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Nicola Napoli, MD PhD
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Nicola Napoli, MD, PhD
Associate Professor
Division of Endocrinology and Diabetes
Patients Who Have Already Fractured:
The Long Hanging Fruit
Those with fractures
are MUCH more likely
to have more fractures
But very few fracture
patients get evaluated
for osteoporosis or
treatment
PROBABILITY OF OSTEOPORORIS MEDICATION USE FOLLOWING HIP FX WITHIN 12 MO AFTER DISCHARGE
Solomon et al., JBMR 29:1929, 2014
TAKE ACTION
Therapeutic Strategies
Bone marrow precursors
OsteoblastsOsteoclast
Lining cells
Stimulators of
Bone Formation
PTH analogs
Romosozumab
Inhibitors of
Bone Resorption
Estrogen, SERMs
Bisphosphonates
RANKL Inhibitors
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Figure 1 (Left) Structure of pyrophosphate and geminal bisphosphonates. (Right) Structures of clinically
used bisphosphonates (acid forms are depicted).
© 2008 American Society for Bone and Mineral Research
From the Primer on the Metabolic Bone Diseases
and Disorders of Mineral Metabolism, 7th Edition.
www.asbmrprimer.orgBisphosphonates
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Figure 2 Schematic presentation of effects of bisphosphonates on bone metabolism and strength in
osteoporosis.
© 2008 American Society for Bone and Mineral Research
From the Primer on the Metabolic Bone Diseases
and Disorders of Mineral Metabolism, 7th Edition.
www.asbmrprimer.org
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Kinetic Binding affinity of BPs
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Bisphosphonates Reduce Fracture Risk up to 5 Years
Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
CMCE/DNB/0011/13
Preparation date: Februrary 2013
Prolia® (Denosumab), a RANK Ligand Inhibitor, Inhibits Osteoclast Formation, Function, and Survival
2Prolia® prevents
RANK ligand from
binding to RANK 3Prolia® inhibits
osteoclast formation
RANK Ligand
RANK
OPG
Prolia®
Differentiated
osteoclast
Activated osteoclast
Osteoclast
precursor
Osteoblasts
1Prolia® binds
to and inhibits
RANK ligand
4Prolia® inhibits
osteoclast function
and survival
Elaborated from Prolia® (denosumab) prescribing information, Amgen. 2012 For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
CMCE/DNB/0011/13
Preparation date: Februrary 2013
Denosumab significantly lowers relative risk of fractures at 36 month Phase 3: The FREEDOM Trial
ARR = absolute risk reduction; RRR = relative risk reduction
Adapted from Cummings SR, et al. N Engl J Med. 2009;361:756-765
RRR = 40%
p = 0.04
RRR = 20%
p = 0.01
RRR = 68%
p < 0.001
ARR = 4.8% ARR = 1.5% ARR = 0.3%
PlaceboDenosumab
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
25
© 2015 Amgen Inc. All rights reserved. Do not copy or distribute.
Ten Years of Denosumab Treatment in Postmenopausal Women With Osteoporosis: Results From the FREEDOM Extension Trial
Placebo Continued DenosumabCross-over Denosumab
Lumbar Spine BMD† Total Hip BMD†
Adapted from Bone HS, et al. 2015; J Bone Miner Res; 30(Suppl 1):S471;LB1157 (Late breaking)
BMD: bone mineral density†Compared with FREEDOM baseline, extension baseline, and previous measurement. All values all P < 0.0001.
FREEDOM Extension
Study
FREEDOM Extension
Study
21.6%
16.3% 7.3%
9.1%
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Mortality after hip fracture
JBMR, 2018
1 year
JBMR, 2018
3 years
5 years
10 years
Month
0
2
4
6
8
10
12
14
16
18 Hazard Ratio, 0.72 (95% CI, 0.56–0.93)P = .0117
Cu
mu
lati
ve I
ncid
en
ce (
%)
0 4 8 12 16 20 24 28 32 36
ZOL 5 mg (n = 1065)
Placebo (n = 1062)
28%
Absolute Risk Reduction, 3.7%
Lyles KW, et al. N Engl J Med. 2007; 357: 1-11
Zoledronic Acid 5 mg: Reduced Risk of All-Cause Mortality
Saag KG, et al. N Engl J Med. 2017.For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
COMPARISONS (3)
An imbalance in adjudicatedserious cardiovascularadverse events was observedduring the double-blindperiod, with 2.5% pt in theromosozumab group vs. 1.9%pt in the alendronate groupreporting these events (oddsratio, 1.31; 95% CI, 0.85 to2.00).A total of 0.8% pt in theromosozumab group and0.3% pt in thealendronate groupreported cardiacischemic events (oddsratio, 2.65; 95% CI, 1.03to 6.77)
McClung MR et al N Engl J Med. 2014
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Romozsozumab Reduces Fracture Risk
Cosman F et al N Engl J Med. 2016
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Why an anabolic treatment?
Bone Remodeling
Anti-resorptive Agents Improve Bone Strength by
Stabilize or increase BMD
Maintain trabecular architecture
Increase mineralization density of bone matrix
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
What the antiresorptivesdon’t do…
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
HisGluSer
Gly
Human Parathyroid Hormone
1 10
20
30
Ser Val Ile Gln Leu Met Asn
Leu
LysHisLeuAsnSerMetGluArgValGlu
Trp
LeuArg Lys Lys Leu Gln Asp Val His Asn Phe
-COOH
H2N
Gly Teriparatide
Inta
ct
PT
H (
1-8
4)
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Effect of Teriparatide on Incidence of Vertebral
and Non-Vertebral Fractures in
Postmenopausal Women with Osteoporosis
Neer RM, et al. N Engl J Med. 2001;344:1434-41
0
2
4
6
8
10
12
14
16
18
20
Non-vertebral fractures
Pa
tie
nts
(%
) w
ith
fra
ctu
re
P< 0.01
53%
20 g PTH
0
2
4
6
8
10
12
14
16
18
20
New vertebral fracture
Pa
tie
nts
(%
) w
ith
fr
ac
ture
P< 0.01
65%
20 g PTH PlaceboPlacebo
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
3.1% (18/574)
5.4%(28/516)
6.0%(35/585)
12.0%(64/533)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
12 months 24 months
Teriparatide RisedronateP
ati
en
ts w
ith
Ne
w V
ert
eb
ral F
rac
ture
s (
%)
Relative risk: 0.44
(95% CI: 0.29, 0.68)
p<0.0001
Relative risk: 0.52
(95% CI: 0.30, 0.91)
p=0.019
Results: New Vertebral Fractures: 12 and 24 months
Incidence of New Vertebral Fractures
46
CI = confidence
interval.Modified from
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Risedronate
Teriparatide
No. at RiskTeriparatide 680 623 589 561 508Risedronate 680 616 584 553 502
Cu
mu
lati
ve In
cid
en
ce (
%)
Time (Months)
CI = confidence interval.
* Clinical vertebral and non-vertebral fragility fractures: clavicle, scapula, ribs, sternum, sacrum, coccyx, humerus, radius, ulna, carpus, pelvis, hip, femur, patella,
tibia, fibula, ankle, calcaneus, tarsus, or metatarsus.
Cumulative Incidence of Pooled Clinical Fractures*: Kaplan-Meier Estimates
47
Hazard ratio: 0.48
(95% CI: 0.32 to
0.74)
p=0.0009
Cumulative Incidence of Pooled Clinical
Fractures
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Risedronate
Teriparatide
No. at RiskTeriparatide 680 626 596 571 520Risedronate 680 624 598 576 525
Cu
mu
lati
ve In
cid
en
ce (
%)
Time (Months)
Cumulative Incidence of Non-Vertebral Major Fragility Fractures*: Kaplan-Meier
Estimates
CI = confidence interval.
*Fracture of hip, radius, humerus, ribs, pelvis, tibia, or femur.
48
Hazard ratio: 0.58
(95% CI: 0.32,
1.05)
p=0.062
Non-Vertebral Major Fragility Fractures
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
0.4% (2/516)
2.3%(12/533)
0
1
2
3
24 months
Teriparatide Risedronate
Pa
tie
nts
wit
h N
ew
Mu
ltip
le
(2 o
r M
ore
)
Vert
eb
ral F
ractu
res (
%)
Relative risk: 0.16
(95% CI: 0.04,
0.74)
p=0.007
Incidence of New Multiple (2 or More)
Vertebral Fractures
Incidence of New Multiple (2 or More) Vertebral
Fractures
49
CI = confidence
interval. Modified from
For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
Fracture prevention: vertebral fractures
VERO: Teriparatide vs Risedronate in Severe Osteoporosis
n, number of patients.
Data labels show rates and statistical significance of differences between periods.
*p<0.05 and **p<0.005 versus the 0 to 6 months reference period; #p<0.05 as shown.
0,88
0,49 0,46
0,13
0,0
0,2
0,4
0,6
0,8
1,0
88280–6
7308>6–12
6465>12–18
5037>18
Fra
ctu
re r
ate
pe
r 1
00
pa
tie
nt-
yea
rs
No. at risk:
Months
*
n=1
7
n=
14n=
3
**
#
n=35
Silverman S, et al. Calcif Tissue Int. 2018. DOI:10.1007/s00223-018-0485-2
Hip Fracture Rates by 6-Month Treatment Period
−48% −85%
Hip Fracture Outcomes
Díez-Pérez A. et al. Bone (2019);120:1-8
0.44 (0.22, 0.87) 10/3118
24/3875 100.00
*p = 0.019
Per quanto tempo trattare?
Combination treatment
Lancet, 9/2015For Internal Training Purposes Only - Not for External Use
IT/RMZ/1809/0016
THANK YOU!SUPPORT YOUR BONES.THEY SUPPORT YOU.
Nicola Napoli, MD, PhD
Associate Professor
Division of Endocrinology and Diabetes -Campus Bio-Medico University of Rome
Division of Bone and Mineral Diseases -Washington University in St Louis
Ph. +39 06 225419151
n.napoli@unicampus.it
nnapoli@wustl.edu
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