In contrast to studies in vitro, in vivo tests of parathyroid gland function in human subjects with secondary hyperparathyroidism present a number of technical and theoretical difficulties. The four-parameter model was originally developed to characterize the secretion of PTH in vitro by a defined number of parathyroid cells in tissue culture, whereas comparisons among in vivo studies in patients with varying degrees of parathyroid gland hyperplasia may not be feasible with this model. Maximum serum PTH levels during hypocalcemic stimuli in vivo reflect not only the amount of PTH released by each parathyroid cell but also the total number of cells available for hormone secretion. Parathyroid gland size varies markedly in patients with secondary hyperparathyroidism, and there is currently no reliable technique for accurately measuring the amount of parathyroid tissue present. Accordingly, in vivo comparisons of calcium-regulated PTH release among subjects with parathyroid glands of substantially different sizes may not be valid with the four-parameter model. Kwan et al. have suggested that parathyroid gland function be assessed over a wide range of different calcium concentrations. In this model, the set point for calcium-regulated PTH secretion is not calculated, but the relationship between serum ionized calcium and PTH levels is examined by linear regression after semilog transformation of the data. Linearizing the calcium-PTH curve eliminates the need for more complex curve-fitting analyses. Differences in parathyroid gland function have been reported before and after calcitriol therapy when this approach is used, but the severity of secondary hyperparathyroidism varied widely in the patients evaluated. Alternatively, the Cica-clamp technique to quantify PTH secretion has been developed by Schwarz et al. By employing sequential standardized hypocalcemia and hypercalcemia, set point values obtained with this method closely agree with in vitro data obtained by Brown in normal parathyroid tissues. Advantages of the Cica-clamp technique include a shorter duration of study, reproducibility of the method, and absence of adverse effects; its utility in evaluating patients with either primary or secondary hyperparathyroidism remains to be determined. Based on data currently available, separate assessments of the pattern of change in serum PTH levels during hypocalcemia and hypercalcemia, expressed as the percent change from baseline values (see Fig 4), may provide more useful information about disturbances in the regulation of PTH release by calcium in patients with secondary hyperparathyroidism. Nevertheless, alterations in the set point for calcium-mediated PTH secretion do not adequately explain the excess PTH secretion of patients with secondary hyperparathyroidism, nor do they account for the reduction in serum PTH levels after treatment with calcitriol.