Introduction: As an age-associated metabolic disease of the skeleton, osteoporosis (OP) causes a significant medical and socio-economic burden. One of the challenges in clinical practice is the adverse effects of widely used bisphosphonates. Therefore, the search for preventive pharmacotherapeutic strategies is needed. Materials and Methods: Sixty female Wistar rats randomized into 6 equal groups were used to study the effects of a single and prolonged intravenous administration of zoledronic acid ( ZA ) without and in combination with an endothelioprotective dose of resveratrol (2 mg/kg intraperitoneally daily), compared with sham-operated and osteoporotic animals. X-ray densitometry and histological methods were used. Results and Discussion: Already at 4 weeks after bilateral ovariectomy (OVx), the typical signs of osteoporotic lesions comparable with OP in humans are present. A single administration of ZA following 4 weeks of OP had a significant corrective effect on bone structure and the fatty component of bone marrow. After a second dose of ZA at 8 weeks after OVx, signs of bone damage were detected by week 12. The addition of 4 weeks of resveratrol therapy after the second dose of ZA (until 12 weeks after OVx) leads to switching of bone marrow precursors to osteoblastic differentiation, reducing the adipocytic component; cytoprotective action on osteocytes with their switching to a synthetic phenotype, reducing the potential activation of osteoclasts and blocking periosteocytic osteolysis; and protection of bone vessels via the endothelioprotective properties of resveratrol . Conclusion: An endothelioprotective dose of resveratrol exerts multitarget cell- and endothelium-dependent mechanisms of protective action when combined with prolonged zoledronic acid therapy, preventing its adverse effects.