Endocrinol Metab.  2024 Apr;39(2):262-266. 10.3803/EnM.2024.1916.

Treatment of Hypoparathyroidism by Re-Establishing the Effects of Parathyroid Hormone

• Rejnmark L

• KMID: 2554630
• DOI: http://doi.org/10.3803/EnM.2024.1916

Abstract

The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.

Keyword

Hypoparathyroidism; Parathyroid hormone; Hypocalcemia; Therapeutics

Reference

1. Harslof T, Rolighed L, Rejnmark L. Huge variations in definition and reported incidence of postsurgical hypoparathyroidism: a systematic review. Endocrine. 2019; 64:176–83.

2. Mannstadt M, Bilezikian JP, Thakker RV, Hannan FM, Clarke BL, Rejnmark L, et al. Hypoparathyroidism. Nat Rev Dis Primers. 2017; 3:17055.

3. Khan AA, Guyatt G, Ali DS, Bilezikian JP, Collins MT, Dandurand K, et al. Management of hypoparathyroidism. J Bone Miner Res. 2022; 37:2663–77.

4. Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE educational program of parathyroid disorders. Eur J Endocrinol. 2022; 186:R33–63.

5. Mannstadt M, Clarke BL, Vokes T, Brandi ML, Ranganath L, Fraser WD, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013; 1:275–83.

6. Tay YD, Tabacco G, Cusano NE, Williams J, Omeragic B, Majeed R, et al. Therapy of hypoparathyroidism with rhPTH (1-84): a prospective, 8-year investigation of efficacy and safety. J Clin Endocrinol Metab. 2019; 104:5601–10.

7. Winer KK, Sinaii N, Peterson D, Sainz B Jr, Cutler GB Jr. Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab. 2008; 93:3389–95.

8. Winer KK, Yanovski JA, Sarani B, Cutler GB Jr. A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab. 1998; 83:3480–6.

9. Winer KK, Zhang B, Shrader JA, Peterson D, Smith M, Albert PS, et al. Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism. J Clin Endocrinol Metab. 2012; 97:391–9.

10. Winer KK, Fulton KA, Albert PS, Cutler GB Jr. Effects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1-34 in children with severe congenital hypoparathyroidism. J Pediatr. 2014; 165:556–63.

11. Holten-Andersen L, Pihl S, Rasmussen CE, Zettler J, Maitro G, Baron J, et al. Design and preclinical development of TransCon PTH, an investigational sustained-release PTH replacement therapy for hypoparathyroidism. J Bone Miner Res. 2019; 34:2075–86.

12. Khan AA, Rejnmark L, Rubin M, Schwarz P, Vokes T, Clarke B, et al. PaTH forward: a randomized, double-blind, placebo-controlled phase 2 trial of TransCon PTH in adult hypoparathyroidism. J Clin Endocrinol Metab. 2022; 107:e372–85.

13. Khan AA, Rubin MR, Schwarz P, Vokes T, Shoback DM, Gagnon C, et al. Efficacy and safety of parathyroid hormone replacement with TransCon PTH in hypoparathyroidism: 26-week results from the phase 3 PaTHway trial. J Bone Miner Res. 2023; 38:14–25.

14. Shimizu M, Joyashiki E, Noda H, Watanabe T, Okazaki M, Nagayasu M, et al. Pharmacodynamic actions of a long-acting PTH analog (LA-PTH) in thyroparathyroidectomized (TPTX) rats and normal monkeys. J Bone Miner Res. 2016; 31:1405–12.

15. Kamenicky P, Takacs I, Mezosi E, Soto A, Figueres L, Lemoine S, et al. OR23-04 Treatment of chronic hypoparathyroidism with eneboparatide (AZP-3601), a novel PTH 1 receptor agonist: results from a phase 2 trial. J Endocr Soc. 2023; 7(Supplement 1):bvad114–562.

16. Toka HR, Pollak MR. The role of the calcium-sensing receptor in disorders of abnormal calcium handling and cardiovascular disease. Curr Opin Nephrol Hypertens. 2014; 23:494–501.

17. Gafni RI, Hartley IR, Roszko KL, Nemeth EF, Pozo KA, Lombardi E, et al. Efficacy and safety of encaleret in autosomal dominant hypocalcemia type 1. N Engl J Med. 2023; 389:1245–7.