Teriparatid – Das molekulare und klinische Profil bei der Therapie der Osteoporose

Zusammenfassung

PTH und PTHrP fördern situationsabhängig Knochenformation, -umbau und -abbau. Sie binden an den PTH Rezeptor Typ 1 (PTH1R) auf Osteoblasten, Osteozyten und T-Zellen und vermitteln Genregulation. Kurze Pulse wirken anabol, chronische Stimulation wirkt stark katabol. Teriparatid ist von PTH abgeleitet (Aminosäuren 1–34) und induziert Knochenformation, die durch mechanische Belastung auch an instabilen Stellen verstärkt wird. Klinische Endpunkte sind Zunahme an Knochenmasse und -struktur und deutliche Reduktion der Frakturrate der Wirbelkörper und – mit geringerer Effizienz – der non-vertebralen Frakturen. Die Wirkung ist in einem umfangreichen Studienprogramm in randomisierten kontrollierten und „Real-Life“-Studien evidenzbasiert belegt. Teriparatid wirkt bei Frauen und Männern, unter Glukokortikoid-Therapie und nach Bisphosphonat-Vorbehandlung. Es kann nur einmalig über 24 Monate verabreicht werden, nachfolgende Gabe von Antiresorptiva verbessert den Outcome. Gesundheitspolitische Vorgaben beschränken seine Anwendung in Deutschland auf die Situation neuer Frakturen unter Antiresorptiva. Teriparatid ist sicher, hat ein sehr gutes Nebenwirkungsprofil und ist das erste Beispiel einer Regenerativen Therapie in der Osteologie.

Abstract

PTH and PTHrP, critically depending on (patho-)physiological circumstances, stimulate bone formation, bone remodelling or bone resorption. Their specific binding to the G-protein-coupled receptor PTH1R on osteoblasts, osteocytes and T-cells elicits gene regulation in the target cells (e. g. via cAMP, proteinkinase C and ERK1/2-activation). Short and intermittent pulses initiate anabolic effects while chronic overstimulation causes substantial bone resorption. The duration of pulses may be modulated by pharmacological or intrinsic means on and within target cells. Teriparatide is an anabolic PTH-derived (amino acid 1–34) polypeptide that opens the anabolic window of PTH-signalling upon intermittent application. Teriparatide given as a subcoutaneous injection of 20 µg/day induces bone formation and tissue regeneration that is mechanically triggered and is especially effective in fragile bone regions. It is the only compound with substantial remodelling activity that is presently available for osteoporosis treatment. Teriparatide application increases bone mass and structure and as clinical endpoints enhances fracture resistance and reduces the rates of vertebral fractures and – albeit with some delay and somewhat lower efficacy – also non-vertebral fractures. The efficacy of teriparatide has been demonstrated in a huge program of clinical studies, comprising both randomized controlled trials and highly sophisticated observational studies that reflect efficacy under conditions of real life. Teriparatide can only be given for 24 months once in a lifetime. It is effective in women and men, under glucocorticoid treatment and after bisphosphonate pretreatment. Sequential treatment with antiresorptive compounds considerably enhances and prolongs the positive effects on clinical outcome parameters. In Germany considerations of health policy render this treatment a second line regimen after inadequate outcome using antiresorptives. Teriparatide is safe and shows a favorable profile of side effects. It represents the first example of a regenerative medicine approach in metabolic bone diseases.

Schlüsselwörter

Teriparatid - Osteoporose - anabole Therapie - Frakturen

Key words

Teriparatide - Osteoporosis - anabolic treatment - fractures

• Literatur

• 1 Cheloha RW, Gellman SH, Vilardaga JP. et al. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 2015; 11 (12) 712-724
• 2 Gardella TJ, Vilardaga JP. International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors–family B G protein-coupled receptors. Pharmacol Rev 2015; 67 (02) 310-337
• 3 Neale Weitzmann M, Pacifici R. Parathyroid Diseases and T Cells. Curr Osteoporos Rep 2017; 15 (03) 135-141
• 4 Yu M, D‘Amelio P, Tyagi AM. et al. Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. EMBO Rep 2018; 19 (01) 156-171
• 5 Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997; 138 (11) 4607-412
• 6 Wein MN. Parathyroid Hormone Signaling in Osteocytes. JBMR Plus 2018; 2 (01) 22-30
• 7 Dempster DW, Cosman F, Parisien M. et al. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993; 14 (06) 690-709
• 8 Lindsay R, Nieves J, Henneman E. et al. Subcutaneous administration of the amino-terminal fragment of human parathyroid hormone-(1–34): kinetics and biochemical response in estrogenized osteoporotic patients. J Clin Endocrinol Metab 1993; 77 (06) 1535-1539
• 9 Schwietert HR, Groen EW, Sollie FA. et al. Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH(1–84)] in healthy postmenopausal volunteers. Clin Pharmacol Ther 1997; 61 (03) 360-376
• 10 Vahle JL, Zuehlke U, Schmidt A. et al. Lack of bone neoplasms and persistence of bone efficacy in cynomolgus macaques after long-term treatment with teriparatide [rhPTH(1–34)]. J Bone Miner Res 2008; 23 (12) 2033-2039
• 11 Vahle JL, Long GG, Sandusky G. et al. Bone neoplasms in F344 rats given teriparatide [rhPTH(1–34)] are dependent on duration of treatment and dose. Toxicol Pathol 2004; 32 (04) 426-438
• 12 Gilsenan A, Harding A, Kellier-Steele N. et al. The Forteo Patient Registry linkage to multiple state cancer registries: study design and results from the first 8 years. Osteoporos Int 2018; 29 (10) 2335-2343
• 13 Cipriani C, Irani D, Bilezikian JP. Safety of osteoanabolic therapy: a decade of experience. J Bone Miner Res 2012; 27 (12) 2419-2428
• 14 Swami S, Johnson J, Bettinson LA. et al. Prevention of breast cancer skeletal metastases with parathyroid hormone. JCI Insight 2017; 2 (17) 1-21
• 15 Neer RM, Arnaud CD, Zanchetta JR. et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344 (19) 1434-1441
• 16 Gallagher JC, Genant HK, Crans GG. et al. Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab 2005; 90 (03) 1583-1587
• 17 Kaufman JM, Orwoll E, Goemaere S. et al. Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int 2005; 16 (05) 510-516
• 18 Reginster JY, Hattersley G, Williams GC. et al. Abaloparatide is an Effective Treatment Option for Postmenopausal Osteoporosis: Review of the Number Needed to Treat Compared with Teriparatide. Calcif Tissue Int 2018; 103 (05) 540-545
• 19 Prince R, Sipos A, Hossain A. et al. Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res 2005; 20 (09) 1507-1513
• 20 Jiang Y, Zhao JJ, Mitlak BH. et al. Recombinant human parathyroid hormone (1–34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 2003; 18 (11) 1932-1941
• 21 Graeff C, Timm W, Nickelsen TN. et al. Monitoring teriparatide-associated changes in vertebral microstructure by high-resolution CT in vivo: results from the EUROFORS study. J Bone Miner Res 2007; 22 (09) 1426-1433
• 22 Eastell R, Nickelsen T, Marin F. et al. Sequential treatment of severe postmenopausal osteoporosis after teriparatide: final results of the randomized, controlled European Study of Forsteo (EUROFORS). J Bone Miner Res 2009; 24 (04) 726-736
• 23 Murphy PZ, Iranikhah M, Deas CM. et al. Fracture Risk Following Discontinuation of Teriparatide: A Review of the Literature. Consult Pharm 2018; 33 (07) 365-375
• 24 Borggrefe J, Graeff C, Nickelsen TN. et al. Quantitative computed tomographic assessment of the effects of 24 months of teriparatide treatment on 3D femoral neck bone distribution, geometry, and bone strength: results from the EUROFORS study. J Bone Miner Res 2010; 25 (03) 472-481
• 25 Diez-Perez A, Marin F, Eriksen EF. et al. Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis. Bone 2018; 120: 1-8
• 26 Metcalf LM, Aspray TJ, McCloskey EV. The effects of parathyroid hormone peptides on the peripheral skeleton of postmenopausal women. A systematic review. Bone 2017; 99: 39-46
• 27 Fahrleitner-Pammer A, Langdahl BL, Marin F. et al. Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the European Forsteo Observational Study (EFOS). Osteoporos Int 2011; 22 (10) 2709-2719
• 28 Jakob F, Oertel H, Langdahl B. et al. Effects of teriparatide in postmenopausal women with osteoporosis pre-treated with bisphosphonates: 36-month results from the European Forsteo Observational Study. Eur J Endocrinol 2012; 166 (01) 87-97
• 29 Ljunggren O, Barrett A, Stoykov I. et al. Effective osteoporosis treatment with teriparatide is associated with enhanced quality of life in postmenopausal women with osteoporosis: the European Forsteo Observational Study. BMC Musculoskelet Disord 2013; 14: 251
• 30 Silverman S, Langdahl BL, Fujiwara S. et al. Reduction of Hip and Other Fractures in Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies. Calcif Tissue Int 2018; 1-8
• 31 Langdahl BL, Silverman S, Fujiwara S. et al. Real-world effectiveness of teriparatide on fracture reduction in patients with osteoporosis and comorbidities or risk factors for fractures: Integrated analysis of 4 prospective observational studies. Bone 2018; 116: 58-66
• 32 Napoli N, Langdahl BL, Ljunggren O. et al. Effects of Teriparatide in Patients with Osteoporosis in Clinical Practice: 42-Month Results During and After Discontinuation of Treatment from the European Extended Forsteo(R) Observational Study (ExFOS). Calcif Tissue Int 2018; 103 (04) 359-371
• 33 Gluer CC, Marin F, Ringe JD. et al. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial. J Bone Miner Res 2013; 28 (06) 1355-1368
• 34 Rizzoli R, Biver E. Glucocorticoid-induced osteoporosis: who to treat with what agent?. Nat Rev Rheumatol 2015; 11 (02) 98-109
• 35 Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine 2018; 61 (01) 7-16
• 36 Wolverton D, Elliott DP. Evaluating the Evidence Behind Treating Osteoporosis in the Oldest Adults. Consult Pharm 2018; 33 (06) 308-16
• 37 Leder BZ. Optimizing Sequential and Combined Anabolic and Antiresorptive Osteoporosis Therapy. JBMR Plus 2018; 2 (02) 62-8
• 38 Finkelstein JS, Hayes A, Hunzelman JL. et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003; 349 (13) 1216-1226
• 39 Cosman F, Eriksen EF, Recknor C. et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J Bone Miner Res 2011; 26 (03) 503-511
• 40 Leder BZ, Tsai JN, Uihlein AV. et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet 2015; 386 (9999): 1147-1155
• 41 Balani DH, Kronenberg HM. Withdrawal of parathyroid hormone after prolonged administration leads to adipogenic differentiation of mesenchymal precursors in vivo. Bone 2018; 118: 16-19
• 42 Lindsay R, Scheele WH, Neer R. et al. Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med 2004; 164 (18) 2024-2030
• 43 Kendler DL, Geusens P, Zerbini CAF. et al. Teriparatide vs risedronate for osteoporosis – Authorsʼ reply. Lancet 2018; 391 (10133): 1896
• 44 Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2016; 8 (06) 225-235
• 45 Hattersley G, Dean T, Corbin BA. et al. Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology 2016; 157 (01) 141-149
• 46 Bastepe M, Turan S, He Q. Heterotrimeric G proteins in the control of parathyroid hormone actions. J Mol Endocrinol 2017; 58 (04) R203-R24