The role of the receptor activator of nuclear factor-κB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism

Context: The mechanisms of action of PTH on bone in vivo remain incompletely understood. The objective of this investigation was to examine changes in serum levels of receptor activator of nuclear factor-κB ligand and osteoprotegerin (OPG) in primary hyperparathyroidism and their relationship to bone loss. Patients and Methods: Twenty-nine patients with primary hyperparathyroidism had baseline circulating soluble receptor activator of nuclear factor-κB ligand (sRANKL) and OPG measured. The relationship to biochemical markers of bone turnover and changes in bone mineral density over 2 yr was examined. Results: Baseline sRANKL levels were elevated (1.7 ± 0.1 pmol/liter), whereas OPG remained in the normal range (5.6 ± 0.4 pmol/liter). Circulating sRANKL did not correlate with PTH but did correlate with markers of bone resorption (urine deoxypyridinoline cross-links: r = 0.51, P < 0.01; serum N-telopeptide of type I collagen: r = 0.37, P < 0.05). Furthermore, sRANKL correlated with both IL-6 and IL-6 soluble receptor (IL-6sR) (r = 0.47, P < 0.05 and r = 0.55, P < 0.005, respectively). Serum sRANKL levels also correlated with bone loss at the total femur (r = −0.53, P < 0.01). Lastly, a high value of sRANKL in combination with values of IL-6 and IL-6sR in the upper quartile (sRANKL ≥ 1.81 pg/ml, IL −6 ≥ 11.8 pg/ml, and IL-6sR ≥ 45.6 ng/ml) defined a group of four women with significantly greater rates of bone loss at the total femur than the remaining patients (−2.7 ± 1.7% vs. +0.5 ± 0.3%; n = 4 vs. n = 19, P < 0.05). Conclusion: Determination of circulating levels of sRANKL may be useful in identifying patients with mild primary hyperparathyroidism at greater risk for bone loss. The fact that circulating sRANKL did not correlate with PTH but did correlate with markers of bone resorption suggests that skeletal responsiveness to PTH may differ in this disease.