The aim of this study was to evaluate the regeneration of bone defects created in the femoral condyle of osteoporotic rats, following intravenous (IV) zoledronate (ZA) treatment in three settings: pre-bone grafting (ZA-Pre), post-bone grafting (ZA-Post), and pre- plus post-bone grafting (ZA-Pre+Post). Twenty-four female Wistar rats were ovariectomized (OVX). After 12 weeks, bone defects were created in the left femoral condyle. All defects were grafted with a particulate inorganic cancellous bovine bone substitute. ZA (0.04 mg/kg, weekly) was administered to six rats 4 weeks pre-bone graft placement. To another six rats, ZA was given post-bone graft placement creation and continued for 6 weeks. Additional six rats received ZA treatment pre- and post-bone graft placement. Control animals received weekly saline intravenous injections. At 6 weeks post-bone graft placement, samples were retrieved for histological evaluation of the bone area percentage (BA%) and remaining bone graft percentage (RBG%). BA% for ZA-Pre (50.1 ± 3.5%) and ZA-Post (49.2 ± 8.2%) rats was significantly increased compared to that of the controls (35.4 ± 5.4%, p-value 0.031 and 0.043, respectively). In contrast, ZA-Pre+Post rats (40.7 ± 16.0%) showed similar BA% compared to saline controls (p = 0.663). For RBG%, all experimental groups showed similar results ranging from 36.3 to 47.1%. Our data indicate that pre- or post-surgical systemic IV administration of ZA improves the regeneration of bone defects grafted with inorganic cancellous bovine-bone particles in osteoporotic bone conditions. However, no favorable effect on bone repair was seen for continued pre- plus post-surgical ZA treatment.