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Terapia e prevenzione dell’osteoporosi

Terapia e prevenzione dell’osteoporosi. Stefania Maggi CNR Sezione Invecchiamento Padova. 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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Terapia e prevenzione dell’osteoporosi

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  1. Terapia e prevenzione dell’osteoporosi Stefania Maggi CNR Sezione Invecchiamento Padova

  2. 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 As trabecular and cortical bone loss progresses, vertebral and hip fracture rates increase exponentially 400 Vertebralfractures Hip fractures 300 Incidence per 10,000 women per year 200 100 0 50−54 55−59 60−64 65−69 70−74 75−79 80−84 85+ Age (years) Adapted from: Sambrook P & Cooper C. Lancet 2006;367:2010–2018.

  3. Multiple Factors May Mitigate Fracture Risk Therapeutic Interventions Lifestyle Modifications Slowing/Stopping Bone Loss Minimizing Factors that Contribute to Falls Maintaining or Increasing Bone Density and Strength Decrease Fracture Risk Maintaining or Improving Bone Microarchitecture Modification of Risk Factors (diet, exercise) Improving Medication Adherence 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.

  4. Effective Treatment Is Based on Efficacy, Safety/Tolerability and Adherence Effective Treatment Efficacy + Safety/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.

  5. Adherence Persistence Compliance Adherence Encompasses Both Persistence and Compliance 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 Payer J, et al. Biomed Pharmacother 2007;61:191-193.

  6. Osteoporosis Therapies and Patient Adherence Less than 50% of patients persist with their osteoporosis therapy for more than 1 year Patients initiating therapy Adherence Patients continuing therapy Siris E.S. et al. Am. J. Med. 2009; 122: S3-S13

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

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

  9. Proprietà farmacologiche di denosumab • Anticorpo monoclonale completamente umano – isotipo IgG2 • Elevata affinità per il RANK Ligando umano • Elevata specificità per il RANK Ligando • Legame con TNF-α, TNF-β, TRAIL, o CD40L non rilevabile • Ad oggi non è stata osservata la formazione di anticorpi neutralizzanti nel corso degli studi clinici Struttura di denosumab Ig = immunoglobuline; TNF = tumor necrosis factor;TRAIL = TNF-α–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.

  10. 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 (Cmax) occurred in 10 days for the 60 mg SC dose (range: 2–28 days) Mean half-life is 25.4 days (SD 8.5 days) with 60 mg SC dosing Serum denosumab concentrations declined over 4–5 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

  11. Studio DAPSDisegno dello studio V I S I T A D I S C R E E N I N G F I N E D E L L O S T U D I O V I S I T A G I O R N O 1 N = 250 Denosumab 60 mg SC Q6M Alendronato 70 mg orale QW Anno 1 Anno 2 Alendronato 70 mg orale QW Denosumab 60 mg SC Q6M Crossover Randomizzazione 1:1 24 mesi 6 mesi 12 mesi 18 mesi Visite dello studio 24 mesi 0-35 giorni • Multicentrico, randomizzato, in aperto, di crossover Tutti i soggetti hanno ricevuto una supplementazione quotidiana con 1000 mg di calcio e ≥ 400 UI di vitamina D Kendler DL et al. OsteoporosInt 2011; 22: 1725-1735

  12. Non-aderenza, non-compliance e non-persistenza maggiori per alendronato al primo anno Anno 1 Denosumab (N = 126) Alendronato (N = 124) RRR = 46% P = 0.026 RRR = 52% P = 0.014 25 RRR = 50% P = 0.029 20 15 10 Percentuale di soggetti 5 0 Non Compliance Non Aderenza Non Persistenza RRR = riduzione rischio relativo Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735 Freemantle N et al. Osteoporos Int 2012;23: 317-326

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

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

  15. CONCLUSIONI • L’Osteoporosi è un problema di salute pubblica molto rilevante e resterà tale nei prossimi anni • Gli interventi di prevenzione e di trattamento ad oggi implementati non riflettono le profonde conoscenze scientifiche raggiunte sull’efficacia degli stessi

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