Context. Patients with elevated parathyroid hormone (PTH) and consistently normal serum calcium levels, in whom secondary causes of hyperparathyroidism have been excluded, may represent the earliest presentation of primary hyperparathyroidism (PHPT).

Objective. To characterize patients with normocalcemic PHPT referred to a Bone Diseases Unit.

Design. Longitudinal cohort study.

Setting. Ambulatory patients referred to metabolic bone disease unit.

Patients. 37 patients (58 yrs, range 32-78; 95% female; serum calcium: 9.4±0.1(SEM) mg/dl (2.3±0.02 mmol/L), reference range: 8.5-10.4 (2.1-2.6 mmol/L); PTH: 93±5 pg/ml).

Interventions. Yearly (median: 3 years; range 1-8y) physical examination, biochemical indices and bone mineral density (BMD).

Main outcome measures. Development of features of PHPT.

Results. Evaluation for classical features of PHPT revealed a history of kidney stones in 5 (14%), fragility fractures in 4 (11%), and osteoporosis in 57% (spine [34%], hip [38%], and/or distal 1/3 radius [28%]). BMD did not show preferential bone loss at the distal 1/3 radius (T-scores spine: -2.00±0.25; hip: -1.84±0.18; 1/3 radius: -1.74±0.22). Further signs of primary hyperparathyroidism developed in 40% (7 hypercalcemia; 1 kidney stone; 1 fracture; 2 marked hypercalciuria; 6 had >10% BMD loss at 1 site(s) including 4 patients developing WHO criteria for osteoporosis). Seven patients (3 hypercalcemic, 4 persistently normocalcemic) underwent successful parathyroidectomy.

Conclusions. Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in PHPT, and develop more features and complications over time. These patients may represent the earliest form of symptomatic, rather than asymptomatic, PHPT.