Studies on the mechanisms of the skeletal anabolic action of endogenous and exogenous parathyroid hormone

Parathyroid hormone (PTH) has been viewed as catabolic for bone. Nevertheless, exogenous PTH is anabolic when administered intermittently, at a frequency that permits complete clearance between doses. In the fetus and neonate, endogenous PTH is required for normal trabecular bone formation. In older animals PTH produces net bone loss in fulfilling its calcium homeostatic role, whereas PTH-related peptide (PTHrP), acting in a paracrine/autocrine mode, is anabolic. The proliferative, differentiating, and anti-apoptotic effects of PTH on cells of the osteoblast lineage leading to anabolism can be direct, or indirect via release of local growth factors. The anabolic effect of PTH is also influenced by osteoclastic activity such that suppression of osteoclasts with anti-resorptive agents, concomitant to administering PTH, may enhance the anabolic effect by delaying a reactive osteoclastic response. In contrast, prolonged suppression of osteoclast activity prior to administering PTH appears to diminish molecular signals that increase the osteoblast pool and thereby reduces the anabolic efficacy of PTH. These observations may define the proper timing of the use of PTH as a therapeutic in diseases of bone loss. Finally, the capacity of exogenous PTH to modulate extra-osseous factors such as 1,25 dihydroxyvitamin D may also modulate its potency as an anabolic agent.