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Abstract

Giant cell tumour of the bone (GCTB) has been classically treated surgically. With the advent of denosumab, there is potential to use it as a targeted therapy to downstage the tumour and control its progression. Like all new therapies, the dosage, duration, and long-term effects of treatment can only be determined over the time through numerous trials and errors. The current recommendation of use of the monoclonal antibody is 3–4 months of neoadjuvant denosumab in patients with advanced GCTB for cases who were not candidates for primary curettage initially, and prolonged use for surgically unsalvageable GCTB. The use of Denosumab in the adjuvant setting to prevent recurrence is not established.

Keywords

bone denosumab giant cell tumour neoadjuvant

Introduction

Denosumab, a fully humanised monoclonal antibody to RANK ligand (RANKL) is a new tool in the armamentarium against giant cell tumour of the bone (GCTB) in orthopaedic oncology. It is approved by the Food and Drug Administration (FDA) and European Medical Agency (EMA) for use in conditions such as osteoporosis, bone metastases, and GCTB. In this article we review the current status and questions regarding the use of denosumab in the treatment of GCTB.

What is giant cell tumour of the bone (GCTB)

GCTB is a relatively rare, locally aggressive but benign osteolytic tumour of the bone that commonly affects young adults (patients aged between 30 and 50 years). It accounts for 4–10% of all primary bone tumours.^1
–3 These are usually solitary tumours but can be multifocal in less than 1% of the cases. It has an estimated incidence of 1.3 per million per year.^4,5 Although it is classically a locally aggressive lesion, it can metastasize to the lungs (1–4%) especially in recurrent cases.^6

–9 In the lungs, these tumours are slow-growing and are considered to be ‘benign pulmonary deposits’. These should be assessed cautiously to differentiate them from malignant deposits from giant cell rich sarcomas or giant cell sarcomas. Figure 1 shows a case of a 19 years old lady with GCT distal tibia. The chest radiograph at presentation showed no evidence of metastatic disease at presentation but subsequently on follow up, she develop progressive lung metastasis. Despite this, clinically she remain asymptomatic and currently is being followed up.

Figure 1.

Shows the chest radiograph of a 19 years old patient with GCT of the distal tibia at presentation and follow up.

Radiographically GCTB appears as an eccentric, expansile, lytic lesion with well-defined borders (narrow zone of transition), arising from the metaphysis of long bones and extending into the epiphysis up to the subarticular region on a plain radiograph (Figure 2). On MRI, it typically appears as intermediate to high signal intensity on T2 and low to intermediate intensity on T1-weighted images (Figure 3). Hemosiderin depositions within the tumour gives rise to areas of low signal intensity on gradient-echo sequences.¹⁰ Fluid–fluid levels can be found in 10–14% of the cases due to secondary aneurysmal bone cyst-like changes.^11,12

Figure 2.

Shows an eccentric expansile lytic lesion involving the metaphysis extending into the epiphysis up to the articular surface.

Figure 3.

Shows MRI images of a GCT of the distal radius. It shows low to intermediate signal on T1 and intermediate to high signal on T2 images.

GCTB is usually classified radiologically with the Campanacci system, where Grade I tumours are well contained within the bone with an intact cortex, Grade II tumours are more extensive with cortical erosion and expansion but no break in the cortex, and Grade III tumours have a cortical break and soft tissue extension¹³ (Figure 4).

Figure 4.

Demonstrates the Campanacci grading for GCT of the bone.

Histologically, the cells are composed of osteoclast-like multinucleated giant cells, rounded mononuclear histiocytic cells, and round or ovoid mononuclear stromal cells, which are considered the neoplastic component of the tumour.^14,15 The reactive multinuclear osteoclast-like giant cells express receptor activator of nuclear factor kappa-B (RANK) and the neoplastic mononuclear stromal cells express RANK ligand (RANKL).¹⁶ RANK-RANKL interactions are important in the recruitment of osteoclastic cells from blood-borne mononuclear osteoclast precursor cells that differentiate into multinucleated osteoclast-like giant cells.^13,14,17,18 Recently, some researchers have identified some immunostaining factors (MIB-1, GPX-1, cyclin D1 and β-catenin) that are associated with predilection for GCTB recurrence.^19
–21 This is all still experimental and has the potential for clinical use to determine cases that are more likely to recur. GCTB is different from Giant Cell Rich Malignancies where there is presence of giant cells in the malignant tumours. These tumours are rare and aggressive with 13.4% having nodal metastasis and 32.9% having distant metastasis. The commonest variety of these tumours being the Giant cell rich Osteosarcoma. The 5-year survival is less than 50%.²²

GCTB are commonly treated by extended curettage, which comprises thorough bone curettage followed by use of a high-speed burr and may be augmented with use of local adjuvants such as phenol, liquid nitrogen, and polymethylmethacrylate cement (PMMA).²³ It is debatable if adjuvants help decrease the recurrence rates²⁴ though some studies have documented PMMA helping to lower the risk of local recurrence.²⁵ Wide resection poses the lowest risk of local recurrence as the whole tumour is removed but does increase the morbidity of the surgery and may result in reduced functional outcomes.^13,26
–28 GCTB of the small bones of the foot traditionally known to be more aggressive have be shown to be the same as GCTB of the long bones and worse outcome is mainly due to a combination of delayed presentation, diagnosis and difficult surgery.²⁹

Treatment in complex cases of GCTB and in anatomically challenging sites may also include the additional use of embolization,^30,31 bisphosphonates,^32,33 or denosumab.^34,35 Chemotherapy is not used as it is not effective in the management of GCTB.^36
–38 Moderate dose radiotherapy (40–55 Gy) has also been used in the treatment of unresectable GCTB, and in cases of residual or recurrent disease where surgery is not feasible. However, radiotherapy does carry a risk of malignant transformation.¹³ Figure 5 demonstrates a case of GCT of the sacrum diagnosed at the age of 17 and treated with embolization and radiotherapy. Seven years later, there is no evidence of recurrence of disease.

Figure 5.

Shows the plain radiographs of a 17 years old girl with GCT sacrum treated initially with embolization and radiotherapy. The radiographs are 7 years apart, showing no evidence of recurrence of disease.

Denosumab and GCTB

Denosumab is a fully humanised monoclonal antibody to RANK ligand (RANKL). It inhibits osteoclastic activity by inhibiting RANK-RANKL interaction, which in turn results in reduction in osteoclast-induced bone destruction.^39,40

For GCTB treatment, denosumab is dosed at 120 mg, administered subcutaneously every 28 days with loading doses on days 8 and 15 (in the first month of therapy). This treatment regimen was established in a proof of principle Phase II study.³⁹ Tumour response was confirmed in 86% of the patients tested, where more than 90% of the giant cells were eliminated on histopathological examination and there was no radiographical progression of the lesion. Denosumab showed an improvement in Quality of Life (QOL), good response in patients with inoperable GCTB, and reduced the need for otherwise morbid surgery in a second, larger Phase 2 clinical trial.⁴⁰ Clinically, the patients start experiencing improvement is symptoms such as reduction pain, improvement in neurology (return of bladder and bowel control for GCT sacrum) and then if patient has swelling, the swelling becomes firmer. Radiologically on plain radiographs, the lesion becomes better demarcated by developing a sclerotic neo-cortex and matrix osteosclerosis. F-FDG-PET shows lower activity.⁴¹

How does denosumab help in the treatment of GCTB?

Denosumab causes new bone to form, downgrading a Campanacci Grade III lesion to a lesser grade.^16,42 With an increasing rim of ossified bone on the periphery, intralesional curettage is facilitated in extensive lesions.⁴³ Even in cases that need resection especially in those cases with a large soft tissue component in close proximity to neurovascular structures where there is a potential risk of intra operative injury, the osseous rim which forms after denosumab helps decrease the possibility of injury to these adjacent neurovascular structures. It also facilitates intraoperative manipulation and prevents inadvertent contamination with tumour.

In addition to the benefit of reducing tumour volume, the potential of denosumab in reducing blood loss from intralesional curettage of pelvic GCT is alluded to by Watanabe et al.⁴⁴ Girolami et al. reported a conversion of the neoplastic stromal cells to a fibrous matrix with decreased angiogenesis, which could explain the decreased vascularity of the treated tumours.²⁵

However, some authors noted higher local recurrence rates after curettage in patients treated with neoadjuvant denosumab.^43,45
–47 There is a concern that the rim of new bone that forms with denosumab treatment may contain neoplastic cells that may reactivate once it is stopped. In the Phase 2 clinical trial, denosumab treatment was given around 2 years prior to surgery, and it resulted in a thick layer of new bone formation on the periphery of the tumour, entrapping the neoplastic tissue. Performing definitive surgery much earlier (3–4 months after starting denosumab) to prevent too thick a rim of bone from forming may make complete removal much more feasible. The use of cryotherapy after curettage may penetrate this layer of new bone and help reduce the incidence of local recurrence⁴⁷

Although early reports recommended the use of Denosumab as an adjuvant treatment to minimise the rate of local recurrence,³⁴ current available evidence suggests that it does not reduce the incidence of local recurrence.⁴⁸ However, there are reports of successful use of denosumab in inoperable cases, where its continuous usage causes regression of the lesion³⁵ and prevents disease progression in cases of lung metastasis.^49

–52 Figure 6 are plain radiographs of the chest of a 16 years old girl who presented with GCT of the left distal femur and presentation she had a metastatic deposit over the right lung attach to the pericardium. She was started on denosumab and this mass eventually regress. She is currently in maintenance therapy.

Figure 6.

Shows lung metastasis right lung attach to right pericardium. Patient was started on denosumab and chest radiograph after 12 months show regression of the metastasis.

Sometimes Denosumab can be given in cases of pathological fractures or Campanacci grade 3 lesions with soft tissue extension to solidify the tumour prior to wide resection. Figure 7 is a case of a 73 year old man who presented with a pathological fracture of the left proximal humerus secondary to GCT and was given four doses of denosumab prior to wide resection and endoprosthesis replacement. Figure 8 is a case of GCT of the sacrum. She was given six doses of denosumab to solidify the tumour prior to wide resection.

Figure 7.

73 years old man who presented with pathological fracture of the humerus. Biopsy confirmed the diagnosis of GCT. He was given four doses of Denosumab to solidify the tumour and subsequently an extra articular resection was done with endoprosthesis reconstruction.

Figure 8.

42 years old lady presented with GCT of the S3–5. She was given six doses of denosumab after which she underwent a wide resection.

The current consensus appears to favour the use of denosumab for a shorter duration in a neoadjuvant setting for a maximum of 3–4 months prior to an intralesional procedure.^48,53,54 Longer duration of treatment results in a gum-like layered substance within the tumour cavity, making complete tumour removal by intralesional curettage more difficult, thus leading to a higher local recurrence rate.⁵⁴

How long should we continue denosumab?

A major concern is the high rate of local recurrence after stopping denosumab^55,56 in the absence of adequate surgery. This suggests that denosumab alone does not give rise to complete eradication of the disease. Mak et al.⁵⁵ found that neoplastic stromal cells persisted and continued to proliferate at a slower rate compared to untreated GCTB and Lau et al.⁵⁶ found that denosumab does not cause apoptosis of the stromal cell but merely has an inhibitory effect. Girolami et al.²⁵ also found H3F3A mutation in both pre-treatment and post-treatment surgical specimen of GCTB, supporting the hypothesis that denosumab does not totally eliminate tumour cells. There is currently insufficient data to quantify this risk, but many recurrences may arise within 7–9 months of treatment stoppage.

In cases such as inoperable GCTB or GCTB with lung metastasis which require long-term treatments, ‘drug holidays’ can be used to minimise side effects. This can be monitored with certain biomarkers for bone turnover to determine the duration of the ‘drug holiday’. Denosumab can be restarted once these markers show an increase in bone turnover. Examples of such markers are Urinary N-telopeptide and serum C-telopeptide.³⁹ Another marker such as Tartrate-resistant acid phosphatase 5b, a bone resorption marker secreted by osteoclasts can also be used as it is shown to correlate with osteoclast activity systemically.⁴⁴

Is there a role for post-operative denosumab after curettage?

Whether continuing denosumab post operatively helps to reduce the rate of recurrence in cases undergoing curettage is debatable. In Errani et al.’s series, patients received post-operative denosumab, yet they reported a 60% rate of local recurrence.^57,58 In a Phase 2 Open-Label Trial by Rutkowski et al. many of the 157 patients that underwent surgery received adjuvant denosumab for 6 months after surgery. Local recurrence still occurred in 34% of patients after curettage.

Agarwal et al.³⁴ suggested the use of denosumab 3 monthly as a ‘maintenance’ dose after treatment of extensive spinal disease. Up to now, it is still not yet clear whether alterations in dosing schedule or ‘drug holidays’ may affect the longevity of tumour response.

Denosumab or zoledronic acid – which acts better in GCTB?

Prior to the introduction of denosumab, zoledronic acid was widely used in the management of GCTB. Denosumab and zoledronic acid both inhibit osteoclast differentiation from mononuclear cells containing osteoclast precursors. In addition, zoledronic acid also inhibits osteoclast survival, which is not seen in denosumab treatment.⁵⁹

However, a non-randomised prospective Phase II trial using adjuvant zoledronic acid post-curettage with adjuvants did not show a lower recurrence rate.⁶⁰ The efficacy of zoledronic acid in a neoadjuvant setting has also not been validated. There may be an advantage in local control by using zoledronic acid admixed with artificial bone or PMMA, but it requires further evaluation and standardisation as the reported series are small.^61,62

Are there complications with denosumab?

Reported complications and side effects from denosumab include bone pain, fatigue, headache, nausea (18–25%), hypocalcaemia (3.2%), hypophosphatemia (2.7%), osteonecrosis of the jaw (1–2%), and atypical femoral fractures^39,40,63

Gossai et al. reported critical hypercalcaemia in one patient 5 months after discontinuation of denosumab and it was attributed to rebound osteoclast activity and osteoporotic bone. They advised careful monitoring of electrolyte status after discontinuation of denosumab.⁵¹ Chawla et al.⁴⁰ recently presented data showing the increasing risk of toxicity after 2 years of treatment.

Till date no definitive causal-relationship between malignancy and denosumab has been established. However, concerns have arisen on progression of GCTB to high-grade sarcoma during denosumab therapy.⁶⁴ Mattei et al. reported malignant transformation in 1.8% of their patients. Two of these had previous radiotherapy and in another two patients, it was attributed to sampling error at initial biopsy.³⁵ Gaston et al. reported a case of high-grade sarcoma development during denosumab therapy for recurrent GCTB.⁴³

Whether these occurrences represent a true malignant transformation or a missed diagnosis of primary malignant GCTB due to sampling error at the time of the initial biopsy remains debatable. As the response rate of denosumab in GCTB is very high, it may be prudent to repeat a biopsy in patients who do not show a positive response to denosumab.

Future considerations

The use of denosumab only indirectly affects GCTB, as the neoplastic stromal cells are not directly targeted, thus making it a temporary therapy.^42,65 Targeted therapy directed towards the neoplastic stromal cells should be identified so as to enable systemic therapy to be utilised as definite therapy for GCTB.

Authors opinion

Cases with GCTB ideally should be referred at a tertiary referral centre, so that an accurate diagnosis can be made and medical or surgical intervention can be used appropriately. This too allows the centres to gain as much experience as possible in the medical management of giant cell tumour cell tumour of bone.

Conclusion

Denosumab is not recommended in cases that can easily be primarily treated by curettage or resection. (Figure 9)

Three to four doses of neoadjuvant denosumab (at a dose of 120 mg subcutaneously at day 1, 8, 15 and 29) can be given in patients with advanced GCTB where denosumab can help facilitate the surgical curettage (convert a lesion needing resection to one that could possibly be treated with curettage).

Three or more doses can be given in cases of advance GCT or pathological fractures to solidify the tumours prior to wide resection to decrease the morbidity of surgery.

Long-term denosumab can be used for surgically unsalvageable GCTB. The ideal dose, duration and frequency that balances disease control against the side effects of long-term treatment have yet to be determined.

Figure 9.

Shows the flow chart of the use of denosumab in GCT of the bone.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Vivek Ajit Singh

References

Amanatullah

Clark

Lopez

, et al. Giant cell tumor of bone. Orthopedics 2014; 37: 112–120.

Jagiello-Wieczorek

Pienkowski

Rutkowski

. Denosumab for treating giant cell tumor of bone. Expert Opin Orphan Drugs 2015; 3: 1219–1229.

Thomas

Skubitz

. Giant cell tumor of bone. Curr Opin Oncol 2009; 21: 338–344.

Liede

Bach

Stryker

, et al. Regional variation and challenges in estimating the incidence of giant cell tumor of bone. J Bone Joint Surg Am 2014; 96(23): 1999–2007.

Rockberg

Bach

Amelio

, et al. Incidence trends in the diagnosis of giant cell tumor of bone in Sweden since 1958. J Bone Joint Surg Am 2015; 97(21): 1756–1766.

Fletcher

(ed): WHO classification of tumours of soft tissue and bone. 4th edn. Lyon: IARC Press, 2013.

Athanassou

Bensal

Forsyth

, et al. Giant cell tumor of bone. In: Fletcher

CDM

Bridge

Hogendoorn

PCW

, et al. (eds) WHO classification of tumours of soft tissue and bone. Lyon: IARC Press, 2013, pp. 321–324.

Chan

Adler

Reith

, et al. Risk factors for pulmonary metastases from giant cell tumor of bone. J Bone Joint Surg Am 2015; 97(5): 420–428.

Dominkus

Ruggieri

Bertoni

, et al. Histologically verified lung metastases in benign giant cell tumours – 14 cases from a single institution. Int Orthop 2006; 30(6): 499–504.

10.

Ruka

Rutkowski

Morysiński

, et al. The megavoltage radiation therapy in treatment of patients with advanced or difficult giant cell tumors of bone. Int J Radiat Oncol Biol Phys 2010; 78(2): 494–498.

11.

Murphey

Nomikos

Flemming

, et al. From the archives of AFIP. Imaging of giant cell tumor and giant cell reparative granuloma of bone: radiologic-pathologic correlation. Radiographics 2001; 21(5): 1283–1309.

12.

Chakarun

Forrester

Gottsegen

, et al. Giant cell tumor of bone: review, mimics, and new developments in treatment. Radiographics 2013; 33(1): 197–211.

13.

Campanacci

Baldini

Boriani

, et al. Giant-cell tumor of bone. J Bone Joint Surg Am 1987; 69(1): 106–114.

14.

Hemingway

Taylor

Knowles

, et al. RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. Bone 2011; 48: 938–944.

15.

Tang

. RANK pathway in giant cell tumor of bone: pathogenesis and therapeutic aspects. Tumour Biol 2015; 36: 495–501.

16.

Branstetter

Nelson

Manivel

, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 2012; 18(16): 4415–4424.

17.

Fletcher

Unni

Mertens

. Pathology and genetics of tumours of soft tissue and bone. Lyon: International Agency for Research on Cancer, 2002.

18.

Thomas

. RANKL, denosumab, and giant cell tumor of bone. Curr Opin Oncol 2012; 24(4): 397–403.

19.

Okubo

Saito

Mitomi

, et al. p53 mutations may be involved in malignant transformation of giant cell tumor of bone through interaction with GPX1. Virchows Arch 2013; 463(1): 67–77.

20.

Cheng

Zhang

, et al. Factors affecting the recurrence of giant cell Tumor of bone after surgery: a clinicopathological study of 80 cases from a single center. Cell Physiol Biochem 2015; 36(5): 1961–1970.

21.

Lujic

Sopta

Kovacevic

, et al. Recurrence of giant cell tumour of bone: role of p53, cyclin D1, beta-catenin and Ki67. Int Orthop 2016; 40(11): 2393–2399.

22.

Gore

. Giant cell rich malignancies: a meta-analysis. Ann Med Health Sci Res 2018; 8(4): 225–232.

23.

Horstmann

Hettwer

Petersen

. Treatment of benign and borderline bone tumors with combined curettage and bone defect reconstruction. J Orthop Surg 2018; 26(3): 2309499018774929.

24.

Algawahmed

Turcotte

Farrokhyar

, et al. High-speed burring with and without the use of surgical adjuvants in the intralesional management of giant cell tumor of bone: a systematic review and meta-analysis. Sarcoma 2010; 2010: 586090.

25.

Girolami

Mancini

Simoni

, et al. Denosumab treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series. J Clin Pathol 2016; 69(3): 240–247.

26.

Klenke

Wenger

Inwards

, et al. Giant cell tumor of bone: risk factors for recurrence. Clin Orthop Relat Res 2011; 469(2): 591–599.

27.

Errani

Ruggieri

Asenzio

, et al. Giant cell tumor of the extremity: a review of 349 cases from a single institution. Cancer Treat Rev 2010; 36(1): 1–7.

28.

Kivioja

Blomqvist

Hietaniemi

, et al. Cement is recommended in intralesional surgery of giant cell tumors: a scandinavian sarcoma group study of 294 patients followed for a median time of 5 years. Acta Orthop 2008; 79(1): 86–93.

29.

Wang

. Giant cell tumor of the small bones of the foot. J Orthop Surg 2018; 26: 1–5. DOI: 10.1177/2309499018801168.

30.

Balke

Henrichs

Gosheger

, et al. Giant cell tumors of the axial skeleton. Sarcoma 2012; 2012: 410973 (Epub ahead of print 8February 2012).

31.

Zhou

Yang

Chen

, et al. Surgical treatment of giant cell tumors of the sacrum and spine combined with pre-operative transarterial embolization. Oncol Lett 2013; 6(1): 185–190.

32.

Cornelis

Truchetet

Amoretti

, et al. Bisphosphonate therapy for unresectable symptomatic benign bone tumors: a long-term prospective study of tolerance and efficacy. Bone 2014; 58: 11–16.

33.

Huang

, et al. Factors affecting prognosis of patients with giant cell tumors of the mobile spine: retrospective analysis of 102 patients in a single center. Ann Surg Oncol 2013; 20(3): 804–810.

34.

Agarwal

Larsen

Buadu

, et al. Denosumab chemotherapy for recurrent giant-cell tumor of bone: a case report of neoadjuvant use enabling complete surgical resection. Case Rep Oncol Med 2013; 2013: 496351 (Epub ahead of print 30 July 2013).

35.

Mattei

Ramos

Rehman

, et al. Sustained long-term complete regression of a giant cell tumor of the spine after treatment with Denosumab. Spine J 2014; 14(7): 15–21.

36.

Stewart

Belanger

Benjamin

. Prolonged disease-free survival following surgical debulking and high-dose cisplatin/doxorubicin in a patient with bulky metastases from giant cell tumor of bone refractory to “standard” chemotherapy. Am J Clin Oncol 1995; 18(2): 144–148.

37.

Yamamoto

Fukushima

Sakamoto

, et al. Giant cell tumor of the sphenoid bone: long-term follow-up of two cases after chemotherapy. Surg Neurol 1998; 49(5): 547–552.

38.

Mella

Dahl

Bang

, et al. Chemotherapy of a malignant, metastasizing giant-cell tumor of bone: report of an unusual case and the response to combination chemotherapy. Cancer 1982; 50(2): 207–211.

39.

Thomas

Henshaw

Skubitz

, et al. Denosumab in patients with giant cell tumour of bone: an open-label phase 2 study. Lancet Oncol 2010; 11: 275–280.

40.

Chawla

Henshaw

Seeger

, et al. 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.

41.

Van Langevelde

McCarthy

. Radiological findings of denosumab treatment for giant cell tumours of bone. Skeletal Radiol 2020; 49: 1345–1358.

42.

Hakozaki

Tajino

Yamada

, et al. Radiological and pathological characteristics of giant cell tumor of bone treated with denosumab. Diagn Pathol 2014; 9: 111.

43.

Gaston

Bhumbra

Watanuki

, et al.

Does the addition of cement improve the rate of local recurrence after curettage of giant cell tumours in bone?

J Bone Joint Surg Br 2011; 93(12): 1665–1669.

44.

Watanabe

Matsumoto

Shimoji

, et al. Early evaluation of the therapeutic effect of denosumab on tartrate-resistant acid phosphatase 5b expression in a giant cell tumor of bone: a case report. BMC Res Notes 2014; 7: 608.

45.

Prosser

Baloch

Tillman

, et al.

Does curettage without adjuvant therapy provide low recurrence rates in giant-cell tumors of bone?

Clin Orthop Relat Res 2005; 435: 211–218.

46.

Zhang

, et al. Short-term preoperative denosumab with surgery in unresectable or recurrent giant cell tumor of bone. Orthop Surg 2019; 11(6): 1101–1108.

47.

Scoccianti

Totti

Scorianz

, et al.

Preoperative denosumab with curettage and cryotherapy in giant cell tumor of bone: Is there an increased risk of local recurrence?

Clin Orthop Relat Res 2018; 476(9): 1783–1790.

48.

Muller

Beltrami

Scoccianti

, et al. Risks and benefits of combining denosumab and surgery in giant cell tumor of bone – a case series. World J Surg Oncol 2016; 14(1): 281.

49.

Karras

Polgreen

Ogilvie

, et al. Denosumab treatment of metastatic giant-cell tumor of bone in a 10-year-old girl. J Clin Oncol 2013; 31(12): 200–202.

50.

Demirsoy

Karadogan

Selek

, et al. Golden bullet-denosumab: early rapid response of metastatic giant cell tumor of the bone. J Pediatr Hematol Oncol 2014; 36(2): 156–158.

51.

Gossai

Hilgers

Polgreen

, et al. Critical hypercalcemia following discontinuation of denosumab therapy for metastatic giant cell tumor of bone. Pediatr Blood Cancer 2015; 62(6): 1078–1080.

52.

Ulas

Bulent Akinci

Silay

, et al. Denosumab: excellent response of metastatic giant cell tumor of the bone. J BUON 2015; 20(2): 666–667.

53.

Gaston

Grimer

Parry

, et al. Current status and unanswered questions on the use of denosumab in giant cell tumor of bone. Clin Sarcoma Res 2016; 6(1): 15.

54.

Gerrand

Athanasou

Brennan

, et al. UK guidelines for the management of bone sarcomas. Clin Sarcoma Res 2016; 6: 7.

55.

Mak

Evaniew

Popovic

, et al. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant Denosumab. J Bone Joint Surg Am 2014; 96(15): 127.

56.

Lau

Huang

Wong

, et al. 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(6): 439–449.

57.

Errani

Tsukamoto

Leone

, et al. Denosumab may increase the risk of local recurrence in patients with giant-cell tumor of bone treated with curettage. J Bone Joint Surg Am 2018; 100(6): 496–504.

58.

Rutkowski

Feng

Jandial

, et al. Surgical outcomes and recurrence following neoadjuvant denosumab treatment in patients with resectable giant cell tumor of bone (GCTB): results of a phase 2 open-label trial. Connective Tissue Oncology Society, 2017; poster 314.

59.

Shibuya

Takami

Miyamoto

, et al. In vitro study of the effects of denosumab on giant cell tumor of bone: comparison with zoledronic acid. Pathol Oncol Res 2019; 25(1): 409–419.

60.

Gouin

Rochwerger

, et al. Adjuvant treatment with zoledronic acid after extensive curettage for giant cell tumours of bone. Eur J Cancer 2014; 50(14): 2425–2431.

61.

Nishisho

Hanaoka

Miyagi

, et al. Local administration of zoledronic acid for giant cell tumor of bone. Orthopedics 2015; 38(1): 25–30.

62.

Chen

, et al. Zoledronic acid-loaded bone cement as a local adjuvant therapy for giant cell tumor of the sacrum after intralesional curettage. Eur Spine J 2015; 24(10): 2182–2188.

63.

Rutkowski

Ferrari

Grimer

, et al. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann Surg Oncol 2015; 22(9): 2860–2868.

64.

Aponte-Tinao

Piuzzi

Roitman

, et al. 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(9): 3050–3055.

65.

Matcuk

Jr Patel

Schein

, et al. Giant cell tumor: rapid recurrence after cessation of long-term denosumab therapy. Skelet Radiol 2015; 44(7): 1027–1031.

The current standing on the use of denosumab in giant cell tumour of the bone

Abstract

Keywords

Introduction

What is giant cell tumour of the bone (GCTB)

Denosumab and GCTB

How does denosumab help in the treatment of GCTB?

How long should we continue denosumab?

Is there a role for post-operative denosumab after curettage?

Denosumab or zoledronic acid – which acts better in GCTB?

Are there complications with denosumab?

Future considerations

Authors opinion

Conclusion

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References