This study will expand upon earlier infusion studies in healthy Caucasian and Asian volunteers in which continuous infusions of PTH and PTHrP were given for six-, 12-, and 48 hours. These studies demonstrated: 1) There is a dose-related increase in 1,25 (OH)2 vitamin D in response to PTHrP and PTH over multiple days. 2) There is a markedly attenuated vitamin D response to PTHrP compared to PTH, particularly during the second 24 hours. 3) The increase in 1,25 (OH)2 vitamin D is almost certainly responsible for the greater calcemic effect of PTH compared to PTHrP. 4) PTHrP is obviously a weaker agonist of 1,25 (OH)2 vitamin D but does not result in its suppression as is seen in Humoral Hypercalcemia of Malignancy (HHM). Thus, the suppression of 1,25 (OH)2 vitamin D seen in HHM remains unexplained. In addition to assessing the effects of an infusion of PTHrP and PTH on calcium handling and 1,25 (OH)2 vitamin D, we also measured their effects on markers of bone turnover. Given the clinical observations seen in primary hyperparathyroidism (HPT) and HHM, we anticipated that PTH would stimulate both bone resorption and formation, while PTHrP would stimulate bone resorption but inhibit formation. However, we observed that infusions of PTHrP and PTH resulted in an equivalent, rapid increase in bone resorption as measured by N-telopeptide (NTx) and C-telopeptide (CTx), as well as a progressive decline in bone formation. There was no difference between PTH and PTHrP. Because of these findings, it was surmised that infusions of a longer duration would lead to an increase in bone formation and 1,25 (OH)2D production with both peptides, as is seen in HPT. Very recently, we have completed a seven-day infusion model in healthy Caucasian and Asian volunteers to test this hypothesis (J. Bone Min. Res., 2011). A total of 22 individuals were given either seven-day infusions of PTH or PTHrP, and maximal safe doses were found to be 2 and 4 picomoles (pmol)/kg/hour, respectively, lower than the doses used in previous, briefer infusion studies. All patients developed sustained but very mild hypercalcemia (mean = 10.3 mg/dL) and hypercalciuria with rapid increase in bone resorption. Surprisingly, bone formation again was suppressed for the entire seven days with a robust rebound in bone formation on cessation of the respective peptide. This is consistent with what may occur during lactation and HHM, but again contrary to what occurs in HPT.