Perspectives on the Search for a True Physiologic Replacement Therapy for Hypoparathyroidism

Abstract Over the past two decades, we have studied various parathyroid hormone (PTH) 1-34 regimens, including once-daily and twice-daily injections without the concurrent conventional therapy. We recently studied PTH delivery by insulin pump, which produced normal, steady-state serum and urine calcium levels. The recent approval of PTH 1-84 represents an important milestone in the treatment of hypoparathyroidism. As PTH 1-84 and PTH 1-34 have similar pharmacokinetic (PK) and pharmacodynamic profiles, one can assume that many of the principles learned from studies of PTH 1-34 also apply to PTH 1-84 in the management of this rare disease.

Hypoparathyroidism is a rare disease, characterised by low or undetectable serum parathyroid hormone (PTH), hypocalcemia, hyperphosphatemia and, frequently, hypomagnesaemia. Symptoms include neuromuscular irritability causing tetany, muscle cramping and seizures. In adults, the disorder is usually a complication of neck surgery.
In children, the condition is most often due to inherited disorders such as autoimmune polyglandular failure syndrome type 1 (APS-1) or an activating mutation in the calcium-sensing receptor (CaR).
PTH is the key endocrine regulator of calcium homeostasis. The principle target organs for PTH action are the kidney and the bone.
PTH has indirect effects on the intestinal tract through the stimulation of 1,25(OH) 2 vitamin D production in the kidney. The calcium receptor, found in many areas of the body, partially controls calcium excretion in the kidney and PTH secretion from the parathyroid gland.
Conventional therapy consists of multiple oral doses of vitamin D analogues and calcium. Although this therapy is effective in raising serum calcium, it does not fully restore normal mineral homeostasis.
It bypasses the PTH effects on the kidney and bone and relies entirely on calcium transport across the gastrointestinal tract to normalise blood calcium. Without the renal calcium-retaining effects of PTH, conventional therapy may lead to renal insufficiency due to progressive nephrocalcinosis.
Until recently, the need for a replacement therapy for hypoparathyroidism had been largely ignored by the endocrine community. Although PTH first became available nearly a century ago, no controlled studies investigating replacement therapy took place before 1990. Ninety years ago, Collip demonstrated that bovine PTH was an effective replacement therapy in parathyroidectomised dogs. 1 In 1925, Albright treated a 14- year old boy with bovine PTH. 2 However, once vitamin D became the treatment of choice for hypoparathyroidism, Albright did not further pursue studies of PTH therapy. Investigation into PTH replacement remained inactive for the next 60 years, until 1990.
In the 1970s, the sequencing of the biologically active fragment, PTH 1-34, led to the study of its physiological effects, which revealed its dose-dependent anabolic effects on bone. The development of PTH 1-34 as an anabolic agent for osteoporosis continued through the next three decades and culminated in 2002 with the approval of teriparatide (rhPTH 1-34) (Forteo ® , Lilly, Indianapolis, US) for osteoporosis. 3 In 1990, Strogmann reported the successful treatment of two adolescents with hypoparathyroidism with PTH 1-38 injections. 4 In 1991, we initiated the first randomised controlled studies of replacement therapy with synthetic human PTH 1-34. 5 The majority of patients referred to us for therapy had evidence of renal calcifications. Some of these patients had renal insufficiency and others were in renal failure. These comorbidities were a direct result of conventional therapy or recurrent intravenous calcium infusions to treat intermittent severe hypocalcemia.  6 A three-year controlled study comparing PTH to conventional therapy in both adults and children confirmed that PTH could maintain normal serum and urine calcium levels and was an effective long-term therapy. Bone density remained stable in adults and children had normal bone accrual. 7,8 To further refine replacement therapy, we studied PTH delivery by insulin pump. A significant therapeutic breakthrough in the study of hypoparathyroidism, pump delivery produced normal, steady-state urine and serum calcium levels. PTH delivered by pump allowed for simultaneous normalisation of bone markers, serum calcium, magnesium and urine calcium excretion levels in patients of all aetiologies, including congenital hypoparathyroidism. 9,10 We have arrived at three essential therapeutic principles that underlie successful treatment of this rare disorder.
• Individualised PTH requirements depend upon the disease aetiology. Although PTH 1-34 and PTH 1-84 likely have identical biological effects, studies of these two peptides represent divergent approaches to replacement therapy, which has led to different treatment guidelines. PTH 1-34 has been given, from its very early investigative stages, as multiple subcutaneous injections titrated individually to normalise both blood and urine calcium levels. PTH 1-84, on the other hand, has been given as a fixed daily dose or on alternate days, along with flexible dosing of conventional therapy. This approach ignores a key principle that has emerged through our work: the PTH dose size and frequency has a remarkable effect on metabolic control. Claims that the longer half-life of PTH 1-84 drives the dosing requirements remain unsupported. Although there are no data comparing the two peptides, separate pharmacokinetic (PK) studies demonstrate that they are very similar. 11,12 Study results with fixed daily PTH 1-84 doses raise questions regarding the potential long-term effects of this approach. Sikjaer et al., showed that 100 mcg of PTH 1-84 given once daily along with conventional therapy produced hypercalcemia six to 14 hours after the injection. 12 The recent multicentre Randomised, Double-blind, Placebo-controlled,

Phase 3 Study to Investigate the Use of NPSP558, a Recombinant
Human Parathyroid Hormone (rhPTH ) for the Treatment of Adults with Hypoparathyroidism (REPLACE) study reported higher mean urine calcium levels in the treatment group than in the placebo group. 13 Longterm treatment studies report both anabolic 14,15 and catabolic effects 16