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Circulating PTHrP concentrations in tumor-induced hypercalcemia: Influence on the response to bisphosphonate and changes after therapy

par Body, Jean-Jacques ;Dumon, Jean Claude;Thirion, Martine ;Cleeren, Anny
Référence Journal of bone and mineral research, 8, 6, page (701-706)
Publication Publié, 1993-06

Article révisé par les pairs

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Résumé :

We studied the influence of circulating parathyroid hormone-related protein (PTHrP) concentrations on the response of hypercalcemic cancer patients to bisphosphonate therapy. We also examined the changes in circulating PTHrP levels during the normalization of serum Ca to determine if part of the increase in PTHrP concentrations is not secondary to hypercalcemia itself, as suggested by some in vitro data. We sequentially measured in 45 hypercalcemic cancer patients treated by pamidronate the circulating concentrations of PTHrP (by an amino-terminal RIA; normal values <9 pmol/liter), Ca, Ca2+, Pi, intact PTH, and the fasting urinary excretion of Ca (Ca/Cr) and cyclic AMP (cAMP). Mean ± SEM baseline PTHrP levels were 9.5 ± 1.3, with a median (range) value of 6.0 (< 3.4–43) pmol/liter. PTHrP levels were elevated in 18 of 45 patients, more often in epidermoid than in glandular carcinomas (P < 0.05), and they were significantly (P < 0.05) correlated with the concentrations of Pi (r = -0.46), Ca/Cr (r = -0.31), and urinary cAMP (r = 0.47). Mean pretreatment Ca levels were not significantly different between patients with elevated and patients with normal PTHrP levels, 13.3 ± 0.4 versus 12.9 ± 0.4 mg/dl, but the concentrations became significantly different (P < 0.005) 4 days after therapy, 10.2 ± 0.3 versus 9.2 ± 0.1 mg/dl, respectively. The fall in fasting urinary Ca excretion was significantly (P < 0.05 from day 4 to day 14) lower in patients with elevated baseline PTHrP levels: for example, Δ (day 4 - day 0), 0.31 ± 0.11 in patients with elevated PTHrP levels versus 0.64 ± 0.08 mg Ca per mg Cr in patients with normal PTHrP levels. In agreement with a lesser effect on serum Ca, intact PTH levels did not increase significantly in patients with elevated PTHrP levels, in contrast with a clear-cut recovery of PTH secretion in the other group. Last, PTHrP levels did not change significantly after bisphosphonate therapy: for example, at the day of the nadir of Ca, the levels were 8.2 ± 1.2 (6.4, < 3.4–28) pmol/liter. In summary, our data suggest that circulating PTHrP concentrations do not change during correction of tumor-induced hypercalcemia but significantly influence the response to bisphosphonate therapy. Elevated PTHrP concentrations in hypercalcemic cancer patients thus constitute a primary phenomenon of pathogenic importance.