Although primary hyperparathyroidism today is often a relatively asymptomatic disease, it has distinct biochemical and skeletal features. These features are present at diagnosis and are generally stable over time, leading to the theory of a biphasic disease course in which alterations occur during a preclinical phase. Measurement of calciotropic hormones in individuals undergoing skeletal evaluation has led to the identification of normocalcemic individuals with elevated PTH levels. We hypothesize that these patients represent the earliest manifestations of primary hyperparathyroidism Twenty-two patients had hyperparathyroidism (94 +/- 29 pg/ml) and normal corrected serum calcium levels (2.40 +/- 0.02 mmol/liter). No secondary causes of hyperparathyroidism were found. PTH levels did not correlate with urinary calcium concentration, renal function, vitamin D concentrations, or bone density. The relationship between PTH and serum calcium (regression slope, +0.004) was identical in normocalcemic and hypercalcemic hyperparathyroid patients. Preferential cortical bone loss, characteristic of patients with primary hyperparathyroidism, was not seen (T-score: spine, -1.6; hip, -1.8; distal one-third radius, -1.3). In up to 12 months of observation, three patients have developed hypercalcemia, and one has had two adenomas removed. These patients with elevated PTH levels in the absence of hypercalcemia may provide a window into this previously unrecognized stage of the disease and permit investigators to track its evolution in ways that have not heretofore been possible.