A Short Course of Preoperative Denosumab Injection Followed by Surgery in High-Risk Giant Cell Tumors of the Extremities: A Retrospective Study

Abstract

Despite early promising results with denosumab treatment in giant cell tumor of bone (GCTB), recent studies have raised concerns about a high local recurrence rate following preoperative denosumab administration and joint preservation surgery. This retrospective study evaluated data from 25 high-risk GCT patients (Campanacci grade II or III with features like soft tissue extension, pathological fracture, minimal periarticular or subarticular bone) treated with five doses of neoadjuvant denosumab injection followed by either curettage and cementing (n = 13) or joint reconstruction with fibular graft/endoprosthesis (n = 12) between 2014 and 2019. With an average follow-up of 40 months, the study found only one patient of local recurrence. All patients were independently ambulant, with a mean MSTS score of 26.32. Subgroup analysis revealed an MSTS score of 27.76 in the joint preservation group, and 24.75 in the excision with reconstruction/prosthetic replacement group (unpaired t-test, p-value < 0.001). Five patients experienced postoperative complications, including two infections, one recurrence, one mediolateral instability in the prosthetic component, and one restriction of wrist movement. A short course of neoadjuvant denosumab, followed by curettage and cementing or wide excision with joint reconstruction/prosthetic replacement, appears to be an effective strategy for high-risk GCTB patients. This approach not only minimizes surgical morbidity but also does not increase the local recurrence rate. The short course regimen may present a cost-effective and practical option in clinical practice.

Introduction

A giant cell tumor of the bone (GCTB) typically manifests at the ends of long bones and is known for its local aggression. Metastatic occurrences are infrequent. The incidence of GCTB is notably higher in young women of middle age. The treatment objective is early diagnosis and joint preservation surgery [1]. This surgery targets the full excision of the tumor without causing significant harm to the patient. Most patients respond well to a combination of extended curettage with bone cementing or grafting. In more severe conditions, marked by extensive bone damage, thinning of the periarticular or subarticular bone, or cortical breach with soft tissue extension (Campanacci grade II or III), procedures such as wide resection with joint replacement or even amputation might be necessary [1, 2]. Local recurrence has been observed in 27–65% of patients after curettage, generally within 2 years post-surgery [3–9]. Using extended curettage along with techniques like phenol, bone cement, cryotherapy, and electrocauterization has reduced the incidence of local recurrence to 12–27% [9], although no randomized control study has definitively proven the effectiveness of these treatment methods. Furthermore, in specific situations such as pathological fractures or soft tissue extension where tumor cells have already spread to the external compartment, these supplementary therapies are not applicable [10].

The utilization of denosumab for treating GCTB has ignited considerable optimism among oncosurgeons due to its high effectiveness in managing the tumor [11–19]. Nevertheless, some recent studies have pointed to a high recurrence rate in the medium term following preoperative denosumab injections paired with joint preservation surgery [11, 14–16, 19]. The increased risk of recurrence is because of the difficulties in completely removing the tumor cells from the sclerotic bone that forms following treatment with denosumab. Perrin et al. observed a 44% local recurrence rate at an average follow-up of 32.5 months after denosumab treatment in high-risk GCTs [16], cautioning surgeons about recurrence risks with extended follow-up. Scoccianti et al. further noted that neoadjuvant denosumab assists in forming a bony rim around the tumor, aiding curettage in high-risk patients, but without reducing the risk of local recurrence [20]. This suggests that denosumab may not affect the biological aggressiveness of the tumor [16].

In most studies, denosumab was applied for six cycles (typically nine doses) before surgery [11–16]. This longer duration of treatment leads to more thickening and mineralization of the lesion, making it difficult to completely curate and thereby increasing the risk of residual disease and subsequent recurrence. For advanced GCTB, where joint preservation is not possible due to severe conditions like neglected displaced pathological fractures or extensive tumors limiting joint functions, a prolonged course of denosumab may not be essential. However, a limited number of preoperative doses of denosumab can be beneficial in consolidating the lesion, thus aiding surgeons in achieving complete resection [1]. We hypothesize that reducing the number of preoperative doses could potentially facilitate more effective removal of the tumor. Puri et al. used a shorter duration (mean dose of 5, range 2 to 7) to ease curettage, simplify resection, or convert resection to curettage in advanced GCTB [11]. A similar protocol was embraced by our institution in 2014. The purpose of this study is to assess the local recurrence rate and functional outcomes of GCT in the extremities, treated with shorter neoadjuvant denosumab injections followed by joint preservation or replacement surgeries.

Material and Methods

We conducted a retrospective review of the clinical data for all patients diagnosed with GCTB who were treated with denosumab injections followed by surgery at our institution. The review encompassed patients between February 2014 and February 2019. Only patients with complete clinical and radiological information and a minimum of 2 years of follow-up were included in this study. The institutional review board granted clearance for the study (T/IM-NF/Ortho/20/207). Out of the 28 patients with GCTB who received denosumab injections followed by surgical intervention during this timeframe, three were excluded due to insufficient follow-up data or incomplete radiological details.

Patients with suspected GCTB were subjected to diagnostic evaluations, including radiographs (anteroposterior and lateral views), computed tomographic scans, and magnetic resonance imaging. The diagnosis was confirmed after a needle biopsy. The clinical symptoms among the patients were as follows: 25 reported swelling, 25 experienced pain, 5 had fractures, and 18 had restricted movement.

High-risk candidates for joint salvage (those with Campanacci grade II characterized by expanded cortex and minimal periarticular or subarticular bone likely to break during curettage, or Campanacci grade III with cortical breach, soft tissue extension, and pathological fracture) were administered preoperative denosumab injections [21]. The treatment regimen consisted of 120 mg of denosumab (used Xgeva by Amgen till 2018, and then started using biosimilar formulation Olimab by the Intas pharmaceuticals) given as a subcutaneous injection on days 0, 8, 15, 30, and 60. Additionally, patients were given supplemental doses of 500 mg calcium and 400 IU vitamin D during denosumab therapy.

Throughout the treatment, patients were regularly evaluated using radiographs and were strictly advised against weight-bearing on the affected limb pending definitive surgery. Specific attention was paid to the radiographs to assess whether the perilesional bony rim had properly formed and whether the subarticular bone had thickened sufficiently to withstand breakage during curettage. In patients of pathological fractures, x-rays were analyzed to ascertain if a well-circumscribed consolidated bony mass had developed. The response to denosumab treatment was evaluated radiographically using four parameters: decrease in size of the lesion, perilesional osteosclerosis, intralesional osteosclerosis, and healing/consolidation of the fracture [22]. The patients showing these radiographic features were considered good responder to denosumab. If the criteria to cease denosumab treatment were not met, an additional dose was administered after a 90-day interval.

Surgery was performed 1 month after the cessation of neoadjuvant denosumab treatment. Surgical options included extended curettage (employing high-speed burr, electrocautery, and hydrogen peroxide) followed by cementing, or en bloc resection and endoprosthesis implantation (Figs. 1, 2, 3, 4, and 5). The decision to undergo resection or prosthesis was decided after completion of denosumab therapy. Joint preservation was performed if the lesion was intraosseous, not causing gross functional limitations of the nearby joint and have not caused painful movement in the joint because of arthritis or articular irregularities (after thickening of expanded cortex or healed displaced articular fracture/breach). Resection and endoprosthesis implantation were performed if there was arthritis, articular incongruity, and gross functional restriction of the nearby joint.

Fig. 1.

A Huge GCT involving Rt proximal femur in an 18-year-old female; B after six doses of neoadjuvant denosumab treatment, the tumor shrunk to some extent and consolidated; C, D complete surgical resection was done, and proximal femur mega prosthesis was implanted. The patient had an immediate postsurgical infection that was managed by debridement and antibiotics; E after 36 months, the prosthesis is well functioning without evidence of loosening or recurrence

Fig. 2.

A 20-year male with proximal tibia GCT (Campanacci grade III); B after five doses of denosumab, the tumor consolidated; C extended curettage and bone cementing was performed, and the proximal tibia was stabilized with a plate; D after 30 months, there is no evidence of recurrence

Fig. 3.

A Recurrent GCT of the proximal tibia in a 52-year male patient; B magnetic resonance imaging shows T2W hyperintense signal with involvement of patellar tendon; C proximal tibia endoprosthesis was implanted after complete tumor resection; D the patient was all right till 2.5 years follow-up (then met a road traffic accident and sustained a periprosthetic fracture, which was fixed with a plate)

Fig. 4.

A Proximal tibia GCT with the cortical breach in a 40-year male patient; B magnetic resonance imaging shows soft tissue extension on the lateral side; C after five doses of denosumab, the tumor consolidated, and the osseous rim delineated the tumor margin; D, E, F extended curettage and cementing was performed, a lateral locking plate was fixed for additional support. G After 36 months of follow-up, this patient is walking normally with a full range motion in the knee joint, and there is no evidence of recurrence

Fig. 5.

A, B, C 23-year-old female presented with distal femur GCT and displaced pathological fracture; D after receiving five doses of denosumab, the tumor mass along with the fracture consolidated. It was resected in toto and a distal femur megaprosthesis was implanted

In the joint salvage group, a cortical window (usually encompassing one surface of the bone for the entire extent of the tumor) was created large enough for complete tumor visualization. The lesion was meticulously removed until healthy-looking bone was reached, followed by expansion of the tumor cavity in all directions using a high-speed burr. Afterward, hydrogen peroxide was applied, and electrocauterization was performed to kill residual tumor tissue. The bone defect was then thoroughly irrigated with saline to ensure a clean bone cavity. The cavity was then filled with bone cement, and plate fixation was employed to reinforce any construct deemed weak by the surgeon. In the resection group, the tumor was excised completely and an endoprostehsis was implanted using bone cement.

Patients were advised to start early active movement and weight-bearing exercises promptly. The joint motion was gradually increased based on the progress indicated by radiographic evaluations showing favorable results. For patients with distal radius GCTB reconstructed with an autogenous fibular graft, the limb was immobilized in a splint for 6 weeks, after which a gradual increase in movement was started. Postoperative follow-up visits were scheduled at intervals of 2 weeks, 6 weeks, 3 months, 6 months, 1 year, and every 6 months thereafter. The patients were followed up with clinical examination (Musculoskeletal Tumor Society score) and local part radiographs (anteroposterior and lateral views) [23]. In patients with suspicious recurrence or lytic areas, magnetic resonance imaging of the part followed by image-guided biopsy was performed.

Results

The patient group consisted of nine males and sixteen females, with a mean age of 31.04 ± 10.55 years (range, 18 to 52 years). They were followed for an average period of 40 months. The anatomical locations of the tumor were distributed as follows: one in the proximal femur, eleven in the distal femur, ten in the proximal tibia, one in the proximal humerus, and two in the distal radius.

Of the total 25 patients, two were recurrent GCTs, and two were GCTs associated with aneurysmal bone cyst. Twenty-one GCTs were Campanacci grade III, characterized by a cortical breach, displaced pathological fracture, and soft tissue extension. Four GCTs were Campanacci grade II, marked by thinned out periarticular and subarticular bone. In terms of preoperative denosumab treatment, twenty-four patients received five doses, while one patient was given six doses (Table 1). All patients responded to denosumab treatment as evaluated using the four radiographic criteria.

Table 1.

The demographic profile, treatment and outcome details of the patients

Sr No	Age/sex	Site	Tumor grade, extension	Denosumab treatment	Curettage, cementing, and fixation	F/u	Complications	MSTS score
1	40/M	Proximal tibia (R)	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing, and proximal tibial plate fixation	36	Nil	29
2	26/F	Distal femur (R)	Campanacci grade II: > 75% lytic lesion with thinned out sub articular and periarticular bone, expanded cortex laterally and posteriorly	0, 8, 15, 30, 60 d	Extended curettage (H2O2), cementing	36	Nil	28
3	23/F	Distal Femur	Campanacci grade III, displaced pathological fracture	0, 8, 15, 30, 60 d	Excision and mega prosthesis	36	Nil	25
4	24/M	Distal femur	Campanacci grade II, > 75% osteolytic lesion with thinned out sub articular and periarticular bone	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing	48	Nil	29
5	20/F	Distal femur	Campanacci grade III, posterior cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing	60	Nil	28
6	18/F	Proximal femur	Campanacci grade III, huge GCT with intermittent cortical breaches and soft tissue extension	0, 8, 15, 30, 60, 90 d	Excision and mega prosthesis	36	Immediate postoperative infection	24
7	20/M	Proximal tibia	Campanacci grade III, displaced pathological fracture with soft tissue extension	0, 8, 15, 30, 60 d	Excision and mega prosthesis	48	Nil	24
8	40/F	Proximal tibia	Campanacci grade III, > 75% osteolytic lesion, cortical breaches, articular collapse, soft tissue extension	0, 8, 15, 30, 60 d	Excision and mega prosthesis	48	Nil	26
9	38/M	Proximal tibia	Campanacci grade II, > 50% osteolytic lesion with indistinct rim, expanded cortex	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing	24	Recurrence observed at 24 months	28
10	38/F	Distal femur	Campanacci grade III, huge GCT with intermittent cortical breaches and expanded cortex	0, 8, 15, 30, 60 d	Excision and megaprosthesis	54	Nil	24
11	20/M	Proximal tibia	Campanacci grade III, > 75% osteolytic lesion with thinned out sub articular and breach in cortex and extension into the soft tissue	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing, plating	30	Late Infection	27
12	52/M	Recurrent GCT proximal tibia	Campanacci grade III, recurrent GCT with cortical breach and soft tissue extension	0, 8, 15, 30, 60 d	Excision and megaprosthesis	36	Periprosthetic fracture, fixation	22
13	45/F	Distal femur (R)	Campanacci grade III, displaced pathological fracture, soft tissue extension	0, 8, 15, 30, 60 d	Excision and megaprosthesis	60	Mediolateral instability of the prosthetic knee	25
14	19/F	Proximal tibia R	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing, plating	36	Nil	27
15	28/M	Proximal Tibia R	Campanacci grade III, displaced pathological fracture with soft tissue extension	0, 8, 15, 30, 60 d	Excision and megaprosthesis	24	Nil	27
16	39/F	Proximal Tibia L	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage (H2O2, electrocauterization), cementing, plating	24	Nil	28
17	22/F	Recurrent GCT Proximal Humerus, Right	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Excision and megaprosthesis	24	Nil	25
18	28/F	Recurrent GCT distal radius	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Excision and fibular graft	48	Restriction of wrist movement	26
19	18/F	GCT distal radius	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Excision and fibular graft	30	Nil	25
20	47/M	GCT Proximal tibia	Campanacci grade III, cortical breach with soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage, cementing, plating	24	Nil	28
21	50/F	Distal femur	Campanacci grade II, expanded cortex with indistinct margin	0, 8, 15, 30, 60 d	Extended curettage, cementing	78	Nil	27
22	34/M	Distal femur	Campanacci grade III, displaced pathological fracture	0, 8, 15, 30, 60 d	Wide excision and megaprosthesis	63	Nil	24
23	31/F	Distal femur	Campanacci grade III, cortical breach	0, 8, 15, 30, 60 d	Extended curettage, cementing	24	Nil	27
24	35/F	Distal femur	Campanacci grade III, expanded cortex, cortical breach, and soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage, cementing	24	Nil	27
25	21/F	Distal femur	Campanacci grade III, expanded cortex, cortical breach, and soft tissue extension	0, 8, 15, 30, 60 d	Extended curettage, cementing	48	Nil	28

Thirteen patients underwent joint preservation surgery in the form of extended curettage (involving curettage and treatment with hydrogen peroxide/electrocautery, and the use of a high-speed burr) and cementing (Figs. 2 and 4). In four of these patients, additional stabilization with a plate was necessary. Two patients with GCTB in the distal radius were treated through wide excision, with the fixation of an ipsilateral fibular graft. Remaining 10 patients were managed with en bloc resection and endoprosthesis implantation (Figs. 1, 3, and 5). In all instances, the tumor was well-defined, allowing complete resection. Postoperative denosumab or bisphosphonate was not administered to any of the patients. The average cost of the denosumab injection per patient was 1500 USD.

As of the latest follow-up, all patients were walking independently, and there was one local recurrence noted in the joint preservation group. The mean MSTS (Musculoskeletal Tumor Society) score was 26.32 ± 1.80. The score for the joint preservation group (n = 13) was 27.76 ± 0.7, and for the excision with joint replacement/reconstruction group (n = 12), it was 24.75 ± 1.23. The functional outcome was significantly more favorable in the joint preservation group (unpaired t-test, p-value < 0.001).

Five patients experienced postoperative complications, including one local recurrence, two infections, one prosthetic instability, and one instance of restricted joint motion, as of the latest follow-up. The patient with local recurrence was evaluated with MRI and biopsy to confirm recurrence. He was treated with removal of cement, curettage, and refilling with cement. In one patient, an infection developed 6 months after joint preservation surgery, which included extended curettage, cementing, and plating. This was managed through plate removal, wound debridement, and the application of antibiotic beads, followed by a prolonged course of postoperative antibiotics. There was no recurrence of the infection up to a 30-month follow-up. Another patient who underwent a proximal femur endoprosthesis developed an early postoperative infection, treated with debridement and wound lavage with vancomycin powder, with no subsequent evidence of infection. The patient with prosthetic instability had a mediolateral instability because of wear at the hinge site.

Discussion

This research demonstrated that utilizing a shorter preoperative denosumab treatment regimen effectively reduced the severity of GCTB, allowing for more manageable extended curettage and cementing or en bloc resection procedures. By employing this shorter regimen, surgical morbidity was minimized without an increase in the local recurrence rate, as has been reported with longer duration denosumab treatments. Additionally, this abbreviated course of treatment was found to be more cost-effective.

Denosumab, a human monoclonal antibody derived from mammalian cell lines, works by binding to RANK ligand, thereby inhibiting the activation and differentiation of osteoclastic-like giant cells and the subsequent process of osteolytic bone destruction [11–16]. The US Food and Drug Administration (USFDA) approved denosumab for inoperable GCTBs or situations where surgical removal might lead to serious morbidity [17]. This approval was based on two phase II trials that demonstrated promising results, both radiologically and histologically [12, 18]. Chawla et al. documented favorable safety and long-term disease control outcomes with denosumab in a multicentric, phase 2 study [12]. However, the long-term cost-effectiveness and potential adverse events of denosumab treatment must be balanced against the merits of alternative surgical interventions. There are still unresolved debates over the ideal duration of preoperative denosumab treatment, as well as its postoperative maintenance role [11–16]. The concern over a potentially higher recurrence rate after preoperative denosumab injections poses a significant challenge to its routine application in giant cell tumor of bone (GCTB). However, the advantage of denosumab in creating a bony rim, thereby enabling a thorough resection or curettage without spillage or iatrogenic fractures in advanced cases of GCTB, is an important consideration that cannot be overlooked.

Several studies have examined the factors that contribute to local recurrence in giant cell tumors of bone (GCTB) [9, 24–27]. Cheng et al. identified risk factors for GCTB recurrence, including the Campanacci grade, the surgical method used, Ki-67, and CD 147; they also found that an associated pathological fracture increases the risk of local recurrence [25]. Specifically, they reported no recurrence in Campanacci grade I but found recurrence rates of 13.51% and 41.67% in grades II and III, respectively. In patients treated with resection and endoprosthesis, the recurrence rate was 4.35% (1/23), whereas it was six times higher at 24.56% (14/57) in the group treated with cementing and blurring [25]. Prosser et al., in a comprehensive retrospective study of 193 patients, analyzed factors leading to GCTB recurrence [26]. They noted a higher recurrence rate when the cortical bone was involved, with a rate of 7% when the tumor did not breach the cortex, and 29% when the cortical bone was involved. Additionally, soft tissue involvement was identified as an independent predictor for GCTB recurrence, with Balke et al. reporting a 16.2% recurrence rate when the surrounding soft tissue was uninvolved, and a 29.7% recurrence rate when the tumor had invaded the soft tissue [27]. The study also indicated that GCTB located in the distal radius and proximal tibia are more susceptible to recurrence [24, 25]. In this specific case series, 10 out of 25 patients (40%) had GCTB in locations considered high risk, and all the tumors were of a high grade, carrying an increased risk of local recurrence.

The use of neoadjuvant denosumab in GCT of bone has demonstrated positive clinical outcomes, including pain relief and reduced morbidity in subsequent surgical procedures [11–16]. Radiological improvements have been consistently observed, although the histological response to denosumab can be variable. Reports indicate that denosumab does not affect metastasis or local recurrence, but the adverse effects of long-term use should not be overlooked [11–16]. In developing countries, the cost of treatment with denosumab poses a significant barrier to its regular use [11], particularly when late presentations of patients may make the joint or even the limb beyond salvage. In such cases, denosumab plays an encouraging role by reducing the tumor size and containing it within an osseous rim. The introduction of biosimilar denosumab has significantly lowered the cost of denosumab treatment. Prior to 2018, Xgeva, produced by Dr. Reddy’s Laboratories, was the primary option available, leading to substantial costs for patients. Following the introduction of biosimilar denosumab (Olimab by Intas pharmaceuticals), both accessibility and affordability have improved markedly, facilitating more widespread and frequent use of the medication.

According to this study, a shorter preoperative regimen of denosumab successfully reduces the tumor size, thickens the bone around the joint, and consolidates the tumor in the patient of pathological fracture. This facilitates joint preservation surgery in selected high-risk GCTs and enables complete resection when the tumor is unsalvageable. With a medium-term follow-up in this series, only one recurrence was observed (4%). However, these findings should be interpreted cautiously, as 48% (12/25) of patients were treated with more aggressive procedures due to the extensive nature of their tumors.

Despite the acknowledged safety and efficacy of denosumab in GCT, an increased rate of local recurrence remains a significant concern [11–16]. Some studies have reported recurrence rates as high as 60% following denosumab treatment and curettage [7], with others finding a 44% recurrence rate at medium-term follow-up [11, 16]. However, studies also show lower recurrence rates following resection than curettage, although functional outcomes can be suboptimal, and there may be additional risks such as infection, aseptic loosening, and prosthetic failure [9, 11, 28].

A conservative approach focusing on limb salvage, even at the risk of higher recurrence, may be a rational choice for young individuals with high-risk GCT. Unfortunately, in developing countries, many patients present with advanced disease, where the tumor has reached a large size, breached the cortex, and extensively involved soft tissue or caused a pathological fracture. In such patients, the expanded cortex with a large tumor may shrink but not revert to its normal size. These tumors often affect critical joints like the knee or hip, leading to severe movement restrictions. In this series, such patients were treated with resection and endoprosthesis to achieve better functional outcomes, with approximately 40% (10/25) of patients requiring this approach.

Currently, there is no consensus on the ideal candidate for denosumab treatment in GCTB or the appropriate dosage schedule [11–16]. While most studies recommend at least 6 months of preoperative denosumab treatment, following a specific sequence of days (0, 8, 15, 30, 60, 90, 120, 160, and 180), these studies have also reported high recurrence rates [12–16]. Some authors hypothesize that the recurrence may be due to the new bone formed within the tumor matrix in response to denosumab treatment. This new bone can be challenging to remove during curettage, and any trapped malignant stromal cells within the bony bridges may cause recurrence. Another explanation could be the inherently aggressive nature of the tumor itself [16].

In this study, the shorter course preoperative denosumab regimen (5 doses) was found to create a rigid shell around the tumor while leaving the internal trabeculae and bony bridges ductile enough to enable complete curettage. The results indicate that a short course of neoadjuvant denosumab followed by definitive surgery may be quite effective in selected high-risk GCT patients. According to our observations, neoadjuvant denosumab plays a definite role in minimizing the morbidity of definitive surgery. The surgical approach should be planned carefully, taking into account factors such as the aggressiveness of the tumor, any soft tissue extension, and the presence of a pathological fracture.

Furthermore, this series revealed a positive radiological response to denosumab treatment even in GCTB patients that were associated with ABC. Recent studies have also demonstrated the effectiveness of denosumab in treating ABC of bone in anatomically critical areas [29–32]. The pathophysiology of GCTB and ABC is thought to be closely related, as denosumab works by binding to the RANK ligand, which regulates the formation and progression of giant cells in both types of tumors [29–32].

This study has some notable limitations. Primarily, the retrospective nature of the data collection and the small sample size are significant constraints, making it challenging to ascertain the long-term outcomes and recurrence rates of the patients involved. While a shorter regimen of treatment has been reported by Puri et al. to have a recurrence rate of 29% (44% in the joint preservation group and 6% in the resection group) [11], our study with a nearly similar regimen only observed one local recurrence (4%). Explaining this discrepancy is difficult, especially since the majority of our patients (48%, 12/25) were treated with excision. One possibility could be the large cortical window created for curettage of the lesion, which may have provided better visualization of the cavity. Although this approach might have weakened the biomechanical stability of the construct, necessitating plate augmentation in many patients, it may have also contributed to the lower recurrence rate. However, this speculation needs further exploration, and a more comprehensive understanding of the biological aggressiveness of the tumor in GCTB would require additional research into tumor markers, radiological parameters, and histological features.

Conclusion

In high-risk patients with GCTB, a shorter course of neoadjuvant denosumab followed by joint preservation or replacement surgeries has proven to be effective. This approach not only offers cost-effective treatment but also reduces surgical morbidity. By diminishing the tumor size, thickening the subarticular and periarticular bone, forming a perilesional osseous rim, and consolidating pathological fractures, a short preoperative regimen of denosumab makes joint preservation surgery feasible in high-risk GCT patients, and allows complete resection when the tumor is unsalvageable. Contrary to some concerns, the shorter regimen in this study did not lead to an increased incidence of local recurrence.

Data Availability

The data will be shared on request.

Declarations

Conflict of Interest

The authors declare no competing interests.