**4. Medical therapy**

### **4.1 Denosumab**

Denosumab is a fully human monoclonal antibody (IgG2) that binds with high affinity and specificity to RANKL [74], thereby inhibiting osteoclast-mediated osteolysis. Given GCTB pathophysiology and its association to RANKL/RANK pathway, denosumab has proven effective in this disease.

In patients with resectable GCTB, adjuvant denosumab at a 120 mg dosage administered subcutaneously every 28 days, with additional loading doses on days 8 and 15 on the first month, during 6 months after complete resection has been approved by both the Food and Drug Administration and European Medicines Agency [72, 75, 76]. However, this treatment is still debated. Studies supporting its use in the adjuvant setting are scarce and mostly rely in level IV evidence. Conversely, evidence from a systematic review by Luengo-Alonso [72] favored adjuvant denosumab, which showed a positive histological and clinical (pain relief) response. In patients with unresectable GCTB (either primary or recurrent) or when complete excision is possible but post-surgical severe morbidity and functional impairment is expected, neoadjuvant denosumab should be started (same dosing scheme as above) and response to treatment evaluated. Should the patient respond to denosumab and surgery be feasible with acceptable morbidity, then complete excision and possibly adjuvant denosumab for six months should be considered. On the other hand, the optimal denosumab duration is still debatable when treatment response is suboptimal or in cases of sacral or spinal GCTB, multiple lesions (including pulmonary metastases), or patient's clinical ineligibility for surgery. Denosumab should be considered until progression or unacceptable toxicity (e.g., osteonecrosis of the jaw), provided at least partial response is achieved.

## **4.2 Bisphosphonates**

Bisphosphonates inhibit osteoclast-mediated bone resorption and are used in cancer patients, especially in bone metastases setting. In GCTB patients, denosumab is the preferred systemic treatment option. However, evidence regarding the use of adjuvant denosumab is not consistent and some studies show lack of benefit in local recurrence rates [77, 78]. Bisphosphonates, like zoledronic acid (ZA), can be an

option in the adjuvant setting. A recent meta-analysis of case–control studies showed that the use of adjuvant bisphosphonates in patients submitted to intralesional curettage may decrease local recurrence rates, independently of Campanacci staging [79]. In patients undergoing wide resection, bisphosphonates seem to have no benefit in local recurrence. A phase II non-randomized clinical trial of adjuvant ZA after extensive curettage in GCTB patients showed that ZA failed to prevent local recurrence [80]. Another phase II multicentric, randomized, openlabel clinical trial showed no benefit with adjuvant ZA, although the study was terminated earlier due to poor accrual [81]. The use of adjuvant bisphosphonates should be evaluated on a case-by-case basis. In unresectable or metastatic GCTB, clinical studies addressing the use of bisphosphonates are also scarce. Overall, the role of bisphosphonates in the treatment of patients with GCTB remains to be clearly defined.

palbociclib) and MET inhibitors (e.g., crizotinib) may be useful in this disease. Although these therapies have been approved in other tumors (CDK inhibitors in breast cancer and crizotinib in lung cancer), no studies are in place in GCTB yet. Another promising target is MMPs, specially MMP-2 and MMP-9, that play an important role in GCTB physiopathology, namely regarding tumor microenvironment, angiogenesis, invasion, and metastatic development. Preclinical studies in breast cancer used ML115, a bone-seeking MMP inhibitor, to prevent bone metastases [91], with promising results. Although still far from use in the clinical practice, this could be another potential therapy worth studying in GCTB. Several other clinical trials continue to investigate the use of denosumab, bisphosphonates, and

We thank Joana Cavaco Silva for her contribution as a medical writer. Authors

local therapy (surgery/RT) [92–97].

*Medical Therapy of Giant Cell Tumor of Bone DOI: http://dx.doi.org/10.5772/intechopen.97114*

acknowledge Joana Cavaco Silva for manuscript revision.

The authors declare no conflict of interest.

BMP-2 Bone morphogenetic protein 2 CCR2 C-C chemokine receptor type 2 CXCR4 C-X-C chemokine receptor type 4 C/EBPβ CCAAT/enhancer binding protein beta

CT Computorized tomography CDK Cyclin-kinase inhibitors

GCTB Giant cell tumor of the bone

MRI Magnetic resonance imaging MMP Matrix metalloprotease

H3.3 Histone 3.3

IL-1 Interleukin 1

IgG Immunoglobulin G IHC Immunohistochemistry IGF Insulin-like growth factor

RT Radiation therapy

SC Subcutaneous

**63**

DC-STAMP Dendritic cell-specific transmembrane protein EMMPRIN Extracellular matrix metalloproteinase inducer

FFPE Formalin-Fixed Paraffin-Embedded

M-CSF Macrophage colony-stimulating factor MIP-1α Macrophage inflammatory protein 1-alpha;

MCP-1 Monocyte chemoattractant protein-1 NFATc1 Nuclear factor of activated T cells c1

PTHrP Parathyroid hormone related peptide

RUNX2 Runt-related transcription factor 2

OC-STAMP Osteoclast stimulatory transmembrane protein

RANKL Receptor activator of nuclear factor kappa-B ligand

**Acknowledgements**

**Conflict of interest**

**Nomenclature**

#### **4.3 Chemotherapy/systemic cytotoxic agents/interferon**

Chemotherapy agents and interferon-α have also been used to treat GCTB, as reported in case reports and small series, but results were poor and there are no clinical trials to guide their use. Anecdotal small retrospective case series and case reports have documented the use of doxorubicin [82, 83], cyclophosphamide [84], cisplatin plus doxorubicin [85], combination therapy with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, followed by high-dose methotrexate and vincristine [86], interferon alpha 2a [87] and interferon alpha 2b [88], with mixed results.
