Extracellular pyrophosphate (PP_i) is well known for its fundamental role as a physiochemical mineralisation inhibitor. However, information about its direct actions on bone cells remains limited. This study shows that PP_i decreased osteoclast formation and resorptive activity by ≤50 %. These inhibitory actions were associated with reduced expression of genes involved in osteoclastogenesis (Tnfrsf11a, Dcstamp) and bone resorption (Ctsk, Car2, Acp5). In osteoblasts, PP_i present for the entire (0–21 days) or latter stages of culture (7–21/14–21 days) decreased bone mineralisation by ≤95 %. However, PP_i present for the differentiation phase only (0–7/0–14 days) increased bone formation (≤70 %). Prolonged treatment with PP_i resulted in earlier matrix deposition and increased soluble collagen levels (≤2.3-fold). Expression of osteoblast (RUNX2, Bglap) and early osteocyte (E11, Dmp1) genes along with mineralisation inhibitors (Spp1, Mgp) was increased by PP_i (≤3-fold). PP_i levels are regulated by tissue non-specific alkaline phosphatase (TNAP) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). PP_i reduced NPP1 expression in both cell types whereas TNAP expression (≤2.5-fold) and activity (≤35 %) were increased in osteoblasts. Breakdown of extracellular ATP by NPP1 represents a key source of PP_i. ATP release from osteoclasts and osteoblasts was decreased ≤60 % by PP_i and by a selective TNAP inhibitor (CAS496014–12-2). Pertussis toxin, which prevents Gαi subunit activation, was used to investigate whether G-protein coupled receptor (GPCR) signalling mediates the effects of PP_i. The actions of PP_i on bone mineralisation, collagen production, ATP release, gene/protein expression and osteoclast formation were abolished or attenuated by pertussis toxin. Together these findings show that PP_i, modulates differentiation, function and gene expression in osteoblasts and osteoclasts. The ability of PP_i to alter ATP release and NPP1/TNAP expression and activity indicates that cells can detect PP_i levels and respond accordingly. Our data also raise the possibility that some actions of PP_i on bone cells could be mediated by a Gαi-linked GPCR.