ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME? ASBMR 2008 Friday, September 12 th, 2008.

ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME?

• ASBMR 2008• Friday, September 12th, 2008

Learning Objectives

After attending this symposium, participants will be able to: • Explain the heterogeneity of bone fragility in terms of pathogenesis

and structural properties and recognize its impact on fracture risk.

• Distinguish between the mechanisms of action of strontium ranelate, anti-resorptives, and PTH in increasing bone strength.

• Critically assess the antifracture efficacy of strontium ranelate.

• Describe the techniques for monitoring strontium ranelate therapy and their appropriate clinical application.

MECHANISMS OF STRONTIUM RANELATE AND OTHER ANTIFRACTURE AGENTS IN INCREASING BONE STRENGTH

David Goltzman, MD, FRCPC

Professor of Medicine and Director of the McGill Centre for Bone and Periodontal Research, McGill University, Montréal, Québec, Canada

Strontium Ranelate and Fractures

• Reduction in vertebral fracture risk as early as the firstyear and over time

• Reduction in hip fracture in high risk patients

• Antifracture efficacy in elderly patients and in patientswith osteopenia

Contributions to Bone Strength

Quantity of bone

Quality of bone • Structural Properties

– Size and shape of bone– Trabecular connectivity – Trabecular orientation

• Material properties – Content and quality of mineral and matrix (primarily collagen)

• Overall condition (microdamage, etc.)

Determinants of Fracture Risk

Bone Remodelling Cycle

Quiescence

Lining cells

OsteoclasticActivation

Osteoblast activation

OsteoblasticNew Bone Formation

Initiation

Osteoclastic BoneResorption

Bone Remodelling

OBOCL

Resorption Formation

Anti-Resorptives

Bone

Anabolics

HCl

Proteases

Relative Risk of New Vertebral Fractures

Adapted from Delmas et al., Lancet 2002, 359:2018–26.

ANTI-RESORPTIVES

Anti-resorptives Inhibit Resorption and Allow Filling of Cavity

OBOCL


Anti-Resorptives

Bone

HCl

Proteases

Local and systemic regulators of bone formation

Inhibited Continues

Anti-resorptives Also Reduce Bone Formation

OBOCL


Anti-Resorptives

Bone

HCl

Proteases

Local and systemic regulators of bone formation

Ephrin/Eph

IGFs, IGFBPs TGF-β,BMPs,

FGFs

Adaptedf from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.

Changes in Biochemical Markers Expressed as Mean Percentage Change from Baseline {+/-} se at 6, 12, and 24 Months (pp approach)

0 3 6 12 -60

-50

-40

-30

-20

-10

0

NTX

BSAP

Time(Months)

Me

an

Ch

an

ge

(%)

Temporal Difference in Reduction of Resorption and Formation Markers

Mean Percentage Changes in BMD from Baseline

Adapted from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.

Bisphosphonates

SERMs

Calcitonin

Boneresorption

Boneformation

Mechanism of Osteoporotic Fracture Reduction by Anti-resorptives

(Filling plushypermineralization)

Antiresorptive Therapy

Reduce Bone Turnover

Decrease Fracture Risk

Stabilize or ImproveMicroarchitecture

Increase BMD

What Anti-resorptives Will Not Do

• Normalize BMD• Restore trabecular architecture

ANABOLICS

Parathyroid Hormone

1 10

20

30

Ser Val Ser Glu Ile Gln Leu Met His AsnLeu

GlyLysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

50

40

6070

80

-COOH

H2N-

Osteoblast

BONE

Osteoclast

Anabolics Initiate New Bone Formation

Osteoblastic stromal

cell

New Bone

PTH

Osteoblast

Osteoclast Progenitor

BONE

PTH

RankLOPG

Osteoclast

Osteoblastic stromal

cell

Resorption is Also Stimulated by PTH

nn

nn

nn

nn

0 1 2 3 4 5 60

10

20

30

40

50

60

70

80M

ea

n %

ch

ang

e in

turn

ove

r m

ark

er

Time (months)

N-telopeptide

Osteocalcin

Adapted from Lindsay et al. Lancet 1997.

Early Changes in Biochemical Markers in Women with Osteoporosis on hPTH(1-34)

n=17

AnabolicWindow

Effect of PTH(1-34) on Lumbar Spine BMD in Postmenopausal Women with Osteoporosis

*P<0.001

Months

% c

han

ge

± S

E

0

2

4

6

8

10

12

14

16

0 6 12 243

**

*

* *

*

End

18

*

*

Placebo PTH(1-34), 20 PTH(1-34), 40

*

Adapted from Neer RM et al. N Engl J Med 2001.

*

Bisphosphonates

SERMs

Calcitonins

PTH

Boneresorption

Boneformation

Strontium Ranelate

Sr++

S N

CN

Sr++

CH 2

H 2C CO -O

COO

OC- O

OC- O

H 2C -

5-[bis (carboxymethyl) amino]-2-carboxy-4-cyano-3-thiopheneacetic acid, distrontium salt

Ranelic acid (organic moiety) + 2 stable strontium atoms

STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VITRO EFFECTS ON BONE TURNOVER

STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VIVO EFFECTS ON BONE TURNOVER

STRONTIUM RANELATE:HUMAN STUDIES

Strontium Ranelate Decreases Osteoclast Differentiation

Adapted from Bonnelye et al. Bone 2008;42:129-38.

Mouse spleen-derived cells (+RANKL & M-CSF)

Strontium Ranelate Decreases Osteoclast Lifespan (induces apoptosis)

OC lifespan

70

80

90

100

Control 6 9 12 24

SR (mM Sr2+)

* **

***

% of living cells

mean + SEM; n=6-12* P<0.05, **P<0.01, *** P<0.001 vs. Control

Adapted from Mentaverri et al. Bone 2005;36(S2):S403.

Strontium Ranelate Inhibits Bone Resorption in vitro

Adapted from Baron et al. Eur J Pharmacol. 2002;450:11-17.

Sr2+

Pit

Are

a In

dex

(% o

f co

ntr

ol)

(mM)

Rat osteoclasts

Strontium Ranelate Increases Osteoprotegerin While Decreasing RANKL in Primary Human Osteoblasts

Mean +/- sem** P<0.01, *** P<0.001 vs. Control

1Control 0.01 0.1

*****

Sr (mM Sr2+)

OPG mRNAas % of control

2

***

RANKL mRNAas % of control

**

******

***

1Control 0.01 0.1

SR (mM Sr2+)

2

RANKLOsteoprotegerin

Adapted from Brennan et al. J Bone Min Res 2006;21(S1):S301.

SR Actions in Bone

Bone

Ca

OBOCL

↓Resorption ↑Formation

Mean + SEM, n = 6-10* P<0.05, ** P<0.01Adapted from Mentaverri et al. Bone 2005;36(S2):S403.

*

*

0

10

20

30

40

50

60

Control10 15 20 25

% of Apoptotic Cells

Control10 15 20 25

Plasmid control Dominant Negative CaSR

***

**

SR (mM Sr2+)

Strontium Ranelate Induces Apoptosis in Rabbit Primary Osteoclasts and this is Decreased with DN-CaSR Transfection

Strontium Ranelate: Anti-resorptive Effects

OsteocytesOsteoclasts

MacrophagesOsteoblasts Bone-lining cells

+ OPG RANKL

-

Brennan ASBMR 2006Chattopadhyay Biochem pharmaco 2007

Sr++ = Differentiation

Wattel Osteoporos Int. 2005

Bonnelye Bone 2008

Sr++ = ActivitySr++ = Apoptosis

Sr++ = CaR agonist

Mentaverri Calc Tissue Int. 2004

Mentaverri Bone 2005

Sr++

SR Increases Replication of Pre-osteoblasts

Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.

Tissue Culture

(10 M-3, 48 h)Control

Rat Calvariae Cells

3H

-Thy

mid

ine

labe

led

cells

(%

)

**66

44

22

00

Osteoblasts

Pre-osteoblasts

10-5 10-3Controls

Strontium ranelate (M))* P < 0.05 vs Control

Strontium Ranelate Increases Osteoblast Survival

SR (mM Sr2+)

1Control 0.01 0.1 2

**

***

Cell number as a ratio of control

* P<0.05, ** P<0.01 vs. ControlAdapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.

Primary Human Osteoblasts

Strontium Ranelate Increases Bone Formation Markers in Primary Human Osteoblasts

** P<0.01 vs. Control

Alkaline phosphatase activity

SR (mM Sr2+)

1Control 0.01 0.1 2

**

ALP activity as % of vehicle(corrected per mg total protein)

**

Adapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.

Strontium Ranelate Increases Collagen Synthesis by Preosteoblasts and Osteoblasts

Adapted from Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.

ControlControl

BoneBone

1010-3-3 M, 48 h M, 48 h

Tissue CultureTissue Culture

**

**

**

ControlsControls 1010-4-4 1010-3-31010-5-5

2525

1515

1010

00

3030

2020

55

Osteoblasts Osteoblasts

Pre-osteoblastsPre-osteoblasts

Col

lage

n S

ynth

esis

Col

lage

n S

ynth

esis

(10(1

0-3-3 d

pm/

dpm

/ wwee l

l)ll)

* P<0.05 vs Controls

Strontium ranelate (M)

Rat Calvariae CellsRat Calvariae Cells

Strontium Ranelate Increases Mineralization and Number of Nodules in Murine Osteoblasts

Adapted from Choudhary S et al. J Bone Miner Res. 2007 Jul;22(7):1002-10.

MineralizationMineralizationNumber of nodulesNumber of nodules

Control 0.1 1

SR (mM Sr2+)

0.3

***

***

***

mean ± SD, n=3, *** P<0.001

Vehicle

SR 1 mMSR 1 mM

SR 3 mMSR 3 mM

Adapted from Bonnelye et al. J Bone Miner Res 2006;21(S1):S426.

SR Actions in Bone

Bone

Ca

OBOCL

↓Resorption ↑Formation

Mean + SEM, n=6*** P<0.001 vs ControlAdapted from Adapted from Chattopadhyay et al. Biochem pharmacol 2007;74:438-47.

SR-induced Proliferation is Decreased inDN-CASR Transfected Rat Primary Osteoblasts

Strontium ranelateStrontium ranelate

CaSR-/-

osteoblasts

REPLICATION

?CaSR

• CaSR is not essential for strontium ranelate-induced osteoblast replication.

• Strontium ranelate may induce osteoblast replication through another receptorin addition to CaSR.

CaSR is Not the Only Receptor Involved in Strontium Ranelate-induced Osteoblast Replication

Strontium ranelateStrontium ranelate

CaSR+/+

osteoblasts

REPLICATION

?CaSR

Strontium Ranelate Bone Formation Effects

Osteocyte Osteoclast

Macrophage

Osteoblast Bone-lining cell

Sr++ = COX-2

PGE2

Choudhary JBMR 2007

Proliferation / Differentiation

Sr++ = CaR agonist

Chattopadhyay Biochem pharmacol 2007

Bonnelye Bone 2008

Activity

Replication

Pre-osteoblast

Osteoclasts

Activity

Matrix

Synthesis

Differentiation

Osteoblastic

Differentiation

Adapted from Marie P. Curr Op Rheum 2006.Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation.

Apoptosis

Osteoblasts

OPG

RANKL

CaSR

RANK

BoneFormation

Bone Resorption

SR

SR

Proximal Tibia Histomorphometry

Control Strontium ranelate 900 mg/kg/d

Adapted from Ammann et al. JBMR 2004.19:2012-20.

38 ± 2 ***BV/TV (%) 27 ± 2

84 ± 5 **Tb.Th (µm) 74 ± 5

4.6 ± 0.1***Tb.N 3.5 ± 0.1

135 ± 5 ***Tb.Sp (µm) 216 ± 13

Treatment of Female Rats for 2 years

Compression testMaximal Load (N)

0

100

200

300

400

Strontium ranelate (mg/kg/d)

0 900

**+ 20 %+ 20 %

3-point bending test Maximal Load (N)

SR Increases Strength of Vertebrae and Long Bones of Intact Rats (2 years of treatment)

200Strontium ranelate (mg/kg/d)

0

50

100

150

0 225 450

*

900

+ 15 %+ 15 %

Mid-Shaft Femur

L4 Vertebra

Adapted from Ammann P. et al. JBMR 2004.19:2012-20.

Distribution of Strontium (SR), in Monkey ILIAC Cancellous Bone Visualized by Secondary Electron Imaging (SEI)

Sr Sr

After treatment with SR(1250 mg/kg/day) for 52 weeks (A) and after 10 weeks of treatment withdrawal (B)

More Sr depositedin new bonethan old bone

More Sr released from new bone than old bone

A B

Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.

Strontium Ranelate Preserves the Degree of Mineralization of Bone

% o

f th

e N

um

ber

of

Mea

sure

men

ts 0 mg/kg/d

200 mg/kg/d

500 mg/kg/d

1250 mg/kg/d

Degree of Mineralization of Bone (g/cm3)

Monkeys, 1-year treatment

Micro radiography - Iliac crest

Young

Old

Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.

Femoral BMD in Strontium Ranelate-treated Female Rats Correlated with Bone Strength

Adapted from Ammann P et al. Bone 2001;28(suppl 5) P537S.

Correlation BMD-Strength

Mean ± SEM, n=28-30, * P<0.05 vs. Control

Adult female rats - 2-year treatment

BMD (g/cm2)

Ult

imat

e S

tren

gth

(N

)

R=0.739

Pre Clinical Studies Conclusions:

Strontium ranelate

•Increases bone formation and decreases bone resorption resutling in an increase in bone

•Improves bone microarchitecture leading to an increase in bone quality

• As a consequence, improves bone strength

Strontium Ranelate Simultaneously Increases Bone Formation Markers and Decreases Bone Resorption Markers

Increased b-ALP and decreased s-CTX

E= Estimate of difference between strontium ranelate group and placebo group

- co-variance analysis, baseline adjusted ***P < 0.001** P < 0.01*P < 0.05

E

SOTI study

- 600

- 300

0

0.4

0.8

1.2

M0 M3 M6 M12 M24 M36

*** ****** * **

**

*** **

S-CTX( pmol/L)

-

-

Months*** ***

*** * **

***

**

*** **

bALP (ng/mL)

- pmol/L)

Adapted from Meunier PJ et al., NEJM 2004 ;350;5:459-68.

b-ALP: bone-specific alkaline phosphataseS-CTX: serum C-telopeptide cross-links

Placebo Strontium ranelate0

5

10

15

20

25

30BV/TV (%)

3D Trabecular and Cortical Microstructure (3 Years of Treatment in Post Menopausal Osteoporotic Patients)

placebo n=21, strontium ranelate n=20

+13%

Bone volume/ Tissue volume

Adapted from Arlot ME et al. JBMR 2008;23:215-22.

Placebo Strontium ranelate0.0

0.5

1.0

1.5

2.0Tb.N p(n/mm)

Trabecular Number

+14% P=0.05


250

500

750

1000

1250

1500Tb.Sp p(µm)

Trabecular separation

-16% P=0.041


250

500

750

1000

1250

1500Ct.Th(µm)

Cortical thickness

+18%, P=0.008

**** **

Placebo 36 Mo

SR 36 Mo

Biopsy Biopsy

Protocol :

10 women treated by bisphosphonates for 32 months followed by strontium ranelate for 12 monthsMean Age 65 yearsPaired iliac crest biopsies performed at M0 and M12Histomorphometric analysis

M0 M12

PAIRED BIOPSIES

PAIRED BIOPSIES

Adapted from Busse et al., 2007 Abstract ASBMR-W477.

BP (32 months)

Strontium Ranelate

Strontium Ranelate Induces New Bone Formation in HumansStrontium Ranelate Induces New Bone Formation in Humans

Strontium Ranelate Improves Trabecular Bone Micro-architecture

Adapted from Busse et al., 2007 Abstract ASBMR-W477.

0

2

4

6

8

10

12

Inclusion after 12 months of Strontium

ranelate treatment

11,12

8,53

%

+30% +30% **

*P 0,05

Trabecular ThicknessTb Th : +10%* (P<0.05)

Trabecular InterconnectionTb Pf : -49%* (P<0.05)

Trabecular Bone Volume

Comparative action of strontium ranelate and other agents on bone metabolism

Bisphosphonates

SERMs

Calcitonin

Strontium ranelate

Teriparatide

Boneresorption

Boneformation

Conclusions

• Strontium Ranelate reduces fractures by increasing bone strength

• The mode of action on bone turnover and in increasing bone strength appears to be unique among anti-fracture compounds

Review of Antifracture Efficacy of Strontium Ranelate: Reducing Fracture Risk Across the Menopause Continuum

• Cyrus Cooper DM, FRCP, FMedSci• Professor of Rheumatology and Director, MRC

Epidemiology Resource Centre, University of Southampton

and

• Norman Collisson Chair of Musculoskeletal Sciences, University of Oxford, United Kingdom

Osteoporosis: Three Millennia

0 1000 AD 2000 AD1000 BC

400 BCHippocrates

of Kos

700 ADSaxon

tomb, Wells

1825 ADSir AstleyCooper

1850 ADOsteoporosis

1950 2000199019801970

1948Albright

1963SPA

1976HRT

1987DXA

1990–07 WHOCalcium/D,BisphosphonatesSERMs, PTH, Sr,RANKL Ab

1940 1960

Adapted from Cooper et al. (2003).

Impact of Osteoporosis-related Fractures in Europe

Hip Spine Wrist

Lifetime risk (%)Women 14 29 13Men 3 14 2

Cases/yr 400,000 810,000 330,000

Hospitalisation (%) 100 2-10 5

Relative survival 0.83 0.82 1.00

Costs: All sites combined ~ 25 billion Euros

Adapted from IOF (2005); Harvey & Cooper (2005).

Osteoporosis Management

• Goal: Prevent or reduce the frequency of vertebral and non-vertebral (especially hip) fractures

• Pharmacological treatment options include bisphosphonates, selective estrogen-receptor modulators, parathyroid hormone, estrogens, and calcitonin– Bisphosphonates remain the standard of care in many

centres throughout the world

Caveats of Fracture Prevention Trials

• Trials of different agents cannot be compared directly

• Within the bisphosphonate class, superiority for prevention of fractures has not been shown for any agent

• Some agents evaluated in clinical trials with insufficient statistical power to examine protection against nonvertebral and hip fracture

• Prevention of vertebral fractures – Good evidence for alendronate, etidronate,

risedronate and zoledronic acid

• Prevention of hip fractures

– Good evidence for alendronate, risedronate – Fair evidence for zolendronic acid

Adapted from MacLean C, et al. Ann Intern Med 2008;148(3):197-213.

Risk Relative to Placebo

Vertebral Hip

Adapted from MacLean C et al. Ann Intern Med 2008;148(3):197-213.

Fracture Risk Reduction with Bisphosphonates in High Risk Patients

Fracture Risk Reduction with Bisphosphonates in Non-high Risk Patients

Risk Relative to Placebo Vertebral Hip

Adapted from MacLean C, et al. Ann Intern Med 2008;148(3):197-213.

European Guidance for Diagnosis and Management of Osteoporosis in Postmenopausal Women

Adapted from Kanis JA, et al. Osteoporos Int 2008;19:399-428.

Antifracture efficacy of the most frequently used treatments for postmenopausal osteoporosis given with calcium and vitamin D

Calcium and Vitamin D supplements throughout the studies.

placebo

strontium ranelate 2g/day

M0 M12 M36M24 M48 M60 (months)

M0 M12 M36M24 M48 M60 (months)

placebo

Mainstatisticalanalysis

SOTISOTI(Vertebral (Vertebral fractures)fractures)N=1649N=1649

TROPOSTROPOS(Peripheral (Peripheral fractures)fractures)N=5091N=5091

FIRST (Run-in)

(2 weeks-6 months)

strontium ranelate 2g/day

Antifracture Efficacy Program of Strontium Ranelate in Postmenopausal Osteoporosis

Efficacy of Strontium Ranelate inReducing Fracture Risk over 5 Years

Adapted from Reginster JY et al. Arthritis Rheum 2008;58(6):1687-95.

20.9%

16.8%

VertebralVertebralfracture riskfracture risk

p=0.032 p<0.00130

0

10

20

RR: -15%

All nonvertebralAll nonvertebralfracture riskfracture risk

0-5 years 0-5 years

n=2183

RR: -24%

RR=0.85; 95% CI [0.73; 0.99] 0.76; 95% CI [0.65; 0.88]

TROPOS

24.9%

20.8%

n=2714

Patients(%)

strontium ranelate

Placebo

RR: 0.57; 95%CI: [0.33;0.97] adjusted cox model

n=1128

0 - 5 years

10.2% RR: -43%

0

5

10

strontium ranelate

Placebo

p=0.036

7.2%

Patients (%)

Patients aged over 74 and 2 T-scores ≤-

2.4

Efficacy of Strontium Ranelate inReducing Fracture Risk over 5 Years

TROPOS

Adapted from Reginster JY, et al. Arthritis Rheum 2008;58(6):1687-95.

HipHip fracture fracture riskrisk

Tolerability Profile of Strontium Ranelate over 5 Years

Post Marketing experience: 16 cases of DRESS among 570 000 patients treated per year.

Phase III program Adverse events

Symptoms(% patients)

placebon=3317

SRn=3352

Dermatitis 2.32.3 2.02.0

Eczema 1.81.8 1.41.4

VTE 4.54.5 3.03.0

Headache 3.33.3 2.72.7

Diarrhoea 7.07.0 5.05.0

Nausea 7.17.1 4.64.6

RR**=0.92 [0.63-1.33]

p=0.646

RR**=1.09 [0.60-2.01]

p=0.773

* Annual incidence for 1000 patient year** relative risk adjusted on age and main risk factors for VTE

versus untreated osteoporotic population

Alendronate

(N=20084)

7.2*

Strontium ranelate(N=2408)

7.0*

No Increase in Incidence of VTE for Strontium Ranelate and Alendronate as Compared to Osteoporotic Population (GPRD)

Efficacy of Strontium Ranelate in Reducing Vertebral Fracture Risk According to the Number of Prevalent Vertebral Fracture(s)

Adapted from Roux C et al. J Bone Miner Res. 2006;21(4):536-42.

14.4%

7.5%

25.2%

14.5%

RR=0.52; CI [0.40-0.67]

0n=2605

1

0.55; CI [0.41-0.74]

n=11100.67; CI [0.55-0.81]

>2n=1365

No. Prev. Vert Fracture(s)

P<0.001

P<0.001

40.3%

29.8%

P<0.001

Over 3 years

Patients(%)

SOTI &TROPOS

0

15

30

45 RR: -48% RR: -45% RR: -33%

strontium ranelatePlacebo

EFFICACY OF STRONTIUM RANELATE IN REDUCING VERTEBRAL FRACTURE RISK IN WOMEN WITH OSTEOPOROSIS (WITH OR WITHOUT A PREVALENT FRACTURE), OSTEOPENIA ALONE OR OSTEOPENIA PLUS A PREVALENT FRACTURE

Seeman E, et al. J Bone Miner Res 2008;23(3):433-438. Meunier PJ, et al. N Eng J Med 2004;350:459-468. Reginster JY, et al. JCE&M 2005;90(5):2816-2822.

Reduction in Vertebral Fracture Risk with Strontium Ranelate According to the Level of Pretreatment Bone Turnover Markers

T1 T2 T30.63CI (0.49 ; 081)

*** P<0.001n=1631

0.68CI (0.54 ; 0.85)*** P<0.001

n=1630

0.53CI (0.42 ; 0.67)*** P<0.001

n=1630

RR=

RR 37%

RR 32%

RR 47%

s-CTX

Over 3 years

strontium ranelate 2g/d

Placebo

Patients(%)

0

5

10

15

20

25

30

SOTI &TROPOS

Nonvertebral and Vertebral Fracture in the Elderly Population (> 80 years old)

SOTI (Spinal Osteoporosis

Therapeutic Intervention)N = 1649

TROPOS(Treatment of Peripheral

Osteoporosis)N = 5091

mean age = 70 (50-96) ≥ 80 years old: n=151 (9%)

mean age = 77 (70-100) ≥ 80 years old:n=1405 (27%)

N = 1556 ≥ 80 years old

Vertebral fracture assessmentN = 896

Nonvertebral fracture assessmentN = 1489

N = 1489 (ITT)

Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.

Baseline Characteristics of the Elderly Population ( 80 years old)

35.1 %37.1 %Proportion (%) of patients with at least one previous nonvertebral fracture

51.4 %46.4 %Proportion (%) of patients with at least one prevalent vertebral fracture

-3.3 (0.7)-3.3 (0.7)Femoral neck BMD T-score

-2.8 (1.7)-2.7 (1.7)Lumbar BMD T-score

35.4 (6.4)35.3 (6.1)Time since menopause (years)

83.5 (2.9)83.5 (3.0)Age (years)

PlaceboStrontium ranelateCharacteristics

N = 739 N = 750


Reduction of Vertebral Fracture Risk with Strontium Ranelate in Elderly Patients (80 years old) Over 3 Years

P = 0.013

RR= 0.68; 95% CI [0.50; 0.92]

N = 895

RR: - 32%


NNT = 14

P = 0.011

RR= 0.69; 95% CI [0.52; 0.92]

N = 1488 RR: - 31%

Adapted from Seeman et al J Bone Miner Res 2006;21:1113–20.

NNT = 18

Reduction of Nonvertebral Fracture Risk with Strontium Ranelate in Elderly Patients(80 Years Old) over 3 Years

Efficacy assessed by comparison of 0-3 years and 5-8 years cumulative

incidence

Extension Study After SOTI and TROPOS

Data on file

Baseline

SOTIStrontium ranelate 2g/day

TROPOSStrontium ranelate 2g/day Extension study

Strontium ranelate 2g/day

2055 included patientswhatever previous

occurrence of fracture

0 4 5 6 7 81 2 3

1420 completers (69%)

Baseline Characteristics in Patients Treated for 8 Years with Strontium Ranelate (n=879)

INCL-M060FromSOTI

n=153

FromTROPOSn=726

Age (years) 72.9 (6.6) 80.5 (4.4)

BMI ( kg/m2) 26.98 (4.36) 25.66 (4.42)

Time since menopause (years)

25.4 (7.9) 32.1 (6.7)

Data on file

Relative Change in BMD Over 8 Years

Data on file * P <0.001

Mean relative change (%)

years

**

** * * * *Lumbar BMD

Mean relative change (%)

years

** * * *

* *Femoral neck BMD

Data on file

Cumulative incidence 0-3 years

14.9%

Vertebral Fracture Incidence Over 8 Years (SOTI+TROPOS)

Cumulative incidence 5-8 years *

13.7%

Fractures incidence (%)Fractures incidence (%)

* First new fractures on the period

Data on file

Cumulative incidence 0-3 years

11.2%

Non Vertebral Fracture Incidence Over 8 Years (TROPOS)

Cumulative incidence 5-8 years *

12%

Fractures incidence (%)Fractures incidence (%)

* First new fractures on the period

RR: - 42%

Strontium Ranelate Reduces the Spine OA Radiological Progression

Percentage of patients with progression of the overall score after 3 years of follow-up among the whole study population

(n=1105)

17.1%

9.9%

RR=0.58 (95% CI (0.42-0.79); P<0.001

Adapted from Bruyère O et al. Ann Rheum Dis 2008; 67:335-39.

0

5

10

15

20

25

30

35

40

45

Strontium ranelate PlaceboPa

tie

nts

wit

h a

n i

mp

rov

em

en

t in

ba

ck

p

ain

aft

er

3 y

ea

rs (

%)

P=0.03

Proportion of patients with improvement in back pain (increase of at least one point on the Likert scale) after a follow-up of 3

years.(only in SOTI patients: n=399)

Adapted from Bruyère et al. Ann Rheum Dis 2008; 67:335-39.

Strontium Ranelate Reduces the Back Pain in Patients with Spine OA

41.8%

31.3%

European Guidance for Diagnosis and Management of Osteoporosis in Postmenopausal Women

Adapted from Kanis JA et al. Osteoporos Int 2008;19:399-428.

Antifracture efficacy of the most frequently used treatments for postmenopausal osteoporosis given with calcium and vitamin D

Conclusions

• Bisphosphonates have been shown to reduce the risk of both vertebral and non-vertebral fractures and remain an integral part of the pharmacological armamentarium for osteoporosis

• Strontium ranelate has demonstrated antifracture efficacy over the long-term and across a wide range of patients

• Overall, current data support the use of strontium ranelate in the management of postmenopausal osteoporosis

Clinical Monitoring of Strontium Ranelate Therapy for Osteoporosis

• David Kendler, MD, FRCPC, CCD• Associate Professor of Medicine (Endocrinology),

University of British Columbia, • Vancouver, British Columbia, Canada

Rationale for Monitoring Osteoporosis Therapy

• Detect non-responders– Use BMD/BTM rather than awaiting fracture endpoints

• Encourage adherence to therapy– Positive results are encouraging to patient and clinician

Relationship Between Vertebral Fracture & Increases in BMD

0 1 2 3 4 5 6 7

Calcitonin1 YesRaloxifene2 YesRaloxifene2 NoRisedronate3 YesRisedronate4 YesAlendronate5 YesAlendronate6 No

0

20

40

60

80

% Increase in BMD

Prevalent Vertebral Fx

% R

edu

ctio

n i

n V

Fx

Ris

k

Adapted from: 1Chesnut CH et al. Am J Med 2000;109:267-76; 2Ettinger B et al. JAMA 1999;282:637-45; & data on file, Eli Lilly and Co; 3Harris ST et al. JAMA 1999;282:1344-52; 4Reginster J-Y et al. Osteoporosis Int 2000;11:83-91; 5Black DM et al. Lancet 1996;348:1535-41; 6Cummings SR et al. JAMA 1998;280:2077-82.

*Not head-to-head comparison; †vs. placebo. Error bars represent 95% confidence intervals.

BMD Change and Fracture Risk

12-Month BMD Change in Treated Patients

2,984 Women, Age 55-81, in FIT with Alendronate

%w

ith

New

Ver

teb

ral F

ract

ure

s at

36-

48 m

on

ths

Adapted from Hochberg MC et al. Arthritis Rheum 1999:42:1246-54.

Placebo Vertebral Fractures = 6.9%

“Losers” “Stable” “Gainers”

Vertebral Fracture Studies 3-Year Data

StudyIncrease in Spine BMD

Reduction in Vertebral Fx

Baseline Spine T-score

Baseline Vertebral Fx

TROPOS 14.7% 39% -2.8 55%

FIT II 8.3% 44% -2.1 0%

FIT I 7.9% 47% -2.5 100%

VERT-MN 7.1% 49% -2.8 100%

VERT-NA 5.4% 41% -2.4 100%

MORE 2.6% 40% -2.6 37%

PROOF 1.2% 36% <-2.0 100%

Adapted from Faulkner KG et al. J Bone Miner Res 2000;15:183-87; Reginster JCEM 2005.

Bone Density Response to Strontium Ranelate Therapy

• Effects of higher atomic number of Sr than Ca

• Effects of increases in bone tissue

Strontium Ranelate Increases Lumbar Spine BMD

Adapted from: Meunier PJ et al. N Engl J Med 2004;350:459-68.Reginster J.Y et al. data on file.

Mean change (%)

- 4

12

16

0

4

8

0 6 12 18 24 30 36

+ 14.4 %

SOTI

**

****

****

**

Relative change from baseline

- 4

0

4

8

12

16

0 6 12 18 24 30 36

Mean change (%)

*

*

*

*

**

+ 14.7 %

TROPOS

* P<0.001, hierarchical step-down procedure

Placebo Strontium ranelate 2 g/day

Months

Femur Mid-shaft BMD in Ovx Rats After 52 Weeks of Strontium Ranelate Preventive Treatment

Adapted from Amman P et al. JBMR 2004;19:2012–20.

Max Load Vs. Measured BMD Max Load Vs. Adj BMD

Raloxifene Logistic Regression CurvesMore Trial Post HOC Analysis

Adapted from Sarkar S et al. JBMR 2002;117:1-10.

Relationship of 3yr FN BMD Changes on Therapy to Vertebral Fracture Risk Reduction

Adapted from Bruyere O et al. J Clin Endocrinol Metab 2007;92:3076-81.

Percent of Fracture Risk Reduction Explained by Change in BMD

• FIT (ALN) 16%• MORE (RLX) 4%• VERT (RIS) 28%• SOTI TROPOS (SR) 75%

Increases in BMD and Antifracture Efficacy

• Individual patient response to the therapy requires knowledge of “Least Significant Change”– ISCD suggests that if not known, assume 5%-7%

• BMD increases on strontium ranelate indicate:– Medication has been ingested– Strontium has been absorbed– Anti-fracture efficacy in keeping with the results from the pivotal

trials will be achieved.

Monitoring Strontium Ranelate Therapy with Bone Turnover Markers

Adapted from Meunier P et al. N Engl J Med 2004;350:459-68.

Resolution of Effect After Discontinuing Therapy

• Preclinical models

• Clinical trials

Bone Strontium in Monkeys 52 Wks on SR Then 10 Wks Off

Adapted from Farlay et al. JBMR 20:9 2005.

New Bone

Old Bone

Change in Spine BMD After Cross-over: SOTI

SWITCH

ITT population

Mean+SEM

-3.4%

SWITCHMean+SEM

Change in Femoral Neck BMD After Cross-over: SOTI

M48 M51 M54 M60

Mean SD

µmoL/L

SOTI: Change in Blood Strontium After Cross-over

Data on file

Change in Bone Markers After Cross-over: SOTI

PLACEBOPLACEBOPLACEBOPLACEBOMean+SEM

b-ALP S-CTX

N=210N=210

PLACEBOPLACEBOPLACEBOPLACEBO

Monitoring Therapy After Strontium Ranelate Discontinuation

• Initial rapid decline in BMD with exchange of easily accessible Sr for Ca– Monkey models show significant mobilization of Sr from bone

within 10 weeks

• Slow mobilization of buried Sr awaiting osteoclastic resorption

• Unknown effects of subsequent therapy, for example bisphosphonates.

DOES MONITORING IMPROVE ADHERENCE TO OSTEOPOROSIS

THERAPIES?

Monitoring Osteoporosis Therapy

• Detect non-responders– Use BMD/BTM rather than awaiting fracture endpoints

• Encourage adherence to therapy– Positive results are encouraging to patient and clinician

ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME? ASBMR 2008 Friday, September 12 th, 2008.

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Transcript of ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME? ASBMR 2008 Friday, September 12 th, 2008.