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Romosozumab in the treatment of osteoporosis

    Alexandra O Kobza

    Department of Medicine, Division of Rheumatology, McMaster University, Hamilton, ON L8N 3Z5, Canada

    ,
    Alexandra Papaioannou

    Department of Medicine, Division of Geriatric Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada

    Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, ON L8S 4K1, Canada

    ,
    Arthur N Lau

    Department of Medicine, Division of Rheumatology, McMaster University, Hamilton, ON L8N 3Z5, Canada

    &
    Jonathan D Adachi

    *Author for correspondence:

    E-mail Address: jd.adachi@sympatico.ca

    Department of Medicine, Division of Rheumatology, McMaster University, Hamilton, ON L8N 3Z5, Canada

    Published Online:https://doi.org/10.2217/imt-2020-0158

    Osteoporosis is a disease characterized by weakening of the bone architecture, which leads to an increased risk of fracture. There has been interest in the development of osteoanabolic agents that can increase bone mass and reverse the deteriorating architecture of osteoporotic bone. Romosozumab is a new agent for osteoporosis that both promotes bone formation and inhibits bone resorption. It is a monoclonal antibody that inhibits the activity of sclerostin, which allows the Wnt pathway to promote osteoblastogenesis and inhibit the activity of bone-resorbing osteoclasts. In clinical trials, it has proven to be superior to other agents in terms of increasing bone mineral density and reducing the incidence of fractures. This review will highlight the pharmacology, clinical efficacy and safety profile of romosozumab and suggest where this medication may fit within our current management of osteoporosis.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. International Osteoporosis Foundation. Global Initiatives [Internet]. (2017). www.iofbonehealth.org/global-initiatives-0
    • 2. Osteoporosis Canada. Osteoporosis Facts and Statistics [Internet]. https://osteoporosis.ca/about-the-disease/fast-facts/. (2017).
    • 3. Franz-Odendaal TA, Hall BK, Witten PE. Buried alive: how osteoblasts become osteocytes. Dev. Dyn. An. Off. Publ. Am. Assoc. Anat. 235(1), 176–190 (2006).
    • 4. Awasthi H, Mani D, Singh D, Gupta A. The underlying pathophysiology and therapeutic approaches for osteoporosis. Med. Res. Rev. 38(6), 2024–2057 (2018).
    • 5. Eastell R, O'Neill TW, Hofbauer LC et al. Postmenopausal osteoporosis. Nature reviews Disease primers. 2(1), 1–6 (2016).
    • 6. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 377(9773), 1276–1287 (2011).
    • 7. Holdsworth G, Roberts SJ, Ke HZ. Novel actions of sclerostin on bone. J. Mol. Endocrinol. 62(2), R167–R185 (2019). • Review summarizing the wealth of information that is known regarding the effects of sclerostin on bone.
    • 8. Ominsky MS, Niu Q, Li C, Li X, Ke HZ. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J. Bone Miner Res. 29(6), 1424 31430 (2014).
    • 9. Kanis JA, Cooper C, Rizzoli R, Reginster J-Y. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos. Int. 30(1), 3–44 (2019).
    • 10. Camacho PM, Petak SM, Binkley N et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2016. Endocr. Pract. 22(suppl. 4), 1–42 (2016). • American Association of Clinical Endocrinologists guidelines for the diagnosis and management of postmenopausal osteoporosis, developed with an evidence-based approach using the GRADE system, which categorizes evidence based on the quality and strength of the contributing evidence.
    • 11. Papaioannou A, Morin S, Cheung AM et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. Cmaj 182(17), 1864–1873 (2010).
    • 12. Murad MH, Drake MT, Mullan RJ et al. Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network meta-analysis. J. Clin. Endocrinol. Metab. 97(6), 1871–1880 (2012).
    • 13. Black DM, Delmas PD, Eastell R et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med. 356(18), 1809–1802 (2007).
    • 14. Reid IR, Horne AM, Mihov B et al. Effects of zoledronate on cancer, cardiac events and mortality in osteopenic older women. J. Bone Miner. Res. 35(1), 20–27 (2020).
    • 15. Vogel VG, Costantino JP, Wickerham DL et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295(23), 2727–2741 (2006).
    • 16. Martino S, Cauley JA, Barrett-Connor E et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J. Natl Cancer Inst. 96(23), 1751–1761 (2004).
    • 17. Cummings SR, Martin JS, McClung MR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361(8), 756–765 (2009).
    • 18. Törring O. Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis. Ther. Adv. Musculoskelet. Dis. 7(3), 88–102 (2015).
    • 19. Greenspan SL, Bone HG, Ettinger MP et al. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann. Intern. Med. 146(5), 326–339 (2007).
    • 20. 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 316(7), 722–733 (2016).
    • 21. Kanis JA, Harvey NC, McCloskey E et al. Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporos. Int. 31(1), 1–12 (2020). •• Recent algorithm for the treatment of osteoporosis published by the International Osteoporosis Foundation that recommends treating those at very high risk of fracture directly with an anabolic agent (such as romosozumab) followed by an antiresorptive agent as first line.
    • 22. Canalis E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat. Rev. Endocrinol. 9(10), 575–583 (2013).
    • 23. Glass DA, Bialek P, Ahn JD et al. Canonical Wnt Signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell. 8, 751–764 (2005).
    • 24. Ominsky MS, Boyce RW, Li X, Ke HZ. Effects of sclerostin antibodies in animal models of osteoporosis. Bone 96, 63–75 (2017).
    • 25. Sebastian A, Loots GG. Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models. Metabolism 80, 38–47 (2018).
    • 26. Brunkow ME, Gardner JC, Van Ness J et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot – containing protein. Am. J. Hum. Genet. 68(3), 577–589 (2001).
    • 27. Li X, Ominsky MS, Niu Q-T et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J. Bone Miner. Res. 23(6), 860–869 (2008).
    • 28. Amgen Canada Inc. Product monograph including patient medication information; Evenity. 1–38 (2019). https://pdf.hres.ca/dpd_pm/00051819.PDF
    • 29. Schemitsch EH, Miclau T, Karachalios T et al. A randomized, placebo-controlled study of romosozumab for the treatment of hip fractures. J. Bone. Joint Surg. Am. 102(8), 693–702 (2020).
    • 30. Li X, Ominsky MS, Warmington KS et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24(4), 578–588 (2009).
    • 31. Ominsky MS, Vlasseros F, Jolette J et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J. Bone Miner. Res. 25(5), 948–9 (2010).
    • 32. Eddleston A, Marenzana M, Moore AR et al. A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis. J. Bone Miner. Res. 24(10), 1662–1671 (2009).
    • 33. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 26(1), 19–26 (2011). • First-in-human study of romosozumab, which demonstrated an increase in bone formation markers, decrease in bone resorption markers and an increase in BMD at the lumbar spine and hip with romosozumab treatment.
    • 34. Padhi D, Allison M, Kivitz AJ et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J. Clin. Pharmacol. 54(2), 168–178 (2014).
    • 35. Waite R, Brown D, Felx M et al. Bone reports decreased osteoprogenitor proliferation precedes attenuation of cancellous bone formation in ovariectomized rats treated with sclerostin antibody. Bone Rep. 8, 90–94 (2018).
    • 36. Mcclung MR, Brown JP, Diez-perez A et al. Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double-blind, Phase 2, parallel group study. J. Bone Miner. Res. 33(8), 1397–1406 (2018).
    • 37. van Lierop AH, Hamdy NAT, Hamersma H et al. Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. J. Bone Miner. Res. 26(12), 2804–11 (2011).
    • 38. Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr. Rev. 33(5), 747–783 (2012).
    • 39. McClung MR, Grauer A, Boonen S et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370(5), 412–420 (2014).
    • 40. Ishibashi H, Crittenden DB, Miyauchi A et al. Romosozumab increases bone mineral density in postmenopausal Japanese women with osteoporosis: a Phase 2 study. Bone. 103, 209–215 (2017).
    • 41. Cosman F, Crittenden DB, Adachi JD et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375(16), 1532–1543 (2016).
    • 42. Saag KG, Petersen J, Brandi ML et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. 377(15), 1417–1427 (2017). • The ARCH randomized control trial that showed an increased risk of cardiovascular events in participants taking romosozumab than those taking alendronate.
    • 43. Langdahl BL, Libanati C, Crittenden DB et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, Phase 3 trial. Lancet (London, England) 390(10102), 1585–1594 (2017).
    • 44. Lewiecki EM, Blicharski T, Goemaere S et al. A Phase III randomized placebo-controlled trial to evaluate efficacy and safety of romosozumab in men with osteoporosis. J. Clin. Endocrinol. Metab. 103(9), 3183–3193 (2018).
    • 45. Kendler DL, Bone HG, Massari F et al. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab. Osteoporos Int. 30(12), 2437–2448 (2019).
    • 46. Cosman F, McMahon D, Dempster D, Nieves JW. Standard Versus cyclic teriparatide and denosumab treatment for osteoporosis: a randomized trial. J. Bone Miner. Res. 35(2), 219–225 (2020).
    • 47. Graeff C, Campbell GM, Pena J et al. Administration of romosozumab improves vertebral trabecular and cortical bone as assessed with quantitative computed tomography and finite element analysis. Bone. 81, 364–369 (2015).
    • 48. Keaveny TM, Crittenden DB, Bolognese MA et al. Greater gains in spine and hip strength for romosozumab compared with teriparatide in postmenopausal women with low bone mass. J. Bone Miner. Res. 32(9), 1956–1962 (2017).
    • 49. Chavassieux P, Chapurlat R, Portero-Muzy N et al. Bone-forming and antiresorptive effects of romosozumab in postmenopausal women with osteoporosis: bone histomorphometry and microcomputed tomography analysis after 2 and 12 months of treatment. J. Bone Miner. Res. 34(9), 1597–1608 (2019).
    • 50. Lewiecki EM, Dinavahi RV, Lazaretti-castro M et al. One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the FRAME extension study. J. Bone Miner. Res. 34(3), 419–428 (2019).
    • 51. Cosman F, Crittenden DB, Ferrari S et al. Romosozumab FRAME study: a post hoc analysis of the role of regional background fracture risk on nonvertebral fracture outcome. J. Bone Miner. Res. 33(8), 1407–1416 (2018).
    • 52. Cosman F, Crittenden DB, Ferrari S et al. FRAME study: the foundation effect of building bone with 1 year of romosozumab leads to continued lower fracture risk after transition to denosumab. J. Bone Miner. Res. 33(7), 1219–1226 (2018).
    • 53. Ettinger B, Martin SJ, Crans G, Pavo I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J. Bone Miner. Res. 19(5), 745–51 (2004).
    • 54. Miller PD, Delmas PD, Lindsay R et al. Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J. Clin. Endocrinol. Metab. 93(10), 3785–3793 (2008).
    • 55. Boonen S, Marin F, Obermayer-Pietsch B et al. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab. 93(3), 852–860 (2008).
    • 56. Liu Y, Cao Y, Zhang S et al. Romosozumab treatment in postmenopausal women with osteoporosis: a meta-analysis of randomized controlled trials. Climacteric 21(2), 189–195 (2018).
    • 57. McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporos Sarcopenia 4(1), 11–15 (2018).
    • 58. Leder BZ, Tsai JN, Uihlein AV et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial. J. Clin. Endocrinol. Metab 99(5), 1694–1700 (2014).
    • 59. McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporosis and sarcopenia. 4(1), 11–15 (2018).
    • 60. Leder BZ, Tsai JN, Uihlein AV, Wallace PM, Lee H, Neer RM et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet (London, England) 386(9999), 1147–1155 (2015).
    • 61. NIH U.S. National Library of Medicine. ClinicalTrials.gov [Internet]. https://clinicaltrials.gov/ct2/results?cond=Osteoporosis&term=romosozumab&cntry=&state=&city=&dist=. (2020)
    • 62. Amgen Inc. Biologics License Application for Romosozumab [Internet]. (2019). www.fda.gov/media/121255/download
    • 63. Lv F, Cai X, Yang W et al. Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: systematic review and meta- analysis. Bone 130, 115121 (2020).
    • 64. Asadipooya K, Weinstock A. Cardiovascular outcomes of romosozumab and protective role of alendronate. Arterioscler. Thromb. Vasc. Biol. 39(7), 1343–1350 (2019).
    • 65. De Maré A, Maudsley S, Azmi A et al. Sclerostin as regulatory molecule in vascular media calcification and the bone–vascular axis. Toxins (Basel) 11(7), 428 (2019).
    • 66. Kranenburg G, Bartstra JW, Weijmans M et al. Bisphosphonates for cardiovascular risk reduction: a systematic review and meta-analysis. Atherosclerosis 252, 106–115 (2016).
    • 67. Chouinard L, Felx M, Mellal N et al. Carcinogenicity risk assessment of romosozumab: a review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study. Regul. Toxicol. Pharmacol. 81, 212–222 (2016).
    • 68. Vahle JL, Sato M, Long GG et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety. Toxicol. Pathol. 30(3), 312–321 (2002).
    • 69. Amgen. European Commission Approves EVENITY® (romosozumab) For The Treatment Of Severe Osteoporosis In Postmenopausal Women At High Risk Of Fracture. (2019). www.ucb.com/stories-media/Press-Releases/article/European-Commission-Approves-EVENITY-Romosozumab-for-the-Treatment-of-Severe-Osteoporosis-in-Postmenopausal-Women-at-High-Risk-of-Fracture
    • 70. FDA Briefing Document Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee BLA 761062 Romosozumab. 1–48 (2019). www.fda.gov/media/121257
    • 71. Tella SH, Gallagher JC. Biological agents in management of osteoporosis. Eur. J. Clin. Pharmacol. 70(11), 1291–1301 (2014).