Bisphosphonate-Related Osteonecrosis of Jaw in the Adjuvant Breast Cancer Setting: Risks and Perspective
+ Author Affiliations
- Corresponding author: Charles L. Shapiro, Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, 320 West 10th St, Starling-Loving Hall, B405, Columbus, OH 43210,
- e-mail: charles.shapiro@osumc.edu.
Bisphosphonate-related osteonecrosis of jaw
(BONJ) is a rare adverse effect of antiresorptive treatments (primarily
zoledronic
acid and more recently denusomab) to my knowledge
first described 10 years ago. The definition of BONJ includes the
presence
of necrotic bone for more than 6 weeks in an area of
the oral cavity normally covered by mucosa, prior or current
bisphosphonate
use, and no prior history of radiation to the head and
neck.1
The risks of BONJ increase with more frequent scheduling (ie, monthly)
and prolonged durations of administration (ie, > 2
years) of intravenous bisphosphonates, and the major
risk factor for BONJ is dental extractions or procedures that expose
bone during antiresorptive therapy. Principally, this
led to the recommendation that, before initiating bisphosphonates, a
dental evaluation and, if needed, dental work be
completed before starting these drugs.2 Small nonrandomized cohort studies suggest that the incidence of BONJ is decreased with dental screening before initiating
intravenous (IV) bisphosphonates.3,4 There is no evidence that routine dental health maintenance increases the risks of BONJ, and patients should be encouraged
to have routine care during treatment with these drugs.
The precise mechanism(s) of BONJ or why it is
confined to the jaw, predisposing risk factors other than dental
extractions,
optimal treatments, and more importantly, the short-
and long-term outcomes and health-related quality of life of patients
who develop BONJ are largely unknown.5–7
Some, but not all, recent studies suggest that genetic polymorphisms in
genes related to bone metabolism, collagen, or aromatase
may predispose patients to BONJ.8,9
As is true of other rare but serious complications of cancer treatment,
health professionals tend to overestimate or underestimate
the risks, depending on their specialty (eg, dentists
or medical oncologists), general knowledge of BONJ, and anecdotal
experience.
In addition, recent small studies in patients seen in
either dental or cancer clinics suggest that awareness and education
about BONJ is lacking.10,11
Rathbone et al,12
on behalf of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE)
trial investigators, have made an important contribution
by providing the incidence and outcomes of BONJ in a
prospective randomized controlled trial of zoledronic acid in more than
3,000 women with localized breast cancer receiving
adjuvant systemic therapy and assessing the oral health-related quality
of life in a small subset of them. Several aspects of
the trial are noteworthy. The trial opened in 2003, which is the same
year that BONJ was first described. In 2004, the
protocol and consent was amended to exclude women with active dental
issues
or recent jaw surgery, consent was reaffirmed for all
prior trial enrollees, educational materials were provided to all trial
participants and investigators, and suspected cases of
BONJ were reported as serious adverse events in real time to the trial
coordinating center. These then triggered requests for
additional information, and the final case determinations were
adjudicated
by the study team, which included an oral surgeon.
Thus to the extent possible, investigators
and trial participants were made aware of the potential of BONJ.
However, we do
not know whether a standard approach to case
ascertainment of BONJ was performed at every clinic visit for all women
enrolled
onto the trial. For example, in recently closed Cancer
and Leukemia Group B (CALGB) trial 70604 (ClinicalTrials.gov trial
number NCT00869206)
trial participants were queried about dental problems, visits, and
procedures they had had in the past 1 to 12 months, and
the information was recorded in the monthly case
report form. Without such a standard approach to case ascertainment, the
potential bias of under- or over-reporting suspected
cases of BONJ is possible.
The schedule of zoledronic acid in the AZURE
trial was intensive, with one 4-mg dose administered every 3 to 4 weeks
for 5
to 6 months, followed by one dose every 3 to 6 months
for 46 months, or a total of 19 doses in 5 years. This schedule
approximates
the 24 once-per-month zoledronic acid doses typically
used to treat women with breast cancer and skeletal metastases. It is
interesting to note that, in the Austrian Breast
Cancer Study Group (ABCSG) trial-12, in which more than 1,800
premenopausal
women received goselerin and were randomly assigned to
either tamoxifen or anastrozole with or without zoledronic acid,
treatment
with zoledronic acid reduced the risk of local
recurrence, bone metastases, and distant metastases (overall hazard
ratio,
0.68; 95% CI, 0.51 to 0.91; P = .009).13 The schedule of zoledronic acid in the ABCSG trial was one 4-mg dose every 6 months for 3 years or a total of 6 doses, and
there were no reports of BONJ (median follow-up, 62 months).
In the AZURE trial, the overall cumulative incidence of BONJ at 108 months was 2.1% (95% CI, 0.9% to 3.3%) and, extrapolating
from Figure 1 of the article,12 was about 1.1% at 36 months. This is comparable with the cumulative estimated incidence of BONJ of 1.4% at 3 years in women
with breast cancer receiving once-per-month zoledronic acid for skeletal metastases.14 The 1.1% rate is about fourfold higher than that reported in a meta-analysis of randomized trials of less frequently scheduled
zoledronic acid to mitigate bone loss in early-stage breast cancer, in which the incidence is about 0.25%.15 More than 80% of the identified patients with BONJ had dental extractions before being diagnosed with BONJ, consistent with
the range of 40% to 90% of dental extractions preceding BONJ.16
The outcome of 26 women with BONJ is provided in Table 3 of their article.12
“Completely recovered” and “improving” were the outcomes for 35% and
19% of the BONJ population, respectively, whereas “recovered
with sequela” and “present and unchanged” were the
outcomes for 12% and 31%, respectively. It is unfortunate that precise
definitions were not provided for these descriptors,
nor were the details of the specific treatments for BONJ described. The
optimal treatment of BONJ is not defined. In a recent
review article, “healing” of BONJ associated with medical treatments,
surgical debridement, and surgical flap and/or
resection was 18%, 17%, and 46%, respectively,6 but these were nonrandomized, retrospective, and cohort studies subject to patient selection and other biases.
Among the relevant questions to women with
breast cancer receiving zoledronic acid or denosumab are “What are my
chances of
developing BONJ, and if I do, how does the disease and
its treatment affect my life in the short- and long-term?” The answer
to the first part of that question is clearly
low—between 0.2% to 2%, depending on whether the treatment is intended
to prevent/treat
osteoporosis, prevent skeletal metastases in the
context of a clinical trial, or treat skeletal metastases. The results
of
a quality-of-life component described by Rathbone et
al12
performed in a subset of trial participants does not address the
quality of life in women who developed and live with BONJ;
rather, at 5 years after random assignment, there were
no differences in the domains of oral health-related quality of life
in a small subset of women respondents randomly
assigned to zoledronic acid or to a control arm using the Oral
Health–Related
Profile 14,17 an instrument well-validated in noncancer populations.
These results may provide a modicum of
reassurance that receiving zoledronic acid does not seem to be
associated with a detectable
impact on oral health–related quality of life 5 years
down the road. However, the authors appropriately recognize that this
one-time retrospective assessment of oral
health–related quality of life limits our ability to make any definitive
conclusions.
There are few data assessing quality of life in women
with BONJ. In a nonrandomized comparison of 42 women with metastatic
breast cancer receiving IV bisphosphonates, quality of
life as assessed by the Head and Neck Quality of Life Questionnaire–35
was statistically significantly worse in the domains
of pain, swallowing, speech, social eating, social contact, and several
others for those who developed BONJ.18
Nearly 50% of women who developed BONJ in the AZURE trial were
characterized as either “recovered with sequela” or “unchanged”
at last follow-up. What happened to these women and
how much impact and interference BONJ is having on their daily lives is
unknown.
The results from two large cooperative trials using IV zoledronic acid—CALGB 70604 in more than 1,800 patients with metastatic
breast cancer, prostate cancer, and multiple myeloma and a SWOG trial (ClinicalTrials.gov number NCT00127205)
of more than 5,000 women with early-stage I-III breast cancers
receiving adjuvant therapy comparing the oral bisphosphonates
clodronate and ibandronate with IV zoledronic
acid—should contribute additional information. CALGB 70604 is designed
to determine
whether once-every-3-months IV zoledronic acid is not
inferior to the standard once-per-month schedule (8 v 24 doses)
with a primary end point of the incidence of skeletal-related events
and secondary end points of the incidences
of BONJ, renal dysfunction, and pharmacogenomics using
whole-genome analysis. In the SWOG trial, the oral bisphosphonates
are administered daily for 3 years with an intense
schedule of zoledronic acid of one 4-mg dose every month for 6 months
followed
by one 4-mg dose every 3 months for 30 months, or a
total of 16 doses in 3 years. The primary end points are disease-free
survival, overall survival, and adverse events.
Results are expected in 2014 for the CALGB trial and 2015 for the SWOG
trial.
The incidence of BONJ is likely decreasing
since it was first reported in 2003 as a result of increasing awareness
and a more
precise definition of the disease, disseminating
recommendations for dental screening, and limiting the schedule and
duration
of monthly treatments. When IV zoledronic acid is used
for cancer treatment–related bone loss, the incidence of BONJ is low
(about 0.25%) and lower still with use of oral
bisphosphonates. Likewise, the 1% to 1.5% incidence of BONJ with 24
once-per-month
zoledronic acid treatments in treating skeletal
metastases in women with breast cancer is probably acceptable in most
cases.
If the results of CALGB 70604 indeed show that less
frequent dosing of zoledronic acid is not inferior to the standard
monthly
dosing, then this will also likely lower the incidence
of BONJ.
The use IV zoledronic acid to improve patient outcomes is a work in progress, and the results from the SWOG trial should provide
additional data.
Overall, the AZURE trial results19
showed that IV zoledronic acid on an intensive schedule did not improve
disease-free survival or overall survival, and therefore
the 2% total cumulative incidence of BONJ, although
low, is clearly not acceptable. Whether there is a subpopulation of
women
with early-stage breast cancer as has been
proposed—premenopausal receiving ovarian suppression13 or postmenopausal women19,20,21—in
which the therapeutic ratio favors using adjuvant zoledronic acid or
clodronate vis-à-vis BONJ and other adverse effects
remains to be verified in subsequent trials. Finally,
the incidence of osteonecrosis of the jaw related to monthly denosumab
is slightly higher than that reported for zoledronic
acid when used in patients with skeletal metastases.22 Phase III trials are addressing the role of denosumab to improve clinical outcomes in women with early-stage breast cancer.
AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
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