**Acknowledgements**

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

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

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

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 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 associ-

ated with GCTB malignant transformation and recurrence. This raises the hypothesis that cyclin-dependent kinase (CDK) inhibitors (e.g., ribociclib,

GCTB medical management needs to be better clarified.

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

*Recent Advances in Bone Tumours and Osteoarthritis*

**5. Conclusions and future directions**

clearly defined.

results.

**62**

of life impairment.

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