Bisphosphonates Therapy in Pediatric Hemato-Oncological Setting

Abstract

The identification of the receptor activator of NF-kappaB ligand (RANKL) /RANK/OPG (osteoprotegerin) system and bisphosphonates (BPs) represents a major advance in bone biology. BPs have also recently become important in the management of tumor-induced osteoclastgenesis, and they now have a widely recognized role for adult patients with malignancy. However, in pediatric hemato-oncological settings, clinical use of BPs is limited except for tumor-induced hypercalcemia. First, in this present review we summarize BP therapy for tumor-induced hypercalcemia and bony morbidity as a complication of treating acute lymphoblastic leukemia. Secondary, we summarize the role of the RANKL /RANK / OPG system in osteolytic lesion and the efficacy of nitrogen-containing BPs due to direct antitumor effect via the inactivation of Ras proteins as a result of these biochemical effects on the mevalonate pathway (leading to caspase-dependent apoptosis, inhibiting matrix metalloproteinases and angiogenesis, and downregulating integrins) and due to indirect anti-tumor effect by expanding γδT cells. Finally, we present our preclinical and clinical study of BP therapy for Langerhans cell histiocytosis (LCH) with refractory osteolytic lesions and discuss the role of RANKL + T cell and abnormal differentiation of myeloid-derived dendritic cells in LCH. Furthermore we highlight now ongoing preclinical BP therapy studies on advanced neuroblastoma with bone metastases, Ph+ leukemia, γδT cell immunotherapy and cancer-induced bone pain. Further preclinical studies are ongoing to fully elucidate these biochemical mechanisms, and well-designed clinical trials are necessary to investigate whether the anti-tumor potential of BPs can be realized in the clinical setting.