Advances in the treatment of hypoparathyroidism with PTH 1-34.

Hypoparathyroidism is a rare disorder of calcium metabolism which is treated with calcium and vitamin D analogs. Although conventional therapy effectively raises serum calcium, it bypasses the potent calcium reabsorption effects of PTH on the kidney which leads to hypercalciuria and an increased risk of nephrocalcinosis and renal insufficiency. Twenty-five years ago, we launched the first systematic investigation into synthetic human PTH 1-34 replacement therapy in both adults and children. These studies led to our current understanding of the complex nature of PTH 1-34 therapy and to the challenges we still face in our pursuit of a safe and effective physiologic replacement therapy for hypoparathyroidism. The normalization and minimal fluctuation of serum and urine calcium levels were the primary management goals. As the frequency of PTH 1-34 injections increased, the total daily dose required to normalize calcium homeostasis decreased and episodes of hypercalcemia and hypercalciuria diminished, producing a more physiologic biochemical profile. Twice-daily injections achieved simultaneous normalization of serum and urine calcium levels in many patients but the persistent elevation of bone markers and the difficulty in reducing urine calcium to normal levels in the more severe cases, suggested an alternative to PTH 1-34 injections was needed. The studies with PTH 1-34 delivered by insulin pump represent an important advance in the management of hypoparathyroidism. PTH 1-34 delivered by insulin pump normalized serum and urine calcium and markers of bone turnover. Additionally, pump delivery of PTH 1-34 produced stable magnesium values within the normal range and reduced magnesium excretion. Currently, PTH 1-34 delivery by pump is the only alternative to PTH injections that has been tested in both adults and children and proven to achieve a physiologic biochemical profile.