Impact of oncopediatric dosing regimen of zoledronic acid on bone growth: preclinical studies and case report of an osteosarcoma pediatric patient.

Osteosarcoma and Ewing sarcoma represent the two most frequent primary bone tumors that arise in the pediatric population. Despite recent improvement in their therapeutic management, no improvement in survival rate has been achieved since early 1980 s. Among new therapeutic approaches, bisphosphonates are promising candidates as potent inhibitors of bone resorption. However, their effects on bone growth must be studied at dosing regimen corresponding to pediatric protocols. To this aim, several protocols using zoledronic acid (ZOL) were developed in growing mice (50 µg/kg every 2 days × 10). Parameters of bone remodeling and bone growth were investigated by radiography, micro-computed tomography, histology, and biologic analyses. Extramedullar hematopoiesis was searched for in spleen tissue. A transient inhibitory effect of ZOL was observed on bone length, with a bone-growth arrest during treatment owing to an impressive increase in bone formation at the growth plate level (8- to 10-fold increase in BV/TV). This sclerotic band then shifted into the diaphysis as soon as endochondral bone formation started again after the end of ZOL treatment, revealing that osteoclasts and osteoblasts are still active at the growth plate. In conclusion, endochondral bone growth is transiently disturbed by high doses of ZOL corresponding to the pediatric treatment of primary bone tumors. These preclinical observations were confirmed by a case report in a pediatric patient treated in the French OS2006 protocol over 10 months who showed a growth arrest during the ZOL treatment period with normal gain in size after the end of treatment.

Preclinical evidence that use of TRAIL in Ewing's sarcoma and osteosarcoma therapy inhibits tumor growth, prevents osteolysis, and increases animal survival.

PURPOSE: Osteosarcoma and Ewing's sarcoma are high-grade neoplasms typically arising in the bones of children and adolescents. Despite improvement in therapy, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. Among new therapeutic strategies, the efficacy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models. EXPERIMENTAL DESIGN: The sensitivity of osteosarcoma and Ewing's sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing's sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells. RESULTS: In vitro, both osteosarcoma and Ewing's sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8-mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model. CONCLUSION: These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors.