**5. Conclusions and future directions**

GCTB is a primary and mostly benign tumor of bone usually arising in the metaepiphysis of long bones and more often affecting young patients. Despite its frequent benign nature, local recurrence rate is high and there is a non-negligible risk of distant metastization, namely to the lungs. Therefore, treatment should provide the best chance of curative outcome with minimal functional sequelae and quality of life impairment.

The main pillar of treatment is surgery, but systemic therapy has a role in adjuvant and palliative settings. Regarding GCTB pathophysiology, RANKL/RANK pathway is central to tumor development and denosumab, a monoclonal antibody against RANKL, is the most studied and most effective systemic therapy for the disease. Its use is particularly established in the palliative setting, i.e., in cases of unresectable disease, patient ineligibility for surgery, or lung involvement. Although less studied, bisphosphonates can also be an option. However, their role in GCTB medical management needs to be better clarified.

GCTB rare nature, particularly malignant GCTB, hampers the development of clinical trials to investigate new drugs for second-line treatment and establish the optimal treatment sequence (neo- vs. adjuvant denosumab or adjuvant denosumab vs. after recurrence, etc.). Currently, one clinical trial (NCT04255576) is studying the use of JMT103, a novel fully human IgG4 monoclonal antibody against RANKL, in GCTB [89]. Another clinical trial (NCT03449108) is using a different approach to address bone tumors, including GCTB [90], by studying the use of LN-145-S1, or autologous tumor infiltrating lymphocytes, in treatment-refractory or relapsed disease. As discussed above, mutations in cyclin D1, p53, and MET have been associated with GCTB malignant transformation and recurrence. This raises the hypothesis that cyclin-dependent kinase (CDK) inhibitors (e.g., ribociclib,

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

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 local therapy (surgery/RT) [92–97].
