INTRODUCTION
Denosumab has been gradually applied as a neoadjuvant therapy for giant cell tumor of bone (GCTB), with remarkable clinical benefits, such as pain relief and surgical downstaging.[ 1–4 ] However, some reports showed that preoperative denosumab might increase the risk of local recurrence after surgery.
Data from several studies showed that patients in the denosumab group who received denosumab before surgery had a higher rate of local recurrence.[ 5–12 ] Our study identifies the association between preoperative denosumab and the postoperative risk of local recurrence and, to some extent, tried to conclude how long denosumab should be used before surgery.
Subjects and Methods
Search strategy
On April 20th , 2022, four electronic databases (Web of Science, EMBASE, Cochrane Library, and PubMed) were comprehensively and separately searched by two researchers. The search strategy included the following medical subject heading terms: denosumab , giant cell tumor, and randomized controlled trial, as well as related entry terms. The terms searched in the Web of Science were “TS = (Osteoclastoma OR Giant Cell Tumor of Bone OR Giant Cell Tumors OR Cell Tumor, Giant OR Cell Tumors, Giant OR Giant Cell Tumor OR Tumor, Giant Cell, Tumors, Giant Cell) AND TS = (Denosumab OR Xgeva OR AMG 162 OR Prolia) AND TS = (Randomized Controlled Trial OR Controlled Clinical Trial OR Random Allocation OR Double-blind OR Single-blind OR Placebo OR Randomly OR Randomized OR Clinical Trial OR Trial OR RCT OR Random).” Additionally, conference reports, references to retrieved studies, and any other sources were also identified.
Selection criteria
No randomized clinical trials were found, so we prioritized retrospective cohort studies. Studies were included only in this analysis if (1) they were clinical trials; (2) the included patients who were diagnosed with GCTB underwent surgery and into two groups according to whether they received perioperative denosumab or not; and (3) clinical outcomes, especially local recurrence, were compared between groups. Studies were excluded if they (1) were reviews, case reports, or other forms instead of clinical trials; (2) lacked the control group in which patients underwent surgery without receiving denosumab ; (3) were still unfinished; (4) compared the efficacy of denosumab with other medicines, such as zoledronic acid or bisphosphonates; or (5) collected inadequate data for this meta-analysis .
Data extraction and quality assessment
Data were collected from the included studies. The first author, year of publication, country, perioperative denosumab administration, surgery method, follow-up time, and number of patients who experienced local recurrence, etcetera were recorded. The collected data were then screened independently by two researchers. Given that the studies included were nonrandomized, the quality of each study was assessed using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I).[ 13 ] The eligibility criteria were independently measured by two researchers, and disagreements were resolved through negotiation and discussion.
Statistical analysis
Statistical analysis was executed using the software Review Manager version 5.4 (Cochrane Collaboration, London, UK). The relationship between preoperative denosumab and the risk of local recurrence was analyzed using odds ratio (OR) with 95% confidence intervals (Cis). The Mantel–Haenszel (M–H) method is usually conducted. Heterogeneity across studies was assessed using the Chi-squared (c2 ) and I-square (I2 ) tests. The fixed effect model was applied when I2 <50% with P >0.05, meaning that it could be assumed that there was no significant heterogeneity. The random effect model was used when I2 >50% with P < 0.05. Publication bias was evaluated using a funnel plot. A P value < 0.05 was considered statistically significant.
Subgroup analysis and sensitivity analysis
A subgroup analysis was performed to explore the sources of heterogeneity in the included studies. We divided the included studies into two or three subgroups according to preoperative denosumab duration, denosumab use period, and sample size, respectively. A sensitivity analysis was also conducted by removing every single study separately to evaluate the influence of an individual study on the overall synthesis analysis.
RESULTS
Study inclusion and basic characteristics of included studies
A comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Science yielded 578 full-text articles. After removing duplicates and thoroughly screening titles, abstracts, and full texts by two researchers independently, eight studies with 1270 cases (195 receiving surgery with perioperative denosumab and 1075 receiving surgery alone) were eventually included in this meta-analysis . Gender distribution and age characteristics were unavailable because several studies provided indefinite data. The flowchart of the study selection is shown in Figure 1 . Basic characteristics of the included studies are provided in Table 1 , including denosumab administration, surgery method, follow-up time, and the number of patients who experienced local recurrence. Curettage was performed in most cases, increasing the validity of this study’s topic. Among the 195 cases in the denosumab group, 121 were treated with denosumab only before surgery, nine only after surgery, and 65 both before and after surgery. Preoperatively, cases treated with denosumab received subcutaneous injections of 120-mg denosumab every four weeks, with additional doses on days eight and fifteen in the first month. Postoperatively, denosumab was administered in the same way for three to seven months and one to fourteen months in several studies.[ 8 , 11 , 12 ] Patients in the denosumab group were all given calcium supplements to prevent hypocalcemia, as denosumab may increase the risk of occurrence.[ 14 ]
Figure 1: Study Flow Diagram
Table 1: Demographic Characteristics of Included Studies
Risk of bias and quality assessment
Few randomized clinical trials on the relationship between preoperative treatment with denosumab and local recurrence after surgery (curettage) were conducted, and as a result, no randomized trials were found. Therefore, the risk of bias and quality assessment of each included study were performed according to the ROBINS-I tool by the two researchers independently. Disagreements were resolved through negotiation and discussion. As shown in Table 2 and Figure 2 , three articles were at low risk, meaning that they are comparable to a well-performed randomized trial, and two articles at moderate risk could provide sound evidence for a nonrandomized study.[ 13 ] Therefore, the degree of reliability of this meta-analysis is considered significant. A funnel plot of the OR with a nearly symmetric result [Figure 3 ] described the detection of publication bias. However, it was impractical to conduct Egger’s test because only eight studies were included. Therefore, publication bias may exist, but it was acceptable.
Overall Local Recurrence: The Denosumab Group Had a Higher Risk of Local Recurrence Than the Control Group
Table 2: Risk of Bias Summary Assessed by ROBINS-I for Each Included Study
Figure 2: Methodological Quality Graph for Non-RCTs: Authors’ Judgments About Each Included Study According to ROBINS-I
Figure 3: Funnel Plot: Publication Bias of Included Studies
A total of 1270 cases in eight included studies were diagnosed with GCTB, and all cases underwent surgical treatment (curettage, resection, or amputation) according to their clinical manifestations, radiographic images, and Campanacci stages.[ 15 ] The cases were divided into two; 195 for the denosumab group (those that received denosumab before or after surgery) and 1075 for the control group (those who received surgery alone). The denosumab group received subcutaneous injections of 120-mg denosumab every four weeks, with additional doses on days eight and fifteen in the first month. Overall, 80 cases in the denosumab group and 209 cases in the control group experienced local recurrence after surgery. To roughly investigate the overall effect of denosumab on local recurrence after surgery in patients with GCTB, we performed a synthetic analysis without considering correlating factors, such as surgery method, denosumab duration, and disease stages. Forest plot [Figure 4 ] indicated an obvious higher risk of local recurrence in the denosumab group (OR: 2.91, 95% CI: 1.52–5.56, P = 0.001, I2 = 66%), suggesting that denosumab as an adjunctive therapy in patients with GCTB may cause an undesirable effect in terms of local recurrence. However, this synthetic analysis aimed to roughly assess the relationship between denosumab and the risk of local recurrence; additionally, heterogeneity was relatively significant (I2 = 66%, P = 0.005), so the result was only for reference.
Figure 4: Forest Plot: Overall Local Recurrence
Denosumab Given Only Before Curettage Increased the Risk of Local Recurrence
The main topics of this study, the risk of local recurrence in patients treated with denosumab only before curettage and patients who underwent curettage alone, were analyzed with emphasis. Pooled analysis was performed in six studies, with 545 cases meeting the standard. In five[ 5 , 6 , 9 , 10 , 12 ] of the six studies in the analysis, a dosage of 120-mg denosumab was administered subcutaneously for at least six months on average before curettage, with additional doses on days eight and fifteen in the first month, except in one study[ 7 ] in which patients received denosumab for three months in the same way before curettage. Some reports showed that there were histopathological changes in patients with GCTB after six months of denosumab treatment.[ 16 , 17 ] Therefore, 48 of 118 cases experienced local recurrence in the preoperative denosumab group, with a local recurrence rate of 41% (95% CI: 29% to 58%, P < 0.00001), using the fixed effect model (I2 = 0%, P = 0.75) [Figure 5a ]. One hundred and eight cases out of 427 cases in the curettage-alone group suffered from local recurrence, and the rate of local recurrence was 25% (95% CI: 17% to 36%, P < 0.00001) with the random effect model (I2 = 57%, P = 0.04) [Figure 5b ]. Forest plot [Figure 6 ] showed a significantly higher risk of local recurrence in the preoperative denosumab group (OR: 2.29, 95% CI: 1.44–3.64, P = 0.0005). A fixed effect model was applied without significant heterogeneity (I2 = 45%, P = 0.11). The results demonstrated that preoperative-only denosumab use might increase the risk of local recurrence after curettage in patients with GCTB.
Figure 5: Rate of Local Recurrence. (a) Preoperative Denosumab Group, (b) Curettage-Alone Group
Figure 6: Forest Plot: Local Recurrence in Preoperative Denosumab Group vs. Curettage-Alone Group
Subgroup analysis
Subgroup analysis was performed based on the following aspects: 1) preoperative denosumab duration at the six-month/dose boundary; 2) denosumab use period; 3) sample size. The outcomes of the subgroup analysis when comparing the risk of local recurrence between the denosumab and control groups are listed in Table 3 . Preoperative denosumab duration and denosumab use period contributed to significant subgroup differences, suggesting that clinical factors, including how long denosumab was administered before surgery and whether denosumab was used postoperatively, may be a source of heterogeneity. At the same time, sample size was not considered a source of heterogeneity. A conspicuous higher risk of local recurrence in patients with GCTB was observed in the denosumab group in all subgroup analyses, except for preoperative denosumab duration ≤six months/doses (P = 0.66) and sample size ranging from 100 to 180 (P = 0.69).
Table 3: Characteristics of Subgroup Analysis
Sensitivity analysis
The results were stable after removing all the studies separately. No individual study was found to significantly influence the holistic analysis of the association between preoperative denosumab and the risk of local recurrence after curettage in patients with GCTB.
DISCUSSION
The giant cell tumor of bone (GCTB), also known as osteoclastoma, is a primary benign neoplasm with a local aggressive tendency. GCTB accounts for approximately 20% of benign bone tumors and 4%–5% of all primary tumors,[ 18–20 ] with most cases occurring in adults aged 20–45.[ 21 ] GCTB consists of osteoclast-like multinucleated giant cell populations and neoplastic stromal cells, with high RANK (receptor activator of nuclear factor-kappa B) and RANKL (ligand of RANK) expressions, respectively. Although these giant cells often cause osteolytic destruction, they are not actual neoplastic cells. The stromal cells with high RANKL expression are believed to be the actual tumor cells, activating the osteoclasts, and causing subsequent bone destruction.[ 22–24 ] RANK-RANKL signaling is essential in regulating bone resorption and the formation, activation, and survival of multinucleated osteoclasts from their precursors under both normal and pathological conditions.[ 25 ] RANKL expressed by neoplastic stromal cells activates RANK, causing the imbalance of bone formation and bone resorption, followed by the osteolytic lesion, which is the hallmark of GCTB. GCTB treatment has been disputed. Currently, operative therapy for primary GCTB remains the first choice, including intralesional curettage, en bloc resection, intramural inactivation, bone grafting, and bone cement filling.[ 26 , 27 ] Since it is commonly localized at the metaphysis of long bones, often causing severe joint disorders, curettage has become the mainstay of GCTB treatment.[ 24 ] However, long-term follow-up has shown that surgical treatment faces a high risk of local recurrence, and treatment outcomes are often unsatisfactory.[ 28 , 29 ] Local recurrence is expected to be observed in 15%–50% of patients after surgery.[ 30 ] For patients with refractory GCTB that are surgically unresectable, or that have experienced recurrent recurrence or metastasis after surgical treatment, the role of surgery is very limited and nonsurgical treatment is preferred.[ 31 ] Cellular biological therapy represented by denosumab has shown great efficacy and biological wholeness in these patients.
Denosumab is a fully human monoclonal antibody with a high RANKL affinity, directly inhibiting osteoclastogenesis. Originally, it was used in osteoporosis and bone metastases from solid tumors. In 2013, the US Food and Drug Administration approved denosumab for treatmenting adults and skeletally mature adolescents with GCTB. Its significant clinical benefits have been reported in several papers, especially regarding tumor responses, pain relief, reducing surgical morbidity, and joint preservation.[ 1–4 ] Even for some very rare diseases that have no treatment guideline, such as pseudomyogenic hemangioendothelioma (PMH), denosumab has unexpectedly been effective.[ 32 ] Denosumab has been shown in vivo and in vitro studies to reduce neoplastic stromal cells with decreased RANKL expression and to promote spindle cell proliferation with reactive bone.[ 3 , 17 , 33 ] However, it has been reported that denosumab might increase the risk of local recurrence in patients with GCTB after surgery, and the long-term effects have been indefinitely portrayed.[ 34 ] Also, there are no rules for administering denosumab in patients with GCTB, so there is a lack of consensus on the duration of preoperative denosumab .
This meta-analysis of eight studies indicated that preoperative denosumab increases the risk of local recurrence after surgery in patients with GCTB, consistent with previous reports.[ 35 ] Puri et al .[ 36 ] reported that 11 of 25 (44%) patients treated with denosumab before curettage suffered from local recurrence with a mean follow-up time of 34 (24–48) months. The overall local recurrence was evaluated in our study (OR: 2.91, 95% CI: 1.52 to 5.56, P = 0.001). To further validate the correlation of denosumab application before curettage on postoperative local recurrence, data screened from included studies were pooled for analysis, and the results indicated that 41% of patients recurred locally, significantly higher than patients receiving curettage alone (25%) (OR: 2.29, 95% CI: 1.44 to 3.64, P = 0.0005).
The reasons why preoperative denosumab would increase the risk of local recurrence after curettage is inconclusive. Several studies claimed that denosumab could promote the formation of new sclerotic bone and the thickened bone cortex around the osteolytic lesion, making it difficult to identify the surgical margin and perform complete curettage, and that residual tumor cells might hide in the new bone as well as in the thickened bone cortex and might recur once denosumab was discontinued.[ 4 , 37 , 38 ] An in vitro study also showed that once denosumab was discontinued, the neoplastic stromal cells whose proliferative capacity had been reduced because of denosumab would proliferate again in a favorable microenvironment, albeit to a lower level.[ 17 ] Moreover, patients in the denosumab group were generally in more severe conditions (higher proportion of Campanacci stage 3, older age, to name a few), which may also be significant in affecting the risk of local recurrence after curettage. Chen et al .[ 39 ] found that although the risk of local recurrence after surgery was increased in patients with preoperative denosumab , there was no significant increased risk of postoperative local recurrence in patients who received both preoperative and postoperative denosumab , suggesting that the denosumab use period influences the risk of local recurrence. However, in our study, patients receiving denosumab both pre- and postoperatively still had a significantly higher risk of local recurrence than patients in the control group (OR: 6.46, 95% CI: 3.63 to 11.48, P < 0.00001). Certainly, due to the small sample size and unavoidable confounding bias, such as surgical techniques, denosumab indications, other adjuvant therapies, etc., the conclusions require more validation by more advanced studies.
The duration of preoperative denosumab has not been explicitly stipulated. Some studies have reported that a six-month duration of denosumab before surgery effectively reduced surgical morbidity and facilitated intraoperative procedures.[ 17 , 40 , 41 ] However, Urakawa et al .[ 12 ] claimed that a duration of six months was thought to be too long in patients with GCTB who could be treated with curettage, whether before or after curettage. In this study, a subgroup analysis suggested that preoperative denosumab use for ≤six months/doses associated insignificantly with an increased risk of local recurrence in patients with GCTB after curettage (P = 0.66). Thus, to prevent the formation of new sclerotic bone and thickened the bone cortex around the osteolytic lesion, a short course of denosumab , approximately three to four months, was recommended to decrease the possibility of residual neoplastic cells hiding within the new bone as well as in the thickened bone cortex.[ 42 , 43 ]
Given that there is no standardized treatment for GCTB, and the efficacy of denosumab is currently in dispute, it is clinically important to find a comprehensive strategy, including surgical treatment, selective arterial embolization, radiotherapy, and antivascular therapy for large GCTB lesions. For instance, Li[ 44 ] presented the first case report of a comprehensive strategy, including apatinib, to treat multicentric GCTB, and the results were promising.
There were some limitations to this meta-analysis . Firstly, randomized controlled studies were excluded in that few relevant studies were conducted to evaluate the relationship of denosumab with the risk of postoperative local recurrence. All included studies were retrospective cohort analyses with the inherent limitation of selection bias of patients in the denosumab group, who were generally in more severe conditions. To reduce the influence of this limitation, subgroup analyses were performed on the basis of preoperative denosumab duration, denosumab use period, and sample size, respectively. Secondly, because there is no standard strategy for the preoperative application of denosumab , our study inevitably has confounding bias. Patient differences in denosumab administration, other chemical adjuncts, surgical techniques, Campanacci stages, and other factors may increase the risk of confounding bias; therefore, the results of our study should be cautiously considered by readers. Thirdly, publication bias must be considered when interpreting the results, as the known statistical insignificance of primary research could negatively affect the reports.
Several highlights of our pooled analysis should be noted. Firstly, we precisely analyzed the association between denosumab use before curettage and the risk of postoperative local recurrence in patients with GCTB, which maximally eliminated the effects of different surgical methods and denosumab use periods. Secondly, subgroup analyses were performed to explore the sources of heterogeneity among the included studies, offering a more comprehensive evidence on this topic. Meanwhile, according to the results of the subgroup analyses, a duration time of fewer than six months might not lead to an increased risk of local recurrence, and this may provide guiding evidence for the use of denosumab . Thirdly, we conducted a sensitivity analysis to verify the results’ stability, and the outcome of the sensitivity analysis confirmed that the studies were stable. Fourth, all included studies were within the last five years, which made our study more instructive and helped draw a more authoritative conclusion.
CONCLUSION
GCTB treatment, particularly regarding tumor responses, pain relief, reducing surgical morbidity, and joint preservation,[ 1–4 ] there exists a possibility that preoperative denosumab in patients with GCTB would increase the risk of local recurrence after curettage. Based on our study’s results, patients with GCTB who could be treated with curettage should adequately weigh an increased risk of local recurrence against the clinical benefits of receiving denosumab before the surgery. If denosumab was used before curettage, we recommend avoiding it for more than six months. However, considering the limitations of this meta-analysis , the results should be considered with caution by readers. Multicenter randomized controlled trials should be conducted to determine whether preoperative denosumab would increase the risk of local recurrence after curettage in patients with GCTB.
Declaration of conflicting interests
The authors declare that no competing interest exists.
Financial support and sponsorship
The National Key Research and Development Program of China (No. 2016YFC0902100), the Science and Technology Commission of Shanghai Municipality (No. 17411950300), and the Innovation Foundation of Changzheng Hospital (No. 2020YLCYJ-Z07).
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, 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;14:901–8.
2. Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP, Pienkowski A, 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;22:2860–8.
3. Branstetter DG, Nelson SD, Manivel JC, Blay JY, Chawla S, Thomas DM, et al.
Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 2012;18:4415–24.
4. Traub F, Singh J, Dickson BC, Leung S, Mohankumar R, Blackstein ME, et al. Efficacy of
denosumab in joint preservation for patients with giant cell tumour of the bone. Eur J Cancer 2016;59:1–12.
5. Agarwal MG, Gundavda MK, Gupta R, Reddy R. Does
denosumab change the giant cell tumor treatment strategy?Lessons learned from early experience. Clin Orthop Relat Res 2018;476:1773–82.
6. Chinder PS, Hindiskere S, Doddarangappa S, Pal U. Evaluation of local recurrence in giant-cell tumor of bone treated by neoadjuvant
denosumab . Clin Orthop Surg 2019;11:352–60.
7. Deventer N, Budny T, Gosheger G, Rachbauer A, Puetzler J, Theil JC, et al.
Giant cell tumor of bone :A single center study of 115 cases. J Bone Oncol 2022;33:100417.
8. Errani C, Tsukamoto S, Leone G, Righi A, Akahane M, Tanaka Y, 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.
9. Medellin MR, Fujiwara T, Tillman RM, Jeys LM, Gregory J, Stevenson JD, et al. Prognostic factors for local recurrence in extremity-located giant cell tumours of bone with pathological fracture. Bone Joint J 2018;100:1626–32.
10. Scoccianti G, Totti F, Scorianz M, Baldi G, Roselli G, Beltrami G, 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;476:1783–90.
11. Tsukamoto S, Mavrogenis AF, Leone G, Righi A, Akahane M, Tanzi P, et al. Correction to:
Denosumab does not decrease the risk of lung metastases from bone giant cell tumour. Int Orthop 2019;43:491.
12. Urakawa H, Yonemoto T, Matsumoto S, Takagi T, Asanuma K, Watanuki M, 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.
13. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I:A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919.
14. Body JJ, Niepel D, Tonini G. Hypercalcaemia and hypocalcaemia:finding the balance. Support Care Cancer 2017;25:1639–49.
15. Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am 1987;69:106–14.
16. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al.
Denosumab in patients with giant-cell tumour of bone:An open-label, phase 2 study. Lancet Oncol 2010;11:275–80.
17. Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A translational study of the neoplastic cells of
giant cell tumor of bone following neoadjuvant
denosumab . J Bone Joint Surg Am 2014;96:e127.
18. Strom TM, Skeie AT, Lobmaier IK, Zaikova O. Giant cell tumor:A rare condition in the immature skeleton-A retrospective study of symptoms, treatment, and outcome in 16 children. Sarcoma 2016;2016:3079835.
19. Xu W, Li X, Huang W, Wang Y, Han S, Chen S, 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;20:804–10.
20. Bihani A, Thiagarajan S, Chaukar D, D'cruz AK. Giant cell tumor of hyoid bone:Diagnostic dilemma with a novel management. J Cancer Res Ther 2022;18:282–5.
21. Basu Mallick A, Chawla SP.
Giant cell tumor of bone :An update. Curr Oncol Rep 2021;23:51.
22. Byers VS, Levin AS, Johnston JO, Hackett AJ. Quantitative immunofluorescence studies of the tumor antigen-bearing cell in
giant cell tumor of bone and osteogenic sarcoma. Cancer Res 1975;35:2520–31.
23. Atkins GJ, Haynes DR, Graves SE, Evdokiou A, Hay S, Bouralexis S, et al. Expression of osteoclast differentiation signals by stromal elements of giant cell tumors. J Bone Miner Res 2000;15:640–9.
24. Li H, Gao J, Gao Y, Lin N, Zheng M, Ye Z.
Denosumab in
giant cell tumor of bone :Current status and pitfalls. Front Oncol 2020;10:580605.
25. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther 2007;9;Suppl 1;S1.
26. Van Der Heijden L, Dijkstra PD, Van De Sande MA, Kroep JR, Nout RA, Van Rijswijk CS, et al. The clinical approach toward
giant cell tumor of bone . Oncologist 2014;19:550–61.
27. Luther N, Bilsky MH, Hartl R. Giant cell tumor of the spine. Neurosurg Clin N Am 2008;19:49–55.
28. Errani C, Ruggieri P, Asenzio MA, Toscano A, Colangeli S, Rimondi E, et al. Giant cell tumor of the extremity:A review of 349 cases from a single institution. Cancer Treat Rev 2010;36:1–7.
29. Arbeitsgemeinschaft K, Becker WT, Dohle J, Bernd L, Braun A, Cserhati M, et al. Local recurrence of
giant cell tumor of bone after intralesional treatment with and without adjuvant therapy. J Bone Joint Surg Am 2008;90:1060–7.
30. Chawla S, Blay JY, Rutkowski P, Le Cesne A, Reichardt P, Gelderblom H, et al.
Denosumab in patients with giant-cell tumour of bone:A multicentre, open-label, phase 2 study. Lancet Oncol 2019;20:1719–29.
31. Naam NH, Jones SL, Floyd J, Memisoglu EI. Multicentric giant cell tumor of the fourth and fifth metacarpals with lung metastases. Hand (N Y) 2014;9:389–92.
32. Pasricha S, Sharma A, Pruthi M, Durga G, Jajodia A, Gupta G, et al. Multifocal primary pseudomyogenic hemangioendothelioma of bone managed with
denosumab :A rare case with diagnostic and therapeutic challenge. J Cancer Res Ther 2022;18:817–9.
33. Hakozaki M, Tajino T, Yamada H, Hasegawa O, Tasaki K, Watanabe K, et al. Radiological and pathological characteristics of
giant cell tumor of bone treated with
denosumab . Diagn Pathol 2014;9:111.
34. Palmerini E, Staals EL, Jones LB, Donati DM, Longhi A, Randall RL. Role of (Neo)adjuvant
denosumab for
giant cell tumor of bone . Curr Treat Options Oncol 2020;21:68.
35. Zhao Y, Cai Z, Tang X, Du Z, Yang Y, Guo W. Preoperative
denosumab may increase the risk of local recurrence of giant-cell tumor of bone treated with curettage:A systematic review and
meta-analysis . J Cancer 2021;12:508–17.
36. Puri A, Gulia A, Hegde P, Verma V, Rekhi B. Neoadjuvant
denosumab :Its role and results in operable cases of giant cell tumour of bone. Bone Joint J 2019;101:170–7.
37. Yang Y, Li Y, Liu W, Xu H, Niu X. A nonrandomized controlled study of sacral giant cell tumors with preoperative treatment of
denosumab . Medicine (Baltimore) 2018;97:e13139.
38. 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.
39. Chen X, Li H, Zhu S, Wang Y, Qian W. Pre-operative
denosumab is associated with higher risk of local recurrence in
giant cell tumor of bone :A systematic review and
meta-analysis . BMC Musculoskel Disord 2020;21:256.
40. Charest-Morin R, Boriani S, Fisher CG, Patel SR, Kawahara N, Mendel E, et al. Benign tumors of the spine:Has new chemotherapy and interventional radiology changed the treatment paradigm?. Spine (Phila Pa 1976) 2016;41;Suppl 20;S178–85.
41. Jamshidi K, Gharehdaghi M, Hajialiloo SS, Mirkazemi M, Ghaffarzadehgan K, Izanloo A.
Denosumab in patients with giant cell tumor and its recurrence:A systematic review. Arch Bone Jt Surg 2018;6:260–8.
42. 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.
43. Mccarthy CL, Gibbons CLMH, Bradley KM, Hassan AB, Giele H, Athanasou NA. Giant cell tumour of the distal radius/ulna:Response to pre-operative treatment with short-term
denosumab . Clin Sarcoma Res 2017;7:19.
44. Li J, Zhou J, Liu Y, Sun X, Song W. Comprehensive treatment for multicentric giant cell tumors of the pelvis and spine using apatinib:A case report and literature review. J Cancer Res Ther 2020;16:1020–6.
