Bisphosphonates, the main drugs to treat osteoporosis, have been shown to protect against bone loss in diabetic osteoporosis. However, the effects of the bisphosphonate zoledronate (ZOL) on osteoclast differentiation and function in a high glucose environment as well as the involvement of the adenosine activated protein kinase (AMPK) pathway remain unclear. In the current study, RAW264.7 cells were induced into osteoclasts, divided into low glucose, high glucose, low glucose + ZOL, and high glucose + ZOL groups, which were tested for cell proliferation, cell migration, integrity of the osteoclast sealing zone, osteoclast differentiation, bone absorption, and protein and mRNA expression of genes in the AMPK pathway. We demonstrated that high glucose promoted the expression of AMPK, p-AMPK, while inhibited nuclear factor of activated T cells 1 (NFATc1), spleen tyrosine kinase (SYK), cathepsin K (CTSK), and tartrate-resistant acid phosphatase (TRAP), which influenced osteoclast differentiation and bone absorption. Upon addition of ZOL to high glucose, the expression of AMPK, p-AMPK increased and the expression of NFATc1, SYK, CTSK, TRAP decreased, while osteoclast differentiation and bone absorption were further inhibited. Further more, when added Compound C (AMPK antagonist), we found the expression of AMPK, p-AMPK, decreased, whereas NFATc1, SYK, and TRAP increased. In contrast, AMPK and p-AMPK increased and NFATc1, SYK, CTSK and TRAP decreased upon addition of AICAR, an AMPK agonist. In conclusion, the results suggest AMPK has potential as a new target for the treatment of osteoporosis, the high glucose environment promoted RAW264.7 cell migration, but suppressed osteoclast differentiation and bone absorption, and ZOL suppressed osteoclast migration, differentiation, and bone absorption via the AMPK pathway. (C) 2018 The Authors. Published by Elsevier Inc.