The capacity of bone to adapt its architecture in response to changing mechanical demands is well recognized. However, the mechanisms by which mechanical stimuli are translated into new bone formation are poorly understood. Prostaglandins (PGs) may play a role. We therefore tested the effect of indomethacin on the cancellous bone formation induced by mechanical stimulation in the 8th caudal vertebrae of adult rats. Rats were given indomethacin 3 h before loading, 3 h before loading and daily thereafter, 6 h after loading, or 6 h after loading and daily thereafter. The increase in bone formation caused by loading was suppressed by a single dose of indomethacin if given before but not after loading. Daily administration of indomethacin suppressed the mechanical response, even when started after loading. These results suggest that PGs are essential for the transduction of mechanical stimuli into bone formation, and also that there may be two distinct phases of PG dependency in the response of bone to mechanical loading:​ an early phase associated with the immediate loading period and a later phase associated with osteogenic interactions entrained by the early phase.