Clin Orthop Relat Res (2018) 476:1783-1790

DOI 10.1007/s11999.0000000000000104

2017 International Society of Limb Salvage Proceedings

Preoperative Denosumab With Curettage and Cryotherapy in

Giant Cell Tumor of Bone: Is There an Increased Risk of
Local Recurrence?
Guido Scoccianti MD, Francesca Totti MD, Maurizio Scorianz MD, Giacomo Baldi MD, Giuliana Roselli MD,
Giovanni Beltrami MD, Alessandro Franchi MD, Rodolfo Capanna MD, Domenico Andrea Campanacci MD

Received: 6 August 2017 / revised: 9 October 2017 / Accepted: 22 November 2017 / Published online: 9 February
2018 Copyright © 2018 by the Association of Bone and Joint Surgeons

Abstract
Background Denosumab is a monoclonal RANKL anti-body,
which was originally introduced for the treatment of
osteoporosis and bone metastases from solid tumors, but more
recently has been used for treatment of giant cell tumor of bone
(GCTB). In GCTB, denosumab has been used as a sin-gle
agent in patients with inoperable tumors; it also has been used
before surgery in some patients with the aim to down-stage the
tumor to facilitate a joint-preserving procedure
(curettage) rather than a resection. However, few studies
are available evaluating the benefits and risks of
denosumab for the latter indication.
Questions/purposes (1) Does preoperative treatment
with denosumab reduce the risk of local recurrence in
patients treated for GCTB? (2) Are there adverse effects
of short-term denosumab use before surgery and, if so,
what are they?

One of the authors (RC) received personal fees from Waldemar Link (Hamburg, Germany) and grants from Adler Ortho SRL
(Milan, Italy), outside the submitted work.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board
members are on file with the publication and can be viewed on request.
Clinical Orthopaedics and Related Research® neither advocates nor endorses the use of any treatment, drug, or device. Readers are
encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.
Each author certifies that his or her institution approved or waived approval for the human protocol for this investigation and
that all investigations were conducted in conformity with ethical principles of research.
This work was performed at the Department of Orthopaedic Oncology and Reconstructive Surgery, Azienda Ospedaliero
Universitaria Careggi, Firenze, Italy.

G. Scoccianti, F. Totti, M. Scorianz, D. A. Campanacci, Department of Orthopaedic Oncology and Reconstructive

Surgery, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy

G. Baldi, Department of Medical Oncology, Hospital of Prato, Prato, Italy

G. Roselli, Department of Radiology, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy

G. Beltrami, Department of Paediatric Orthopaedic Oncology, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy

A. Franchi, Department of Translational Research and New Technologies, Department of Anatomic Pathology, Azienda
Ospedaliero Universitaria Pisana, Pisa, Italy

R. Capanna, Department of Orthopaedics and Traumatology, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy

G. Scoccianti (✉), Department of Orthopaedic Oncology and Reconstructive Surgery, Azienda Ospedaliero Universitaria
Careggi, Largo Brambilla 1, 50134, Firenze, Italy, email: scocciantig@aou-careggi.toscana.it

Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 1784 Scoccianti et al.
Methods All patients with a diagnosis of GCTB surgically
treated at our institution from June 2009 to June 2016 with
curettage and cryotherapy were retrospectively evaluated to
compare patients treated with curettage alone versus
patients treated with curettage after preoperative therapy
with denosumab. During that period, we treated 97 patients
for GCTB; 30 patients were excluded because they received
a resection; 34 patients were excluded because they
received curettage without cryotherapy. Of the remaining
33 patients, four were excluded because they received
denosumab only after surgery, one because she received
zoledronic acid, one because she received a curettage after
her refusal of a re-section that was the advised procedure,
two because they were lost to followup early, and four
because they were treated for recurrence rather than a new
diagnosis of GCTB. The remaining 21 patients were
included. Twelve lesions had been treated with surgery after
denosumab and nine with surgery alone. During the study
period, we preferentially used denosumab for the more
aggressive-looking lesions. After curettage, cryotherapy of
the residual bone walls was performed with argon
cryoprobes to -150° C after pouring gel into the cavity, and
we then used cement (17 patients) or morcellized allograft
(four patients). Tumors were Campa-nacci Grade 3 in eight
of 12 patients in the denosumab group and in two of nine
patients in the surgery-only group (p = 0.08), but the extent
of epiphyseal juxtaarticular bone involvement was not
different between the groups with the numbers available.
Median followup was 39 months (range, 14-55 months) in
the denosumab group and 27 months (range, 18-92 months)
in the surgery-only group. We used chart review to record
the proportion of patients in each treatment group who had
a local recurrence and to tally adverse events.
Results With the numbers available, there was no difference in
the proportion of patients experiencing a recurrence (five of 12
in the denosumab group and one of nine in the surgery-only
group; p = 0.18). We found no adverse effects associated with
denosumab either during or after treatment; specifically, we
found no alterations in electrolyte levels, blood count, or liver
and renal function parameters. In this small series, no patient
has developed osteonecrosis of the jaw.
Conclusions In this small series, use of denosumab before
surgery for GCTB appeared to allow the reforming of a
bone peripheral rim around the tumor, perhaps facilitating
curettage rather than osteoarticular resection in some
patients. However, we did not observe a decrease in the risk
of local recurrence with the use of denosumab, suggesting
that it may not decrease the aggressiveness of the disease;
according to our preliminary results, we cannot exclude that
the rate of local recurrence could be even higher after
curettage in denosumab-treated patients than in nontreated
patients, and until or unless larger studies demonstrate such
a reduction, primary intralesional surgery without deno-
sumab seems more prudent when curettage is feasible at
Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
presentation. We did not observe any adverse effects with
denosumab, but we caution readers that this study was
underpowered to detect even relatively common compli-
cations and relatively large differences in the risk of local
recurrence. Future studies should evaluate denosumab
prospectively; given the relative rarity of this tumor, we
suspect multicenter studies are needed to achieve this.
Level of Evidence Level III, therapeutic study.
Introduction
Denosumab, a monoclonal antibody that acts as a receptor
inhibitor of nuclear factor-kb ligand (RANKL), origi-nally
was used to treat osteoporosis and bone metastases from
solid tumors. Because it acts to reduce the formation and
survival of osteoclasts, denosumab has more recently been
introduced in the treatment of patients with giant cell tumor
of bone (GCTB) [4, 21, 22]. Because of its relative novelty,
in this setting, denosumab generally is used (1) as the only
treatment in patients with locally advanced in-operable
tumors or in those with metastatic tumors; (2) as
preoperative treatment to facilitate surgery; or (3) in cer-tain
patients with large juxtaarticular tumors to make
intralesional therapy (like curettage) possible instead of
osteoarticular resection [8, 15, 17, 19, 21, 23].
After the first proposals of the use of denosumab in
GCTB [4, 21, 22], many articles were published ad-
dressing the histopathologic effects of denosumab sug-
gesting that denosumab does not kill the neoplastic
stromal cells but rather inhibits their activity, forcing
them to a quiescent status. By contrast, giant cells, which
are not the real tumor cells, disappear and bone regrowth
is made possible around and also inside the lesion area
[5, 11, 13, 14, 18, 20, 25]. However, few studies are
available concerning clinical results of this treatment in
terms of recurrence rate [8, 15, 17, 23], especially when
denosumab is used as neoadjuvant therapy before sur-
gical intralesional procedures.
Therefore, we decided to evaluate our series of patients
treated with preoperative denosumab and surgical curettage
to try to answer the following questions: (1) Does
preoperative treatment with denosumab reduce the risk of
local recurrence? (2) Are there adverse effects of short-term
denosumab use before surgery and, if so, what are they?
Patients and Methods
Between June 2009 and June 2016, we treated 97 patients
for GCTB at one institution. For this study, we wished to
focus on more aggressive and/or juxtaarticular lesions,
 Volume 476, Number 9
which we treated with curettage and cryotherapy and which
made up 34% (33 of 97) of the patients with GCTB we
treated during that time. Starting in 2012, we began to use
denosumab before surgery in patients who we felt were at
particularly high risk of recurrence. The current study
sought to evaluate the efficacy of that treatment, comparing
the group of patients treated only with surgery with the
group that received preoperative denosumab.
Because the aim of our study was to evaluate the results
in terms of local recurrences of joint-sparing surgery, we
excluded 30 patients because they were treated with a re-
section procedure (24 without preoperative denosumab and
six with preoperative denosumab). Thirty-four patients
received a curettage, but they were excluded because they
did not receive intraoperative cryotherapy. Four more
patients were excluded because they had received deno-
sumab only after surgery and one because she had received
zoledronic acid. Of the remaining 28 patients, 24 presented
with a primary lesion and four with a recurrent lesion.
Because we decided to exclude also the patients treated
because of recurrent lesions, these four patients also were
excluded. Two more patients (both treated only with sur-
gery and cryotherapy) were excluded because they were lost
to followup soon after surgery. One more patient (a young
woman affected by aggressive GCTB of the distal radius)
was excluded because, after denosumab, the CT
modifications in tumor characteristics were considered not
sufficient to perform a curettage confidently and it was
decided that the patient should undergo resection of the
distal radius, but the patient refused this kind of surgery and
asked for joint-preserving surgery. In this patient, local
recurrence was particularly likely to occur because curet-
tage could not guarantee adequate tumor removal and we
therefore excluded the patient from the series to avoid bias
in the rate of local recurrences.
Twenty-one patients remained for evaluation: 12 patients
had surgery after receiving denosumab and nine patients were
treated with surgery alone. Cryotherapy was used in
juxtaarticular lesions with involvement of subchondral bone
when “aggressive” surgical curettage was not possible without
damaging the joint or it was considered at high risk for being
inadequate; cryotherapy was adopted also in non-juxtaarticular
lesions in case of wide involvement of the bone segment both
for its adjuvant effect and to decrease bleeding in locations
unfit for tourniquet use such as the pelvis or shoulder girdle.
The decision to use denosumab during that period for this
indication was generally driven by the ex-tension and
aggressiveness of the lesion on the basis of the imaging
findings (cortical erosion, soft tissue involvement, subchondral
bone involvement). We strongly considered denosumab
treatment for patients at definite risk for a re-section procedure
because of extraosseous expansion of the tumor and only a thin
or even interrupted peripheral bone rim around the tumor and
patients with a lesion widely involving
Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Denosumab in Giant Cell Tumor of Bone 1785
the subchondral bone, in whom the surgeon was
concerned about risks to the joint surface with curettage.
No definite criteria exist to guide between resection
and curettage for patients with GCTB. Therefore, an
element of subjectivity necessarily remains affecting
surgeon choice and the readers must be aware of this
when analyzing and comparing the results we present.
In the 97 patients of the whole series, we used deno-
sumab preoperatively in 23 patients; 16 of them received
a curettage, one received excision of a soft tissue re-
currence, and six received a resection despite denosumab
treatment. In the patients who were treated with a
resection, the lesions involved the proximal fibula in
three patients and the proximal radius, distal femur, and
proximal tibia in one patient each.
All the patients were evaluated before surgery with
radiographs of the GCTB lesion, MRI with gadolinium,
and CT scanning of the lesion and chest. In patients pre-
operatively treated with denosumab, restaging with local
MRI and CT was performed after the end of neoadjuvant
therapy, before the surgical procedure. All the tumors
were active Stage 2 or aggressive Stage 3 lesions
according to the Campanacci classification [7].
Along with the use of Campanacci grading, with the aim
to compare the two groups of patients including different
tumoral sites, ranging from the femur to segments as small
as a finger phalanx, we decided to evaluate the proportion of
epiphyseal bone involvement at presentation, setting as an
evaluation parameter the ratio between the maximum di-
ameter of the lesion and the maximum diameter of the
epiphyseal bone at the level of subchondral bone or at the
level of the lesion most near to the subchondral bone mea-
sured on axial two-dimensional CT scan images. For axial
or girdle lesions (sacrum, pelvis), the evaluation was
conducted similarly, defining as diameter of the involved
bone the AP length of the sacral wing and the maximum
width of the iliac wing at the involved level. No volumetric
evaluation of the tumor was accomplished to analyze tumor
size mod-ifications before and after denosumab treatment,
because it was not the purpose of the study. According to
this param-eter, all patients were subdivided into three
groups: 76% to 100% involvement, 50% to 75%
involvement, or < 50% involvement.
Denosumab treatment was administered at the
medical oncology department by a medical oncologist
(G. Baldi) according to the following schedule: 120-mg
subcutaneous weekly administration for 3 weeks and
then 120 mg sub-cutaneous monthly for 3 months. If the
CT evaluation at 3 months showed a peripheral bone rim
still inadequate to permit aggressive curettage, the
schedule was prolonged for 3 more months to try to
obtain a better response. Nine of 12 patients received
denosumab also in the adjuvant setting (same dosage of
monthly administration for 6 months) as per protocol.
 1786 Scoccianti et al.
Intraoperative cryotherapy was administered with cry-
oprobes reaching -150° C (Endocare Cryocare Systems;
HealthTronics, Austin, TX, USA) after filling the void
resulting from curettage with a sterile gel. Number and
size of the cryoprobes used and number of cycles of
freezing (two to three) varied according to size of the
lesion and its localization (presence of nearby nerves,
vessels, or skin at risk for damage). Filling of the cavity
after curettage was performed with cement in most cases
(17) or morcellized bone allografts (four).
All the histopathologic specimens were evaluated by an
expert pathologist in bone and soft tissue diseases at our
pathology department (AF). Radiologic imaging was
evaluated by a radiologist (GR) and an orthopaedic surgeon
(DAC, GS) dedicated to bone and soft tissue oncology.
After surgery, followup was performed with clinical
and local radiographic evaluation after 1 month and then
every 3 months for the first year, every 4 months for the
second year, every 6 months for the third and fourth
years, and annually thereafter. In case of suspicion for
local re-currence, an MRI with gadolinium was used for
further evaluation. If the suspicion was confirmed by
MRI, a CT-guided needle biopsy was performed. A chest
radiograph was performed once a year.
The patients were followed during denosumab treatment
and during followup by a medical oncologist (G. Baldi) and
an orthopaedic surgeon (GS, G. Beltrami) dedicated to or-
thopaedic oncology. During preoperative and postoperative
treatment, clinical evaluation was performed by a medical
oncologist (G. Baldi) before every administration of deno-
sumab to detect any possible adverse effect in the period
between the two administrations. Adverse events and labo-
ratory abnormalities were assessed according to Common
Terminology Criteria for Adverse Events (CTCAE; version
3.0), which was in current use at the time of study start.
Standard assessments of blood count, liver function, renal
function, and electrolytes including calcium were done
weekly in the induction phase and then monthly in the
maintenance phase. Moreover, every patient underwent at
baseline a dental radiograph and a dental visit to exclude
risk factors for osteonecrosis of the jaw; then the patients
un-derwent a dental visit every 3 months during treatment.
All patients received daily supplemental doses of cal-
cium and vitamin D.
We used chart review to record the proportion of patients in
each treatment group who had a local recurrence and to tally
adverse events. In terms of adverse events, we specifi-cally
looked for abnormalities in calcium and other electro-lytes
metabolism or in blood count, liver or renal dysfunction
occurrence, osteonecrosis of the jaw, or any other unexpected
adverse events observed during denosumab treatment.
At the time of treatment, for each patient receiving
denosumab, we requested and obtained authorization by the
Regional Therapeutic Commission of Tuscany. At the
Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
time of data gathering and evaluation, the study was ret-
rospective and no objection/exception was formulated by
the local institutional review board. The study was
performed in accordance with the 1975 Declaration of
Helsinki.
Statistical Analysis
Differences between groups in terms of clinical and surgical
characteristics were assessed using Fisher’s exact test. The
statistical analysis was performed using R software [16]. A
p value of # 0.05 was considered statistically significant.
The median age at presentation was 42 years (range,
17-66 years). The most frequent site of the tumor was the
distal femur (seven patients) followed by the distal tibia
(four). The other tumors were located in the distal radius
and sacrum (two patients at each site) and proximal
humerus, distal humerus, finger phalanx, iliac wing,
proximal tibia, and patella (one at each site) (Table 1).
Median followup was 39 months (range, 14-55
months) in the denosumab group and 27 months (range,
18-92 months) in the surgery-only group.
All of the patients treated with denosumab showed
new bone formation around and partially inside the
lesion at the radiologic posttreatment evaluation. This
allowed us to perform a curettage procedure more
confidently. In all nine lesions treated with only surgery,
curettage was considered feasible already at presentation.
Tumors in the denosumab group were of a higher grade
than in the surgery-only group (Campanacci Grade 3 in
eight of 12 patients in the denosumab group and two of nine
in the surgery-only group; p = 0.08). However, they were
not different in terms of epiphyseal juxtaarticular bone in-
volvement; in terms of this measure, dividing them into
those with > 75%, 50% to 75%, and < 50%, the results were
eight, four, and zero patients, respectively, in the
denosumab group and two, five, and two patients,
respectively, in the surgery-only group (p = 0.12).
Results
Local Recurrence
With the numbers available, there was no difference in the
proportion of patients experiencing a recurrence (five of 12
in the denosumab group and one of nine in the surgery-only
group; p = 0.18; Table 2). The recurrences in the denosu-
mab group occurred at a median of 23 months (range, 7-54
months); one of these patients presented three subsequent
recurrences and also pulmonary metastases. One patient in
the group treated only with surgery and cryotherapy de-
veloped a local recurrence at 14 months from surgery. All
 Volume 476, Number 9 Denosumab in Giant Cell Tumor of Bone 1787

Table 1. Patient demographics and surgical details of the two groups of patients included in the study
Preoperative denosumab + curettage Only curettage and cryotherapy
Patient characteristics and cryotherapy (denosumab group) (surgery-only group)
Number 12 9
Median age (years; range) 30 (17-66) 47 (20-55)
Sex F 7, M 5 F 3, M 6
Site Lower limb 7 Lower limb 7
Upper limb 3 Upper limb 1
Pelvis/sacrum 2 Pelvis/sacrum 1
Followup (months; median/range) 39 (14-55) 27 (12-92)
Cement 8 9
Bone graft 4 0
Plate fixation 6/12 4/9
F = female
M = male.

the recurrences were histopathologically confirmed. The site
of the tumor in patients affected by local recurrence was the
iliac wing, distal femur, patella (multiple recur-rences and
pulmonary metastases), proximal tibia, distal tibia, and
finger phalanx in one patient each. All six patients
underwent revision surgery. Two patients underwent a re-
section procedure with reconstruction (iliac wing peri-
acetabular region with a custom-made prosthesis; finger
phalanx with a composite prosthesis using an autologous
bone graft from the iliac crest). Four patients were again
treated with curettage. The patient affected by pulmonary
metastases was treated with surgery for the local recurrence
and was restarted on denosumab, which was recently dis-
continued, and she is now under strict monitoring.
Adverse Effects
No adverse effect of the use of denosumab was detected
either during or after treatment. All the patients completed
the treatment schedule without interruption. No alterations
in serum levels of calcium or other electrolytes could be
found nor did we observe any hematologic or liver and
renal function abnormalities. No patient thus far has de-
veloped signs of osteonecrosis of the jaw. No malignant
neoplastic transformation has been observed in the
evalu-ation of the specimens either from pretreated
tumors or from recurrences.
Discussion
The use of denosumab for GCTB in the preoperative set-
ting was greeted with much interest by the orthopaedic
community in the hopes of avoiding some osteoarticular
resections and complex reconstructive procedures in young
patients. Although the use of denosumab in GCTB was
introduced almost 10 years ago [22], few clinical data about
its results are yet available [8, 15, 17, 19, 23]. Prior work
suggests that denosumab does not eliminate tumor cells but
only suppresses their activity [11, 13, 14]. As such, the
issue of local recurrence risk seems important, considering
that the surgeon operating on a patient with GCTB pre-
treated with denosumab now faces a different looking tu-
mor than what surgeons have grown accustomed to seeing.

Table 2. Results in terms of local recurrence

Preoperative denosumab + curettage Only curettage and cryotherapy
Results(local recurrence) and cryotherapy (denosumab group) (surgery-only group)
Total number of patients 12 9
Patients presenting a local recurrence 5 1
Time from surgery to local recurrence 7-54 (mean 26) 14
(months)
Site of local recurrence Lower limb 3 Lower limb 1
Upper limb 1 Upper limb 0
Pelvis/sacrum 1 Pelvis/sacrum 0
Treatment of local recurrence Resection 2 Curettage 3 Curettage 1

Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 1788 Scoccianti et al.
Specifically, these denosumab-treated lesions often have a
sclerosis in the lesions and a peripheral rim of bone be-
tween tumor tissue and remaining healthy bone, which may
make it harder for surgeons to appreciate or adjuvant
therapies to extend the margins of the curettage. Perhaps
because of this, it is possible that the risk of recurrence after
treatment with denosumab is greater than patients not thus
treated. Although we could not prove this to be the case
(because of relatively small numbers and relatively short
followup), our data still suggest it may be so, and future
studies are needed to confirm this supposition.
The major limitation on this study was selection bias.
Because this was a retrospective study, randomization was
impossible; moreover, because we recently have been
treating more aggressive lesions with denosumab, a case-
control study with contemporaneous controls was not
possible. Instead, we tried to identify a suitable control
group by limiting the study to patients treated with cryo-
therapy; these patients’ lesions tended to be more aggres-
sive lesions among those we treated. However, as
determined by Campanacci grading, selection bias toward
the most aggressive tumors being treated with denosumab
remained; however, in terms of the extent of epiphyseal
involvement, there was no difference between the groups,
suggesting the two groups may indeed have been reason-
ably comparable, at least with respect to that surrogate for
aggressiveness. Another limitation was the very small
sample size. With the numbers available, we did not see an
increased risk of local recurrence in the denosumab group,
and we could not demonstrate either a benefit of denosu-
mab on local recurrence control nor an increased risk of
recurrence in patients pretreated with denosumab. None-
theless, the crude incidence of local recurrence in
denosumab-treated patients was more than three times
higher than in nontreated patients, even if this was not a
statistical difference given the small sample size. The low
statistical power should cause the reader to interpret our no
difference findings cautiously; it is possible that larger
studies could demonstrate that indeed there are differences
in the risk of local recurrence with or without the use of
denosumab that were missed. Likewise, this study is se-
verely underpowered also to detect even relatively com-
mon complications and adverse events and therefore we
cannot draw any inferences about safety. Even so, we offer
the tentative conclusion that denosumab does not prevent
local recurrences, which can occur as often or even more
often than in nontreated patients. Our purpose in sharing
these findings was to share our concerns that the pre-
operative use of denosumab may be associated with an
increased risk of local recurrences of GCTB, even if we
could not prove it here. This concern warrants further in-
quiry by future, larger studies.
The risk of local recurrence we observed after denosu-
mab treatment (41%) is higher than that seen in prior large
Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
series of patients with GCTB treated without denosumab
but with intralesional surgery and local adjuvants, which
have estimated the risk to be between 14% and 19% [2, 9,
10, 12]. We note that those studies included all patients,
whereas ours included only the most aggressive lesions,
which, as a result of their characteristics, were selected to
receive preoperative denosumab. This makes comparing the
recurrence risk difficult, and we believe this is important
when comparing these results. Two other papers about local
control after curettage with preoperative denosumab found a
recurrence risk of 15% and 20% [17, 19], but mean fol-
lowup in those reports was short, at 13 and 18 months,
respectively; we note two of six recurrences in our series
occurred > 2 years after surgery (37 and 54 months) and
another occurred at 23 months. In terms of the timing of
recurrences, our data tentatively suggest that recurrences in
patients with giant cell tumors treated with denosumab
might occur later than usually observed in historical series
[3] and therefore the recurrence rates reported by those
other authors could be underestimated.
In our series, local recurrences occurred after denosu-
mab treatment not only in patients who were at
presentation particularly at risk for resection surgery
(Campanacci Grade 3 lesions with > 75% involvement
of the epiphysis at the juxtaarticular level; four of the five
recurrences in the denosumab group), but also in one
patient with a less aggressive-looking lesion (one of the
five recurrences in that group). In fact, it is possible that
by using denosumab—which seems to cause sclerosis in
the lesions and to create a peripheral rim of bone around
them—may make it more difficult for surgeons to
appreciate or adju-vant therapies to extend the margins,
perhaps making it more likely that local recurrence might
occur. We suggest that surgeons pay special attention to
aggressive curettage after use of denosumab in patients
with GCTB. Even so, the reduction in tumor size caused
by denosumab and above all the restoration of a
peripheral bone rim around the tumor can make curettage
more attractive than resection [19, 23, 24], which may be
a risk worth taking in young patients to preserve
function. In this clinical setting, an increased risk of local
recurrence can be consciously ac-cepted to try to save
the joint and to avoid complex osteoarticular
reconstructions in young patients (Fig. 1A-H).
In our very small series, we did not observe any com-
plications associated with denosumab, but we caution
readers that even common complications may not be
detected when so few patients are evaluated. Because of
that, we can draw no inferences about the safety of deno-
sumab in this setting, and in other series, several adverse
effects have been reported [8, 19, 24], including arthralgia,
fatigue, pain in the extremity, headache, nausea, back pain,
hypophosphatemia, hypocalcemia, osteonecrosis of the jaw,
osteitis, fracture, pneumothorax (in patients affected
 Volume 476, Number 9 Denosumab in Giant Cell Tumor of Bone 1789

Fig. 1 A-H Plain radiographs showing a Grade 3 GCTB of the distal tibia in a 19-year-old woman (A-B). Radiographic (C-D)
appearance after 6 months’ treatment with denosumab: new bone formation is evident at the periphery and within the lesion.
The patient underwent intralesional curettage and cryotherapy was used as a local adjuvant; the intraoperative photographs
show the freezing process with three probes inside the cavity filled with sterile gel (E). The bony defect was packed with cement
and allogeneic bone grafts in contact with subchondral bone. Plain radiographs at 2-year followup showing no evidence of local
recurrence (F). Fifty-four months after primary surgery, coronal MRI shows local recurrence in the distal fibula (G). The patient
underwent surgery with cement removal, curettage, and new cementation in both the distal tibia and fibula (H).

by pulmonary metastases) and even other neoplasms, my-
eloproliferative disorders, and malignant transformation of
GCTB. Our series used a shorter course of denosumab than
some other series [8, 19, 24], and this could account for the
absence of complications in our patients; however, again,
we caution readers that the small size of our treatment
group also could explain the lack of observed
complications. Rekhi et al. [17], who reported the results of
a series of patients treated with a short course of
neoadjuvant deno-sumab, did not report adverse events
either, but in their article, this issue was not clearly dealt
with. Further mon-itoring is mandatory, particularly for the
reported occur-rence of malignant transformation of the
tumor after treatment with denosumab [1, 6, 19].
Although denosumab may decrease the size or extent of
these lesions before surgical treatment and may result in the
formation of a peripheral rim of bone around the lesions, we
remain concerned that it does not decrease the aggres-
siveness of the disease. The result of this might be that
curettage even with adjuvants may not eradicate all of the
tumor, and in fact by causing sclerosis in the lesion, it may
interfere with the ability of surgeons to appreciate or ad-
juvant therapies to extend the margins, perhaps increasing
the risk of local recurrence. On the basis of this consider-
ation, at present, when the characteristics of a lesion make a
curettage procedure feasible at presentation, a primary
intralesional surgical procedure without denosumab treat-
ment appears to be the more prudent choice. However,
future, larger studies are needed to confirm or refute this
premise. In addition, because we have observed some late
recurrences among patients pretreated with denosumab, we
recommend continued clinical and radiographic surveil-
lance of these patients.
References
1. Aponte-Tinao LA, Piuzzi NS, Roitman P, Farfalli GL. A high-
grade sarcoma arising in a patient with recurrent benign giant
cell tumor of the proximal tibia while receiving treatment with
denosumab. Clin Orthop Relat Res. 2015;473:3050–3055.
2. Arbeitsgemeinschaft Knochentumoren, Becker WT, Dohle J,
Bernd L, Braun A, Cserhati M, Enderle A, Hovy L, Matejovsky

Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
 1790 Scoccianti et al.
Z, Szendroi M, Trieb K, Tunn PU. J Bone Joint Surg Am.
2008; 90:1060–1067.
3. Athanasou NA, Bansal M, Forsyth R, Reid RP, Sapi Z. Giant
cell tumor of bone. In: Fletcher CD, Bridge JA, Hogendoorn
PCW, Mertens F, eds. World Health Organization (WHO)
Classifica-tion of Tumors of Soft Tissue and Bone. 4th ed.
Lyon, France: IARC Press; 2013:321–324.
4. Balke M, Hardes J. Denosumab: a breakthrough in treatment of
giant-cell tumour of bone? Lancet Oncol. 2010;11:218–219.
5. Branstetter DG, Nelson SD, Manivel JC, Blay JY, Chawla S,
Thomas DM, Jun S, Jacobs I. Denosumab induces tumor re-
duction and bone formation in patients with giant-cell tumor of
bone. Clin Cancer Res. 2012;18:4415–4424.
6. Broehm CJ, Garbrecht EL, Wood J, Bocklage T. Two cases of
sarcoma arising in giant cell tumor of bone treated with deno-
sumab. Case Rep Med. 2015;2015:767198.
7. Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell
tumor of bone. J Bone Joint Surg Am. 1987;69:106–114.
8. Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S,
Kroep J, Grimer R, Reichardt P, Rutkowski P, Schuetze S,
Skubitz K, Staddon A, Thomas D, Qian Y, Jacobs I. Safety
and efficacy of denosumab for adults and skeletally mature
adolescents with giant cell tumour of bone: interim analysis of
an open-label, parallel-group, phase 2 study. Lancet Oncol.
2013; 14:901–908.
9. Errani C, Ruggieri P, Asenzio MA, Toscano A, Colangeli S,
Rimondi E, Rossi G, Longhi A, Mercuri M. Giant cell tumor of
the extremity: a review of 349 cases from a single institution.
Cancer Treat Rev. 2010;36:1–7.
10. Gaston CL, Bhumbra R, Watanuki M, Abudu AT, Carter SR,
Jeys LM, Tillman RM, Grimer RJ. Does the addition of ce-
ment improve the rate of local recurrence after curettage of
giant cell tumours in bone? J Bone Joint Surg Br. 2011;93:
1665–1669.
11. Girolami I, Mancini I, Simoni A, Baldi GG, Simi L, Campanacci
D, Beltrami G, Scoccianti G, D’Arienzo A, Capanna R, Franchi A.
Denosumab treated giant cell tumour of bone: a morphologi-cal,
immunohistochemical and molecular analysis of a series. J Clin
Pathol. 2016;69:240–247.
12. Kivioja AH, Blomqvist C, Hietaniemi K, Trovik C, Walloe A,
Bauer HC, Jorgensen PH, Bergh P, Folleras˚ G. Cement is rec-
ommended in intralesional surgery of giant cell tumors: a
Scan-dinavian Sarcoma Group study of 294 patients followed
for a median time of 5 years. Acta Orthop. 2008;79:86–93.
13. Lau CP, Huang L, Wong KC, Kumta SM. Comparison of the
anti-tumor effects of denosumab and zoledronic acid on the
neoplastic stromal cells of giant cell tumor of bone. Connect
Tissue Res. 2013;54:439–449.
Copyright 2018 by the Association of Bone and Joint Surgeons. Unauthorized reproduction of this article is prohibited.
Clinical Orthopaedics and Related Research®
14. Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A trans-
lational study of the neoplastic cells of giant cell tumor of
bone following neoadjuvant denosumab. J Bone Joint Surg
Am. 2014; 96:e127.
15. Muller¨ DA, Beltrami G, Scoccianti G, Campanacci DA,
Franchi A, Capanna R. Risks and benefits of combining
denosumab and surgery in giant cell tumor of bone–a case
series. World J Surg Oncol. 2016;14:281.
16. R Core Team. R: A Language and Environment for Statistical
Computing. Vienna, Austria; 2014. Available at:
http://www.r-project.org. Accessed October 4, 2017.
17. Rekhi B, Verma V, Gulia A, Jambhekar NA, Desai S, Juvekar
SL, Bajpai J, Puri A. Clinicopathological features of a series of
27 cases of post-denosumab treated giant cell tumors of bones:
a single institutional experience at a tertiary cancer referral
centre, India. Pathol Oncol Res. 2017;23:157–164.
18. Roitman PD, Jauk F, Farfalli GL, Albergo JI, Aponte-Tinao LA.
Denosumab-treated giant cell tumor of bone. Its histologic spec-trum
and potential diagnostic pitfalls. Hum Pathol. 2017;63:89–97.
19. Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP,
Pienkowski A, Vaz G, Wunder JS, Seeger LL, Feng A,
Roberts ZJ, Bach BA. Surgical downstaging in an open-label
phase II trial of denosumab in patients with giant cell tumor of
bone. Ann Surg Oncol. 2015;22:2860–2868.
20. Steensma MR, Tyler WK, Shaber AG, Goldring SR, Ross FP,
Williams BO, Healey JH, Purdue PE. Targeting the giant cell
tumor stromal cell: functional characterization and a novel
therapeutic strategy. PLoS One. 2013;26:e69101.
21. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A,
Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S.
Denosumab in patients with giant-cell tumour of bone: an
open-label, phase 2 study. Lancet Oncol. 2010;11:275–280.
22. Thomas D, Skubitz K. Giant cell tumour of bone. Curr Opin
Oncol. 2009;21:338–344.
23. Traub F, Singh J, Dickson BC, Leung S, Mohankumar R,
Blackstein ME, Razak AR, Griffin AM, Ferguson PC, Wunder JS.
Efficacy of denosumab in joint preservation for patients with giant
cell tumour of the bone. Eur J Cancer. 2016;59:1–12.
24. Ueda T, Morioka H, Nishida Y, Kakunaga S, Tsuchiya H, Matsu-
moto Y, Asami Y, Inoue T, Yoneda T. Objective tumor re-sponse
to denosumab in patients with giant cell tumor of bone: a
multicenter phase II trial. Ann Oncol. 2015;26:2149–2154.
25. Wojcik J, Rosenberg AE, Bredella MA, Choy E, Hornicek FJ,
Nielsen GP, Deshpande V. Denosumab-treated giant cell
tumor of bone exhibits morphologic overlap with malignant
giant cell tumor of bone. Am J Surg Pathol. 2016;40:72–80.