To define the role of parathyroid gland function in the pathophysiology of bone loss in type I (postmenopausal) osteoporosis, we measured serum intact parathyroid hormone (PTH) concentration by immunoradiometric assay (IRMA) and by multisite immunochemiluminometric assay (ICMA) in 63 postmenopausal osteoporotic women (PMOp) with vertebral compression fractures and in 75 age-comparable postmenopausal normal women (PMNl). Also, tetracycline-based histomorphometric indices in cancellous bone were assessed in iliac biopsy samples from 61 PMOp and 28 PMNl women. Serum PTH concentrations by IRMA were similar in PMOp and PMNl (medians, 3.92 and 3.77 pmol/l; NS) but were significantly lower in PMOp by the more sensitive ICMA (medians, 2.82 and 3.14 pmol/l; P less than 0.01). By multiple linear regression analysis, serum PTH was directly related (P less than 0.001) to activation frequency, bone resorption rate, bone formation rate, and the calculated rate of bone loss. For each unit (pmol/l) increase in serum PTH by ICMA, activation frequency increased by 1.3%/year more (P = 0.01), bone resorption rate increased by 3.9%/year more (P = 0.003), and the rate of cancellous bone loss was 2.8% greater (P = 0.0003) in the PMOp women compared with the PMNl women. Concentrations of serum estradiol, but not serum estrone, had a weak opposing effect to PTH, especially for bone formation rate. These data suggest that in PMOp the bone has increased sensitivity to the biologic effects of PTH. This may represent one of the fundamental pathophysiologic defects in PMOp and, in the setting of estrogen deficiency, may explain, in part, their greater rate of bone loss.