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Terapia e prevenzione dellosteoporosi Stefania Maggi CNR Sezione Invecchiamento Padova

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Age (years) Incidence per 10,000 women per year 400 300 200 100 0 505455596064656970747579808485+ Hip fractures Vertebral fractures As trabecular and cortical bone loss progresses, vertebral and hip fracture rates increase exponentially Adapted from: Sambrook P & Cooper C. Lancet 2006;367:20102018. Early increased incidence of vertebral fracture correlating with early trabecular bone loss Later increased incidence of hip fracture correlating with accumulation of trabecular and cortical bone loss

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Multiple Factors May Mitigate Fracture Risk Slowing/Stopping Bone Loss Minimizing Factors that Contribute to Falls Maintaining or Increasing Bone Density and Strength NAMS Position Statement. Menopause. 2006;13:340-367. Heaney, RP. Bone. 2003;33:457-465. Siris ES, et al. Mayo Clin Proc. 2006;81:1013-1022. Improving Medication Adherence Modification of Risk Factors (diet, exercise) Lifestyle Modifications Therapeutic Interventions Maintaining or Improving Bone Microarchitecture Decrease Fracture Risk

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Effective Treatment Is Based on Efficacy, Safety/Tolerability and Adherence Effective Treatment EfficacySafety/Tolerability + Adherence + The capacity for beneficial change, or therapeutic effect of a given intervention Defined as freedom from undesirable side- effects/adverse events, and decrease in susceptibility to the effects of a medication resulting from continued administration Reflects a combination of behaviours determining the extent to which patients take medications as prescribed Payer J, et al. Biomed Pharmacother 2007;61:191-193.

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Adherence Encompasses Both Persistence and Compliance Payer J, et al. Biomed Pharmacother 2007;61:191-193. Adherence PersistenceCompliance + Reflects a combination of behaviours determining the extent to which patients take medications as prescribed The length of time from beginning to completion or discontinuation of therapy The consistency and accuracy with which a prescribed regimen is followed

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Osteoporosis Therapies and Patient Adherence Less than 50% of patients persist with their osteoporosis therapy for more than 1 year Siris E.S. et al. Am. J. Med. 2009; 122: S3-S13 Patients initiating therapy Patients continuing therapy Adherence Side effects Safety concerns Health problems Lack of results Lack of motivation Cost Inconvenient dosing Withdrawn by others

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Poor Adherence is Associated with Increased Fracture Risk Huybrechts KF, et al. Bone. 2006;38:922-928. 1 1.09 1.18 1.21 Increased Risk of Fracture Fracture Risk by Adherence Level Data from 38,000 women in a managed care database p < 0.0001 p = 0.0002 p = 0.12 highlow high Adherence Level

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Denosumab lega il RANK Ligando inibendo la formazione, la funzione e la sopravvivenza degli osteoclasti RANKL RANK OPG Denosumab Formazione ossea Inibizione del riassorbimento osseo Inibizione della formazione, funzione e sopravvivenza degli osteoclasti CFU-M Pre- Osteoclasti Osteoblasti Ormoni Fattori di crescita Citochine Adattato da: Boyle WJ, et al. Nature. 2003;423:337-342. In presenza di M-CSF CFU-M= unit formante colonie macrofagiche M-CSF= fattore stimolante le colonie macrofagiche

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Propriet farmacologiche di denosumab Anticorpo monoclonale completamente umano isotipo IgG 2 Elevata affinit per il RANK Ligando umano Elevata specificit per il RANK Ligando Legame con TNF-, TNF-, TRAIL, o CD40L non rilevabile Ad oggi non stata osservata la formazione di anticorpi neutralizzanti nel corso degli studi clinici Ig = immunoglobuline; TNF = tumor necrosis factor; TRAIL = TNF-related apoptosis-inducing ligand. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. N Engl J Med. 2006;354:821-831. Struttura di denosumab

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Pharmacokinetic and Pharmacodynamic Properties of Denosumab Administered via subcutaneous (SC) injection Reduction in bone turnover markers within 3 days and sustained for up to 6 months The maximum denosumab serum concentration (C max ) occurred in 10 days for the 60 mg SC dose (range: 228 days) Mean half-life is 25.4 days (SD 8.5 days) with 60 mg SC dosing Serum denosumab concentrations declined over 45 months No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing Dosing schedule: every 6 months SD = standard deviation Denosumab Summary of Product Characteristics, 2012

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Tutti i soggetti hanno ricevuto una supplementazione quotidiana con 1000 mg di calcio e 400 UI di vitamina D VISITADISCREENINGVISITADISCREENING Denosumab 60 mg SC Q6M Anno 1 VISITAGIORNO1VISITAGIORNO1 Alendronato 70 mg orale QW Denosumab 60 mg SC Q6M Alendronato 70 mg orale QW Anno 2 FINEDELLOSTUDIOFINEDELLOSTUDIO Crossover 0-35 giorni 24 mesi Randomizzazione 1:1 6 mesi 12 mesi 18 mesi Visite dello studio 24 mesi Studio DAPS Disegno dello studio N = 250 Multicentrico, randomizzato, in aperto, di crossover Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735

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Freemantle N et al. Osteoporos Int 2012;23: 317-326 Non-aderenza, non-compliance e non-persistenza maggiori per alendronato al primo anno 0 5 10 15 20 25 Non Aderenza Non Compliance Non Persistenza RRR = 46% P = 0.026 RRR = 52% P = 0.014 RRR = 50% P = 0.029 Denosumab (N = 126)Alendronato (N = 124) RRR = riduzione rischio relativo Anno 1 Percentuale di soggetti

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RRR = riduzione rischio relativo Percentuale di soggetti Anno 2 Denosumab (N = 106)Alendronato (N = 115) Non Aderenza Non Compliance Non Persistenza RRR = 80% P < 0.001 RRR = 80% P < 0.001 RRR = 91% P < 0.001 0 10 20 30 40 Non-aderenza, non-compliance e non-persistenza maggiori per alendronato anche al 2 anno Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735 Freemantle N et al. Osteoporos Int 2012;23: 317-326

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Maggiore soddisfazione e preferenza per denosumab rispetto ad alendronato 0 20 40 60 80 100 ConvenienzaModalit: Compressa vs Iniezione DMab ALN DMab ALN DMab ALN Frequenza di somministrazione Percentuale di soggetti 38% 62% 7% 93% 31% 69% 9% 91% 37% 63% 5% 95% Per niente/scarsa/moderata Abbastanza/Molto Compressa Iniezione 0 20 40 60 80 100 Percentuale di soggetti 92% 91% 8%9% Preferita Preferita nel lungo termine Soddisfazione Preferenza Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735 Freemantle N et al. Osteoporos Int 2012;23: 317-326

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CONCLUSIONI LOsteoporosi un problema di salute pubblica molto rilevante e rester tale nei prossimi anni Gli interventi di prevenzione e di trattamento ad oggi implementati non riflettono le profonde conoscenze scientifiche raggiunte sullefficacia degli stessi