Most of what we know on PTH bioactivity has been associated with the first 34 amino acids of the PTH structure acting on the type I PTH/PTHrP receptor, leaving little place to the carboxyl-terminal structure. This reality has dictated the evolution of the PTH assay. The first generation of PTH assays has permitted the description of circulating PTH immunoreactivity and of its acute regulation by calcium concentration. Most assays reacted with the dominant forms of circulating PTH, PTH fragments devoid of bioactivity. This was believed to limit their clinical performance, particularly in the diagnosis of hypercalcemic disorders and the evaluation of secondary hyperparathyroidism and/or bone diseases associated with chronic renal failure. This brought up the development of a 2nd generation of PTH assays, the Intact (I) PTH assay. These assays were initially demonstrated to react only with hPTH(1-84), the bioactive form of the hormone. They greatly improved the differential diagnosis of hypercalcemic disorders, facilitated studies of parathyroid function in renal failure patients but were still limited in their capacity to dissociate the various bone diseases associated with chronic renal failure. Eventually, it was demonstrated that these assays, which used 13-34 epitopes, reacted with large C-PTH fragments having a partially preserved amino-terminal (N) structure, also called non-(1-84) PTH. These fragments accounted for up to 50% of I-PTH immunoreactivity in renal failure patients. hPTH(7-84), a surrogate of non-(1-84) PTH fragments, was demonstrated to cause hypocalcemia and to antagonize hPTH(1-34) and hPTH(1-84) calcemic effect in vivo and to inhibit bone resorption in vitro via a C-PTH receptor, different from the type I PTH/PTHrP receptor. This suggested a dual control of calcium concentration via N- and C-PTH molecular forms. This also explained why the ratio of C-PTH fragments/I-PTH was so well regulated both acutely and chronically in various experimental conditions. The fact that I-PTH assays detected circulating PTH molecular forms with biological effects opposite to those of hPTH(1-84) was believed to explain their limitations, particularly in renal failure, and prompted the evolution of a third generation of PTH assays. The last is based on a 1-4 epitope to reveal PTH(1-84) and not hPTH(7-84). It also permits an indirect evaluation of non-(1-84) PTH fragments by subtracting a 3rd generation PTH value from a 2nd generation PTH value and the calculation of a PTH(1-84)/non-(1-84) PTH ratio. The combination of a third generation PTH value with the PTH(1-84)/non-(1-84) PTH ratio value has in some studies improved the differential diagnosis of bone diseases associated with renal failure. But more studies are required to see whether PTH(1-84)/PTH fragment ratios will improve the clinical performance of PTH concentrations used alone.
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