European Journal of Orthodontics, 2019, 1–12

doi:10.1093/ejo/cjz021
Systematic review

Systematic review

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Effects of systematic bisphosphonate use
in patients under orthodontic treatment: a
systematic review
Vasileios F. Zymperdikas1,2, Maria P. Yavropoulou3,
Eleftherios G. Kaklamanos4, and Moschos A. Papadopoulos1,
1
Department of Orthodontics, School of Health Sciences, Faculty of Dentistry, Aristotle University of Thessaloniki,
2
Department of Training and Operations, 424 Military Hospital of Thessaloniki, 31st Propaedeutic Department of In-
ternal Medicine, National and Kapodistrian University of Athens, Greece, and 4Hamdan Bin Mohammed College of
Dental Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates

Correspondence to: Moschos A. Papadopoulos, Department of Orthodontics, School of Health Sciences, Faculty of Den-
tistry, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece. E-mail: [email protected]

Summary
Background:  Bisphosphonates are a class of drugs prescribed for several osseous related disorders
owing to their ability to regulate bone turnover, which could in turn affect orthodontic treatment
outcomes.
Objective:  To examine the effect of bisphosphonate (BP) use on orthodontic patients through
clinical and radiographic measurements.
Search methods: Systematic and unrestricted search of 17 databases complemented with
additional hand-searches were performed up to March 2019.
Selection criteria: Articles reporting on human patients with a history of BPs administration that
received orthodontic treatment were eligible for inclusion.
Data collection and analysis:  Data regarding the medical profile of the patients, the specific type of
malocclusion and the performed treatment plan, as well as the clinical and radiographic outcomes
were extracted. Quality assessment was performed by the ROBINS-I tool for the cohort studies and by
a slightly modified checklist from the original one proposed by Agbabiaka et al. for the case reports.
Results:  7 articles (1 retrospective cohort study and 6 case reports) were eventually included in the
present review including 122 subjects (29 patients and 93 controls) reporting on the clinical and
radiographic changes following orthodontic treatment of patients during or after BPs use. BPs seem
to have a controversial effect on the clinical and patient-reported variables, even though the majority
of the included patients presented with compromised treatment results and a rather slow rate of tooth
movement. Most radiographic findings revealed mild root resorption, widened periodontal ligament
spaces and sclerotic changes on the surrounding alveolar bone. However, these results should be
interpreted with caution, due to the limited number of the eligible articles and their limitations.
Limitations:  The included studies were of rather low quality due to study design and incomplete
reporting.
Conclusions and implications: BP administration seems to be associated with compromised
clinical outcomes, prolonged treatment time, and moderate changes on the roots and surrounding
tissues of orthodontic patients.
Registration:  Non-registered.
Funding:  None.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Orthodontic Society.
1
All rights reserved. For permissions, please email: [email protected]
2 European Journal of Orthodontics, 2019

Introduction the fact that this review focuses only on orthodontic patients, the
search strategy was conducted a priori in a way that could include
Rationale
the majority of the performed dental procedures/disorders as well
Bisphosphonates (BPs) are a group of pyrophosphate analogues as the several types of BPs, in order to eliminate the possibility of
that bind with high affinity in bone surfaces with active osseous omission of pertinent studies. For every database, keywords and
remodelling and are locally released from the bone matrix dur- Medical Subject Headings (MeSH) terms were carefully chosen,
ing osteoclastic bone resorption (1, 2). Contrary to pyrophos- while the search strategy was structured appropriately so as to fit

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phates, the BP molecule has two additional side chains: R1, which the specific requirements of the respective database. In addition, the
enhances BPs affinity for calcium and R2, which regulates the phar- reference lists of the included articles as well as of relative reviews
macodynamic properties of the corresponding BP (3). These drugs were searched for the identification of possibly relevant studies.
are known to inhibit bone resorption via regulation of osteoclastic Grey literature was assessed via independent registers and databases.
function, either directly or indirectly through inducing changes on Furthermore, when complementary information and/or clarifica-
the osteoclast cytoskeleton (4, 5). Efficacy and safety of BPs in the tions were needed, the respective authors where contacted as well.
management of osteoporosis and other bone loss-related diseases Two authors (VFZ and MPY) conducted the search strategy.
have been proven in numerous studies and are currently considered
the golden standard of anti-osteoporotic treatment (6–9).
Eligibility criteria and study selection
The effects of BPs administration on dental tissues have been
The eligibility criteria for the present review were predetermined
extensively assessed by several randomized controlled trials
(Supplementary Table 2). Owing to ethical reasons, prospective or
(RCTs). On the basis of those trials, BPs seem to provoke signifi-
retrospective studies providing an appropriate control group were
cant changes on the alveolar bone of periodontal patients having
not retrieved, as expected. As a result, any type of study reporting
bone-related disorders (10, 11) that could be translated as alveolar
on clinical and radiographic treatment outcomes of orthodontic
bone gain. Similar to the latter, the administration of BPs in peri-
patients with a history of systematic BP use were considered eligible
odontal patients without diseases that could affect bone turnover
for the qualitative synthesis of the present review. The provision of a
led to significant improvement of alveolar bone height, as judged
control group in the respective trials was not a prerequisite for inclu-
by the radiographic measurements (12–15). On the basis of the
sion. After duplicates removal, the remaining articles were examined
latter and as orthodontic treatment depends greatly on bone
on the basis of title, abstract, and full text. If a study was reported
turnover (16), what has to be additionally examined is the pos-
several times, the respective versions were grouped together. Finally,
sible influence of systematic administration of BPs on orthodontic
for studies published in more than one language, the English study
patients.
was assessed.
In the literature there are several animal studies assessing the effec-
tiveness of BPs on orthodontic treatment, yet the reported outcomes
are rather controversial. In detail, although there are trials propagat- Data collection process and data items
ing on favourable clinical outcomes such as slower tooth movement, Data extraction was performed independently by two review
which in turn could be translated as anchorage reinforcement (17–19), authors (VFZ and MPY) in predetermined piloted forms, which
other studies report no significant differences in tooth movement rates were prepared by the third author (EGK). In case of ambiguities,
(20) between BP-treated and drug-naive animals. Moreover, there are the final decision was made after consulting the last author (MAP).
studies that claim either reduced (21, 22), or no significant effects (20) Clinical and dental radiographic measurements were selected as pri-
on orthodontically induced root resorption after BPs administration. mary outcomes in an effort to assess the effect of systematic BPs use
in orthodontic patients. The extracted data were classified according
to their source of acquisition in two groups of variables: clinical and
Objective
radiographic.
The objective of this systematic review was to assess, in an evidence- Furthermore, in an effort to identify possible factors that could
based manner, the existing evidence regarding human patients with a influence the treatment results, various factors were predetermined
history of systematic BP administration receiving orthodontic treatment, to be investigated for their possible effect on the respective out-
and more specifically to examine the effect of BP use on orthodontic come through subgroup analyses. These factors were categorized as
patients through assessment of clinical and radiographic measurements. patient-related (age, sex, existence of bone-related disorder), drug-
related (exact drug administered, route of administration, dosage,
BPs use duration) as well as orthodontic treatment-related (initial
Materials and methods malocclusion, type of orthodontic movement planned, use of remov-
Protocol and registration able/fixed appliances, exact biomechanics applied).
The protocol for the present review was conducted a priori in
accordance with the Cochrane Handbook for Systematic Reviews Risk of bias in individual studies
of Interventions (23), and the respective results are reported on the The risk of bias assessment of the included cohort studies was
basis of the Preferred Reporting Items for Systematic Reviews and performed with the Risk Of Bias In Non-randomized Studies–of
Meta-Analyses (PRISMA) statement (24) and the corresponding Interventions (ROBINS-I) tool (26), which comprises seven domains:
abstract extension (25). This protocol is not registered and it is avail- 1. bias due to confounding, 2. bias in selection of participants into
able upon request. the study, 3.  bias in classification of interventions, 4.  bias due to
deviations from intended interventions, 5. bias due to missing data,
Information sources and search 6. bias in measurement of outcomes, and 7. bias in selection of the
Seventeen electronic databases were systematically and unrestrict- reported result. Each of the aforementioned domains could be given
edly search up to March 2019 (Supplementary Table 1). Despite of one of the following ratings: ‘low risk’, ‘moderate risk’, ‘serious risk’,
V. F. Zymperdikas et al. 3

‘critical risk’, or ‘no information’. A rating regarding the overall risk from lateral cephalometric radiographs). For variables regarding
of bias for the respective study was reached as follows: ‘low risk’ the frequency of possible side-effects (i.e. root resorption, compro-
(when all domains were rated with ‘low risk’), ‘moderate risk’ (when mised treatment results) the risk ratios and the respective 95% CIs
all domains were rated with ‘low risk’ and at least one with ‘moder- would be computed. If at least five included trials reported on the
ate risk’), ‘serious risk’ (when at least one domain was rated with same measurement and hence a meta-analysis could be performed,
‘serious risk’, but no domain was rated with ‘critical risk’), ‘critical a random-effects model as the one suggested by DerSimonian and
risk’ (when at least one domain was rated with ‘critical risk’), and ‘no Laird (33) would be implemented, due to the fact that it takes into

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information’ (when no domain was rated with ‘serious risk’ or ‘criti- account existing heterogeneity. The latter was a priori suspected to
cal risk’ and at least one domain was rated with ‘no information’). exist due to sample variations regarding patient characteristics (race,
For the case reports, a slightly modified checklist from the one age, gender), the orthodontic treatment performed (exact kind of
originally proposed by Agbabiaka et al. (27) regarding the quality initial malocclusion, biomechanics, and appliances used) as well
assessment of case reports reporting on adverse effects was imple- as the exact pharmaceutical protocol implemented (exact BP used,
mented. The original checklist is composed of 18 principal items route, duration and dosage of administration). Finally, heterogene-
grouped in 3 domains, that assess the adverse effects of all possible ity between studies was planned to be assessed via inspecting forest
drugs and 3 additional items that assess specifically the side-effects plots and calculating the τ2 and I2 statistics.
of herbal preparations. In this study, only the first 18 items were
implemented. Each item was given 2 points if it was completely ful- Additional analyses
filled, 1 point if it was unclear whether it was fulfilled or not, and Possible sources of heterogeneity were a priori planned to be
0 points if it was not fulfilled, for a maximum of 36 points. Finally, searched via subgroup analyses and random-effects meta-regression.
the overall quality of the case report was considered as: ‘low quality’ In order to minimize excessive significance testing, the aforemen-
for 0–14 points, ‘lower medium quality’ for 15–21 points, ‘upper tioned analyses would be performed only for meta-analyses that
medium quality’ for 22–28 points, and ‘high quality’ for 29–36 include a minimum of five studies.
points. The risk of bias assessment was independently performed by Moreover, robustness of the results was planned to be assessed
two review authors (VFZ and MPY). through predetermined sensitivity analyses, according to the study
design, and the duration of BPs treatment.
Risk of bias across studies
The existence of reporting biases (including publication bias and/
or ‘small study effects’) was a priori planned to be assessed through Results
the inspection of contour-enhanced funnel plots (28), Begg’s rank Study selection
correlation test (29) and Egger’s weighted regression test (30) if at The electronic search complemented by the respective manual
least 10 studies could be included in a meta-analysis. The Duval and searches resulted in 11856 hits, which were reduced to 7689 after the
Tweedie’s trim and fill procedure (31) would be performed in case removal of duplicates (Figure 1). Following the sequential elimina-
these tests tended towards the existence of publication bias. tion of 7524 studies on the basis of title and abstract (Supplementary
Similarly, an assessment for the overall quality of evidence for Table 3), 165 full texts were considered eligible for further evalu-
every primary outcome was a priori planned to be performed accord- ation. From the latter, 158 were excluded for various reasons and
ing to the Grades of Recommendation, Assessment, Development finally 7 articles were included in the qualitative synthesis of the
and Evaluation (GRADE) approach (32), based on the following present review.
interpretations: ‘high quality’: we are very confident that the true One author was contacted for additional information and clarifi-
effect lies close to that of the estimate of the effect, ‘moderate qual- cations and replied back providing the requested data (details avail-
ity’: we are moderately confident in the effect estimate: the true effect able upon request).
is likely to be close to the estimate of the effect, but there is a possi-
bility that it is substantially different, ‘low quality’: our confidence in
Study characteristics and risk of bias within studies
the effect estimate is limited: the true effect may be substantially dif-
The general characteristics of the seven included articles are pre-
ferent from the estimate of the effect, and ‘very low quality’: we have
sented in brief in Table 1. Only one study (34) was a retrospective
very little confidence in the effect estimate: the true effect is likely to
cohort trial, whereas the remaining six studies (35–40) were case
be substantially different from the estimate of effect.
reports, reporting on 122 individuals (29 treated patients and 93
controls). When more than one case was presented in the same arti-
Summary measures and synthesis of results cle, the latter was divided to respective data sets. An interesting find-
After summarizing, data would be considered appropriate for pool- ing is that only one man was included in the total of 122 examined
ing if they reported on similar types on initial malocclusion and individuals. The majority of these studies took place in University
similar treatment approaches. In case this option could not be under- settings whereas two of them (34, 40) were performed in private
taken the classification would be performed based on the principal practices. However, owing to both the small simple size originating
dimension that the respective orthodontic treatment concerned as from all included studies, but most importantly to the serious hetero-
well as the method of examination implemented for the diagnosis geneity and low quality of the eligible articles, a meta-analysis was
and observation of the respective treatment outcomes (i.e. clinical not possible to be performed. Hence, the respective results of each
or radiographic). study, after the aforementioned classification, are presented without
Mean differences and the corresponding 95% confidence inter- being statistically processed.
vals were planned to be calculated for variables assessing the exact As far as the pharmaceutical treatment is concerned, alen-
changes in the dental (for example, range of tooth movement and/or dronate was the most commonly prescribed BP and it was most
inclination) and the skeletal structures (for example, measurements often administered orally, while the duration of BPs treatment
4 European Journal of Orthodontics, 2019

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Figure 1.  Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram depicting the process followed for the selection of the
included studies.

ranged between 1 and 120  months. In addition, the majority of Results of individual studies
the treated patients had osteoporosis. Regarding the orthodontic On the basis of results of the present systematic review, BPs admin-
treatment characteristics (Table 2), in the majority of the patients istration seems to have ambiguous impact on orthodontic treatment
the treatment performed was adjunctive and it did not include the outcomes, yet the majority of the reported cases are presented with
whole dentition but only specific groups of teeth. Patients were compromised results and rather slow progress of tooth movement
treated with either fixed or removable appliances, while treatment (Table 3).
duration ranged between 2 and 54  months. Some patients began Regarding the sagittal dimension, it seems that when space closure
the orthodontic treatment after discontinuation of BP adminis- is planned, either in extraction cases or in patients presenting with
tration whereas in other patients orthodontic treatment was per- diastemata, BP patients were found to present slower tooth move-
formed simultaneously with BP use. All included studies provided ment resulting into greater treatment time, remaining of residual
both clinical and radiographic outcomes. spaces and poor root parallelism. The latter is attributed to the fact
Regarding risk of bias assessment, the cohort study of Lotwala that in these patients, space closure was primarily accomplished by
et al. (34) was found to present critical risk of bias (Supplementary tipping rather than bodily movement of the adjacent teeth. Exception
Table 4), whereas only one case report (two data sets) (37) was to this was one patient with normal closure of the extraction space
judged with ‘high quality’, whereas the remaining articles were (40). In addition, successful unilateral distalization of the upper
found to present quality limitations, even though the overall quality canine and premolars was reported following maxillary sinus aug-
of the case reports was judged as ‘upper medium’ according to the mentation on the respective side (39). Moreover, there were also some
modified checklist (22.4 points) (Supplementary Table 5). reports regarding increased mobility of the treated teeth (35, 40).
V. F. Zymperdikas et al. 5

Table 1.  General characteristics of the articles included in the present systematic review. Tx, treatment; CR, case report; RCS, retrospective
cohort study; Gp, experimental group; Ctr, control group; NR, not reported

A/A Article Design Setting General characteristics n (M/F)

1 Krieger CR University; Ger- Female patient with reduced dental arch and compromised periodontal Gp: 1 (0/1)
et al. (35) many structures, vertical support only present in the anterior segment and
impaired mastication.

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2 Lotwala RCS Private practices; Female patients aged more than 50 years treated from 2002 through 2008 Gp: 20 (0/20) Ctr:
et al. (34) USA 93 (0/93)
3 Morita CR University; Japan A 55-year-old woman diagnosed with extranodal NK/T cell lymphoma at Gp: 1 (0/1)
et al. (36) 52 years of age, treated with irradiation, referred for extraction of the left
maxillary second premolar
4 Rinchuse CR Private practice; Female patient with Addison’s disease. Gp: 1 (0/1)
et al. (37) USA
CR University; USA Male patient under treatment for cancer (sacral plasmacytoma) and mul- Gp: 1 (1/0)
tiple myeloma
5 Smidt CR University; Israel Female patient with osteoporosis. Gp: 1 (0/1)
et al. (38)
6 Vitral CR University; Brazil Female patient, with loss of maxillary first and second molars, referred for 1 (0/1)
et al. (39) proper repositioning of her teeth
7 Zahrows- CR Private practice; Female patient 1 (0/1)
ki (40) CR USA Female patient 1 (0/1)
CR Female patient 1 (0/1)
Bone-related disorder Age in years Type of drug Dosage Administra- Tx duration Timing of BPs
Mean (SD) tion route (months) administration
Osteoporosis 66.0 Alendronate 70 mg/week Oral 7 Simultaneous with
orthodontic tx
19: osteoporosis Gp: 56.1 (4.1) 17: alendronate sodium NR 19: oral Gp: 27.9 (11.9) NR
1: cancer Ctr: 55.6 (4.8) 2: ibandronate 1: intraven- Ctr: 24.1 (7.3)
1: zoledronic acid ous
Extranodal NK/T cell lymphoma 55.0 Alendronate 35 mg, Oral 1 Stopped before
(nasal type IVB) once/week orthodontic tx
Addison’s disease 35.0 Alendronate sodium 70 mg/week Oral 58 Simultaneous with
orthodontic tx
Cancer (sacral plasmacytoma), mul- 77.8 Zoledronic acid 500 mg per Intravenous 24 Simultaneous with
tiple myeloma month orthodontic tx
Osteoporosis 70.0 NR NR Oral 120 Simultaneous with
orthodontic tx
Osteoporosis 68.0 Ibandronate sodium NR NR NR Simultaneous with
orthodontic tx
Osteoporosis 60.0 Alendronate NR NR 42 Partly simultan-
eous and partly
discontinued
NR 50.0 Alendronate NR NR 18 Partly simultan-
eous and partly
discontinued
NR 74.0 Alendronate Oral 36 Stopped before
orthodontic tx

With regard to the changes in the vertical dimension, the types and unilateral distalization (39), where normal bone healing was
of orthodontic movement that were more beneficial were ante- observed.
rior teeth intrusion (35) and selective extrusion of residual roots Regarding the assessment of several factors that could assess the
(36, 38). However, when correction of a unilateral open bite was treatment outcomes, even though the use of skeletal anchorage was
attempted, the results were rather compromising with uneven not associated with undesirable adverse effects (35, 39), these out-
occlusal contacts on the respective side. Finally, regarding the ini- comes should be interpreted with caution due to the limited number
tial stages of orthodontic treatment, no differences were observed and low quality of the corresponding studies. Finally, due to inad-
between BPs users and control individuals in matters of incisor equate data, no subgroup analyses could be performed regarding the
alignment (35). influence of the drug administration protocol (exact type of drug,
Furthermore, the main findings of the radiographic outcomes dosage, duration, route of administration, cessation or continua-
consisted of mild root resorption of the respective teeth, sclerotic tion of BP administration during orthodontic treatment), the patient
changes of the surrounding alveolar bone as well as widened peri- characteristics (sex, age, systematic disease), the orthodontic treat-
odontal ligament (PDL) spaces. Exception to the latter were the ment protocol (exact malocclusion, biomechanics, treatment dura-
patients that underwent selective extrusion treatment (36, 38) tion, exact type of appliances) and the reported treatment outcomes.
 6

Table 2.  Characteristics of the malocclusion and the implemented treatment plan of the included studies. Tx, treatment; BP, bisphosphonate; Gp, experimental group; Ctr, control group; NR,
not reported

Appli-
ance used Orthodontic Type of
(fixed/re- tx duration Type of orthodontic anchor-
A/A Article Type of malocclusion movable) (months) movement Type of biomechanics age

1 Krieger Extremely protruded and Fixed 13 Intrusion and retrusion Combined segmental-arch and straight-wire technique was Skeletal
et al. (35) overerupted anterior teeth in both of the anterior teeth and applied with super-elastic nickel–titanium and stainless steel
jaws, diastemata in the maxilla, correction of the shifted archwires with skeletal anchorage (via osseointegrated dental
left shift of the mandibular dental mandibular midline implants, which were placed in pairs on the posterior region of
midline, overjet of 10 mm each quadrant)
2 Lotwala Patients without significant dif- Fixed and Extraction No specific type of move- NR NR
et al. (34) ferences regarding proportions removable Gp: 22.3 ment indicated
of Class I, II, and III, proportions (10.6)
of crossbites and measurements Ctr: 22.3 (7.2)
for overbite, overjet, arch-length Non-extrac-
discrepancy or crowding tion
Gp: 38.3 (5.1)
Ctr: 27.7 (6.1)
3 Morita Severe caries of the left maxil- Fixed 2 Extrusion of upper pre- The left maxillary first premolar and the respective first molar Dental
et al. (36) lary second premolar, which was molar residual root were bridged with 0.9-mm diameter stainless wire and an
endodontically treated and up- elastic orthodontic ligature. A wire hook crafted by bending
righted so as to be later prepared 0.7-mm diameter stainless wire was embedded with composite
for prosthetic restoration resin in the residual tooth root
4 Rinchuse Class II division 1 subdivision fixed 3 Closing the extraction A conservative unilateral extraction pattern, consisting of the Dental
et al. (37) right malocclusion (Class II on spaces and paralleling maxillary right and the mandibular right first premolars, was
the right and Class I on the left) the roots planned in conjunction with full banded/bonded orthodontic
and deep bite treatment
Extraction of an ectopically po- Fixed 13 Closing the extraction Brackets were bonded only on the lower anterior teeth (canine Dental
sitioned mandibular right lateral spaces to canine) and the forces were applied by both a tight-chain
incisor and space closure elastic over a round 0.016-in stainless steel archwire and by an
orthodontic elastic thread under-tie
5 Smidt et al. Extrusion of separated lower first Fixed 4 Extrusion of sepa- NR Dental
(38) and second molar mesial roots rated lower molar roots
and bloodless extraction of the (bloodless extraction)
respective distal roots
6 Vitral et al. Maxillary and mandibular right Fixed 6.8 Distalization of right After right maxillary sinus lifting and placement of autogen- Skeletal
(39) canines with a Class II relation- maxillary canine and first ous bone graft from the mandibular symphysis, a rigid straight
ship–distalization need for the and second premolars fixation plate with three 2 × 8-mm screws was placed into the
maxillary canine and first and body of the zygomatic bone to provide the necessary anchor-
second premolars age for tooth distalization. After 6 months, the plate was used
to provide skeletal anchorage for the distalization
European Journal of Orthodontics, 2019

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V. F. Zymperdikas et al. 7

Risk of bias across studies

anchor-
Type of

Dental
Dental

Dental
Despite the initial plan, due to inadequate number of eligible studies,

age
an evaluation for the existence of reporting biases was not possible
to be performed. For the same reasons, the overall quality of the
primary outcomes was not possible to be rated using the GRADE
approach.

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Additional analyses
Similar to the previous, because of limited number of included arti-
cles, the assessment for possible heterogeneity sources though sub-
group analyses or meta-regression was not possible to be performed.
Likewise, sensitivity analyses were not performed as well.

Discussion
Summary of evidence
Type of biomechanics

This review summarized the current evidence regarding the effec-

tiveness of orthodontic treatment in human patients with a history
of systematic BPs use. Even though, there are several animal studies
assessing the potential influence of BPs on specific types of ortho-
dontic tooth movements, the respective data on humans are rather
scarce. Hence, in our analyses only a cohort study and some case
NR
NR

NR

reports were considered eligible, which were of rather low quality,

implying a need for a very careful interpretation of the reported out-
extraction of the remain-

comes. Moreover, due to the severe heterogeneity and small sam-

premolars for alignment
Extraction of #41, fixed
ing mandibular left first

between the lower first

appliances placed only
Comprehensive ortho-
dontic treatment with

ple size, the reported results cannot be reliably generalized to the

Type of orthodontic

premolar and space

average patient. According to the included articles, the orthodontic

and space closure

treatment results of patients after and/or during BPs administration

are controversial, whereas the majority of them are associated with
movement

slow rates of tooth movement, prolonged treatment duration, and

closure

compromised outcomes.
NR

In an effort to effectively assess the respective outcomes, the

latter were grouped according to the plane that was principally
affected (i.e. sagittal or vertical) and further presented based on
Orthodontic
tx duration

the exact type of movement performed (space closure, extrusion,

(months)

intrusion, etc).
54
19

14

Sagittal plane
With regard to the clinical outcomes, the main differences between
ance used

movable)
(fixed/re-

orthodontic patients that received BPs and the ones who did not,
Appli-

Fixed
Fixed

Fixed

were found in the sagittal plane and particularly in cases demanding

space closure, either due to extraction treatment or due to initially
existing spacing. In detail, the rate of tooth movement was rather
slow, resulting in increased duration of treatment, compared to the
premolars, moderate mandibular

fractured mandibular left central

incisor crowding, lower midline

dibular incisor crowding, and a

incisor that was clinically unre-

corresponding treatment times of similar cases without BPs use (41).

Class I occlusion, severe man-
malocclusion, 3 missing first

Furthermore, the treatment results could be considered as rather

Class II (3-mm left molar)
Right posterior open bite

compromising, judging by the remaining spaces between the roots

Type of malocclusion

and lack of appropriate root parallelism.

The slower pace of tooth movement is supported by several rel-
ative animal studies in the literature that mainly assess maxillary
to the right

molar mesialization (17–19, 42). The majority of the former studies

storable

report on slower progression of tooth movement in BP-treated ani-

mals compared to BP-naive ones, except for the study of Brunet et al.,
(20) who found no significant differences in matters of tooth move-
ment rate between experimental and control animals. However, all
Zahrowski
Table 2.  Continued

et al. (40)

the aforementioned studies have two important limitations regard-

Article

ing outcome assessment: (1) the treatment duration is very small,

ranging from few days to 14 weeks, which do not reflect the actual
duration required for a routine orthodontic treatment and (2) there
is no information about the actual type of tooth movement that took
A/A

place (i.e. tipping or bodily movement).

7
8 European Journal of Orthodontics, 2019

Table 3.  Characteristics of the clinical and radiographic orthodontic treatment outcomes of the included studies. BP, bisphosphonate; CBCT,
cone beam computed tomography; PDL, periodontal ligament

Clinical Radiographical

A/A Article Clinical Panorax CBCT Periradicular

1 Krieger Improved vertical arrangement Mild apical root resorption

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et al. (35) and retrusion of the anterior Widened periodontal spaces
teeth Sclerotic changes in alveolar
improved gingival recession on bone
the buccal surface of tooth 11
increased mobility of lower an-
terior teeth
2 Lotwala No differences regarding incisor Significantly poorer root parallelism in
et al. (34) alignment longer treatment BPs users, especially in extraction cases
time for the extraction patients
receiving BPs
Poor space closure in BP users
with spacing or after extractions
3 Morita Extrusion of approximately Bone regeneration around the
et al. (36) 2 mm of the upper premolar root of the extruded molar
residual root
4 Rinchuse Not totally corrected deep bite Not parallel roots in the extraction ar-
et al. (37) Retroclined maxillary incisors eas radiopaque areas and sclerotic lines
Not perfect finish on the right around the roots (furcations) of the pos-
side terior teeth where the mandibular right
first premolar was extracted
A small extraction space Space closure was the result of tipping
remained and not bodily movement.
5 Smidt Elimination of the bony defect Elimination of the bony defect
et al. (38) Bloodless extraction
6 Vitral Class I canine relationship was The right posterior max-
et al. (39) obtained illary bone mineral dens-
ity showed above normal
values as the donor site
had higher density than
the receptor site
7 Zahrows- Uneven posterior occlusion Diffuse sclerosis and widened PDL No root resorption
ki (40) Heavy occlusal contact on an- spaces
terior bridge
Minor posterior spacing
Slow tooth movement
Long treatment time
Extremely slow tooth movement Compromised parallel roots and scler-
Mandibular incisor mobility otic bone area at the extraction site
Normal extraction healing No sclerotic changes, PDL spaces within Mild sclerosis and PDL spaces
Normal space closure normal limits, and mild root resorption between the lower incisors
No mobility on lower central incisor

The slower tooth movement could be attributed to several possible accomplished, no information is provided regarding the exact type of
reasons. One of them could be the significantly lower number of osteo- movement for the distalized teeth as well as the remaining teeth in the
clasts that was found on BP-treated animals compared to the untreated upper arch. Similarly, there are no data regarding possible changes on
animals (21, 43). This finding in turn could be explained by the the respective roots. The existing literature regarding distalization of
BP-induced prevention of osteoclast recruitment, stimulation of their the upper jaw using skeletal anchorage includes systematic reviews
apoptosis, or a combination of the two (1, 44). Furthermore, according that mainly focus on the effects on the upper molars. According to the
to an in vitro study by Liu et al. (21) on human periodontal cells in clo- latter, the average distance of molar distalization ranged from 1.87
dronate culture, in an effort to simulate conditions of orthodontic stress, to 6.4  mm (45–47), whereas the mean spontaneous premolar dis-
the inhibitory effect of BPs on orthodontic tooth movement could be tal drift was between 2.7 and 5.4 mm (45). The only data reporting
partially attributed to the decreased PGE2 production. The latter in turn exclusively on distalization effects on premolars derive from a clini-
reduces receptor activator of nuclear factor kappa-B ligand (RANKL) cal study including both upper and lower distalized premolars (48).
expression, resulting in deterred capability of PDL cells to promote On the basis of the latter, premolars were distalized by an average
osteoclast formation and/or prevent osteoclast apoptosis. distance of 9.4 mm but a distal inclination of 11.8 degrees was also
Moreover, Vitral et  al. (39) reported on mini-plate reinforced noted. Regarding the radiologic findings, a mean apical root resorp-
unilateral maxillary premolars and canine distalization in 26 weeks. tion of 0.9  mm, a mean marginal alveolar bone level reduction by
Even though the authors claim that a Class I canine relationship was 0.5 mm mesial to the premolars were detected.
V. F. Zymperdikas et al. 9

Vertical plane simple restorative protocols. Indicative of the latter is the fact that
Regarding the vertical dimension, successful extrusion of residual published clinical guidelines on dental management of BP patients
roots was reported in both included case reports (36, 38). The exact either do not include orthodontic treatment recommendations at all
rate of extrusion was reported in only one study (36) and it was (56, 57) or simply indicate the slower tooth movement rates and
approximately 1.5 mm per month. This is in accordance with similar the possibility for bisphosphonate-related osteonecrosis of the jaws
orthodontic extrusion approaches in patients without a history of (BRONJ) development (58, 59).
BP administration, in whom the rate of extrusion ranges between Regarding the BPs influence on the various types of orthodon-

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1 mm per week (49) and 1–2 mm per month (50). In addition, both tic treatment, it seems that orthodontic extrusion of residual roots
articles reported on a retention period of 3 months subsequent to the was the type of movement that showed almost no adverse effects.
completion of the required extrusion, which is in accordance with However, regarding the current available literature, the types of
existing protocols (50). Moreover, the subsequent prosthetic reha- tooth movement that have been examined through animal stud-
bilitation was successful, whereas normal healing of the surrounding ies are mainly maxillary molar mesialization and rapid maxil-
alveolar bone defects was observed, which is similar to the respective lary expansion (RME). Moreover, these studies mainly report on
findings on drug-naive patients (51). tooth movement rate as well as alveolar bone changes without
Contrary to the latter, when correction of a unilateral open bite providing details on the exact type of movement accomplished
was attempted (40), the final results were rather compromising (tipping or translation movement). The only pertinent data derive
despite the extended treatment duration of 54 months. This is not in from the in vitro study of Jacobs et al. (60) who stated that high
agreement with published case reports with similar patients, where orthodontic forces should be avoided during orthodontic treat-
bilateral posterior open bite was successfully corrected either by the ment due to their potential of promoting osteoclastogenesis. On
use of skeletal anchorage and control of the inclination of the pos- the other hand, light forces should be preferred in conjunction
terior teeth (52) or by the extraction of four premolars and use of with BPs administration, as this combination could enhance bone
intermaxillary elastics (53). apposition.
With regard to the drug-related factors, there cannot be a clear
Main radiographic findings conclusion regarding the efficacy between different types of drugs or
With regard to the radiographic findings, root resorption was a com- administration protocols. In the literature, even in animal studies, no
mon finding in the majority of the included studies, ranging from direct comparison between various types of BPs or administration
mild to moderate. Owing to the fact that the majority of the respec- routes was reported, disabling thus safe conclusions regarding poten-
tive findings were reported exclusively from case reports whereas the tial differences between them. However, with regard to the drug dosage
only study including a control group (34) did not report on radio- protocols, there are ambiguous results in the existing studies. In detail,
graphic outcomes, no accurate conclusions can be drawn regarding although Fujimura et al. (18) report on inhibition of rat molar mesi-
the severity of the detected root resorption between BP-treated and alization in a dose-dependent manner after 12 days of treatment (i.e.
untreated patients. Moreover, as different sources of acquisition of the decrease of the orthodontic tooth movement was greater in higher
the respective radiographic images were used in the respective arti- BP solution concentrations), Salazar et al. (61) showed no differences
cles and also no standardized method was used for the classifica- either in tooth movement rate or in preservation of surrounding alveo-
tion of the exact resorption stages, the discrimination between the lar bone after 7 days of similar orthodontic treatment protocol.
respective degrees of resorption is not entirely valid. According to Moreover, the present review included patients that received
existing literature, BPs are found to have a rather beneficial effect BPs either before or during the orthodontic treatment. According
on resorption of the teeth, with fewer and smaller lacunae (18, 21, to our findings, there cannot be a clear discrimination regarding
22). This seems to be true also for ovariectomized rats, a situation the effectiveness of preceding or simultaneous BP administration.
that is similar to osteoporosis and directly influences bone turnover However, results from existing animal studies seem to be in favour
and thus orthodontic treatment as well (54). Moreover, significant of a short-term drug discontinuation in orthodontic patients. For
preservation of alveolar bone and lack of signs of bone remodel- example, Kaipatur et al. (62) compared the results following max-
ling were observed after maxillary second molar protraction in illary molar mesialization reinforced by mini-implants in rats that
BP-treated rats (19). However, based on the study of Brunet et  al. received alendronate sodium either prior or during the mesialization
(20) after 14 days of molar mesialization, no significant difference process. The authors documented on 20 per cent greater reduction of
was observed between BP-treated and control animals in matters of molar mesialization in the drug discontinuation group after 4 weeks
root resorption. of orthodontic treatment. Moreover, Jacobs et al., (60) claimed that
orthodontic mechanical loading should not be applied immediately
Assessment of factors potentially modifying the treatment after BPs administration due to the deterring effects of BPs at high
outcomes concentrations on periodontal fibroblasts’ function and viability.
Despite the initial plan to examine the possible influence of several Finally, with regard to the type of anchorage, two patients were
factors on the treatment outcomes via subgroup analyses, these treated with skeletal anchorage devices, whereas in seven patients
analyses were not executed due to inadequate data. Regarding the dental anchorage was used during the treatment. On the basis of the
patients’ characteristics, nearly all of the assessed patients and con- available data of the eligible articles, there cannot be a clear indi-
trol individuals were women of rather old age (on average 57.9 and cation for superiority of any type of anchorage used. In the litera-
55.6 years for the experimental and control groups, respectively), due ture, BPs have proven to enhance anchorage when used in animal
to the increased prevalence of postmenopausal compared to male experiments (19, 63, 64). Moreover, in similar study designs, BPs
osteoporosis (55, 56). The very small number of included patients are reported to enhance stability of mini-implants over time (65).
could also be explained by the fact that existing protocols support However, all the aforementioned studies note the need for further
limited dental treatment in patients with a history of BPs adminis- clinical trials before safely recommending BPs for anchorage support
tration including mainly maintenance of proper oral hygiene and in human patients.
10 European Journal of Orthodontics, 2019

Strengths and limitations Supplementary material

The strengths of the present review include the a priori conducted Supplementary data are available at European Journal of
protocol that was meticulously followed at every stage, in accord- Orthodontics online.
ance to up-to-date guidelines. Moreover an extensive search strat-
egy was undertaken in order to identify as many pertinent studies
as possible. In addition, a quality analysis for all included studies Funding
was performed, on the basis of the exact study design, as indicated
None.

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by existing protocols. Furthermore, a small variety of orthodontic
malocclusions, systemic bone-affecting disorders and treatment
plans were able to be assessed. Acknowledgements
However, there are also several limitations such as the small num-
The authors wish to thank to Dr T.B. Agbabiaka for her assistance
ber and the study design of the eligible articles that were assessed, as
regarding the provision of the checklist for the quality analysis of
well as the rather low quality in the majority of the included studies
the case reports.
and the existing heterogeneity between them. Moreover, exploration
of the possible influence of several patient-, drug-, and orthodontic-
related factors on the respective treatment outcomes was not pos- Conflict of interest
sible to be performed due to the limited number of pertinent data.
None declared.
Finally, important aspects of the performed treatment, such as the
type of biomechanics used, the exact type and rate of tooth move-
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