Giant cell tumor of bone (GCTB) is a benign, locally aggressive tumor that primarily affects the epiphysis of long bones, especially around the knee (distal femur and proximal tibia, 44%), followed by the distal radius, proximal humerus, small bones, and sacrum. Representing 5% of primary and 15–20% of benign bone tumors, GCTBs usually occur in adults aged 20–40 years, show slight female predominance, and are more common in Asian populations [1-6].
The precise etiology of giant cell tumor (GCT) remains uncertain, with debate over its neoplastic versus reactive nature. Giant cell tumor (GCT) of bone is primarily driven by the overexpression of RANKL by neoplastic stromal cells, which stimulates the differentiation and fusion of monocyte-derived precursors into osteoclastic giant cells. These giant cells are responsible for aggressive bone resorption through Cathepsin K and MMP-13 activity. Stromal cells also secrete osteoprotegerin, a natural RANKL inhibitor that regulates osteoclastogenesis. Somatic mutations in the H3F3A gene, found in over 90% of cases, are exclusive to stromal cells, which exhibit features of immature osteoblasts and are central to tumor development [7].
Giant cell tumor lesions typically present as soft, spongy, chocolate-brown masses with marked fragility. On gross examination, there is often cortical expansion and varying degrees of cortical disruption, although the periosteum generally remains preserved. These features aid in distinguishing GCT from other bone lesions [8]. Giant cell tumors are histologically composed of numerous multinucleated giant cells dispersed among mononuclear stromal cells. Giant cells have centrally clustered, oval nuclei with prominent nucleoli and are unevenly distributed [9]. Stromal cells may express vimentin, consistent with their mesenchymal origin, while being negative for markers of epithelial or hematopoietic lineage (e.g., cytokeratin, CD45). CD68 highlights the osteoclastic giant cells, confirming their monocytic/ macrophage lineage, but is non-specific. The most specific marker for GCT is the H3F3A G34W mutation, which is present in >90% ofcases. IHC for H3F3A G34W allows highly sensitive and specific identification of neoplastic stromal cells, distinguishing GCT from other giant cell–containing lesions [10].
Patients typically report persistent localized pain, swelling, and reduced joint mobility, with symptoms often progressing over weeks to months. Pathological fractures occur in approximately 10%–30% of cases [11,12] particularly in weight-bearing bones. Tumors involving the spine or sacrum can present with neurological deficits or bowel/bladder dysfunction. In rare cases, GCTB may metastasize to the lungs.
Blood investigations including complete blood count, liver and renal function test, Serum electrolytes and Calcium,are to be done during evaluation.A plain Xray typically reveals an epiphyseal lesion with characteristic radiolucent geographic appearance with a narrow transition zone at the lesion margin, lacks a prominent sclerotic rim at the lesion margin which is called soap bubble appearance in epiphysis. CT imaging is used for assessing cortical disruption evaluating patterns of mineralization, new bone formation and overall lesion characteristics, which can assist in distinguishing between GCT and malignant conditions like osteosarcoma. A chest CT is routinely used to screen for potential lung metastases. On Magnetic resonance imaging (MRI) lesions are typically well-circumscribed, showing low signal intensity on T1-weighted and intermediate to high signal on T2-weighted images. MRI is pivotal for assessing soft tissue extension, joint involvement, and proximity to neurovascular structures in giant cell tumors supporting precise surgical planning and postoperative monitoring [8, 13]. Positron emission tomography- computed tomography (PET-CT) may help to differentiate between residual/recurrent disease from post-treatment changes and assess response to Denosumab therapy [13]. Core needle biopsy is generally preferred for confirmation of diagnosis and ruling out other malignant or benign bone tumors.In anatomically complex cases, open biopsy may be required. The Campanacci grading system for giant cell tumor of bone classifies lesions as Grade I (well-marginated intraosseous tumors with intact cortex), Grade II (larger intraosseous lesions with thinned cortex, subdivided into IIA without and IIB with pathological fracture), and Grade III (aggressive tumors with cortical breach and soft tissue extension) [14].
Surgery is the primary treatment modality for GCTB.
The choice of surgical procedure is influenced by the tumor’s anatomical location, Campanacci classification, and proximity to critical neurovascular or articular structures. The two main approaches are intralesional curettage and wide en bloc resection.Intralesional curettage is the standard for most Campanacci Grade I and II lesions, particularly those near joints. This approach preserves function and bone stock but carries a higher risk of recurrence. To minimize this risk, curettage is often combined with local adjuvants such as high-speed burring, phenol, cryotherapy, or polymethylmethacrylate (PMMA) cement, which also provides mechanical stability and allows early mobilization [15]. Wide resection is reserved for aggressive or recurrent tumors (typically Grade III) with cortical breach or soft tissue extension. Although this method reduces recurrence, it may compromise function, especially when joint-sacrificing procedures are involved. Reconstruction options include endoprostheses, allografts, or arthrodesis, depending on location and extent of resection [16]. Radiotherapy serves as an effective therapeutic option in cases where surgical resection is incomplete, not feasible, or would result in significant functional impairment or located in anatomically complex regions like spine and pelvis or in case of recurrent disease [17]. Commonly used dose and schedule for Radiotherapy is 50Gy in 28 fractions, 5 fraction/week over 6 weeks. Radiotherapy achieves ~80–85% 5 year local control across various settings. Larger tumor size > 8.5cm and recurrent disease are the factors associated with poor outcome [18].
Even though surgery is the standard of care,in anatomically complex or surgically morbid locations such as the spine, sacrum, or pelvis complete resection may be challenging. Denosumab acts by blocking RANKL effectively inhibit osteoclast formation and tumor activity (Figure 1).
Denosumab is evolved as a valuable neoadjuvant therapy in this context by inducing tumor regression and facilitating more conservative surgical approaches.The pivotal phase II trial by Thomas et al. demonstrated the initial efficacy of Denosumab in 37 patients with recurrent or unresectable GCTB. Denosumab led to the near-complete elimination of giant cells in 86% of patients, with radiographic evidence of bone formation and significant symptomatic improvement [19]. These promising findings prompted a larger phase II study by Chawla et al, involving 282 patients. In this trial, 96% of patients achieved at least a 90% reduction in osteoclast-like giant cells. Among the cohort where surgery was initially planned, 74% experienced reduced surgical morbidity, including conversion from planned en bloc resections to curettage or limb-sparing procedures [20]. Similarly, another study by Beresford-Cleary et al noted the use of Denosumab in spine GCT in acute setting showed significant reduction in pain and size of tumor enabling less invasive surgeries [21]. The European multicenter experience of 138 patients with locally advanced GCTB treated with Denosumab reported that neoadjuvant Denosumab facilitated wide resections or curettage. Two-year PFS was 81%; significant recurrence reduction with wide resection (93% vs 55%) [22]. A retrospective study from India recruited 25 high-risk Campanacci II/ III patients who received five neoadjuvant doses prior to surgery (curettage or prosthesis). Only 1 recurrence at 40-month follow-up; functional scores were excellent [23]. In Another study from India 44 GCTB patients were treated with 5–7 preoperative Denosumab cycles. Surgery intentions were met in 95%; 2 year LRFS was 76%, with better control after resection vs curettage (94% vs 64% [24]. A Russian study demonstrated that neoadjuvant Denosumab reduced the risk of progression compared to surgery alone [25]. The JCOG1610 phase 3 trial which tried to confirm the superiority of preoperative Denosumab to curettage with adjuvant local therapy was terminated early due to poor patient enrollment and results did not show any benefit in recurrence free survival without large post-op bone defect [26].
There are limited data for the exclusive adjuvant use of Denosumab after curettage. A study by Akyıldız et al. used a post operative Denosumab in 18 patients and reported stable disease in 94% of the patients [27]. Most guidelines recommend individualized consideration for adjuvant Denosumab, particularly in patients with high-risk features for recurrence or those unfit for repeat surgery. Trials of Denosumab in GCTB are summarized as Table 2.
| Study/Series | Design and patient number | Regimen | Key Findings |
| Thomas et al. [19] | Phase II, n=35 | Neoadjuvant, 3–7 doses pre-op | 86% response, >90% giant-cell reduction |
| Chawlaet al. [20] | Phase II, n≈282 | Extended neoadjuvant | -No progression at 13 months.- 62% patients who had surgery underwent a less morbidprocedure |
| Rutkowskiet al. [22] | Retrospective, 138 pts | ~11 cyclesNeoadjuvant | 81% PFS at 2 yrs; better outcomes with resection |
| Tripathy SK et al [23] | Retrospective, 25 pts | 5 doses Neoadjuvant | Reduces local recurrence. high function preservation |
| JCOG1610 [26] | RCT (n=106 intended)Terminated early | 5 pre-op doses Neoadjuvant | 1 yearRFS were 90.0%2 year RFS :60.0% |
| Akyıldız et al., [27] | Retrospective, N=16 | Postoperative | Partial response 6%Stable disease 94% |
However, concerns regarding local recurrence after Denosumab have emerged and studies report varying rate of recurrence. Errani et al. compared patients who underwent curettage with and without prior Denosumab and found significantly higher recurrence in the Denosumab group (60% vs. 16%). This increased risk is thought to be related to altered tumor histology and masked residual disease due to new bone formation [28].
A multicenter study observed a 35% local recurrence rate after curettage in patients treated with Denosumab as a neoadjuvant therapy [29]. Another systematic review encompassing seven studies found recurrence rates ranging from 20% to 100% in the neoadjuvant Denosumab group, compared to 0% to 50% in the curettage-alone group [30]. A meta-analysis of eight studies indicated that preoperative Denosumab increases the risk of local recurrence after surgery in patients with GCTB. The analysis revealed a higher risk of local recurrence in the Denosumab group compared to the curettage-alone group, with an odds ratio of 2.29 [31]. The increased risk of local recurrence following Denosumab therapy underscores the importance of considering additional treatment strategies and close postoperative monitoring to improve long-term outcomes for patients with GCTB.
Bisphosphonates inhibit osteoclast-mediated bone resorption by binding to bone surfaces and disrupting osteoclast function. This leads to osteoclast apoptosis, reduced bone turnover, preserved bone density which has demonstrated in preclinical trials to control the growth of GCTB.In one randomized trial involving 30 patients with extremity GCTB, the use of neoadjuvant zoledronic acid resulted in no local recurrences at a median follow-up of 28 months [32]. Studies exploring use of Bisphosphonate- loaded polymethylmethacrylate (PMMA) cement, which allows for local drug delivery after curettage has shownto reduce local recurrence (6%) with minimal adverse events [33]. A recent meta-analysis of 181 patients enrolled in 8 clinical studies from 2008-2020 confirmed that preoperative/postoperative Bisphosphonate reduces recurrence rates [34]. Bisphosphonate can be used as an alternative option for patients with GCTB who cannot afford Denosumab especially from the low middle income countries like India but the long-term toxicities like osteonecrosis of jaw and renal toxicity should be kept in mind. The PDL1 expression is around 28% and Immunotherapy may be an option for unresectable or Metastatic GCTB progressing on Denosumab [35].
Tumors of the spine, sacrum, or pelvis have higher recurrence due to surgical complexity. Recurrence risk increases with higher Campanacci grade. Wide resection (<10% recurrence) is superior to curettage (20–50%), and adjuvants like phenol, PMMA, or cryotherapy reduce recurrence. Neoadjuvant Denosumab shrinks tumors but may obscure margins, increasing recurrence if resection is incomplete. Pulmonary metastasis (1–4%) and malignant transformation (<2%) are rare, emphasizing close follow-up [13].
The case series comprised various presentations, ranging from first presentation, recurrence to metastasis. 3 patients with localised disease underwent curettage with liquid nitrogen application and one patient underwent wide excision with reconstruction. Two patients who declined surgery continued on Denosumab with durable disease control. Two patients with symptomatic distant Metastasis achieved symptomatic benefit and radiologic response with Denosumab therapy. One patient developed persistent transaminitis and required to stop Denosumab. In conclusion, the neoadjuvant Denosumab helped in performing less morbid surgery in our patients. Patients who were unwilling for surgery had excellent clinical and radiologic responses and durable disease control. The use of Denosumab in metastatic/recurrent GCTB lead toclinical and radiologic response and prolonged disease control. Accessibility to Denosumab and Curetting with liquid Nitrogen is limited to high end centres in the LMIC setting. Our study shows the real-world challenges faced by clinicians in managing GCTB.
Authors declare that they have no conflicts of interest
The data sets used during the current study are available from the corresponding authors per reasonable request.
Authors’ contributions: All authors contributed equally to the data collection and preparation of manuscript.
This study was approved by the Institutional Ethics Committee of Government Medical College Kozhikode(Ref. No. GMCKKD/RP 2025/IEC/72).
Written informed consent was obtained from all participants, and the trial was conducted in accordance with the Declaration of Helsinki.
Written informed consent was obtained from all participants, and the trial was conducted in accordance with the Declaration of Helsinki.