It remains unclear whether mild primary hyperparathyroidism results in accelerated bone loss, with recent studies reaching different conclusions. This could be due to intrinsic differences in disease activity not captured by the classical biochemical markers of the disease. Because circulating levels of IL-6 and IL-6 soluble receptor (IL-6sR) are reportedly elevated in patients with hyperparathyroidism, we sought to determine whether measures of this cytokine axis could be helpful in determining the risk for bone loss in hyperparathyroidism. We prospectively followed 23 patients with hyperparathyroidism for 22 +/- 1.5 months and found that baseline circulating levels of IL-6sR correlated significantly with xrates of bone loss at the total femur (r = -0.53, P < 0.01). Furthermore, the combination of a scrum IL-6sR in the upper tertile (greater than or equal to45.6 ng/ml) and IL-6sR in the upper half (greater than or equal to11.8 pg/ml) of values in the whole group defined a subset of patients with a significantly greater rate of yearly bone loss at the total femur than the remainder of the group (-2.6 +/- 1.3%. vs. +0.4 +/- 0.3% c, P < 0.05). We conclude that the combined measurements of serum IL-6sR and IL.6 may be helpfid in identifying patients with untreated hyperparathyroidisra who are more likely to experience bone loss at the total femur.