Neue Therapien bei chronischem Hypoparathyreoidismus

Elena Tsourdi; Holger Henneicke; Carmina T. Fuss; Corinna Grasemann; Heide Siggelkow

doi:10.1055/a-1245-7539

Osteologie, Inhaltsverzeichnis

CC BY 4.0 · Osteologie 2020; 29(04): 283-292
DOI: 10.1055/a-1245-7539

Originalarbeit

Neue Therapien bei chronischem Hypoparathyreoidismus

Novel treatment modalities in chronic hypoparathyroidism

Elena Tsourdi

¹Bereich Endokrinologie, Diabetes und Knochenerkrankungen, Medizinische Klinik III, Universitätsklinikum der Technischen Universität Dresden

²Zentrum für Gesundes Altern, Medizinische Fakultät der Technischen Universität Dresden

,

Holger Henneicke

¹Bereich Endokrinologie, Diabetes und Knochenerkrankungen, Medizinische Klinik III, Universitätsklinikum der Technischen Universität Dresden

²Zentrum für Gesundes Altern, Medizinische Fakultät der Technischen Universität Dresden

³Zentrum für Regenerative Therapien Dresden, Technische Universität Dresden

,

Carmina T. Fuss

⁴Schwerpunkt Endokrinologie & Diabetologie, Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg

,

Corinna Grasemann

⁵Abteilung für Seltene Erkrankungen, Universitätskinderklinik Bochum und CeSER der Ruhr-Universität Bochum

,

Heide Siggelkow

⁶MVZ Endokrinologikum Göttingen, Zentrum für Hormon-, Knochen- und Gelenkerkrankungen, Endokrinologie, Osteologie, Rheumatologie, Nuklearmedizin und Humangenetik

⁷Universitätsmedizin Göttingen, Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie

› Institutsangaben

Abstract

Zusammenfassung

Der chronische Hypoparathyreoidismus (hypoPT) ist geprägt durch einen Mangel an Parathormon (PTH) und als Konsequenz auch an Calcitriol [1, 25 (OH)2 Vitamin D]. Neben der Hypocalcämie kommt es zu einer Reihe biochemischer Veränderungen mit Hyperphosphatämie und Hypercalciurie. Trotz Therapie mit Calcium und aktivem Vitamin D haben Betroffene eine Vielzahl von Beschwerden und eine erhöhte Langzeitmorbidität und -mortalität.

Es kann zu Komplikationen wie Nierenfunktionsstörungen, Nephrocalcinose, Nierensteinen, Basalganglienverkalkungen, Katarakten, zu einem verminderten Knochenumsatz und zu einem erhöhten Infektionsrisiko kommen.

Seit 2017 ist das rekombinante humane Parathormon [rhPTH (1-84)] als Ersatz des beim hypoPT fehlenden PTHs für die Therapie zugelassen. In der initial durchgeführten Zulassungsstudie konnten ca. 40% der Patienten nach 24 Wochen rhPTH (1-84) Therapie auf die orale Einnahme von Calcitriol verzichten und gleichzeitig die Calciumzufuhr reduzieren. Aktuell sind Daten über acht Jahre Therapie mit rhPTH (1-84) vorliegend. Die Therapie wird gut vertragen, es kommt zur Normalisierung des Knochenstoffwechsels sowie zur Verbesserung der Lebensqualität im Vergleich zum Therapiebeginn bei unveränderter Nierenfunktion. Eine Verminderung der Hypercalciurie kann allerdings erst ab dem siebten Jahr der Therapie gezeigt werden.

Aktuell sind weitere Medikamente in Entwicklung, die in der Zukunft neue Therapiemöglichkeiten für Betroffene mit hypoPT eröffnen.

Abstract

During recent years, it has become apparent that chronic hypoparathyroidism (hypoPT) is a complex disease characterized by the deficiency of parathyroid hormone (PTH) and as a consequence calcitriol [1, 25 (OH)₂ vitamine D]. Besides hypocalcemia, hypoPT is associated with additional biochemical disturbances, such as hyperphosphatemia and hypercalciuria. Moreover, patients suffer from impaired quality of life (QoL) and an increased risk of various co-morbidities. These include renal impairment, stones and/or nephrocalcinosis, impaired bone quality, neuropsychiatric diseases, infections and an increased mortality. Lately, different hypoparathyroidism-specific tailored instruments were developed to assess the nature and the degree of symptoms or complaints in hypoPT patients. These instruments highlighted differences compared to control groups as well as a correlation to laboratory values, especially the calcium-phosphate product.

In addition to growing insights into its clinical consequences, in recent years recombinant human parathyroid hormone (1-84) [rhPTH (1-84)] has become available as a replacement of the missing hormone. Data demonstrating efficacy and safety of rhPTH (1-84) in both short-term and long-term studies are now available. Long-term administration of rhPTH (1-84) resulted in sustained, and in some cases, progressive reductions in supplemental calcium and calcitriol requirements. With regard to bone structure, rhPTH (1-84) led to an increase in bone turnover in both the trabecular and cortical compartment and to a restoration of bone metabolism towards a euparathyroid state. Studies that have attempted to quantify QoL in hypoPT with widely used questionnaires such as the Short-Form-36 (SF-36) have revealed large deviations from the general population and improvement during long-term hormone replacement. However, evidence of improvement of QoL with rhPTH (1-84) when compared to placebo-treated control groups is still lacking. Moreover, hypercalciuria is reduced by treatment with rhPTH (1-84) only after the seventh year of treatment.

Currently, a number of other treatment options are being developed offering physicians and patients a wider set of therapeutic options in the future.

Schlüsselwörter

chronischer Hypoparathyreoidismus - Hypocalcämie - Hypercalciurie - rekombinantes humanes Parathormon

Key words

chronic hypoparathyroidism - hypocalcemia - hypercalciuria - renal impairment - human recombinant parathyroid hormone

Volltext

Referenzen

Literatur
1 Bolleslev J, Schalin-Jantti C, Rejnmark L. et al. MANAGEMENT OF ENDOCRINE DISEASE: Unmet therapeutic, educational and scientific needs in parathyroid disorders. Eur J Endocrinol 2019; 181: P1-P19
2 Mitchell DM, Regan S, Cooley MR. et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012; 97: 4507-4514
3 Underbjerg L, Sikjaer T, Rejnmark L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: A case-control study. J Bone Miner Res 2018; 33: 822-831
4 Bolleslev J, Rejnmark L, Marcocci C. et al. European society of endocrinology clinical guideline: treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol 2015; 173: G1-20
5 Hadker N, Egan J, Sanders J. et al. Understanding the burden of illness associated with hypoparathyroidism reported among patients in the paradox study. Endocr Pract 2014; 20: 671-679
6 Bilezikian JP, Khan A, Potts Jr. JT. et al. Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res 2011; 26: 2317-2337
7 Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008; 359: 391-403
8 Siggelkow H, Clarke BL, Germak J. et al. Burden of illness in not adequately controlled chronic hypoparathyroidism: Findings from a 13-country patient and caregiver survey. Clinical endocrinology. Clin Endocrinol (Oxf) 2020; 92: 159-168
9 Cusano NE, Rubin MR, McMahon DJ. et al. PTH(1-84) is associated with improved quality of life in hypoparathyroidism through 5 years of therapy. J Clin Endocrinol Metab 2014; 99: 3694-3699
10 Astor MC, Lovas K, Debowska A. et al. Epidemiology and health related quality of life in hypoparathyroidism in Norway. J Clin Endocrinol Metab 2016; 101: 3045-3053
11 Sikjaer T, Moser E, Rolighed L. et al. Concurrent hypoparathyroidism is associated with impaired physical function and quality of life in hypothyroidism. J Bone Miner Res 2016; 31: 1440-1448
12 Underbjerg L, Sikjaer T, Rejnmark L. Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism. Clin Endocrinol (Oxf) 2018; 88: 838-847
13 Vokes T. Quality of life in hypoparathyroidism. Bone 2019; 120: 542-547
14 Sikjaer T, Moser E, Rolighed L. et al. Concurrent hypoparathyroidism is associated with impaired physical function and quality of life in hypothyroidism. J Bone Miner Res 2016; Jul; 31 (07) : 1440-1448
15 Arlt W, Fremerey C, Callies F. et al. Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D. Eur J Endocrinol 2002; 146: 215-222
16 Coles T, Chen K, Nelson L. et al. Psychometric evaluation of the hypoparathyroidism symptom diary. Patient Relat Outcome Meas 2019; 10: 25-36
17 Brod M, Waldman LT, Smith A. et al. Assessing the patient experience of hypoparathyroidism symptoms: Development of the hypoparathyroidism patient experience scale-symptom (HPES-Symptom). Patient. 2020; 13: 151-162
18 Wilde D, Wilken L, Stamm B. et al. The HPQ – development and first administration of a questionnaire for hypoparathyroid patients. JBMR Plus 2019; 4: e10245
19 Wilde D, Wilken L, Stamm B. et al. Quantification of symptom load by a disease-specific questionnaire HPQ 28 and analysis of associated biochemical parameters in patients with postsurgical hypoparathyroidism. JBMR Plus 2020; 4: e10368
20 Albright F, Ellsworth R. Studies on the physiology of the parathyroid glands. J Clin Invest 1929; 7: 183-201
21 Melick RA, Gill JR, Berson SA. et al. Antibodies and clinical resistance to parathyroid hormone. N Engl J Med 1967; 276: 144-147
22 Winer KK, Yanovski JA, Cutler GB. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA 1996; 276: 631-636
23 Mannstadt M, Clarke BL, Vokes T. 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: 275-283
24 Sikjaer T, Rejnmark L, Rolighed L. et al. Hypoparathyroid study group. The effect of adding PTH(1-84) to conventional treatment of hypoparathyroidism: A randomized, placebo-controlled study. J Bone Miner Res 2011; 26: 2358-2370
25 Lakatos P, Bajnok L, Lagast H. et al. An open-label extension study of parathyroid hormone RHPTH(1-84) in adults with hypoparathyroidism. Endocr Pract 2016; 22: 523-532
26 Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7: 172
27 Macdonald HM, Nishiyama KK, Hanley DA. et al. Changes in trabecular and cortical bone microarchitecture at peripheral sites associated with 18 months of teriparatide therapy in postmenopausal women with osteoporosis. Osteoporos Int 2011; 22: 357-362
28 Sikjaer T, Rejnmark L, Thomsen JS. et al. Changes in 3-dimensional bone structure indices in hypoparathyroid patients treated with PTH(1-84): A randomized controlled study. J Bone Miner Res 2012; 27: 781-788
29 Rubin MR, Dempster DW, Sliney J. et al. PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res 2011; 26: 2727-2736
30 Rubin MR, Zwahlen A, Dempster DW. et al. Effects of parathyroid hormone administration on bone strength in hypoparathyroidism. J Bone Miner Res 2016; 31: 1082-1088
31 Cipriani C, Abraham A, Silva BC. et al. Skeletal changes after restoration of the euparathyroid state in patients with hypoparathyroidism and primary hyperparathyroidism. Endocrine 2017; 55: 591-598
32 Misof BM, Roschger P, Dempster DW. et al. PTH(1-84) Administration in hypoparathyroidism transiently reduces bone matrix mineralization. J Bone Miner Res 2016; 31: 180-189
33 Clarke BL, Kay Berg J, Fox J. et al. Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: An open-label, single-dose, phase I study. Clin Ther 2014; 36: 722-736
34 Winer KK, Zhang B, Shrader JA. 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: 391-399
35 Mannstadt M, Clarke BL, Bilezikian JP. et al. Safety and efficacy of 5 years of treatment with recombinant human parathyroid hormone in adults with hypoparathyroidism. J Clin Endocrinol Metab 2019; 104: 5136-5147
36 Tay YD, Tabacco G, Cusano NE. et al. Therapy of hypoparathyroidism with rhPTH(1-84): A prospective eight year investigation of efficacy and safety. J Clin Endocrinol Metab 2019; 104: 5601-5610
37 McHorney CA, Ware Jr. JE, Lu JF. et al. 36-item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care 1994; 32: 40-66
38 Ware Jr. JE, Sherbourne CD, The MOS. 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473-483
39 Tabacco G, Tay YD, Cusano NE. et al. Quality of life in hypoparathyroidism improves with rhPTH(1-84) throughout 8 years of therapy. J Clin Endocrinol Metab 2019; 104: 2748-2756
40 Bottler C, Blaschke M, Wilde D. et al. Effect of rhPTH 1–84 medication in patients with hypoparathyroidism on quality of life using the hypoparathyroidism patient questionnaire 28 (HPQ 28). German Congress of Endocrinology; Gießen, 2020
41 Underbjerg L, Sikjaer T, Mosekilde L. et al. Postsurgical hypoparathyroidism–risk of fractures, psychiatric diseases, cancer, cataract, and infections. J Bone Miner Res 2014; 29: 2504-2510
42 Underbjerg L, Sikjaer T, Mosekilde L. et al. The epidemiology of nonsurgical hypoparathyroidism in Denmark: A nationwide case finding study. J Bone Miner Res 2015; 30: 1738-1744
43 Cusano NE, Rubin MR, Williams JM. et al. Changes in skeletal microstructure through four continuous years of rhPTH(1-84) therapy in hypoparathyroidism. J Bone Miner Res 2020; 35: 1274-1281
44 Rubin MR, Zhou H, Cusano NE. et al. The effects of long-term administration of rhPTH(1-84) in hypoparathyroidism by bone histomorphometry. J Bone Miner Res 2018; 201 (33) : 1931-1939
45 Brandi ML, Bilezikian JP, Shoback D. et al. Management of hypoparathyroidism: Summary statement and guidelines. J Clin Endocrinol Metab 2016; 101: 2273-2283
46 Gordon RJ, Levine MA. Genetic disorders of parathyroid development and function. Endocrinol Metab Clin North Am 2018; 47 (04) : 809-823
47 Mannstadt M, Bilezikian JP, Thakker RV. et al. Hypoparathyroidism. Nat Rev Dis Primers 2017; 3: 17055
48 Kim JH, Shin YL, Yang S. et al. Diverse genetic aetiologies and clinical outcomes of paediatric hypoparathyroidism. Clin Endocrinol (Oxf) 2015; 83: 790-796
49 Winer KK, Sinaii N, Peterson D. et al. Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab 2008; 93: 3389-3395
50 Winer KK, Sinaii N, Reynolds J. et al. Long-term treatment of 12 children with chronic hypoparathyroidism: A randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab 2010; 95: 2680-2688
51 Linglart A, Rothenbuhler A, Gueorgieva I. et al. Long-term results of continuous subcutaneous recombinant PTH (1-34) infusion in children with refractory hypoparathyroidism. J Clin Endocrinol Metab 2011; 96: 3308-3312
52 Theman TA, Collins MT, Dempster DW. et al. PTH(1-34) replacement therapy in a child with hypoparathyroidism caused by a sporadic calcium receptor mutation. J Bone Miner Res 2009; 24: 964-973
53 Shiohara M, Shiozawa R, Kurata K. et al. Effect of parathyroid hormone administration in a patient with severe hypoparathyroidism caused by gain-of-function mutation of calcium-sensing receptor. Endocr J 2006; 53: 797-802
54 Gonzales MC, Lieb DC, Richardson DW. et al. Recombinant human parathyroid hormone therapy (1-34) in an adult patient with a gain-of-function mutation in the calcium-sensing receptor-a case report. Endocr Pract 2013; 19: e24-8
55 Guo J, Khatri A, Maeda A. et al. Prolonged pharmacokinetic and pharmacodynamic actions of a pegylated parathyroid hormone (1-34) peptide fragment. J Bone Miner Res 2017; 32: 86-98
56 Shimizu M, Joyashiki E, Noda H. 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: 1405-1412
57 Karpf DB, Pihl S, Mourya S. et al. A randomized double-blind placebo-controlled first-in-human Phase 1 trial of TransCon PTH in healthy adults. J Bone Miner Res 2020; [epub ahead of print]