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Denosumab^[1] is a fully human monoclonal antibody for the treatment of osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma, and giant cell tumor of bone.^[2]^[3] It was developed by the biotechnology company Amgen.^[4]

Denosumab is designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defenses against bone destruction.

In June 2010, denosumab was approved by the U.S. Food and Drug Administration (FDA) for use in postmenopausal women with risk of osteoporosis under the trade name Prolia,^[5] and in November 2010, as Xgeva, for the prevention of skeleton-related events in patients with bone metastases from solid tumors.^[6] Denosumab is the first RANKL inhibitor to be approved by the FDA.^[7] In the summer of 2011 clinical trials were investigating denosumab in giant cell tumors, multiple myeloma with bone metastases, and hypercalcemia of malignancy, and further investigating its dosing and safety.^[8]

Mechanism of action[edit]

Bone remodeling is the process by which the body continuously removes old bone tissue and replaces it with new bone. It is driven by various types of cells, most notably osteoblasts (which secrete new bone) and osteoclasts (which break down bone). The role of osteocytes is still not well understood.

Precursors to osteoclasts, called "pre-osteoclasts", express surface receptors called RANK – short for receptor activator of nuclear factor-kappa B. RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily. RANK is activated by RANKL (the RANK-Ligand), which exists as cell surface molecules on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. This mimics the natural action of osteoprotegerin, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased avidity) in patients who are suffering from osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.^[2]

Effectiveness[edit]

Amgen has reported on two clinical trials that were designed and funded by the company.^[9]

In a Phase III clinical trial ('FREEDOM') involving 7,808 women aged 60 to 90, there were significant improvements in the subset of women with more severe disease (two or more prevalent vertebral fractures and/or one or more prevalent vertebral fractures with moderate or severe deformity) at the beginning of the study. Researchers reported a 35% risk reduction with denosumab compared to placebo (17% vs. 49%). Within this subset, only 31% of those taking denosumab developed new vertebral fractures, versus 71% of those receiving placebo.^[10]^[11]

The second phase III clinical trial involved 1,468 prostate cancer patients receiving hormone-deprivation therapy who were randomized to receive either denosumab or a placebo every 6 months over a 36 month period (all patients also received supplemental calcium and vitamin D). Of those taking the placebo, 3.9% experienced bone fractures during the 36 months, compared with 1.5% of those who received denosumab.^[12]

Both studies showed a decrease in fracture rates comparable to those achieved with zoledronic acid and teriparatide, and slightly more than under oral nitrogenous bisphosphonates.

Other studies have been discussed by Baqir and Copeland (Clinical Pharmacist 2010; 2:400),^{[full citation needed]} including the DEFEND, DECIDE and STAND trials. One et al.^{[citation needed]} investigated the effects of denosumab on bone mineral density (BMD) in women with BMD T-scores between −1.0 and −2.5 in a randomized trial comparing it with placebo. The primary endpoint was BMD change in the lumbar spine over two years as compared to baseline. The T-score for patients receiving danosumab increased by +6.5%, while the change in patients receiving placebo was −0.6% (ARR =7%; p<0.0001).

Brown et al.^[13] compared denosumab with alendronate "head-to-head" using total hip BMD as the primary outcome measure. There were increases in total hip BMD of 3.5% and 2.6% in the denosumab and alendronate groups respectively (ARR =1%; p<0.0001; NNT = 100). Although this study was not adequately powered to compare fracture rates, fractures were reported in 4% of the denosumab group and 3.2% of the alendronate group. Kendler et al.^[14]^[15] investigated denosumab therapy following on after alendronate. Women on alendronate 70 mg weekly for a "run-in" period of 1 month were then switched to denosumab or maintained on alendroanate (with matching placebo). The primary hypothesis was that denosumab was non-inferior to alendronate, and the primary endpoint was percentage change in total hip BMD at 12 months. BMD increase was +1.9% vs. +1.05% in patients given denosumab vs. those continuing on alendronate (ARR = 0.85%; p<0.0001; NNT = 118). Again, the study was not powered to compare fracture rates, but fractures were reported as adverse events in 8 patients (3.2%) in the denosumab group and 4 patients (1.6%) in the alendronate group.

Adverse effects[edit]

The most common side effects include infections of the urinary and respiratory tracts, cataracts, constipation, rashes, and joint pain.^[16] A small study found a slightly increased risk of cancer and severe infections, but these results did not reach statistical significance.^[2] Another trial showed significantly increased rates of eczema and hospitalization due to infections of the skin.^[11] It has been proposed that the increase in infections under denosumab treatment might be connected to the role of RANKL in the immune system.^[17] RANKL is expressed by T helper cells, and is thought to be involved in dendritic cell maturation.^[18]

Contraindications and interactions[edit]

Denosumab is contraindicated in patients with hypocalcemia, and sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy.^[19] Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.^[19]

Similarly to bisphosphonates, denosumab appears to be implicated in increasing the risk of osteonecrosis of the jaw (ONJ) following extraction of teeth or oral surgical procedures.

Regulatory approval[edit]

United States[edit]

On 13 August 2009, a meeting was held between Amgen and the Advisory Committee for Reproductive Health Drugs (ACRHD) of the (FDA) to review the potential uses of Prolia. A press release summarizing this meeting said:

"After reviewing safety and efficacy data from 30 clinical studies involving more than 12,000 patients, the Committee recommended approval of Prolia for the treatment of postmenopausal osteoporosis, and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer.^[20]

In October 2009, the U.S. Food and Drug Administration (FDA) delayed approval of denosumab, ostensibly because they needed more information.^[21]

On 2 June 2010, denosumab was approved for post-menopausal osteoporosis by the US FDA.^[7]

In November 2010, the US FDA approved denosumab (to be marketed as Xgeva) for the prevention of skeletal-related events in patients with bone metastasis from solid tumors.^[6] Dosing is one 60 mg subcutaneous injection every six months (for postmenopausal osteoporosis) and 120 mg every 4 weeks (for patients with solid tumors).

On 13 June 2013, the US FDA approved denosumab for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where resection would result in significant morbidity.^[22] Dosing is 120 mg subcutaneous injection every four weeks with additional 120 mg doses on days 8 and 14 of the first month.

Europe[edit]

On 17 December 2009, the Committee for Medicinal Products for Human Use (CHMP) issued a Positive Opinion for denosumab for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with hormone ablation therapy for prostate cancer.^[16]^[23] Denosumab was approved for marketing by the European Commission on 28 May 2010.

Sales and pricing[edit]

Internationally, because of Amgen's relatively weak GP sales force, Amgen is partnering^[when?] with GlaxoSmithKline (GSK) in Europe, Australia, New Zealand and Mexico to distribute Prolia.^[24]

In September 2009, the firm Sanford Bernstein projected that annual worldwide sales of the drug would reach $5 billion in the year 2015.^[25] It projected 2010 sales of over $650 million, mostly from use as a twice-yearly injectable for osteoporosis treatment in post-menopausal women over 50.^[26]

Actress Blythe Danner is now appearing in commercials for Prolia.

References[edit]

^ Pageau, Steven C. (2009). "Denosumab". MAbs 1 (3): 210–215. doi:10.4161/mabs.1.3.8592. PMC 2726593. PMID 20065634.
^ ^a ^b ^c McClung, Michael R.; Lewiecki, E. Michael; Cohen, Stanley B.; Bolognese, Michael A.; Woodson, Grattan C.; Moffett, Alfred H.; Peacock, Munro; Miller, Paul D. et al. (2006). "Denosumab in Postmenopausal Women with Low Bone Mineral Density". New England Journal of Medicine 354 (8): 821–31. doi:10.1056/NEJMoa044459. PMID 16495394. |displayauthors= suggested (help)
^ Ellis, G. K.; Bone, H. G.; Chlebowski, R.; Paul, D.; Spadafora, S.; Smith, J.; Fan, M.; Jun, S. (2008). "Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer". Journal of Clinical Oncology 26 (30): 4875–82. doi:10.1200/JCO.2008.16.3832. PMID 18725648.
^ "Prolia (denosumab)". Products. Amgen. Retrieved 6 May 2012.
^ Matthew Perrone (June 2, 2010). "FDA clears Amgen's bone-strengthening drug Prolia". BioScience Technology.
^ ^a ^b "Amgen's Denosumab Cleared by FDA for Second Indication". 19 Nov 2010.
^ ^a ^b "FDA Approves Denosumab for Osteoporosis". 2 June 2010.
^ Russell S. Crawford, BPharm; Morgane C. Diven, PharmD; Laura Yarbro, PharmD (2011). "Denosumab: A Review of Its Pharmacology and Clinical Implications". Contemporary Oncology 3 (1).
^ Thomas H. Maugh II (August 12, 2009). "New osteoporosis drug shown to reduce spinal fractures". Los Angeles Times.
^ Donald A. Bergman (September 16, 2009). "Denosumab: Fracture risk reduced in high-risk subset in FREEDOM". Endocrine Today.
^ ^a ^b Cummings, Steven R.; Martin, Javier San; McClung, Michael R.; Siris, Ethel S.; Eastell, Richard; Reid, Ian R.; Delmas, Pierre; Zoog, Holly B. et al. (2009). "Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis". New England Journal of Medicine 361 (8): 756–65. doi:10.1056/NEJMoa0809493. PMID 19671655. |displayauthors= suggested (help)
^ John Otrompke (September 15, 2009). "Experimental Drug Reduces Fractures Related to Prostate Cancer Treatment: Presented at ASBMR". Doctor's Guide.
^ Zhu, M.; Tang, D.; Wu, Q.; Hao, S.; Chen, M.; Xie, C.; Rosier, R. N.; O'Keefe, R. J.; Zuscik, M.; Chen, D.; Austin, M.; Wagman, R. B.; Newmark, R.; Libanati, C.; San Martin, J.; Bone, H. G. (2009). "Activation of β-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult β-Catenin Conditional Activation Mice". Journal of Bone and Mineral Research 24 (1): 12–21. doi:10.1359/jbmr.080901. PMC 2640321. PMID 18767928. edit
^ Kendler, D. L.; Roux, C.; Benhamou, C. L.; Brown, J. P.; Lillestol, M.; Siddhanti, S.; Man, H. S.; San Martin, J. S.; Bone, H. G. (2010). "Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy". Journal of Bone and Mineral Research 25 (1): 72–81. doi:10.1359/jbmr.090716. PMID 19594293. edit
^ Freemantle, N.; Satram-Hoang, S.; Tang, E. -T.; Kaur, P.; MacArios, D.; Siddhanti, S.; Borenstein, J.; Kendler, D. L.; on behalf of the DAPS Investigators (2011). "Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: A 24-month, randomized, crossover comparison with alendronate in postmenopausal women". Osteoporosis International 23 (1): 317–326. doi:10.1007/s00198-011-1780-1. PMC 3249211. PMID 21927922. edit
^ ^a ^b "Summary of Positive Opinion for Prolia". European Medicines Agency. 17 December 2009. Retrieved 7 January 2010.
^ Khosla, S (2009). "Increasing options for the treatment of osteoporosis". New England Journal of Medicine 361 (8): 818–820. doi:10.1056/NEJMe0905480. PMID 19671654.
^ EntrezGene 8600
^ ^a ^b Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. ^{[page needed]}
^ "Amgen Issues Statement on Outcomes of Advisory Committee for Reproductive Health Drugs (ACRHD) Meeting". PRNewswire/FirstCall. August 13, 2009.
^ Pollack, Andrew (19 October 2009). "F.D.A. Says No to an Amgen Bone Drug". The New York Times.
^ http://www.cancer.gov/cancertopics/druginfo/fda-denosumab
^ "Amgen Receives CHMP Positive Opinion for Prolia (Denosumab) in the European Union". Amgen. 18 December 2010. Retrieved 7 January 2010.
^ Zacks Equity Research (December 21, 2009). "Amgen Closer to Prolia Approval". Yahoo Finance News.
^ Jacob Goldstein (August 14, 2009). "Analysts React to FDA Panel: 'It Wasn't a Perfect Day for Amgen'". The Wall Street Journal.
^ Dimitra Defotis (September 7, 2009). "At Amgen, a Prescription for Success". Barrons.

External links[edit]

Prolia
Xgeva
Prolia full prescribing information
Xgeva full prescribing information

UpToDate Contents

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1. 骨粗鬆症に対するデノスマブ denosumab for osteoporosis
2. Medication-related osteonecrosis of the jaw in patients with cancer
3. 転移性癌患者におけるビスホスホネートおよびデノスマブ bisphosphonates and denosumab in patients with metastatic cancer
4. 閉経後の女性における骨粗鬆症のマネージメントの概要 overview of the management of osteoporosis in postmenopausal women
5. 進行前立腺癌における骨転移：マネージメント bone metastases in advanced prostate cancer management

English Journal

Differing effects of denosumab and alendronate on cortical and trabecular bone.

Zebaze RM1, Libanati C2, Austin M3, Ghasem-Zadeh A4, Hanley DA5, Zanchetta JR6, Thomas T7, Boutroy S8, Bogado CE9, Bilezikian JP10, Seeman E11.Author information 1Austin Health, University of Melbourne, Melbourne, Australia. Electronic address: zebaze@unimelb.edu.au.2Amgen Inc., Thousand Oaks, CA, USA. Electronic address: cesarl@amgen.com.3Amgen Inc., Thousand Oaks, CA, USA. Electronic address: maustin@amgen.com.4Austin Health, University of Melbourne, Melbourne, Australia. Electronic address: alig@unimelb.edu.au.5University of Calgary, Calgary, Canada. Electronic address: dahanley@ucalgary.ca.6Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina. Electronic address: jrz@idim.com.ar.7INSERM U1059, University Hospital of St-Etienne, St-Etienne, France. Electronic address: thierry.thomas@univ-st-etienne.fr.8INSERM U1033, Université de Lyon, Lyon, France. Electronic address: Stephanie.boutroy@inserm.fr.9Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina. Electronic address: bogadoc@idim.com.ar.10College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: jpb2@columbia.edu.11Austin Health, University of Melbourne, Melbourne, Australia. Electronic address: egos@unimelb.edu.au.AbstractVertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non-vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human anti-RANKL antibody, reduces the rate of bone remodeling more than alendronate. The aim of this study was to quantify the effects of denosumab and alendronate on cortical and trabecular bone. Postmenopausal women, mean age 61years (range 50 to 70), were randomized double blind to placebo (n=82), alendronate 70mg weekly (n=82), or denosumab 60mg every 6months (n=83) for 12months. Porosity of the compact-appearing cortex (CC), outer and inner cortical transitional zones (OTZ, ITZ), and trabecular bone volume/total volume (BV/TV) of distal radius were quantified in vivo from high-resolution peripheral quantitative computed tomography scans. Denosumab reduced remodeling more rapidly and completely than alendronate, reduced porosity of the three cortical regions at 6months, more so by 12months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12months were [mean (95% CI)]; CC: -1.26% (-1.61, -0.91) versus -0.48% (-0.96, 0.00), p=0.012; OTZ: -1.97% (-2.37, -1.56) versus -0.81% (-1.45, -0.17), p=0.003; and ITZ: -1.17% (-1.38, -0.97) versus -0.78% (-1.04, -0.52), p=0.021. Alendronate reduced porosity of the three cortical regions at 6months relative to baseline and controls but further decreased porosity of only the ITZ at 12months. By 12months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) versus 0.19% (0.13, 0.30), p=0.208. The greater reduction in cortical porosity by denosumab may be due to greater inhibition of intracortical remodeling. Head to head studies are needed to determine whether differences in porosity result in differing fracture outcomes.
Bone.Bone.2014 Feb;59:173-9. doi: 10.1016/j.bone.2013.11.016. Epub 2013 Nov 22.
Vertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non-vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human a
PMID 24275677

Denosumab: A cost-effective alternative for older men with osteoporosis from a Swedish payer perspective.

Parthan A1, Kruse M2, Agodoa I3, Silverman S4, Orwoll E5.Author information 1OptumInsight, One Main Street, Cambridge, MA 02142, USA. Electronic address: anju.parthan@optum.com.2OptumInsight, One Main Street, Cambridge, MA 02142, USA. Electronic address: morgan.kruse@optum.com.3Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: iagodoa@amgen.com.4Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Electronic address: stuarts@slsdss.net.5Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L607, Portland, OR 97239, USA. Electronic address: orwoll@ohsu.edu.AbstractOBJECTIVE: To assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥75years old from a payer perspective in Sweden.
Bone.Bone.2014 Feb;59:105-13. doi: 10.1016/j.bone.2013.11.002. Epub 2013 Nov 12.
OBJECTIVE: To assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥75years old from a payer perspective in Sweden.METHODS: A lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporot
PMID 24231131

Omic-profiling in breast cancer metastasis to bone: implications for mechanisms, biomarkers and treatment.

Wood SL, Westbrook JA, Brown JE.Author information Wolfson Molecular Imaging Centre, University of Manchester, Manchester M20 3LJ, UK. Electronic address: steven.wood@manchester.ac.uk.AbstractDespite well-recognised advances in breast cancer treatment, there remain substantial numbers of patients who develop metastatic disease, of which up to 70% involves spread to bone, resulting in skeletal complications which have a major negative impact on mortality and quality of life. Bisphosphonates and newer bone-targeted agents have reduced the prevalence of skeletal complications, yet there remains significant unmet clinical need, particularly for the development of more specific therapies for the prevention and treatment of metastatic bone disease, for the prediction of risk of its development in individual patients and for the prediction of response to treatments. Modern 'omic' strategies can potentially make a major contribution to meeting this need. Technological advances in the field of nucleic acid sequencing, mass spectrometry and metabolic profiling have driven progress in genomics, transcriptomics (functional genomics), proteomics and metabolomics. This review appraises the recent application of these approaches to studies of breast cancer metastasis (particularly to bone), with a focus on understanding how omic approaches may lead to new therapeutic options and to novel biomarker molecules or molecular signatures with potential value in clinical practise. The increasingly recognised need for rigorous sample quality control and both pre-clinical and clinical validation to meet the ultimate goals of clinical utility and patient benefit is discussed. Future directions of omic driven research in breast cancer metastasis are considered, in particular micro-RNAs and their role in the post-transcriptional regulation of gene function and the possible role of cancer-stem cells and epigenetic modifications in the development of distant metastases.
Cancer treatment reviews.Cancer Treat Rev.2014 Feb;40(1):139-52. doi: 10.1016/j.ctrv.2013.07.006. Epub 2013 Aug 16.
Despite well-recognised advances in breast cancer treatment, there remain substantial numbers of patients who develop metastatic disease, of which up to 70% involves spread to bone, resulting in skeletal complications which have a major negative impact on mortality and quality of life. Bisphosphonat
PMID 23958309

Japanese Journal

骨粗鬆症に対する抗体療法 (第1土曜特集抗体医療Update--コンセプトから最新治療実績まで) -- (臨床:その他の疾患に対する抗体治療)

根岸-古賀貴子,高柳広
医学のあゆみ 238(6), 730-737, 2011-08-06
NAID 40018917319

骨粗鬆症の最新治療法 (特集骨粗鬆症--骨粗鬆症研究の進歩) -- (骨粗鬆症の治療法の進歩)

竹内靖博
日本臨床 69(7), 1248-1252, 2011-07
NAID 40018884229

Related Pictures

★リンクテーブル★

リンク元	「mab」「デノスマブ」

「mab」

Denosumab ^?
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	RANK ligand
Clinical data
Trade names	Prolia, Xgeva
AHFS/Drugs.com	monograph
MedlinePlus	a610023
Licence data	US FDA:link
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	subcutaneous injection, every six months
Pharmacokinetic data
Bioavailability	N/A
Metabolism	proteolysis
Identifiers
CAS number	615258-40-7
ATC code	M05BX04
UNII	4EQZ6YO2HI
KEGG	D03684
ChEMBL	CHEMBL1237023
Synonyms	AMG 162
Chemical data
Formula	C6404H9912N1724O2004S50
Mol. mass	144.7 kDa
(what is this?) (verify)

　　[★]

関: モノクローナル抗体

mab

abciximab
adahmumab
adalimumab
afelimomab
alemtuzumab
apolizumab
arcitumomab
basiliximab
bevacizumab
cantuzumab
certolizumab
cetolizumab
cetuximab
clenoliximab
daclizumab
デノスマブ denosumab 抗RANKL抗体
eculizumab
edrecolomab
efalizumab
epratuzumab
galiximab
gemtuzumab
ibritumomab
インフリキシマブ infliximab 抗TNF-α抗体クローン病 Ph⁺ALL
inotuzumab
keliximab
natalizumab
nebacumab
omalilzumab
omalizumab
oregovomab
palivizumab
panitumumab
pertuzumab
pexelizumab
リツキシマブ rituximab：抗CD20抗体：慢性リンパ性白血病、B細胞リンパ腫

「デノスマブ」

　　[★]

英: denosumab
商: ランマーク、プラリア
関: mab; 他に分類されない代謝性医薬品

抗RANKL抗体
抗悪性腫瘍薬;抗RANKL単クローン抗体

[1] Pageau, Steven C. (2009). "Denosumab". MAbs 1 (3): 210–215. doi:10.4161/mabs.1.3.8592. PMC 2726593. PMID 20065634.

[pmid16495394-2] McClung, Michael R.; Lewiecki, E. Michael; Cohen, Stanley B.; Bolognese, Michael A.; Woodson, Grattan C.; Moffett, Alfred H.; Peacock, Munro; Miller, Paul D. et al. (2006). "Denosumab in Postmenopausal Women with Low Bone Mineral Density". New England Journal of Medicine 354 (8): 821–31. doi:10.1056/NEJMoa044459. PMID 16495394. |displayauthors= suggested (help)

[pmid18725648-3] Ellis, G. K.; Bone, H. G.; Chlebowski, R.; Paul, D.; Spadafora, S.; Smith, J.; Fan, M.; Jun, S. (2008). "Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer". Journal of Clinical Oncology 26 (30): 4875–82. doi:10.1200/JCO.2008.16.3832. PMID 18725648.

[4] "Prolia (denosumab)". Products. Amgen. Retrieved 6 May 2012.

[5] Matthew Perrone (June 2, 2010). "FDA clears Amgen's bone-strengthening drug Prolia". BioScience Technology.

[Nov2010-6] "Amgen's Denosumab Cleared by FDA for Second Indication". 19 Nov 2010.

[FDA-deno-7] "FDA Approves Denosumab for Osteoporosis". 2 June 2010.

[8] Russell S. Crawford, BPharm; Morgane C. Diven, PharmD; Laura Yarbro, PharmD (2011). "Denosumab: A Review of Its Pharmacology and Clinical Implications". Contemporary Oncology 3 (1).

[LAT-12Aug09-9] Thomas H. Maugh II (August 12, 2009). "New osteoporosis drug shown to reduce spinal fractures". Los Angeles Times.

[10] Donald A. Bergman (September 16, 2009). "Denosumab: Fracture risk reduced in high-risk subset in FREEDOM". Endocrine Today.

[Cummings-11] Cummings, Steven R.; Martin, Javier San; McClung, Michael R.; Siris, Ethel S.; Eastell, Richard; Reid, Ian R.; Delmas, Pierre; Zoog, Holly B. et al. (2009). "Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis". New England Journal of Medicine 361 (8): 756–65. doi:10.1056/NEJMoa0809493. PMID 19671655. |displayauthors= suggested (help)

[12] John Otrompke (September 15, 2009). "Experimental Drug Reduces Fractures Related to Prostate Cancer Treatment: Presented at ASBMR". Doctor's Guide.

[13] Zhu, M.; Tang, D.; Wu, Q.; Hao, S.; Chen, M.; Xie, C.; Rosier, R. N.; O'Keefe, R. J.; Zuscik, M.; Chen, D.; Austin, M.; Wagman, R. B.; Newmark, R.; Libanati, C.; San Martin, J.; Bone, H. G. (2009). "Activation of β-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult β-Catenin Conditional Activation Mice". Journal of Bone and Mineral Research 24 (1): 12–21. doi:10.1359/jbmr.080901. PMC 2640321. PMID 18767928. edit

[14] Kendler, D. L.; Roux, C.; Benhamou, C. L.; Brown, J. P.; Lillestol, M.; Siddhanti, S.; Man, H. S.; San Martin, J. S.; Bone, H. G. (2010). "Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy". Journal of Bone and Mineral Research 25 (1): 72–81. doi:10.1359/jbmr.090716. PMID 19594293. edit

[15] Freemantle, N.; Satram-Hoang, S.; Tang, E. -T.; Kaur, P.; MacArios, D.; Siddhanti, S.; Borenstein, J.; Kendler, D. L.; on behalf of the DAPS Investigators (2011). "Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: A 24-month, randomized, crossover comparison with alendronate in postmenopausal women". Osteoporosis International 23 (1): 317–326. doi:10.1007/s00198-011-1780-1. PMC 3249211. PMID 21927922. edit

[EMEA-16] "Summary of Positive Opinion for Prolia". European Medicines Agency. 17 December 2009. Retrieved 7 January 2010.

[17] Khosla, S (2009). "Increasing options for the treatment of osteoporosis". New England Journal of Medicine 361 (8): 818–820. doi:10.1056/NEJMe0905480. PMID 19671654.

[18] EntrezGene 8600

[AustriaCodex-19] Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. ^{[page needed]}

[20] "Amgen Issues Statement on Outcomes of Advisory Committee for Reproductive Health Drugs (ACRHD) Meeting". PRNewswire/FirstCall. August 13, 2009.

[21] Pollack, Andrew (19 October 2009). "F.D.A. Says No to an Amgen Bone Drug". The New York Times.

[22] ttp://www.cancer.gov/cancertopics/druginfo/fda-denosumab

[23] "Amgen Receives CHMP Positive Opinion for Prolia (Denosumab) in the European Union". Amgen. 18 December 2010. Retrieved 7 January 2010.

[YF-21Dec09-24] Zacks Equity Research (December 21, 2009). "Amgen Closer to Prolia Approval". Yahoo Finance News.

[25] Jacob Goldstein (August 14, 2009). "Analysts React to FDA Panel: 'It Wasn't a Perfect Day for Amgen'". The Wall Street Journal.

[26] Dimitra Defotis (September 7, 2009). "At Amgen, a Prescription for Success". Barrons.

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