journal of dentistry 38 (2010) 603–611

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Review

Influence of bisphosphonates in orthodontic therapy:

Systematic review

Alejandro Iglesias-Linares a, Rosa-Marı́a Yáñez-Vico a, Enrique Solano-Reina a,

Daniel Torres-Lagares a, Miguel Ángel González Moles b,*
a
School of Dentistry, University of Seville, Spain
b
School of Dentistry, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain

article info abstract

Article history: Objective: The objective of this paper was to analyse the effects of bisphosphonates and their
Received 11 November 2009 influence on orthodontic therapy.
Received in revised form Data/sources: The literature was systematically reviewed using PubMed/Medline, Scopus,
25 March 2010 Ebsco Host, Scirus and Cochrane databases up to December 31, 2008.
Accepted 14 May 2010 Study selection: Articles were independently selected by two different researchers based on
previously established inclusion and exclusion criteria, finding a good concordance (kappa
index of 0.862). The methodological quality of the reviewed papers was assessed. The search
Keywords: strategy identified 205 titles. Thirteen articles were selected after application of the inclu-
Bisphosphonates sion/exclusion criteria, and only one of these had a high methodological quality. Bispho-
Orthodontics sphonate applications in orthodontic therapy were divided between two main groups: tooth
Tooth movement movement and skeletal relapse.
Root resorption Conclusions: Topical or systemic application of bisphosphonates decreases orthodontic
Relapse tooth movement and reduces orthodontic tooth movement relapse and skeletal relapse
Review after maxillary expansion or mandibular distraction and similar procedures. Further longer-
Relapse term studies are required to assess possible adverse effects after bisphosphonate treatment
Maxillary expansion for these purposes.
Mandibular distraction # 2010 Elsevier Ltd. All rights reserved.
Orthodontic anchorage
Diphosphonates

1. Introduction erably.1,2 Nitrogenous bisphosphonates are more potent than

Bisphosphonates are potent bone resorption inhibitors that
are frequently used to treat bone metabolism disorders. There
are two types of bisphosphonate: nitrogenous and non-
nitrogenous. They act via different pathways but both inhibit
bone resorption, although their effectiveness differs consid-
those without the nitrogen atom2 and may inhibit the
production of isoprenoid compounds in the mevalonate
pathway, thereby preventing protein lipidation, that is, the
addition of hydrophobic molecules to the protein. Non-
nitrogenous bisphosphonates can be incorporated into
adenosine triphosphate (ATP) analogues, and act by inhibit-

* Corresponding author. Tel.: +34 958246358; fax: +34 958240908.

E-mail addresses: aiglesiaslinares@gmail.com (A. Iglesias-Linares), rosayanezvico@gmail.com (R.-M. Yáñez-Vico),
esolano@us.es (E. Solano-Reina), danieltl@us.es (D. Torres-Lagares), magonzal@ugr.es (M.lez Moles).
0300-5712/$ – see front matter # 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jdent.2010.05.012
604 journal of dentistry 38 (2010) 603–611
ing protein synthesis and inducing osteoclast apoptosis.1,3
Induction of osteoclast apoptosis is considered the main
action mechanism by which bisphosphonates inhibit bone
resorption.4 Bone is constantly being remodelled even when
growth is complete. Bone remodelling is a complex cyclical
process in which the osteoclasts resorb the bone mineral
matrix and release biomolecular bone-stimulating factors
that would otherwise induce stem cells to differentiate into
osteoblasts and form new bone. Bisphosphonates attach to
bone because of the affinity of their parachlorophenol moiety
for hydroxyapatite, and are subsequently phagocytised by the
osteoclasts. The incorporation of bisphosphonates by the
osteoclast triggers apoptosis (programmed cell death) by
competing with ATP or interfering with the 3-hydroxy-3-
methyl-glutaryl-Coenzime A reductase (HMG-CoA reductase)
pathway.5 Osteoblast-mediated osteoclastic resorption is
described as equally inhibited. Bisphosphonates are incorpo-
rated into the bone matrix and can have a half-life of >10
years, implying that the bone metabolism of patients may be
affected for many years after pharmacological therapy has
ceased.6
Various diseases (such as multiple myeloma, bone metas-
tasis, hypercalcaemia and Paget’s disease) are treated with
intravenous (iv) administration of bisphosphonates,7,8 de-
creasing bone remodelling and limiting bone destruction.
Furthermore, since bisphosphonates are shown to have
improved the clinical outcome in osteogenesis imperfecta,9
they are very commonly used to treat this disease that affects
dentinogenesis in several of its subtypes. Oral administration
is largely indicated to treat osteoporosis and peri- and post-
menopause osteopenia,10 which are characterized by a
decrease in bone density and subsequent fragility and
propensity to fracture.
Bisphosphonates have been reported as possessing anti-
angiogenic properties. The accumulation of high concentra-
tions of these compounds in bone tissue has been shown to
inhibit endothelial proliferation and reduce capillary forma-
tion.11,12 The over-accumulation of bisphosphonates in
alveolar bone may result in the reduction of endothelial cells
and capillary neoformation, establishing a predisposing
condition for the development of avascular osteonecrosis.13
Intravenous and chronic oral bisphosphonate administration
have been associated with osteonecrosis of the maxillary
bones,14 and there have also been reports of oesophagitis and
mucosal ulcerations in relation to oral bisphosphonate
treatment.14 In most cases, bisphosphonate-related osteone-
crosis is secondary to dental extraction procedures, periodon-
tal disease or mucosal trauma,15 although it may also arise
spontaneously.16 The American Society of Bone and Mineral
Research has issued a consensus document,17 one of whose
conclusions, among others, was that the risk of osteonecrosis
was higher in cancer patients treated with high doses of
intravenous bisphosphonates than with oral bisphosphonate
therapy.
There are numerous references in the literature to the use
of bisphosphonates with dental patients in general,18 and
orthodontic patients in particular.19 The main purpose of this
systematic review was to analyse the available scientific
evidence about the effect of bisphosphonate application in
orthodontic therapy.
2. Materials and methods
2.1. Search strategy
The search strategy followed the indications of the National
Health Service Centre for Reviews and Dissemination,20 exploring
the Medline database (Entrez PubMed, www.ncbi.nim.nih.gov)
for papers published between 1953 and December 31, 2008.
The key MeSH (Medical Subject Headings) terms used were:
‘‘diphosphonates’’ or ‘‘bisphosphonates’’ combined with ‘‘ortho-
dontics’’ or ‘‘tooth movement’’. The search was expanded by
including the following databases: Scopus (from 1966 to
December 31, 2008), Ebsco Host (from 1997 to December 31,
2008), Scirus (from 1966 to December 31, 2008), and Cochrane
(from 2001 to December 31, 2008), using the key words
bisphosphonates and diphosphonates combined with orthodontics,
tooth movement, corrective orthodontics, orthodontic anchorage
procedures or orthodontic appliances. Selected article references
were reviewed in order to extend the search for relevant
articles.
2.2. Selection critera
Inclusion criteria were:
1. Experimental animal study, clinical or in vitro investigation
including at least one experimental group and one control
group.
2. Minimum of five animals or samples per experimental
group.
3. Systemic or topical administration of bisphosphonate.
4. Description of administration dose and regimen.
5. Application of force by orthodontic or orthopaedic device.
6. Description of direction and magnitude of the force.
7. Appropriate data analysis.
8. English language.
We excluded case reports, case series, descriptive studies,
review articles, opinion articles, letters, and articles that did
not correspond to the objectives of this review.
2.3. Data gathering and analysis
The initial selection of articles was based on title and abstract,
with a review of the complete article whenever there was any
doubt as to whether to include it or not. Two reviewers (A.I.L.
and R.Y.V.), independently applied the inclusion and exclu-
sion criteria to every article, with good concordance being
shown (kappa index, 0.862). Studies were classified and stored
by: main author, publication year, study design, sample size,
type of bisphosphonate and administration, bisphosphonate
concentration and dose, type of force (expansion or contrac-
tion) and amount of force, tests conducted and conclusions.
Data were independently extracted by each reviewer, with
intraexaminer conflicts being resolved by discussing the
article in question until consensus was reached.
The methodological quality of the selected papers was
assessed by using a modified version of the method reported
by Antczak et al.21 and Jadad et al.22 The following character-
istics were considered: sample size, previous estimation of
 journal of dentistry 38 (2010) 603–611 605

Table 1 – Articles included in the review and quality assessment.

Article Sample size Predeter- Measure- Appropriate Method Blinded Loss of Quality
mined ment statistics error measure- animals to
sample size methods analysis ments the study

Adachi et al.28 Appropriate No Appropriate Yes Yes Yes No High

Igarashi et al.29 Appropriate ( ) No Appropriate Yes Yes Yes No Medium
Alatli et al.30 Small No Appropriate No No No No Low
Igarashi et al.31 Appropriate No Appropriate Yes No No No Medium
Kim et al.32 Appropriate No Appropriate Yes No No No Medium
Sato et al.33 Small No Appropriate Yes No No No Low
Lee et al.34 Small No Appropriate (#) Yes No No No Low
Liu et al.35 Appropriate No Appropriate Yes No No No Medium
Pampu et al.36 Small No Appropriate Yes No No Yes Low
Liu et al.37 Appropriate ($) No Appropriate Yes No No No Medium
Keles et al.38 Small No Appropriate Yes No No No Medium
Tekin et al.39 Small No Appropriate Yes No No No Medium
Pampu et al.40 Small No Appropriate Yes No No Yes Low

( ): Not appropriate in experiment 3 and last item of experiment 1.

(#): Expansion measured on photographs with subsequent computer calibration induces possible distortion factors, although an attempt was
made to standardize the magnification. ($): Sample size was not clearly specified.

sample size, validity of measuring methods, appropriate
statistics, method error analysis, blinding of measurements,
and losses of subjects/animals to the study. Quality was
classified as low, medium and high.
3. Results
3.1. Search results
The search strategy yielded 205 titles/abstracts: 60 from
PubMed, 7 from Scopus, 4 from Ebsco, 131 from Scirus and 3
from a manual search. After applying the inclusion/exclusion
criteria, 187 papers were removed, largely because they were
reviews, case reports or unrelated to orthodontic therapy. The
remaining 18 articles were then read in full, and a further five
papers excluded: three23,24,25 because force was not applied
using an orthodontic or orthopaedic device, and two26,27
because there was no assessment of bisphosphonate action.
Only 13 articles28–40 fulfilled all the criteria for inclusion in the
review.
3.2. Analysis quality
Twelve of the selected articles were based on animal studies
and one on an in vitro study of human periodontal cells.37 Only
one of the thirteen articles was considered to have high
methodological quality, seven were rated as of medium
quality and five of low quality (Table 1). The main quality
defects were: inadequate size of study sample subgroups;
absence of method error analysis and absence of blinding in
measurements.
3.3. Effects on orthodontic tooth movement
There is general consensus in the papers selected that
orthodontic tooth movement is reduced after bisphosphonate
administration (Table 2), which supports its clinical use in
improving anchorage. Studies by Liu, Igarashi and Ada-
chi28,29,35 used similar models and protocols, and applied
expansion forces of between 120 and 165 mN. They reported a
significant decrease in orthodontic tooth movement after
subperiosteal injections adjacent to the molar under study
(topical administration)28,29,35 or after subcutaneous injec-
tions (systemic administration).28 Comparing these three
studies,28,29,35 risedronate appears to be the most effective
in reducing orthodontic tooth movement, followed by 4-
amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP),
then clodronate. In another study, however, the reduction
in orthodontic tooth movement after systemic pamidronate
administration and the application of contraction forces was
not significant, probably due to the small sample size,
although there was a significant decrease in osteoclasts of
around 70%.38 The reduction in orthodontic tooth movement
relapse that several authors found28,29,32 could be explained by
the decrease in osteoclasts28,38 and structural changes
(undulating margins, cytoplasmic polarity) and resorptive
functions,31,33 significantly reducing the subcellular localiza-
tion and expression of H(+)-ATPase and cathepsin K during
orthodontic movement.33 The only in vitro study in this
review,37 conducted with human cells, reported a decrease
in mechanical stress on the periodontal ligament, reflected in
lower prostaglandin E2 levels and cyclooxygenase 2 and the
messenger ribonucleic acid levels of receptor activator of
nuclear factor kappa B ligand, which would lead to a reduction
in the range of orthodontic movement.
3.4. Effects on root resorption
The literature reviewed is somewhat contradictory about the
effect of bisphosphonates on root resorption after applying
tooth movement force. Some authors29,31 found a reduction in
root resorption after systemic (AHBuBP) or topical (risedro-
nate) administration of bisphosphonate. They undertook a
wider study in their second publication,31 with local subper-
iosteal injections every 3 days for 21 days. From day 7, there
was a significant dose-dependent reduction in root resorption
with the orthodontic device still in the mouth. There were no

Table 2 – Summary of the articles included in the review.
Author Sample Bisphosphonate
administration
Adachi 126 male Wistar rats Local injection 3 days
et al.28 aged 9–10 weeks before placing the device
and every 3 days of 0, 125,
250 or 500 mmol/l
risedronate one group,
and injection of the same
dose on the day of device
withdrawal in the other group
Igarashi 72 rats aged 9–10 weeks Subcutaneous injection of 0.02,
et al.29 for experiments 1 and 2 0.1 or 0.5 mg AHBuBP (P)/kg
(40 and 32, respectively) every day for 21 days in
and 6 rats aged 9 weeks experiments 1 and 2
for experiment 3 Injection 50 mm3 of AHBuBP
solution (0.1 mmol/l) in
subperiostal area every 3
days (topical administration)
Alatli 30 Sprague–Dawley Single injection of subcutaneous
et al.30 rats divided into 5 HEBP (0.01 ml/g body weight)
groups (n = 6) dissolved in distilled water at
concentration of 4 mg/ml at
12 days
Igarashi 53 male Wistar rats aged Subperiostal injection of
et al.31 9–10 weeks (divided in risedronate at
two experiments concentration of 0.9, 125,
of 38 and 15) 250 or 500% NaCl mmol/l
every 3 days for 3 weeks
with device in mouth of
one group; injection of
500 mmol/l every 3 days
after device withdrawal
at 21 days in the other group
606
Method Tests Conclusions
Expansion spring of Measurements on models Inhibition of dose-dependent tooth
165 mN between Optical microscopy movement up to 49.6%
first molars for 21 days Significant inhibition of dose-dependent
orthodontic relapse up to 56.7%
No effect on general growth
NiTi expansion spring Images of plaster models Inhibition of dose-dependent tooth
of 16.8 gf (approximately using callipers to measure movement (83, 51, 40% at
164 mN) on first molars tooth movement concentrations of 0.02, 0.1 and 0.5 mgP/
journal of dentistry 38 (2010) 603–611
Optical microscopy kg, respectively)
Histology: haematoxylin Dose-dependent inhibition of tooth
eosin staining movement relapse (85, 71, 49% at doses
of 0.01, 0.1 and 0.5 mgP/kg, respectively)
Decrease in number of osteoclasts on
bone surface and of bone and root
resorption
Inhibition of tooth movement after
topical administration
Own expansion spring Optical microscopy Injection before device placement
device using Australian Histology: haematoxylin caused the formation of a layer of
wire with expansion eosin staining atypical hyperplastic cementum instead
force of 150 mN of acellular cementum
Root resorption on sides with pressure
and tension in study rats and on the side
with pressure in control rats
Produces the absence of acellular
cementum (protects from resorption)
and the presence of hyperplastic
cementum
Spring of 165 mN Optical microscopy Significant reduction of root resorption
on each expansion Histology: from day 7 in a dose-dependent manner
side on first molars haematoxylin eosin staining. No significant differences in the number
for 21 days of odontoclasts between treated and
non-treated side; morphological
changes in odontoclasts of treated side,
including loss of polarity and increased
number of nuclei
No evidence of root resorption repair
due to administering bisphosphonate
after withdrawing the device
Kim 42 male Wistar rats aged Intravenous injection of Elastic band Scanning electron microscopy The administration of bisphosphonates
et al.32 7 weeks divided between 1.5 mg/1.0 mL/kg between first and Transmission electron reduced orthodontic movement relapse
groups killed at 0.5 and 10 pamidronate 1 day before second molars for 21 days microscopy by changing the structure and resorptive
days withdrawing band Optical microscopy functions of osteoclasts

Sato 12 male Wistar rats aged Intravenous injection of Elastic band between first Immunohistochemical analysis Bisphosphonate
et al.33 8 weeks 1.5 mg/1.0 ml/kg and second molars administration affects
pamidronate 1 day before for 4 days osteoclast structure
inserting band (undulating margins) and
reduces the expression of
H+ATPase and cathepsin
K during orthodontic
movement

Lee 44 male Wistar rats Subcutaneous injection Expansion of palatine Measurements of Statistically significant decrease in
et al.34 divided in 4 groups of of 5 mg/kg risedronate suture for 3 days with relapse distances relapse in groups with bisphosphonate;
5 or 6 animals (concentration not stated) own device made of on photographs using specific highest in group without retention after

journal of dentistry 38 (2010) 603–611

Unknown age for 3 and 7 days every day 0.5 mm Cr–Co with software 7 days of bisphosphonate injection
with and without 60 g force. Surgical Optical microscopy (32.53% vs. 54.11%) and after 3 days of
retention device (7 days) exposure of suture Histology: injection in retention group (6.86% vs.
haematoxylin and eosin staining 23.80%)
Histochemistry: Statistically significant decrease in the
TRAP number of osteoclasts in
bisphosphonate groups
Bisphosphonate injection after
mechanical expansion of suture
produces a safer retention that is greater
if combined with mechanical retention

Liu 26 male Wistar Local injection every 3 Expansion spring of Measurements on models Dose-dependent and significant
35
et al. rats aged 7 weeks days of 50 ml clodronate 120 mN in first Histological analysis reduction of up to 56% of orthodontic
at 0, 2.5, 10, or 40 mM molars for 21 days movement with bisphosphonates
Inhibition of root resorption after
orthodontic movements

Pampu 18 male white New Single intraoperative 15- Distractor with 2 Observation of bone formation by Statistically significant increase in pin
et al.36 Zealand rabbits aged min infusion of 0.1 mg/kg bicortically inserted mandibular deviation (clinical) regeneration region, in regeneration
20 weeks divided in of zoledronic acid diluted pins (1.5 mm diameter) and X-ray region and in posterior pin region in
two groups in 15 ml of saline Activation of 0.5 mm Measurement of bone mineral BMD (23, 20 and 31%, respectively) and
solution. Systemic every 12 h for 5 days density (BMD) and bone mineral BMC (22, 24 and 32%, respectively)
administration Consolidation period content (BMC) by DEXA Zoledronic acid has positive effects on
of 32 days bone formation around distraction gaps
in mandibles

607
 608
Table 2 (Continued )
Author Sample Bisphosphonate Method Tests Conclusions
administration

Liu Healthy periodontal Cells are cultured in a Compressive force RT-PCR for COX-2 and RANK-L Inhibiting effect of PGE2 on mechanical
et al.37 ligament cells from specific medium and are of 2 g/cm2 conducted HPLC-Griess method for nitrite stress
two individuals (18 transferred to a fresh by a glass containing and nitrate concentrations Inhibiting effect of 125 mM clodronate on
plates per individual medium with different granules that make (for NO) NO
with density of 3  105 concentrations of 5, 25 or direct pressure on Specific enzymatic Significant inhibiting effect of COX2 and
cells/plate 125 mM clodronate cell walls for 48 h immunoassay for PGE2 and IL-1 RANK-L mRNA

journal of dentistry 38 (2010) 603–611

The inhibiting effect of clodronate on
orthodontic tooth movement and
osteoclasts is partly due to the inhibition
of PGE2 production-dependent COX2,
leading to a decrease in RANKL in
periodontal ligament cells subjected to
mechanical stress

Keles 19 male C57B1 rats Subcutaneous injection Own contraction X-rays 70% reduction in the number of
et al.38 aged 8 weeks of pamidronate at doses spring of 20.1 g in High power microscopy osteoclasts and 34% inhibition of tooth
of 5 mg/kg 1 for 8 days first molars for 4, 8 movement (latter not statistically
and 12 days significant)

Tekin 15 male white New Postoperative daily
et al.39 Zealand rabbits aged injection for 3 days of
20 weeks divided in 1 mg/kg alendronate
three groups diluted in 10 ml saline
solution. Not known
whether local or systemic
administration
Distractor with two Histology: haematoxylin eosin Significant acceleration of bone repair
1.5-mm pins staining and grading scale and increase in bone mineral density in
activated 1 or X-rays, transmission bisphosphonate groups
2 mm/day to reach densitometry No statistically significant differences in
10 mm. 30-day DEXA transmission densitometry
consolidation period Acceleration of bone formation in
distraction gap

Pampu 18 male white New Single intraoperative Activation of one Optical microscopy with Regular ossification in bisphosphonate
et al.40 Zealand rabbits aged infusion of 0.1 mg/kg of distractor of haematoxylin eosin staining. group versus irregular in control group.
20 weeks divided in zolendronic acid diluted 0.5 mm every 12 h Measurements on photographs Significant differences in number of
two groups in 15 ml of saline solution for 5 days using specific computer software osteoblasts and osteoclasts in area of
for 15 min. Systemic 32 days consolidation the pin and regeneration area, and also
administration. period in collagen amount, fibroblast count and
areas of newly formed bone
 journal of dentistry 38 (2010) 603–611
significant differences between the treated and untreated
sides in odontoclast numbers. However, the osteoblasts on the
treated side showed evidence of morphological change,
including loss of polarity and an increase in the number of
nuclei. When the device was removed, there was no evidence
of root resorption repair after bisphosphonate administration.
Another study35 also found less root resorption after local
administration of clodronate.
One study30 showed root resorption on the side under
pressure and the side under tension in 1-hydroxyethylidene-
1,l-bisphosphonate-treated rats, but only on the side under
pressure in untreated animals. It was also reported that
administering systemic bisphosphonate in a single injection
before the placement and activation of an orthodontic device
generated the formation of atypical hyperplastic cementum
instead of the acellular cementum that protects against root
resorption. However, these results should be interpreted with
caution due to the small sample size.
3.5. Effects on mid-palatine suture
Rapid maxillary expansion is a widely used technique in
clinical orthodontics that produces the separation of two
halves of the maxilla and sutural remodelling with an
orthopaedic appliance. Mid-palatine suture expansion by
mechanical forces is accompanied by the stretching of
collagen fibre and the formation of new bone. When the
active expansion period ends, the suture undergoes remodel-
ling, including resorption, bone formation and change in
fibres. It was therefore postulated that bisphosphonates might
prevent skeletal relapse after palatine expansion. We found
one article that addressed this issue.34 Forty-four Wistar rats
of unspecified age underwent rapid expansion of a surgically
exposed palatine suture. Mechanical retention was applied for
7 days to a group of these animals, and in which animals
subcutaneously injected with etinodrate showed a signifi-
cantly lower relapse rate after 3 days of treatment (6.86%)
compared to animals that were untreated (23.80%), and an
even lower rate after 7 days of treatment (relapse in 9.60% of
treated vs. 25.13% of untreated animals). The effects were less
favourable in the group without mechanical retention,
however, with relapses in 32.53% of treated animals (versus
54.11% of untreated animals) after 7 days of etinodrate
treatment. Consequently, the authors suggested combining
the administration of a local bisphosphonate injection with
mechanical retention for a much safer retention of rapid
palatine expansion. They also found a significant difference in
the number of osteoclasts, which were much lower in the
bisphosphonate-treated groups.
3.6. Effects on mandibular osteogenic distraction
Two of the selected studies36,40 addressed the effects of
zoledronic acid on mandibular osteogenic distraction. Both
reported that a single intraoperative application of bispho-
sphonate (systemic administration) shortened the consolida-
tion period and favoured bone formation around mandibular
gaps. One study found increases in bone density of 23%36 in
the anterior pin region, of 20% in the regeneration region and
of 31% in the region posterior to the pin, with significant
609
mineral bone content increases36 of 22, 24 and 32%, respec-
tively in the same regions. According to the authors, these
results demonstrate that the use of zoledronic acid accelerates
the bone remodelling process in osteogenic distractions of the
craniofacial region, decreases osteoporosis round the pin
regions and shortens the consolidation period, also reducing
the risk of infection round external pins.
More recently, a similar experiment40 showed a significant
increase in the number of osteoblasts and a significant
decrease in the number of osteoclasts in both the pin and
the regeneration regions. These results showed significant
improvements in bone remodelling during osteogenic distrac-
tion, which causes an increase in callus length at an early
stage and permits the functional improvement of the jaw by
shortening the fixation period. In another article,39 alendro-
nate was used postoperatively after activation of the dis-
tractor, but it was not specified whether administration was
systemic or topical. The results, which found a greater
acceleration of bone formation in the distraction gap when
bisphosphonate was administered, corroborated previous
experiments.
4. Discussion
This systematic review applied a strict protocol and a well-
defined search strategy to analyse the effect of bispho-
sphonate application in orthodontic therapy. After applying
our inclusion and exclusion criteria, 13 articles were finally
selected. When the methodological quality assessment was
applied to these publications, only one had a high qualifica-
tion, seven were of medium quality and five of low quality. It is
difficult to compare the results of these studies due to
differences in the bisphosphonate administration regimens
(type and concentration) and forces applied. Importantly, all
selected papers were of animal or in vitro studies and cannot be
directly extrapolated to the clinical setting because there was
no clinical trial research or studies involving patients in our
search strategy that fulfilled the selection criteria.
It was possible to subdivide the selected studies into those
relating to tooth movement and those relating to bone
remodelling and skeletal relapse. The former studies demon-
strated a significant and dose-dependent decrease in the range
of orthodontic tooth movement after both topical and
systemic bisphosphonate administration, suggesting that it
might possibly be used clinically to improve anchorage. The
mean administration period for bisphosphonate is around 21
days, and most authors28,29,35 report that animals remain in
good health during this time. However, no data are available
on the effect of longer treatment, which is an important issue
given the well-known side effects of this type of drug, which
include maxillary osteonecrosis.41 Bisphosphonate therapy is
applied to increase bone density42 and inhibit bone resorption
through the loss of the osteoclastic function due to loss of
activity related to the Nf-kappa beta ligand, the primary
mediator of osteoclastic activation and differentiation.15 This
loss is expressed histologically in the absence of ruffled
borders that could be a marker of cell death or apoptosis of
osteoclasts.1,43 The bisphosphonate action directly influences
post-treatment orthodontic relapse by producing aggregations
610 journal of dentistry 38 (2010) 603–611
of osteoclasts in the vascular channels of the alveolar bone,
and occasionally on the bone surface of the periodontal
ligament,32 that change the resorptive functions of the
osteoclast and so reduce post-orthodontic tooth movement
and the number of relapses.28,29,32 This finding is potentially
encouraging for orthodontists, since post-treatment relapse is
not uncommon and can be difficult to explain and combat,
often requiring the use of mechanical retention mechanisms
for an indefinite time period. Nevertheless, there are few
papers on this issue, and the few animal studies that have
been published did not include any long-term follow-up to
detect possible adverse effects of using bisphosphonate
therapy for this purpose.
With regard to root resorption after orthodontic tooth
movement, it was found30 that a single exposure to bispho-
sphonate before placing the device removed the acellular
cementum that protects against resorption and replaced it
with an atypical hyperplastic cementum that produces greater
resorption.44 Some authors31 found a significant reduction in
root resorption from day 7 of bisphosphonate administration,
in agreement with two other studies that reported lower root
resorption after bisphosphonate administration.29,35
The second group of articles in the review addressed
skeletal relapse after application of an orthodontic-surgical
procedure, such as surgically assisted rapid maxillary expan-
sion or mandibular osteogenic distraction. It was reported that
bisphosphonate use reduced relapses after such interven-
tions.34,35,39,40 However, once again, these results were
obtained in animal experimental studies with a short
follow-up period and used drugs with very different anti-
resorptive powers, such as etinodrate34 or zoledronic acid.36,40
They36,40 reported that the main drawback of osteogenic
distraction was a decrease in mineral bone density and
mineral content, which may lead to the bone adjacent to the
pin becoming osteoporotic. In another study39 with a different
administration regime from the one published by Pampu
et al.,36,40 alendronate was given in the postoperative period at
a relative antiresorptive power of 100–100042; a higher bone
mineral density was found using dual energy X-ray absorpti-
ometry although this cannot be statistically demonstrated by
transmission densitometry.
5. conclusions
The conclusions of this systematic review of the literature
should be considered with caution due to the generally low
level of evidence found. Based on the findings of the 13
selected articles, we conclude that:
 The result of bisphosphonate therapy bone turnover is
delayed so that a longer period of orthodontic treatment
would be expected, as extrapolated from experimental
studies.
 The topical or systemic administration of bisphosphonates
reduces tooth movement, which may be beneficial for
anchorage procedures. Further research is needed involving
patients to verify the results involving animals.
 The topical or systemic application of bisphosphonates
reduces skeletal relapse in procedures that require bone
neoformation, such as maxillary expansion or mandibular
distraction. Future studies are needed to prove that this is
the case in humans.
 In order to obtain a better quality of scientific evidence, more
prospective studies or randomized clinical trials are re-
quired on the use of bisphosphonates in orthodontic
therapy and their possible adverse effects.
Contributors
Alejandro Iglesias-Linares and Rosa-Marı́a Yáñez-Vico: Sub-
stantial contributions to conception and design, data acquisi-
tion, analysis and interpretation of data.
Enrique Solano-Reina, Daniel Torres-Lagares and Miguel
Ángel González Moles: Drafting the article and critical review.
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