Advertisement
Review Article| Volume 37, ISSUE 3, P433-452, August 2011

The RANKL Pathway and Denosumab

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Rheumatic Disease Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hofbauer L.C.
        • Schoppet M.
        Clinical implications of the osteoprotegerin RANKL/RANK system for bone and vascular diseases.
        JAMA. 2004; 292: 490-495
        • Zhao L.
        • Huang J.
        • Guo R.
        • et al.
        Smurf 1 inhibits MSC proliferation and differentiation into osteoblasts through Jun beta degradation.
        J Bone Miner Res. 2010; 25: 1246-1256
        • Turner C.H.
        • Robling A.G.
        • Duncan R.L.
        • et al.
        Do bone cells behave like a neuronal network?.
        Calcif Tissue Int. 2002; 70: 435-442
        • Compston F.E.
        • Vedi S.
        • Kaptoge S.
        • et al.
        Bone remodeling rate and remodeling balance are not co-regulated in adulthood: Implications for the use of activation frequency as an index of remodeling rate.
        J Bone Miner Res. 2007; 22: 1031-1036
        • Lacey D.L.
        • Timms E.
        • Tan H.L.
        • et al.
        Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
        Cell. 1998; 93: 165-176
        • Eghbali-Fatourechi G.
        • Khosla S.
        • Sanyal A.
        • et al.
        Role of RANK ligand in mediating increased bone resorption in early postmenopausal women.
        J Clin Invest. 2003; 111: 1221-1230
        • Shevde N.K.
        • Bendixen A.C.
        • Dienger K.M.
        Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression.
        Proc Natl Acad Sci U S A. 2000; 97: 7829-7834
        • Hofbauer L.C.
        • Gori F.
        • Riggs B.L.
        • et al.
        Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells.
        Endocrinology. 1999; 40: 4382-4389
        • Sasaki N.
        • Kusano E.
        • Ando Y.
        • et al.
        Glucocorticoid decreases circulating osteoprotegerin (OPG).
        Nephrol Dial Transplant. 2001; 16: 479-482
        • Fahrleitner A.
        • Prenner G.
        • Leb G.
        • et al.
        Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation.
        Bone. 2003; 89: 180-190
        • Browner W.S.
        • Lui L.Y.
        • Cummings S.R.
        Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures and mortality in elderly women.
        J Clin Endocrinol Metab. 2001; 86: 631-637
        • Bekker P.J.
        • Holloway D.
        • Nakanishi A.
        • et al.
        The effect of a single dose of osteoprotegerin in post-menopausal women.
        J Bone Miner Res. 2001; 16: 348-360
        • Kostenuik P.J.
        • Nguyen H.Q.
        • 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
        • Kostenuik P.J.
        Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength.
        Curr Opin Pharmacol. 2005; 5: 618-625
        • Bekker P.J.
        • Holloway D.L.
        • Rasmussen A.S.
        • 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: 1059-1066
        • Kong Y.Y.
        • Yoshida H.
        • Sarosi I.
        • et al.
        OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis.
        Nature. 1999; 397: 315-323
        • Lewiecki E.M.
        • Miller P.D.
        • McClung M.R.
        • et al.
        Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density.
        J Bone Miner Res. 2007; 22: 1832-1841
        • Miller P.D.
        • Bolognese M.A.
        • Lewiecki E.M.
        • et al.
        Effect of denosumab on bone density and turnover in postmenopausal with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial.
        Bone. 2008; 43: 222-229
        • Miller P.D.
        • Wagman R.B.
        • 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: 394-402
        • Bone H.G.
        • Bolognese M.A.
        • Yuen C.K.
        • et al.
        Effects of denosumab on bone mineral density and bone turnover in postmenopausal women.
        J Clin Endocrinol Metab. 2008; 93: 2149-2157
        • Genant H.K.
        • Engelke K.
        • Hanley D.A.
        • et al.
        Denosumab improves density and strength parameters as measured by QCT of the radius in postmenopausal women with low bone mineral density.
        Bone. 2010; 47: 131-139
        • Bone H.G.
        • Bolognese M.A.
        • Yuen C.K.
        • et al.
        Effects of denosumab therapy and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass.
        J Bone Miner Res. 2009; 24 (presentation 1243)
        • Cummings S.R.
        • Martin J.S.
        • McClung M.R.
        • et al.
        Denosumab for prevention of fractures in postmenopausal women with osteoporosis.
        N Engl J Med. 2009; 361: 756-765
        • Reid I.R.
        • Miller P.D.
        • Brown J.P.
        • et al.
        Effects of denosumab on bone histomorphometry: The FREEDOM and STAND studies.
        J Bone Miner Res. 2010; 25: 2256-2265
      1. Chupurlat R, Papapoulos S, Bone HG, et al. Long-term denosumab treatment of postmenopausal women with osteoporosis: results from the first two years of the FREEDOM extension study. American College of Rheumatology Annual Meeting. November 7–11, Atlanta, 2011. p. S903.

        • Kendler D.L.
        • Roux C.
        • Benhamou C.L.
        • et al.
        Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy.
        J Bone Miner Res. 2010; 25: 72-81
        • Brown J.P.
        • Prince R.L.
        • 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: 153-161
        • Kendler D.L.
        • Bessette L.
        • Hill C.D.
        • et al.
        Preferences and satisfaction with a 6-month subcutaneous injection versus a weekly tablet for treatment of low bone mass.
        Osteoporos Int. 2010; 21: 837-846
        • Kendler D.L.
        • Kaur P.
        • Siddhanti S.
        Open-label, crossover study evaluating the adherence, preference and satisfaction of denosumab and alendronate treatment in postmenopausal women: results of the second year of the study.
        J Clin Densitom. 2011; 14: 158
        • Smith M.R.
        • Egerdie B.
        • Toriz N.H.
        • et al.
        Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
        N Engl J Med. 2009; 361: 745-755
        • Smith M.R.
        • Saad F.
        • Egerdie B.
        • et al.
        Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.
        J Urol. 2009; 182: 2670-2672
        • Ellis G.K.
        • Bone H.G.
        • Chlebowski R.
        • et al.
        Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.
        J Clin Oncol. 2008; 26: 4875-4882
        • Ellis K.E.
        • Bone H.G.
        • Chlebowski R.
        Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study.
        Breast Cancer Res Treat. 2009; 118: 81-87
      2. Prolia (denosumab) prescribing information. 2010.

      3. Jamal SA, Ljunggren O, Stehman-Breen C, et al. The effects of denosumab on bone mineral density and vertebral fracture by level of renal function. Annual Meeting of the American Society for Bone and Mineral Research. Toronto, 2010. Presentation 1068.

        • Adami S.
        • Gilchrist N.
        • Lyritis G.
        • et al.
        Effect of denosumab on fracture healing in postmenopausal women with osteoporosis: results from the FREEDOM trial.
        ECTS. 2010; (OP24 [online])
        • Martin T.J.
        Paracrine regulation of osteoclast formation and activity: milestones in discovery.
        J Musculoskelet Neuronal Interact. 2004; 4: 243-253
        • Walsh M.C.
        • Kim N.
        • Kadono Y.
        • et al.
        Osteoimmunology: interplay between the immune system and bone metabolism.
        Annu Rev Immunol. 2006; 24: 33-63
        • Stolina M.
        • Dwyer D.
        • Ominsky M.S.
        • et al.
        Rats overexpressing soluble osteoprotegerin from a prenatal stage have high bone mass but no alterations in the development of lymphoid organs or innate immune response.
        J Bone Miner Res. 2006; 2: S153