Bone Morphogenetic Proteins (BMPs) strongly induce the recruitment and differentiation of mesenchymal progenitor cells into mature osteoblasts, but also directly and indirectly stimulate differentiation of osteoclast progenitor cells and acceleration of mature osteoclasts function leading excessive bone resorption. Bisphosphonates, such as zoledronate (ZOL), inhibit osteoclasts function and osteoclasts mediated bone resorption. The short or middle term effect of BMP5 and bisphosphonates on bone formation were previously reported, but there was no study that argue about the long term effect of bisphosphonates on BMP-induced bone anabolism. The present study demonstrated that the local administration of ZOL with recombinant human BMP-2 (rh-BMP-2) using beta tricalcium phosphate ((3TCP) as a carrier had superior efficacy not only to augment the BMP-induced new ectopic bone formation but to maintain the trabecular bone structure inside the new bone for long period. Histological analysis showed that rh-BMP-2/I3-TCP composite induced trabecular bone resorption especially inside the new bone nodules over time, whereas no trabecular bone resorption was seen in rh-BMP-2/ZOL/P-TCP composite reducing the number of TRAP-positive cells. Thus, inhibition of bone resorption by bisphosphonate, such as ZOL, would be one of the advantageous ways to augment the new bone formation induced by rh-BMP-2, and moreover local co-application of ZOL using D-TCP as a carrier can be a useful material for long term suppression of osteoclastic resorption and thereby maintain the structure of new bone formation induced by rh-BMP-2. (C) 2016 Elsevier Inc. All rights reserved.