Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor that mainly affects the long bones . Their occurrence is most frequent in patients between 30 and 40 years old . Although a large part of its morbidity is derived from local complications, like pain, joint involvement and pathological fractures, the tumors do have rare metastatic potential . GCTB consists of reactive osteoclast-like giant cells expressing receptor activator of nuclear factor kappa-B (RANK) , mononuclear osteoclast precursor cells and spindle-shaped cells expressing RANK-ligand, which constitute the neoplastic cell population . RANK signaling promotes the generation of multinuclear osteoclast, resulting in bone resorption [5–7].
Treatment of GCTB mainly consists of surgery, either en-bloc resection or curettage with or without local adjuvants like phenol, liquid nitrogen or polymethylmethacrylate (PMMA) [8–12]. Currently, the biggest challenge in GCTB management is the recurrence rate after surgery, which has been described as high as 19–50% after curettage alone [8–11,13,14]. The majority of recurrences after primary intralesional surgery are seen in so-called high-risk GCTB. This group includes tumors with extension into surrounding soft tissue, pathologic fracture, absence of local adjuvant therapy after primary curettage, recurrent tumors and localization in the spine or sacrum [14,15].
Alternatively, systemic treatment with bisphosphonates was explored on a limited scale before the introduction of denosumab. Two small prospective trials investigated the effects of adjuvant treatment with bisphosphonates (alendronate and zoledronic acid) after intralesional curettage. Recurrence rates were 0 and 15%, respectively, after an average follow-up of 28 and 63.6 months [16,17]. The results of a small phase II, randomized study with adjuvant zoledronic acid vs. placebo in high-risk GCTB patients (NCT00889590) was thus far only presented in abstract form .
Denosumab is a human monoclonal IgG2 antibody derived from mammalian cell lines that inhibits activation and differentiation of osteoclast-like giant cells and consequent osteolytic damage by binding RANK-ligand [4,19]. Denosumab was approved by the U.S. Food and Drug Administration (FDA) in 2013 and European Medicines Agency (EMA) in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. This approval was granted after publication of the results of two phase II trials showing an objective and lasting response in this patient group [20,21]. The first trial resulted in an 86% (30/35) objective response rate, defined as elimination of osteoclast-like giant cells on histology or no radiological progression . The second larger study showed no disease progression in 69% of surgically unsalvageable patients after median 13 months of treatment, and of 100 patients with salvageable GCTB 74 needed no surgery and 16/26 less morbid surgery than previously scheduled .
The introduction of denosumab has changed the treatment landscape of GCTB drastically. However, the best use of this new systemic treatment modality is currently subject of discussion. The scope of this article is to discuss the current challenges of GCTB treatment with denosumab and review recent publications and new insights on this subject. Denosumab treatment of giant cell-rich tumors of bone will be highlighted as well.
CURRENT CHALLENGES OF DENOSUMAB IN GIANT-CELL TUMOUR OF BONE
Neoadjuvant treatment with denosumab
Prospective trials have investigated the use of denosumab in the neoadjuvant setting or as definitive treatment for tumors that are considered unresectable [20–24]. The majority of unresectable GCTB are recurrent lesions or lesions located in the axial skeleton, such as the sacrum or posterior part of the spine, where resection often causes unacceptable nerve damage. Rutkowski et al. reported on successful downstaging of unresectable tumors in 222 patients from the largest phase II trial, either resulting in less morbid procedures than planned, like native joint preservation (24/25 patients, 96%) and conversion of en-bloc resection to curettage (39/85, 46%), or avoidance of high-morbid procedures like hemipelvectomy (8/10, 80%) or amputation (32/40, 80%) . During a median follow-up of 13 months, 15% recurrences were seen after (mostly intralesional) surgery , which is comparable to recurrence rates in literature [8,10,11,14,15]. Many of these patients received additional adjuvant denosumab therapy for 6 months; however, this was not randomized, so this does not answer the question whether adjuvant denosumab is useful .
Some recent literature suggests that neoadjuvant treatment followed by curettage might lead to higher recurrence rates [26▪,27▪▪,28▪]. This could be explained by the transformation of the original soft tissue tumor matrix to a more osseous and fibrotic mass [29–31], which could make it more difficult to distinguish and mechanically remove the tumor from adjacent bone and to perform an optimal intralesional curettage. Neoplastic cells can easily be left behind in the curettage space, increasing the risk of recurrence .
On the other hand, it is reported that denosumab facilitates en-bloc resection of GCTB, because of decreased vascularity, leading to less perioperative blood loss [29,33]. The formation of a sclerotic rim of bone around the lesion facilitates resection, especially in case of soft tissue involvement [30,31,34,35].
Additional data on recurrences after neoadjuvant treatment is available from retrospective series. In a series from Rutkowski, 89 patients with advanced GCTB were treated with neoadjuvant denosumab. Local recurrence rate was 21% (7.7% after wide excision and 32% after curettage) [36▪▪]. Urakawa et al. reported recurrence rates of 28.6% (6/21 patients), 22.2% (2/9 patients) and 0% (0/10 patients) after neoadjuvant, adjuvant and neoadjuvant plus adjuvant denosumab, versus 21.5% (34/158 patients) in a nondenosumab-treated group [27▪▪]. In this report, a higher cumulative dose of preoperative denosumab was associated with lower relapse rates [27▪▪]. Smaller series have shown a wide range of recurrence rates ranging from 8% to as high as 67% [31,35,37,38].
In a series by Errani, neoadjuvant denosumab treatment was a risk factor for local recurrence (P < 0.0001), based on 25 patient treated with denosumab and curettage. Median follow-up was 42.1 months, and recurrence rate was 60% (15/25 patients), versus 16% (36/222 patients) in the nondenosumab-treated group [26▪]. Patients in the denosumab group did have more disease recurrences (P < 0.0001), less adjuvant treatment with phenol (<0.0001) and higher Campanacci stage (P = 0.053), which might have led to selection bias in favor of the group that underwent curettage alone.
Definitive treatment with denosumab
In the setting of definitive or palliative treatment, the benefits of denosumab are clear: halt of tumor progression and symptom improvement [20,21]. The main unanswered questions involve optimal treatment duration versus cumulative toxicity. In the largest phase II trial published by Chawla et al., patients were treated for up to 13 months with acceptable toxicity and sustained response to denosumab. Palmerini evaluated the long-term toxicity in a retrospective series in which 97 patients were treated for a median of 12 months (range 6–45 months). Overall, six patients (6%) developed ONJ, and patients on prolonged treatment developed mild peripheral neuropathy (6/54, 54%), skin rash (5/54, 9%), hypophosphatemia (2/54, 4%) and atypical femoral fracture (2/54, 4%) . More data on toxicity can be derived from the osteoporotic patient population in which patients are treated with denosumab for up to 2 years . Information on longer term toxicity is not yet available at this moment. Main safety issues of concern with longer term treatment are cumulative dose-dependent osteonecrosis of the jaw (ONJ) and atypical femoral fractures [41,42].
Relapse after cessation of denosumab is a major concern. Especially as histological evaluation of surgical specimens after denosumab treatment only show disappearance of osteoclast-like giant cells, and no apoptosis of the stromal cell population [43,44,45▪,46]. Girolami et al. published on the persistent presence of the H3F3A mutation in surgical specimens, further supporting the persistence of the neoplastic cell population . From the osteoporotic patient population, we have learned that the positive effects of denosumab on bone mineral density disappear within several months after discontinuation of treatment, as denosumab is not incorporated into the bone matrix, in contrast to bisphosphonates for example .
Reintroduction of denosumab after recurrence is a strategy that has been applied, nonetheless this does not solve above-mentioned toxicity issues. Reducing dose density in maintenance treatment could be a good alternative to complete withdrawal of denosumab. This strategy has been described in case reports , and will be further investigated in a prospective trial. The EORTC-REDUCE trial, which is now in set-up, is a multicenter phase II trial investigating reduced dose density of denosumab as maintenance therapy for unresectable GCTB (http://clinicaltrials.gov,NCT03620149). Denosumab will be administered at intervals of 12 weeks until progression or unacceptable toxicity occurs, starting after 1 year of initial standard treatment at 4-week intervals. The aim is to reduce the cumulative dose-dependent toxicity while maintaining efficacy. A similar trial in the United States is being discussed.
In rare cases, transformation of benign GCTB to a malignant bone tumor like osteosarcoma has been described . This can be a consequence of dedifferentiation of the tumor because of prior radiation therapy, misdiagnosis or malignant transformation. A handful of case reports on malignant transformation after denosumab therapy have been published [50–52]. However, the phase II trials by Chawla et al. and Thomas et al. reported secondary malignant transformation in only 1 of 282 versus 1 out of 37 patients in total. Different theories on the mechanism by which denosumab could increase the risk of malignant transformation have been postulated. Inhibition of RANK ligand could increase susceptibility to oncogenes, and affect T-cell and B-cell differentiation and dendritic cell survival and cause immunosuppression leading to new malignancies . We would suggest caution is warranted for the development of malignancy in GCTB in general, this is not specific for denosumab-treated cases. A denosumab nonresponding GCTB should, therefore, always be re-biopsied.
DENOSUMAB IN OTHER GIANT CELL-RICH LESIONS
Giant cell-rich tumors of bone are a group of rare bone tumors that harbour different clinical and histological features, but are all characterized by the presence of osteoclast-like giant cells . This group includes aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG) amongst others. Resection or curretage is usually the approach in this group of tumors if and when they cause unacceptable morbidity [54,55].
As the histological presence of osteoclastic giant cells and expression of RANK/RANKL is a feature that GCTB and other giant cell-rich tumors have in common , it is hypothesized that giant cell-rich tumors show the same reponse to denosumab as previously seen in classical GCTB (see below).
Aneurysmal bone cysts
ABC are rare cystic lesions of bone typically found in the long bones or vertebral bodies, accounting for approximately 9.1% of benign bone tumors with an incidence of 0.14 per 100 000 [57,58▪]. The cysts contain fibroblasts, osteoclast-type giant cells and reactive woven bone, and are most frequently seen in the first two decades of life [57,59]. ABC can present as a primary bone lesion (in about 70% of cases) or as a secondary lesion as a consequence of a reactive process to a preexisting osseous lesion (30%).
Surgery is the current mainstay of treatment for ABC, for example, curretage, resection, embolization. En-bloc resection is the treatment modality with the lowest recurrence rate, though is associated with the high morbidity because of the loss of bone and need for reconstructive surgery. Curretage usually involves local adjuvant therapies, such as sclerotherapy or cryotherapy to lower the risk of recurrence, which has been described as high as 31% [57,60]. The current role of other, nonsurgical treatments of ABC-like radiotherapy  or bisphosphonates  is limited.
Increasing experience with the use of denosumab in patients with ABC is derived from a number of published case series and case reports. Kurucu et al. described nine pediatric patients with ABC treated with denosumab 70 mg/m2 monthly for a median of 12 (range 6–14) months. Within 3 months, all patients experienced reduction in pain and volume reduction of tumors radiologically ranging from 18 to 82% [58▪]. Two cases of rebound hypercalcemia because of increased osteoclast activity were seen after cessation of treatment.
Another case series by Palmerini et al.[61▪] of nine patients treated with 120 mg denosumab monthly with a median of eight (range 3–61) injections, showed replacement of the cystic formations with solid, bone-like tissue by computed tomography as well as pain relief in all treated patients. No significant side effects of denosumab were seen in these cases, apart from asymptomatic hypocalcemia . Several other case reports on patients with sacral ABC presented comparable results [62–69].
Central giant cell granuloma
CGCG is another giant cell-rich benign bone tumor, and is believed not to be a true neoplasm, but the result of a local reparative reaction [55,70]. CGCG are rare with an estimated incidence of 1.1 per million with most patients aged 10–25 years old [55,71]. When multiple lesions are present, the condition is often associated with an underlying syndrome, such as Noonan syndrome or neurofibromatosis type 1, or cherubism [72,73].
A differentiation can be made between aggressive and indolent lesions based on clinical and radiological findings. CGCG usually present as a slow-growing, painless swelling, mostly affecting the jaw bones . In aggressive lesions, pain, paresthesia, rapid growth and cortical perforation can be seen, and these lesions are generally bigger and associated with higher postsurgical recurrence rates . Histologically these aggressive forms of CGCG show a higer percentage of giant cells within the cellular fibroblastic stroma than is typically seen in CGCG .
Surgical procedures including enucleation and curettage are still the most frequently used therapy for GCT. En-bloc resection often leads to unacceptable loss of function and poorer esthetic results. Recurrence rates after curettage are high, ranging from 11 to 49% and up to 72% in aggressive lesions . Several alternative treatments have been suggested in the literature, such as intralesional corticosteroid injection, systemic calcitonin, interferon alpha and antibone resorption agents like bisphosphonates and also denosumab [55,76▪].
Several case series and reports describing cases of patients with CGCG treated with denosumab have been published to date [76▪,77–81,82▪]. Most of these cases were CGCG of the jaw, one adult female presented with a CGCG of the lumbar spine . All patients were treated with denosumab injections 120 mg subcutaneously monthly, either as an alternative to surgery or if disease had recurred after initial surgery. In all cases, ossification of CGCG lesions was described, and in some regression. Several responses were confirmed histologically with a repeat biopsy that did not show any residual osteoclast-like giant cells or granular tissue [77,78,81,82▪]. All symptomatic patients reported improvement of pain [76▪,78,79,81,82▪]. Follow-up was limited in most reports, the recurrence rate after discontinuation of denosumab is, therefore, still unclear.
A European phase II trial is currently opened for recruitment to assess the use of denosumab in giant cell-rich tumors of bone. Patients with ABC, CGCG and other nonmalignant giant cell-rich lesions like will be treated with denosumab 120 mg once monthly, either as definitive treatment for unresectable disease or as neoadjuvant treatment until surgery. Primary endpoint for salvageable lesions is surgical outcome, and for unresectable disease a combined endpoint including radiological response, clinical disease assessment and patient-reported outcomes. Translational research will be performed on tumor material including evaluation of USP6 rearrangement and proportion of patients with pathological response for patients undergoing surgery (http://clinicaltrials.gov,NCT03605199).
In conclusion, the available evidence supports the use of neoadjuvant denosumab for downstaging high-risk GTCB to facilitate less-morbid surgical procedures or avoid surgery altogether. En-bloc resection of GCTB, especially in the case of soft-tissue involvement, can be facilitated by a neoadjuvant denosumab regime. There is no confirmation of improved local control postsurgery, but more importantly no increase of recurrence rates has been confirmed either. Different publications suggest to limit the neoadjuvant treatment time to 3–4 months in order to avoid excessive new bone formation and fibrosis and allowing surgeons to perform an optimal curettage [32,35,36▪▪]. Longer follow-up information from prospective trials regarding recurrence rates is pending, and could provide more insight. Further trials on the addition of adjuvant treatment in this setting are awaited as well.
In the palliative setting, an optimal balance between treatment duration and control of cumulative toxicity is currently being studied. Further studies on maintenance strategies with reduced dose levels and intervals are awaited.
For the related group of giant cell-rich tumors of bone, the place of denosumab is still up for further investigation, but given reported case series and the successes in GCTB, this could be still a promising treatment option for selected patients with advanced disease.
Financial support and sponsorship
Conflicts of interest
The author's institution LUMC has received research grants from Amgen.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Athanasou N, Bansal M, Forsyth R. Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, et al. Giant cell tumour of bone. WHO classification of tumours in soft tissue and bone International Agency for Research on Cancer (IARC), 4th ed.Lyon: 2013.
2. Liede A, Bach BA, Stryker S, et al. Regional variation and challenges in estimating the incidence of giant cell tumor of bone
. J Bone Joint Surg Am 2014; 96:1999–2007.
3. Forsyth RG, De Boeck G, Baelde JJ, et al. CD33+ CD14- phenotype is characteristic of multinuclear osteoclast-like cells in giant cell tumor of bone
. J Bone Miner Res 2009; 24:70–77.
4. Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab
induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 2012; 18:4415–4424.
5. Atkins GJ, Kostakis P, Vincent C, et al. RANK Expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. J Bone Miner Res 2006; 21:1339–1349.
6. Lindeman JH, Hanemaaijer R, Mulder A, et al. Cathepsin K is the principal protease in giant cell tumor of bone
. Am J Pathol 2004; 165:593–600.
7. Maggiani F, Forsyth R, Hogendoorn PC, et al. The immunophenotype of osteoclasts and macrophage polykaryons. J Clin Pathol 2011; 64:701–705.
8. Arbeitsgemeinschaft K, Becker WT, Dohle J, et al. Local recurrence of giant cell tumor of bone
after intralesional treatment with and without adjuvant therapy. J Bone Joint Surg Am 2008; 90:1060–1067.
9. Algawahmed H, Turcotte R, Farrokhyar F, Ghert M. 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: pii: 586090.
10. Balke M, Schremper L, Gebert C, et al. Giant cell tumor of bone
: treatment and outcome of 214 cases. J Cancer Res Clin Oncol 2008; 134:969–978.
11. Kivioja AH, Blomqvist C, Hietaniemi K, 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; 79:86–93.
12. van der Heijden L, Dijkstra PD, van de Sande MA, et al. The clinical approach toward giant cell tumor of bone
. Oncologist 2014; 19:550–561.
13. Gao ZH, Yin JQ, Xie XB, et al. Local control of giant cell tumors of the long bone after aggressive curettage with and without bone cement. BMC Musculoskelet Disord 2014; 15:330.
14. Klenke FM, Wenger DE, Inwards CY, et al. Giant cell tumor of bone
: risk factors for recurrence. Clin Orthop Relat Res 2011; 469:591–599.
15. van der Heijden L, van de Sande MA, Dijkstra PD. Soft tissue extension increases the risk of local recurrence after curettage with adjuvants for giant-cell tumor of the long bones. Acta Orthop 2012; 83:401–405.
16. Gouin F, Rochwerger AR, Di Marco A, et al. Adjuvant treatment with zoledronic acid after extensive curettage for giant cell tumours of bone. Eur J Cancer 2014; 50:2425–2431.
17. Yu X, Xu M, Xu S, Su Q. Clinical outcomes of giant cell tumor of bone
treated with bone cement filling and internal fixation, and oral bisphosphonates. Oncol Lett 2013; 5:447–451.
18. Heijden Lvd, Dijkstra PDS, Jutte FPC. Adjuvant zoledronic acid in high-risk giant cell tumor of bone
– preliminary results of a randomized phase II study. CTOS; 2016.
19. Kostenuik PJ, Nguyen HQ, McCabe J, et al. Denosumab
, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 2009; 24:182–195.
20. Chawla S, Henshaw R, Seeger L, 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.
21. Thomas D, Henshaw R, Skubitz K, et al. Denosumab
in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010; 11:275–280.
22. Ueda T, Morioka H, Nishida Y, et al. Objective tumor response to denosumab
in patients with giant cell tumor of bone
: a multicenter phase II trial. Ann Oncol 2015; 26:2149–2154.
23. Traub F, Singh J, Dickson BC, et al. Efficacy of denosumab
in joint preservation for patients with giant cell tumour of the bone. Eur J Cancer 2016; 59:1–12.
24. Deveci MA, Paydas S, Gonlusen G, et al. Clinical and pathological results of denosumab
treatment for giant cell tumors of bone: prospective study of 14 cases. Acta Orthop Traumatol Turc 2017; 51:1–6.
25. Rutkowski P, Ferrari S, Grimer RJ, 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; 22:2860–2868.
26▪. Errani C, Tsukamoto S, Leone G, 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; 100:496–504.
Large European retrospective study on the effecacy of denosumab in advanced and unresectable GCTB from the six largest European referral centers.
27▪▪. Urakawa H, Yonemoto T, Matsumoto S, et al. Clinical outcome of primary giant cell tumor of bone
after curettage with or without perioperative denosumab
in Japan: from a questionnaire for JCOG 1610 study. World J Surg Oncol 2018; 16:160.
Extensive Japanese retrospective study on the effects of peri-operative denosumab in advanced and unresectable GCTB.
28▪. Medellin MR, Fujiwara T, Tillman RM, et al. Prognostic factors for local recurrence in extremity-located giant cell tumours of bone with pathological fracture. Bone Joint J 2018; 100-B:1626–1632.
Important artile on the prognostic factors for recurrence in patients with pathological fractures in GCTB.
29. Girolami I, Mancini I, Simoni A, et al. Denosumab
treated giant cell tumour of bone: a morphological, immunohistochemical and molecular analysis of a series. J Clin Pathol 2016; 69:240–247.
30. Gaston CL, Grimer RJ, Parry M, et al. Current status and unanswered questions on the use of Denosumab
in giant cell tumor of bone
. Clin Sarcoma Res 2016; 6:15.
31. Muller DA, Beltrami G, Scoccianti G, et al. Risks and benefits of combining denosumab
and surgery in giant cell tumor of bone
-a case series. World J Surg Oncol 2016; 14:281.
32. van der Heijden L, Dijkstra PDS, Blay JY, Gelderblom H. Giant cell tumour of bone in the denosumab
era. Eur J Cancer 2017; 77:75–83.
33. Yang Y, Li Y, Liu W, et al. A nonrandomized controlled study of sacral giant cell tumors with preoperative treatment of denosumab
. Medicine (Baltimore) 2018; 97:e13139.
34. Hakozaki M, Tajino T, Yamada H, et al. Radiological and pathological characteristics of giant cell tumor of bone
treated with denosumab
. Diagn Pathol 2014; 9:111.
35. Borkowska A, Goryn T, Pienkowski A, et al. Denosumab
treatment of inoperable or locally advanced giant cell tumor of bone
. Oncol Lett 2016; 12:4312–4318.
36▪▪. Rutkowski P, Gaston L, Borkowska A, et al. Denosumab
treatment of inoperable or locally advanced giant cell tumor of bone
- multicenter analysis outside clinical trial. Eur J Surg Oncol 2018; 44:1384–1390.
Important retrospective study on the efficacy of denosumab in advanced and unresectable GCTB from six largest European referral centers.
37. Boye K, Jebsen NL, Zaikova O, et al. Denosumab
in patients with giant-cell tumor of bone in Norway: results from a nationwide cohort. Acta Oncol 2017; 56:479–483.
38. Fedenko AA, Tararykova A. Neoadjuvant denosumab
for the treatment of resectable giant cell tumor of bone
: first results of Russian multicenter study. J Clin Oncol 2018; 36:15.
39. Palmerini E, Chawla NS, Ferrari S, et al. Denosumab
in advanced/unresectable giant-cell tumour of bone (GCTB): for how long? Eur J Cancer 2017; 76:118–124.
40. Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term denosumab
therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer 2016; 24:447–455.
41. Uday S, Gaston CL, Rogers L, et al. Osteonecrosis of the jaw and rebound hypercalcemia in young people treated with denosumab
for giant cell tumor of bone
. J Clin Endocrinol Metab 2018; 103:596–603.
42. Chawla NS, Sudan M, Syed I, et al. Long-term treatment of giant cell tumors of bone (GCTB) with denosumab
: a two institutions 8-year experience. J Clin Oncol 2016; [Conference].
43. Lau CP, Huang L, Wong KC, Kumta SM. Comparison of the antitumor effects of denosumab
and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone
. Connect Tissue Res 2013; 54:439–449.
44. Mak IW, Evaniew N, Popovic S, 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:e127.
45▪. Shibuya I, Takami M, Miyamoto A, et al. In vitro study of the effects of denosumab
on giant cell tumor of bone
: comparison with zoledronic acid. Pathol Oncol Res 2017; 25:409–419.
Seminal preclinical study on the in-vitro effects of denosumab versus zoledronic acid on osteoclast differentiation, survival and bone resorption in a GCTB cell-line.
46. van der Heijden L, van de Sande MA, Hogendoorn PC, et al. Neoadjuvant denosumab
for extensive giant cell tumor in os ischium: a case report. Acta Orthop 2015; 86:393–395.
47. Tsourdi E, Langdahl B, Cohen-Solal M, et al. Discontinuation of denosumab
therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 2017; 105:11–17.
48. Agarwal A, Larsen BT, Buadu LD, 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.
49. Lopez-Pousa A, Martin Broto J, Garrido T, Vazquez J. Giant cell tumour of bone: new treatments in development. Clin Transl Oncol 2015; 17:419–430.
50. Tsukamoto S, Righi A, Vanel D, et al. Development of high-grade osteosarcoma in a patient with recurrent giant cell tumor of the ischium while receiving treatment with denosumab
. Jpn J Clin Oncol 2017; 47:1090–1096.
51. Broehm CJ, Garbrecht EL, Wood J, Bocklage T. Two cases of sarcoma arising in giant cell tumor of bone
treated with denosumab
. Case Rep Med 2015; 2015:767198.
52. 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.
53. Flanagan AM, Tirabosco R, Gikas PD. D H. Osteoclast-rich lesions of bone: a clinical and molecular overview. Bone cancer 2nd ed.MA, USA: Academic Press; 2015. 257–272.
54. Park HY, Yang SK, Sheppard WL, et al. Current management of aneurysmal bone cysts
. Curr Rev Musculoskelet Med 2016; 9:435–444.
55. de Lange J, van den Akker HP, van den Berg H. Central giant cell granuloma of the jaw
: a review of the literature with emphasis on therapy options. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 104:603–615.
56. Won KY, Kalil RK, Kim YW, Park YK. RANK signalling in bone lesions with osteoclast-like giant cells. Pathology 2011; 43:318–321.
57. Hakim DN, Pelly T, Kulendran M, Caris JA. Benign tumours of the bone: a review. J Bone Oncol 2015; 4:37–41.
58▪. Kurucu N, Akyuz C, Ergen FB, et al. Denosumab
treatment in aneurysmal bone cyst: evaluation of nine cases. Pediatr Blood Cancer 2018; 65:4.
Large retrospective series on the use of denosumab in advanced or recurrent ABC.
59. Cottalorda J, Bourelle S. Current treatments of primary aneurysmal bone cysts
. J Pediatr Orthop B 2006; 15:155–167.
60. Rosenberg AE, Nielsen GP. Giant cell containing lesions of bone and their differential diagnosis. Curr Diagn Pathol 2001; 7:235.
61▪. Palmerini E, Ruggieri P, Angelini A, et al. Denosumab
in patients with aneurysmal bone cysts
: a case series with preliminary results. Tumori 2018; 300891618784808.
Retrospective series on the use of denosumab in advanced or recurrent ABC from a large orthopedic center.
62. Lange T, Stehling C, Frohlich B, et al. Denosumab
: a potential new and innovative treatment option for aneurysmal bone cysts
. Eur Spine J 2013; 22:1417–1422.
63. Skubitz KM, Peltola JC, Santos ER, Cheng EY. Response of aneurysmal bone cyst to denosumab
. Spine (Phila Pa 1976) 2015; 40:E1201–E1204.
64. Pelle DW, Ringler JW, Peacock JD, et al. Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts
: verification of target and therapeutic response. Transl Res 2014; 164:139–148.
65. Dubory A, Missenard G, Domont J, Court C. Interest of denosumab
for the treatment of giant-cells tumors and aneurysmal bone cysts
of the spine. About nine cases. Spine (Phila Pa 1976) 2016; 41:E654–E660.
66. Ghermandi R, Terzi S, Gasbarrini A, Boriani S. Denosumab
: nonsurgical treatment option for selective arterial embolization resistant aneurysmal bone cyst of the spine and sacrum. Case report. Eur Rev Med Pharmacol Sci 2016; 20:3692–3695.
67. Ntalos D, Priemel M, Schlickewei C, et al. Therapeutic management of a substantial pelvic aneurysmatic bone cyst including the off-label use of denosumab
in a 35-year-old female patient. Case Rep Orthop 2017; 2017:9125493.
68. Patel RS, Dhamne CA, Gopinathan A, et al. Denosumab
: a potential treatment option for aneurysmal bone cyst of the atlas. Eur Spine J 2018; 27 (Suppl 3):494–500.
69. Pauli C, Fuchs B, Pfirrmann C, et al. Response of an aggressive periosteal aneurysmal bone cyst (ABC) of the radius to denosumab
therapy. World J Surg Oncol 2014; 12:17.
70. Jaffe HL. Giant-cell reparative granuloma, traumatic bone cyst, and fibrous (fibro-oseous) dysplasia of the jawbones. Oral Surg Oral Med Oral Pathol 1953; 6:159–175.
71. Whitaker SB, Waldron CA. Central giant cell lesions of the jaws. A clinical, radiologic, and histopathologic study. Oral Surg Oral Med Oral Pathol 1993; 75:199–208.
72. Cohen MM Jr, Gorlin RJ. Noonan-like/multiple giant cell lesion syndrome. Am J Med Genet 1991; 40:159–166.
73. Ficarra G, Sapp JP, Eversole LR. Multiple peripheral odontogenic fibroma, World Health Organization type, and central giant cell granuloma: a case report of an unusual association. J Oral Maxillofac Surg 1993; 51:325–328.
74. Chuong R, Kaban LB, Kozakewich H, Perez-Atayde A. Central giant cell lesions of the jaws: a clinicopathologic study. J Oral Maxillofac Surg 1986; 44:708–713.
75. Ficarra G, Kaban LB, Hansen LS. Central giant cell lesions of the mandible and maxilla: a clinicopathologic and cytometric study. Oral Surg Oral Med Oral Pathol 1987; 64:44–49.
76▪. Bredell M, Rordorf T, Kroiss S, et al. Denosumab
as a treatment alternative for central giant cell granuloma: a long-term retrospective cohort study. J Oral Maxillofac Surg 2018; 76:775–784.
Relevant review and largest case series up to date on the use of denosumab in GCG.
77. Schreuder WH, Coumou AW, Kessler PA, de Lange J. Alternative pharmacologic therapy for aggressive central giant cell granuloma: denosumab
. J Oral Maxillofac Surg 2014; 72:1301–1309.
78. Naidu A, Malmquist MP, Denham CA, Schow SR. Management of central giant cell granuloma with subcutaneous denosumab
therapy. J Oral Maxillofac Surg 2014; 72:2469–2484.
79. Gupta B, Stanton N, Coleman H, et al. A novel approach to the management of a central giant cell granuloma with denosumab
: a case report and review of current treatments. J Craniomaxillofac Surg 2015; 43:1127–1132.
80. Akeda K, Kasai Y, Sakakibara T, et al. Effect of denosumab
on recurrent giant cell reparative granuloma of the lumbar spine. Spine (Phila Pa 1976) 2015; 40:E601–E608.
81. O’Connell JE, Bowe C, Murphy C, et al. Aggressive giant cell lesion of the jaws: a review of management options and report of a mandibular lesion treated with denosumab
. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120:e191–e198.
82▪. Kim TS, Usera GL, Ruggiero SL, Weinerman SA. Improvement of giant cell lesions of the jaw treated with high and low doses of denosumab
: a case series. JBMR Plus 2017; 1:101–106.
Relevant case series on the use of denosumab in giant cell lesions of the jaw.