Nicola Napoli, MD PhD · From the Primer on the Metabolic Bone Diseases and Disorders of ... Purposes Only - Not for External Use IT/RMZ/1809/0016 . Figure 2 Schematic presentation

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


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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


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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


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Kinetic Binding affinity of BPs


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Bisphosphonates Reduce Fracture Risk up to 5 Years

Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012


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


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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%


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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

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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


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Romozsozumab Reduces Fracture Risk

Cosman F et al N Engl J Med. 2016


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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


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What the antiresorptivesdon’t do…


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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)


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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


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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


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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


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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


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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


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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

[email protected]

[email protected]

Documents

Nicola Napoli, MD PhD · From the Primer on the Metabolic Bone Diseases and Disorders of ... Purposes Only - Not for External Use IT/RMZ/1809/0016 . Figure 2 Schematic presentation