Terapia e prevenzione
dell’osteoporosi
Stefania Maggi
CNR Sezione Invecchiamento
Padova
Incidence per 10,000 women per year
As trabecular and cortical bone loss progresses,
vertebral and hip fracture rates
increase exponentially
Vertebral fractures
Hip fractures
400
Early increased incidence
of vertebral fracture
correlating with early
trabecular bone loss
300
Later
increased
incidence of
hip fracture
correlating
with
accumulation
of trabecular
and cortical
bone loss
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.
Multiple Factors May Mitigate Fracture Risk
Therapeutic Interventions
Lifestyle Modifications
Slowing/Stopping
Bone Loss
Minimizing Factors
that Contribute
to Falls
Modification of
Risk Factors
(diet, exercise)
Decrease
Fracture
Risk
Maintaining
or Increasing
Bone Density and Strength
Maintaining or Improving
Bone
Microarchitecture
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.
Effective Treatment Is Based on Efficacy,
Safety/Tolerability and Adherence
Effective Treatment
Efficacy
The capacity for
beneficial
change, or
therapeutic
effect of a given
intervention
+
Safety/Tolerability
Defined as freedom
from undesirable sideeffects/adverse events,
and decrease in
susceptibility to the
effects of a medication
resulting from continued
administration
Payer J, et al. Biomed Pharmacother 2007;61:191-193.
+
Adherence
Reflects a
combination of
behaviours
determining the
extent to which
patients take
medications as
prescribed
Adherence Encompasses Both
Persistence and Compliance
Reflects a combination of
behaviours determining the
extent to which patients take
medications as prescribed
Adherence
Persistence
+
The length of time
from beginning to
completion or
discontinuation of
therapy
Payer J, et al. Biomed Pharmacother 2007;61:191-193.
Compliance
The consistency and
accuracy with which a
prescribed regimen is
followed
Osteoporosis Therapies and Patient Adherence
Less than 50% of patients persist with their
osteoporosis therapy for more than 1 year
Patients initiating therapy
Side effects
Lack of
motivation
Safety
concerns
Cost
Adherence
Health
problems
Inconvenient
dosing
Withdrawn
by others
Lack of
results
Patients continuing therapy
Siris E.S. et al. Am. J. Med. 2009; 122: S3-S13
Poor Adherence is Associated with
Increased Fracture Risk
low
Fracture Risk by Adherence Level
high
p < 0.0001
Increased Risk of Fracture
p = 0.0002
1,4
p = 0.12
1.09
1,2
1.18
1.21
50 to < 80%
< 50%
1
1,0
0,8
0,6
0,4
0,2
0,0
> 90%
80 to 90%
high
Huybrechts KF, et al. Bone. 2006;38:922-928.
Adherence Level
low
Data from 38,000 women in a managed care database
Denosumab lega il RANK Ligando inibendo
la formazione, la funzione e la sopravvivenza degli osteoclasti
RANKL
Pre- Osteoclasti
CFU-M
RANK
OPG
Denosumab
Ormoni
Fattori di crescita
Citochine
Inibizione della formazione, funzione e
sopravvivenza degli osteoclasti
Osteoblasti
Formazione ossea
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.
Inibizione del
riassorbimento osseo
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
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.
Struttura di denosumab
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
V
I
S
I
T
A
D
I
S
C
R
E
E
N
I
N
G
V
I
S
I
T
A
G
I
O
R
N
O
Studio DAPS
Disegno dello studio
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
1
Randomizzazione
1:1
6 mesi
12 mesi
18 mesi
F
I
N
E
D
E
L
L
O
S
T
U
D
I
O
24 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. Osteoporos Int 2011; 22: 1725-1735
Non-aderenza, non-compliance e non-persistenza
maggiori per alendronato al primo anno
Anno 1
Denosumab (N = 126)
RRR = 46%
P = 0.026
Percentuale di soggetti
25
Alendronato (N = 124)
RRR = 52%
P = 0.014
RRR = 50%
P = 0.029
20
15
10
5
0
Non
Aderenza
RRR = riduzione rischio relativo
Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735
Freemantle N et al. Osteoporos Int 2012;23: 317-326
Non
Compliance
Non
Persistenza
Non-aderenza, non-compliance e non-persistenza
maggiori per alendronato anche al 2° anno
Anno 2
Denosumab (N = 106)
RRR = 80%
P < 0.001
Percentuale di soggetti
40
Alendronato (N = 115)
RRR = 80%
P < 0.001
RRR = 91%
P < 0.001
30
20
10
0
Non
Aderenza
RRR = riduzione rischio relativo
Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735
Freemantle N et al. Osteoporos Int 2012;23: 317-326
Non
Compliance
Non
Persistenza
Maggiore soddisfazione e preferenza per
denosumab rispetto ad alendronato
Soddisfazione
Preferenza
Per niente/scarsa/moderata
Compressa
Abbastanza/Molto
Iniezione
100
80
62%
93%
69%
91%
63%
95%
60
40
20
38%
9%
7%
0
ALN
37%
31%
DMab
Convenienza
ALN
DMab
5%
ALN
DMab
Modalità:
Frequenza
Compressa
di
vs
somministrazione
Iniezione
Kendler DL et al. Osteoporos Int 2011; 22: 1725-1735
Freemantle N et al. Osteoporos Int 2012;23: 317-326
Percentuale di soggetti
Percentuale di soggetti
100
80
92%
91%
8%
9%
Preferita
Preferita
nel
lungo
termine
60
40
20
0
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