giant cell tumor of bone ( gctb ) constitutes ~5% of all bone tumors ( 1 ) .
although treatable with surgical curettage followed by adjuvant therapy , such as liquid nitrogen and phenol , the recurrence rate of gctb is high ( 24 ) .
since curettage of gctb in the sacral vertebrae is difficult due to its location , en bloc resection is preferred to prevent recurrence .
however , surgery in that site is difficult , and there are issues such as intraoperative bleeding and postoperative dysfunction .
furthermore , the surgical results are not always satisfactory and the recurrence rates for sacral gctb can not be reduced through adjuvant therapy . therefore , conservative treatment must be considered as an option ( 5 ) . although radiotherapy is effective for sacral gctb , there is a risk of inducing a secondary malignant bone tumor ( 6 ) . alternatively
, several studies have demonstrated that selective arterial embolization may reduce and control tumors , and is an effective treatment for preserving function ( 79 ) .
in addition , infusion of the aminobisphosphonate zoledronic acid ( zol ) reportedly inhibits bone destruction at inoperable sites and prevents recurrence ( 1012 ) .
while treatments with selective arterial embolism and zol are normally performed independently , patients who do not respond to these treatments require other measures .
the anti - receptor activator of nuclear factor -b ligand ( anti - rankl ) monoclonal antibody , denosumab , was recently released .
denosumab characteristically plays a role in preventing osteolysis by inhibiting the function of osteoclast - like giant cells that are present in gctb ( 1315 ) .
in fact , the efficacy of denosumab against gctb has been evaluated in a number of studies ( 13,16,17 ) ; however , there has been no report of a patient receiving all three treatments ( selective arterial embolization , zol and denosumab ) to date .
we herein report a case of a patient with sacral gctb showing a poor response to combination therapy with arterial embolization and zol , who was subsequently treated with denosumab .
a 32-year - old woman visited a local clinic with a 5-month history of progressive buttock pain and numbness in the bilateral posterior thighs .
the patient had a history of hepatitis b. the physical findings included tenderness in the buttocks and difficulty walking due to persistent buttock pain in the sitting as well as standing positions .
computed tomography ( ct ) scans revealed an inner structure without a septal wall and thinning of the surrounding cortical bone ( fig .
the imaging findings were suggestive of an aggressive bone tumor and gctb was diagnosed by ct - guided bone biopsy ( fig .
the patient was informed on the risks of surgery and recurrence rates , provided informed consent and opted for conservative therapy .
the embolization was performed using gelfoam ( pfizer co. new york , ny , usa ) once a month for 3 months , but there was no improvement of the clinical symptoms after three procedures , and a hypervascular tumor stain was observed .
the response was considered to be poor and intravenous infusion of 4 mg zol was initiated concurrently .
this combination was repeated for 10 months , but the pain did not subside and daily activities were impaired .
in addition , ct scans did not reveal distinct bone sclerosis of the sacral cortex ( fig .
the patient received monthly injections of denosumab 120 mg subcutaneously , in addition to daily doses of calcium 610 mg , vitamin d 400 iu and magnesium 30 mg orally .
the pain had drastically decreased by the third dose of denosumab , and pain on sitting had completely resolved .
ct scans taken 5 and 10 months after the initiation of denosumab revealed gradual appearance of bone sclerosis around the sacrum in the transverse and sagittal planes ( fig .
3 ) . unfortunately , the patient had a history of hepatitis b and developed hepatic impairment . hence , denosumab was discontinued after 12 months and treatment for hepatitis was initiated . at that time , a ct - guided needle biopsy was performed to determine the efficacy of our treatment strategy .
the tissues displayed remodeled bone formation and a partly fibrous stroma , but no functional stromal cell or osteoclast - like giant component was identified ( fig .
the blood levels of tartrate - resistant acid phosphatase 5b ( tracp-5b ) were monitored throughout the course of treatment . during combination therapy with arterial embolization and zol ,
the tracp-5b level was 1,423 mu / dl ( normal range , 120420 mu / dl ) ; by the time denosumab was discontinued , the level had decreased to 233 mu / dl .
two years after treatment discontinuation , the patient remains symptom - free , shows no radiographic progression of the disease and has not required surgery .
written informed consent for the publication of this case report and related images was obtained from the patient .
the standard treatment for gctb is surgery , including adjuvant treatment with liquid nitrogen and ethanol at the time of curettage .
however , the recurrence rate with or without adjuvant therapy , particularly for gctb in the sacral vertebrae , is high
. therefore , practitioners must be cautious when deciding on surgical intervention ( 15 ) . in the present case ,
lin et al ( 7 ) reported that tumors were controlled and symptoms improved in 14 of 18 patients , although long - term follow - up to monitor for recurrence was recommended .
however , the condition did not improve ; therefore , zol was added to improve efficacy .
however , there was no shell formation around the tumor , and angiography revealed a tumor stain .
the tracp-5b levels , which have recently been shown to be effective for monitoring gctb ( 18 ) , began to decrease after the initiation of denosumab and did not increase after discontinuation of treatment .
the tumor did not progress and was deemed stable . the reasons for our observations may be explained as follows : gctb consists of osteoclast - like giant cells and oval mononuclear cells ( stromal cells ) .
osteoclast - like giant cells and their precursor cells express receptor activator of nuclear factor -b ( rank ) , whereas oval mononuclear cells express rank ligand ( rankl ) ( 19 ) , which regulates osteoclast function and plays a role in the formation , function and survival of osteoclasts .
theoretically , bisphosphonates regulate gctb by reducing the number of osteoclasts and inhibiting osteolysis , and they are reportedly effective for the treatment of gctb at sites that are difficult to operate ( 10 ) . for example , a study by lau et al ( 20 ) comparing the antitumor effect of zol ( a bisphosphonate ) with denosumab ( another bisphosphonate ) on gctb stromal cells in vitro demonstrated that zol acts against tumors in a dose - dependent manner . furthermore , denosumab has little impact on cell viability , as it does not directly block the rankl signaling pathway in osteoclast - like giant cells .
by contrast , denosumab was developed as a rankl - targeted antibody in the field of osteoporosis .
unlike traditional bisphosphonates that induce apoptosis of osteoclasts by adsorbing to the bone surface , denosumab inhibits the formation of osteoclasts and impedes their function and survival ( 21 ) .
since denosumab is present in body fluids , it enters the haversian canal independent of body surface area , and it may completely inhibit bone remodeling and improve the porosity of cortical bone and the volume of cancellous bone . as such , denosumab has been proven to act on both cortical and cancellous bone ( 22 ) .
finally , bone destruction in gctb is caused by infiltration of osteoclast - like giant cells into the bone . while zol exerts antitumor effects on osteoclast - like giant cells through its accumulation in the bone ,
therefore , denosumab may act more extensively on tumors . to the best of our knowledge ,
no report has compared the efficacy of zol with that of denosumab in a single patient to date .
however , as there have been no long - term studies of patients with unresectable tumors controlled with denosumab , future researchers may wish to investigate when surgery should be added . in conclusion , we reported a case of a patient responding poorly to combination therapy with arterial embolization and zol , a treatment traditionally considered effective for sacral gctb .
our patient was instead successfully treated with denosumab . to the best of our knowledge ,
this is the first report of a patient who received arterial embolization , zol and denosumab in stages , resulting in a positive clinical response to denosumab .
 giant cell tumor of bone ( gctb ) is commonly treated with surgery ; however , surgery of gctb in the sacrum may be challenging due to the associated risk 
 . a conservative approach may be selective arterial embolization or zoledronic acid ( zol ) treatment ; however , there are currently no studies investigating the efficacy of combining these two treatments . 
 denosumab may also be used ; however , to the best of our knowledge , there are no reports of a stepwise approach for the use of all three treatments in a single patient . 
 we herein present such a case . 
 a 32-year - old woman diagnosed with sacral gctb was treated with selective arterial embolization for 3 months . 
 no improvement was observed , and monthly infusions of zol were added ( administered 2 weeks after each arterial embolization treatment ) . 
 ten months after the initiation of zol , there was still no improvement . 
 the therapy was changed to denosumab 120 mg , injected subcutaneously once a month . by the third dose , 
 the buttock pain had decreased and the patient became ambulatory . at 5 and 10 months , 
 computed tomography scans revealed bone sclerosis gradually appearing around the sacrum . by 1 year 
 , needle biopsy detected no neoplastic cells . 
 at that point , the patient discontinued treatment , as there was hepatic function impairment due to a history of hepatitis b. despite treatment discontinuation , the patient exhibited no further symptoms , there were no signs of progression on radiography , and surgery was not required . 
 our patient experienced treatment failure with selective arterial embolization . 
 the combination of zol with selective arterial embolization also did not improve the patient 's condition . 
 denosumab was found to be superior to both treatments , achieving tumor remission . 
 the patient remains symptom- and disease - free . 
 further studies are required , but our results suggest that patients with unresectable gctb who fail to respond to selective arterial embolization may benefit from denosumab treatment , but not from combination therapy with selective arterial embolization and zol . 
Introduction
Case report
Discussion