental extractions and 86% vs. 95% among the controls. These
osteoclast-mediated bone resorption and the insertion of dental implants (Yarom authors concluded that treatment with BPs
have been widely used in the management et al. 2007). Although a number of studies reduces the dental implant success rate. A
of skeletal metastases and for the treatment (Madrid & Sanz 2009; Javed & Almas 2010) retrospective study by Zahid et al. (2011)
of primary and secondary osteoporosis (Ro- have concluded that dental implant place- examined whether patients who receive BPs
dan & Reszka 2002). As BPs significantly ment in patients receiving BPs via the oral are at greater risk of implant failure than
reduce bone turnover, it is not surprising route does not imply a risk of BRONJ, the patients not taking these drugs in a group of
that a patient receiving BPs may have a literature describes several cases of such an 26 patients receiving oral BPs and a control
problem with dental implant integration association (Brooks et al. 2007; Wang et al. group of 300 patients. The authors found
(Goss et al. 2010). Some studies have 2007; Bedogni et al. 2010; Narongroeknawin 94.1% of the implants placed in patients
directly examined the outcomes of dental et al. 2010; Park et al. 2010; Shin et al. receiving oral BPs and 97.1% of the implants

6 | Clin. Oral Impl. Res. 0, 2014 / 1–9 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Ata-Ali et al
Bisphosphonates and dental implants

Table 5. Osteonecrosis of the jaws due to bisphosphonate administration after dental implant placement
Article Disease Drug Duration (months) No. patients BRONJ site
Yarom et al. (2007) O and RA Alendronate 72 2 2 mandible
Lazarovici et al. (2010) O, MM, BC, and PC Alendronate, zoledronate, 16.4–68 27 20 mandible and 7 maxilla
pamidronate, or combination
of BP
Goss et al. (2010) O Alendronate and risedronate 50.5 7 5 mandible and 2 maxilla
Manfredi et al. (2011) O Alendronate 42 2 2 mandible
Kwon et al. (2014) O and MM Zoledronate, ibandronate, 60.5 19 9 mandible, 8 maxilla, and 2 in
pamidronate, alendronate, and both jaws
risedronate
Tam et al. (2014) O, MM, and BC Alendronate, zoledronate, or 37 6 4 mandible and 2 maxilla
combination of BP
 pez-Cedru
Lo  n et al. (2013) O, PR, and OA Alendronate, ibandronate, and 60 9 8 mandible and 1 maxilla
risedronate
Jacobsen et al. (2013) O, MM, BC, LC, and PC Zoledronate, pamidronate, 38–50 14 11 mandible and 3 maxilla
ibandronate, and alendronate

No, Number; BP, bisphosphonate; O, osteoporosis; MM, multiple myeloma; BC, breast carcinoma; PC, prostate carcinoma; LC, lung carcinoma; RA, rheuma-
toid arthritis; PR, polymyalgia rheumatica; OA, osteoarthritis; BRONJ, bisphosphonate-related osteonecrosis of the jaws.

Table 6. Implant success or failure criteria of the articles included in the meta-analysis
Article Definition of implant failure or success
Jeffcoat (2006) Success was defined as <2 mm of alveolar bone loss over the 3-year study period, lack of mobility, lack of infection and absence of
pain, and osteonecrosis of the jaws
Bell & Bell (2008) Less than 2 mm of alveolar bone loss over the 3-year study
Grant et al. (2008) An individual, unattached implant is immobile when tested clinically. A radiograph does not show any evidence of peri-implant
radiotransparency. Vertical bone loss is <0.2 mm annually after the implant’s first year of service. Individual implant performance is
characterized by an absence of persistent and/or irreversible signs and symptoms such as pain, infection, neuropathies, paresthesia,
or violation of the mandibular canal. To be considered successful, the dental implant should provide functional service for 5 years in
75% of the cases
Kasai et al. (2009) Recorded whether the implant is lost or removed
Koka et al. (2010) Implant failure was defined as its loss or removal. For each implant, the duration of follow-up was calculated from the time of
placement to the date of failure or date of last follow-up in the specified time period
Zahid et al. (2011) The criteria for implant success were clinical osseointegration of implants without radiotransparency and bone loss <0.2 mm annually
after the first year of service. Implant failure criteria were implant mobility and the implant no longer present
Memon et al. (2012) Early implant success was based on the following criteria: (i) The implant was clinically immobile at stage two surgery/abutment
connection; (ii) the radiographs did not demonstrate any evidence of peri-implant radiotransparency at stage two surgery/abutment
connection; and (iii) the individual implant had no persistent and/or irreversible signs and symptoms such as pain, infections,
neuropathies, paresthesia, or violation of the mandibular canal
Siebert et al. (2013) Implant survival was evaluated using Buser’s criteria (Buser et al. 1991)

in the control group to be functioning suc-
cessfully. No statistically significant differ-
ences were found, although statistically
significant associations were observed
between implant thread exposure and the
use of BPs (OR = 3.25) – 13 implants exhibit-
ing thread exposure among the 51 implants
placed. Memon et al. (2012) in turn recorded
a loss of 10 dental implants of a total of 153
implants placed in 100 patients administered
oral BPs. The implant success rate was
93.5% in the bisphosphonate group and
95.5% in the control group, in which 132
implants were placed in 100 patients.
On examining the individual results of
each of the studies included in our meta-
analysis, none were seen to report signifi-
cant effects, with the sole exception of the
article published by Kasai et al. (2009). In
this latter study, the 95% confidence inter-
val for the estimated measure of effect was
1.09 to 12.32 (1 being excluded at the lower
limit by a narrow margin). This was there-
fore the only publication offering statistical
evidence that BPs reduce dental implant
success. On the other hand, it is logical to
assume that antibiotic use is indicated in
patients who do not receive BPs, as has
been demonstrated in a meta-analysis in
which antibiotic use significantly lowered
the implant failure rate (P = 0.003), with an
odds ratio of 0.331, thus implying that anti-
biotic treatment reduced the odds of failure
by 66.9% (Ata-Ali et al. 2014). Antibiotics
should be prescribed in patients receiving
BPs both to reduce implant failure and to
minimize the risk of osteonecrosis of the
jaws. According to the summary effect, the
NNH was 509 dental implants. In this
regard, it can be affirmed that for every 509
dental implants placed in patients receiving
BPs, we can expect one case of dental fail-
ure which would not have occurred if the
patients were not receiving BPs.
Study limitations
A first limitation of our systematic review is
the fact that the included publications were
observational studies, which are rated as
having a lower level of evidence than ran-
domized controlled trials (RCTs). The
absence of more RCTs therefore means that
our review is based on rather limited evi-
dence. Secondly, the main limitation of our
meta-analysis is the small number of articles
available for review, which may cause penal-
ization by a degree of type b error. However,
we have preferred to limit the sample to
studies where methodological homogeneity
is guaranteed rather than “artificially”
increase the size with a view to gaining
increased statistical power. A third limita-
tion is the fact that we accepted the criteria
of implant success or failure defined by the
authors in each study (Table 6). Hence, the
definition of outcomes may have varied
among studies. A variable to be taken into

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 7 | Clin. Oral Impl. Res. 0, 2014 / 1–9
Ata-Ali et al
Bisphosphonates and dental implants
account in interpreting the results of this
meta-analysis is the methodological quality
of the included studies. In this context, five
studies were of high quality, while three
were of low quality. Nonetheless, the 386
cases and 902 controls included in our meta-
analysis involved the placement of a total of
1090 and 3472 dental implants, respectively.
In comparison, the high-quality studies con-
tributed a total of 293 cases and 577 con-
trols, with the placement of 837 and 1969
dental implants, respectively. Despite the
above-mentioned limitations, the statistical
power of the study was 99.8%. The meaning
of the total NNH is questionable, because
the outcome is not measured exactly during
the same period, and because the baseline
risk of implant failure could be different
across the implants included in the studies
of our analysis. NNH therefore must be
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