The Effect of Leptin Replacement on Parathyroid Hormone, RANKL-Osteoprotegerin Axis, and Wnt Inhibitors in Young Women With Hypothalamic Amenorrhea

Context: Recombinant leptin (metreleptin) treatment restores bone mineral density in women with hypothalamic amenorrhea (HA), a condition characterized by hypoleptinemia, which has adverse impact on bone health. Objective: The objective of the study was to investigate how metreleptin exerts its positive effect on bone metabolism in humans. Design: This was a randomized, double-blinded, placebo-controlled study. Setting: The study was conducted at Beth Israel Deaconess Medical Center (Boston, Massachusetts). Patients and Interventions: Women (n = 18) with HA and hypoleptinemia for at least 6 months were randomized to receive either metreleptin or placebo for 36 weeks. Serum samples were obtained at baseline and 12, 24, and 36 weeks of treatment. Main Outcome Measures: Circulating levels of leptin, intact PTH (iPTH), receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), sclerostin, dickkopf-1, and fibroblast growth factor-23. Results: Metreleptin administration significantly increased leptin levels throughout the treatment period (P = .001). iPTH decreased over the 36 weeks of treatment (P = .01). There was a trend toward a decrease in serum RANKL and increase in serum OPG in the metreleptin-treated group. The RANKL to OPG ratio was significantly decreased within the metreleptin (P = .04) but not the placebo group. Metreleptin had no effect on serum sclerostin, dickkopf-1, and fibroblast growth factor-23. Conclusions: Metreleptin treatment over 36 weeks decreases iPTH and RANKL to OPG ratio levels in hypoleptinemic women with HA.