The Role of Mifamurtide in Chemotherapy-induced Osteoporosis of Children with Osteosarcoma

Abstract

Background: Osteosarcoma is the most frequent malignant bone tumor in childhood and young adulthood. Long-term survivors of osteosarcoma patients show high prevalence of osteoporosis and fractures. The immunomodulatory mifamurtide, which modulates macrophages activity, improves disease outcome.

Objective: To evaluate the role of mifamurtide on macrophage component of bone, the osteoclasts, during chemotherapy in children with osteosarcoma.

Method: Osteoclasts, obtained from peripheral blood cells of healthy donors were harvested in the presence or not of mifamurtide. Moreover, osteoclast cultures were obtained from osteosarcoma patients, at onset and during chemotherapy, alone or with mifamurtide. Pro-osteoporotic tartrateresistant acid phosphatase (TRAP), phosphokinase-β-2 (PKCβ2), vanilloid receptor type 1 (TRPV1), and anti-osteoporotic cannabinoid receptor type 2 (CB2) biomarkers were analyzed by bio-molecular (qPCR), biochemical (Western Blotting), and morphological (TRAP assay) approaches.

Results: Osteoclasts from osteosarcoma patients show significant increase of TRAP and decrease of CB2 with respect to osteoclasts from healthy donors. This osteoclast hyperactivity is more evident in osteoclasts from osteosarcoma patients during chemotherapy. Mifamurtide reduces pro-osteoporotic TRAP, PKCβ2, TRPV1 levels and increases CB2 in osteoclasts from healthy donors. Moreover, chemotherapy-induced effects on bone resorption markers are fully reverted in osteoclasts derived from osteosarcoma patients in chemotherapy plus mifamurtide.

Conclusion: Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma.

Keywords: Osteosarcoma-associated bone loss; cancer associated disease; osteoclast activation; osteosarcoma follow-up; resorption; tumor outcome.