J Oral Maxillofac Surg

68:790-796, 2010

Bisphosphonate-Related Osteonecrosis of
the Jaw Associated With Dental Implants
Towy Sorel Lazarovici, DMD,* Ran Yahalom, DMD,†
Shlomo Taicher, DMD,‡ Devorah Schwartz-Arad, DMD, PhD,§
Oren Peleg, DMD,储 and Noam Yarom, DMD¶

Purpose: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented devastating side

effect of long-term bisphosphonate (BP) use. There is scarce information in the literature on BRONJ associated
with dental implants (DIs). The purpose of this study was to present a large series of cases of this association.
Patients and Methods: The files of all patients with BRONJ associated with DIs who were treated in
the department of oral and maxillofacial surgery from 2003 to 2009 were reviewed. Data on demograph-
ics, medical background, type, and duration of BP treatment before the development of BRONJ, mode of
therapy, and therapeutic outcome were retrieved.
Results: Of the 27 patients enrolled into the study, 11 (41%) developed BRONJ while taking oral BPs
and 16 (59%) developed BRONJ associated with intravenous BPs. BRONJ developed after mean periods
of 68 months (median, 60), 16.4 months (median, 13), and 50.2 months (median, 35) in patients on
alendronate, zoledronic acid, and pamidronate, respectively. Only 6 patients developed BRONJ during
the first 6 months after DI placement. When BP treatment had been started before DI placement, there
was a mean duration of 16.2 months (median, 11) until the appearance of BRONJ development.
Long-term antibiotics and only essential surgical procedures comprised the treatment of choice, and the
response rate was considerably better for patients taking the oral type of BPs. There was no significant
association between BRONJ and diabetes, steroid intake, or smoking habits.
Conclusion: Patients undergoing BP treatment and who receive DIs require a prolonged follow-up
period to detect any development of BRONJ associated with DIs.
© 2010 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 68:790-796, 2010

Bisphosphonates (BPs) have been widely used as
bone antiresorptive drugs for more than a decade.
Oral BPs became available in 1995 (alendronate) and
intravenous (IV) BPs in 1996 (pamidronate) and 2002
(zoledronic acid). Oral BPs, which are being used
much more extensively than the IV BPs, are pre-
scribed for the treatment of metabolic bone diseases,
mainly osteopenia or osteoporosis.1 IV BPs are used
for the treatment of life-threatening hypercalcemia
caused by multiple myeloma and breast and prostate
carcinomas.2-5 They are also used to inhibit the emer-
gence of new bone metastases and for preventing the
enlargement of existing ones.6-8
Although IV BPs produce their initial effect after
a few days,9 the effect of oral BPs is observed only
after a few weeks10 due to their comparatively
decreased absorption rate.11 Long-term BP treat-
ment is speculated to affect bone turnover for many
years. This is attributed to the fact that they are not
metabolized. Moreover, BPs are incorporated into
the bone whose osteoclastic activity is suppressed
or abolished.12,13

*Resident, Department of Oral and Maxillofacial Surgery, Sheba
Medical Center, Tel Hashomer, Israel.
†Deputy, Department of Oral and Maxillofacial Surgery, Sheba
Medical Center, Tel Hashomer, Israel.
‡Head, Department of Oral and Maxillofacial Surgery, Sheba
Medical Center, Tel Hashomer, Israel.
§Director, Schwartz-Arad Surgical Center, Ramat Hasharon, Israel.
储Resident, Department of Oral and Maxillofacial Surgery, Sheba
Medical Center, Tel Hashomer, Israel.
¶Director, Oral Medicine Clinic, Department of Oral and Maxil-
lofacial Surgery, Sheba Medical Center, Tel Hashomer, and Depart-
ment of Oral Pathology and Oral Medicine, The Maurice and Gab-
riela Goldschleger School of Dental Medicine, Tel Aviv University,
Tel Aviv, Israel.
Address correspondence and reprint requests to Dr Laz-
arovici: Department of Oral and Maxillofacial Surgery, Sheba
Medical Center, Tel Hashomer, Israel; e-mail: towy_lazarovici@
yahoo.com
© 2010 American Association of Oral and Maxillofacial Surgeons
0278-2391/10/6804-0013$36.00/0
doi:10.1016/j.joms.2009.09.017

790
LAZAROVICI ET AL 791

Bisphosphonate-related osteonecrosis of the jaws Table 1. DEMOGRAPHIC BACKGROUND OF PATIENTS

(BRONJ) is a well-documented devastating side effect of
long-term use of BPs. Numerous reports on BRONJ have Patients
been published in the previous 5 years.12,14-26 Most of
Gender
those reports state that tooth extraction is the most Male 7
common event for triggering the development of Female 20
BRONJ.16,17,20,22-24 Information on the association of Mean age (yrs) 70
dental implants (DIs) with the development of BRONJ is BP indications
Osteoporosis 11
scarce.17,26,27
Multiple myeloma 7
The purpose of this study was to report a series of 27 Breast carcinoma 7
cases of BRONJ associated with DIs and to characterize Prostate carcinoma 2
its clinical presentation. We believe that this is the larg- Type of BP
est series of BRONJ cases associated with DIs thus far Alendronate 11
Zoledronic acid 7
reported.
Pamidronate 5
Concomitant BPs* 4
Comorbidities
Patients and Methods Smoking habits 2
SELECTION CRITERIA Type 2 diabetes mellitus 3
Long-term steroid use† 2
The study included all patients who used BPs and
Abbreviation: BP, bisphosphonate.
developed BRONJ associated with DIs who were diag-
*Concomitant use of BPs pamidronate and zoledronic
nosed and treated in the Department of Oral and Max- acid.
illofacial Surgery, Sheba Medical Center (Tel Hashomer, †Both patients received steroids and BPs concurrently.
Israel) from April 2003 to January 2009. The criteria for One patient was started on steroids 58 months after place-
inclusion into the study were based on the American ment of dental implants.
Association of Oral and Maxillofacial Surgeons position Lazarovici et al. Dental Implants and Osteonecrosis of the Jaw.
paper of 200723 and consisted of a history of BP therapy, J Oral Maxillofac Surg 2010.
intraoral lesions (eg, exposed necrotic bone, pus exu-
dates, fistulas), or extraoral manifestations of swelling or (26%) received IV zoledronic acid (4 mg every 3 to 4
fistulae persisting longer than 8 weeks and related to weeks), and 5 (18%) received IV pamidronate (90 mg
existing DIs or to the surgical procedure of placing DIs. every 3 to 4 weeks). Four patients (15%) received
The single exclusion criterion was a history of radiation zoledronic acid (4 mg every 3 to 4 weeks) and pam-
therapy to the affected jaw. idronate (90 mg every 3 to 4 weeks) concomitantly.

DURATION OF BISPHOSPHONATE USE

METHODS
The patients who fulfilled the entry criteria were
followed periodically in the outpatient department,
and data on demographics, medical backgrounds,
type and duration of BP use, history of existing DIs or
the surgical procedure of placing DIs (in the region in
which the BRONJ developed), mode of therapy, and
treatment outcome were recorded and reviewed.
Results
PATIENTS
One hundred forty-five patients diagnosed with
BRONJ were followed in the department of oral and
maxillofacial surgery during the study period, of
whom 27 (18.6%) developed BRONJ associated with
DIs. Table 1 presents their gender, age, indication for
BP use, type of BP, and comorbidities.
Table 2 presents how long BPs were taken before
DI placement, length of time between DI placement
and development of BRONJ, and the overall time from
the initiation of the use of BPs before the develop-
ment of BRONJ. Table 3 presents the data of the 4
cases in which the DIs were placed before initiating
BP treatment.
Mean lengths of time from the first use of BPs to the
development of signs or symptoms of BRONJ for all
cases were 68 months (median, 60) for the 11 pa-
tients who received alendronate, 16.4 months (me-
dian, 13) for the 7 who received zoledronic acid, 50.2
months (median, 35) for the 5 who received pamid-
ronate, and 53 months (median, 55.5) for the 4 who
received pamidronate and zoledronic acid concomi-
tantly.
All patients stopped receiving the BPs soon after
the diagnosis of BRONJ was established.

BISPHOSPHONATE CONSUMPTION BRONJ ETIOLOGY

Eleven of 27 patients (41%) received oral alendro- The development of BRONJ in association with DIs
nate (70 mg once weekly or 10 mg once daily), 7 was classified in this study as surgically related or
792 DENTAL IMPLANTS AND OSTEONECROSIS OF THE JAW

Table 2. INTAKE DURATION OF BP RELATED TO DI

PLACEMENT AND DEVELOPMENT OF BRONJ

Duration Duration Overall

of BP Between DI Duration of
Intake Placement BP Intake
Before DI and BRONJ Before BRONJ
BP Placement Development Development
Case Intake (mos) (mos) (mos)

1 A 42 0 42
2 A 50 10 60
3 A 0 46 46
4 A 42 7 49
5 A 18 0 18
6 A 108 3 111
7 A 59 1 60
8 A 36 15 51
9 A 78 0 78
10 A 66 6 72
11 Z 15 13 28
12 Z 3 7 10
13 Z 0 17 17
14 Z 36 7 43
15 Z 10 3 13
16 P 24 11 35
17 P 18 7 25
18 P 20 8 28
19 P 18 30 48
20 P 96 19 115
21 Con 24 20 44
22 Con 15 53 68
23 Con 54 13 67
Abbreviations: A, alendronate; BP, bisphosphonate; Con,
concomitant use of pamidronate and zoledronic acid; DI,
dental implant; P, pamidronate; Z, zoledronic acid.
Lazarovici et al. Dental Implants and Osteonecrosis of the Jaw.
J Oral Maxillofac Surg 2010.

spontaneous (Figs 1, 2). BRONJ that developed less

than 6 months from the time of DI placement was
classified as surgically related, and it was observed in FIGURE 1. BRONJ developing spontaneously around an existing
6 patients (22.2%). BRONJ that developed after at DI in a 65-year-old man with multiple myeloma (patient 4 in Table
3). DIs were placed 58 months before commencing IV BP therapy.
least 6 months was classified as spontaneous, and it A, Radiograph of DIs at the right posterior mandible before initia-
tion of BP therapy. B, Radiograph of the same area 33 months after
commencing IV BP therapy, demonstrating a sequestrum attached
to the mesial side of the anterior DI.
Table 3. INTAKE DURATION OF BP AS RELATED TO
DI PLACEMENT AND DEVELOPMENT OF BRONJ Lazarovici et al. Dental Implants and Osteonecrosis of the Jaw.
J Oral Maxillofac Surg 2010.
Duration Between Duration of BP
DI Placement and Intake Before
BP Start of BP Intake BRONJ Development
Case Intake (mos) (mos) was observed in 21 patients (77.8%). The mean length
of time for the spontaneous development of BRONJ
1 A 22 156
2 Z 115 3 was 16.2 months (median, 11) in the 23 cases in
3 Z 125 1 which the DIs were placed after BP treatment was
4 Con 58 33 started.
Abbreviations: A, alendronate; BP, bisphosphonate; Con, LOCATION OF BRONJ
concomitant use of pamidronate and zoledronic acid; DI,
dental implant; Z, zoledronic acid. Twenty patients (74%) had lesions in the mandible,
Lazarovici et al. Dental Implants and Osteonecrosis of the Jaw. 15 of which developed in the posterior segment and
J Oral Maxillofac Surg 2010. 5 in the anterior segment. Seven patients (26%) had
LAZAROVICI ET AL
FIGURE 2. BRONJ developing spontaneously in a 60-year-old
man (patient 13 in Table 2) 17 months after placement of DIs. The
patient commenced IV zoledronic acid for treatment of multiple
myeloma at the same time as DI placement. A, Area of exposed
necrotic bone involving the maxillary alveolar ridge around the DIs.
B, Because the patient did not respond to nonsurgical treatment, the
DIs were removed. Note the necrotic bone integrated with the DIs.
Lazarovici et al. Dental Implants and Osteonecrosis of the Jaw.
J Oral Maxillofac Surg 2010.
lesions in the maxilla, of which 4 were in the poste-
rior segment and 3 in the anterior segment.
TREATMENT PROTOCOLS
All patients who presented with purulent or painful
BRONJ associated with DI use were initially treated
with oral antibiotics. At the beginning of the study, all
patients were prescribed oral amoxicillin (1.5 to 3
g/d) unless they were allergic to penicillin, in which
case oral doxycycline (100 to 200 mg/d) was pre-
scribed. Later on, after we acquired more experience
with treating BRONJ, all patients were prescribed oral
doxycycline (100 to 200 mg/d). The antibiotics were
administered orally for a period of several months to
more than 1 year. Overall, 7 patients received oral
amoxicillin and 20 received oral doxycycline.
793
The DIs were removed in cases in which long-term
antibiotic treatment failed to alleviate the signs and
symptoms of BRONJ. Overall, 16 patients (59%) had
their involved DIs removed and continued on the
antibiotic treatment. The antibiotic treatment was
usually continued for several weeks after the first
indication of improvement of the signs and symp-
toms.
FOLLOW-UP AND TREATMENT OUTCOME
Follow-up ranged from 3 to 43 months (mean, 11.4;
median, 7). The response to treatment was classified
as a complete response (CR) when there was com-
plete resolution of the BRONJ manifestations, a partial
response (PR) when there was a reduction of bone
exposure, significant pain relief, and cessation of pus
exudates, and a negligible or no response (NR) when
there was no sign of improvement. Table 4 presents
the type of antibiotic regimen and the response to the
treatment according to the type of BP regimen. Of the
16 patients whose DIs were removed and who con-
tinued on antibiotic treatment, 7 (44%) had CR, 7
(44%) had PR, and 2 (12%) had NR. Eleven patients
did not require the removal of their DIs due to an
acceptable improvement in their BRONJ symptoms:
(45%) had CR, 6 (55%) had PR, and none had NR.
Overall, 12 patients (44%) had CR, 13 (49%) had PR,
and only 2 (7%) had NR. Seven patients (63%) taking
oral BPs had CR compared with 5 patients (31%)
receiving IV BPs. All patients who were receiving IV
BPs and exhibited CR had been treated with doxycy-
cline (100 to 200 mg/d).
Discussion
BPs have an efficacious effect of suppressing
bone turnover, but they can also cause a devastat-
Table 4. TREATMENT AND RESPONSE
Patients Treated Patients Treated
With With
Amoxicillin Doxycycline
Type of BP (1.5-3 g/d) (100-200 mg/d) Response
Alendronate 3 4 CR
1 3 PR
0 0 NR
IV 0 5 CR
2 7 PR
1 1 NR
Abbreviations: BP, bisphosphonate; CR, complete response;
IV, intravenous BPs (zoledronic acid, pamidronate, or con-
comitant use of both); NR, negligible or no response; PR,
partial response.
Lazarovici et al. Dental Implants and Osteonecrosis of the Jaw.
J Oral Maxillofac Surg 2010.
794
ing side effect, that of BRONJ.12,14-26 Numerous re-
ports of the occurrence of BRONJ suggest that dental
extraction is the main triggering event for its devel-
opment.16,17,20,22-24 There are only a few sporadic
reports on BRONJ associated with the placement of
DIs26-28 or failure of DIs associated with BP therapy.29
No series of cases have thus far been published.
Four recent studies have examined the occurrence
of BRONJ after placement of DIs in patients under
treatment with oral BPs.30-33 Fugazzotto et al30 placed
169 DIs in 61 patients, Grant et al31 placed 468 DIs in
115 patients, Bell and Bell32 placed 101 DIs in 42
patients, and Jeffcoat33 placed 102 DIs in 25 patients.
None of these researchers found any cases of BRONJ
associated with the DIs. Bell and Bell32 concluded that
patients who take oral BPs are at no greater risk of
implant failure than other patients. Moreover, several
studies have demonstrated a positive effect of oral BPs
on the osseointegration of DIs and the treatment of
periodontitis.34-39 Notably, no retrospective or pro-
spective studies on the placement of DIs in patients
receiving IV BPs have been reported, thus adding
greater importance to the new data that emerged
from the present series of cases.
One of the most important issues concerning
BRONJ is the timing of the development of BRONJ in
reference to the placement of the DIs. BRONJ associ-
ated with DIs was classified in the present study as
surgically related or spontaneous. We found that only
22.2% of cases were surgically related, and that 77.8%
developed spontaneously and occurred as a late com-
plication (mean, 16.2 months; median, 11 months) in
the 23 patients whose DIs were placed after the
initiation of their BP treatment. Moreover, 4 cases of
spontaneous BRONJ were associated with DIs that
were placed a few years (2 to 10 years) before BP
treatment was started. We believe that the low inci-
dence of surgically related BRONJ was due to the
decreasing frequency of DI placement in patients un-
dergoing BP treatment after recent reports that
sounded an alarm against that practice.23,40,41 These
findings stress the need for an extended follow-up of
patients who are taking BPs and who undergo DI
placement.
We divided the duration of BP intake before BRONJ
development according to the type of BP treatment,
IV or oral. BRONJ developed after a shorter period in
patients receiving IV BPs compared with patients
who ingested oral BPs. These differences in time are
in accordance with the potency (especially that of
zoledronic acid) and bioavailability of IV BPs10-13 com-
pared with oral BPs.
Although the data on BRONJ associated with DIs
are limited, we assume that most cases will develop in
patients receiving IV BPs because this is the general
rule for the development of BRONJ from any cause.
DENTAL IMPLANTS AND OSTEONECROSIS OF THE JAW
The largest series of BRONJ in the literature reported
that 77% to 97.5% of cases developed in patients
receiving IV BP treatment.16,17,24-26 Specifically, Marx
et al17 reported that 97.5% of the cases of BRONJ
developed after IV BP therapy, Ruggierro et al16 re-
ported 89%, Mavrokokki et al24 reported 77%, and
Abu-Id et al25 reported 93.6%. We recently reported a
series of 101 patients of whom 84% of BRONJ cases
were associated with IV BP treatment.26 In the
present study, only 59% of patients who developed
BRONJ associated with DIs were receiving IV BP treat-
ment, whereas 41% were ingesting oral BPs. This
difference is probably because DI placement is usu-
ally not performed in patients undergoing IV BP treat-
ment after the alarming reports in recent years on the
occurrence of BRONJ and the compromised state of
these patients.12,14-26,40,41 The fact that many more
patients in the general population receive BPs
through the oral rather than the IV route may explain
the relatively high occurrence of BRONJ associated
with DIs in the patients in the present study who used
oral BPs.
Comorbidities, such as type 2 diabetes mellitus,25
prolonged steroid therapy,23 and health-threatening
habits such as smoking,42,43 were suggested as predis-
posing conditions for the development of BRONJ. In the
present study, only 3 patients (11%) had a history of
type 2 diabetes mellitus, which is lower than the
reported incidence in Western society in this age
group.44,45 Two patients (7%) had a history of pro-
longed steroid therapy, and only 2 had a history of
previous or current smoking. Thus, we propose that
these medical conditions appear not to pose an in-
creased risk for the development of BRONJ associated
with DIs.
The response to the treatment among patients tak-
ing oral BPs was better than that for the patients
receiving IV BPs. Sixty-three percent of the former
patients had a CR compared with only 31% of the
latter. The overall CR rate was 44%. This high re-
sponse rate was probably due to the large percentage
(40%) of patients taking oral BPs who showed an
improved response to treatment. Although no comor-
bidities were found to be associated with the devel-
opment of BRONJ, the better general health of pa-
tients ingesting oral BPs might contribute to the
comparatively better response rate. In addition, the
high affinity of doxycycline to bones46-48 may corre-
spond to the improved rate of response for patients
treated with doxycycline 100 to 200 mg/d.
The few reports in the literature of BRONJ associ-
ated with DIs have reached conflicting conclusions.
In 2007, the American Association of Oral and Maxil-
lofacial Surgeons recommended that DIs should be
avoided in patients receiving IV BP treatment, but the
position paper did not prohibit elective oral surgery
LAZAROVICI ET AL
in patients taking oral BPs.23 Scully et al41 claimed that
BP treatment is a contraindication for performing oral
surgery, including DI placement. The American Den-
tal Association Council on Scientific Affairs recently
recommended that, when extensive implant place-
ment is necessary, other treatment options should be
considered, but they did not prohibit the placement
of DIs in patients receiving oral BPs treatment.40
We expect that increasingly more cases of BRONJ
associated with DIs will be encountered in the future.
We base our reasoning on the fact that the graying
population of Western society will be accompanied
by an increase in the number of cases of multiple
myeloma, prostate carcinoma, and bone resorption
diseases that are treated with BPs. The improvement
in treatment protocols for patients with cancer and
the increase in their life expectancy will probably
lead to larger numbers of patients who are treated
with BPs and for longer periods of treatment. Some of
these patients will require DIs that carry the risk for
the development of BRONJ associated with them.
In conclusion, BRONJ associated with DIs is a dev-
astating side effect of BP treatment. Our study re-
vealed that the development of BRONJ associated
with DIs is a late complication and that it is usually
not related to the oral surgery. Thus, patients treated
with BPs who receive DIs should be followed for long
periods. Patients who develop BRONJ associated with
DIs should undergo long-term treatment with doxy-
cycline 100 to 200 mg/d, and their DIs should be
removed only if the antibiotic treatment fails to alle-
viate the signs and symptoms of BRONJ.
Acknowledgment
The authors thank Prof Amos Buchner for his valuable contribu-
tion to the preparation of the manuscript and Ms Esther Eshkol for
editorial assistance.
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