Parathyroid hormone-related protein-(1-36) stimulates renal tubular calcium reabsorption in normal human volunteers: Implications for the pathogenesis of humoral hypercalcemia of malignancy

All would agree that hypercalcemia occurs among patients with humoral hyper calcemia of malignancy (HHM) as a result of osteoclastic bone resorption. S ome studies suggest that enhanced renal calcium reabsorption, which plays a n important pathophysiological role in the hypercalcemia occurring in prima ry hyperparathyloidism, is also important pathophysiologically in HHM. Othe r studies have not agreed. In large part, these differences result from the inability to accurately assess creatinine and calcium clearance in critica lly ill subjects with HHM. To circumvent these issues, we have developed st eady state 48-h PTH-related protein (PTHrP) infusion and 8-h hypercalcemic calcium clamp protocols. These techniques allow assessment of the effects o f steady state PTHrP and calcium infusions in normal healthy volunteers in a setting in which renal function is stable and measurable and in which the filtered load of calcium can be matched in PTHrP- and calcium-infused subj ects. Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subj ects receiving PTHrP, as expected, displayed mild hy percalcemia (10.2 mg/d L), suppression of endogenous PTH-(1-84), and phosphaturia. Subjects receiv ing the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hyperca lcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp gr oup was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the P THrP-infused subjects was approximately 50% lower (between 2.5-3.7%), and n o different from that in the normal controls, which ranged from 1.5-3.0%. These studies demonstrate that PTHrP is able to stimulate renal calcium rea bsorption in healthy volunteers. These studies suggest that PTHrP-induced r enal calcium reabsorption, in concert with the well established acceleratio n of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.