Spontaneous recovery of parathyroid secretion during correction of tumor-associated hypercalcemia by bisphosphonates provides a unique clinical opportunity to further unravel the complex relationship between Ca and PTH levels. We measured plasma ionised Ca (Ca2+) and serum intact PTH concentrations in 31 hypercalcemic cancer patients every 2 (range, 1-3) days over a period of 3-21 (median, 7) days after pamidronate therapy. The mean (+/- SD) initial Ca2+ concentration was 1.64 +/- 0.20 mmol/L (normal, 1.05-1.26 mmol/L), with a corresponding PTH level of 4.9 +/- 2.6 (median, 4.5; range, less than 2.0-14.7) ng/L. PTH levels were subnormal in 30 of 31 patients. During correction of hypercalcemia, the relationship between Ca2+ and PTH concentrations was best described by a polynomial regression (r = 0.89; P less than 0.001). The curve of the regression entered the normal range of PTH levels (10.5 ng/L) for a Ca2+ concentration of 1.21 mmol/L. Similarly, the mean Ca2+ level that caused a reproducible increase in PTH levels compared to baseline values was 1.21 +/- 0.12 (median, 1.17; range, 1.00-1.45) mmol/L. Comparable values were obtained when day to day variations in PTH levels were considered; the mean Ca2+ threshold level was 1.24 +/- 0.12 (median, 1.25; range, 1.00-1.43) mmol/L. This PTH secretory threshold was not significantly influenced by several factors, including the type of cancer hypercalcemia, the day to day variations in Ca2+ levels, various biochemical parameters of calcium metabolism, or the number of days to obtain a normal Ca2+ concentration. In summary, contrary to previous reports, our data show that the PTH secretory threshold during correction of tumor-associated hypercalcemia lies in the upper part of the normal range of Ca2+ concentrations and is not significantly influenced by the rate of change in Ca2+ levels.