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 beneficial 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 benefit 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 first time a significant inhibition of primary
osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in
osteosarcoma patients.