Q U I N T E S S E N C E I N T E R N AT I O N A L
ORAL MEDICINE
Bisphosphonates and dental implants: A meta-analysis
Bruno Ramos Chrcanovic, DDS, MSc1/Tomas Albrektsson, MD, PhD2/Ann Wennerberg, DDS, PhD3
Objective: To test the null hypothesis of no difference in the
implant failure rates, marginal bone loss, and postoperative
infection for patients receiving or not receiving bisphospho-
nates, against the alternative hypothesis of a difference.
Method and Materials: An electronic search was undertak-
en in October 2015 in PubMed/Medline, Web of Science, and
Embase, plus hand-searching and databases of clinical trials.
Eligibility criteria included clinical human studies, either ran-
domized or not. Results: A total of 18 publications were
included in the review. Concerning implant failure, the
meta-analysis found a risk ratio of 1.73 (95% confidence inter-
val [CI] 1.21–2.48, P = .003) for patients taking bisphospho-
nates, when compared to patients not taking the medicament.
The probability of an implant failure in patients taking bisphos-
phonates was estimated to be 1.5% (0.015, 95% CI 0.006–
Key words: bisphosphonates, dental implants, implant failure rate, marginal bone loss , meta-analysis, postoperative infection
Dental implants have become common as replace-
ments for missing teeth. A recent review evaluated 14
prospective studies with follow-up periods of 10 years
or more, and observed survival rates for dental
implants averaging 94.6%, with mean marginal bone
loss (MBL) values of 1.3 mm.1 Even though the survival
1
PhD Student, Department of Prosthodontics, Faculty of Odontology, Malmö
University, Malmö, Sweden.
2
Retired Professor and former Head of the Department of Biomaterials, Göteborg
University, Göteborg, Sweden; Guest Professor of the Department of Prostho-
dontics, Faculty of Odontology, Malmö University, Malmö, Sweden.
3 Professor and Head of the Department of Prosthodontics, Faculty of Odontolo-
gy, Malmö University, Malmö, Sweden.
Correspondence: Dr Bruno Ramos Chrcanovic, Department of Prostho-
dontics, Faculty of Odontology, Malmö University, Carl Gustafs väg 34,
SE-205 06, Malmö, Sweden.
Email: bruno.chrcanovic@mah.se; brunochrcanovic@hotmail.com
VOLUME 47 • NUMBER 4 • APRIL 2016
Bruno Ramos
Chrcanovic
0.023, standard error [SE] 0.004, P < .001). It cannot be
suggested that bisphosphonates may affect the marginal bone
loss of dental implants, due to a limited number of studies
reporting this outcome. Due to a lack of sufficient information,
meta-analysis for the outcome “postoperative infection” was
not performed. Conclusion: The results of the present study
cannot suggest that the insertion of dental implants in patients
taking BPs affects the implant failure rates, due to a limited
number of published studies, all characterized by a low level of
specificity, and most of them dealing with a limited number of
cases without a proper control group. Therefore, the real effect
of BPs on the osseointegration and survival of dental implants
is still not well established. (Quintessence Int 2016;47:329–342;
doi: 10.3290/j.qi.a35523)
rates are high, a small percentage of implants still fail,
and several studies suggest that the survival of dental
implants depends on many local and systemic factors,
as well as on the intake of some medicaments.2 The
effects of bisphosphonates (BPs) on the osseointegra-
tion of titanium implants have drawn the attention of
some clinicians and researchers.
BPs are a class of drugs that prevent the loss of bone
mass, used to treat osteoporosis and malignant dis-
eases involving bone resorption, such as bone lesions of
multiple myeloma and metastatic bone diseases. BPs
inhibit osteoclast-mediated bone resorption and
renewal, therefore retaining existing bone. This
increases mineralization under normal function, result-
ing in an increase in bone mineral density and theoreti-
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Chrcanovic et al
cally an increased resistance to osteoporosis-related
fractures.3 However, more recent studies have been
showing that preventing osteoclast-mediated bone
resorption/renewal results only in the retention of old
bone, which lives out its natural life span and becomes
brittle and thus even more prone to fracture.4 This abil-
ity to affect systemic bone remodeling raises natural
questions about the drug’s influence on dental implants’
osseointegration. The increase of implant failure rates
due to BPs is hypothesized to be related mainly to the
impairment and cellular death (apoptosis) of not only
adult osteoclasts but osteoclast precursors in the bone
marrow by BPs.5,6 In the normal bone, in areas of greater
stress, the osteoblasts/osteocytes reduce their secretion
of osteoprotegerin, which is a decoy receptor for the
receptor activator of nuclear factor kappa B ligand
(RANKL). Osteoprotegerin is also known as osteoclasto-
genesis inhibitory factor and inhibits both differentia-
tion and function of osteoclasts. The osteoblasts/osteo-
cytes also increase their secretion of RANKL, so that the
area can resorb and re-form to accommodate this
greater stress, an adaptive response.7 If the now-stimu-
lated osteoclast attempts to resorb this stressed bone
that contains a BP, it begins to do so but dies off before
completing the resorption. This disrupts the resorp-
tion-renewal cycle. The osteocytes then succumb to the
stress and die before their usual 180-day life span, or
they live out their life span but are not replaced. The
bone may first become sclerotic (overmineralized), but
then it often becomes necrotic and exposed.8 More-
over, an animal study demonstrated that alendronate (a
type of oral BP) inhibited the repair of normal bone
microdamage, leading to the accumulation of
microdamage and possible osteonecrosis.9 As bone
remodeling is decreased by BPs, an infection into the
bone exposure site or microcrack area might lead to a
continuous and deeper progression of the inflamma-
tory process and infection, which are not always
observed in peri-implantitis, where bone resorption
exists along with the bone–implant interface. Thus,
when bisphosphonate-related osteonecrosis of the jaw
(BRONJ) is not triggered by peri-implantitis or surgical
trauma but developed at the well-functioning implant,
330
bacterial infection to the microcrack area in peri-im-
plant trabecular bone might contribute to the en bloc
sequestration of a BRONJ lesion.10 All the above-men-
tioned mechanisms could presumably interfere with
the healing process after implant placement, and con-
sequently increase the failure rates.
Several studies showed that BPs may not only cause
apoptosis of osteoclast cells, but also inhibit angiogen-
esis.5,6,11,12 These processes may lead to increased
amounts of avascular and acellular bone that may be
less tolerant to oral bacterial insult and lead to
increased MBL.13 Moreover, the microdamage accumu-
lation reduces the mechanical properties of bone,
enhancing the effect of occlusal forces and leading to
increased MBL.9 Although animal studies14,15 have
shown that BPs may be useful in minimizing MBL
around osseointegrated implants, those implants were
placed in rat tibia. Thus, those findings may not be
directly comparable to results of clinical trials since
occlusal forces and bacterial flora are absent and may
not be directly applicable to humans. These facts raise
questions about the drug’s influence on the MBL
around dental implants and whether patients taking
BPs could develop a higher occurrence of infection
after the insertion of dental implants.
BP drugs have now been in use for more than 15
years, and the number of patients who have used them
or continue to use them is increasing.16 Researchers
have been trying to evaluate whether the insertion of
implants in patients taking BPs may influence the sur-
vival of dental implants. However, some studies may
lack statistical power, given the small number of
patients per group in the clinical trials comparing the
techniques. The ability to anticipate outcomes is an
essential part of risk management in an implant prac-
tice. Recognizing conditions that place the patient at a
higher risk of failure will allow the surgeon to make
informed decisions and refine the treatment plan to
optimize the outcomes.2 The use of implant therapy in
special populations requires consideration of potential
benefits to be gained from the therapy. To better
appreciate this potential, a systematic review and
meta-analysis was conducted to compare the survival
VOLUME 47 • NUMBER 4 • APRIL 2016

rate of dental implants, postoperative infection, and
MBL in patients taking and not taking BPs.
METHOD AND MATERIALS
This study followed the PRISMA Statement guidelines.17
A review protocol does not exist.
Objective
The purpose of the present review was to test the null
hypothesis of no difference in the implant failure rates,
MBL, and postoperative infection for patients receiving
or not receiving BPs, against the alternative hypothesis
of a difference. The focused question was elaborated
by use of the PICO format (Participants, Interventions,
Comparisons, and Outcomes): In patients treated with
dental implants and taking BPs, compared to those not
taking BPs, what are the outcomes of dental implant
failure rates, MBL, and postoperative infection? (Partic-
ipants = patients taking BPs; Intervention = dental
implant; Comparator = patients not taking BPs; Out-
comes = implant failure rates, MBL, postoperative infec-
tion).
Search strategies
A structured electronic systematic search without time
or language restrictions was undertaken in October
2015 in the following databases: PubMed/Medline,
Web of Science, Embase, and the Cochrane Oral Health
Group Trials Register.
The following terms were used in the search
strategy on PubMed/Medline, refined by selecting the
term: Subject AND Adjective; (dental implant OR oral
implant [all fields]) AND (bisphosphonate OR diphos-
phonate [all fields]).
The following terms were used in the search
strategy on Web of Science, in all databases: Subject
AND Adjective; (dental implant OR oral implant [topic])
AND (bisphosphonate OR diphosphonate [topic]).
The following terms were used in the search
strategy on Embase: Subject AND Adjective; (dental
implant OR oral implant [topic]) AND (bisphosphonate
OR diphosphonate [topic]).
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Q U I N T E S S E N C E I N T E R N AT I O N A L
Chrcanovic et al
The following terms were used in the search
strategy on the Cochrane Oral Health Group Trials Reg-
ister: (dental implant OR oral implant AND (bisphos-
phonate OR diphosphonate)).
A manual search of dental implants-related journals,
including British Journal of Oral and Maxillofacial Sur-
gery, Clinical Implant Dentistry and Related Research,
Clinical Oral Implants Research, European Journal of
Oral Implantology, Implant Dentistry, International
Journal of Oral and Maxillofacial Implants, International
Journal of Oral and Maxillofacial Surgery, International
Journal of Periodontics and Restorative Dentistry, Inter-
national Journal of Prosthodontics, Journal of Clinical
Periodontology, Journal of Craniofacial Surgery, Journal
of Cranio-Maxillofacial Surgery, Journal of Dental
Research, Journal of Dentistry, Journal of Maxillofacial
and Oral Surgery, Journal of Oral Implantology, Journal
of Oral and Maxillofacial Surgery, Journal of Oral Reha-
bilitation, Journal of Periodontology, Journal of Pros-
thetic Dentistry, Journal of Prosthodontics, Oral Surgery
Oral Medicine Oral Pathology Oral Radiology and
Endodontology, and Quintessence International, was
also performed, without time restriction.
The reference list of the identified studies and the
relevant reviews on the subject were also scanned for
possible additional studies. Moreover, other sources
included online databases providing information about
clinical trials in progress were checked (clinicaltrials.
gov; www.centerwatch.com/clinical-trials; www.clini-
calconnection.com).
Inclusion and exclusion criteria
Eligibility criteria included clinical human studies com-
paring implant failure rates, MBL, and/or postoperative
infection in any group of patients receiving and not
receiving BPs. Ideally, only randomized clinical trials
(RCTs) were selected. However, observational studies
were also selected when the lack of RCTs could not
provide enough studies for a possible meta-analysis.
For this review, implant failure represents the complete
loss of the implant. Exclusion criteria were clinical stud-
ies of patients taking BPs but reporting only the cases
with osteonecrosis of the jaws, case reports, technical
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Chrcanovic et al
reports, biomechanical studies, finite element analysis
(FEA) studies, animal studies, in vitro studies, and
review papers.
Study selection
The titles and abstracts of all reports identified through
the electronic searches were read independently by the
three authors. For studies appearing to meet the inclu-
sion criteria, or for which there were insufficient data in
the title and abstract to make a clear decision, the full
report was obtained. Disagreements were resolved by
discussion between the authors.
Quality assessment
Quality assessment of the studies was executed accord-
ing to the Newcastle-Ottawa scale (NOS).18 The NOS
was developed to assess the quality of nonrandomized
studies with its design, content, and ease of use
directed to the task of incorporating the quality assess-
ments in the interpretation of meta-analytic results. The
NOS calculates the study quality on the basis of three
major components: selection, comparability, and out-
come for cohort studies. It assigns a maximum of four
stars for selection, a maximum of two stars for compa-
rability, and a maximum of three stars for outcome.
According to that quality scale, a maximum of nine
stars/points can be given to a study, and this score rep-
resents the highest quality, where six or more points
were considered high quality.
For the component “outcome-follow-up long
enough”, 5 years of follow-up was chosen to be enough
for the outcome “implant failure” to occur, as this is the
minimum time to allow the survival and success of
implants to be analyzed appropriately.19
Data extraction and meta-analysis
From the studies included in the final analysis, the fol-
lowing data were extracted (when available): year of
publication, study design, single-center or multicenter
study, number of patients, patients’ age, follow-up,
days of antibiotic prophylaxis, mouth rinse, implant
healing period, failed and placed implants, postopera-
tive infection, MBL, BP therapy details, implant surface
332
modification, type of prosthetic rehabilitation, jaws
receiving implants (maxilla and/or mandible), opposing
dentition. Contact with authors for possible missing
data was performed.
Implant failure and postoperative infection were the
dichotomous outcome measures evaluated. Weighted
mean differences were used to construct forest plots of
MBL, a continuous outcome. The statistical unit for all
outcomes (implant failure, MBL, postoperative infec-
tion) was the implant. Whenever outcomes of interest
were not clearly stated, the data were not used for
analysis. The I2 statistic was used to express the percent-
age of the total variation across studies due to hetero-
geneity, with 25% corresponding to low heterogeneity,
50% to moderate, and 75% to high. The inverse variance
method was used for random-effects or fixed-effects
model. Where statistically significant (P < .10) heteroge-
neity was detected, a random-effects model was used
to assess the significance of treatment effects. Where no
statistically significant heterogeneity was found,
analysis was performed using a fixed-effects model.20
The estimates of relative effect for dichotomous out-
comes were expressed in risk ratio (RR) and in mean
difference (MD) in millimeters for continuous outcomes,
both with a 95% confidence interval (CI). Only if there
were studies with similar comparisons reporting the
same outcome measures was meta-analysis to be
attempted. In the case where no events (or all events)
were observed in both groups the study provided no
information about relative probability of the event and
was automatically omitted from the meta-analysis. In
this (these) case(s), the term “not estimable” is shown
under the column of RR of the forest plot table. The
software used here automatically checks for problem-
atic zero counts, and adds a fixed value of 0.5 to all cells
of study results tables where the problems occur.
A funnel plot (plot of effect size versus standard
error [SE]) was drawn. Asymmetry of the funnel plot
may indicate publication bias and other biases related
to sample size, although the asymmetry may also repre-
sent a true relationship between trial size and effect size.
The data were analyzed using the statistical soft-
ware Review Manager (version 5.3.3, The Nordic
VOLUME 47 • NUMBER 4 • APRIL 2016

836 records identified; 293 in PubMed/Medline, 266
in Web of Science, 277 in Embase
412 records after duplicates removed
140 full-text articles selected
141 full-text articles assessed for eligibility
18 studies included qualitative synthesis
18 studies included quantitative synthesis (meta-analysis)
Fig 1 Study screening process.
Cochrane Centre, The Cochrane Collaboration, Copen-
hagen, Denmark, 2014).
RESULTS
Literature search
The study selection process is summarized in Fig 1. The
search strategy resulted in 836 papers. Five additional
sources were identified through other sources. A total
of 429 articles were cited in more than one research of
terms (duplicates). The three reviewers independently
screened the abstracts for those articles related to the
focus question. Of the resultant 412 studies, 272 were
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Chrcanovic et al
5 additional records identified through other sources
272 records excluded
1 record identified through
hand-searching
123 full-text articles excluded:
42 animal studies, 32 reviews,
28 case reports, 9 papers not
evaluating implant failures, 7
papers evaluating only patients
with osteonecrosis, 2 papers
evaluating only patients with
failures, 2 histologic studies, 1
letter to the editor
excluded for not being related to the topic, resulting in
140 entries. Additional hand-searching of the reference
lists of selected studies yielded one additional paper.
The full-text reports of the remaining 141 articles led to
the exclusion of 123 because they did not meet the
inclusion criteria (42 animal studies, 32 review articles,
28 case reports, 9 clinical studies not evaluating
implant failures, 7 papers evaluating only the patients
with osteonecrosis of the jaws, 2 papers evaluating only
patients with implant failures, 2 histologic studies, 1
letter to the editor; Appendix 1, available in the online
version at http://quintessenz.de). Thus, a total of 18
publications were included in the review.
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Table 1 Detailed data of the included studies (part 1)

Year Patients’ age range

Study published Study design Patients (n) (average; years) Follow-up visits (or range)
Jeffcoat21 2006 CCT (single-center) 50 (25, G1: 25, G2) NM > 3 years
Wagenberg and
2006 RA (single-center) 891 (NM) 14–94 (57.9) Mean 71 months (range 12–193)
Froum25
Fugazzotto et al26 2007 RA (multicenter) 61 (61, G1; 0, G2) 51–83 (NM) 2 years
Mean 3 years 1 month
Bell and Bell27 2008 RA (single-center) NM (42, G1; NM, G2) NM
(range 4 months – 7 years 5 months)
Grant et al28 2008 RA (single-center) 458 (115, G1; 343, G2) > 40 (67.4) NM
29
Kasai et al 2009 RA (single-center) 51 (11, G1; 40, G2) 52–73 (NM) Mean 84 months (range 64–146)
Koka et al30 2010 RA (single-center) 137 (55, G1; 82, G2) > 50 NM
Shabestari et al16 2010 RA (multicenter) 21 (21, G1; 0, G2) 42–79 (53) 8 years
31
Bell et al 2011 RA (single-center) 655 (NM) NM Mean 20 months (range 3–93)
Famili et al32 2011 RA (single-center) 120 (22, G1; 98, G2) > 50 30 months
Zahid et al13 2011 RA (single-center) 300 (26, G1; 274, G2) 17–87 (56) Mean 26 months (range 2–78)
Leonida et al22 2012 PS (single-center) 9 (9, G1; 0, G2) 45–68 (NM) 2 years
Memon et al33 2012 RA (single-center) 200 (100, G1; 100, G2) 47–90 (63) 4–6 months
Yip et al34 2012 RA (multicenter) 337 (20, G1; 317, G2) > 40 Mean 6 years (range 0.33–11.89)
Wagenberg et al35 2013 RA (single-center) 541 (NM) 12–88 (58) Mean 10 years (range 1–22)
Al-Sabbagh et al 36 2015 RA (single-center) 203 (20, G1; 183, G2) 21–90 (55.5) Mean 7 years (range 0.84–10)
Mozzati et al23 2015 PS (single-center) 235 (235, G1; 0, G2) 48–79 (60.7) > 24 months
Tallarico et al24 2015 PS (multicenter) 32 (32, G1; 0, G2) 46–80 (64.6) Mean 47.6 months (range 36–72)
*Unpublished information was obtained by personal communication with one of the authors.
†This study evaluated only patients taking bisphosphonates.

‡Wagenberg et al35 did not provide the number of implant failures in each group.

CCT, controlled clinical trial; G1, group bisphosphonate; G2, group non-bisphosphonate;
NA, not applicable; NM, not mentioned; PS, prospective study; RA, retrospective analysis.

Description of the studies Meta-analysis

21
One controlled clinical study (CCT), three prospective
studies,22-24 and 14 retrospective studies13,16,25-36 were
included in the meta-analysis. Detailed data of the 18
included studies are listed in Tables 1 and 2.
Of the 12 studies comparing the procedures (five
studies16,22-24,26 evaluated only patients taking BP, and
one study35 only reported information about MBL), a
total of 1,284 dental implants were placed in patients
taking BP, with 47 failures (3.66%), and 7,997 implants
in patients not taking BP, with 307 failures (3.84%).
Quality assessment
Six studies were of high quality, ten were of moderate
quality, and two studies were of low quality. The scores
are summarized in Table 3.
In this study, a random-effects model was used to eval-
uate the implant failure between groups because of
variability of the included studies, even though statis-
tical heterogeneity was not found (I2 = 9%; P = .36). The
statistical heterogeneity stands for the variability in the
intervention effects being evaluated in the different
studies, and is a consequence of clinical or method-
ologic diversity, or both, among the studies. The low
level of heterogeneity observed when the outcome
“implant failure” was analyzed is surprising, given the
variability of the included studies (varying lengths of
follow-up, patient ages, number of implants, classifica-
tion of severity of periodontitis, etc.). For this reason, a
random-effects model was used to incorporate hetero-
geneity among studies. Some argue that, since clinical

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Chrcanovic et al

Antibiotics / Postoperative
mouth rinse (days) Healing period / loading Failed / placed implants (n) Implant failure rate (%) infection
NM NM 0/102 (G1); 0/108 (G2) 0 (G1); 0 (G2) NM
6 months (maxilla); 3 months (mandible);
12 / NM 0/35 (G1); 77/1,890 (G2) 0 (G1); 4.07 (G2) NM
(64 immediately loaded)
10 / 21 6 weeks 0/169 (G1); (G2)† 0 (G1); (G2) † 0 (G1); NA (G2)

NM NM 5/100 (G1); 26/734 (G2) 5.00 (G1); 3.54 (G2) NM

NM NM 2/468 (G1); 14/1,450 (G2) 0.43 (G1); 0.97 (G2) NM

3–5 / NM NM 5/35 (G1); 7/161 (G2) 14.29 (G1); 4.35 (G2) NM
NM NM 1/121 (G1); 3/166 (G2) 0.83 (G1); 1.81 (G2) NM
NM 3–5 months 0/46 (G1); (G2)† 0 (G1); (G2)† NM
1/1 3 months 0/24 (G1); 15/898 (G2) 0 (G1); 1.67 (G2) NM
NM NM 1/75 (G1); 0/272 (G2) 1.33 (G1); 0 (G2) NM
NM NM 3/51 (G1); 16/610 (G2) 5.88 (G1); 2.62 (G2) NM
7/7 Immediate 0/54 (G1); (G2)† 0 (G1); (G2)† 0 (G1); NA (G2)
NM 4–6 months 10/153 (G1); 6/132 (G2) 6.54 (G1); 4.55 (G2) NM
NM NM 20/74 (G1); 143/1,107 (G2)* 27.03 (G1); 12.92 (G2) NM
NM Immediate (n = 42); Delayed (n = 1,145) NM‡/35 (G1); NM‡/1,151 (G2) ‡
NM
NM NM 0/46 (G1); 0/469 (G2) 0 (G1); 0 (G2) NM
6 / NM Immediate (36%); Delayed (64%) 16/1,267 (G1); (G2)† 1.26 (G1); (G2)† 0 (G1); NA (G2)
14/14 3 months 1/98 (G1); (G2)† 1.02 (G1); (G2)† 0 (G1); NA (G2)

Table 2 Detailed data of the included studies (part 2)

Marginal Region / pros-

bone loss thetic rehabilita-
(mean ± SD; Implant surface modi- tion / opposing
Study mm) Bisphosphonate therapy fication (brand) dentition Observations
All patients were postmenopausal
Jeff- Maxilla, mandible women with BMD scores indicative
NM Mean 3 years NM
coat21 / NM / NM of osteoporosis, 2 smokers, no cases
of osteonecrosis
All implants placed in fresh
Turned (Brånemark, extraction sockets, bone grafts were
Wagen- Maxilla, mandible
Nobel Biocare; utilized in all cases in which there
berg / SC (n = 383), FPP
NM Alendronate n = 1,398), acid-etched was a residual space around the
and (1,471 implants) /
(Osseotite, 3i Implant implant, 13 implants in sinus-lifts,
Froum25 NM
Innovations; n = 527) 323 implants in smokers, no cases of
osteonecrosis
Fugaz- Alendronate or risedronate, 39 implants inserted in fresh
Maxilla, mandible
zotto NM 35 or 70 mg/week, SLA (Straumann) extraction sockets, GBR in some
/ NM / NM
et al26 mean 3.3 years cases, no cases of osteonecrosis
Grafting procedures in 30 patients of
Alendronate (34 patients),
Bell and Maxilla, mandible G1. Smokers were also included, but
NM risedronate (6 patients), NM
Bell27 / NM / NM the exact number was not informed.
ibandronate (2 patients)
No cases of osteonecrosis
Alendronate, risedronate, iban-
Grant dronate. Mean 38 months. Maxilla, mandible All female patients, no cases of
NM NM
et al28 Before implant: 89 patients. / NM / NM osteonecrosis, 2 diabetic patients
After implant: 26 patients
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continuation from previous page

Kasai “All implants were from Maxilla, mandible All female patients, no smokers, no
NM Alendronate
et al29 only one manufacturer” / NM / NM cases of osteonecrosis
Koka Maxilla, mandible All female patients/postmenopausal
NM NM NM
et al30 / NM / NM women, no cases of osteonecrosis
Maxilla, mandible
Alendronate 35–70 mg/week,
Shabe- / FPP (12 patients), All female patients, grafting proced-
mean 20.5 months. Before
stari NM SLA (Straumann) overdenture (9 ures in 5 patients, no cases of osteo-
implant: 7 patients. After
et al16 patients) / natural, necrosis
implant: 14 patients
fixed, removable
All implants placed in fresh
Bell Maxilla, mandible extraction sockets, 83 implants in
NM NM SLA (Straumann)
et al31 / SC, FPP / NM diabetic patients, 123 implants in
smokers, no cases of osteonecrosis
Alendronate (16 patients),
risedronate (4 patients),
ibandronate (2 patient).
Famili Duration of use: > 6 months – 1 All female patients, no cases of
NM NM NM
et al32 year (6 patients), > 1 year osteonecrosis
(9 patients), > 5 years
(5 patients), unknown
(2 patients)
Turned (Brånemark,
Nobel Biocare; n = 389),
“Presence of
unknown (Zimmer;
implant Grafting procedures in 173 implant
Zahid n = 158), SLA (Strau- Maxilla, mandible
thread expo- 35–70 mg/week, 6–192 months sites, 56 implants in smokers, no
et al13 mann; n = 111), / NM / NM
sure” was cases of osteonecrosis
unknown (ADI, Ameri-
used instead
can Dental Implant;
n = 3)
Risedronate (5 patients), alen-
All patients had residual teeth with
dronate (4 patients), for less Laser-modified (Way
Leonida Mandible/ FAP / severe periodontal disease, 19
NM than 3 years. Suspension of bis- implant, Syntegra sur-
et al22 NM implants in fresh extraction sockets,
phosphonate therapy 1 month face, Geass)
no cases of osteonecrosis
after the surgery
Turned (Brånemark,
Risedronate (23 patients), iban-
Nobel Biocare; n = 119), Maxilla, mandible
0.81 ± 1.02 dronate (5 patients), alendro-
SLA (Straumann; n = 66), / SC (235 All female patients, 8 smokers, 7 dia-
(G1, n = 145); nate (72 patients). Duration of
Memon unknown (Biomet 3i; implants), FPP (10 betic patients, grafting procedures in
0.78 ± 0.71 use: < 1 year (20 patients), 1–3
et al33 n = 55), unknown implants), 88 implant sites, 60 nonsubmerged
(G2, n = 130) years (19 patients), > 3 years (15
(Thommen; n = 28), overdenture implants, no cases of osteonecrosis
(4–6 months) patients), unknown (46
unknown (AstraTech; (n = 40) / NM
patients)
n = 17)
“Machined” (n = 85); All female patients, 52 smokers, 20
Yip Maxilla, mandible
NM Alendronate, risedronate “moderately rough- diabetic patients, no cases of osteo-
et al34 / NM / NM
ened” (n = 1,096) necrosis
0.61 ± 0.87
Maxilla, mandible
Wagen- (G1, n = 35); All implants in fresh extraction sock-
“Machined” (n = 873); / SC (n = 217),
berg 0.53 ± 0.83 NM ets, 184 implants in smokers, no
“roughened” (n = 314) “splinted”
et al35 (G2, n = 1151) cases of osteonecrosis
(n = 970) / NM
(NM)
Maxilla, mandible
Al-Sab-
History of oral bisphosphonate / SC (n = 393), 1 male and 19 females, no cases of
bagh NM SLA (Straumann)
therapy for 3 years or more overdenture osteonecrosis
et al36
(n = 122) / NM
Oral BP: alendronate (141
Sinus lift for 54 implants, no cases of
Mozzati patients), ibandronate (68 Maxilla, mandible
NM NM osteonecrosis, 51 smokers, 21 dia-
et al23 patients), risedronate (45 / NM / NM
betic patients
patients)
Alendronate 70 mg/week or or
Tallarico 1.35 ± 0.21 Oxidized (NobelReplace, Maxilla, mandible All implants in healed sites, no cases
5–10 mg/day, for at least 3
et al24 (G1) (3 years) Nobel Biocare) / NM / NM of osteonecrosis
years before implant placement
BMD, bone mineral density; FAP, full-arch prosthesis; FPP, fixed partial prosthesis; G1, group bisphosphonate; G2, group non-bisphosphonate; GBR, guided bone regeneration; NM, not
mentioned; SC, single crown; SLA, sand-blasted, large-grit, acid-etched.

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Table 3 Quality assessment of the studies by NOS

Selection Comparability of cohorts Outcome

Represen- Selec- Ascer- Outcome
tativeness tion of tain- of inter-
of the exter- ment of est not Addi- Assess- Follow-up Adequacy
exposed nal expo- present Main fac- tional fac- ment of long of fol- Total
Study cohort control sure at start tor tor outcome enough* low-up (9/9)
Jeffcoat21 0 1 1 1 1 0 1 0 0 5/9
Wagenberg and
0 1 1 0 1 1 1 1 0 6/9
Froum25
Fugazzotto et al26 0 0 1 0 0 0 1 0 0 2/9
Bell and Bell27 1 1 1 0 1 1 1 0 0 6/9
Grant et al28 0 1 0 0 1 0 1 0 0 3/9
29
Kasai et al 0 1 1 0 1 0 1 1 0 5/9
Koka et al30 0 1 1 0 1 1 1 0 0 5/9
16
Shabestari et al 0 0 1 0 0 0 1 1 0 3/9
Bell et al31 0 1 1 0 1 1 1 0 0 5/9
Famili et al32 0 1 1 0 1 0 1 0 0 4/9
13
Zahid et al 1 1 1 0 1 1 1 0 0 6/9
Leonida et al22 0 0 1 0 0 0 1 0 0 2/9
33
Memon et al 0 1 1 0 1 1 1 0 1 6/9
Yip et al34 0 1 1 0 1 1 1 1 0 6/9
Wagenberg et al35 0 1 1 0 1 1 1 1 0 6/9
36
Al-Sabbagh et al 0 1 0 0 1 0 1 1 0 4/9
Mozzati et al23 0 0 1 1 0 0 1 0 0 3/9
24
Tallarico et al 0 0 1 1 0 0 1 0 0 3/9
*5 years of follow-up was chosen to be enough for the outcome “implant failure” to occur.

and methodologic diversity always occur in a
meta-analysis, statistical heterogeneity is inevitable.37
The insertion of dental implants in patients taking
BPs statistically affected the implant failure rates (RR
1.73, 95% CI 1.21–2.48, P = .003; Fig 2). There were no
apparent significant effects of dental implants inserted
in patients taking BPs on the occurrence of MBL (MD
0.05, 95% CI −0.12–0.22; P = .59; heterogeneity:
fixed-effects model, I2 = 0%; P = .78, Fig 3). Due to lack
of enough information, meta-analysis for the outcome
“postoperative infection” was not performed.
The overall proportion from studies reporting a sin-
gle proportion was calculated (Fig 4). Since a statisti-
cally significant heterogeneity was detected (τ2 = 0.000,
χ2 = 51.137, df = 16, I2 = 68.712%, P < .001) a random-ef-
fects method was performed, according to the DerSi-
monian-Laird estimator38). The estimate of an event
was 1.5% (0.015, 95% CI 0.006–0.023, SE 0.004, P < .001).
It is the probability of implant failure in patients taking
BPs.
Publication bias
The funnel plot showed asymmetry when the studies
reporting the outcome “implant failure” were analyzed
(Fig 5), indicating possible presence of publication bias.
DISCUSSION
The purpose of this systematic review was to compare
the implant failure rates, MBL, and postoperative infec-
tion for patients receiving or not receiving BPs. The
results of the present study cannot suggest that BPs
may affect the MBL of dental implants, due to the lim-
ited number of studies33,35 reporting this outcome. Due

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BP Non-BP
Risk ratio (IV, Risk Ratio IV,
Study or subgroup Events Total Events Total Weight Random, 95% CI) Year Random, 95% Cl
Jeffcoat21 0 102 0 108 Not estimable 2006
Wagernberg and Froum25 0 35 77 1,890 1.7% 0.34 [0.02–5.36] 2006
27
Bell and Bell 5 100 26 734 12.9% 1.41 [0.55–3.59] 2008
Grant et al28 2 468 14 1,450 5.6% 0.44 [0.10–1.94] 2008
Kasai et al29 5 35 7 161 9.9% 3.29 [1.1–9.75] 2009
Koka et al30 1 121 3 166 2.5% 0.46 [0.05–4.34] 2010
32
Famili et al 1 75 0 272 1.3% 10.78 [0.44–261.87] 2011
Bell et al31 0 24 15 898 1.6% 1.16 [0.07–18.85] 2011
Zahid et al13 3 51 16 610 8.2% 2.24 [0.68–7.44] 2011
Yip et al34 20 74 143 1,107 44.6% 2.09 [1.40–3.14] 2012
Memon et al33 10 153 6 132 11.8% 1.44 [0.54–3.85] 2012
Al-Sabbagh et al 36 0 46 0 469 Not estimable 2015
Total (95% CI) 1,284 7,997 100.0% 1.73 [1.21–2.48]
Total events 47 307
Heterogeneity: Tau = 0.03, χ = 9.89, df = 9 (P = .36); I2 = 9%
2 2 0.02 0.1 1 10 50
Test for overall effect: Z = 3.00 (P = .003) Favors BP Favors non-BP

Fig 2 Forest plot for the event “implant failure”.

BP Non-BP
Mean difference Mean Difference IV,
Study or subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Year Fixed, 95% Cl
Memon et al33 0.81 1.02 145 0.78 0.71 130 66.8% 0.03 [−0.18–0.24] 2012
Wagernberg et al35 0.61 0.87 35 0.53 0.83 1,151 33.2% 0.08 [−0.21–0.37] 2013
Total 95% CI 180 1,281 100.0% 0.05 [−0.12–0.22]
Heterogeneity: χ2 = 0.08; df = 1 (P = .78); I2 = 0% – 0.2 – 0.1 0 0.1 0.2
Test for overall effect: Z = 0.54 (P = .59) Favors BP Favors non-BP

Fig 3 Forest plot for the event “marginal bone loss”.

to lack of sufficient information, meta-analysis for the
outcome “postoperative infection” was not performed.
Even though the meta-analysis may suggest that BP
affects the implant failure rates, this must be inter-
preted with extreme caution, due to the limitations of
the present study.
Firstly, confounding factors may have affected the
long-term outcomes and not just the fact that patients
were receiving or not receiving BPs, and the impact of
these variables on the implant survival rate, postopera-
tive infection, and MBL39-48 is difficult to estimate if
these factors are not identified separately between the
two different procedures in order to perform a meta-re-
gression analysis. Most of the studies, if not all, did not
report how many implants were inserted and survived/
lost in several different conditions. The use of grafting
in some studies is a confounding risk factor, as well as
the insertion of some or all implants in fresh extraction
sockets, the insertion of implants in different locations,
different healing periods, different prosthetic configu-
rations, type of opposing dentition, different implant
angulation ranges, splinting of the implants, the pres-
ence of smokers, and the use of implants with different
designs and surfaces. It is known that the surface prop-
erties of dental implants such as topography and
chemistry are relevant for the osseointegration process,
influencing ionic interaction, protein adsorption, and
cellular activity at the surface.49
The studies included here made use of implants
with different brands and surface treatments. Titanium

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Proportion
Study Estimate (95% CI) Events/Total 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35
Jeffcoat21 0.005 (0.000–0.018) 0/102
Wagernberg and Froum25 0.014 (0.000–0.052) 0/35
Fugazzotto et al26 0.003 (0.000–0.011) 0/169
27
Bell and Bell 0.050 (0.007–0.093) 5/100
Grant et al28 0.004 (0.000–0.010) 2/468
29
Kasai et al 0.143 (0.027–0.259) 5/35
Koka et al30 0.008 (0.000–0.024) 1/121
16
Shabesteri et al 0.011 (0.000–0.040) 0/46
Bell et al31 0.020 (0.000–0.075) 0/24
Zahid et al13 0.059 (0.000–0.123) 3/51
32
Famili et al 0.013 (0.000–0.039) 1/75
Leonida et al22 0.009 (0.000–0.034) 0/54
33
Memon et al 0.065 (0.026–0.105) 10/153
Yip et al34 0.270 (0.169–0.371) 20/74
Al-Sabbagh et al36 0.011 (0.000–0.040) 0/46
23
Mozzati et al 0.013 (0.006–0.019) 16/1,267
Tallarico et al24 0.010 (0.000–0.030) 1/98
2
Overall (I = 69%, P < .001) 0.015 (0.006–0.023) 64/2,918

Fig 4 Forest plot of proportion for the event “implant failure”.

with different surface modifications shows a wide

0
range of chemical and physical properties, and surface
topographies or morphologies, depending on how Yip et al
they are prepared and handled,50-52 and it is not clear
whether, in general, one surface modification is better Bell and Bell
than another.49 It is important to stress that differences 0.5
Memon et al Kasai et al
in the BPs therapy also interferes with the occurrence of Zahid et al
Grant et al
osteonecrosis, which may directly influence the implant
SE(log[RR])

survival rates.
The different methods of BP administration should 1
also be considered; for example, osteonecrosis caused Koka et al
by intravenous BPs is more prevalent and more severe
than osteonecrosis induced by oral BPs,28 being a result
Bell et al
of the immediate uptake and binding of BPs to bone 1.5 Wagenberg
and Froum
via the intravenous route, as compared to the oral Famili
route, where less than 0.7% is absorbed through the et al

gastrointestinal mucosa before it circulates and binds

to bone.53 Thus, it can be said that intravenous BPs load 2
and accumulate in bone at a rate 142.8 times higher 0.02 0.1 1 10 50
than oral BP.8 As none of the studies included here that Risk ratio (RR)
provided information about the BP therapy evaluated Fig 5 Funnel plot for the studies reporting the outcome event
patients taking intravenous BPs, an underestimation of “implant failure”.

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the implant failure rates can exist. Still, the present
meta-analysis suggests that BPs affect the implant fail-
ure rates.
Another point concerning the BP therapy is that
variations in the chemical molecular structure of the
BPs confer different degrees of potency, with zolendro-
nate being the most potent of the intravenous BPs and
alendronate being the most potent of the oral BPs,
therefore causing the majority of the cases of osteo-
necrosis of the jaws for intravenous54 and oral types,55
respectively.
A final point is the fact that the effect of patient
compliance and adherence to their medication regi-
mens is unknown. Evidence indicates that adherence to
BP therapy at 6 months may be less than 50% for both
once-weekly and daily dosing regiments.56 The real fact
is that individual patients sometimes present with
more than one risk factor, and groups of patients are
typically heterogenous with respect to risk factors and
susceptibilities so the specific effect of an individual risk
factor could be isolated neither for individual studies
nor for the present review. This is understandable and
expected because study populations are typically rep-
resentative of normal populations with various risk
factors.57 To precisely assess the effect of a risk factor on
implant outcomes, it would be ideal to eliminate all
other risk factors from the study population. Not only
does the coexistence of multiple risk factors within a
study population create an inability to assess the spe-
cific effect of one individual risk factor, but there is a
possibility that certain risk factors together may be
more detrimental than the individual risk factors
alone.57 The lack of control of the confounding factors
limited the potential to draw robust conclusions.
As well as these confounding factors, a second lim-
itation is that most of the included studies had a retro-
spective design, and the nature of a retrospective study
inherently results in flaws. These problems were mani-
fested by the gaps in information and incomplete
records. Furthermore, all data rely on the accuracy of
the original examination and documentation. Items
may have been excluded in the initial examination or
not recorded in the medical chart. Studies involving a
340
retrospective chart review do not usually provide infor-
mation regarding the duration of BP usage. This would
have been an important variable to examine, as the
absorbed nitrogen-containing BPs remain bound to
their bone targets until they are released when the
bone is resorbed.58 This limitation prevented us from
stratifying the population of oral BPs users by duration
to analyze the effect of increasing duration on implant
failure rate.
Thirdly, much of the research in the field is limited
by small cohort size and short follow-up periods. It is
important to stress that some publications included in
this review have a short-term follow-up period. A lon-
ger follow-up period can lead to an increase in the fail-
ure rate, especially if it extended beyond functional
loading, because other prosthetic factors can influence
implant failure from that point onward. This might have
led to an underestimation of actual failures in some
studies. Moreover, the occurrence of osteonecrosis can
also exert some influence on the implant survival
rates.10 Some studies show that effects of BPs persist for
extended periods, which could explain why osteo-
necrosis appears after long-term treatment and even in
cases in which BP treatment was discontinued.59,60 This
is concerning because oral BPs are intended for ongo-
ing use over several years in, for example, postmeno-
pausal women. However, it is hard to define what
would be considered a short follow-up period to evalu-
ate implant failures in patients taking BPs.
Fourth, some of included studies are characterized
by a low level of specificity, where the assessment of
BPs as a complicating factor for dental implants was
seldom the main focus of the investigation.
The authors of the present study believe that future
controlled studies with a larger number of patients in
the BP group (several studies included far fewer
patients taking BPs than patients not taking BPs) are
required to determine the real effect of this medica-
ment on the dental implant outcome. Given the large
number of postmenopausal women, and an increasing
number of elderly men, who are being treated for
osteopenia or osteoporosis with BPs medications,
whether dental implant therapy leads to lower survival
VOLUME 47 • NUMBER 4 • APRIL 2016

rates is important information to discuss with patients
during the treatment planning phase.30 There is also a
need to weigh the benefits of a “drug holiday” (a tem-
porary discontinuation of a BP to allow bone marrow
recovery and the formation of new osteoclasts to
repopulate the population that has been depleted by
the BP8) for implant therapy against the risk of progres-
sion of osteoporosis in the absence of oral BP therapy.34
CONCLUSION
The results of the present study cannot suggest that
the insertion of dental implants in patients taking BPs
affects the implant failure rates, due to a limited num-
ber of published studies, all characterized by a low level
of specificity, and most of them dealing with a limited
number of cases without a proper control group. There-
fore, the real effect of BPs on the osseointegration and
survival of endosteal dental implants is still not well
established. Due to lack of sufficient information, it
cannot be suggested whether BPs may affect the MBL
around implants or the incidence of postoperative
infection.
ACKNOWLEDGMENTS
The authors would like to thank Rita Ann Vitolo for having sent us Dr
Pouran Famili’s article, and Dr Julie K. Yip and Dr Barry Wagenberg,
who provided us some missing information about their studies. This
work was supported by CNPq, Conselho Nacional de Desenvolvimen-
to Científico e Tecnológico – Brazil.
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Appendix 1 List of the publications not included in the study and reasons for exclusion

Reason for
exclusion Article
Chatterjee M, Hatori K, Duyck J, Sasaki K, Naert I, Vandamme K. High-frequency loading positively impacts titanium implant osse-
Animal study
ointegration in impaired bone. Osteoporos Int 2015;26:281–290.
Alghamdi HS, Bosco R, Both SK, et al. Synergistic effects of bisphosphonate and calcium phosphate nanoparticles on peri-implant
Animal study
bone responses in osteoporotic rats. Biomaterials 2014;35:5482–5490.
Cuairán C, Campbell PM, Kontogiorgos E, Taylor RW, Melo AC, Buschang PH. Local application of zoledronate enhances miniscrew
Animal study
implant stability in dogs. Am J Orthod Dentofacial Orthop 2014;145:737–749.
Animal study Oh KC, Moon HS, Lee JH, Park YB, Kim JH. Effects of alendronate on the peri-implant bone in rats. Oral Dis 2015;21:248–256.
Pyo SW, Kim YM, Kim CS, Lee IS, Park JU. Bone formation on biomimetic calcium phosphate-coated and zoledronate-immobilized
Animal study
titanium implants in osteoporotic rat tibiae. Int J Oral Maxillofac Implants 2014;29:478–484.
de Oliveira MA, Asahi DA, Silveira CA, Lima LA, Glick M, Gallottini M. The effects of zoledronic acid and dexamethasone on osseointe-
Animal study
gration of endosseous implants: histological and histomorphometrical evaluation in rats. Clin Oral Implants Res 2015;26:e17–e21.
Hazzaa HH, Amin G, Abo Hager EA, El Shiekh MA. Influence of alendronate administration regimen on the final outcome of implant
Animal study
osseointegration in an osteoporotic model. J Int Acad Periodontol 2014;16:19–30.
Park R, Kim JH, Choi H, Park YB, Jung HS, Moon HS. Effect of alendronate on bone remodeling around implant in the rat. J Adv Prost-
Animal study
hodont 2013;5:374–381.
Kim I, Ki H, Lee W, Kim H, Park JB. The effect of systemically administered bisphosphonates on bony healing after tooth extraction
Animal study
and osseointegration of dental implants in the rabbit maxilla. Int J Oral Maxillofac Implants 2013;28:1194–1200.
Stadlinger B, Korn P, Tödtmann N, et al. Osseointegration of biochemically modified implants in an osteoporosis rodent model. Eur
Animal study
Cell Mater 2013;25:326–340.
Abtahi J, Agholme F, Sandberg O, Aspenberg P. Effect of local vs. systemic bisphosphonate delivery on dental implant fixation in a
Animal study
model of osteonecrosis of the jaw. J Dent Res 2013;92:279–283.
Yaman F, Ağaçayak S, Atilgan S, et al. Effects of systemic zoledronic acid administration on osseointegration of hydroxyapa-
Animal study
tite-coated and resorbable blast material surface implants in rabbit models. Int J Oral Maxillofac Implants 2012;27:1443–1447.
Ayan M, Dolanmaz D, Mihmanlı A, Ayan A, Kürkçü M. The effect of systemically administrated zoledronic acid on the osseointegra-
Animal study
tion of dental implants. Oral Dis 2012;18:802–808.
Tsetsenekou E, Papadopoulos T, Kalyvas D, Papaioannou N, Tangl S, Watzek G. The influence of alendronate on osseointegration of
Animal study
nanotreated dental implants in New Zealand rabbits. Clin Oral Implants Res 2012;23:659–666.
Qi M, Hu J, Li J, et al. Effect of zoledronate acid treatment on osseointegration and fixation of implants in autologous iliac bone
Animal study
grafts in ovariectomized rabbits. Bone 2012;50:119–127.
Animal study Kim JH, Park YB, Li Z, et al. Effect of alendronate on healing of extraction sockets and healing around implants. Oral Dis 2011;17:705–711.
Lee SJ, Oh TJ, Bae TS, Lee MH, Soh Y, Kim BI, Kim HS. Effect of bisphosphonates on anodized and heat-treated titanium surfaces: an
Animal study
animal experimental study. J Periodontol 2011;82:1035–1042.
Huja SS, Kaya B, Mo X, D’Atri AM, Fernandez SA. Effect of zoledronic acid on bone healing subsequent to mini-implant insertion.
Animal study
Angle Orthod 2011;81:363–369.
Mardas N, Schwarz F, Petrie A, Hakimi AR, Donos N. The effect of SLActive surface in guided bone formation in osteoporotic-like
Animal study
conditions. Clin Oral Implants Res 2011;22:406–415.
Sugata Y, Sotome S, Yuasa M, Hirano M, Shinomiya K, Okawa A. Effects of the systemic administration of alendronate on bone for-
Animal study mation in a porous hydroxyapatite/collagen composite and resorption by osteoclasts in a bone defect model in rabbits. J Bone Joint
Surg Br 2011;93:510–516.
Giro G, Coelho PG, Pereira RM, Jorgetti V, Marcantonio E Jr, Orrico SR. The effect of oestrogen and alendronate therapies on post-
Animal study
menopausal bone loss around osseointegrated titanium implants. Clin Oral Implants Res 2011;22:259–264.
Huja SS, Mason A, Fenell CE, et al. Effects of short-term zoledronic acid treatment on bone remodeling and healing at surgical sites
Animal study
in the maxilla and mandible of aged dogs. J Oral Maxillofac Surg 2011;69:418–427.
Yildiz A, Esen E, Kürkçü M, Damlar I, Dağlioğlu K, Akova T. Effect of zoledronic acid on osseointegration of titanium implants: an
Animal study
experimental study in an ovariectomized rabbit model. J Oral Maxillofac Surg 2010;68:515–523.
Blazsek J, Dobó Nagy C, et al. Aminobisphosphonate stimulates bone regeneration and enforces consolidation of titanium implant
Animal study
into a new rat caudal vertebrae model. Pathol Oncol Res 2009;15:567–577.
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Berardi D, Raffaelli L, Perfetti G, Paolantonio M, Trisi P. Clodronate combined with a surfactant (Tween 20) does not improve osse-
Animal study
ointegration: a rabbit immunohistomorphometric study. Int J Immunopathol Pharmacol 2009;22:829–835.
Gao Y, Zou S, Liu X, Bao C, Hu J. The effect of surface immobilized bisphosphonates on the fixation of hydroxyapatite-coated tita-
Animal study
nium implants in ovariectomized rats. Biomaterials 2009;30:1790–1796.
Gao Y, Luo E, Hu J, Xue J, Zhu S, Li J. Effect of combined local treatment with zoledronic acid and basic fibroblast growth factor on
Animal study
implant fixation in ovariectomized rats. Bone 2009;44:225–232.
Zuffetti F, Bianchi F, Volpi R, et al. Clinical application of bisphosphonates in implant dentistry: histomorphometric evaluation. Int J
Animal study
Periodontics Restorative Dent 2009;29:31–39.
Giro G, Gonçalves D, Sakakura CE, Pereira RM, Marcantonio Júnior E, Orrico SR. Influence of estrogen deficiency and its treatment
Animal study with alendronate and estrogen on bone density around osseointegrated implants: radiographic study in female rats. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2008;105:162–167.
Viera-Negrón YE, Ruan WH, Winger JN, Hou X, Sharawy MM, Borke JL. Effect of ovariectomy and alendronate on implant osseointe-
Animal study
gration in rat maxillary bone. J Oral Implantol 2008;34:76–82.
Giro G, Sakakura CE, Gonçalves D, Pereira RM, Marcantonio E Jr, Orrico SR. Effect of 17beta-estradiol and alendronate on the removal
Animal study
torque of osseointegrated titanium implants in ovariectomized rats. J Periodontol. 2007;78:1316–1321.
Chacon GE, Stine EA, Larsen PE, Beck FM, McGlumphy EA. Effect of alendronate on endosseous implant integration: an in vivo study
Animal study
in rabbits. J Oral Maxillofac Surg 2006;64:1005–1009.
Kajiwara H, Yamaza T, Yoshinari M, et al. The bisphosphonate pamidronate on the surface of titanium stimulates bone formation
Animal study
around tibial implants in rats. Biomaterials 2005;26:581–587.
Duarte PM, de Vasconcelos Gurgel BC, Sallum AW, Filho GR, Sallum EA, Nociti FH Jr. Alendronate therapy may be effective in the
Animal study
prevention of bone loss around titanium implants inserted in estrogen-deficient rats. J Periodontol 2005;76:107–114.
Narai S, Nagahata S. Effects of alendronate on the removal torque of implants in rats with induced osteoporosis. Int J Oral Maxillofac
Animal study
Implants 2003;18:218–223.
Tokugawa Y, Shirota T, Ohno K, Yamaguchi A. Effects of bisphosphonate on bone reaction after placement of titanium implants in
Animal study
tibiae of ovariectomized rats. Int J Oral Maxillofac Implants 2003;18:66–74.
Yoshinari M, Oda Y, Inoue T, Matsuzaka K, Shimono M. Bone response to calcium phosphate-coated andbisphosphonate-immobi-
Animal study
lized titanium implants. Biomaterials 2002;23:2879–2885.
Denissen H, Montanari C, Martinetti R, van Lingen A, van den Hooff A. Alveolar bone response to submerged bisphosphonate-com-
Animal study
plexed hydroxyapatite implants. J Periodontol 2000;71:279–286.
Nepal M, Li L, Bae TS, Kim BI, Soh Y. Evaluation of osseointegration around tibial implants in rats by ibandronate-treated nanotubu-
Animal study
lar Ti-32Nb-5Zr alloy. Biomol Ther (Seoul) 2014;22:563–569.
Karlsson J, Harmankaya N, Allard S, et al. Ex vivo alendronate localization at the mesoporous titania implant/bone interface. J Mater
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2015;46:990–995.
Guimarães MB, Bueno RS, Blaya MB, Shinkai RS, Marques LM. Influence of the local application of sodium alendronate gel on osse-
Animal study
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ment. Int J Dent 2014;2014:471035.
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Chadha GK, Ahmadieh A, Kumar S, Sedghizadeh PP. Osseointegration of dental implants and osteonecrosis of the jaw in patients
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Case report Kim JW, Kwon TG. Bisphosphonate-related osteonecrosis of the jaw at a previously grafted sinus. Implant Dent 2014;23:18–21.
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Case report bone graft and recombinant human BMP-7 with subsequent endosseous implant in a patient with bisphosphonate-related osteo-
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of the jaws. J Oral Maxillofac Surg 2014;72:1937e1–e8.
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osteonecro-
implants: a microcomputed tomography study. Implant Dent 2014;23:258–263.
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osteonecro-
phonate treatment. Clin Oral Implants Res 2014;25:632–640.
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implants: clinical observations. Clin Oral Investig 2013;17:167–175.
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ated with dental implants. J Oral Maxillofac Surg 2010;68:790–796.
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McLeod NM. Oral bisphosphonates and dental implants. J Oral Maxillofac Surg 2009;67:1355.
editor

VOLUME 47 • NUMBER 4 • APRIL 2016 e5

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