PATHOLOGY

Temporal Correlation Between

Bisphosphonate Termination and Symptom
Resolution in Osteonecrosis of the Jaw:
A Pooled Case Report Analysis
Andrew M. Hinson, BS,* Eric R. Siegel, MS,y and Brendan C. Stack Jr, MDz
Purpose:

To investigate whether termination of bisphosphonates (BPs) affects resolution of bone

exposure and symptomatic disease in patients with established medication-related osteonecrosis of the
jaw (MRONJ).

Patients and Methods:

The studied population included 84 patients with established MRONJ who

discontinued BP therapy before treatment (n = 21), at treatment initiation (n = 38), or later (or never)
in the treatment course (n = 25). These 3 groups were compared using Kaplan-Meier curves and
log-rank tests for differences in the respective times to resolution of 1) bone exposure for any treatment
modality, 2) bone exposure not requiring radical surgery, and 3) disease symptoms.
Results:

Patients who continued BPs after the start of treatment exhibited significantly delayed resolution of symptoms (median 12 months; 95% confidence interval 8 to 15) compared with those who
discontinued BPs before (3 months; 2 to 5) and at (6 months; 3 to 7) presentation (P < .005).

Conclusions: Independent of treatment modality and MRONJ stage at presentation, discontinuing BP

before or at treatment initiation is associated with faster resolution of MRONJ symptoms compared
with continuing the drug throughout jaw treatment. Patients should be counseled that continuing their
BP medication after an established MRONJ diagnosis (compared to stopping the BP at diagnosis) may delay
resolution of maxillofacial symptoms by approximately 6 months.
! 2015 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 73:53-62, 2015

Medication-related osteonecrosis of the jaw (MRONJ)

may be considered in a patient with 1) current or previous treatment with antiresorptive or antiangiogenic
agents, 2) exposed maxillofacial bone (or bone that
can be probed through an intraoral or extraoral fistula)
that has persisted for longer than 8 weeks, and 3) no
history of radiation therapy to the jaws or obvious metastatic disease of the jaws.1 MRONJ is most commonly
diagnosed in patients exposed to intravenous bisphosphonates (BPs) for skeletal-related events associated with metastasis2 and has a wide range of clinical

findings that include necrotic bone exposure, pain,

swelling, erythema, purulent exudate, paresthesia,
and sinus tract formation. More severe findings
include presence of an extraoral fistula, oroantral fistula, and pathologic fracture.3
The mechanism of MRONJ remains elusive. In all
likelihood, the pathophysiology is multifactorial,
owing to inhibition of osteoclasts, decreased vascularity, direct soft tissue toxicity, impaired wound
healing, micro-cracks in bone, inflammation, and
infection.4-9

Received from the University of Arkansas for Medical Sciences, Little

Address correspondence and reprint requests to Dr Stack: 4301

Rock, AR.

West Markham Street, #543, Little Rock, AR 72205; e-mail: hinson.

*Medical Student, College of Medicine.

drew@gmail.com

yStatistician, Department of Biostatistics.

Received June 17 2014

zProfessor, Department of OtolaryngologyHead and Neck

Accepted July 11 2014

Surgery.

! 2015 American Association of Oral and Maxillofacial Surgeons

Conflict of Interest Disclosures: None of the authors reported

any disclosures.

0278-2391/14/01225-7
http://dx.doi.org/10.1016/j.joms.2014.07.012

53

54
The effects of the inciting drugs in regard to these
mechanisms overlap considerably, but have been
shown to vary depending on class. Antiresorptive
drugs such as BPs and denosumab have been shown
to inhibit osteoclasts and increase apoptosis preferentially within the alveolar bone of the mandible and
maxilla.10 Antiangiogenic drugs, including tyrosine
kinase inhibitors and monoclonal vascular endothelial
growth factor antibodies, interrupt the vascular supply,
resulting in the development of necrotic bone, inability
to ward off infection, and decreased wound healing
after oral trauma.11 Zoledronic acid has been shown
to inhibit angiogenesis in in vitro cancer studies,12
whereas the receptor activator of nuclear factor-kB
ligand (RANK-L) inhibitor denosumab seems to have
little effect in this regard.1 Another exacerbating factor
is direct toxicity to cells other than osteoclasts. BPs
inhibit the growth and migratory capacity of oral fibroblasts and downregulate the transcription of type 1
collagen, all of which are functions necessary for deposition of granulation tissue and re-epithelization.13
Similarly, the antiangiogenic sunitinib has been implicated to cause soft tissue damage that exacerbates
MRONJ lesions.14 No direct soft tissue toxicity has
yet been reported with denosumab.1
There are very few data supporting or refuting the
cessation of BP (or other implicated drugs) before
invasive dental procedures in patients at high risk for
development of MRONJ. The Food and Drug Administration reported that there is no substantial evidence
available to guide decisions regarding the initiation
or duration of a drug holiday in this patient population.15 The lack of data can be extrapolated to cases
of established MRONJ, with little to no clinical
evidence for or against claims that discontinuing the
offending agents will aid in timely recovery. The
updated 2014 AAOMS guidelines state that, if MRONJ
develops, the physician may consider discontinuing
antiresorptive therapy until resolution of bone exposure has occurred, depending on disease status.1 Current practice is based primarily on bone physiology,
pharmacokinetics, and when, theoretically, the drugs
should have minimal effect. Currently, there are no
large studies investigating whether discontinuing the
offending agents in established MRONJ has any effect
clinically. In the present study, the authors pooled all
MRONJ case studies reporting individualized patient
data in an effort to observe whether discontinuing
BPs was associated with improved outcomes as
measured by disease stage and temporal symptomatic
recovery.

Patients and Methods

A retrospective pooled analysis of all MRONJ case
reports was performed in an institutional review

BISPHOSPHONATE AND OSTEONECROSIS OF THE JAW

boardexempted study. A PubMed and Medline search

using MeSH terms osteonecrosis and jaw was performed (Fig 1). The results were filtered to include
only human studies and articles written in English.
The resulting titles and abstracts were filtered by
year, and titles and abstracts were read for potentially
eligible studies. Potential articles for inclusion were
read in full to determine inclusion status. Articles
that did not have patient-level data, including followup, were excluded from further study.
Data were organized by the following categories:
1) demographics and medical history: gender, age,
medication-related drug type, previous duration of
exposure of at-risk medication, malignancy, benign
disease (osteoporosis, rheumatoid arthritis, diabetes
mellitus), concurrent steroids or chemotherapy exposure, history of a precipitating dental trigger, and
American Association of Oral and Maxillofacial Surgeons (AAOMS) disease stage; 2) clinical presentation:
maxillofacial location, necrotic bone exposure, probing mobile bone, pain, skin lesions, swelling, pus,
erythema, paresthesia, sinus tract, intraoral fistula,
sinus symptoms, pathologic fracture, extraoral fistula,
and oroantral fistula; 3) histology and culture results:
inflammatory infiltrate, bacterial colonization, filamentous bacteria, and presence of actinomyces on culture
media; 4) imaging: signs of osteonecrosis, sequestration, alveolar bone destruction, trabecular or unremodeled bone at extraction socket, osteosclerosis,
periodontal ligament thickening, and osteolysis extending to the inferior border of the mandible or sinus
floor; 5) treatments: antibiotic therapy, conservative
debridement, surgical debridement or resection, and
use of alternative treatments (ie, hyperbaric oxygen,
teriparatide, and plasma-related protein).
The population was divided into 3 BP discontinuation (BPD) groups according to when discontinuation
occurred: BPD group 1, patients who discontinued BP
before MRONJ treatment; BPD group 2, patients who
discontinued BP at MRONJ treatment initiation; and
BPD group 3, patients who discontinued BP late into
MRONJ treatment course or not at all. Time to resolution of bone exposure was defined as the time in
months from presentation to resolution, with right
censoring if bone exposure never occurred at last
follow-up. Because radical surgery likely incorporated
mucosal coverage, further analysis examined time to
resolution of bone exposure in cases excluding radical
surgery. The time to resolution of disease symptoms
was defined as the time in months from presentation
to disappearance of symptoms, with right censoring
if symptoms persisted at last follow-up. These 3 times
to resolution were analyzed for differences among the
BPD groups using Kaplan-Meier methods and log-rank
tests using the LIFETEST procedure (SAS 9.3, SAS Institute, Cary, NC). General log-rank tests tested for any

55

HINSON, SIEGEL, AND STACK

FIGURE 1. PubMed and Medline search for inclusion of study population.

Hinson, Siegel, and Stack. Bisphosphonate and Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2015.

difference among the 3 groups, whereas log-rank

trend tests tested for trends in resolution time with
the intrinsic discontinuation-time ordering (before,
at, and after treatment initiation) of the BPD groups.
Median times to resolution were accompanied by
95% confidence intervals (95% CIs) calculated by the
method of Brookmeyer and Crowley.16 All P values
were 2-sided and were evaluated using the slidingscale approach of Mendenhall et al,17 which is as
follows: P < .01, highly significant; .01 # P < .05,
statistically significant; .05 # P < .10, tending
toward statistical significance; P $.10, not statistically
significant.

Results
PATIENTS AND DEMOGRAPHICS

The PubMed and Medline search initially identified

1,974 articles. After exclusion of nonEnglish-language articles and animal studies, 1,413 articles were
eligible for review. After exclusion of articles lacking
patient-level data and follow-up, 57 articles including
84 patients remained (Fig 1).14, 18-73 Age ranged from
26 to 91 years (mean, 67.9 ! 10.9 yr), with a maleto-female ratio of 1:1.6 (31 male and 50 female patients; gender was not reported in 3 cases). Seventeen
patients (20.2%) received oral administration and
66 (79.8%) received parenteral, intramuscular, or

subcutaneous administration of the at-risk medication.

Eighty-two (97.6%) received BPs, 8 (9.52%) received
antiangiogenic drugs, and 1 (1.2%) received a RANKL inhibitor.
Twenty-one patients discontinued BPs before treatment (mean, 5.9 months; range, 1 to 36 months), 38
discontinued at the start of treatment (mean, 0.0
months), and 25 discontinued late, or not at all, in
the treatment course (mean, 10.6 months; range, 1
to 22 months). Overall mean BP duration was 45.5
months (range, 6 to 168 months). Fifty-one patients
(60.1%) had a primary malignancy (breast cancer in
16.7%, prostate cancer in 9.5%, renal cell carcinoma
in 8.3%, multiple myeloma in 21.4%, other in 4.8%).
The remaining 33 patients reported BP use indicated
for benign disease, namely osteoporosis, in 24 cases.
Comorbidities or other risk factors in the studied population included rheumatoid arthritis (9.5%), diabetes
mellitus (10.7%), steroid exposure (25.0%), and
chemotherapy (27.4%). A recent precipitating event
(ie, dentoalveolar procedure, tooth extraction,
implant procedure) or severe periodontal disease
occurred in 35 patients (41.7%).
PRESENTATION AND CLINICAL FINDINGS

Mandibular and maxillary involvement was reported in 58 (69.0%) and 25 (30.1%), respectively.

56
Initial presentation was stage 0 in 17 (20.7%), stage 1
in 9 (11.0%), stage 2 in 35 (42.7%), and stage 3 in 23
(28.0%) of 82 reported patients (presentation stage
could not be interpreted in 2 cases). On initial presentation, bone exposure or probing bone was reported
in 64 patients (78.0%), in whom mobile bone was
found in 10 patients (12.2%). Pain was the most common presenting symptom in 63 cases (76.8%). Other
symptoms included skin lesions (3.7%), mucosal
swelling (53.4%), purulent exudate (32.9%), erythema
(28.0%), paraesthesia (14.6%), sinus tract formation
(15.8%), intraoral fistula (11.0%), paranasal sinus
symptoms (6.1%), pathologic fracture (6.0%), and oroantral fistula (6.0%). Individual group profiles are
presented in Figures 2 and 3.
The most common histologic findings, reported in
52 cases, consisted of necrotic bone (82.7%), inflammatory infiltrate (46.2%), bacterial colonization
(48.1%), and filamentous-like bacteria (19.2%). Culture was reported in 18 cases (21.4%), with only 3

BISPHOSPHONATE AND OSTEONECROSIS OF THE JAW

(16.7%) reporting actinomyces growth. Imaging findings were reported in at least 1 modality in 64 cases
(76.2%), with the most common findings being
destruction of alveolar bone (57.8%), trabecular remodeling (51.6%), osteosclerosis (28.1%), periodontal
ligament thickening (7.8%), and osteolysis extending
to the inferior border of the mandible or sinus
floor (25.0%).
TREATMENT

Treatment included systemic antibiotics in 68

(82.9%), with type specified in 71 cases (b-lactams in
62.0%, b-lactams with inhibitors in 40.0%, quinolones
in 7.0%, metronidazole in 14.0%, clindamycin in
18.3%, doxycycline in 2.8%, macrolide in 5.6%, and
fluconazole in 4.2%). Alternative therapies were used
in 14 cases (16.7%; hyperbaric oxygen in 7.1%, teriparatide in 4.8%, plasma-related protein in 2.4%, and
low-level laser exposure in 2.4%). Debridement to

FIGURE 2. Clinical presentation of studied populations by bisphosphonate groups. Group 1, patients who discontinued bisphosphonate
before treatment; group 2, patients who discontinued bisphosphonate at treatment initiation; group 3, patients who discontinued bisphosphonate late into treatment course or not at all.
Hinson, Siegel, and Stack. Bisphosphonate and Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2015.

57

HINSON, SIEGEL, AND STACK

FIGURE 3. American Association of Oral and Maxillofacial Surgeons stage 3 clinical symptoms at presentation of studied populations by
bisphosphonate discontinuation groups. Group 1, patients who discontinued bisphosphonate before treatment; group 2, patients who discontinued bisphosphonate at treatment initiation; group 3, patients who discontinued bisphosphonate late into treatment course or not at all.
Hinson, Siegel, and Stack. Bisphosphonate and Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2015.

relieve soft tissue irritation and infection control was

performed in 42 cases (50.0%). Major surgical debridement or resection for long-term palliation of infection
and pain was performed in 33 cases (39.3%). Individual
group profiles are presented in Figure 4.
OUTCOMES

No significant difference among BPD groups was

observed in MRONJ stage at treatment initiation.
Further, all BPD groups showed similar progression
of disease and overall outcome as measured by disease
stage. The time in months to resolution of bone exposure for any reason, including radical surgery, had
Kaplan-Meier medians (95% CIs) of 5 (3 to 16) in
BPD group 1, 9 (6 to 15) in BPD group 2, and 15 (8
to 22) in BPD group 3. These differences among
BPD groups were not significant (P = .13) by general
log-rank test for any difference, but tended toward
significance (P = .064) by log-rank test for trend with
the groups BPD times. When bone exposure resolution not requiring radical surgery was considered,
the time in months to resolution had Kaplan-Meier

medians (95% CIs) of 12 (4 to 16) in BPD group 1,

15 (8 to not reached) in BPD group 2, and 21 (12 to
22) in BPD group 3. These differences among BPD
groups were likewise not significant (P = .11) by
general log-rank test for any difference, but attained
statistical significance (P = .042) by log-rank test for
trend with the groups BPD times.
A highly significant overall difference (P = .0041 by
general log-rank test) was observed among the BPD
groups when comparing their times to resolution of
symptomatic disease (Fig 5). The median time (95%
CI) to symptom resolution was 3 months (2 to 5) for
BPD group 1, 6 months (3 to 7) for BPD group 2,
and 12 months (8 to 15) for BPD group 3. Moreover,
the trend in these resolution times with the BPD
groups discontinuation times was highly significant
(P = .0010 by log-rank trend test).

Discussion
In the synthesis of BPs, replacing the oxygen skeleton of pyrophosphate with carbon allows the
medication to bind irreversibly to hydroxyapatite in

58

BISPHOSPHONATE AND OSTEONECROSIS OF THE JAW

FIGURE 4. Treatment type separated by bisphosphonate discontinuation groups. Alternative treatment included treatment with hyperbaric
oxygen (n = 6), teriparatide (n = 3), and plasma-related protein (n = 2). Group 1, patients who discontinued bisphosphonate before treatment;
group 2, patients who discontinued bisphosphonate at treatment initiation; group 3, patients who discontinued bisphosphonate late into treatment course or not at all.
Hinson, Siegel, and Stack. Bisphosphonate and Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2015.

bone.74 This property is essential to drug effectiveness, allowing high concentrations of BPs to accumulate at the surface of remodeling bone, preventing
osteoclast-mediated bone resorption. After absorption of the drug, approximately half the drug is bound
at these surfaces. Elimination of the drug is complex,
and BPs are best described as having 3 separate halflives depending on the concentration location in
the body.75
The most rapid half-life, measured in hours to days,
represents the concentration of drug that is exposed
to soft tissues. At infrequent dosing and short durations, the drug is rapidly eliminated by osteoclasts,
with the excess drug undergoing rapid renal excretion.75,76 An intermediate half-life, measured on the
scale of days to weeks, represents the drug bound to
surface hydroxyapatite, which is responsible for the
therapeutic effects of the drug in skeletal-related disease states. Osteoclasts, slowed by BP inhibition, are
responsible for elimination. Some drug may bind to
quiescent bone surfaces when exposed at higher concentrations. Then, the drug is buried by de novo bone
formation, representing the slowest half-life, measured
in years, and is not released until bone remodeling or
resection exposes the underlying concentrations to

the systemic vasculature (ie, tooth extraction, dentoalveolar surgery, debridement, etc).75
After discontinuation of the BP, maintenance of the
effects may persist. Lasseter et al75 theorized that after
treatment with alendronic acid 10 mg daily for 10
years, the estimated release of the BP from skeletal
remodeling would be similar to that of an oral daily
dose of 2.5 mg. Although lower than the oral therapeutic dose, they suggested that this might explain, in
part, why frequent dosing over long periods may
have effects that linger several months after discontinuation of the drug.
The effects have been shown to be longer lasting and
of greater effect in higher-potency drugs (ie, zoledronic
acid).75 It is difficult to describe and quantify exactly at
what level these maintenance concentrations are for
the myriad BP types and other at-risk MRONJ drugs.
Further, the complex pharmacokinetics (and the multiple comorbidities commonly affecting the studied population) make it even more difficult to predict what
clinical effect cessation of BP at the time of treatment
will have in cases of established MRONJ.
The effect of BP drug holidays before and after invasive dental procedures (which can be extrapolated to
treatment of established MRONJ) is controversial.

59

HINSON, SIEGEL, AND STACK

FIGURE 5. A significant difference (P = .0041) was observed when comparing mean time to resolution of symptomatic disease. Group 1,
patients who discontinued BP before treatment; group 2, patients who discontinued BP at treatment initiation; group 3, patients who discontinued BP late into treatment course or not at all. BP, bisphosphonate.
Hinson, Siegel, and Stack. Bisphosphonate and Osteonecrosis of the Jaw. J Oral Maxillofac Surg 2015.

Some have suggested that even if discontinuing the

drugs, decade-long half-lives make any potential
short-term benefit unlikely (and may place the patient
at further risk for fracture secondary to discontinuing
the BP). However, this view overly simplifies BP pharmacokinetics and does not account for the impact that
might occur from decreased drug concentration inhibiting osteoclasts at the bone surface in addition to
other cell types (ie, soft tissues).
Damm and Jones77 reported that if 50% of serum BP
undergoes renal excretion, the major reservoir of BP is
the osteoclast, whose life span is 2 weeks. Thus, the
majority of free BP within the serum should be
extremely low 2 months after the last dose of oral
BPs, suggesting that a 2- to 3-month drug-free period
before and after invasive dental surgery may be sufficient, systemic conditions permitting.3,77 Others
have suggested that at least 6 months may be
necessary, depending on drug type and route of
delivery, previous duration of at-risk medication exposure, and other relevant risk factors, such as concurrent steroid use, chemotherapy exposure, diabetes
history, etc.1 The ambiguity within the literature has
translated into ineffective communication between
practitioner and patient in clinical practice. In a study
by Migliorati et al,78 upward of 80% of patients lacked
recall of being told by a medical professional about the
potential risks associated with BP use.
In the present study, all groups presented at similar
MRONJ stages and were exposed to similar treat-

ments. At last follow-up, there was no difference

observed among final disease stage, bone exposure
resolution, and symptomatic disease. However, the
rate at which symptomatic recovery occurred was
considerably different among BPD groups. The
median time to resolution of symptoms for those
patients who discontinued BP before and at treatment initiation was 3 and 6 months, respectively. In
contrast, those who continued their BP therapy did
not see resolution until 1 year after the start of
treatment. A similar effect could not be shown for
the time it took to resolve bone exposure (which is
a defining feature of MRONJ). The authors initially
proposed that this might be due to the immediate
mucosal closure that frequently occurs with more
advanced treatment (ie, surgical resection). Accordingly, when advanced surgical treatment was
excluded, there was a significant trend (P = .042) in
the resolution time of bone exposure with
the timing of BPD (before, at or after treatment
initiation).
The discrepancy between resolution of bone exposure and symptomatic disease may be artificial. Although
bone exposure is a defining measurement in MRONJ
classification, it is merely 1 manifestation of a complex
disease. Thus, the discrepancy may be explained by
the fact that grouping of all MRONJ maxillofacial symptoms allowed for greater sensitivity in detecting persistence of pathology at large. Absence of bone exposure
may provide a false sense of security to the provider

60
and patient in established MRONJ. Approximately 70%
of patients in this study presenting without bone exposure developed bone exposure later in the disease
course. Further, the cases in which mucosal coverage
was obtained by surgical closure frequently had evidence of persistent disease (ie, other maxillofacial symptoms, radiologic evidence of disease exacerbation, etc).
The present study is limited in that the studied population consists of pooled case reports, which may
introduce selection bias. Case reports and case series
frequently present unusual or novel cases, and pooling
of such studies may include cases not representative of
the actual population. However, in diseases with
extremely low incidence such as MRONJ, case reports
offer helpful patient-level details that chart reviews or
databases cannot replicate. Further, case reports
frequently report novel therapies that were associated
with a positive outcome. The present study shows that
(even when these novel therapies are included) treatment outcome was associated with the timing of
discontinued BP therapy alone (independent of any
of these treatments). Another limitation of the present
study is that several cases were limited to only a few
months of follow-up after successful treatment. It
would be helpful to know clinically if discontinuing
BP therapy is associated with less disease recurrence.
In conclusion, independent of treatment modality
and disease stage at presentation, discontinuing BP
before or at treatment initiation is associated with
faster resolution of MRONJ symptoms compared with
continuing the drug throughout treatment. Effective
communication between the prescribing physician
(ie, oncologist, family practitioner, etc) and the dentist
and maxillofacial surgeon is essential to prevent excess
morbidity in this difficult-to-treat disease. It is the
authors best estimate that continuing BP therapy
after an established MRONJ diagnosis (compared to
stopping the BP at diagnosis) may delay resolution of
maxillofacial symptoms by approximately 6 months.

Press Release
This articles Press Release can be found, in the
online version, at http://dx.doi.org/10.1016/j.joms.
2014.07.012.

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