Aktuelle und zukünftige pharmakologische Therapieoptionen zur Behandlung der Osteoporose und deren Wirkmechanismen – ein Überblick

Zusammenfassung

Aktuell verfügbaren pharmakologischen Therapien zur Behandlung der Osteoporose verfolgen entweder einen antiresorptiven oder osteoanabolen Ansatz oder sind dual wirksam. Antiresorptive Therapien (Bisphosphonate, Denosumab, Östrogene und selektive Östrogenrezeptormodulatoren (SERMs)) erhöhen die Knochenmasse durch Hemmung der Knochenresorption. Osteoanabole Therapien (Teriparatid und Abaloparatid) erhöhen die Knochenmasse durch Stimulierung der Knochenbildung. Als dual wirksam gilt Romosozumab. In diesem Übersichtsartikel werden die aktuellen pharmakologischen Therapieformen bei Osteoporose und ihre Wirkmechanismen vorgestellt. Darüber hinaus werden neue Behandlungsansätze besprochen, wie der Einsatz mesenchymaler Stammzellen (MSCs), Extrazellulärer Vesikel (EVs), die Blockierung des follikelstimulierenden Hormons (FSH) sowie eine individuelle Anpassung der Bisphosphonat-Dosis.

Abstract

Currently available pharmacological therapies for the treatment of osteoporosis pursue either an antiresorptive or osteoanabolic approach or have a dual effect. Antiresorptive therapies (bisphosphonates, denosumab, oestrogens and selective oestrogen receptor modulators (SERMs)) increase bone mass by inhibiting bone resorption. Osteoanabolic therapies (teriparatide and abaloparatide) increase bone mass by stimulating bone formation. Romosozumab is considered to have a dual effect. This review article presents the current pharmacological therapy options for osteoporosis treatment and their mechanisms of action. In addition, new treatment approaches are discussed, such as the use of mesenchymal stem cells (MSCs), extracellular vesicles (EVs), the blocking of follicle-stimulating hormone (FSH) and individualised adjustment of the bisphosphonate dose.

Schlüsselwörter

Osteoporose - antiresorptive Therapie - osteoanabole Therapie - Wirkmechanismus

Keywords

osteoporosis - antiresorptive therapy - osteoanabolic therapy - mechanism of action

Publikationsverlauf

Eingereicht: 07. Januar 2024

Angenommen: 10. April 2024

Artikel online veröffentlicht:
16. Mai 2024

• Literatur

• 1 Kanis JA, Odén A, McCloskey EV.. et al. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 2012; 23: 2239-2256
• 2 Bouxsein ML, Eastell R, Lui LY. et al. Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials. J Bone Miner Res 2019; 34: 632-642
• 3 Russell RGG. Bisphosphonates: The first 40 years. Bone 2011; 49: 2-19
• 4 Bolland MJ, Grey A. Ten years too long: Strontium ranelate, cardiac events, and the European Medicines Agency. BMJ 2016; 354
• 5 Ebetino FH, Sun S, Cherian P. et al. Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use. Bone 2022; 156: 116289
• 6 Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin Proc 2008; 83: 1032-1045
• 7 Hanley DA, Adachi JD, Bell A. et al. Denosumab: Mechanism of action and clinical outcomes. Int J Clin Pract 2012; 66: 1139-1146
• 8 Moen MD, Keam SJ. Denosumab: A review of its use in the treatment of postmenopausal osteoporosis. Drugs and Aging 2011; 28: 63-82
• 9 Farkas S, Szabó A, Hegyi AE. et al. Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions. Biomedicines 2022; 10
• 10 Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: An inflammatory tale. J Clin Invest 2006; 116: 1186-1194
• 11 Stepan JJ, Alenfeld F, Boivin G. et al. Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis. Endocr Regul 2003; 37: 225-238
• 12 Gartlehner G, Patel SV., Reddy S. et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2022; 328: 1747-1765
• 13 Nethander M, Vandenput L, Eriksson AL. et al. Evidence of a Causal Effect of Estradiol on Fracture Risk in Men. J Clin Endocrinol Metab 2018; 104: 433-442
• 14 Yan MZ, Xu Y, Gong YX. et al. Raloxifene inhibits bone loss and improves bone strength through an Opg-independent mechanism. Endocrine 2010; 37: 55-61
• 15 Riggs BL, Hartmann LC. Selective Estrogen-Receptor Modulators — Mechanisms of Action and Application to Clinical Practice. N Engl J Med 2003; 348: 618-629
• 16 Peng L, Luo Q, Lu H. Efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: A systematic review and meta-analysis. Med (United States) 2017; 96
• 17 Rendina-Ruedy E, Rosen CJ. Parathyroid hormone (PTH) regulation of metabolic homeostasis: An old dog teaches us new tricks. Mol Metab 2022; 60: 101480
• 18 Martin TJ, Sims NA, Seeman E. Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R. Endocr Rev 2021; 42: 383-406
• 19 Wittelsberger A, Corich M, Thomas BE. et al. The mid-region of parathyroid hormone (1-34) serves as a functional docking domain in receptor activation. Biochemistry 2006; 45: 2027-2034
• 20 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: 4607-4612
• 21 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: 1434-1441
• 22 Rauner M, Taipaleenmäki H, Tsourdi E. et al. Osteoporosis treatment with anti-sclerostin antibodies – mechanisms of action and clinical application. J Clin Med 2021; 10: 1-21
• 23 Grey A, Garg S, Dray M. et al. Low-dose fluoride in postmenopausal women: A randomized controlled trial. J Clin Endocrinol Metab 2013; 98: 2301-2307
• 24 Statham LA, Aspray TJ. Odanacatib: the best osteoporosis treatment we never had?. Lancet Diabetes Endocrinol 2019; 7: 888-889
• 25 Downs RW, Bell NH, Ettinger MP. et al. Comparison of Alendronate and Intranasal Calcitonin for Treatment of Osteoporosis in Postmenopausal Women. J Clin Endocrinol Metab 2000; 85: 1783-1788
• 26 Sun LM, Lin MC, Muo CH. et al. Calcitonin nasal spray and increased cancer risk: A population-based nested case-control study. J Clin Endocrinol Metab 2014; 99: 4259-4264
• 27 Overman RA, Borse M, Gourlay ML. Salmon Calcitonin Use and Associated Cancer Risk. Ann Pharmacother 2013; 47: 1675-1684
• 28 Hadji P, Schweikert B, Kloppmann E. et al. Osteoporotic fractures and subsequent fractures: imminent fracture risk from an analysis of German real-world claims data. Arch Gynecol Obstet 2021; 304: 703-712
• 29 Ayub N, Faraj M, Ghatan S. et al. The treatment gap in osteoporosis. J Clin Med 2021; 10: 1-13
• 30 DVO Dachverband Osteologie e.V. DVO Leitlinie Osteoporose 2023. 2023; Im Internet https://leitlinien.dv-osteologie.org/; Stand: 03.03.2024
• 31 Kanis JA, Johansson H, Harvey NC. et al. An assessment of intervention thresholds for very high fracture risk applied to the NOGG guidelines: A report for the National Osteoporosis Guideline Group (NOGG. Osteoporos Int 2021; 32: 1951-1960
• 32 Camacho PM, Petak SM, Binkley N. et al. American association of clinical endocrinologists/American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract 2020; 26: 1-46
• 33 Carey JJ, Chih-Hsing Wu P, Bergin D. Risk assessment tools for osteoporosis and fractures in 2022. Best Pract Res Clin Rheumatol 2022; 36
• 34 Glüer CC, Engelke K, Thomasius F. The Concept of the DVO Fracture Risk Calculator. Osteologie 2023; 32: 123-132
• 35 Chang LL, Eastell R, Miller PD. Continuation of Bisphosphonate Therapy for Osteoporosis beyond 5 Years. N Engl J Med 2022; 386: 1467-1469
• 36 Tsourdi E, Langdahl B, Cohen-Solal M. et al. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone 2017; 105: 11-17
• 37 Farlay D, Rizzo S, Dempster DW. et al. Bone Mineral and Organic Properties in Postmenopausal Women Treated With Denosumab for Up to 10 years. J Bone Miner Res 2022; 37: 856-864
• 38 Tsourdi E, Zillikens MC, Meier C. et al. Fracture Risk and Management of Discontinuation of Denosumab Therapy: A Systematic Review and Position Statement by ECTS. J Clin Endocrinol Metab 2021; 106: 264-281
• 39 Langdahl BL, Uitterlinden AG, Ralston SH. Where is bone science taking us. Best Pract Res Clin Rheumatol 2022; 36: 101791
• 40 Fuggle N, Al-Daghri N, Bock O. et al. Novel formulations of oral bisphosphonates in the treatment of osteoporosis. Aging Clin Exp Res 2022; 34: 2625-2634
• 41 Farr JN, Xu M, Weivoda MM. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 2017 239 2017; 23: 1072-1079
• 42 Pignolo RJ, Passos JF, Khosla S. et al. Reducing Senescent Cell Burden in Aging and Disease. Trends Mol Med 2020; 26: 630-638
• 43 Zhu Y, Tchkonia T, Pirtskhalava T. et al. The achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell 2015; 14: 644-658
• 44 Sharma AK, Roberts RL, Benson RD. et al. The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice. Front Cell Dev Biol 2020; 8
• 45 Raffaele M, Vinciguerra M. The costs and benefits of senotherapeutics for human health. Lancet Heal Longev 2022; 3: e67-e77
• 46 Jiang Y, Zhang P, Zhang X. et al. Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis. Cell Prolif 2021; 54: e12956
• 47 Lu L, Dai C, Zhang Z. et al. Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: A prospective, randomized, double-blind, active-controlled, phase IIb clinical trial. Stem Cell Res Ther 2019; 10
• 48 Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cell Intravenous Infusion for Osteoporosis - Full Text View - ClinicalTrials.gov. Im Internet https://clinicaltrials.gov/ct2/show/NCT05152381 Stand: 15.11.2022
• 49 Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014; 30: 255-289
• 50 Qin Y, Wang L, Gao Z. et al. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci Rep 2016; 6: 1-11
• 51 Shen M, Wu R, Jin R. et al. Injection of synthetic mesenchymal stem cell mitigates osteoporosis in rats after ovariectomy. J Cell Mol Med 2018; 22: 3751-3757
• 52 Tkach M, Théry C. Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell 2016; 164: 1226-1232
• 53 Sun L, Peng Y, Sharrow AC. et al. FSH Directly Regulates Bone Mass. Cell 2006; 125: 247-260
• 54 Østergren PB, Kistorp C, Fode M. et al. Metabolic consequences of gonadotropin-releasing hormone agonists vs orchiectomy: a randomized clinical study. BJU Int 2019; 123: 602-611
• 55 Guo Y, Zhao M, Bo T. et al. Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol. Cell Res 2019; 29: 151-166
• 56 Xiong J, Kang SS, Wang Z. et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature 2022; 603: 470-476
• 57 Gera S, Kuo T-C, Gumerova AA. et al. FSH-blocking therapeutic for osteoporosis. Elife 2022; 11
• 58 Ensrud KE, Crandall CJ. Osteoporosis. Ann Intern Med. 2017. 167. ITC17–ITC31
• 59 Cornelissen D, Boonen A, Evers S. et al. Improvement of osteoporosis Care Organized by Nurses: ICON study - Protocol of a quasi-experimental study to assess the (cost)-effectiveness of combining a decision aid with motivational interviewing for improving medication persistence in patients with a. BMC Musculoskelet Disord 2021; 22
• 60 Foessl I, Dimai HP, Obermayer-Pietsch B. Long-term and sequential treatment for osteoporosis. Nat Rev Endocrinol 2023 199 2023; 19: 520-533
• 61 Vlot MC, den Heijer M, de Jongh RT. et al. Clinical utility of bone markers in various diseases. Bone 2018; 114: 215-225
• 62 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: 1147-1155
• 63 Cosman F, Kendler DL, Langdahl BL. et al. Romosozumab and antiresorptive treatment: the importance of treatment sequence. Osteoporos Int 2022; 33: 1243-1256
• 64 Liberman UA, Weiss SR, Bröll J. et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995; 333: 1437-1444
• 65 Schnitzer T, Bone HG, Crepaldi G. et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin Exp Res 2000; 12: 1-12
• 66 Black DM, Cummings SR, Karpf DB. et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541
• 67 Axelsson KF, Wallander M, Johansson H. et al. Hip fracture risk and safety with alendronate treatment in the oldest-old. J Intern Med 2017; 282: 546-559
• 68 McClung MR, Balske A, Burgio DE. et al. Treatment of postmenopausal osteoporosis with delayed-release risedronate 35 mg weekly for 2 years. Osteoporos Int 2013; 24: 301-310
• 69 McClung MR, Geusens P, Miller PD. et al. Effect of Risedronate on the Risk of Hip Fracture in Elderly Women. N Engl J Med 2001; 344: 333-340
• 70 Reginster JY, Minne HW, Sorensen OH. et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11: 83-91
• 71 Harris ST, Watts NB, Genant HK. et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999; 282: 1344-1352
• 72 Miller PD, Recker RR, Harris S. et al. Long-term fracture rates seen with continued ibandronate treatment: Pooled analysis of DIVA and MOBILE long-term extension studies. Osteoporos Int 2014; 25: 349-357
• 73 Harris ST, Blumentals WA, Miller PD. Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis: Results of a meta-analysis of phase III studies. In: Current Medical Research and Opinion. Taylor & Francis; 2008: 237-245
• 74 Delmas PD, Recker RR, Chesnut CH. et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int 2004; 15: 792-798
• 75 Chesnut CH, Skag A, Christiansen C. et al. Effects of Oral Ibandronate Administered Daily or Intermittently on Fracture Risk in Postmenopausal Osteoporosis. J Bone Miner Res 2004; 19: 1241-1249
• 76 Black DM, Delmas PD, Eastell R. et al. Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis. N Engl J Med 2007; 356: 1809-1822
• 77 Lyles KW, Colón-Emeric CS, Magaziner JS. et al. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N Engl J Med 2007; 357: 1799-1809
• 78 Recker RR, Kendler D, Recknor CP. et al. Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone 2007; 40: 843-851
• 79 Delmas PD, Genant HK, Crans GG. et al. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: Results from the MORE trial. Bone 2003; 33: 522-532
• 80 Ettinger B, Black DM, Mitlak BH. et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999; 282: 637-645
• 81 Ellis AG, Reginster JY, Luo X. et al. Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral fractures in postmenopausal osteoporotic women. Curr Med Res Opin 2014; 30: 1617-1626
• 82 Ellis AG, Reginster JY, Luo X. et al. Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture: a network meta-analysis. Value Health 2014; 17: 424-432
• 83 De Villiers TJ, Chines AA, Palacios S. et al. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int 2011; 22: 567-576
• 84 Kanis JA, Johansson H, Oden A. et al. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 2009; 44: 1049-1054
• 85 Kendler DL, Marin F, Zerbini CAF. et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 2018; 391: 230-240
• 86 Reginster JY, Bianic F, Campbell R. et al. Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis. Osteoporos Int 2019; 30: 1465-1473
• 87 McCloskey EV, Fitzpatrick LA, Hu MY. et al. Effect of abaloparatide on vertebral, nonvertebral, major osteoporotic, and clinical fractures in a subset of postmenopausal women at increased risk of fracture by FRAX probability. Arch Osteoporos 2019; 14
• 88 Miller PD, Hattersley G, Riis BJ. et al. Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA 2016; 316: 722-733
• 89 Cosman F, Cooper C, Wang Y. et al. Comparative effectiveness and cardiovascular safety of abaloparatide and teriparatide in postmenopausal women new to anabolic therapy: A US administrative claims database study. Osteoporos Int 2022; 33: 1703-1714
• 90 Cummings SR, Martin JS, McClung MR. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361: 756-765
• 91 Broadwell A, Chines A, Ebeling PR. et al. Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease. J Clin Endocrinol Metab 2021; 106: 397-409
• 92 Geusens P, Oates M, Miyauchi A. et al. The Effect of 1 Year of Romosozumab on the Incidence of Clinical Vertebral Fractures in Postmenopausal Women With Osteoporosis: Results From the FRAME Study. JBMR Plus 2019; 3
• 93 Saag KG, Petersen J, Brandi ML. et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med 2017; 377: 1417-1427
• 94 Zhu L, Jiang X, Sun Y. et al. Effect of hormone therapy on the risk of bone fractures: A systematic review and meta-analysis of randomized controlled trials. Menopause 2016; 23: 461-470
• 95 Bagger YZ, Tankó LB, Alexandersen P. et al. Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004; 34: 728-735
• 96 Banks E, Beral V, Reeves G. et al. Fracture Incidence in Relation to the Pattern of Use of Hormone Therapy in Postmenopausal Women. JAMA 2004; 291: 2212-2220
• 97 Anderson GL, Limacher M, Assaf AR. et al. Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy: The Women’s Health Initiative Randomized Controlled Trial. JAMA 2004; 291: 1701-1712
• 98 Rossouw JE, Anderson GL, Prentice RL. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333
• 99 Hadji P, Ryan KA, Yu CR. et al. CE/BZA effects on bone and quality of life in European postmenopausal women: a pooled analysis. Climacteric 2016; 19: 482-487
• 100 Cauley JA, Robbins J, Chen Z. et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003; 290: 1729-1738
• 101 Torgerson DJ, Bell-Syer SEM. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 2001; 285: 2891-2897