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Cadmium (Cd), an environmental pollutant, induces osteoporosis by directly destroying bone tissue, but its direct damaging effect on bone cells is not fully illustrated. Here, we treated mouse bone marrow stem cells (BMSC) and bone marrow macrophages (BMM) with Cd, and gave BALB/c mice Cd in water. Long-term Cd exposure significantly inhibited BMSC osteogenesis and osteoclast differentiation in vitro , and induced osteoporosis in vivo. Cd exposure also reduced P2X7 expression dramatically. However, P2X7 deletion significantly inhibited osteoblast and osteoclast differentiation; P2X7 overexpression obviously reduced the suppression effect of Cd on osteoblast and osteoclast differentiation. The suppression of P2X7–PI3K–AKT signaling aggravated the effect of Cd. In mice, short-term Cd exposure did not result in osteoporosis, but bone formation was inhibited, RANKL expression was increased, and osteoclasts were significantly increased in vivo. In vitro , short-term Cd exposure not only increased osteoclast numbers, but also promoted osteoclast adhesion function at late-stage osteoclast differentiation. Cd exposure also reduced P2X7 expression in vivo and in vitro. Our results demonstrate that short-term Cd exposure does not affect osteoblast and osteoclast apoptosis in vivo and in vitro , but long-term Cd exposure significantly increases bone tissue apoptosis. Overall, our results describe a novel mechanism for Cd-induced osteoporosis. ga1 • Long-term Cd exposure induced osteoporosis in mice. • Cd exposure decreased P2X7 greatly in vitro and in vivo. • In vitro , deleting P2X7 inhibited osteoblast and osteoclast differentiation. • Cd exposure inhibited osteogenesis and osteoclast differentiation in vitro. • P2X7 overexpression decreased this suppressive effect of Cd. [ABSTRACT FROM AUTHOR]