In mature dogs with comparable levels of bone remodeling, we produced either increased (with adenosine triphosphate) or decreased (with epinephrine) blood flow to one hindlimb. In 13 dogs (five control, four with increased flow, and four with decreased flow), we compared uptake, at 3 h after injection of radiolabeled diphosphonate in the mid-tibia, with blood flow as determined by microspheres. Blood flow was determined with 85Sr-labeled microspheres, and determination of uptake of 99mTc methylene diphosphonate (99mTc-MDP) was by a gamma detector. There was a linear relationship between changes in diphosphonate uptake and changes in blood flow at decreased and normal flows; however, at high flows the relationship was nonproportional, indicating a disproportionately slower increase in 99mTc-MDP uptake with increasing blood flow. In six dogs an initial 1-h uptake curve of 99mTc-MDP was determined in both control and experimental limbs under states of increased and decreased blood flow. The 30-min uptake value, 60-min uptake value, area under the curve, and the slope of the curve were related to flow as determined by microspheres. The data are consistent with the hypothesis that deposition of bone-concentrating isotopes such as 99mTc-MDP is partly controlled by blood flow; at supranormal and normal flows tracer uptake is closely related to blood flow, but at supranormal flow rates it is not and appears to be diffusion limited.