Giant Cell Tumor of Bone in Childhood: Clinical Aspects and Novel Therapeutic Targets

Abstract

Giant cell tumor of bone (GCTB) is a rare primary bone tumor that primarily affects young adults, but can be seen in children. The primary modality of treatment is surgical resection; however, this is not always possible given the location and extent of the neoplasm. Recent developments in the understanding of the underlying molecular pathogenesis of disease have pointed to interactions between the stromal component producing receptor activator of nuclear factor-kappaB (RANK) and RANK-ligand (RANKL) causing the formation of osteoclast-like giant cells that drive bone destruction. The development of a monoclonal humanized antibody to RANKL, denosumab, has been shown to reduce skeletal-related events from osteoporosis and from bony metastases from solid tumors. Recent phase II clinical trials with denosumab in skeletally mature adolescents over age 12 years and adults with GCTB, have shown both safety and efficacy, leading to its accelerated US FDA approval on 13 June 2013. In children who are skeletally immature, safety and efficacy has not been established, and there has been only published anecdotal use.

Bone resorption: an actor of dental and periodontal development?

“…These powerful pharmacological inhibitors were developed for the treatment of pathologies characterized by excessive bone resorption such as juvenile Paget's disease, osteoporosis, primary or metastatic bone tumors and familial expansile osteolysis (Silverman, 2011 ; Zwolak and Dudek, 2013 ; Tella and Gallagher, 2014 ). In pediatric patients, a RANKL-blocking antibody (Denosumab) is currently under clinical evaluation for osteogenesis imperfecta (phase 2 clinical trial NCT01799798) and for Giant Cell Tumor of Bone (phase 2 clinical trial NCT00680992) with promising preliminary reports in both cases (Semler et al, 2012 ; Chawla et al, 2013 ; Karras et al, 2013 ; Demirsoy et al, 2014 ; Federman et al, 2014 ). Bisphosphonates are currently used for the treatment of osteogenesis imperfecta (Barros et al, 2012 ; Bishop et al, 2013 ; Ward and Rauch, 2013 ; Sousa et al, 2014 ) and juvenile Paget's disease (Demir et al, 2000 ; Cundy et al, 2004 ; Polyzos et al, 2010 ; Saki et al, 2013 ).…”

Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases

“…D enosumab, a monoclonal antibody against RANKL, has been used successfully to treat diseases associated with osteoclast overactivity, including giant cell tumor of bone (GCTB), osteoporosis, and lytic lesions associated with bony metastases. (1)(2)(3) Increasingly, denosumab has been used offlabel for other disorders of bone thought to result, at least in part, from similar osteoclastic pathology. These include central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), cherubism, and fibrous dysplasia (FD).…”

Prompt clinical and biochemical response to denosumab in a young adult patient with craniofacial fibrous dysplasia

“…240 mg/year) to obtain the pain relief and that during the follow-up no drug holiday could be applied. Therefore, the long-term safety of this Dmab treatment schedule might be a matter of concern in these subjects (17). Our patient showed a transient secondary hyperparathyroidism and hypovitaminosis D. The increase of PTH levels after the first Dmab administration is in keeping with data in patients with osteoporosis or FD treated with intravenous bisphosphonates or Dmab (9, 10) The persistent hypovitaminosis D could be due in part to the elevated consumption due to the hyperactivation of 1-α-hydroxylase enzyme, secondary to PTH increase.…”