Effects of zoledronic acid on osteonecrosis and acute lymphoblastic leukemia treatment efficacy in preclinical models.

Abstract

Osteonecrosis is a devastating side effect of acute lymphoblastic leukemia (ALL) therapy. Associations between bone density loss and osteonecrosis have sparked interest in using bisphosphonates to reduce this complication. We assessed the impact of zoledronic acid (ZA) on the development of osteonecrosis in murine models when used either throughout therapy (continuous administration) or late in therapy after vascular lesions have developed but before osteonecrosis has occurred. Effects on bone density were measured using microcomputed tomography (μCT)-assessed tibial cortical thickness, while osteonecrosis was assessed histologically in the distal femur. Effects on antileukemic efficacy of chemotherapy were evaluated in both immunocompetent/syngeneic and patient-derived xenograft (PDX) models. Continuous administration of ZA with chemotherapy prevented chemotherapy-associated bone loss (p<.001) and reduced osteonecrosis (p=.048). Late initiation of ZA diminished bone loss (p<.001) but had no impact on the development of osteonecrosis (p=.93). In the immunocompetent murine ALL model, mice treated with ZA and chemotherapy succumbed to leukemia sooner than mice treated with chemotherapy alone (p=.046). Analysis using PDX showed a nonsignificant decrease in survival with ZA (p=.17). Our data indicate ZA may prevent osteonecrosis if begun with chemotherapy but showed no benefit when administered later in therapy. However, ZA may also reduce the antileukemic efficacy of chemotherapy.