Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by
osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic
Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for
the treatment of osteosarcoma and Ewing sarcoma. The beneicial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl
Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated
to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential
therapeutic beneit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma,
as a prerequisite before translation to patients. The effects of ZA (100 µg/kg) and L-mifamurtide (1 mg/kg) were
investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation,
spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological
and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection
and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association
induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide
has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor
site whatever the treatment. This study evidenced for the irst time a signiicant inhibition of primary osteosarcoma
progression when both drugs are combined. This result constitutes a irst proof-of-principle for clinical application in osteosarcoma patients