A review of denosumab for the treatment of osteoporosis

: Osteoporosis is an age-related systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility. Bone remodeling involves two types of cells: osteoblasts and osteoclasts. Receptor activator of nuclear factor- κ B ligand (RANKL) is a key regulator of the formation and function of bone-resorbing osteoclasts, and its cell surface receptor, receptor activator of nuclear factor- κ B (RANK), is expressed by both osteoclast precursors and mature osteoclasts. Denosumab is a fully human monoclonal anti-RANKL antibody that inhibits the binding of RANKL to RANK, thereby decreasing osteoclastogenesis and bone-resorbing activity of mature osteoclasts. Although there are many medications available for the treatment of osteoporosis, inhibition of RANKL by denosumab has been shown to significantly affect bone metabolism. Denosumab appears to be a promising, highly effective, and safe parenteral therapy with good adherence for osteoporosis. Moreover, denosumab may be cost-effective therapy compared with existing alternatives. Therefore, in this review, we focus on studies of denosumab and the risks and benefits identified for this type of treatment for osteoporosis.

[1]  N. Yurgin,et al.  Cost Effectiveness of Denosumab versus Oral Bisphosphonates for Postmenopausal Osteoporosis in the US , 2013, Applied Health Economics and Health Policy.

[2]  Hang Lee,et al.  Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial , 2013, The Lancet.

[3]  H. Takayanagi,et al.  Immunology and bone. , 2013, Journal of biochemistry.

[4]  F. Kronenberg,et al.  Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus , 2013, Nature Medicine.

[5]  J. Penninger,et al.  Developmentally Regulated Availability of RANKL and CD40 Ligand Reveals Distinct Mechanisms of Fetal and Adult Cross-Talk in the Thymus Medulla , 2012, The Journal of Immunology.

[6]  R. Goeree,et al.  Cost-effectiveness of denosumab in the treatment of postmenopausal osteoporosis in Canada , 2012, Journal of medical economics.

[7]  P. Miller,et al.  Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial , 2012, Osteoporosis International.

[8]  Toshitaka Nakamura,et al.  Dose–response study of denosumab on bone mineral density and bone turnover markers in Japanese postmenopausal women with osteoporosis , 2012, Osteoporosis International.

[9]  J. Bilezikian,et al.  Sclerostin: Therapeutic Horizons Based Upon Its Actions , 2012, Current Osteoporosis Reports.

[10]  S. Cummings,et al.  Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[11]  Y. Kumagai,et al.  A randomized, double-blind, placebo-controlled, single-dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of denosumab administered subcutaneously to postmenopausal Japanese women. , 2011, Bone.

[12]  Jacques P. Brown,et al.  Bone remodeling in postmenopausal women who discontinued denosumab treatment: Off‐treatment biopsy study , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[13]  P. Miller A review of the efficacy and safety of denosumab in postmenopausal women with osteoporosis , 2011, Therapeutic advances in musculoskeletal disease.

[14]  M. Hiligsmann,et al.  Cost Effectiveness of Denosumab Compared with Oral Bisphosphonates in the Treatment of Post-Menopausal Osteoporotic Women in Belgium , 2011, PharmacoEconomics.

[15]  R. Goeree,et al.  Clinical efficacy and safety of denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis. , 2011, Seminars in arthritis and rheumatism.

[16]  Kosaku Kurata,et al.  Evidence for osteocyte regulation of bone homeostasis through RANKL expression , 2011, Nature Medicine.

[17]  N. Freemantle,et al.  Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women , 2011, Osteoporosis International.

[18]  P. Kostenuik,et al.  Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. , 2011, Bone.

[19]  J. Kanis,et al.  Cost-effectiveness of Denosumab for the treatment of postmenopausal osteoporosis , 2011, Osteoporosis International.

[20]  J. S. San Martin,et al.  Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. , 2011, The Journal of clinical endocrinology and metabolism.

[21]  E. Posvar,et al.  Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  Jacques P. Brown,et al.  Effects of denosumab on bone histomorphometry: The FREEDOM and STAND studies , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[23]  M. Hiligsmann,et al.  Potential cost-effectiveness of denosumab for the treatment of postmenopausal osteoporotic women. , 2010, Bone.

[24]  M. Hiligsmann,et al.  Cost-effectiveness of denosumab compared with oral bisphosphonates in the treatment of postmenopausal osteoporotic women , 2010 .

[25]  D. Padhi,et al.  57: A Single Dose Study of Denosumab in Patients With Various Degrees of Renal Impairment , 2010 .

[26]  K. Toulis,et al.  Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab , 2010, Osteoporosis International.

[27]  Jacques P. Brown,et al.  Kidney function and rate of bone loss at the hip and spine: the Canadian Multicentre Osteoporosis Study. , 2010, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[28]  Claus Christiansen,et al.  Denosumab for prevention of fractures in postmenopausal women with osteoporosis. , 2009, The New England journal of medicine.

[29]  P. Kostenuik,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 , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[30]  J. S. San Martin,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. , 2008, Bone.

[31]  S. Cummings,et al.  Renal function and rate of hip bone loss in older men: the Osteoporotic Fractures in Men Study , 2008, Osteoporosis International.

[32]  P. Miller,et al.  Two‐Year Treatment With Denosumab (AMG 162) in a Randomized Phase 2 Study of Postmenopausal Women With Low BMD , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  M. McClung Role of RANKL inhibition in osteoporosis , 2007, Arthritis research & therapy.

[34]  H. Takayanagi Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems , 2007, Nature Reviews Immunology.

[35]  Y. Kadono,et al.  Negative Regulation of Osteoclastogenesis by Ectodomain Shedding of Receptor Activator of NF-κB Ligand* , 2006, Journal of Biological Chemistry.

[36]  E. Barrett-Connor,et al.  Measures of Renal Function, BMD, Bone Loss, and Osteoporotic Fracture in Older Adults: The Rancho Bernardo Study , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[37]  R. Weinstein,et al.  Bisphosphonate-associated osteonecrosis of the jaw: the rheumatologist's role , 2006, Arthritis research & therapy.

[38]  D. Burr,et al.  Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. , 2006, Bone.

[39]  Steven W. Martin,et al.  A Single‐Dose Placebo‐Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  R. Recker,et al.  Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women. , 2005, Mayo Clinic proceedings.

[41]  David Greenblatt,et al.  Treatment of Postmenopausal Osteoporosis , 2005, Pharmacotherapy.

[42]  H. Tilg,et al.  The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss , 2005, Gut.

[43]  D. Hans,et al.  Risk factors for hip fracture in women with high BMD: EPIDOS study , 2005, Osteoporosis International.

[44]  C. Christiansen,et al.  Prevention of postmenopausal bone loss: six-year results from the Early Postmenopausal Intervention Cohort Study. , 2004, The Journal of clinical endocrinology and metabolism.

[45]  Krista F. Huybrechts,et al.  The impact of compliance with osteoporosis therapy on fracture rates in actual practice , 2004, Osteoporosis International.

[46]  O. Johnell,et al.  Fracture risk following an osteoporotic fracture , 2004, Osteoporosis International.

[47]  R. Faggioni,et al.  Regulatory effects of osteoprotegerin on cellular and humoral immune responses. , 2003, Clinical immunology.

[48]  G. Morgan,et al.  Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. , 2003, Immunity.

[49]  T. Dufresne,et al.  Risedronate Preserves Bone Architecture in Early Postmenopausal Women In 1 Year as Measured by Three-Dimensional Microcomputed Tomography , 2003, Calcified Tissue International.

[50]  B. L. Riggs,et al.  Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone , 2003, Journal of cellular biochemistry.

[51]  E. Wagner,et al.  Reaching a genetic and molecular understanding of skeletal development. , 2002, Developmental cell.

[52]  P. Lips,et al.  Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. , 2001, Endocrine reviews.

[53]  William Maloney,et al.  Receptor Activator of NF-κB and Osteoprotegerin Expression by Human Microvascular Endothelial Cells, Regulation by Inflammatory Cytokines, and Role in Human Osteoclastogenesis* , 2001, The Journal of Biological Chemistry.

[54]  A. Nakanishi,et al.  The Effect of a Single Dose of Osteoprotegerin in Postmenopausal Women , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[55]  S. Yamasaki,et al.  Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-kappaB ligand: modulation of the expression by osteotropic factors and cytokines. , 2000, Biochemical and biophysical research communications.

[56]  D. Lacey,et al.  Stimulation of Osteoprotegerin Ligand and Inhibition of Osteoprotegerin Production by Glucocorticoids in Human Osteoblastic Lineage Cells: Potential Paracrine Mechanisms of Glucocorticoid-Induced Osteoporosis1. , 1999, Endocrinology.

[57]  D. Lacey,et al.  Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. , 1999, Endocrinology.

[58]  T. Martin,et al.  Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. , 1999, Endocrine reviews.

[59]  R. Steinman,et al.  TRANCE, a Tumor Necrosis Factor Family Member Critical for CD40 Ligand–independent T Helper Cell Activation , 1999, The Journal of experimental medicine.

[60]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[61]  S. Morony,et al.  osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. , 1998, Genes & development.

[62]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[63]  K Yano,et al.  Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  C. Christiansen,et al.  Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. , 1997, The New England journal of medicine.

[65]  R. Dubose,et al.  A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function , 1997, Nature.

[66]  Brian R. Wong,et al.  TRANCE Is a Novel Ligand of the Tumor Necrosis Factor Receptor Family That Activates c-Jun N-terminal Kinase in T Cells* , 1997, The Journal of Biological Chemistry.

[67]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[68]  B. Hollis,et al.  Vitamin D deficiency in homebound elderly persons , 1996, JAMA.

[69]  A. Parfitt Osteonal and hemi‐osteonal remodeling: The spatial and temporal framework for signal traffic in adult human bone , 1994, Journal of cellular biochemistry.

[70]  T. Martin,et al.  Modulation of osteoclast differentiation. , 1992, Endocrine reviews.

[71]  T. Martin,et al.  Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[72]  T. Martin,et al.  The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. , 1989, Endocrinology.

[73]  Sheila J. Jones,et al.  Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. , 1988, Endocrinology.

[74]  E. Eriksen,et al.  Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. , 1986, Endocrine reviews.

[75]  B. Clarke,et al.  Five Years of Denosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the First Two Years of the FREEDOM Extension , 2012 .

[76]  N. Freemantle,et al.  Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis , 2012, Osteoporosis International.

[77]  J. Kalmar,et al.  Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. , 2006, Annals of internal medicine.

[78]  Y. Yazici,et al.  Denosumab in postmenopausal women with low bone mineral density. , 2006, The New England journal of medicine.

[79]  L. Lum,et al.  Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. , 2001, The Journal of biological chemistry.

[80]  T. Suda,et al.  An adherent condition is required for formation of multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand. , 2000, Blood.

[81]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[82]  O. Johnell,et al.  World-wide Projections for Hip Fracture , 1997, Osteoporosis International.

[83]  Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. , 1996, JAMA.