Denosumab Review

Other Names

Trade name for osteoporosis indications: Prolia

Marketed by Amgen, Glaxo Smith Kline (Europe, selected ROW), Daiichi Sankyo (Japan).

Trade name for cancer indications: not available.

Uses

USA

Treatment of postmenopausal osteoporosis in women with increased risk of fractures under REMS

EU (approved by EMA)

Treatment of osteoporosis in postmenopausal women at increased risk of fractures.

Treatment of bone loss in prostate cancer patients on hormone ablation therapy.

How Denosumab Is Taken

Dose 60 mg injection sc every 6 months for Osteoporosis

Dose 2X60 mg injection every month for Cancer bone loss

Cost of 1 year treatment for osteoporosis patients $ 1650

Cost of treatment of bone loss in cancer patients $19800/year

Cost $ 825 per injection 60 mg dose.

How Denosumab Works

Denosumab (Dmab) is a human IgG2 monoclonal antibody which binds to RANKL( Receptor Activator for Nuclear factor k B Ligand) and prevents activation of RANKL. RANKL overproduction plays an important role in the pathogenesis of osteoporosis, rheumatoid arthritis, immune system and certain cancers. Inhibition of RANKL in turn results in inhibition of osteoclast formation, function and survival. Osteoclast play major role in bone loss during menopause and after hormone ablation therapy, resulting in bone thining and increased susceptibility to fractures after falls.

Denosumab (Prolia, Amgen) Review 

The approval of denosumab under the trade name Prolia (Amgen) by the FDA on June 1, 2010 for treatment of bone loss in post menopausal women with high risk of fractures gives a new therapeutic option to osteoporosis experts. European Medicinal Agency EMA approved the drug on 28 May, 2010 for the above indication and for the prevention of bone loss in prostate cancer patient undergoing hormone ablation therapy. Denosumab 2 injections per year are required. The cost of the yearly treatment is $1650, which is competitive with current treatment

Denosumab innovative breakthrough drug for Osteoporosis, breast cancer bone loss and fractures. This new drug is considered important for the future of Amgen and its revival as the biotechnology industry leader and trend setter.

Denosumab is a breakthrough fully human monoclonal antibody awaiting FDA and EMA approval (both likely within the next few months in 2010). It has been fast tracked by FDA for treatment and prevention of postmenopausal osteoporosis, treatment and prevention of bone loss in hormone treated prostate and breast cancer patients. The FDA advisory committee (August 13, 2009) to review the safety and efficacy has recommend approval for treatment of high risk bone loss postmenopausal osteoporosis in women and hormone ablation treated men with prostate cancer, with black box warnings for serious side effects and under REMS program. New additional indications may follow and it may cross sales of $1 billion in 2012 due to unmet medical need from patients and healthcare providers. Clinical data published and in public domain indicates a superior safety and efficacy profile.

FDA has asked for modifications and details of the REMS for treatment of osteoporosis. Denosumab (Prolia, Amgen) after FDA Review is likely to be approved with black box warning and under REMS by the 25 July 2010. For prevention of osteoporosis and cancer indications, FDA has asked for new studies to show that there was no incidence of increased cancer. The European Committee for Human Medicinal Products CHMP has recommended its approval in late 2009 and it was approved by European Medicinal Agency on 28 June 2010. Glaxo Smith Kline is the marketing partner for Amgen in osteoporosis and it can be launched there in the 2Q2010? A new Biologics License application for the prevention of bone loss in cancer patients was submitted by Amgen to the FDA in June 2010. Under priority review, FDA decision is expected within 6 months.

Introduction

Denosumab (Dmab) is a human IgG2 monoclonal antibody which binds to RANKL( Receptor Activator for Nuclear factor k B Ligand) and prevents activation of RANKL. RANKL overproduction plays an important role in the pathogenesis of osteoporosis, rheumatoid arthritis, immune system and certain cancers. Inhibition of RANKL in turn results in inhibition of osteoclast formation, function and survival. Osteoclast play major role in bone loss during menopause and after hormone ablation therapy, resulting in bone thining and increased susceptibility to fractures after falls.

It is in advanced clinical studies for additional indications for bone cancer and bone metastases, multple myeloma and rheumatoid arthritis.

Denosumab is a breakthrough fully human monoclonal antibody awaiting FDA and EMEA approval (both likely within the next few months). It has been fast tracked by FDA for treatment and prevention of postmenopausal osteoporosis, and treatment and prevention of bone loss in hormone treated prostate and breast cancer patients. Denosumab is a fully human monoclonal antibody given as a subcutaneous injection 60 mg every 6 month. The price of the treatment has not been fixed but it may be in the range of $1500 to $6000 per injection or $1000 per month.

Under Creative Commons Attribution 3.0 License

Denosumab (Prolia, Amgen) FDA Review & Approval Images From CDC PHIL ID 2647 http://phil.cdc.gov/phil/details.asp

CDC PHIL ID 6511 Micrograph of Gonorrhea stained with a specific fluorescent Antibody

From Wikipedia http://en.wikipedia.org/wiki/Monoclonal_antibody

FDA Review & Approval

The FDA Response letters were disclosed by Amgen in its 3Q 2009 report on 22 October. In one letter FDA has asked for additional details about communication, monitoring of adverse events and education of patients and healthcare providers under REMS. D-mab will be the first biologic aimed at primary care and GPs rather than oncologists or rheumatologists.

Denosumab has been approved for treatment of osteoporosis under REMS. Amgen has announced that it has filed its reply to FDA with REMS plans, medication guide, training and ADR monitoring ( 25 January, 2010). Since Amgen has already submitted these plans, the changes required are considered major by the FDA thus starting a new 6 months clock.

Amgen has set up very good web page for Prolia for information,prescribing information and medication guide.

http://www.prolia.com/

For compilation, evaluation and analysis of adverse drug events in real time, the ADR monitoring system used by CDC (VERS) and EMA for 2009 H1N1 pandemic vaccines and Tamiflu can be used as a good model.

The second response letter from FDA requested new clinical studies to support prevention of bone loss in osteoporosis. These studies must clearly establish that denosumab does not promote cancer or bone fractures and has no negative effect on disease progression or overall survival.

A third complete response letter for prostate and breast cancer from the FDA is pending. Amgen should petition the FDA that cancer indications are reviewed by its Oncology Drug Advisory Committee and not by the ACRHD. In oncology efficacy is the major criteria for approval and has higher priority over concerns about safety.

Positive results from 3 Phase III studies indicate a new filing for cancer indications. The results of the prostate skeltal related event study are expected in 1Q10 and the prevention of bone metastasis study in prostate cancer in the 2Q2010. Two more studies are ongoing. June 01, 2010 - FDA Approves New Injectable Osteoporosis Treatment for Postmenopausal Women US FDA to decide on Amgen osteoporosis drug by July Reuters - Deena Beasley, Tim Dobbyn - ‎Feb 19, 2010‎ Amgen Provides Update on Status of Prolia(TM) (Denosumab) Amgen's Fourth Quarter 2009 Adjusted Earnings Per Share Decreased 1 Percent to $1.05; Full Year 2009 Adjusted Earnings Per Share Increased 8 Percent to $4.91 http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1378596 The FDA Advisory Committee for Reproductive Health Drugs ( ACRHD, August 13-14, 2009) to review the safety and efficacy has recommend approval with black box warnings for serious side effects and under the risk evaluation and mitigation strategy REMS as for newer mAbs. Under REMS a medication guide and a healtcare provider communication and training plan may be required by the FDA. The advisory panel recommended for the approval of denosumab for the treatment of postmenopausal osteoporosis and treatment of Bone loss in patients undergoing hormone ablation for prostate cancer. The Committee recommended against approval of Prolia to treat or prevent bone loss in women with breast cancer undergoing hormone ablation until additional data are available. The Committee also recommended against approval of Prolia to prevent bone loss in low-risk patients in all three populations. Wall street has reacted negatively to the news and Amgen shares were down after the news. FDA has to make a decision by July 2010 and frequently follows its advisory committee recommendations. The dossier submitted to the FDA and EMEA for regulatory approval contained data from 30 clinical studies and included 10500 patients with postmenopausal osteoporosis and 1700 patients with hormonal ablation treated breast and prostate cancer patients. Amgen cancer trials program included 8000 patients. No other monoclonal antibody or biologic agent had studied so many patients over prolonged periods ranging from 2-5 years before approval. Amgen proposed to FDA to follow 5000 osteoporosis and cancer patients in its clinical trials for as long as ten years to detect any increased risk of infections, CV events and cancer. An observational study using healthcare data base involving 380000 postmenopausal women for 5 years was proposed by Amgen. Direct comparative studies with market leader Fosamax (current Gold standard treatment) for osteoporosis show superior safety and efficacy profile for Dmab. In bone cancer patients, direct comparison with Zometa showed some advantags for denosumab in one study but similar results in a second trial. A third comparative Phase III bone metastases trial in 2046 women with advanced breast cancer showed clear advantages over Zometa. The drug met both its primary and secondary criteria for efficacy and was significantly better than Zometa. Clinical trials indicate clear efficacy of the active drug versus placebo in long term double blind studies. The active drug was injected as 60 mg dose by sc route every 6 months. A phase III study in 7868 female post menopausal osteoporosis patients (age range 60-90 years) treated for 3 years (DB, placebo control, randomized), denosumab reduced the risk of fractures by 68% as compared to placebo. There was no increase in the risk of cancer, cardiovascular events, serious infections in the treated group. In another Phase III study in men receiving androgen deprivation therapy for prostate cancer ( DB, randomized, placebo control, n=734 in each group) were treated for 2 and 3 years (60 mg sc every 6 month). The bone mineral density had increased in the treated group while it decreased in the placebo group. Differences were significant after 1 month and remained during the study at all time points. There was higher incidence in the treated group: of skin infections(cellulitis) in women and cataracts in men. Other adverse events like deaths, CV effects, cancer, fracture related complications. infections and drug hypersensitivity was similar in the 2 groups. YouTube Video Amgen has announced (February 8, 2010) that a pivotal, Phase 3, head-to-head trial evaluating denosumab versus Zometa® (zoledronic acid) in the treatment of bone metastases in 1,901 men with advanced prostate cancer met its primary and secondary endpoints. Denosumab demonstrated superiority over Zometa for both delaying the time to the first on-study skeletal related event (SRE) (fracture, radiation to bone, surgery to bone or spinal cord compression) (hazard ratio 0.82, 95 percent CI: 0.71, 0.95), and reducing the rate of multiple SREs (hazard ratio 0.82, 95 percent CI: 0.71, 0.94). Both results were statistically significant. Overall rates of adverse events and serious adverse events, including infections, were generally similar between the two arms. Osteonecrosis of the jaw was infrequent (22 patients receiving denosumab as compared with 12 patients receiving Zometa) and there was no statistically significant difference between treatment arms. As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosumab arm. Both overall survival and the time to cancer progression were balanced between treatment arms. An international mulicenter Phase 3, randomized, double-blind study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced prostate cancer. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously as at least a 15 minute infusion at a dose of 4 mg every four weeks as per the labeled instructions. The study consisted of 1,901 patients, mean age of 71, who have bone metastases from hormone-refractory prostate cancer. Treatment success was measured reduction or delay in the bone complications, or SREs, caused by the bone metastases. The primary and secondary endpoints of the denosumab bone metastases studies used a composite endpoint of four SREs - fracture, radiation to bone, surgery to bone, and spinal cord compression - to measure the effectiveness of denosumab versus Zometa. The primary endpoint was to evaluate if denosumab is non-inferior to Zometa with respect to the first on-study SRE in patients with advanced prostate cancer and bone metastases. Secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first on-study SRE, as well as first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa. European Approval The European Committee for Human Medicinal Products (CHMP) has recommended approval of Prolia for the treatment of osteoporosis in postmenopausal women at increased risk of fractures and for the treatment of bone loss in hormone ablation in prostate cancer men at increased risk of fractures. The CHMP recommendation was made in late December 2009. The European Medicinal Agency EMA generally follows the advice of CHMP and announced its approval on 28 June 2010 for the above indications. The drug can be launched in the 2Q2010 in 30 European countries. Amgen has kept the marketing for cancer indications and joined forces with Glaxo Smith Kline (50-50 partnership) the European marketing rights for bone loss in osteoporosis. Europe as the second largest global market after the US may contribute $ 1 billion annual sales within the next 2-3 years depending on the price negotiations with national health schemes and governments.

Research

RANK Pathway

The RANK pathway was discovered by Amgen scientists wayback in 1995 and landmark papers published in Nature and Cell in 1997 with cloning and description. A natural inhibitor Osteoprotegerin OPG was identified and entered clinical testing followed by its Fc fraction. The first clinical study of denosumab was published in 2004. Amgen scientists established RANKL as the regulator of osteoclasts and the RANK ligand pathway is essential for bone formation.

RANK/RANKL Pathway Historical Milestones Image kindly provided by Amgen

RANKL( Receptor Activator for Nuclear factor k B Ligand) overproduction plays an important role in the pathogenesis of osteoporosis, rheumatoid arthritis, immune system and certain cancers. Inhibition of RANKL in turn results in inhibition of osteoclast formation, function and survival.

RANK/RANKL Pathway Description

DMab in Rank Pathway

Source : http://cellbiology.med.unsw.edu.au/units/medicine/REbone02.htm

Osteoclast Functions Osteoclast play a major role in bone loss during menopause and after hormone ablation therapy, resulting in bone thining and increased susceptibility to fractures after falls in elderly patients.

Image/Slides

From: cancergrace.org/.../04/16/intro-to-denosumab/ http://cancergrace.org/cancer-101/files/2009/04/denosumabandimmunity.jpg

http://en.wikipedia.org/wiki/Osteoclast

Osteoclasts cell cultures

Activated Osteoclast

Indications for Denosumab

Treatment of postmenopausal osteoporosis Treatment of Bone loss in patients undergoing hormone ablation for prostate cancer

Additional Data Required

Prevention of postmenopausal osteoporosis Treatment and Prevention of Bone loss in patients undergoing hormone ablation for breast cancer Prevention of Bone loss in patients undergoing hormone ablation for prostate cancer

Future Indications

Rheumatoid Arthritis Psoriatic Arthritis Multiple Myeloma Bone cancer Cancer Metastase Prevention

Amgen Market Cap Amgen was the most valued biotech company in 2007 with a market cap of $100 billion. Its market value declined to almost $46 billion last year due to regulatory action by FDA(Black Box Warnings and dose Reduction and restrictions) and market entry of biosimilar EPOs in Europe resulting in almost 30% loss of sales of its EPO brands. High expectations of Denosumab have revived the market value of Amgen to over $63 billion and is the most valued biotechnology company with annual sales of $15 billion in 2008.

Amgen brand Enbrel was the best selling biologic in 2008 and is likely to retain the position in 2009.

Interesting Facts

Current Market for Osteoporosis

IMS Health estimates the 2008 osteoporosis market at $8.4 billion. The market leader in 2008 was Glaxo/Roche Boniva with sales of $2.67 billion followed by Fosamax with sales of over $1.55 billion (patent expiry) and P&G Actonel $ 1.2 billion. There are 10 million patients suffering from osteoporosis in the USA (8 million females, 2 million men) and 34 million have low bone mass with increased risk of osteoporosis.

World Osteoporosis Day (WOD) provides an all-important focal point for informing and educating the general public and policy makers about the prevention of a disease which still suffers from poor general awareness. With the number of participating countries and scheduled events increasing steadily year by year, the impact of WOD has grown significantly. http://www.iofbonehealth.org/about-iof/iof-programs/outreach-education/world-osteoporosis-day.html Market Forecast for Denosumab Glaxo acquired the marketing rights for Europe and BRIC (Brazil, Russia, India, China) markets for a total of $120 million. The current market forecasts is for peak sales of over $5 billion annual sales within 5-7 years after launch and crossing the $1 billion sales in the second full year after launch in the US and Europe. It is based on a sale price of $1500-2000 per injection at twice per year rate. It assumes FDA and EMEA approval for all indications and new indications added during the patent protected life cycle of the drug. Projections for worst case scenario are included. There are 10 million patients in the US with osteoporosis and upto 45 million are at risk due to weaked bones. The unmet medical need and high demand indicates premium price for the drug in comparison to $100 per month for current osteoporosis treatment. The event may be similar to the paradigm shift in rheumatoid arthritis treatment with the marketing of TNF blockers. Introduction of Denosumab will expand the osteoporosis market. Denosumab (Prolia, Amgen) Competitors Currently there are 5 Bisphosphonates 2 iv and 3 po 1 Estrogen mixed agonist/antagonist 1 PTH analog 3 calcitonins 1 sc, 2po Biphosphonates are effective in reducing the risk of breast cancer in treated patients. Reclast Zoledronic acid (marketed as Reclast/Aclasta and Zometa by Novartis ) is a bisphosphonate drug that works by inhibiting osteoclast-mediated bone resorption, slowing the breakdown of bone to help reduce the risk of fractures. Reclast 5 mg was approved by the FDA in 2007 as a once-yearly intravenous treatment for osteoporosis in postmenopausal women and for the treatment of Paget’s disease of bone. In 2008, Reclast was approved for the treatment of osteoporosis in men and, in 2009, it was approved for the treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months. Zometa was FDA-approved in 2001 for the treatment of hypercalcemia of malignancy, multiple myeloma, and in conjunction with standard antineoplastic therapy in solid tumor patients with documented bone metastases. http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm167883.htm From April 2007 until February 17, 2009, FDA’s Adverse Event Reporting System (AERS) received 24 evaluable postmarket cases of renal impairment and acute renal failure associated with the use of Reclast. The use of zoledronic acid is associated with flu like symptoms (fever, nausea , vomiting) and rare cases of severe bone, muscle or joint pain and atrial fibrillation. There is a large safety data base of 1.5 million cancer patients treated with Zometa. The cost of a 5mg/100 ml infusion solution (15 minutes) once a year treatment is $1300. Sales of Zometa and Reclast as reported by Novartis were $1.38 billion and around $100 million respectively in 2008. In a landmark clinical study in 7700 postmenopausal women (double blind, placebo control, randomized, 3 years treatment, 5 mg/100 ml yearly infusion) the active drug reduced the risk of spine fractures by 70% and hip fractures by 41%. These reductions were sustained for 3 years of treatment. Bone mineral density increased by 6% vs placebo control group (NEJM May 3, 2007, FDA dossier, EMEA Review). Novartis claims that over 425000 patients have been treated with Reclast. The sales in the 1 Q 2009 were $40 million indicating a strong uptake in the osteoporosis market. Bonviva Actonel (Procter & Gamble/Sanofi Aventis) Fosamax (Merck) and Generics Indications for EVISTA EVISTA is indicated for the treatment of osteoporosis and for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. • FORTEO is used in both men and postmenopausal women with osteoporosis who are at high risk for having broken bones (fractures). • FORTEO is used in both men and women with osteoporosis due to use of glucocorticoids, such as prednisone, for several months, who are at high risk for having broken bones. Kyphon Balloon Kyphoplasty Medtronic Marks World Osteoporosis Day with Milestone in Kyphon Balloon Kyphoplasty Procedures More than 500,000 Vertebral Compression Fractures Repaired Since 2000 Acknowledgements Thanks are due to Mr. Jean-Antoine de Mandato (PDP, Geneva) for providing office facilities and administrative support. Internal Links [[Bone, Bone Cancer, Bone Density, Bone Density, Bone Mass, and Bone Mineral Density, Bone Fracture, Bone Health, Osteoporosis (Clinical) Osteoporosis Osteoporosis: Fracture Prevention Treatments for Postmenopausal Women Osteoporosis and African American Women Osteoporosis and Arthritis Osteoporosis and Fracture Osteoporosis and Menopause ]]

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FDA opinion about Denosumab

Amgen Background information Denosumab.

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Ellis GK, Bone HG, 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. [Free Full Text] Miller PD, Bolognese MA, Lewiecki EM, 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. Bone 2008;43:222-229. [CrossRef][Web of Science][Medline]

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Jean-Jacques Body1, Thierry Facon2, Robert E. Coleman3, Allan Lipton4, Filip Geurs1, Michelle Fan5, Donna Holloway5, Mark C. Peterson5 and Pirow J. Bekker5 Clinical Cancer Research Vol. 12, 1221-1228, February 2006

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Allan Lipton, Guenther G. Steger, Jazmin Figueroa, Cristina Alvarado, Philippe Solal-Celigny, Jean-Jacques Body, Richard de Boer, Rossana Berardi, Pere Gascon, Katia S. Tonkin, Robert Coleman, Alexander H.G. Paterson, Mark C. Peterson, Michelle Fan, Amy Kinsey, Susie Jun

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Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R;Denosumab Rheumatoid Arthritis Study Group.

Arthritis Rheum. 2008 May;58(5):1299-309. comments in

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20. Effects of denosumab and alendronate at the ultradistal radius in postmenopausal women with low bone mass Bone, Volume 44, Supplement 2, June 2009, Page S241 E. Seeman, T. Thomas, S.K. Boyd, S. Boutroy, E. Shane, D.A. Hanley, C. Bogado, A.M. Cheung, S. Majumdar, D. Sellmeyer, A. Kearns, P.D. Delmas, M. Fan, C. Libanati, J. Zanchetta

21.EFFECTS OF TWICE-YEARLY SUBCUTANEOUS DENOSUMAB ON BONE MINERAL DENSITY IN MEN RECEIVING ANDROGEN-DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER The Journal of Urology, Volume 181, Issue 4, Supplement 1, April 2009, Page 229 Matthew R Smith, Blair Egerdie, Maciej Szwedowski, Chunlei Ke, Ben Leder, Carsten Goessl

22.846 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF DENOSUMAB IN MEN RECEIVING ANDROGEN DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER European Urology Supplements, Volume 8, Issue 4, March 2009, Page 332 M.R. Smith, B. Egerdie, Toriz N. Hernández, R. Feldman, T.L.J. Tammela, F. Saad, M. Urban, M. Szwedowski, C. Ke, A. Kupic, B. Leder, C. Goessl

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Regenerated Bone Tissue NIAMS Image Gallery ID 00186 http://images.niams.nih.gov

External Links

Republished from (by self permission of the author)

Denosumab (Prolia, Amgen) FDA Review & Approval http://knol.google.com/k/krishan-maggon/denosumab-prolia-amgen-fda-review/3fy5eowy8suq3/60#

In French

Denosumab (Prolia, Amgen) pour l'ostéoporose.

http://knol.google.com/k/denosumab-prolia-amgen-pour-l-ost%C3%A9oporose#

Osteoporosis By Nelson B. Watts MD

Bone mineral density measurement with DXA. By Abdellah El Maghraoui[[Category:|Category:]]