Two-Year Treatment With Denosumab (AMG 162) in a Randomized Phase 2 Study of Postmenopausal Women With Low BMD
Open accessAbstract
Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo-controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women. Introduction: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD. Materials and Methods: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of −1.8 to −4.0 or femoral neck/total hip T-scores of −1.8 to −3.5 were randomly assigned to receive double-blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety. Results: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and ≥60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment. Conclusions: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo.
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During year 2, denosumab continued to suppress serum CTx and uNTX/creatinine.
“During yr 2, in response to denosumab, serum C-telopeptide (CTx) and uNTX/creatinine demonstrated continued suppression.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
Optimal increases in BMD appeared to occur at denosumab doses of 30 and 60 mg, administered at 3 and 6 months, respectively.
“Optimal increases in BMD appeared to occur at denosumab doses of 30 and 60 mg, administered at 3 and 6 months, respectively.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
The duration of suppression of bone turnover appeared to be dose dependent.
“The duration of the suppression of bone turnover appeared to be dose dependent.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
In a 2-year extension, denosumab treatment resulted in persistent reductions in bone resorption and continued significant increases in BMD from baseline in 337 women who completed 2 years.
“In a planned extension of this study, denosumab treatment for 2 yr resulted in persistent reductions in bone resorption and continued, significant increases in BMD from baseline in the 337 women (82%) who completed 2 yr of study (38 placebo, 259 denosumab, 40 alendronate) (435).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
Across dose groups, women treated with denosumab for 2 years had significantly greater improvements in BMD compared with placebo at the lumbar spine, total hip, and distal radius; these improvements were similar to or greater than those with alendronate.
“Across dose groups, women treated with denosumab for 2 yr had significantly greater improvements in BMD compared with placebo (P Ͻ 0.001) at the lumbar spine, total hip, and distal radius; these improvements were similar to or greater than those observed in the open-label alendronate group.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
Hypertension and urinary tract infections were reported more often in the denosumab group than in the placebo group (P=0.01).
“Hypertension and urinary tract infections were reported more often in the denosumab group than the placebo group (P ϭ 0.01)”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
Dyspepsia and osteoarthritis appeared to occur with significantly greater frequency in the open-label alendronate group (P=0.01).
“whereas dyspepsia and osteoarthritis appeared to occur with significantly greater frequency in the open-label alendronate group (P ϭ 0.01).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
Few significant differences were observed between adverse event profiles in the denosumab groups and those in the placebo and alendronate groups.
“Few significant differences were observed between the profiles of adverse events in the denosumab groups and those in the placebo group and the alendronate group.”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
The percentages of patients experiencing adverse events (92.0%, 93.5%, and 93.5%) and serious adverse events (13.4%, 13.0%, and 8.7%) in the denosumab, alendronate, and placebo groups were similar.
“Indeed, the percentages of patients experiencing adverse events (92.0, 93.5, and 93.5%, respectively) and serious adverse events (13.4,13.0, and 8.7%, respectively) in the denosumab, alendronate, and placebo groups were similar (435).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [435]
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Cites
Prediction of Creatinine Clearance from Serum Creatinine
Cockcroft, D. W., & Gault, H. (2008) · The Nephron journals/Nephron journals · doi:10.1159/000180580 · Cited by 15,291 · see citing works
Osteoclast differentiation and activation
Boyle, W. J., Simonet, W. S., & Lacey, D. L. (2003) · Nature · doi:10.1038/nature01658 · Cited by 6,670 · cited 1× · see citing works
“RANK, the receptor for RANKL, has been identified on the surface of osteoclasts at several stages of differentiation, including prefusion osteoclasts and mature osteoclasts.((5,7))”
BackgroundOsteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
Lacey, D. L., Timms, E., Tan, H.-L., Kelley, M. J., Dunstan, C. R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81569-x · Cited by 5,439 · see citing works
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M.-S., Lüthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80209-3 · Cited by 5,130 · see citing works
A sharper Bonferroni procedure for multiple tests of significance
HOCHBERG, Y. (1988) · Biometrika · doi:10.1093/biomet/75.4.800 · Cited by 4,829 · see citing works
Kong, Y.-Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., Capparelli, C., Li, J., Elliott, R., McCabe, S., et al. (1999) · Nature · doi:10.1038/46303 · Cited by 1,856 · see citing works
Epidemiology of osteoporotic fractures
Johnell, O., & Kanis, J. А. (2004) · Osteoporosis International · doi:10.1007/s00198-004-1702-6 · Cited by 1,253 · see citing works
Denosumab in postmenopausal women with low bone mineral density.
McClung, M. R., Lewiecki, E. M., Cohen, S. B., Bolognese, M. A., Woodson, G. C., Moffett, A. H., Peacock, M., Miller, P. D., Lederman, S. N., Chesnut, C. H., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa044459 · Cited by 1,228 · see citing works
Self-citationClinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases
Hofbauer, L. C. (2004) · JAMA · doi:10.1001/jama.292.4.490 · Cited by 979 · see citing works
An estimate of the worldwide prevalence, mortality and disability associated with hip fracture
Johnell, O., & Kanis, J. A. (2004) · Osteoporosis International · doi:10.1007/s00198-004-1627-0 · Cited by 962 · see citing works
Role of RANK ligand in mediating increased bone resorption in early postmenopausal women
Eghbali-Fatourechi, G., Khosla, S., Sanyal, A., Boyle, W. J., Lacey, D. L., & Riggs, B. L. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17215 · Cited by 825 · see citing works
Bekker, P. J., Holloway, D. L., Rasmussen, A. S., Murphy, R., Martin, S. W., Leese, P. T., Holmes, G. B., Dunstan, C. R., & DePaoli, A. M. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040305 · Cited by 770 · see citing works
Body, J.-J., Facon, T., Coleman, R. E., Lipton, A., Geurs, F., Fan, M., Holloway, D., Peterson, M. C., & Bekker, P. J. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1933 · Cited by 490 · see citing works
Giuliani, N., Bataille, R., Mancini, C., Lazzaretti, M., & Barillé, S. (2001) · Blood · doi:10.1182/blood.v98.13.3527 · Cited by 415 · see citing works
Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo.
Lacey, D. L., Tan, H. L., Lu, J., Kaufman, S., Van, G., Qiu, W., Rattan, A., Scully, S., Fletcher, F., Juan, T., et al. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64556-7 · Cited by 391 · see citing works
Role of RANKL and RANK in bone loss and arthritis
Jones, D. H., Kong, Y.-Y., & Penninger, J. M. (2002) · Annals of the Rheumatic Diseases · doi:10.1136/ard.61.suppl_2.ii32 · Cited by 222 · see citing works
Quality of life, morbidity, and mortality after low trauma hip fracture in men
Pande, I., Scott, D. L., O'Neill, T. W., et al. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2004.034611 · Cited by 139 · see citing works
Hip fracture: Risk factors and outcomes
Wehren, L. E., & Magaziner, J. S. (2003) · Current Osteoporosis Reports · doi:10.1007/s11914-003-0013-8 · Cited by 117 · see citing works
Capparelli, C., Morony, S., Warmington, K., Adamu, S., Lacey, D., Dunstan, C. R., Stouch, B., Martin, S., & Kostenuik, P. J. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.5.852 · Cited by 103 · see citing works
Kostenuik, P. J., Bolon, B., Morony, S., Daris, M., Geng, Z., Carter, C., & Sheng, J. (2004) · Bone · doi:10.1016/j.bone.2003.12.006 · Cited by 82 · see citing works
Moxness, M. S., Tatarewicz, S. M., Weeraratne, D. K., et al. (2005) · Clinical Chemistry · doi:10.1373/clinchem.2005.053272 · Cited by 81 · see citing works
Campagnuolo, G., Bolon, B., & Feige, U. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10369 · Cited by 78 · see citing works
Comparison of WOMAC with SF-36 for OA of the knee or hip
Jones, J., Leighton, F., Angst, F., et al. (2002) · Annals of the Rheumatic Diseases · doi:10.1136/ard.61.2.182-a · Cited by 30 · see citing works
Mochizuki, S.-I., Fujise, N., Higashio, K., & Tsuda, E. (2002) · Journal of Bone and Mineral Metabolism · doi:10.1007/s774-002-8441-x · Cited by 24 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Atkinson J, Cranmer P, Saunders T, Niehaus M, Smith SY, Varela A, Ominsky MS, Cosenza ME, Kostenuik PJ 2005 AMG 162, a fully human RANKL antibody, increases bone mass and bone strength in cynomolgus monkeys. J Bone Miner Res 20:S1;S294.
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Kantoff, P. W., Higano, C. S., Shore, N. D., Berger, E. R., Small, E. J., Penson, D. F., Redfern, C. H., Ferrari, A. C., Dreicer, R., Sims, R. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1001294 · Cited by 5,572 · see citing works
Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis
Cummings, S. R., Martin, J. S., McClung, M. R., Siris, E. S., Eastell, R., Reid, I. R., Delmas, P., Zoog, H. B., Austin, M., Wang, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0809493 · Cited by 3,489 · see citing works
Self-citationOsteoporosis: now and the future
Rachner, T. D., Khosla, S., & Hofbauer, L. C. (2011) · The Lancet · doi:10.1016/s0140-6736(10)62349-5 · Cited by 2,696 · see citing works
Functions of RANKL/RANK/OPG in bone modeling and remodeling
Boyce, B. F., & Xing, L. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.03.018 · Cited by 1,844 · see citing works
for the IOF-IFCC Bone Marker Standards Working Group, Vasikaran, S., Eastell, R., Bruyère, O., Foldes, A. J., Garnero, P., Griesmacher, A., McClung, M., Morris, H. A., Silverman, S., et al. (2011) · Osteoporosis International · doi:10.1007/s00198-010-1501-1 · Cited by 1,212 · see citing works
Self-citationKearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824 · see citing works
A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling
Peterson, M. C., & Riggs, M. M. (2010) · Bone · doi:10.1016/j.bone.2009.08.053 · Cited by 198 · see citing works
Unexpected Bone Formation Produced by RANKL Blockade
Portal-Núñez, S., Mediero, A., Esbrit, P., Sánchez-Pernaute, O., Largo, R., & Herrero-Beaumont, G. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2017.06.003 · Cited by 32 · see citing works
- Authors
- Lewiecki, E. M., Miller, P. D., McClung, M. R., Cohen, S. B., Bolognese, M. A., Liu, Y., Wang, A., Siddhanti, S., & Fitzpatrick, L. A.
- Affiliations
- New Mexico Clinical Research & Osteoporosis Center (US)
- Colorado Center for Bone Research (US)
- Oregon Osteoporosis Center, Portland, Oregon, USA
- Radiant Research (United States) (US)
- National Institutes of Health (US)
- Amgen (United States) (US)
- Corresponding author
- Lewiecki, E Michael
- ORCID
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-12-01
- Volume
- 22
- Issue
- 12
- Pages
- 1832-1841
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W1989860636
- Cited by
- 319
- References
- 24
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 9 · 2023: 10 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 17 · 2017: 11 · 2016: 9 · 2015: 17 · 2014: 15 · 2013: 20 · 2012: 24
- FWCI
- 35.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Biogen
- IC Design Education Center
- Servier
- Genentech
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- denosumab, RANKL inhibition, postmenopausal osteoporosis, osteopenia, bone mineral density, bone turnover markers, alendronate, osteoclastogenesis, bone resorption, treatment safety, dosing frequency, subcutaneous administration, osteoporosis treatment efficacy, adverse events, osteoporosis prevention, osteoporosis treatment, osteoporosis
- MeSH terms
- Denosumab, Aged, Antibodies, Monoclonal, Bone Resorption, Double-Blind Method, Female, Humans, Middle Aged, Time Factors, Biomarkers, Bone Density, Osteoporosis, Postmenopausal, Postmenopause, Alendronate, Bone Density Conservation Agents, RANK Ligand, Antibodies, Monoclonal, Humanized
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