original reports

Teriparatide Promotes Bone Healing in

Medication-Related Osteonecrosis of the Jaw: A
Placebo-Controlled, Randomized Trial
Ie-Wen Sim, MBBS1,2; Gelsomina L. Borromeo, MScMed, PhD3; Claudine Tsao, MPH, PhD3; Rita Hardiman, PhD3;
Michael S. Hofman, MBBS4; Christian Papatziamos Hjelle, MScMed5; Musib Siddique, PhD5; Gary J. R. Cook, MBBS, MSc, MD5;
John F. Seymour, MBBS, PhD1,6; and Peter R. Ebeling, MBBS, MD2
abstract

PURPOSE Medication-related osteonecrosis of the jaw (MRONJ) is an infrequent but morbid and potentially
serious condition associated with antiresorptive and antiangiogenic therapies. Although MRONJ can be pre-
vented by optimizing oral health, management of established cases is supportive and remains challenging.
Teriparatide, an osteoanabolic agent that improves bone healing in preclinical studies and in chronic peri-
odontitis, represents a potential treatment option.
PATIENTS AND METHODS In a double-blind, randomized, controlled trial, 34 participants with established
MRONJ, with a total of 47 distinct MRONJ lesions, were allocated to either 8 weeks of subcutaneous teriparatide
(20 mg/day) or placebo injections, in addition to calcium and vitamin D supplementation and standard clinical
care. Participants were observed for 12 months, with primary outcomes that included the clinical and radiologic
resolution of MRONJ lesions. Secondary outcomes included osteoblastic responses as measured biochemically
and radiologically and changes in quality of life.
RESULTS Teriparatide was associated with a greater rate of resolution of MRONJ lesions (odds ratio [OR], 0.15 v
0.40; P 5 .013), and 45.4% of lesions resolved by 52 weeks compared with 33.3% in the placebo group.
Teriparatide was also associated with reduced bony defects at week 52 (OR, 8.1; P 5 .017). The incidence of
adverse events was balanced between groups, including nausea, anorexia, and musculoskeletal pain, most of
mild severity.
CONCLUSION Teriparatide improves the rate of resolution of MRONJ lesions and represents an efficacious and
safe treatment for it.
J Clin Oncol 38:2971-2980. © 2020 by American Society of Clinical Oncology

INTRODUCTION the likelihood of developing MRONJ.10-13 There is no

Medication-related osteonecrosis of the jaw (MRONJ) standard approach to treatment because there is
is an uncommon but potentially serious condition as- a lack of high-quality data to support efficacy; thera-
sociated with medications such as antiresorptive and peutic options range from conservative management
antiangiogenic therapies.1-4 The estimated risk of MRONJ with antiseptic mouthwashes and antibiotics to sur-
gical debridement.2,5 Although case reports and small
ASSOCIATED in the setting of antiresorptive treatment of osteoporosis is
case series suggest possible benefit from investigational
CONTENT between 1 in 10,000 and 1 in 100,000 patient-years,5 but
treatments such as hyperbaric oxygen therapy, ozone
See accompanying the reported incidence of MRONJ is higher in patients
editorial on therapy, and vitamin E, benefit has not been demon-
receiving higher doses of antiresorptive treatment for
page 2949 strated in randomized controlled trials.14-16
metastatic bone cancer.6,7 Although infrequent, the health
Protocol
burden of disease attributable to MRONJ for affected in- Teriparatide (recombinant human parathyroid hor-
Author affiliations
dividuals is high because it may have long-term persistence mone 1-34) is an osteoanabolic medication used to
and support
treat osteoporosis.17 Short-term teriparatide therapy for
information (if with considerable morbidity and impairment of quality
applicable) appear 8 weeks has been demonstrated to promote bone
of life.8,9 Clinical sequelae of MRONJ can include chronic
at the end of this growth and healing in chronic periodontitis,18 and
article. suppuration, fistula formation, and pathologic fracture.
there are also isolated case reports of successful
Accepted on May 21, Currently, the emphasis is on preventing MRONJ treatment of established MRONJ with teriparatide.19
2020 and published at
because managing established cases is still a chal- On this basis, we conducted a prospective double-
ascopubs.org/journal/
jco on July 2, 2020:
lenge. Risk factor modification, including optimizing blind, placebo-controlled, randomized trial in patients
DOI https://doi.org/10. oral health through prophylactic oral assessment and with MRONJ to assess its efficacy and safety in im-
1200/JCO.19.02192 active dental intervention, has been shown to reduce proving the healing of established MRONJ lesions.

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 Sim et al

CONTEXT
Key Objective
Although medication-related osteonecrosis of the jaw (MRONJ) can be effectively prevented by optimizing oral health,
managing established cases is still a challenge. This placebo-controlled randomized trial examined the efficacy and
safety of a 2-month course of teriparatide therapy in healing established MRONJ lesions over the following 12 months in
patients with cancer or osteoporosis.
Knowledge Generated
Teriparatide treatment was associated with an improved rate of resolution of established MRONJ lesions. Teriparatide
treatment was not associated with any safety concerns, and there were few severe adverse events and no cases of new
malignancy or worsening of preexisting malignancy.
Relevance
In patients who develop MRONJ, short-term teriparatide therapy represents an efficacious and safe therapeutic option to
improve healing of established bone lesions.

PATIENTS AND METHODS saline injections (placebo group). Both groups received oral
Trial Oversight calcium carbonate 600 mg once per day and vitamin D
1,000 IU once per day in addition to standard clinical care
The trial was investigator-initiated, and the authors were for MRONJ. Standard clinical care included antiseptic
solely responsible for trial design, conduct, and analysis. mouthwashes, antibiotic therapy, and limited surgical de-
The trial was funded by the Australian National Health and bridement. Random assignment was performed in blocks
Medical Research Council. The subcutaneous teriparatide and was stratified according to duration of MRONJ di-
and placebo pens used in the trial were provided by Eli Lilly agnosis: , 12 months or $ 12 months.
(Indianapolis, IN), but they did not have any influence on
trial design, conduct, or analysis. The trial protocol was Participants were observed for 12 months from the start of
approved by the Melbourne Health Human Research and the trial, including 7 trial visits at weeks 0, 4, 8, 12, 24, 36,
Ethics Committee and the local ethics committee of each and 52. At each visit, participants underwent an oral ex-
participating site. The trial was prospectively registered amination by a single qualified dental practitioner to assess
with the Australian New Zealand Clinical Trials Registry for the clinical stage of MRONJ according to the staging
(ACTRN12612000950864) and was performed in accor- system described by the American Association of Oral and
dance with the principles of the Declaration of Helsinki. All Maxillofacial Surgeons,1,20 as well as resolution of each
participants provided written informed consent before any individual MRONJ lesion. In addition, participants recorded
trial-related intervention. adverse events and changes in medication and treatment.
An early-morning, fasting blood sample was taken for
Trial Participants analysis of bone turnover markers (carboxy-terminal
type 1 collagen crosslinks [CTXs] and procollagen type 1
The trial enrolled participants $ 18 years of age who had N-propeptide [P1NP]) and standard biochemistry, in-
a diagnosis of MRONJ as defined by the American Society cluding serum calcium and parathyroid hormone levels.
for Bone and Mineral Research Task Force3 and had
previous exposure to either bisphosphonate therapy or Conical beam computerized tomography (CBCT) was
denosumab. Potential participants were referred by med- performed at weeks 0, 4, 8, and 52 to evaluate radiologic
ical practitioners across Australia, and diagnosis of MRONJ resolution of MRONJ, and acquired images were analyzed
was confirmed by a single qualified dental practitioner using 3D Slicer21 to measure change in bone volumes
experienced in managing MRONJ. Exclusion criteria in- associated with each lesion.21 Quality of life was evaluated
cluded previous craniofacial radiotherapy, hypercalcemia, by having patients complete the validated Oral Health
hyperparathyroidism, severe renal impairment (estimated Impact Profile 14 (OHIP-14) questionnaire,22 and bone
glomerular filtration rate , 30 mL/min per 1.73 m2), and mineral density was measured at baseline and at the end of
pregnancy. the follow-up period on the same densitometer. 18F-fluoride
positron emission tomography/computed tomography
Trial Procedures (PET-CT) imaging was performed at weeks 0 and 8 to
Participants were randomly assigned in a 1:1 ratio to re- measure osteoblastic responses to teriparatide. Dynamic
ceive 8 weeks of either once-per-day subcutaneous ter- imaging centered on the jaw was performed for 60 minutes,
iparatide 20 mg (teriparatide group) or matching normal and kinetic analysis was performed using a 3-tissue

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 Teriparatide Promotes Bone Healing in MRONJ

compartmental model and spectral, deconvolution, and incidence of MRONJ in Australia after adoption of dental
Patlak analysis.23 hygiene guidelines,11 national recruitment was closed after
30 months.
Outcomes
The primary outcomes were the clinical and radiologic Categorical variables were reported using frequencies and
resolution of MRONJ lesions, as evaluated by oral exami- percentages, and continuous or interval data were sum-
nation and CBCT imaging, respectively. The secondary marized using means (with standard deviations) or me-
outcomes included improvement in MRONJ stage, change dians (with 25th and 75th percentiles) for skewed data.
in MRONJ lesion size, quality of life, bone mineral density, and Pearson x2 tests were used to compare categorical baseline
evidence of osteoblastic response measured biochemically demographic and clinical characteristics between groups,
using P1NP and radiologically using 18F-fluoride PET-CT im- simple linear regression was used to compare means, and
aging. Safety outcomes, including new malignancy, pro- Mann-Whitney U test was used to compare distributions of
gression of preexisting malignancy, and hypercalcemia skewed data. Logistic regression was used to estimate the
were prespecified, and other safety outcomes were based strength of the relationship between treatment and binary
on reports of adverse events. outcomes. When data were analyzed per lesion, the
clustered sandwich error estimator24,25 was obtained be-
Statistical Analysis cause it accounted for the lack of independence across
The trial was designed to recruit 68 participants to allow observations. For longitudinal data, such as change in
80% power to detect a significant difference between MRONJ lesions, trial visit was used as the underlying time
groups, assuming that two thirds of the patients in the variable in the analyses and was entered into the model as
placebo group would have resolution of MRONJ during a continuous variable with values 0 (baseline) to 7 (52
the study and allowing for a 20% dropout rate of recruited weeks). In these analyses, an interaction between time and
participants. Because of a lower-than-anticipated re- treatment group was added to compare change over time
cruitment rate, which was a result of the decreasing between the 2 treatment groups. All analyses were based

Potential participants assessed

for eligibility (n = 76)

Did not meet inclusion

criteria (n = 3)

Eligible participants with

confirmed MRONJ (n = 73)

Declined participation (n = 37)

Randomly assigned FIG 1. CONSORT diagram showing enroll-

(n = 36) ment, random assignment, and follow-up of
trial participants.

Died pre-intervention (n = 1)
MRONJ self-resolved (n = 1)

Assigned to placebo group (n = 19) Assigned to teriparatide group (n = 15)

Completed follow-up at 12 months (n = 17)

Died during follow-up period (n = 1) Completed follow-up at 12 months (n = 15)
Lost to follow-up (n = 1)

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 Sim et al

TABLE 1. Participant Characteristics at Baseline

Placebo Teriparatide
(n 5 19) (n 5 15)

Characteristic No. % No. %

Median age, years (IQR) 64 (58 to 74) 64 (59 to 71)
Female sex 9 47.4 7 46.7
Duration of MRONJ, months
, 12 9 47.4 9 60.0
$ 12 10 52.6 6 40.0
No. of MRONJ sites
1 14 73.7 10 66.7
$2 5 26.4 5 33.3
Clinical stage
0 or 1 7 36.8 6 40.0
2 9 47.4 7 46.2
3 3 15.8 2 13.3
Indication for antiresorptive therapy
Malignant bone disease 14 73.7 13 86.7
Myeloma 10 10
Breast cancer 2 1
Prostate cancer 2 2
Osteoporosis 5 26.3 2 13.3
MRONJ precipitant
Dental extraction 12 63.2 7 46.7
Implant insertion 1 5.3 0
Ill-fitting dentures 1 5.3 0
None identified 5 26.3 8 53.3
Previous MRONJ treatment
Surgical intervention 8 42.1 5 33.3
Antibiotic therapy 13 68.4 8 53.3
Dental status
Median No. of teeth (IQR) 18 (11 to 24) 16 (6 to 25)
Maxillary dentures 9 47.4 6 40.0
Mandibular dentures 4 21.1 1 6.7
Periodontal disease prevalence 9 59.3 8 66.7
Tobacco use
Never 11 57.9 4 26.7
Ex-smoker 5 26.3 7 46.7
Current smoker 3 15.8 4 26.7
Heavy alcohol consumption ($ 2 standard drinks/day)
Never 16 84.2 7 46.7
Previous 2 10.5 4 26.7
Current 1 5.3 4 26.7
Diabetes mellitus 7 36.8 2 13.3
(continued on following page)

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 Teriparatide Promotes Bone Healing in MRONJ

TABLE 1. Participant Characteristics at Baseline (continued)

Placebo Teriparatide
(n 5 19) (n 5 15)

Characteristic No. % No. %

Glucocorticoid exposure
Nil 7 36.8 6 40.0
Previous 6 31.6 7 46.7
Current 6 31.6 2 13.3
Bone turnover markers, median (IQR)
P1NP, mg/L 19.5 (12 to 36) 21 (16 to 33)
CTX, ng/L 111 (84 to 158) 109 (85 to 26)
Bone mineral density, femoral neck T score 21.3 (–2.2 to –0.4) 21.4 (–2.4 to –0.7)

NOTE. There were no statistically significant differences between study groups (P $ .05).
Abbreviations: CTX, carboxy-terminal type 1 collagen crosslink; IQR, interquartile range; MRONJ, medication-related osteonecrosis of the jaw; P1NP,
procollagen type 1 N-propeptide.

on the intention-to-treat principle, and a P value of less than clinical stage. Furthermore, the proportion of patients with
.05 indicated statistical significance. All data for those lost at least 1 unresolved lesion at 52 weeks was similar
to follow-up or those who were deceased were included in (72.2% in the control group v 73.3% in the teriparatide
analyses. Analyses were performed using STATA Statistical group (OR, 0.95; 95% CI, 0.15 to 5.69; P . .999). Although
Package version 14.0. the proportion of resolved lesions was higher in the latter
group, this difference was not statistically significant (OR,
RESULTS 1.67; 95% CI, 0.41 to 6.83; P 5 .478). Teriparatide was
associated with increased bone volume and thus reduced
Participants bony defect size in a greater proportion of patients at
A total of 34 participants were enrolled in the trial from 52 weeks (80.0% teriparatide v 31.3% placebo; OR, 8.1;
November 2012 through May 2015 (Fig 1). Of those, 15 95% CI, 1.36 to 66.20; P 5 .017). Although 79.4% of
were randomly assigned to the teriparatide group and 19 participants described improved OHIP-14 scores at week
were assigned to the placebo group. All analyses were 52, there was no significant difference between treatment
based on the 34 participants who were randomly assigned groups (P 5 .677).
and received intervention. Among trial participants, there
The only significant predictor of MRONJ resolution was low
were 46 MRONJ lesions, and 10 participants had MRONJ
gingival index, which is an indicator of good oral hygiene
at multiple sites.
Overall, the baseline demographic and clinical character-
istics were balanced between groups (Table 1). The me-
dian duration of MRONJ before enrollment was 12 months; 100
clinical staging was similar between groups. The indication
MRONJ Positive Sites (%)

90
for antiresorptive therapy was treatment of malignant bone 80
disease in 79.4% of participants. 70
60
Treatment Outcomes
50
Change in ONJ sites over time
MRONJ lesions progressively resolved in both groups 40 Placebo OR, 0.40; 95% CI, 0.22 to 0.74
during the follow-up period, resulting in 45.4% of the le- 30 Teriparatide OR, 0.15; 95% CI, 0.07 to 0.33
sions being resolved by 52 weeks in the teriparatide group 20
1
P = .013
Placebo
(odds ratio [OR] for resolution at each visit, 0.15; 95% CI, 10 Teriparatide
0.07 to 0.33; P , .001) and 33.3% of lesions resolved in
the placebo group (OR for resolution at each visit, 0.40; 0 12 24 36 48
95% CI, 0.22 to 0.74; P 5 .003) (Figs 2 and 3). Teriparatide Week
was significantly associated with a greater rate of resolution
of MRONJ lesions compared with placebo (OR for change FIG 2. Proportion of medication-related osteonecrosis of the jaw
over time in the control group, 0.40 v 0.15 in the ter- (MRONJ)–positive sites at each visit. The P value is for a comparison
iparatide group; P 5 .013). Among participants with per- between rates of healing in teriparatide and placebo groups. OR,
sistent MRONJ, there was no significant improvement in odds ratio.

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 Sim et al

with a three-fold increase in P1NP compared with placebo

Week 0
at both weeks 4 and 8 (P , .001), and P1NP increased by
at least 10 mg/L in 85.7% of participants who received
teriparatide. Similarly, those randomly assigned to ter-
iparatide were more likely to have increased uptake on
18
F-fluoride PET-CT scans, as measured by both stan-
dardized uptake value (SUV) and kinetic models (including
the 4K compartment and Patlak models) and defined as
25% increase in uptake. Teriparatide treatment was also
associated with a 30% increase in CTX at week 8. No
between-group differences were seen in bone mineral
density responses to therapy at any skeletal site.

Adverse Events
The incidence of reported adverse events, including GI
symptoms, musculoskeletal pain, and injection site re-
actions, was comparable between groups and most were
mild in severity (Table 3). There were 3 serious adverse
events reported in each group, including 1 death in the
placebo group. In addition, 1 patient in the placebo group
Week 52 was diagnosed with a new malignancy; however, no new
malignancies or worsening of preexisting malignancies
were reported in the teriparatide group.

DISCUSSION
Our study shows that 8 weeks of once-per-day sub-
cutaneous teriparatide injections improves the rate of
resolution of established MRONJ lesions. Our data repre-
sent, to our knowledge, the first and only randomized,
placebo-controlled trial to demonstrate therapeutic efficacy
in MRONJ and support the role of teriparatide as a treat-
ment of established MRONJ. This is clinically significant
because current recommendations and guidelines for
managing MRONJ are hampered by a lack of good-quality
data and thus tend to be consensus-driven rather than
evidence-based.26 As a result, the current approach to
therapy has relied upon conservative management, in-
cluding oral antiseptic rinses and antibiotics, as well as
limited debridement of necrotic bone.2,5 The rate of MRONJ
FIG 3. Clinical resolution of medication-related osteonecrosis of the
resolution of 33.3% over 1 year in the placebo group of our
jaw with Teriparatide at week 0 and week 52. trial is consistent with published data regarding outcomes
with conservative therapy6 and highlights the burdensome
chronicity of the condition and further need for proven
(Table 2). Participants with concurrent glucocorticoid use, therapies to promote healing of MRONJ.
diabetes mellitus, or lower baseline P1NP were numerically Although adjunctive therapies, including hyperbaric oxy-
less likely to have resolution of MRONJ, although these gen therapy, ozone therapy, and pentoxifylline and vitamin
characteristics did not meet statistical significance. MRONJ E have been advocated on the basis of isolated case reports
duration or clinical stage, concurrent MRONJ-directed and small uncontrolled case series, their utility has not been
therapy including surgical intervention and antibiotic established by randomized trials. In contrast, our placebo-
therapy, biochemical response to therapy, and increased controlled clinical trial builds on published case reports of
uptake on 18F-fluoride PET-CT were not predictive of res- successful treatment of MRONJ with teriparatide.19 As
olution of MRONJ. an osteoanabolic treatment for osteoporosis, a plausible
Marked differences were observed between treatment pathobiological explanation for the effect of teriparatide on
groups in terms of both biochemical and PET markers of MRONJ is through augmentation of osteoblastic activity at
anabolic responses to therapy. Teriparatide was associated the site of MRONJ lesions within the jaw, thus resulting in

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 Teriparatide Promotes Bone Healing in MRONJ

TABLE 2. Predictors of Response to Teriparatide Therapy

MRONJ Resolution at 52 weeks

Unadjusted
Characteristic No. % OR 95% CI P
Age 0.96 0.90 to 1.02 .211
Sex
Female 7 35.0
Male 11 42.3 1.36 0.31 to 6.00 .683
Duration of MRONJ 1.01 0.99 to 1.03 .275
Current tobacco use
No 13 39.4
Yes 5 38.5 0.96 0.18. to 5.25 .964
Current heavy alcohol consumption
No 9 25.0
Yes 9 90.0 27.0 3.05 to 238.69 .003
Glucocorticoid use
No 16 45.7
Yes 2 18.2 0.26 0.05 to 1.28 .099
Diabetes mellitus
No 15 45.5
Yes 3 23.1 0.36 0.09 to 1.44 .148
Dental status
Plaque index ($ 1 sites, score $ 2) 4 36.4
No
Yes 10 43.5 1.35 0.26 to 6.90 .721
Gingival index ($ 1 sites, score $ 2)
No 11 57.9
Yes 3 20.0 0.18 0.04 to 0.86 .032
Concurrent therapy
Antibiotics
No 7 46.7
Yes 11 35.5 0.63 0.14 to 2.88 .550
Surgery
No 9 32.1
Yes 9 50.0 2.11 0.72 to 6.19 .173
Biochemistry
Baseline PTH 0.83 0.52 to 1.32 .438
Baseline P1NP 1.06 1.00 to 1.12 .061
P1NP increase $ 10 mg/L at 4 weeks
No 9 37.5
Yes 9 50.0 1.67 0.37 to 7.45 .504
PET response: SUV increase $ 25%
No 12 46.2
Yes 2 33.3 0.58 0.09 to 3.67 .566

Abbreviations: MRONJ, medication-related osteonecrosis of the jaw; OR, odds ratio; P1NP, procollagen type 1 N-propeptide; PET, positron
emission tomography; PTH, parathyroid hormone; SUV, standardized uptake value.

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 Sim et al

TABLE 3. Adverse Events

Placebo Teriparatide
(n 5 19) (n 5 15)

Adverse Events No. % No. % P

Any adverse event 14 73.7 13 86.7 .43
Any serious adverse event 3 15.8 3 20.0 . .99
Death from any causea 1 5.3 0
New malignancya 1 5.3 0
Electrolyte disturbances
Hypercalcemia 0 0
Hypomagnesemia 0 0
GI effects
Nausea or vomiting 4 21.1 5 33.3 .46
Abdominal discomfort 2 10.5 3 20.0 .63
Constipation 2 10.5 1 6.7 . .99
Injection site reaction 1 5.3 3 20.0 .30
Musculoskeletal pain
Myalgia 2 10.5 2 13.3 . .99
Arthralgia 2 10.5 1 6.7 . .99
Jaw pain 2 10.5 2 13.3 . .99
Other
Corneal ulcer 0 1 6.7
Conjunctivitis 1 5.3 0
Parasthesia 0 1 6.7
Lymphadenopathy, self-limiting 1 5.3 0
a
Death as a result of newly diagnosed metastatic lung cancer.

a reduction in the bony defect volume and eventually duration to minimize any potential osteosarcoma risk.28
improved mucosal coverage and resolution. In our trial, Reassuringly, no causal relationship between teriparatide
teriparatide resulted in reduction of bony defect volume, and osteosarcoma has been demonstrated in humans in
and this anabolic effect on bone defects within the jaw is post-marketing surveillance.29 In addition, in our trial,
further supported by a placebo-controlled trial in adults with participants had minimal exposure to teriparatide; they
periodontal disease who underwent periodontal surgery.18 received only 8 weeks of subcutaneous injections and thus
Furthermore, notwithstanding that most participants the theoretical risk of developing osteosarcoma would be
previously received high doses of potent antiresorptive considered extremely low. Second, given the osteoanabolic
therapies, teriparatide was able to elicit an osteoblastic mechanism of teriparatide, there are potential concerns
response as demonstrated both biochemically and radio- that it may stimulate cellular proliferation within bone and
logically. Teriparatide was associated with a clinically thus lead to exacerbation of active malignant bone disease
significant increase in P1NP in 85.7% of participants, or recurrence in patients who have been successfully
whereas 18F-fluoride PET-CT demonstrated increased up- treated and are in remission. No cases of new malignancy
take of tracer within the jaw with teriparatide. 18F-fluoride or worsening of pre-existing malignancy were identified
binds avidly to hydroxyapatite and, when used as a tracer among participants who received teriparatide in our trial.
for PET-CT, it provides high spatial resolution and is an ideal Although we acknowledge that our trial was not powered to
marker for local osteoblastic activity.27 Overall, our findings demonstrate safety for these prespecified outcomes, our
support the osteoanabolic action of teriparatide within the trial data provide some reassurance, and exposure has
craniofacial region in the setting of MRONJ. been minimized through a low cumulative teriparatide
Whereas teriparatide is an approved and effective treat- dose. Moreover, any potential small risk in the setting of
ment of osteoporosis,17,28 there are potential challenges to patients with cancer should be balanced with the potential
its use in patients with malignant bone disease. First, be- benefits of therapy, especially considering the substantial
cause of cases of osteosarcoma in preclinical studies, morbidity that may be attributed to MRONJ.8,9 The ad-
teriparatide therapy is limited to 24 months cumulative verse event data from the trial did not identify any safety

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 Teriparatide Promotes Bone Healing in MRONJ

concerns, with most adverse events being mild in severity life and clinical staging may be ascribed to various factors.
and consistent with those seen in previously published trials Although the OHIP-14 is a validated tool for assessment
of teriparatide therapy for osteoporosis. There were no of oral health, participant factors such as malignancy and
significant biochemical changes, particularly no instances its treatment may have adversely influenced OHIP-14
of hypercalcemia. scoring and thus reduced its sensitivity to the specific
The major strength of our trial is that it is the only placebo- MRONJ elements and hence utility in our trial. Likewise,
controlled clinical trial investigating treatment of estab- MRONJ clinical staging represents a qualitative measure
lished MRONJ. Furthermore, all phases of trial design and that is not purposely designed as an outcome measure
its conduct were investigator-driven, and the efficacy was for clinical research.20 Finally, the treatment duration
supported by a range of supportive translational mecha- of 8 weeks in our trial was based on the randomized trial
nistic studies. Notably, although we demonstrated signifi- in periodontal disease, as well as a published case
cant improvement in the rate of MRONJ resolution, the report.18,19 A longer duration of teriparatide therapy may
magnitude of effect is likely conservative given the relatively promote ongoing resolution of bony defects and thus
small trial population and the lower-than-expected event produce more profound results. However, the efficacy
rate. Although the small trial population is reflective of the and safety of a larger cumulative dose of teriparatide
reduced incidence of MRONJ through optimization of oral cannot be extrapolated from our study.
hygiene and minimization of exposure to antiresorptive In conclusion, we have shown that 8 weeks of once-per-day
therapy,10,11 MRONJ remains a widely feared and poten- teriparatide improves the rate of resolution of established
tially debilitating consequence of antiresorptive therapy. In MRONJ lesions and thus represents an efficacious and safe
addition, the lack of documented improvement in quality of therapeutic option for MRONJ.

AFFILIATIONS CLINICAL TRIAL INFORMATION

1
Melbourne Medical School, University of Melbourne, Melbourne, ACTRN12612000950864
Victoria, Australia
2
Department of Medicine, School of Clinical Sciences, Monash
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
University, Clayton, Victoria, Australia
3
Melbourne Dental School, University of Melbourne, Melbourne, Victoria,
INTEREST AND DATA AVAILABILITY STATEMENT
Australia Disclosures provided by the authors and data availability statement (if
4
Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, applicable) are available with this article at DOI https://doi.org/10.1200/
Australia JCO.19.02192.
5
School of Biomedical Engineering and Imaging Sciences, King’s College
London, London, United Kingdom AUTHOR CONTRIBUTIONS
6
Department of Haematology, Peter MacCallum Cancer Centre and Royal Conception and design: Ie-Wen Sim, Gelsomina L. Borromeo, John F.
Melbourne Hospital, Melbourne, Victoria, Australia Seymour, Peter R. Ebeling
Financial support: Peter R. Ebeling
CORRESPONDING AUTHOR Administrative support: Peter R. Ebeling
Peter R Ebeling, Department of Medicine, School of Clinical Sciences, Provision of study materials or patients: Peter R. Ebeling
Monash University, Level 5, Block E, 246 Clayton Road, Clayton, Victoria Collection and assembly of data: Ie-Wen Sim, Claudine Tsao, Michael S.
3168 Australia; email: [email protected]. Hofman, Peter R. Ebeling
Data analysis and interpretation: Ie-Wen Sim, Gelsomina L. Borromeo, Rita
Hardiman, Michael S. Hofman, Christian Papatziamos Hjelle, Musib
PRIOR PRESENTATION Siddique, Gary J. R. Cook, John F. Seymour, Peter R. Ebeling
Presented at the American Society for Bone and Mineral Research 2017 Manuscript writing: All authors
Annual Scientific Meeting, Denver, CO, September 8-11, 2017 and the Final approval of manuscript: All authors
2018 Annual Scientific Meeting of the Endocrine Society of Australia, Accountable for all aspects of the work: All authors
Adelaide, South Australia, Australia, August 19-22, 2018.

ACKNOWLEDGMENT
SUPPORT The authors thank StellaMay Gwini, PhD, for assistance with statistical
Supported by Project Grant No. 1030371 from the Australian National analysis and interpretation.
Health and Medical Research Council.

Journal of Clinical Oncology 2979

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 Sim et al

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 Teriparatide Promotes Bone Healing in MRONJ

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Michael S. Hofman John F. Seymour

Consulting or Advisory Role: Endocyte, Janssen Honoraria: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis Pharmaceuticals,
Research Funding: Endocyte (Inst) Takeda
Travel, Accommodations, Expenses: Ipsen, Genzyme, Janssen Consulting or Advisory Role: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis
Pharmaceuticals, Takeda
Christian Papatziamos Hjelle
Speakers’ Bureau: AbbVie, Celgene, Roche
Stock and Other Ownership Interests: AstraZeneca (I)
Research Funding: AbbVie, Celgene, Janssen, Roche
Gary J. R. Cook Expert Testimony: Roche
Consulting or Advisory Role: GE Healthcare, NanoMab Technology Travel, Accommodations, Expenses: AbbVie, Roche
Research Funding: Serac Healthcare (Inst), Theragnostics (Inst), NanoMab
Peter R. Ebeling
Technology (Inst)
Honoraria: Amgen (Inst), Sanofi (Inst)
Travel, Accommodations, Expenses: GE Healthcare, Alliance Medical
Consulting or Advisory Role: Amgen (Inst)
Speakers’ Bureau: Amgen (Inst)
Research Funding: Amgen (Inst), Eli Lilly (Inst), Alexion Pharmaceuticals (Inst)
No other potential conflicts of interest were reported.

Journal of Clinical Oncology

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