Dalibor Pacík Urologická klinika FN Brno, LF MU Brno

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1 Dalibor Pacík Urologická klinika FN Brno, LF MU Brno
Nové horizonty možností léčby kostního postižení při hormonální léčbě nebo metastatickém karcinomu prostaty Dalibor Pacík Urologická klinika FN Brno, LF MU Brno

2 Skelet a jeho funkce Skládá se z cca 200 kostí
Dynamický, multifunkční orgán Mechanická, protektivní, metabolická ≤75% trabecular >75% cortical Haversian system Femur Anatomists talk about both bone and bones: Bone is the material of the mineralised skeleton and is a type of connective tissue Bones are the discrete structures that make up the skeleton. Bone: Exists in two forms Cortical (compact) Trabecular (cancellous, spongy). The distribution of the two types of bone maximises the strength-to-weight ratio of bones, according to their function: The humerus (and femur) is over 75% cortical bone Vertebrae comprise up to 75% trabecular bone. The distribution of cortical and trabecular bone reflects the prevailing input of stresses and strain on a bone: The trabecular cascades of the proximal femur distribute the forces and moments to the cortical shell of the diaphysis1 The vertebral body distributes axial compressive forces throughout its tightly woven network of trabecular bone.1 Trabecular bone Periosteum Cortical bone Reference 1 Sommerfeldt DW and Rubin CT. Biology of the bone and how it orchestrates the form and function of the skeleton. Eur Spine J 2001; 10 (Suppl. 2): S86–S95

3 PTH, parathyroid hormone
Remodelace kosti – kostní obrat umožňuje kosti reagovat na mechanické a metabolické potřeby organizmu Remodelace je konstantní proces Mechanické vlastnosti kosti se mohou přizpůsobovat potřebě v závislosti na jejím zatížení Kost je rezervoárem vápníku a fosforu Kostní dřeň – tvůrce krve Through remodelling, the skeleton constantly redefines its mass and morphology to accommodate subtle changes in mechanical and metabolic demands.1 The shape, anatomy and mechanical properties of a bone, such as strength, stiffness and toughness, are adapted to mechanical stimuli experienced throughout the lifetime of an individual. This continual adaptation in bone was first proposed in 1892 and is widely referred to as Wolff’s law. The diagram shows how the trabecular pattern in the proximal human femur reflects the trajectories of the stresses encountered by the bone. Bone remodelling is also one of the principal mechanisms governing the continuous process of mineral homeostasis. Ca+2, Pi from bone PTH Low serum Ca+2 PTH, parathyroid hormone Reference 1 Sommerfeldt DW and Rubin CT. Biology of the bone and how it orchestrates the form and function of the skeleton. Eur Spine J 2001; 10 (Suppl. 2): S86–S95

4 Při zvýšeném kostním obratu dominuje resorpce
Kostní resorpce a tvorba jsou provázány pomocí spolupráce mezi osteoblasty a osteoklasty Activace Resorpce: 10 dnů Při zvýšeném kostním obratu dominuje resorpce The adult skeleton is a dynamic tissue, being continually broken down and reformed, This turnover or remodeling occurs in discrete packets throughout the skeleton. Bone remodeling consists of phases: resting, resorption, reversal, and formation.1-4 Resting bone surface is converted to a remodeling surface during activation.1-4 Recruitment of osteoclast precursors to the bone and their differentiation into functional osteoclasts occurs.1-4 During the resorption phase, osteoclasts remove both mineral and organic components of bone matrix by generating an acidic microenvironment between the cell and bone surface.1-4 The resorbing surface has a scalloped, eroded appearance known as Howship’s or resorption lacuna.2 The reversal phase begins once the osteoclasts have resorbed most of the mineral and organic matrix. Apoptosis of osteoclasts occurs in this phase at which point osteoblasts are recruited to the bone surface.1-4 In the formation phase, osteoblasts deposit collagen, which mineralizes to form new bone.1-4 The complete remodeling process lasts about 3–6 months.1 Bone remodelling is the process by which old bone is replaced by new bone. Bone remodelling consists of four phases: resting, resorption, reversal and formation.1 During the resorption phase, osteoclasts remove both mineral and organic components of bone matrix by generating an acidic microenvironment between the cell and bone. Once the osteoclasts have resorbed most of the mineral and organic matrix, they undergo apoptosis during the reversal phase and osteoblasts are recruited to the bone surface. In the formation phase, osteoblasts deposit new, healthy osteoid (unmineralised collagen matrix), which is subsequently mineralised, resulting in good-quality bone. Novotvorba: 3 měsíce Odpočinek OB Nástup OB Adapted from Baron, R. General Principles of Bone Biology. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Favus MJ (Ed.) 5th Edition. American Society for Bone and Mineral Research, Washington DC, 2003: 1–8 Reference 1 Baron, R. General Principles of Bone Biology. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Favus MJ (Ed.) 5th Edition. American Society for Bone and Mineral Research, Washington DC, 2003: 1–8

5 Remodelace kosti je dynamický proces
Provázání OB a OK Mechanicky senzorická funkce Seeman et al. N Engl J Med 2006;354:

6 Pre-Fusion Osteoclast Multinucleated Osteoclast
RANK Ligand je důležitým mediátorem tvorby, funkce a přežívání osteoklastů CFU-M M-CSF Pre-Fusion Osteoclast RANKL RANK Multinucleated Osteoclast Hormony Růstové faktory Cytokiny In the presence of low levels of macrophage colony-stimulating factor (M-CSF), RANK Ligand is an essential mediator for osteoclast formation, function, and survival in both cortical and trabecular bone throughout the skeleton.1-6 The RANK Ligand polypeptide is a type II transmembrane protein found on the surface of expressing cells as well as in a proteolytically released (cleaved) soluble form1,4 RANK Ligand is expressed (both in a transmembrane and soluble form) from the osteoblast lineage cells.1,3 Additionally, RANK Ligand is expressed in various cell types including, but not limited to: lymphoid cells,7 basal epithelial, luminal epithelial and stromal cells from normal prostate8 and non-malignant breast tissue,9 including mammary epithelial cells,10 tumor cells including breast cancer cells,9 prostate cancer cells and subsequent bone metastases;8 dendritic cells, activated T-cells and B-cells,11 osteoclasts, mesenchymal cells, proliferative chondrocytes, early osteocytes and periosteal cells; synovial tissue,12 cardiomyocytes, vascular smooth muscle cells, endothelial cells,13 and the GI tract.14 The clinical significance of these findings is unknown RANK Ligand subsequently binds to its receptor, RANK, on immature and mature osteoclasts, which leads to maturation of pre-fusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts1 RANK is another member of the TNF receptor family and is expressed on osteoclasts and osteoclast progenitors.11,15 In addition, RANK has been observed on cartilage cells (chondrocytes), mammary gland epithelial cells, and trophoblast cells1,10,15 1. Boyle WJ, et al. Nature. 2003;423: 2. Fuller K, et al. J Exp Med. 1998;188: 3. Lacey DL, et al. Am J Pathol. 2000;157: 4. Lacey DL, et al. Cell. 1998;93: 5. Yasuda H, et al. Proc Natl Acad Sci USA. 1998;95: 6. Hofbauer LC, Schoppet M. JAMA. 2004;292: 7. Kong Y-Y, et al. Nature. 1999;397: 8. Brown JM, et al. Urology. 2001;57: 9. Van Poznak C, et al. J Clin Pathol. 2006;59:56-63. 10. Fata JE, et al. Cell :103:41-50. 11. Anderson DM, et al. Nature. 1997;390: 12. Crotti TN, et al. Ann Rheum Dis. 2002;61: 13. Ueland T, et al. Circulation. 2005;111: 14. Moschen AR, et al. Gut. 2005;54: 15. Hsu H, et al. Proc Natl Acad Sci USA. 1999:96: Activated Osteoclast Osteoblasts Tvorba kosti Odbourávání kosti CFU-M=colony forming unit macrophage M-CSF=macrophage colony stimulating factor Adapted from Boyle WJ, et al. Nature. 2003;423:

7 Osteoprotegerin (OPG) je receptor zamezující vazbě RANK Ligandu na RANK a formování, fungování a přežívání osteoklastů CFU-M M-CSF Pre-Fusion Osteoclast RANKL RANK OPG Hormony Růstové faktory Cytokiny Inhibice tvorby, funkce a přežívání osteoklastů The body naturally produces a protein called osteoprotegerin (OPG) to neutralize the effects of RANK Ligand and defend against bone loss.1,2 When RANK Ligand is bound and neutralized by osteoprotegerin (OPG), osteoclasts cannot form3,4, function3 or survive.5 OPG, a natural endogenous inhibitor of RANK Ligand, acts as a decoy receptor by binding with RANK Ligand, thereby inhibiting osteoclastogenesis and the survival of pre-existing osteoclasts1,2,6,7 OPG, a member of the tumor necrosis factor (TNF) receptor family, binds to and neutralizes the effects of RANK Ligand, thereby inhibiting bone resorption1,2,6,7 OPG is an important inhibitor of the terminal differentiation and function of osteoclasts1,2,6,7 Boyle WJ, et al. Nature. 2003;423: Simonet WS, et al. Cell. 1997;89: Fuller K, et al. J Exp Med. 1998;188: Yasuda H, et al. Proc Natl Acad Sci USA. 1998;95: Lacey DL, et al. Am J Pathol. 2000;158: Lacey DL, et al. Cell. 1998;93: Bekker PJ, et al. J Bone Miner Res. 2001;16: Osteoblasts Resorpce kosti zastavena Tvorba kosti Estrogeny podporují tvorbu OPG v OB CFU-M=colony forming unit macrophage M-CSF=macrophage colony stimulating factor Adapted from Boyle WJ, et al. Nature. 2003;423:

8 RANK Ligand zvyšuje aktivitu osteoklastů
OPG RANK Ligand Podpora aktivace OK Zábrana aktivace OK Aktivita osteoklastů Porušení rovnováhy mezi RANK Ligandem a OPG je kritické ve vývoji onemocnění kosti spojené s úbytkem kostní hmoty a kostní resorpcí1-3 1Hofbauer LC, et al. JAMA. 2004;292:490-5; 2Lacey DL, et al. Cell. 1998;93:165-76; 3Boyle WJ, et al. Nature. 2003;423:

9 Mnoho faktorů stimuluje osteoblasty k produkci RANKL
CFU-M RANKL RANK Glucocorticoids PTH Pre-fusion Osteoclast PGE2 Vitamin D IL-11 IL-6 Multinucleated Osteoclast IL-1 PTHrP TNF- Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss.1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity.1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption.1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption.2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures.1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models.2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand.2 Boyle WJ, et al. Nature. 2003;423: Kostenuik PJ, et al. Curr Pharm Des. 2001;7: Hofbauer LC, et al. JAMA. 2004;292: Activated Osteoclast ET-1 Osteoblast CFU-M = colony-forming unit-macrophage; PTH = parathyroid hormone; PGE2 = prostaglandin E2; IL = interleukin; PTHrP = PTH-related peptide; RANKL = receptor activator of nuclear factor kappa B ligand. ET-1 = endothelin Adapted from: Boyle WJ, et al. Nature. 2003;423: Clines et al. Mol Endocrinol February; 21(2): Hofbauer LC, et al. JAMA. 2004;292:

10 RANK Ligand hraje hlavní roli při ztrátě kostní hmoty a destrukci kosti
Post-Menopausal Osteoporosis Treatment-Induced Bone Loss Cancer-Related Bone Destruction Bone Erosion of RA RANK Ligand plays a key role in osteoclast-mediated bone loss and destruction across a broad range of conditions.1,2 The effects of RANK Ligand are physiologically counterbalanced by the soluble receptor, OPG.1 When RANK Ligand overwhelms the effects of OPG, the imbalance in the bone remodeling process results in bone loss and destruction, including the following:1,2 Postmenopausal osteoporosis.3 Treatment-induced bone loss resulting from sex hormone ablative therapies, chronic exposure to glucocorticoids, and immunosuppression.1,4,5 Rheumatoid arthritis.6,7 Bone metastases.8,9 1. Hofbauer LC, Schoppet M. JAMA. 2004;292: 2. Kostenuik PJ. Curr Opin Pharmacol. 2005;5: 3. Eghbali-Fatourechi G, et al. J Clin Invest. 2003;111: 4. Hofbauer LC, et al. Endocrinology. 1999;140: 5. Theriault RL. Oncology. 2004;18(Suppl 3):11-15. 6. Gravallese EM, et al. Arthritis Rheum. 2000;43: 7. Kong Y-Y, et al. Nature. 1999;420: 8. Roodman GD. N Engl J Med. 2004;350: 9. Kitazawa S, et al. J Pathol. 2002;198: Gravallese EM, et al. Arthritis Rheum. 2000;43: Roodman GD. N Engl J Med. 2004;350: Kong Y-Y, et al. Nature. 1999;402: Kitazawa S, et al. J Pathol. 2002;198: Hofbauer LC, Schoppet M. JAMA. 2004;292: Eghbali-Fatourechi G, et al. J Clin Invest. 2003;111: Hofbauer LC, et al. Endocrinology. 1999;140: Theriault RL. Oncology. 2004;18(Suppl 3):11-15.

11 PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT
“Vicious Cycle” – začarovaný kruh kostní destrukce u metastazující rakoviny RANKL RANK OPG Buňky nádoru PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs CA+2 The “vicious cycle” hypothesizes that tumor cells interact with the bone marrow microenvironment to drive bone destruction and tumor growth in a symbiotic relationship. Tumor cells secrete parathyroid-hormone-related peptide (PTHrP), which is the primary stimulator of osteoblast production of RANK Ligand1 PTHrP induces both the production of RANK Ligand and down-regulates OPG production by osteoblasts, thereby stimulating osteoclastogenesis2 Other factors produced and secreted by tumor cells (endothelin-1(ET-1), IL-6, prostaglandin E2, TNF, and macrophage colony-stimulating factor) also increase the expression of RANK Ligand1,4 The increased expression of RANK Ligand in the tumor environment leads to increased formation, activation and survival of osteoclasts, and resulting osteolytic lesions3 Osteolysis (process of bone resorption) then leads to the release of growth factors derived from bone, including: 1,2 transforming growth factor-β (TGF-β) insulin-like growth factors (IGFs) fibroblast growth factors (FGFs) platelet-derived growth factor (PDGF) bone morphogenetic proteins (BMPs) These factors increase the production of PTHrP or promote tumor growth directly1 Specifically, the growth factors bind to receptors on the surface of the tumor cells activating autophosphorylation and signaling through pathways involving SMAD (cytoplasmic mediators of most TGF-β signals) and mitogen-activated protein kinase (MAPK)2 Bone destruction increases local extracellular calcium (Ca2+) concentrations, which have also been shown to promote tumor growth and the production of PTHrP2 Thus, tumor-cell proliferation and production of PTHrP through the signaling of these pathways is promoted and the cycle continues Roodman GD, N Engl J Med ;350: Mundy GR, et al. Nature Reviews Cancer. 2002;2: Kitazawa S, et al. J Pathol. 2002;198:228–36. Guise TA, et al. Endocrin Rev. 1998;19:18-54. Activated Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

12 Farmakologické vlastnosti Denosumabu
Model molekuly Denosumabu Plně humánní monoklonální protilátka typu IgG2 Vysoká afinita k RANK Ligandu Vysoká specificita k RANK Ligand neváže se na TNFα, TNFβ, TRAIL, CD40L Nevyvolává tvorbu neutralizujících protilátek v klinických studiích Denosumab, an investigational fully human monoclonal antibody (IgG2), binds with high affinity and specificity to human RANK (receptor activator of nuclear factor kappa B) ligand, an essential mediator of osteoclast activity.1-3 No neutralizing antibodies have been detected in clinical trials to date.1,3 Binding of denosumab to RANK Ligand was investigated in an in-vitro study using flow cytometry and ELISA. Binding affinity was measured using BIAcore and a kinetic exclusion assay. Denosumab bound both soluble and membrane-bound forms of human RANK Ligand. This binding was inhibited by excess human RANK Ligand, but not by TNF-, TNF-, TRAIL or CD40 Ligand. The dissociation constants of denosumab were calculated to be 9.5 x 10-11M and x 10-12M using the BIAcore and kinetic exclusion assay, respectively.2 No neutralizing antibodies have been detected in clinical trials to date: In a phase 1, double-blind study, 49 healthy postmenopausal women were randomized to receive a single dose of denosumab 0.01, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg or placebo. No anti-denosumab antibodies were detected in subjects enrolled in this study.1 In a phase 2 study, 412 postmenopausal women with low bone mineral density (BMD) were randomized to receive denosumab SC either every three months (6, 14, or 30 mg) or every six months (14, 60, 100, or 210 mg), open-label alendronate (70mg orally once weekly), or placebo. Denosumab-binding antibodies were observed in two subjects—one at 1 month and the other at 12 months. These antibodies were not neutralizing and were not detected in subsequent samples in either subject.3 The effects of denosumab on bone resorption appear reversible.3 Note: The graphic in the slide is a ribbon depiction of denosumab. Bekker PJ, et al. J Bone Miner Res. 2004;19: Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354: Bekker PJ, et al. J Bone Miner Res. 2004;19: 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: TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand

13 Mechanismus účinku: Denosumab se váže na RANK Ligand a brzdí destrukci kosti osteoklasty
CFU-M Pre-Fusion Osteoclast RANKL RANK Denosumab Hormones Growth factors Cytokines Inhibice tvorby, funkce a přežívání osteoklastů Denosumab is the first fully human monoclonal antibody in clinical development that specifically targets RANK Ligand, an essential mediator of osteoclast formation, function, and survival.1,2 Lewiecki EM, et al. Exper Opin Biol Ther. 2006;6: McClung ER, et al. New Engl J Med. 2006;354: Osteoblasts Tvorba kosti Resorpce kosti zastavena In the presence of M-CSF CFU-M=colony forming unit macrophage M-CSF=macrophage colony stimulating factor

14 PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT
RANKL Inhibice může přerušit “Vicious Cycle” kostní destrukce vyvolané nádorem RANKL RANK Denosumab Buňky nádoru Inhibice tvorby OK PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs, Ca2+ Apoptotic Osteoclast Osteoblasts

15 Důležité pojmy : CIBD, CTIBL a SRE
CIBD = Cancer Induced Bone Disease = Onemocnění kosti způsobené rakovinou zvýšení kostní resorpce a metastázy CTIBL = Cancer Treatment (CHT, hormony) Induced Bone Loss = Ztráta kostní hmoty vyvolaná léčbou rakoviny prořídnutí kosti a další následky vyvolané tzv. „hormonal ablative treatment“ tj. zejména léčbou antiandrogeny (prostata) a antiestrogeny (prs) SRE = Skeletal Related Events = Události související s kostrou, způsobené metastázami

16 Skeletal Related Events
Radioterapie kosti pro bolest4 Patologická fraktura2 Útlak míchy3 Nutnost operace1 Skeletal morbidity includes pathological fractures, spinal cord or nerve root compression, and pain that requires radiotherapy or surgery.5 Background Surgical stabilization may be required in the case of pathological fractures or when bone areas need to be stabilized to preempt the occurrence of fractures5 Pathologic fractures are caused by the destruction of bone by metastatic disease, reducing the bone load-bearing capabilities, resulting initially in painful microfractures and subsequently full fractures5 Spinal cord compressions are considered an oncologic emergency and suspected cases need urgent evaluation and treatment5 The role of radiotherapy to bone has been well established. The optimal treatment schedule (single vs. multiple fractions) has been an issue of controversy with data showing that single fraction had equal efficacy in pain reduction, but significant higher retreatment rates were seen with single fractions6 Hypercalcemia can also be included and most often occurs in patients with SCLC, breast and kidney cancer and certain hematological malignancies, especially myeloma and lymphoma. Hypercalcemia results from bone destruction; osteolytic metastases being present in 80% of cases.5 Available at: Accessed August 10, Provided by John Hopkins Arthritis Center at John Hopkins University. Available at: Accessed August 10, ©2007 Data Trace Publishing Company. All rights reserved. Higdon ML, et al. Am Fam Physician. 2006;74: Permission obtained. This image is licensed under the GNU Free Documentation License. Coleman RE. Clin Cancer Res. 2006;12(20 Suppl):6243s-6249s. Chow E et al. J Clin Oncol. 2007;25: 1. Available at: Accessed 8/2007 Provided by John Hopkins Arthritis Center at John Hopkins University 2. Wheeless' Textbook of Orthopaedics. © 2007 Data Trace Publishing Company. All rights reserved 3. Higdon ML, et al. Am Fam Physician 2006;74: Permission obtained 4. This image is licensed under the GNU Free Documentation License 16

17 Riziko karcinomu prostaty (CaP), kostních metastáz a následeného postižení kostí
Pravděpodobnost vzniku karcinomu prostaty během života muže 68% pravděpodobnost kostních metastáz u pacientů s pokročilým CaP2 Prostate cancer is the most common cancer, other than skin cancers, in American men. The American Cancer Society estimated that during 2007 about 218,890 new cases of prostate cancer would be diagnosed in the United States.1 Background 1 in 6 men will develop prostate cancer at some point in their lifetime,2 but only 1 man in 35 will die of it.1 More than 2 million men in the United States who have been diagnosed with prostate cancer at some point are still alive today.1 Prostate cancer is the third leading cause of cancer death in American men, behind lung and colorectal cancers. Prostate cancer accounts for about 9% of cancer-related deaths in men.2 Bone is the most common site for metastasis in cancer and is of particular clinical importance in breast and prostate cancers because of the prevalence of these diseases.2 In one study, at postmortem examination, more than two-thirds (68%) of patients dying of metastatic breast or prostate cancers had evidence of metastatic bone disease.3 In one study in patients with hormone-refractory metastatic prostate carcinoma, at least one skeletal-related event (SRE) occurred in 44.2% (92/208) patients who received placebo over 15 months (vs 33.2% [71/214] of patients who received zoledronic acid at 4 mg).5 1. American Cancer Society. Cancer Reference Information: Detailed Guide: Prostate Cancer. Available at: prostate_cancer_36.asp?rnav=cri 2. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66. 3. Coleman RE. Clin Cancer Res. 2006;12:6243s-6249s. 4. Available at Reproduced with permission from GNU Free Documentation. 5. Saad F, et al. J Natl Cancer Inst. 2002;94: SRE se vyskytnou u 44% pacientů s kostními metastázami u hormonálně-refrakterní CaP *,3,4 SRE = skeletal-related event; *Placebo arm of study. 1. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66; 2. Coleman RE. Clin Cancer Res. 2006;12:6243s-6249s; 3. Saad F, et al. J Natl Cancer Inst. 2002;94: ;4. Available at Reproduced with permission from GNU Free Documentation.

18 2007 incidence (US) 218,890 (estimated)
Pacienti s karcinomem prostaty žijí déle, zvyšuje se pravděpodobnost výskytu onemocnění související s léčbou. 250 200 2007 incidence (US) 218,890 (estimated) 150 100 50 1979 1983 1987 1991 1995 1999 2003 Rate per 100,000 Population 40 2007 mortality (US) 27,050 (estimated) 30 Top graph shows annual age-adjusted prostate cancer incidence rates* among men in the US (1977 to 2003). The bottom graph shows annual age-adjusted cancer death rates† among men in the US (1977 to 2003).1 [Jemal CA J Clin 2007/p47] Background The spike observed in the incidence of prostate cancer in the early 1990s correlates to the introduction and wide adoption of prostate-specific antigen (PSA) testing.1 [Jemal CA J Clin 2007/p49] *Rates are age-adjusted to the 2000 US standard population and adjusted for delays in reporting with the exception of melanoma. Source: Surveillance, Epidemiology, and End Results (SEER) program, nine oldest registries, 1975 to 2003, Division of Cancer Control and Population Sciences, National Cancer Institute.1 [Jemal CA J Clin 2007/p52 Figure 3] †Rates are age-adjusted to the 2000 US standard population. Incidence rates are delay-adjusted. Source: Incidence data from SEER program, nine oldest registries, 1975 to 2003, Division of Cancer Control and Population Sciences, National Cancer Institute, Mortality data from US Mortality Public Use Data Tapes, 1960 to 2002, National Center for Health Statistics, Centers for Disease Control and Prevention, [Jemal CA J Clin 2007/p54] 1. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66. 20 10 1979 1983 1987 1991 1995 1999 2003 Year Jemal A, et al. CA Cancer J Clin. 2007;57:43-66.

19 Komplikace kostních metastáz (Prostate Ca)
Patients with SRE, % n = 208 *24-mon Data of Placebo Arms in randomized Studies. Saad F, et al. J Urol, 2003.

20 Změny kostní hustoty během ADT léčby karcinomu prostaty: snížení BMD v různých lokalizacích
Páteř Months 6 12 Celý kyčel -4 -2 2 Celé tělo 2 1  BMD, % -2 -1 -2 -4 -3 -6 -4 6 12 6 12 Therapy-induced bone loss may increase fracture risk in prostate cancer patients.1 Background This was a 12-month prospective study in 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, ≥ 6 months; and 72 with no ADT) and 43 healthy age-matched controls1 After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 ± 0.6% at the total hip, 2.4 ± 1.0% at the trochanter (not shown), 2.6 ± 0.5% at the total radius (not shown), 3.3 ± 0.5% at the total body, and 4.0 ± 1.5% at the spine (all P < .05)1 Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD1 Both the use and duration of ADT were associated with change in bone mass at the hip (P < .05).1 The study showed that men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture1 1. Greenspan SL, et al. J Clin Endocrin Metab. 2005;90: Months Months PC chronic ADT (n = 50) PC acute ADT (n = 30) Control (n = 43) PC no ADT (n = 72) BMD = bone mineral density. Adapted from Greenspan SL, et al. J Clin Endocrin Metab. 2005;90:

21 Fracture-Free Survival (%)
Delší trvání antiandrogenní léčby je spojeno se zkrácením období bez výskytu zlomenin (Fracture-Free Survival) 100 80 Fracture-Free Survival (%) 60 40 No ADT GnRH agonist, 1-4 doses 20 GnRH agonist, 5-8 doses Therapy-induced bone loss may increase fracture risk in prostate cancer patients.1 Background This study looked at the records of 50,613 men listed in the SEER database and Medicare as having received a diagnosis of prostate cancer in the period from 1992 through 1997 and with follow-up through 20011 Of men surviving at least five years after diagnosis, 19.4% of those who received ADT had a fracture, compared with 12.6% of those who did not receive ADT (P < .001)1 There was a statistically significant relation between the number of doses of GnRH received during the 12 months after diagnosis and the subsequent risk of fracture1 1. Shahinian VB, et al. N Engl J Med. 2005;352: GnRH agonist, ≥ 9 doses Orchiectomy 2 4 6 8 10 Years After Diagnosis N = 50,613 men listed in the SEER database and Medicare as having received a diagnosis of prostate cancer in the period from 1992 through 1997 and with follow-up through 2001 Adapted from Shahinian VB. et al. N Engl J Med. 2005;352:

22 Kostní nemoc spojená s rakovinou
CTIBL Cancer treatment-induced bone loss CIBD Cancer Induced Bone Disease SRE Skeletal-related events

23 Charakteristika kostních metastáz u ca prostaty a kostní mikroarchitektura
Normální obratel1 X-ray images of osteoblastic metastasis from prostate cancer appear radiodense, however synchrotron radiation (SR)-µCT analysis of the microarchitecture and mineralization of osteoblastic metastasis reveal the disorganized woven bone and the deterioration of the trabecular structure that provides strength in the normal bone.8 Background: Representative images are shown in the slide: The top panel shows a normal control subject. The soft X ray and 3D volume-rendered SR-μCT images of normal trabecular bone from the L2 vertebral body taken from a 37-year-old man The organized trabecular structure can be observed in the soft x-ray The 3D image clearly shows both rod- and plate-like structures of the trabecular bone The bottom panel shows a patient with osteoblastic metastasis from prostate cancer. The soft X ray and 3D volume-rendered SR-μCT images of metastatic trabecular bone from the L3 vertebral body, taken from a 67-year-old man with bone metastases from prostate cancer The irregular, disorganized woven bone structure can be observed in the osteoblastic bone lesion. The 3D image shows an increased number of trabeculae with an irregular surface. The trabecular number was greater than that in normal tissue, whereas no difference in trabecular thickness was observed Although the osteoblastic lesion in the soft x-ray on this slide appears radiographically opaque due to the increase in bone volume1, the increased bone volume is a result of formation of woven bone. This woven bone is poorly mineralized with insufficient mechanical strength1-5 due to increased bone turnover as compared to the normal bone6,7 Clarke NW, et al. Br J Urol. 1991;68:74-80. Charhon SA, et al. Cancer. 1983;51: Roudier M, et al. J Urology. 2008; In Press. Roodman GD, Windle JJ. J Clin Invest. 2005;115: Martin RB, et al. Skeletal Biology. In: Skeletal Tissue Mechanics. 1989;29-78. Kanis JA, McCloskey EV. Cancer. 1997;80:1538–1545. Urwin GH, et al. Br J Urol. 1985;57: Sone T, et al. Bone. 2004;35: (reprinted with permission Elsevier). Soft X-ray SR-µCT Soft X-ray SR-µCT Osteoblastická metastáza1 ve srovnání s normální kostí: Kostní obrat2 Vznik vláknité kosti3 Mineralizace1 SR- µCT = Synchrotron radiation-µCT Reprinted from Sone T, et al. Bone. 2004;35: © 2004 with permission from Elsevier. Kanis JA, McCloskey EV. Cancer. 1997;80:1538– Clarke NW, et al. Br J Urol. 1991;68:74-80.

24 Typická aberantní kolagenní vlákna a porušena mikroarchitektura
U osteoblastických metastáz dochází ke vzniku zvýšeně vláknité kosti se špatnými mechanickými vlastnostmi Typická aberantní kolagenní vlákna a porušena mikroarchitektura Špatná mineralizace The newly formed bone typically seen in osteoblastic bone metastases related to prostate cancer shows characteristics of woven bone, with marked defects in mineralization and microstructure. Adding to the reduced mechanical strength of prostate cancer related bone metastases is an increasingly recognized osteolytic component.1 Note: This slide builds in Slide Show mode Saad F, et al. Br J Urology advance online publication, 7 Dec 2007; doi: /j X x Image from: This image is licensed under the GNU Free Documentation License.

25 nmol/mmol Creatinine (median)
Markery kostní resorpce a kostní novotvorby u metastatického postižení kostí různými nádory Baseline BAP Baseline Ntx 300 100 268 89 250 76 80 202 68 68 200 57 162 155 60 U/L (median) nmol/mmol Creatinine (median) 150 134 40 100 Bone turnover markers are elevated in patients with both osteoblastic and osteolytic metastatic bone disease.2 Background Coleman et al. used data from 3 large, multicenter, randomized, controlled phase 3 trials of zoledronic acid to determine a correlation between bone marker levels and clinical outcomes, including SREs, disease progression and death in various tumor types1 Patients with prostate cancer, on average had the highest baseline values of both uNTX and BAPs1 Left figure: An increase in BSAP with osteoblastic lesions was observed as expected. High BAP was associated with a significant two-fold increase in the risk of SREs compared to low BAP, with the strongest correlation seen for prostate cancer (RR = 3.29; P< .001) Right figure: The uNTx was increased with blastic lesions, showing there is also an increase in bone resorption in osteoblastic lesions. In contrast, patients with multiple myeloma, on average, had the lowest baseline NTX levels. Urinary N-Telopeptide (uNTx) levels and bone specific alkaline phosphatase (BSAP) were significantly correlated with the number of skeletal sites involved with the metastases (P < 0.05)2 There was a significant correlation between marker level and extent of skeletal involvement and survival1,2,3 Both markers were higher in patients with osteoblastic disease than in patients with osteolytic disease2 Coleman RE, et al. JCO. 2005;23(22):1-11. Demers LM, et al. Cancer. 2000;88: Lipton A, et al. Semin Oncol. 2001;28(suppl 11):54-59. 20 50 BC PC NSCLC Other ST MM BC PC NSCLC Other ST MM n = 762 n = 626 n = 366 n = 379 n = 319 n = 744 n = 611 n = 263 n = 247 n = 318 NSCLC=non–small-cell lung cancer; Ntx=urinary N-telopeptide; BAP=bone alkaline phosphatase; U=International Units; SRE=skeletal-related event. Other solid tumors include solid tumors other than breast, prostate, or non–small cell lung cancers. Number of patients available for baseline assessment Coleman RE, et al. JCO. 2005;23(22):1-11.

26 Hlavní body a cíle klinického programu denosumabu v onkologii
Léčba CITBL, tj. zábrana dalšího úbytku kostní hmoty tam, kde již je zjištěna Karcinom prsu léčený inhibitory aromatáz – pokles tvorby estrogenů Karcinom prostaty léčený androgen deprivační léčbou – pokles aktivity androgenů, které jsou v těle přeměňovány na estrogeny Oddálení tvorby kostních metastáz – ca prostaty Oddálení vzniku SRE

27 Klinický program u karcinomu prostaty
Death Tichá prevalence SRE Treatment of Bone Mets n ~ 1900 HSPC Diagnóza a chir. léčba ADT Bone Mets Prevention of Bone Mets n ~ 1400 Treatment-Induced Bone Loss n ~ 1500 HRPC Time HSPC – hormonálně senzitivní karcinom prostaty HRPC – hormonálně rezistentní karcinom prostaty *

28 Děkuji za pozornost