Abstract and Introduction
Introduction
Hypoparathyroidism occurs when the parathyroid glands are unable to control calcium homeostasis, with consequent hypocalcemia, hyperphosphatemia and hypercalciuria. The differential diagnosis of hypoparathyroidism recognizes two main conditions: primary and secondary forms. Primary hypoparathyroidism encompasses several congenital rare conditions,[1] and secondary hypoparathyroidism is most commonly seen as a complication of surgery (i.e., thyroidectomy, parathyroidectomy or radical neck surgery).[2]
Unlike most hormone insufficiency states, primary hypoparathyroidism is not treated by replacing the missing hormone. Therapy for hypoparathyroidism is limited to symptomatic management, often with large amounts of calcium and calcitriol. However, not all patients are well controlled when treated with calcium and calcitriol, frequently experiencing symptoms of either hyper- and/or hypo-calcemia. As parathyroid hormone (PTH) maintains serum calcium in the normal range and reduces urine calcium excretion, conventional therapy with calcium and calcitriol normalizes serum calcium without the renal calcium-retaining effect needed to normalize urinary calcium. This is the reason of the often observed hypercalciuria in hypoparathyroid patients treated with calcitriol, with an increased risk of nephrocalcinosis, nephrolithiasis or kidney failure.[3] This is certainly true in the refractory hypoparathyroid patients and universal in children affected by autosomal dominant hypoparathyroidism.[4,5] An improved treatment is, therefore, warranted.
Replacement therapy with the biologically active amino-terminal portion of the PTH molecule has been investigated during the past two decades. The first published study on the short-term effects of PTH 1–38 in two adolescents with autoimmune hypoparathyroidism was that by Stögmann et al. in 1990.[6] A number of randomized controlled open-label studies followed this first case report. In 1996, Winer et al. published the results of a randomized controlled trial of ten adults treated for 20 weeks with PTH 1–34 or calcitriol, with superiority of PTH 1–34 in the control of serum and urinary calcium levels.[7] Following this pilot study, the same group carried out a randomized crossover clinical study in 17 hypoparathyroid adults comparing once-daily and twice-daily PTH 1–34 regimens, with a favorable calcium homeostatic profile with twice-daily treatment.[8] These results were subsequently confirmed in a long-term treatment study in 27 adults with hypoparathyroidism[9] and in children 4–17 years of age with chronic hypoparathyroidism.[10,11]
These results, together with the descriptions from case reports,[12–15] led to the conclusion that recombinant PTH is a reasonable therapeutic option in patients with refractory hypoparathyroidism and hypercalciuria. However, approval for the use of recombinant PTH in hypoparathyroidism is still lacking for known reasons. Despite the evident rationale for PTH replacement in hypoparathyroidism, the first clinical studies of recombinant human PTH 1–34 (teriparatide, Eli Lilly, IN, USA) were for the treatment of osteoporosis, with approval from the US FDA for severe adult osteoporostic patients.[16] As long-term supraphysiological doses of teriparatide given to rats with normal functioning parathyroid glands led to osteosarcomas,[17] the product label warned against pediatric use. This resulted in a lack of interest by the manufacturer to sponsor investigational use of teriparatide in children.
Use of the native full-length molecule, PTH 1–84, in hypoparathyroidism has been investigated recently. PTH 1–84, developed by NPS Pharmaceuticals (NJ, USA) for the prevention of osteoporotic fractures, is approved in Europe for the treatment of severe osteoporosis in postmenopausal women, making devices for the easy subcutaneous administration of the hormone available. The studies on PTH 1–84 were either based on case series[18,19] or were performed in a randomized placebo-controlled double-blind setting.[20] Overall, the results obtained support the use of PTH 1–84 in hypoparathyroidism, with a significant reduction in the need for calcium and calcitriol and prevention of the overmineralized bone typical of hypoparathyroidism. The recently completed randomized double-blind placebo-controlled study to assess the safety and efficacy of PTH 1–84 in reducing the need for large doses of calcium and calcitriol opens the possibility for the manufacturer (NPS Pharmaceuticals) to have the hormone approved for use in hypoparathyroidism.
The future of hormone replacement therapy in hypoparathyroidism can be viewed with optimism, even if we are left with several unanswered questions, similar to those involving the use of insulin in diabetes several decades ago. The possibility of having a true replacement therapy approved for hypoparathyroidism will be the basis of building an optimal treatment for these patients.
Expert Rev Endocrinol Metab. 2012;7(3):255-257. © 2012 Expert Reviews Ltd.
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