Daily subcutaneous injections of parathyroid hormone (PTH), or its biologically-active amino-terminal fragments, increase bone formation dramatically, and "cure" estrogen-deficiency trabecular and cortical osteoporosis in rats. PTH's effects on bone formation are also dramatic in humans but its effects on bone mass are much smaller in humans than in rats: there is no increase in cortical bone and the increase in trabecular bone is not large enough to reverse the effects of chronic estrogen deficiency completely. The anabolic effects of PTH on trabecular and cortical bone are linearly dose-dependent in rats. PTH doses used in humans are much lower than those used in rats, because PTH has a greater hypercalcemic effect in humans. We believe this results from a species difference in the skeletal calcium-mobilizing and bone- resorbing effects of PTH. By administering an anti-resorptive drug to PTH-treated osteoporotic humans, we believe it will be possible to augment PTH's anabolic effects on their skeleton. In experimental animals, this strategy had variable success, varying with the species or the anti-resorptive regimen. To test whether an anti-resorptive agent enhances PTH's ability to increase bone mass in osteopenic postmenopausal women, we will give them exogenous parathyroid hormone chronically and serially measure their bone mass in the spine, hip, arm, and total body with dual-energy x-ray absorptiometry as PTH administration is either continued, supplemented with alendronate, switched to alendronate, or withdrawn. Such an experiment provides an unusual opportunity to investigate bone resorption-formation coupling in humans. The relative importance of newly-synthesized growth factors, vs. pre-formed growth factors released locally by bone resorption, to PTH's skeletal anabolic effects in humans is unclear. If the liberation of pre-formed growth factors is unnecessary for the skeletal anabolic effect of PTH in humans, as we hypothesize, then concomitant treatment with an agent that blocks bone resorption will not reduce PTH's ability to stimulate bone formation. We plan to test this hypothesis in postmenopausaI osteoporotic women by treating them with PTH until their bone resorption is increased and then adding alendronate and following serial changes in serum and urine indices of type I collagen secretion and degradation, and skeletal retention of tracer radioactivity, as their elevated bone resorption is suppressed to control levels by the addition of alendronate. We will make parallel observations in appropriate control patients.