Efficacy of bisphosphonates as adjuvant therapy in surgically treated giant cell tumours of bone: a randomized comparative study

INTRODUCTION

Giant cell tumor (GCT) of bone is a relatively uncommon, benign but locally aggressive skeletal neoplasm that constitutes approximately 30% of all benign bone tumors.^1,2 Although histologically classified as benign, its behaviour often contradicts this definition due to its propensity for local aggressiveness, recurrence, and in rare cases (1-4%), pulmonary metastasis.^3,4 The World Health Organization describes GCT as an "aggressive, potentially malignant lesion," highlighting its unpredictable clinical course despite benign histological features.⁵ GCT typically presents in the third to fourth decade of life, with slight female preponderance, and demonstrates marked predilection for the epiphyseal and metaphyseal regions of long bones around the knee joint, particularly the distal femur and proximal tibia, followed by the distal radius and proximal humerus.^6,7

The tumor is characterized by multinucleated osteoclast-like giant cells interspersed within neoplastic stromal cells. The key molecular pathway implicated in GCT pathogenesis is the RANK/RANKL/OPG signaling axis, which provides a strong biological rationale for using anti-resorptive agents.^8,9 The cornerstone of treatment remains surgical excision, with intralesional curettage being the most widely accepted primary approach. However, simple curettage is associated with unacceptably high local recurrence rates ranging between 25-50%.^10,11 Extended curettage using adjuvants such as phenol, hydrogen peroxide, and bone cement has improved local control but fails to eliminate recurrence completely.^12,13 Wide resection offers lower recurrence rates but at the cost of significant functional disability in young patients.¹⁴ Bisphosphonates, widely used in osteoporosis and metastatic bone disease, have emerged as promising adjuvants in GCT treatment.

They act primarily by binding to hydroxyapatite crystals and inducing apoptosis of osteoclasts, thereby inhibiting bone resorption. Additionally, bisphosphonates exert direct anti-tumor effects by inducing apoptosis of neoplastic stromal cells, inhibiting angiogenesis, and promoting osteogenic differentiation.^15-17

Several studies have demonstrated reduced recurrence rates with bisphosphonate therapy, particularly zoledronic acid and alendronate.^18-20 This study was designed to investigate the role of oral alendronate as adjuvant therapy in surgically treated patients with GCT of extremities.

METHODS

Study design

This prospective randomized double-blind comparative study was conducted in the Department of Orthopedics, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, from January 2024 to December 2024, following approval from the Institutional Ethics Committee.

Sample size and randomization

A total of 60 patients with histologically confirmed GCT of extremities were enrolled. Randomization was performed using computer-generated allocation sequence in 1:1 ratio.

Group A (n=30) received surgery plus oral Alendronate 10 mg daily for 6 months; Group B (n=30) underwent surgery alone without bisphosphonate therapy.

Inclusion criteria

Patients aged ≥12 years with histologically confirmed GCT of extremities, Campanacci Grade I-III, who were medically fit for surgery and provided written informed consent.

Exclusion criteria

Axial skeleton involvement, impaired renal function, hypersensitivity to bisphosphonates, metastasis at presentation, and pathological fractures.

Surgical technique

All patients underwent intralesional extended curettage with high-speed burr. Adjuvants (phenol, hydrogen peroxide) were applied to cavity margins. Cavity reconstruction was performed using polymethylmethacrylate (PMMA) bone cement or autologous cancellous bone graft. Endoprosthesis was used for extensive lesions requiring wide resection.

Follow-up protocol

Patients were evaluated at 1, 2, 3, and 6 months postoperatively. Assessments included radiological evaluation (NCCT), VAS for pain, joint range of motion, and MSTS functional scoring.

Statistical analysis

Data were analysed using appropriate statistical software. Continuous variables were compared using unpaired t-test; categorical variables using Chi-square or Fisher's exact test. A p value <0.05 was considered statistically significant.

RESULTS

In this study, both groups were comparable at baseline in terms of age and gender distribution (Table 1), with most tumors located around the knee region, particularly the distal femur and proximal tibia, followed by distal radius and distal tibia (Table 2).

Campanacci grading revealed Grade II predominance overall, with slightly more Grade III tumors in the control group, though differences were not statistically significant (Table 3). Surgical techniques were similar across groups, with most patients undergoing extended curettage using phenol, hydrogen peroxide, and burr, and reconstruction predominantly with cement; endoprosthesis was required only in the control group (Table 4). Recurrence outcomes showed a marked difference, with only one recurrence (3.33%) in the bisphosphonate group compared to five (16.67%) in the control group, most occurring by six months (Table 5). Pain relief was significantly better in the bisphosphonate group, with mean VAS scores dropping to 1.70 compared to 2.97 at six months (Table 6).

Functional recovery, assessed by MSTS scores, was consistently superior in the bisphosphonate group, reaching 26.9 versus 23.4 at six months (Table 7). Complications were fewer in the bisphosphonate group (6.67% vs 20%), with recurrence being the predominant complication in controls, while only one minor surgical site infection occurred in the bisphosphonate group and resolved with treatment (Table 8).

DISCUSSION

This prospective randomized study evaluated the efficacy of oral bisphosphonate (Alendronate) as adjuvant therapy in surgically treated GCT of bone. Our findings demonstrate that bisphosphonate therapy significantly reduces recurrence rates while improving pain relief and functional recovery.

The recurrence rate in our bisphosphonate group was 3.33% compared to 16.67% in the control group, representing an 80% relative reduction in recurrence risk. These findings are consistent with Tse et al who reported recurrence in 4.2% of bisphosphonate-treated patients versus 30% of controls, and Xu et al who demonstrated 3-year recurrence-free survival of 89.5% versus 56.3% with bisphosphonate therapy.^18,21 The meta-analysis by Shi et al also confirmed that bisphosphonates significantly reduce recurrence after curettage (p<0.01).²² The mechanism of bisphosphonate action in GCT involves multiple pathways. Bisphosphonates bind to hydroxyapatite in bone and are internalized by osteoclasts, where they inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, leading to osteoclast apoptosis.¹⁵ Additionally, bisphosphonates induce apoptosis of neoplastic stromal cells through similar mechanisms, thereby targeting both cellular components of GCT.^16,17 This dual mechanism explains their effectiveness in reducing both recurrence and local tumor activity.

Pain scores improved more rapidly and significantly in the bisphosphonate group throughout follow-up. At 6 months, mean VAS was 1.70±0.84 in Group A versus 2.97±0.89 in Group B. This enhanced pain relief likely reflects the anti-inflammatory and anti-osteolytic effects of bisphosphonates, which reduce ongoing bone destruction and periosteal irritation. Similar findings were reported by Balke et al who noted disease stabilization and symptom improvement in patients with aggressive GCT treated with bisphosphonates.²⁰

Functional outcomes, assessed using the MSTS scoring system, were consistently superior in the bisphosphonate group. At 6 months, mean MSTS was 26.9±1.53 in Group A versus 23.4±1.87 in Group B. This functional improvement correlates with better pain control, reduced local recurrence, and enhanced bone healing. The preserved joint function is particularly important given that GCT predominantly affects young adults in whom limb salvage and functional preservation are paramount goals of treatment.

Oral alendronate offers several practical advantages over intravenous bisphosphonates: ease of administration, lower cost, better accessibility, and favourable safety profile with long-term use. While intravenous zoledronic acid has been more extensively studied in GCT, oral bisphosphonates provide a more practical option for routine adjuvant therapy, particularly in resource-limited settings.^23,24 Our study supports the use of oral alendronate as an effective and accessible adjuvant in GCT management.

Limitations

This study has limitations including relatively small sample size, short 6-month follow-up duration (GCT may recur later), single-centre design, and heterogeneity in surgical adjuvants used. Longer follow-up and multi centretrials with larger sample sizes are recommended to validate these findings.

CONCLUSION

Adjuvant oral bisphosphonate therapy with Alendronate following surgical treatment of giant cell tumour of bone effectively reduces recurrence rates (3.33% vs 16.67%) while providing superior pain relief and functional recovery compared to surgery alone. The treatment is well-tolerated with minimal adverse effects. These findings support the routine use of bisphosphonate therapy as an adjuvant in surgically treated GCT of extremities, particularly in conjunction with intralesional curettage and cementation.

ACKNOWLEDGEMENTS

The authors express sincere gratitude to the faculty and staff of the Department of Orthopaedics, SMS Medical College, Jaipur, for their support during this study also acknowledging all the patients who participated in this research.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

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