Advances in the treatment of hypoparathyroidism with PTH 1–34

Abstract

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.

Introduction

Hypoparathyroidism is a rare disorder of calcium homeostasis characterized by low or undetectable levels of parathyroid hormone (PTH) with hypocalcemia and hyperphosphatemia. Over the past century, this rare disorder has been treated with active vitamin D and calcium supplements given in numerous pills throughout the day. The goal of conventional therapy is to raise serum calcium through potentiating intestinal absorption of dietary calcium in the GI tract. Therapy with active vitamin D bypasses the direct homeostatic actions of parathyroid hormone on the kidney and bone and leads to phosphate retention and elevated urinary calcium excretion. Although there are no clinically apparent adverse effects of conventional therapy on bone, it has adverse effects on the kidney including nephrocalcinosis, nephrolithiasis, and chronic renal insufficiency. Hypoparathyroidism due to autoimmune polyendocrine syndrome type 1 (APS-1) is associated with malabsorption in the majority of patients. As this and other GI diseases preclude normal absorption of oral medications, such patients may require intermittent intravenous (IV) calcium infusions to maintain normal levels of blood calcium. 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.

In 1925, JP Collip's novel use of bovine parathyroid hormone (bPTH) extract in hypocalcemic parathyroidectomized dogs was the first experiment in the field of PTH replacement of hypoparathyroidism and laid the groundwork for studies in human subjects [1,2]. Albright and Ellsworth described, in 1929, their first attempt at PTH replacement therapy in a 14-year old boy with post-surgical hypoparathyroidism [3] who received a single-daily subcutaneous PTH injection over four days (Fig. 1). PTH alleviated symptoms of neuromuscular irritability, raised serum calcium and urine phosphate excretion, and lowered serum phosphate levels. After three PTH doses, urine calcium excretion levels increased more than ten-fold. Based on these preliminary observations, Albright concluded that PTH modified urine phosphate excretion. He also incorrectly concluded that a primary action of PTH was to increase urine calcium excretion. The single-daily 50-unit bPTH dose was too high and should have been titrated down to achieve a more physiologic response, but the experiment was aborted after four doses and Albright did not further pursue studies into PTH replacement therapy for hypoparathyroidism. Vitamin D was discovered in 1924 and soon after became the treatment of choice for hypoparathyroidism [4,5].