The deposition of mineralized bone matrix by differentiated osteoblasts was studied in rats in vivo by labeling the bone with three doses of tetracycline given at 48-h intervals. Only bone formation loci bearing all three tetracycline doses were measured, thus eliminating sites where bone formation was not continuous during the labeling period. Using this technique, the effects of intact bovine parathyroid hormone [bPTH-(1-84)] and of a synthetic amino-terminal fragment of human PTH [hPTH-(1-34)] were measured in thyroparathyroidectomized animals. bPTH-(1-84), administered sc, and hPTH-(1-34), administered iv, caused a dose-dependent increase in the bone apposition. Subcutaneous administration of hPTH-(1-34) in doses varying from 2.7-173.0 pmol/rat.day had no effect, probably due to the degradation of the hormone when administered this way. We also compared the effects of bPTH-(1-84) when administered by either daily sc injections or continuous infusion. Continuous infusion of bPTH-(1-84) resulted in an increased apposition rate. Using a morphometric technique, we also found an increase in both formation and resorption surfaces and a net decrease in the trabecular bone volume in this group. Daily injection of the hormone caused an increase in the bone apposition rate, accompanied by an increase in the formation surface without an increase in the resorption surface. This resulted in a net increase in trabecular bone volume. The results thus suggest that the resorptive effects of bPTH-(1-84) can be separated from the effects of the hormone on the apposition rate.

Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis. The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors (PTH1Rs), which mediate the classical biological actions of the hormone. It is well known that multiple carboxyl-terminal fragments of PTH are present in blood, where they comprise the major form(s) of circulating hormone, but these fragments have long been regarded as inert by-products of PTH metabolism because they neither bind to nor activate PTH1Rs. New in vitro and in vivo evidence, together with older observations extending over the past 20 yr, now points strongly to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone. This review traces the development of this field in the context of the evolution of our understanding of the "classical" receptor for amino-terminal PTH and the now convincing evidence for these receptors for carboxyl-terminal PTH. The review summarizes current knowledge of the structure, secretion, and metabolism of PTH and its circulating fragments, details available information concerning the pharmacology and actions of carboxyl-terminal PTH receptors, and frames their likely biological and clinical significance. It seems likely that physiological parathyroid regulation of calcium and bone metabolism may involve receptors for circulating carboxy-terminal PTH ligands as well as the action of amino-terminal determinants within the PTH molecule on the classical PTH1R.