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