The Journal of EVIDENCE-BASED DENTAL PRACTICE

FEATURE ARTICLE

EFFECT OF LOCALLY DELIVERED

BISPHOSPHONATES ON ALVEOLAR BONE:
A SYSTEMATIC REVIEW AND
META-ANALYSIS

KUMAR KC a , BISHWA PRAKASH BHATTARAI b , SHILU SHRESTHA c , BIJAYA SHRESTHA d,

AND MANASH SHRESTHA e
a
BDS, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
b
BDS, MScD, Department of Clinical Dentistry, Walailak University International College of Dentistry, Bangkok, Thailand
c
BDS, MDS, Department of Periodontology, People’s Dental College and Hospital, Kathmandu, Nepal
d
BPT, MPH, Department of Society and Health, Faculty of Social Sciences and Humanities, Mahidol University, Nakhon Pathom, Thailand
e
BDS, MPH, Department of society and Health, Faculty of Social Sciences and Humanities, Mahidol University, Nakhon Pathom, Thailand

ABSTRACT CORRESPONDING AUTHOR: Shilu

Shrestha, Department of
Objective
Periodontology, People’s Dental
To assess the effect of locally applied bisphosphonate drugs on alveolar bone de-
College and Hospital, Kathmandu,
fects caused by periodontitis and marginal bone level after placement of dental
Nepal. Tel no.: +977-9851141858.
implants.
E-mail: shilu.sht@gmail.com
Materials and Methods
Three electronic databases (PubMed/MEDLINE, Web of Science, and Scopus) KEYWORDS
were searched from January 2010 until May 2020 for randomized controlled clin- Alveolar bone, Bisphosphonates,
ical trials reporting the effect of locally delivered bisphosphonates on alveolar Bone loss, Bone regeneration
bone. The risk of bias was assessed and quantitative synthesis was conducted
with both fixed and random-effects meta-analyses by using RevMan version 5.3.
SOURCES OF FUNDING: This
Subgroup and sensitivity analyses were performed whenever required.
research did not receive any specific
Results grant from funding agencies in the
Among the included studies, the effect of locally delivered bisphosphonates on public, commercial, or not-for-profit
alveolar bone regeneration in periodontitis was measured by 15 studies and sectors.
on marginal bone level after installation of dental implants by three studies.
CONFLICT OF INTEREST: The
Bisphosphonates showed significantly higher intrabony defect depth reduction
authors declare that they have no
than placebo/control in vertical bone defects treated with non-surgical approach
competing interests.
(MD = 1.69mm; 95% CI, 1.32-2.05; P < 0.00001; I²=93%) or surgical approach
(MD = 0.70mm; 95% CI, 0.23-1.16; P = 0.003; I² = 78%) and in class II furcation
defects treated with non-surgical approach (MD = 1.61mm; 95% CI, 1.15-2.07;
P < 0.00001; I² = 99%) or surgical approach (MD = 0.24mm; 95% CI, 0.05-0.42; Received 11 October 2020; revised 23
P = 0.01; I² = 62%). Clinical attachment loss increased by 1.39mm (95% CI, 0.92- February 2021; accepted 10 April
1.85; P < 0.01; I²=93%) and 1mm (95% CI, 0.75-1.26; P < 0.001; I² = 0%) in verti- 2021
cal bone defects after non-surgical and surgical treatments, respectively, and by
1.95mm (95% CI, 1.37-2.53; P < 0.00001; I² = 96%) and 0.84mm (95% CI, 0.58-1.10; J Evid Base Dent Pract 2021: [101580]
P < 0.01, I² = 47%) after non-surgical and surgical treatment in class II furcation 1532-3382/$36.00
defects, respectively. Lesser marginal bone loss during pre-loading (MD = -0.18 © 2021 Elsevier Inc.
mm; 95% CI, -0.24- -0.12; P<0.00001; I²=0%) and 1-year post-loading (MD = -0.33 All rights reserved.
mm; 95% CI, -0.59–0.07; P = 0.01; I² = 0%) periods was observed when bisphos- doi: https://doi.org/10.1016/
phonate coated dental implants were used. j.jebdp.2021.101580

September 2021 1
 The Journal of EVIDENCE-BASED DENTAL PRACTICE
Conclusion
Locally delivered bisphosphonates induce bone regenera-
tion in periodontal defects and decrease the rate of marginal
bone loss after dental implant therapy.
INTRODUCTION
M anagement of alveolar bone loss is one of the con-
temporary challenges in modern dentistry. Bone re-
sorption is a physiologic process which is central to the un-
derstanding of many pathologies.1 Among all the conditions
that can lead to alveolar bone resorption, periodontitis re-
mains the most common, especially among older age, male,
Asian race, and smokers.2 Globally, periodontitis is a highly
prevalent oral disease with an age-standardized prevalence
of around 10-44% in adults (35-44 years) and 40-58% in older
person (65-74 years).3 Soft and hard tissues of the peri-
odontium get destroyed in severe periodontitis as a conse-
quence of the host’s immune-inflammatory response against
the bacterial infection.4
Periodontitis can exhibit variations in the pattern and mor-
phology of bone destruction. The defects may be verti-
cal or horizontal, with or without furcation involvement,
and osseous craters, depending upon the etiology and the
anatomic features of surrounding periodontium.5 Since it is
established that the destruction of the alveolar bone is due
to bacterial challenge primarily and the host response secon-
darily, its treatment approach should be focused on reduc-
ing the bacterial count along with the modulation of host re-
sponse.6 Scaling and root planing (SRP), chlorhexidine, and
antibiotics such as doxycycline, minocycline, and tetracycline
are used to reduce the bacterial infection. In addition, antire-
sorptive agents such as bisphosphonates, and growth fac-
tors such as platelet rich fibrin (PRF) are being used in current
practice as adjuncts to SRP to repair the periodontal hard
and soft tissue insults.7 However, precise methods of treat-
ment which provide reliable and successful outcomes are still
not fully known.
Alveolar bone loss is also commonly observed around dental
implants, which is the rehabilitative treatment of choice for
many dental prostheses.8 After dental implant therapy, the
marginal alveolar bone that cuffs the dental implant at its
crest gets resorbed gradually, so much so that the success
of the implant is dependent on the marginal bone loss rate.
A dental implant is deemed successful if the marginal bone
loss is limited to 1-1.5 mm during the first year of loading and
less than 0.2 mm yearly thenceforth.9
Bisphosphonates are a group of antiresorptive agents that
have shown some promise in recent years.10 Along with
its medical applications in the cases of osteopenia, os-
teoporosis, and preventing fractures in women with post-
menopausal osteoporosis, bisphosphonates have gained
the attention of dental professionals as a promising alveolar
2 Volume 21, Number 3
bone repair agent.11-13 As synthetic analogues of inorganic
pyrophosphate, they can prevent calcification and hydroxya-
patite breakdown, and, therefore, reduce bone resorption.14
Furthermore, nitrogen-containing bisphosphonates (such as
alendronate, risedronate, ibandronate, pamidronate, and
zoledronic acid) are more potent than those not containing
nitrogen (such as clodronate) due to a different mechanism
of action as they promote osteoclast apoptosis by inhibiting
farnesyl pyrophosphate synthase in the mevalonate path-
way.14 Bisphosphonates can also be beneficial around dental
implants to reduce marginal bone loss. For example, zole-
dronate, a third-generation bisphosphonate, has high bone
mineral affinity,15 and has been used as a local and systemic
agent to enhance osseointegration and fixation of dental im-
plants.16-18
Despite the encouraging potential of bisphosphonates, till
date, very few systematic reviews are available to our knowl-
edge on the effect of bisphosphonate alone or in adjunct to
other treatment modalities for various osseous defects and
dental implant procedures. The objectives of this study were
to analyze the effect of bisphosphonates as a topical bio-
chemical agent on alveolar bone in patients with periodon-
tal bone defects and subsequently their clinical attachment
level (CAL); and marginal bone level around dental implants.
MATERIALS AND METHODS
Protocol Registration
This study has been reported according to PRISMA
(Preferred Reporting Items for Systematic Review and
Meta-Analyses) guidelines (Supplemental File).19 The study
protocol was registered in PROSPERO (The International
Prospective Register of Systematic Reviews) database with
protocol number: CRD42020187523 (www.crd.york.ac.uk/
PROSPERO).
Eligibility Criteria
Randomized controlled trials (RCT) assessing the effect
of local bisphosphonate drugs primarily on alveolar bone
and secondarily on CAL were included for this review. We
also included RCTs evaluating the effect of locally deliv-
ered bisphosphonates on the marginal bone loss asso-
ciated with dental implants. Literature reviews, case re-
ports, observational studies, case series, systematic reviews,
meta-analyses, in vitro and animal studies were not in-
cluded. Additionally, studies involving antiresorptive drugs
like denosumab and those comparing bisphosphonate
drugs in bones other than maxilla and mandible were ex-
cluded. The Population, Intervention, Comparison, and Out-
come (PICO) criteria was specified as:
P: Dental patients under local bisphosphonate drug therapy
I: Bisphosphonate(s)

C: Comparison with placebo or any other drugs if available
O: Alveolar bone loss/regeneration/ clinical attachment level
Information Source and Search strategy
An electronic search of journal articles limited to English lan-
guage and published within the last 10 years (2010 - 15th May
2020) was performed using the three electronic databases of
PubMed/MEDLINE, Web of Science, and Scopus. The key-
words used for the literature search were “bisphosphonate”,
“zoledronic acid”, “alendronate”, “alveolar bone”, “max-
illa”, “mandible”, and “bone loss” (Supplemental Table 1).
Furthermore, a manual bibliographic search was conducted
based on the references of the selected studies and relevant
systematic reviews to identify additional studies.
Study Selection
Three authors (KK, BPB, and SS) individually assessed the
eligibility of all the retrieved studies. The study titles and
abstracts of all the studies derived from the search were
screened for inclusion. When the information in the title or
the abstract were insufficient for exclusion, the study’s full
text was reviewed for the final decision on selection of the
study. Disagreements regarding the included studies were
resolved by consultation with other two authors (BS and MS).
Data Items And Data Collection Process
Two authors (KK and BPB) extracted data independently us-
ing pre-specified extraction tables covering study charac-
teristics (design and country), patient characteristics (num-
ber, age, sex, and disease type), study groups (comparing
bisphosphonate with placebo/control), study variables (drug
dose, route, and follow-up period) and outcome (parame-
ters of bone level change). Disagreements were resolved in
consensus with other three authors (SS, BS, and MS). Stud-
ies lacking any information related to our outcome parame-
ters were not included in the meta-analysis. When multiple
articles reporting data from the study with the same clini-
cal or protocol registration number were recognized, only
the latest and most compendious data were pooled. Non-
overlapping data were extracted from studies reporting on
follow-up periods.
Risk of Bias Within and Across Studies
Two authors (KK and BPB) evaluated the risk of bias of in-
cluded studies independently and resolved any disagree-
ments in consultation with the other three authors (SS, BS,
and MS). The assessment of the quality of included studies
was based on the revised Cochrane collaboration tool for as-
sessing the risk of bias.20 Publication bias across the studies
was evaluated using funnel plots.
Summary Measures and Synthesis of Results
Review Manager software (RevMan) version 5.3 (Cochrane,
London, UK) was used for the meta-analysis. We reviewed in-
trabony defect depth reduction (IBDDR) (mm), bone fill (%),
The Journal of EVIDENCE-BASED DENTAL PRACTICE
CAL gain (mm) in studies evaluating the effect of local bis-
phosphonates on osseous defects (vertical bone defect and
Class II furcation defect) by clinico-radiographic measure-
ments. We considered the bone gain in the vertical plane
after the intervention (reported as linear bone fill or linear
bone growth in some studies) as IBDDR. In each of the above
three outcomes, studies were grouped based on the surgical
or non-surgical treatment approach (Supplemental Figure 1).
We also separately evaluated marginal bone loss in the stud-
ies involving dental implants. All outcomes were analyzed
using a weighted mean difference (MD) and 95% confidence
interval (CI). Initially, MD was estimated using a fixed effect
model; whenever there was a high heterogeneity, a random
effect model was used. The level of significance was set at
P < 0.05 and heterogeneity between the studies was eval-
uated with the I2 tests. Subgroup analyses were conducted
according to differing baseline patient conditions and out-
come measurement periods that could impact periodontal
healing. Sensitivity analyses were carried out in presence of
further substantial heterogeneity. I2 <50% was considered as
low heterogeneity.
Ethical Consideration
Since this study was a systematic review and meta-analysis
that evaluated secondary data, ethical approval was not re-
quired.
RESULTS
Study Selection
The electronic search generated a total of 1710 hits and 9
additional records were identified through manual literature
search (Figure 1). After removing 117 duplicates, another
1568 records were excluded after reviewing the titles and ab-
stracts. In total, 35 studies were screened against the eligibil-
ity criteria, which led to exclusion of 17 articles due to various
reasons, leaving 18 unique studies in the present systematic
review (Figure 1).
General Studies Characteristics
The information regarding population characteristics, sam-
ple size, study design, drug dose and route of administra-
tion, follow-up period, and outcomes are summarized in
Table 1 and 2. Overall, the studies enrolled a total of 693 pa-
tients aged 20-89 years with follow-up periods ranging from
2 months - 5 years.
Risk of Bias Within and Across Studies
In the risk of bias assessment of the 18 included stud-
ies, seven studies16 , 17 , 21-25 were found to have a low risk of
bias and four26-29 had some concerns, while the remaining
seven studies30-36 were deemed to have a high risk of bias
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Table 1. Characteristics of selected studies.

S.N. Author/ Study Country Sample size included in Patient Characteristics Clinical
Year design this meta-analysis scenario

No. of No. of Age in Sex ratio Study

participants sites years (range) (Male/Female) population

1 Abtahi, RCT Sweden 14 28 45-89 NS Healthy Dental

2016 implant

2 Abtahi, RCT split Sweden 16 30 45-89 4/12 Healthy Dental

2019 mouth implant

3 Dutra, RCT split India 20 40 30-60 8/12 Healthy CP

2017 mouth

4 Gupta, RCT India 15 30 30-50 10/5 Healthy CP

2011

5 Gupta, RCT India 40 39 30-50 17/23 Healthy CP

2018

6 Ipshita, RCT India 60 60 NS NS Healthy C II FD

2018

7 Kanoriya, RCT India 60 60 30-50 43/47 Healthy CP

2016

8 Kanoriya, RCT India 52 49 30-50 36/36 Healthy C II FD

2017

9 Naineni, RCT India 32 30 30-50 15/17 Healthy CP

2016

10 Pradeep, RCT India 43 70 20-35 23/20 Type 2 CP

2012 Diabetes
Mellitus

11 Pradeep, RCT India 69 60 30-50 37/32 Healthy C II FD

2013

12 Pradeep RCT India 60 60 30-50 NS Healthy CP

2017

13 Sharma, RCT India 73 66 30-50 39/34 Healthy CP

2012a

14 Sharma, RCT India 20 52 20-35 12/8 Healthy AP

2012b

15 Sharma RCT India 46 75 30-50 NS Smokers CP

2017

16 Sheokand, RCT India 17 60 30-50 NS Smokers CP

2019 Non-smokers

17 Wanikar, RCT split India 20 40 38-56 6/14 Healthy C II FD

2019 mouth

18 Zuffetti, RCT split Italy 36 NS 38-68 22/17 Healthy Dental

2015 mouth implant

Abbreviations: No., Number; RCT, Randomized Control Trial; NS, Not Specified; CP, Chronic Periodontitis; AP, Aggressive periodontitis; C II FD, Class II
Furcation Defect.

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Table 2. Clinical characteristics of selected studies.

Intervention Drug Dose

Author/ Follow-up Clinical
Study Control/Placebo Concentration Volume
S.N. year (Months) Outcomes

1 Abtahi, P+ I coated on Non-coated NS NS 60 MBL

2016 Implant Implant

2 Abtahi, ZLN coated on Non-coated 2% ZLN NS 2 MBL

2019 Implant Implant

3 Dutra, ALN Placebo 1% ALN gel NS 6 IBDD, CAL

2017

4 Gupta, HA + ALN HA 2% ALN gel 10 μl 6 LBF, CAL

2011

5 Gupta, ZLN Placebo 0.05% ZLN gel 20 μl 6 BF%, CAL

2018

6 Ipshita. SRP + ALN SRP + AV 1% ALN gel 10 μl 12 IBDD, BF%, CAL

2018 SRP + Placebo

7 PRF + ALN PRF 1% ALN gel 10 μl 9 IBDD, BF%, CAL

Kanoriya, Placebo

2016

8 PRF + ALN PRF 1% ALN gel 10 μl 9 IBDD, BF%, CAL

Kanoriya, Placebo
2017

9 Naineni, ALN + β-TCP β-TCP 1% ALN gel 40 μl 6 IBDD, BF%, CAL

2016

10 ALN Placebo 1% ALN gel 10 μl 6 IBDD, BF%, CAL

Pradeep,
2012

11 ALN + SRP Placebo + SRP 1% ALN gel 10 μl 12 IBDD, BF%, CAL

Pradeep,
2013

12 ALN Placebo 1% ALN gel 10 μl 9 IBDD, BF%, CAL

Pradeep, ATV
2017

13 Sharma, ALN Placebo 1% ALN gel 10 μl 6 IBDD, BF%, CAL

2012a

14 Sharma. ALN Placebo 1% ALN gel 10 μl 6 IBDD, BF%, CAL

2012b

15 Sharma, ALN + SRP Placebo + SRP 1% ALN gel 10 μl 6 IBDD, BF%, CAL
2017

16 ALN Placebo 1% ALN gel 100 μl 6 IBDD, CAL

Sheokand,
2019

17 Wanikar, PRF + ALN PRF 1% ALN gel 10 μl 6 IBDD, CAL

2019

18 Zuffetti, CLN coated Non-coated 3% CLN NS 60 MBL

2015 implant

Abbreviations: NS, Not Specified; P+I, Pamidronate + Ibandronate; ZLN, Zolendronate; ALN, Alendronate; HA, Hydroxyapatite; SRP, Scaling and Root
Planing; AV, Aloe Vera; PRF, Platelet Rich Fibrin; β-TCP, Beta-Tricalcium phosphate; ATV, Atorvastatin; CLN, Clodronate; MBL, Marginal Bone Loss; LBF,
Linear Bone Fill; IBDD, Intra bony defect depth in millimeters; BF%: Bone fill percentage, CAL: Clinical Attachment Level in millimeter. September 2021 5
 The Journal of EVIDENCE-BASED DENTAL PRACTICE
Figure 1. Prisma flow chart diagram of study selection.
(Figure 2). Based on the symmetry of funnel plots, no signifi-
cant publication bias was observed across the studies (Sup-
plemental Figure 2).
Evaluation of Intrabony Defect Depth Reduction
(mm)
Vertical bone defect
In total, ten studies assessed the effect of local bisphos-
phonate on vertical bone defects. Seven of them used a
non-surgical approach,24 , 26 , 28 , 32 , 34-36 in which IBDDR was sig-
nificantly higher in the bisphosphonate group when com-
pared to the placebo (MD = 1.69mm; 95% CI, 1.32-2.05; P <
0.00001; Figure 3). However, there was a high heterogeneity
(P < 0.00001; I² = 93%); thus, we performed subgroup analy-
6 Volume 21, Number 3
ses based on patients’ pre-existing conditions that can affect
periodontal healing and severity of periodontitis as shown in
Figure 3. The heterogeneity was still high, so we performed
a sensitivity analysis to identify the study contributing to the
heterogeneity. When each study was excluded from the anal-
ysis in turns, no significant difference was observed in the
overall effect size (Supplemental Table 2).
Three studies used a surgical approach to assess the ef-
ficacy of bisphosphonates combined with alloplast or PRF
in vertical bone defects.22 , 30 , 31 Both study and active con-
trol group were treated by open flap debridement and used
either a bone graft30 , 31 or PRF.22 However, only the study
group received additional bisphosphonate. The IBDDR was
significantly greater in the study group than the active
 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 2. Risk of Bias Assessment of the included studies based on Revised Cochrane risk-of-bias tool for randomized
trials (RoB 2.0). Green – low risk; yellow – some concerns; and red – high risk.

Author (Year) Bias arising Bias due to Missing Bias in Bias in

from the deviations outcome measurement selection
randomization from the data of the of the
process intended outcome reported
interventions result
Abtahi, (2016)

Abtahi, (2019)

Dutra, (2017)

Gupta, (2011)

Gupta, (2018)

Ipshita, (2018)

Kanoriya, (2016)

Kanoriya, (2017)

Naineni, (2016)

Pradeep, (2012)

Pradeep, (2013)

Pradeep, (2017)

Sharma, (2012a)

Sharma, (2012b)

Sharma, (2017)

Sheokand (2019)

Wanikar, (2019)

Zuffetti, (2015)

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 3. Forest plot from random effects of meta-analysis evaluating the difference in mean intrabony defect depth
reduction (mm) after non-surgical delivery of local bisphosphonate in vertical defects in healthy patients, patients with
pre-existing conditions that can affect periodontal healing, and patients with aggressive periodontitis.

Figure 4. Forest plot from random effects of meta-analysis evaluating the difference in mean intrabony defect depth
reduction (mm) after surgical delivery of local bisphosphonate in combination with alloplast or platelet rich fibrin (PRF)
compared to control group of alloplast or PRF alone in vertical defects.

control group (MD = 0.70mm; 95% CI, 0.23-1.16; P = 0.003;
Figure 4). Heterogeneity of this meta-analysis was high
(P = 0.01; I²=78%), the source of which was not identified in
a sensitivity analysis (Supplemental Table 2).
Class II furcation defect
Four studies assessed the effect of bisphosphonate on
class II furcation defect. In two studies,21 , 33 non-surgical ap-
proach was used which showed significantly more IBDDR
in the bisphosphonate group compared to the placebo
(MD = 1.61mm; 95% CI, 1.15-2.07; P < 0.00001; Figure 5). The
heterogeneity was still high in subgroup analyses based on
the different follow-up periods (P < 0.00001; I² = 99%). In the
other two studies,23 , 25 bisphosphonate was delivered with a
surgical approach in combination with PRF and showed a
MD of 0.24 mm (95% CI, 0.05-0.42; P = 0.01; I² = 62%) com-
pared with PRF alone (Figure 6). However, the measure-
ments were recorded at six months (Wanikar et al.)25 and nine
months (Kanoriya et al.).23
Evaluation of Bone Fill (%)
Vertical bone defect
The non-surgical group consisted of six studies24 , 27 , 32 , 34-36
with a total of 362 patients. The meta-analysis result showed

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 5. Forest plot from random effects of meta-analysis evaluating the difference in mean intrabony defect depth
reduction (mm) after non-surgical delivery of local bisphosphonate in Class II furcation defects at 6 months and 12
months follow-up.

Figure 6. Forest plot from random effects of meta-analysis evaluating the difference in mean intrabony defect depth
reduction (mm) after surgical delivery of local bisphosphonate in combination with PRF compared to control group of
PRF alone in Class II furcation defects.

Figure 7. Forest plot from random effects of meta-analysis evaluating the difference in mean bone fill (%) after non-
surgical delivery of local bisphosphonate in vertical defects.

an average of 39.55% higher bone fill in the bisphospho-
nate group (95% CI, 38.38-40.72; P < 0.0000; I² = 40%) com-
pared to placebo (Figure 7). In two studies with surgical ap-
proach,22 , 31 the intervention group that received bisphos-
phonate (Ie, alendronate) combined with alloplastic bone
graft or PRF achieved significantly higher bone fill than that
of the control group without alendronate (MD = 14.12%; 95%
CI, 0.89-27.36; P = 0.04; Figure 8). However, the heterogene-
ity was high (P = 0.03; I2 = 89%).
Class II furcation defect
The data on bone fill percentage couldn’t be extracted from
the study by Wanikar et al.25 Therefore, only the non-surgical
group21 , 33 was analyzed in which the bone fill % was higher in

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Figure 8. Forest plot from random effects of meta-analysis evaluating the difference in mean bone fill (%) after surgical
delivery of local bisphosphonate in combination with alloplast or PRF compared to control group of alloplast or PRF
alone in vertical defects.

Figure 9. Forest plot from random effects of meta-analysis evaluating the difference in mean bone fill (%) after non-
surgical delivery of local bisphosphonate in Class II furcation defects at 6 months and 12 months follow-up.

the bisphosphonate group than the placebo (MD = 34.25%;
95% CI, 28.94-39.55; P < 0.01; Figure 9). The heterogeneity
persisted in subgroup analyses based on the follow-up peri-
ods in 6 months follow-up (P = 0.003; I²= 94%) and 12 months
follow-up (P < 0.00001; I² = 97%).
Evaluation of CAL (mm)
Vertical bone defect
The meta-analysis of the gain in the CAL in studies with non-
surgical approach,24 , 26-28 , 32 , 34-36 favored the bisphosphonate
group over the placebo (Overall MD: 1.39mm; 95% CI, 0.92-
1.85; P < 0.01; Figure 10). The high heterogeneity per-
sisted even after subgroup analyses in healthy patients (P <
0.00001; I² = 93%) and pre-existing conditions (P < 0.00001;
I² = 95%). In the surgical group, meta-analysis of three stud-
ies22 , 30 , 31 showed significant CAL gain when bisphospho-
nates were used with alloplastic bone graft or PRF compared
to the active control group that did not contain bisphos-
phonate (Overall MD: 1.00mm; 95% CI, 0.75-1.26; P < 0.001;
I² = 0%) (Figure 11).
Class II furcation defect
In the non-surgical treatment approach,21 , 33 the meta-
analysis showed a significantly greater gain in CAL in
the bisphosphonate group than the placebo (Overall
MD = 1.95mm; 95% CI, 1.37-2.53; P < 0.00001) (Figure 12).
The heterogeneity was not reduced in subgroup analysis
based on follow-up periods in 6 months (P = 0.0002; I² = 96%)
only. In studies that employed a surgical approach,23 , 25
the meta-analysis showed higher CAL gain in the study
group compared to the control group where PRF was used
alone (MD = 0.84 mm; 95% CI, 0.58-1.10; P < 0.01, I² = 47%)
(Figure 13).
Evaluation of Marginal Bone Loss (mm)
Three studies used bisphosphonate coatings on implant sur-
faces and compared marginal bones loss with uncoated im-
plants.16 , 17 , 29
Pre-Loading
In the preloading period (i.e. follow-up at 2 months of fix-
ture placement without implant loading), there was lesser
marginal bone loss around bisphosphonate-coated implants

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 10. Forest plot from random effects of meta-analysis evaluating the difference in mean clinical attachment level
(CAL) gain (mm) after non-surgical delivery of local bisphosphonate in vertical defects in healthy patients, patients with
pre-existing conditions that can affect periodontal healing, and patients with aggressive periodontitis.

Figure 11. Forest plot from fixed effects of meta-analysis evaluating the difference in mean clinical attachment level
(CAL) gain (mm) after surgical delivery of local bisphosphonate in combination with alloplast or PRF compared to
control group of alloplast or PRF alone in vertical defects.

compared to the uncoated ones (MD = -0.18 mm; 95% CI, -
0.24 - -0.12; P < 0.00001; I² = 0%) (Figure 14).
Post-loading
The marginal bone loss was lesser at the end of the first year
of implant loading with the bisphosphonate coated implants
than the uncoated implants (MD = -0.33 mm; 95% CI, -0.59–
0.07; P = 0.01; I² = 0%) (Figure 15). At 5 years follow-up, the
marginal bone loss around bisphosphonate coated implants
was comparable to the uncoated ones (MD = -0.28 mm; 95%
CI, -0.57–0.00; P = 0.05; I² = 0%) (Figure 16).
DISCUSSION
Bisphosphonate group of drugs are increasingly being used
in dentistry as host modulating agents due to their known
bone affinity and the mechanism of inhibiting osteoclast me-
diated alveolar bone resorption.6 , 37 This meta-analysis in-
cluded studies that delivered various types of bisphospho-
nates locally for treating periodontal osseous defects and
marginal bone loss around dental implants. Our results show
that local bisphosphonates increased bone defect fill and
CAL in periodontitis, and reduced marginal bone loss asso-
ciated with dental implants.

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 12. Forest plot from random effects of meta-analysis evaluating the difference in mean clinical attachment level
(CAL) gain (mm) after non-surgical delivery of local bisphosphonate in Class II furcation defects at 6 months and 12
months follow-up.

Figure 13. Forest plot from fixed effects of meta-analysis evaluating the difference in mean CAL gain (mm) after
surgical delivery of local bisphosphonate in combination with PRF compared to control group of PRF alone in Class II
furcation defects.

Figure 14. Forest plot from fixed effects of meta-analysis evaluating the difference in mean marginal bone loss (mm)
after local delivery of local bisphosphonate as a coating around dental implants compared to uncoated dental implants
before loading the dental prosthesis.

Our findings are in line with those of previous meta-
analyses,38 , 39 in which 1% alendronate regenerated greater
quantities of bone and produced higher gain in CAL, ei-
ther alone or in combination with PRF. Most of the studies in
our analysis also used nitrogen-containing bisphosphonates,
particularly 1% alendronate, which are known to promote
osteocyte apoptosis that inhibits alveolar bone resorption
in periodontitis patients.6 , 40 The studies delivering bisphos-
phonates through the surgical approach in our meta-analysis
had a combination of 1% ALN and PRF or alloplast (β-TCP
or HA) in the study group and only PRF or alloplast in the
control. Although the combination therapy provided better
bone regeneration, the true effect of ALN alone in these
studies could not be estimated. Therefore, studies compar-

12 Volume 21, Number 3

 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 15. Forest plot from fixed effects of meta-analysis evaluating the difference in mean marginal bone loss (mm)
after local delivery of local bisphosphonate as a coating around dental implants compared to uncoated dental implants
after one year of prosthesis loading.

Figure 16. Forest plot from fixed effects of meta-analysis evaluating the difference in mean marginal bone loss (mm)
after local delivery of local bisphosphonate as a coating around dental implants compared to uncoated dental implants
at 5 years follow-up.

ing 1% ALN with PRF or allografts are necessary to estimate
the actual role of 1% ALN in alveolar bone regeneration.
Moreover, as flap surgery or open flap debridement may
result in postoperative pain, discomfort, and some level of
gingival recession, non-surgical periodontal therapy has be-
come a treatment of choice for mild to moderate periodon-
titis provided adequate plaque control is maintained. How-
ever, the ultimate decision on the treatment approach relies
on various clinical factors, including the size of the defects,
ease of access to such defects, and the clinician’s judgement
based on recent evidence and experience.41
While Chen et al. had found the systemic administration of
bisphosphonates to increase CAL by 0.39 mm (95% CI 0.11-
0.68),38 osteoradionecrosis of jaw remains a potential ad-
verse event associated with systemic bisphosphonates.38 , 42
Additionally, previous research has shown that higher local
concentrations of bisphosphonate can be achieved through
local administration than with systemic treatment.43 When
a bisphosphonate is added topically to a cancellous bone,
most of it gets adsorbed to the bone surface while a small
amount stays unbound in solution between the trabeculae.44
Therefore, local delivery of bisphosphonates is a better treat-
ment option in periodontal diseases as it assures a controlled
drug concentration required for inhibition of osteoclasts and
reducing bone loss. Our results of more than 33% bone fill
and more than 1.5 mm increase in CAL display better clin-
ical outcomes of local administration than those reported
of systemic administration of bisphosphonates by Chen
et al.38
The rate of marginal bone loss associated with dental im-
plants seems to be reduced with local bisphosphonates
based on the outcomes of various periods of follow-up
in our analysis. Different studies have demonstrated that
bisphosphonate-coated implants osseointegrate better and
have higher survival than the uncoated ones.45 , 46 De Sarkar
et al. showed that extraction sockets that received bispho-
sphonate via collagen sponges produced lesser marginal
bone loss compared to those that received collagen
sponges alone.47 Although there have been few systematic
reviews,48 , 49 this is the first meta-analysis, to the best of our
knowledge, to evaluate the effect of bisphosphonate-coated
implants on marginal bone loss. Nonetheless, there were
only three RCT that met our inclusion criteria and these stud-
ies used three different types of bisphosphonates. Hence,
our results should be considered in light of the limited evi-
dence.
Our analysis has some limitations. First, heterogeneity was
high in most of our analyses, excluding the studies of den-
tal implants. In our subgroup analyses, severity of disease
(aggressive or chronic periodontitis), and pre-existing condi-
tions (Type II DM and smoking) did not affect heterogeneity
substantially. The heterogeneity may be attributed to the dif-
fering doses and volumes of local bisphosphonates in our in-
cluded studies. Mostly, 10 μl (1% ALN gel) were used in stud-

September 2021 13
 The Journal of EVIDENCE-BASED DENTAL PRACTICE
ies, but some used different concentration of ALN drug so-
lution 10 μl (2% ALN), 40 μl (1% ALN), 20 μl (0.05% ZLN gel),
and 100 μl (1% ALN). Different measurement techniques
may have also contributed to the heterogeneity. For exam-
ple, while vertical defects were measured in the same units
(millimeters), some included studies measured intrabony de-
fect depth referencing cementoenamel junction to the base
of the defect,22 , 24 , 32 , 34-36 whereas others measured the dis-
tance to base of defect from alveolar crest,26 , 28 , 31 or adja-
cent cuspal tip.30 Other factors that could have impacted
the heterogeneity may include differences in diagnostic cri-
teria of furcation involvement, sex ratio, follow-up periods,
sample sizes, and the number of sites in each participant.
Nonetheless, there was no significant change in the overall
effect size in our sensitivity analysis, indicating that our esti-
mates were stable and robust. Second, since there were lim-
ited studies in our meta-analyses for each outcome measure,
we could not conduct a formal analysis to assess publica-
tion bias. Third, limitations in individual studies such as lack
of three-dimensional radiographic evaluation, lack of stan-
dardization regarding the type of vertical defects (one, two
or three walled) or furcation defects (class or grade), lack of
allocation concealment, lack of randomization information,
could also have impacted our estimates. Fourth, as most
of the included studies were conducted in India, and par-
ticularly in the same organization, our results may not be
readily generalizable. RCT from different parts of the world
are needed to improve the external generalizability of future
meta-analyses.
CONCLUSION
In conclusion, the local application of bisphosphonate is
likely to regenerate alveolar bone in periodontal defects and
reduce the rate of marginal bone loss around dental im-
plants. However, multicenter controlled clinical trials involv-
ing diverse populations with specific drug doses are required
to confirm our assertions. Additionally, further studies are
recommended for combined application of local bisphos-
phonates with other bone regenerative materials for pre-
venting bone resorption in periodontitis and dental im-
plants.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Sagar Tiwari and Jintana
Chaiwan for their technical assistance during the conduction
of this study.
AUTHOR CONTRIBUTIONS
Conceptualization: KK, SS, BPB, BS, MS. Data Curation: KK,
SS, BPB. Formal analysis: KK, SS, BPB. Methodology: KK,
BPB, BS, MS. Supervision: MS. Validation: SS, BS, MS. Visual-
ization: KK, BPB, MS. Writing-original draft: KK, BPB. Writing-
reviewing, editing, and final approval: KK, SS, BPB, BS, MS.
14 Volume 21, Number 3
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jebdp.2021.
101580.
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