OSTEONECROSI DEI MASCELLARI (ONJ): PREVENZIONE, DIAGNOSI, TRATTAMENTO UPDATE 2010 Alessandria, 5 giugno 2010 Novità nel trattamento dell osteoporosi Stefania Boldini Francesco Bertoldo Dipartimento di Scienze Biomediche e Chirurgiche Università di Verona
Many Factors Stimulate Osteoblast Expression of RANK-Ligand 1,2 Colony-Forming Unit-Macrophage Osteoclast Precursor Multinucleated Osteoclast RANKL RANK PTH PGE 2 Glucocorticoids Vitamin D IL-11 IL-6 IL-1 PTHrP TNF- Bone Formation +mcsf Osteoblasts and Bone Marrow Stromal Cells OPG Activated Osteoclast Bone Resorption Abbreviations: IL, interleukin; mcsf, macrophage colony-stimulating factor; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein.. 1. Boyle WJ, et al. Nature. 2003;423:337-342. 2. Hofbauer LC, et al. JAMA. 2004;292:490-495.
New and Emerging Treatments Antiresorptive (anticatabolic) Denosumab Odanacatib Lasofoxifene Bazedoxifene New delivery systems oral salmon calcitonin Osteo-anabolic (bone-forming) Sclerostin inhibitor Variations of PTH Endogenous PTH stimulation calcium sensing receptor antagonist (calcilytic) New delivery systems transdermal PTH Strontium ranelate Combinations of antiresorptive and anabolic
Osteoprotegerin Prevents RANKL Binding to RANK and Inhibits Osteoclast Activity Osteoclast Precursor Colony-Forming Unit-Macrophage X Multinucleated Osteoclast RANKL RANK OPG Hormones Growth Factors Cytokines Ab anti RANK-L Osteoblasts X Activated Osteoclast Ab anti Sclerostina Boyle WJ, et al. Nature. 2003;423:337-342. SERM X Bone Resorption Ab anti catepsina K
New treatments Anti RANKL MoAb (Denosumab) Cathepsin K inhibitors SERM Anti Sclerostin Ab
Denosumab: anti RANKL MoAb Fully human monoclonal antibody IgG 2 isotype High affinity for human RANKL High specificity for RANKL No detectable binding to TNFα, TNFβ, TRAIL, or CD40L No neutralizing antibodies detected in clinical trials to date Model of Denosumab Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Data on file, Amgen. Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354:821-31. TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand
Dmab Mechanism of Action RANKL RANK OPG Dmab CFU-M Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Osteoclast Osteoblast Lineage Bone Abbreviation: CFU-M, colony forming unit macrophage.
Serum Level (ng/m) Dmab Serum Levels (1 mg/kg s.c.) 10 10 10 10 4 3 2 1 EC 50 0 0 1 2 3 4 5 6 9 Study Month With permission from Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
-68% p <.000 Cummings SR et al N. Eng.J. Med 2009: 361:1-10
Denosumab in post menopausal osteoporosis: the Freedom trial -20% p<.011-40% p<.036 Cummings SR et al N. Eng.J. Med 2009: 361:1-10
Denosumab and potential applications in medical oncology Denosumab and SREs in metastatic disease Denosumab and CTIBL (Cancer treatmentinduced bone loss) Denosumab and adjuvant setting
Denosumab Oncology Programme Overview Phase 1 Phase 2 Phase 3 BrCa & MM - PK/PD Breast cancer - PK/PD (Bisphosphonate naïve) 2 Solid tumours & MM - PK/PD (Bisphosphonate treated) 3,4 Giant cell tumour 6 Breast cancer AI bone loss 7 Prostate cancer ADT bone loss 8 Prostate cancer delay bone mets Multiple myeloma 5 Breast cancer - SRE Prostate cancer - SRE Final results published ECCO Meeting, 2009 Solid tumours & MM - SRE SRE = skeletal-related event 1 Body J J, et al. Clin. Cancer Res 2006; 12:1221-1228; 2 Lipton A, et al. J Clin Oncol 2007; 25:4431-4437; 3 Suarez T et al. J Clin Oncol 2006;24(S18):6S:8562; 4 Fizazi K, et al. J Clin Oncol 2009;27:1564-71 5 Vij et al. Blood 2007; 110(11):3604; 6 Thomas et al. CTOS, 2007:787; 7 Ellis G, et al. J Clin Oncol 2008;26:4875-82; 8 Smith MR et al. N Engl J Med, 2009
Phase 3 Study of Denosumab in Women Receiving Aromatase Inhibitor Therapy Study Design: Multi-center, randomized, double-blind, placebocontrolled study conducted in the United States and Canada Women Receiving Aromatase Inhibitor Therapy For Hormone- Receptor-Positive, Non- Metastatic Breast Cancer N = 127 Denosumab 60 mg SC every 6 months (x 4 doses) T-score of -1.0 to -2.5 at lumbar spine, total hip (proximal femur), or femoral neck (osteopenia) Exclusion: BPs N = 125 Placebo SC every 6 months (x 4 doses) Baseline 12 month 24 month Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
Percentage Change (± 95% CI) From Baseline in Lumbar Spine Bone Mineral Density Primary endpoint: lumbar spine BMD changes at 12 m 8 7 6 5 4 3 2 1 0-1 -2-3 * * * * P < 0.0001 versus Placebo Placebo (N = 122) * Denosumab (N = 123) 5.5% Difference at Month 12 7.6% Difference at Month 24 1 3 6 12 24 Months Ellis GK et al. J Clin Oncol, 26:4875-82, 2008 *
Percentage Change (± 95% CI) From Baseline in Bone Mineral Density At 12 and 24 months, total hip and distal radius BMD increased in the denosumab group versus placebo Total Hip (Proximal Femur) Placebo (N = 122) Denosumab (N = 123) Distal 1/3 Radius Placebo (N = 106) Denosumab (N =115) 5 4 3 2 1 0-1 -2 * * * 3.7% Difference at Month 12 1 3 6 12 24 Months * 4.7% Difference at Month 24 4 3 2 1 0-1 -2-3 -4-5 3.8% Difference at Month 12 * * 6.1% Difference at Month 24 12 24 Months * P < 0.0001 versus Placebo Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
Phase 3 Study of Denosumab in ADT nonmetastatic hormone-sensitive prostate cancer men Study Design: Multi-center, randomized, double-blind, placebocontrolled study conducted in the United States and Canada Men Receiving Adrogen Deprivation Therapy For Non-Metastatic hormonesensitive Prostate Cancer N = 734 Denosumab 60 mg SC every 6 months (x 4 doses) T-score of -1.0 to -2.5 at lumbar spine, total hip (proximal femur), or femoral neck (osteopenia) Exclusion: BPs N = 734 Placebo SC every 6 months (x 4 doses) Baseline 12 month 24 month Smith M et al. N Engl J Med, 361:745-55, 2009.
Denosumab therapy was also associated with significant increases in bone mineral density at all bone sites in ADT prostate cancer patients p<0.001 p<0.001 p<0.001 p<0.001 Smith M et al. N Engl J Med, 361:745-55, 2009.
Denosumab therapy was also associated with significant decreases of new vertebral fractures at 12, 24, 36 months Smith M et al. N Engl J Med, 361:745-55, 2009.
Safety of Dmab in Freedom trial
New treatments Anti RANKL MoAb (Denosumab) Cathepsin K inhibitors (Odanacatib) SERM Anti Sclerostin Ab
Weekly dose of Odonacatib increase BMD in all sites in a phase III with 400 PMO trial Bone H. et al, JBMR 2010; 25(5):937-47
New treatments Anti RANKL MoAb (Denosumab) Cathepsin K inhibitors SERM (Bazedoxifene, Lasofoxifene) Anti Sclerostin Ab
New SERMs for Postmenopausal Osteoporosis Lasofoxifene Bazedoxifene Efficacy Increases BMD Reduces BTMs Decreases risk of VFs and NVFs Decreases risk of ER+ breast cancer Improves signs and symptoms of vulvovaginal atrophy Safety Increases risk of venous thromboembolisms (VTEs), hot flushes, muscle spasm, and vaginal bleeding Efficacy Increases BMD Reduces BTMs Decreases risk of VFs Safety Increases risk of VTEs, hot flushes, muscle cramps Cummings SR, et al. J Bone Miner Res. 2008;23:S81. Silverman SL, et al. J Bone Miner Res. 2008;23:1923-1934. Eastell R, et al. J Bone Miner Res. 2008;23:S81.
Oral Bazedoxifene 20-40 mg/die increase BMD in Lumbar spine (A) and in Total hip (B) in a phase 7492 PMO III trial A) Lumbar spine B) Total hip Silverman SL et al. JBMR 2008;23 (12):1923-34
Reduction on vertebral fracture incidence in oral Bazedoxifene 20-40 mg/die Silverman SL et al. JBMR 2008;23 (12):1923-34
Risk reduction for new/worsening vertebral (A) and non v. fracture (B) after 3 years of LAS treatment in PMO compared to placebo (phase III PEARL trial) Gennari L. et al. Clinical Interventions in Aging 2010; 5:19-29
New treatments Anti RANKL MoAb (Denosumab) Cathepsin K inhibitors SERM Anti Sclerostin Ab
Dkk ~Pathway Dead~ Sclerostin Unliganded State WIF Wnt sfrp Liganded State LRP (No New Bone Made) OSTEOBLAST APC Gsk3 P axin -Catenin Proteosomal Degradation Nucleus With permission from Shoback D. J Clin Endocrinol Metab. 2007;92:747-753. -Catenin Tcf/Lef Frizzled SMRT/ NCoR APC p300/cbp axin Frat-1 Gsk3 -Catenin Dsh -Catenin Frizzled -Catenin Nuclear Localization Altered Transcription of Genes BONE FORMATION
BMD (g/cm 2 ) Sclerostin MAb Increases BMD in Rats 0,34 Sham Vehicle PTH Mab 0,32 0,30 0,28 0,26 0,24 0,22 0,20 Lumbar Spine Tibia-Femur 1.5-year-old rats 1 year post-ovariectomy MAb 25 mg/kg 2x/wk x 5 wk PTH 1-34 100 mcg/kg 5x/wk x 5 wk Warmington K, et al. J Bone Miner Res. 2005;20(suppl 1):S22. Li X, et al. J Bone Miner Res. 2009;24:578-588.
There is a lot ongoing work.. Target RANKL MIP-1a DKK1/sFRP- 2 Activin A Potential Therapy Anti-RANKL CCR1 antagonist Wnt Agonist, anti-dkk1, bortezomib ACE-011 And much remains to be done..