Evidence that the IL-6/IL-6 soluble receptor cytokine system plays a role in the increased skeletal sensitivity to PTH in estrogen-deficient women.

Estrogen-deficient women show increased skeletal sensitivity to the resorbing actions of PTH. The basis for this effect is not known. To examine the influence of estrogen deficiency on PTH-induced proresorptive cytokine production in humans, the response of five young women to a 36-h infusion of (1-34)human PTH (hPTH) was studied. PTH induced significant increases in circulating levels of IL-6 (mean values, T(0)-->T(36 h); 2.2-->19.2 pg/ml), IL-6 soluble receptor (IL-6sR; 29.8-->67.2 ng/ml), urine N-telopeptide of type I collagen (NTX) (38.6-->148 nM bone collagen equivalent/mM creatinine) and serum calcium (2.12-->2.62 mmol/liter). To examine the impact of hormonal status on this response, PTH infusions were next undertaken in seven estrogen-deficient and seven estrogen-treated postmenopausal women. When compared with estrogen-treated women, and correcting for differences in baseline values, estrogen-deficient women demonstrated an exaggerated increase in circulating levels of IL-6 (5.0-->31.7 vs. 3.2-->14.4 pg/ml; P = 0.0001) and IL-6sR (49.2-->102.1 vs. 37.7-->66.7; P = 0.0001). This was accompanied by greater increases in NTX excretion in the estrogen-deficient women (61.2-->201.6 vs. 44.8-->114.8, E(-) vs. E(+), P = 0.0001). Estrogen deficiency was not associated with augmented PTH-induced increases in colony-stimulating factor-1, IL-1beta, IL-11, or TNF-alpha. In a multiple regression model controlling for group, age, years since menopause both IL-6 and IL-6sR were strong predictors of NTX. These data, along with previous animal studies, support the conclusion that the IL-6/IL-6SR cytokine system plays a role in the increased skeletal sensitivity to PTH seen in estrogen-deficient women.