Denosumab in postmenopausal women with low bone mineral density

Michael R. McClung, E. Michael Lewiecki, Stanley B. Cohen, Michael A. Bolognese, Grattan C. Woodson, Alfred H. Moffett, Munro Peacock, Paul D. Miller, Samuel N. Lederman, Charles H. Chesnut, Douglas Lain, Alan J. Kivitz, Donna L. Holloway, Charlie Zhang, Mark C. Peterson, Pirow J. Bekker

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Abstract

Background: Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. Methods: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Results: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. Conclusions: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis.

Original languageEnglish
Pages (from-to)821-831
Number of pages11
JournalNew England Journal of Medicine
Volume354
Issue number8
DOIs
StatePublished - Feb 23 2006

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Bone Density
Alendronate
Placebos
Spine
Bone Remodeling
Bone and Bones
Denosumab
Osteoclasts
Bone Resorption
Cytoplasmic and Nuclear Receptors
Serum
Femur
Osteoporosis
Alkaline Phosphatase
Hip
Monoclonal Antibodies
Urine
Ligands
Safety
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

McClung, M. R., Michael Lewiecki, E., Cohen, S. B., Bolognese, M. A., Woodson, G. C., Moffett, A. H., ... Bekker, P. J. (2006). Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine, 354(8), 821-831. https://doi.org/10.1056/NEJMoa044459

Denosumab in postmenopausal women with low bone mineral density. / McClung, Michael R.; Michael Lewiecki, E.; Cohen, Stanley B.; Bolognese, Michael A.; Woodson, Grattan C.; Moffett, Alfred H.; Peacock, Munro; Miller, Paul D.; Lederman, Samuel N.; Chesnut, Charles H.; Lain, Douglas; Kivitz, Alan J.; Holloway, Donna L.; Zhang, Charlie; Peterson, Mark C.; Bekker, Pirow J.

In: New England Journal of Medicine, Vol. 354, No. 8, 23.02.2006, p. 821-831.

Research output: Contribution to journalArticle

McClung, MR, Michael Lewiecki, E, Cohen, SB, Bolognese, MA, Woodson, GC, Moffett, AH, Peacock, M, Miller, PD, Lederman, SN, Chesnut, CH, Lain, D, Kivitz, AJ, Holloway, DL, Zhang, C, Peterson, MC & Bekker, PJ 2006, 'Denosumab in postmenopausal women with low bone mineral density', New England Journal of Medicine, vol. 354, no. 8, pp. 821-831. https://doi.org/10.1056/NEJMoa044459
McClung MR, Michael Lewiecki E, Cohen SB, Bolognese MA, Woodson GC, Moffett AH et al. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine. 2006 Feb 23;354(8):821-831. https://doi.org/10.1056/NEJMoa044459
McClung, Michael R. ; Michael Lewiecki, E. ; Cohen, Stanley B. ; Bolognese, Michael A. ; Woodson, Grattan C. ; Moffett, Alfred H. ; Peacock, Munro ; Miller, Paul D. ; Lederman, Samuel N. ; Chesnut, Charles H. ; Lain, Douglas ; Kivitz, Alan J. ; Holloway, Donna L. ; Zhang, Charlie ; Peterson, Mark C. ; Bekker, Pirow J. / Denosumab in postmenopausal women with low bone mineral density. In: New England Journal of Medicine. 2006 ; Vol. 354, No. 8. pp. 821-831.
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AU - Cohen, Stanley B.

AU - Bolognese, Michael A.

AU - Woodson, Grattan C.

AU - Moffett, Alfred H.

AU - Peacock, Munro

AU - Miller, Paul D.

AU - Lederman, Samuel N.

AU - Chesnut, Charles H.

AU - Lain, Douglas

AU - Kivitz, Alan J.

AU - Holloway, Donna L.

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AU - Peterson, Mark C.

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N2 - Background: Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. Methods: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Results: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. Conclusions: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis.

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