Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

Athanasios D Anastasilakis, Konstantinos A Toulis, Stergios A Polyzos, Chrysostomos D Anastasilakis, Polyzois Makras, Athanasios D Anastasilakis, Konstantinos A Toulis, Stergios A Polyzos, Chrysostomos D Anastasilakis, Polyzois Makras

Abstract

Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.

Keywords: adverse event; denosumab; efficacy; fracture; osteoporosis; safety.

References

    1. Ahlborg HG, Rosengren BE, Järvinen TL, et al. Prevalence of osteoporosis and incidence of hip fracture in women – secular trends over 30 years. BMC Musculoskelet Disord. 2010;11:48.
    1. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 2010;95(4):1555–1565.
    1. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–323.
    1. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–319.
    1. Anastasilakis AD, Toulis KA, Polyzos SA, Terpos E. RANKL inhibition for the management of patients with benign metabolic bone disorders. Expert Opin Investig Drugs. 2009;18(8):1085–1102.
    1. Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol. 2005;5:618–625.
    1. Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res. 2001;16(2):348–360.
    1. Body JJ, Greipp P, Coleman RE, et al. A Phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer. 2003;97(Suppl 3):887–892.
    1. Morony S, Lu J, Capparelli C, Dunstan CR, Lacey DL, Kostenuik PJ. Osteoprotegerin (OPG) prevents bone loss in a rat model of glucocorticoid- induced osteopenia. J Bone Miner Res. 2001;16:S148.
    1. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–342.
    1. Bekker P, Holloway D, Rasmussen A, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19(7):1059–1066.
    1. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29(2):155–192.
    1. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, Phase 3 trial. J Bone Miner Res. 2009;24(1):153–161.
    1. Miller PD, Wagman RB, Peacock M, et al. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin Endocrinol Metab. 2011;96(2):394–402.
    1. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972–980.
    1. Boonen S, Ferrari S, Miller PD, et al. Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk-a perspective. J Bone Miner Res. 2012;27(5):963–974.
    1. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50(12):793–807.
    1. Amgen Inc. Prolia (denosumab) package insert. Thousand Oaks, CA: Amgen Inc; 2010.
    1. Bridgeman MB, Pathak R. Denosumab for the reduction of bone loss in postmenopausal osteoporosis: a review. Clin Ther. 2011;33(11):1547–1559.
    1. Body JJ, Facon T, Coleman RE, et al. A study of the biological receptor activator of nuclear factor K-B ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastasis from breast cancer. Clin Cancer Res. 2006;12:1221–1228.
    1. Rodriguez RD, Sutjandra L, Peterson MC, Jang GR, Perez Ruixo J. Population pharmacokinetic meta-analysis of denosumab in healthy and cancer subjects and postmenopausal women with osteopenia or osteoporosis. AAPS J. 2009;11:S1.
    1. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645–2668.
    1. Lewiecki EM. Denosumab – an emerging treatment for postmenopausal osteoporosis. Expert Opin Biol Ther. 2010;10(3):467–476.
    1. Wang J, Lee J, Burns D, et al. Fit-for-purpose method validation and application of a biomarker (C-terminal telopeptides of type 1 collagen) in denosumab clinical studies. AAPS J. 2009;11(2):385–394.
    1. Kostenuik PJ, Nguyen HQ, McCabe J, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res. 2009;24:182–195.
    1. Ominsky MS, Schroeder J, Smith SY, Farrell DJ, Atkinson JE, Kostenuik PJ. Denosumab (AMG 162), a fully human RANKL antibody, improves cortical and cancellous bone mass and bone strength in ovariectomized cynomolgus monkeys. J Bone Miner Res. 2007;22:S23.
    1. Ominsky MS, Schroeder J, Smith SY, Farrell JP, Kostenuik PJ, Atkinson JE. Denosumab (AMG 162, a fully human RANKL antibody) increases cortical and cancellous bone mass in aged ovariectomized cynomolgus monkeys. J Bone Miner Res. 2006;21:S72.
    1. Anastasilakis AD, Toulis KA, Goulis DG, et al. Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res. 2009;41(10):721–729.
    1. Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):530–537.
    1. Papapoulos S, Chapurlat R, Libanati C, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012;27(3):694–701.
    1. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.
    1. McClung M, Lewiecki E, Cohen S, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821–831.
    1. Bone H, Bolognese M, Yuen C, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008;93(6):2149–2157.
    1. 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. 2012 March 30; [Epub ahead of print.]
    1. McCloskey EV, Johansson H, Oden A, et al. Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX®. J Bone Miner Res. 2012 March 10; [Epub ahead of print.]
    1. McClung M, Boonen S, Törring O, et al. Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res. 2011 October 4; [Epub ahead of print.]
    1. Boonen S, Adachi JD, Man Z, et al. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011;96(6):1727–1736.
    1. Jamal SA, Ljunggren O, Stehman-Breen C, et al. Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res. 2011;26(8):1829–1835.
    1. Beck TJ, Lewiecki EM, Miller PD, et al. Effects of denosumab on the geometry of the proximal femur in postmenopausal women in comparison with alendronate. J Clin Densitom. 2008;11(3):351–359.
    1. Toulis KA, Anastasilakis AD, Polyzos SA, Makras P. Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis. Hormones (Athens) 2011;10:174–195.
    1. Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390(6656):175–179.
    1. Bachmann MF, Wong BR, Josien R, Steinman RM, Oxenius A, Choi Y. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med. 1999;189(7):1025–1031.
    1. Wong B, Josien R, Lee SY, et al. TRANCE (tumor necrosis factor [TNF]-related activation induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997;186(12):2075–2080.
    1. Schwartzman J, Yazici Y. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(22):2390–2391.
    1. Ferrari-Lacraz S, Ferrari S. Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporos Int. 2010;22:435–446.
    1. Watts NB, Roux C, Modlin JF, et al. Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association? Osteoporos Int. 2012;23(1):327–337.
    1. Sobacchi C, Frattini A, Guerrini MM, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet. 2007;39(8):960–962.
    1. Toulis KA, Anastasilakis AD. Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int. 2010;21(11):1963–1964.
    1. von Keyserlingk C, Hopkins R, Anastasilakis A, et al. Clinical efficacy and safety of denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis. Semin Arthritis Rheum. 2011;41(2):178–186.
    1. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273:14363–14367.
    1. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3(6):673–682.
    1. Gonzalez-Suarez E, Jacob AP, Jones J, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–107.
    1. Loser K, Mehling A, Loeser S, et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12(12):1372–1379.
    1. Schousboe JT, Taylor BC, Kiel DP, Ensrud KE, Wilson KE, McCloskey EV. Abdominal aortic calcification detected on lateral spine images from a bone densitometer predicts incident myocardial infarction or stroke in older women. J Bone Miner Res. 2008;23:409–416.
    1. Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol. 2001;21(10):1610–1616.
    1. Helas S, Goettsch C, Schoppet M, et al. Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol. 2009;175(2):473–478.
    1. Jono S, Ikari Y, Shioi A, et al. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation. 2002;106(10):1192–1194.
    1. Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B, Hofbauer LC. Increased osteoprotegerin serum levels in men with coronary artery disease. J Clin Endocrinol Metab. 2003;88(3):1024–1028.
    1. Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab. 2001;86(2):631–637.
    1. Kiechl S, Schett G, Wenning G, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109(18):2175–2180.
    1. Pennisi P, Signorelli SS, Riccobene S, et al. Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels. Osteoporos Int. 2004;15(5):389–395.
    1. Visekruna M, Wilson D, McKiernan F. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab. 2008;93(8):2948–2952.
    1. Kyrgidis A, Triaridis S, Vahtsevanos K, Antoniades K. Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients. Expert Rev Anticancer Ther. 2009;9:1125–1134.
    1. Rizzoli R, Reginster JY, Boonen S, et al. Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis. Calcif Tissue Int. 2011;89(2):91–104.
    1. Kyrgidis A, Tzellos TG, Toulis K, Antoniades K. The facial skeleton in patients with osteoporosis: a field for disease signs and treatment complications. J Osteoporos. 2011;16:147689.
    1. Kyrgidis A, Toulis KA. Denosumab-related osteonecrosis of the jaws. Osteoporos Int. 2011;22(1):369–370.
    1. Pazianas M. Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer Inst. 2011;103(3):232–240.
    1. Flick LM, Weaver JM, Ulrich-Vinther M, et al. Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing. J Orthop Res. 2003;21(4):676–684.
    1. Delos D, Yang X, Ricciardi BF, Myers ER, Bostrom MP, Camacho NP. The effects of RANKL inhibition on fracture healing and bone strength in a mouse model of osteogenesis imperfecta. J Orthop Res. 2008;26(2):153–164.
    1. Ota N, Takaishi H, Kosaki N, et al. Accelerated cartilage resorption by chondroclasts during bone fracture healing in osteoprotegerin-deficient mice. Endocrinology. (11):4823–4834. 2009003B150.
    1. Gerstenfeld LC, Sacks DJ, Pelis M, et al. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res. 2009;24(2):196–208.
    1. Adami S, Adachi J, Boonen S, et al. Denosumab administration is not associated with fracture healing complications in postmenopausal women with osteoporosis: results from the FREEDOM trial. J Bone Miner Res. 2010;25(Suppl 1):MO0405.
    1. Rizzoli R, Yasothan U, Kirkpatrick P. Denosumab. Nat Rev Drug Discov. 2010;9(8):591–592.
    1. Rittmaster R, Bolognese M, Ettinger M, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 2000;85(6):2129–2134.
    1. Hiligsmann M, Reginster JY. Potential cost-effectiveness of denosumab for the treatment of postmenopausal osteoporotic women. Bone. 2010;47(1):34–40.
    1. Hiligsmann M, Reginster JY. Cost effectiveness of denosumab compared with oral bisphosphonates in the treatment of post-menopausal osteoporotic women in Belgium. Pharmacoeconomics. 2011;29(10):895–911.
    1. Jönsson B, Ström O, Eisman JA, et al. Cost-effectiveness of denosumab for the treatment of postmenopausal osteoporosis. Osteoporos Int. 2011;22(3):967–982.
    1. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927–2938.
    1. Makras P, Vaiopoulos G, Lyritis GP. 2011 guidelines for the diagnosis and treatment of osteoporosis in Greece. J Musculoskelet Neuronal Interact. 2012;12(1):38–42.
    1. Stolina M, Kostenuik PJ, Dougall WC, Fitzpatrick LA, Zack DJ. RANKL inhibition: from mice to men (and women) Adv Exp Med Biol. 2007;602:143–150.
    1. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276–1287.
    1. Silverman S, Christiansen C. Individualizing osteoporosis therapy. Osteoporos Int. 2012;23(3):797–809.
    1. Palacios S. Bazedoxifene acetate for the management of postmenopausal osteoporosis. Drugs Today (Barc) 2011;47(3):187–195.
    1. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007;22(12):1832–1841.
    1. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):222–229.

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