PTH-related protein-(107-139) [PTHrP-(107-139)] has been reported previously to be a potent inhibitor of osteoclast activity. However, this finding has not been reproduced in other in vitro models. We have now examined the effects of this peptide in an in vivo model, employing intact adult mice. Four groups of eight male mice were given injections of either vehicle or one of three doses of PTHrP-(107-139) (4 x 10(-13), 4 x 10(-11), or 4 x 10(-9) mol) over the periosteum of the right hemicalvaria for 5 consecutive days. The animals were killed 1 week after the last injection. There were significant decreases in bone resorption indexes after all doses of PTHrP-(107-139), with a 70% decrease in osteoclast number (P < 0.001), a 70% decrease in osteoclast perimeter (P = 0.004) and a 50% decrease in eroded perimeter (P = 0.001). In addition, some indexes of bone formation were significantly decreased, with 40% decreases in both osteoblast number (P = 0.05) and osteoblast perimeter (P = 0.02), but no significant change in osteoid area. There was a dose-related upward trend in mineralized bone area, reaching 12% at the highest dose, but this was not statistically significant. It is concluded that PTHrP-(107-139) is a potent inhibitor of bone resorption in vivo. As this model is very dissimilar to that of isolated osteoclasts, in which this peptide is also active, the present findings suggest that osteoclast inhibition is an authentic action of the C-terminus of PTHrP, which may, therefore, play a role in the regulation of bone turnover in vivo.