Osteoporosbehandling idag och imorgonÖsten Ljunggren

Uppsala Osteoporosis Research UnitDepartment of EndocrinologyUppsala University HospitalSweden

Målet är att förebygga frakturer

Fall är den vanligaste orsaken till fraktur hos patienter med osteoporos

MuskelstyrkaFallprevention

Osteoporos är en stark och behandlingsbar riskfaktor

Severe Osteoporosis

Boyde A, London Male, age 89 years

Hämma nerbrytning

Stimulera formation

Osteoporosbehandling i dag

*Benuppbyggande TeriparatidePTH 1-84

*Resorptionsbromsande AlendronateRisedronateDidronateZoledronateIbandronateSERMSr-ranelate

* Kalcium och vitamin D

Högriskpopulation

BMDTidigare frakturKortison

Antiresorptiv behandling dominerande

Estrogen / SERM

Bisphosphonates

Strontium

(Denosumab)

Snabb effekt pga “filling in of remodelling”?

Osteoclast inhibition

Rapid filling in of remodeling

Less ”weak spots” in trabeculi

50% reduction in vertebral fractures within 6-12 months

Bisphosphonates

March 31, 2006, analysis report 9

Cumulative Risk of Clinical Vertebral Fracture (Strata I & II)

Relative risk reduction (95% confidence interval) vs placeboBlack DM, et al. Presented at: ASBMR 28th Annual Meeting; September 15-19, 2006; Philadelphia, Pa. Abstract 1054

Time to First Clinical Vertebral Fracture (months)

1

2

3

00 3 6 9 12 15 18 21 24 27 30 33 36

Placebo (n = 3861) ZOL 5 mg (n = 3875)

Cum

ulat

ive

Inci

denc

e (%

)

75%(60%, 85%)

P < .0001

Excess RANK Ligand Can Increase Bone Resorption Leading to Osteoporosis

Bone Formation

Bone Resorption

Activated Osteoclast

CFU-GM PrefusionOsteoclast

MultinucleatedOsteoclast

Osteoblasts

RANKL

RANK

OPG

Decreased Estrogen Leads to Increased RANK Ligand

Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.© 2009 Amgen. All rights reserved. Do not copy or distribute.

Denosumab Is the First Fully Human Monoclonal Antibody Targeting RANK Ligand in Clinical

Development

Fc-OPG OPG-Fc RANK-Fc Denosumab

Present1997

Fully human monoclonal

antibodyFusion proteins

OPG = osteoprotegerin.Simonet WS, et al. Cell. 1997;89:309-319. Data on file, Amgen.

Fc OPGRANK

The Effect of Denosumab on Fracture Risks at 36 Months

Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65

7,2%

8,0%

1,2%

6,5%

0,7%

2,3%

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

New Vertebral Nonvertebral Hip

Inci

denc

e at

Mon

th 3

6 (%

)

PlaceboDenosumab

40%P = 0.04

20%P = 0.0168%

P < 0.001

Antiresorptiv behandling

Alendronate (FIT)

Once Weekly

Denosumab

Injektions bisfofonater

As good as it gets?

EffektCompliance

Frakturreduktion vid optimal antiresorptiv behandling

50-70%?

20-40%?

20%?

För att bli bättre?

Fallprevention?(sarkopeni)

Långtidsanabol behandling?

ECTSIs there a need for more osteoporosis treatment?

1. Yes, still we can not cure our patients! We need better drugs to e.g reduce hip fracture rate.

2. No, we have enough of therapeutic options by now. Let us use them and spend our money on other diseases

Is there a need for better treatment?Totalantalet frakturer I samhället?

Enskilda patienten?

Is there a need for better treatment?Totalantalet frakturer I samhället?

71 årKotkompressionT score -2.8

Bisfosfonat i 6 år

Is there a need for better treatment?Totalantalet frakturer I samhället?

71 årKotkompressionT score -2.8

Bisfosfonat i 6 år

Därefter?

Ljunggrens spåkula

Osteoporosbehandling framgent

• Längre tids behandling?

• Kombinationsbehanlding / sekventiell?

• Anabol behandling överlägsen?

“treat to target”? Dvs bota osteoporos

Osteoporosbehandling framgent

• Längre tids behandling?

• Kombinationsbehanlding / sekventiell?

Raloxifen?

Sr-Ranelat?

Osteoporosbehandling framgent

• Längre tids behandling?

• Kombinationsbehanlding / sekventiell?

Raloxifen?

Sr-Ranelat?

Katepsin K hämmare

• Cathepsin K is a cysteine protease expressed exclusively by osteoclasts

• Cathepsin K is responsible for degradation of collagen

• ODANACATIB is a selective and reversible inhibitor of cathepsin K

• ODANACATIB has in preclinical studies been demonstrated to rapidly decrease bone resorption

Odanacatib: Cathepsin K inhibitor

Odanacatib in postmenopausal osteoporosis

Bone et al. JBMR ePub 2010

• 399 postmenopausal women• 55 - 85 years old• osteoporosis

• T-score < -2 at spine or hip• No fragility fractures

• Treatment for 2 years • Odanacatib 3, 10, 25 or 50

mg weekly• placebo• 500 mg calcium daily +

5600 IU vitamin D weekly

Odanacatib in postmenopausal osteoporosis

• 399 postmenopausal women• 55 - 85 years old• osteoporosis

• T-score < -2 at spine or hip• No fragility fractures

• Treatment for 2 years • Odanacatib 3, 10, 25 or 50

mg weekly• placebo• 500 mg calcium daily +

5600 IU vitamin D weekly

Bone, et al. JBMR ePub 2010

Osteoporosbehandling framgent

• Anabol behandling överlägsen?

“treat to target”? Dvs bota osteoporos?

Bone forming treatment

Fluoride

Growth Hormone

Teriparatide

Sclerostin interference?

Teriparatide or Alendronatein Glucocorticoid-induced

Osteoporosis*Kenneth G. Saag1, Elizabeth Shane2, Steven Boonen3,Fernando Marin4, David W Donley4, Kathleen A. Taylor4,

Gail P. Dalsky4, Robert Marcus4

1University of Alabama at Birmingham, Birmingham, AL2Columbia University, New York, NY

3Katholieke Universiteit-Leuven, Leuven, Belgium4Lilly Research Laboratories, Indianapolis IN

Saag KG et al. N Eng J Med. (2007); 357:2028-39*ClinicalTrials.gov number NCT00051558

ObjectivesPrimary• Compare effects of teriparatide versus alendronate

on lumbar spine bone mineral density (BMD) after 18 months of treatment in patients with glucocorticoid-induced osteoporosis

Secondary• Compare effects of teriparatide versus alendronate:

– Total hip and femoral neck BMD– Time course of BMD response– Markers of bone turnover– Vertebral and nonvertebral fractures– Adverse events

Saag KG et al. N Eng J Med. (2007); 357:2028-39

Methods• Randomized, double-blind, double-dummy, active-

comparator, controlled clinical trial (76 sites)• Men (n=83) and women (n=345) aged > 21 years

– > 5 mg/d prednisone equivalent for > 3 months before screening

– Lumbar spine, total hip or femoral neck T-score ≤ -2.0 or ≤ -1.0 plus > 1 fragility fracture

• Patients randomized to:– Injectable teriparatide 20 µg/d plus oral placebo OR– Oral alendronate 10 mg/d plus injectable placebo

• All patients received 1000 mg/d calcium and vitamin D 800 IU/d

Saag KG et al. N Eng J Med. (2007); 357:2028-39

Baseline CharacteristicsAlendronate

(n=214)Teriparatide

(n=214)Age (years) 57 ± 14 56 ± 13Caucasian 148 (69%) 153 (72%)Women 173 (81%) 172 (80%)Prior bisphosphonate use* 20 (9%) 20 (9%)Prednisone equivalent (mg/d) 7.8 (5.0, 10.0) 7.5 (5.0, 10.0)Duration of GC therapy (years) 1.2 (0.3, 5.7) 1.5 (0.3, 5.2)Lumbar spine T-score -2.6 ± 0.9 -2.5 ± 0.9Total hip T-score -1.9 ± 0.9 -2.0 ± 0.9Number of subjects with prevalent Radiographic vertebral fxs Nonvertebral fxs

53 (25%)89 (42%)

62 (30%)93 (44%)

*Total exposure ≤ 2 months

mean ± SD; n (%), or median (25th and 75th percentiles). No significant between group differencesSaag KG et al. N Eng J Med. 2007

Baseline- underlying glucocorticoid- requiring disorders

Alendronate(n=214)

Teriparatide(n=214)

Rheumatologic Rheumatoid arthritis 111 (52%) 98 (46%) Systemic lupus erythematosus 21 (10%) 28 (13%) Polymyalgia rheumatica 8 (4%) 10 (5%) Vasculitis 3 (1%) 5 (2%) Other rheumatic disorders 18 (8%) 20 (9%)

Respiratory disorders 31 (15%) 29 (14%) Inflammatory bowel disease 4 (2%) 3 (1%) Other conditions

n (%). No significant between group differences

18 (8%) 20 (9%)

Saag KG et al. N Eng J Med. (2007); 357:2028-39

Lumbar Spine BMD

Alendronate N= 195 184 173 159 148 195Teriparatide N= 198 183 178 170 156 198

‡P<0.001 Teriparatide vs. AlendronateSaag KG et al. N Eng J Med. (2007); 357:2028-39

Total Hip BMD

Alendronate N= 176 157 144 176Teriparatide N= 185 167 156 185

*P<0.05; †P<0.01 Teriparatide vs. AlendronateSaag KG et al. N Eng J Med. (2007); 357:2028-39

Number of Patients with New Vertebraland Nonvertebral Fractures

Alendronate Teriparatide P-value

Vertebral radiographic 10/165 (6.1%) 1/171 (0.6%) 0.004

Clinical vertebral 3/165 (1.8%) 0/171 (0%) 0.07

Nonvertebral 8/214 (3.7%) 12/214 (5.6%) 0.362

Nonvertebral fragility 3/214 (1.4%) 5/214 (2.3%) 0.455

Saag KG et al. N Eng J Med. (2007); 357:2028-39

SclerosteosisSclerosteosisHigh Bone Mass Human Genetic DisorderHigh Bone Mass Human Genetic Disorder

SclerosteosisNormal

Increased bone formation

Increased bone mass throughout skeleton

Good quality, fracture resistant bone

Life long bone overgrowth causes clinical problems in the skull(Brunkow et al., 2001; Janssens et al., 2002).

SclerostinSclerostin

Am. J. Hum. Genet.Am. J. Hum. Genet. 2001 2001 Celltech R & D (now UCB)Celltech R & D (now UCB)

Genetic Mapping of Genetic Mapping of Sclerosteosis MutationSclerosteosis Mutation

Discovery of novelDiscovery of novelcystine-knot proteinscystine-knot proteins

Amgen Inc.Amgen Inc.

Genomic Search for Genomic Search for Novel Cystine-knot Novel Cystine-knot

ProteinsProteins

Cystine-knot pattern used for Cystine-knot pattern used for electronic mining of Human electronic mining of Human

Genome DNA SequenceGenome DNA Sequence

ChromosomeChromosome1717

**

Discovery of SclerostinDiscovery of Sclerostin

CxGxC…..1 C 3…..CxC

OA MacDougald et al., JCI, 116(5) 1202 (2006)

Potential MOA for Sclerostin:Potential MOA for Sclerostin:Inhibiting Wnt Signaling and Bone FormationInhibiting Wnt Signaling and Bone Formation

Sclerostin is thought to Sclerostin is thought to bind to the Wnt co-bind to the Wnt co-receptor, LRP5, and receptor, LRP5, and block Wnt signaling thus block Wnt signaling thus inhibiting bone inhibiting bone formation.formation.

Median Images based on Bone Volume Fraction. (18 μm resolution)

70% ofVertebral

BodyHeight

SHAM OVX Scl-mAb0

10

20

30

40

50

**^

Bone

Vol

ume

Frac

tion

(%)

Mean ± SE; *p<0.01 vs. OVX, ^p < 0.01 vs. Sham

Rats treated for 5 wks, 13 months after OVX

SHAM OVX + VEH Scl-mAb0.00

0.05

0.10

0.15

0.20

0.25 *^*

Cor

tical

Thi

ckne

ss (m

m)

Scl-mAb

SHAM

OVX

Sclerostin Antibody Increases Trabecular Bone Sclerostin Antibody Increases Trabecular Bone Volume and Cortical Thickness in Lumbar VertebraVolume and Cortical Thickness in Lumbar Vertebra

SHAM OVX Scl-mAb0

50

100

150

200

250

300

350

*^

*

Max

imum

Loa

d (N

)

2 4 6 8 100

100

200

300

400

500R2=0.67

TOTAL BONE AREA (mm2)

MAX

IMU

M L

OAD

(N)

Sclerostin Antibody Treatment Increased Bone Strength Sclerostin Antibody Treatment Increased Bone Strength of Lumbar Vertebral Body in OVX Ratsof Lumbar Vertebral Body in OVX Rats

Mean ± SE; *p<0.01 vs. OVX, ^p < 0.01 vs. Sham

Dose-related Increases in BSAP and Decreases in Dose-related Increases in BSAP and Decreases in CTX1 Following Single-dose SC Administration of Scl-CTX1 Following Single-dose SC Administration of Scl-

Ab to Healthy Postmenopausal WomenAb to Healthy Postmenopausal Women

BSAP

% C

hang

e Fr

om B

asel

ine

(Mea

n ±

SE

M)

Time (day)0 7 14 21 28 35 42 49 56 63 70 77 84

–50

0

50

100

150

–50

–25

0

25

50

Time (day)0 7 14 21 28 35 42 49 56 63 70 77 84

% C

hang

e Fr

om B

asel

ine

(Mea

n ±

SEM

)

Serum CTX

0.3 mg/kg (N = 6)1.0 mg/kg (N = 6)

Placebo (N = 11)5 mg/kg (N = 6)3 mg/kg (N = 6) 10 mg/kg (N = 6)

0.1 mg/kg (N = 6)

Padhi, et al. ASBMR. 2007.

Total HipSpine

Mea

n %

Cha

nge

From

Bas

elin

e

Mea

n %

Cha

nge

From

Bas

elin

eTime (day)

28 56 84

Time (day)28 56 84

7

Single Doses of Sclerostin Antibody Resulted in an Single Doses of Sclerostin Antibody Resulted in an Increase in BMD in Healthy Postmenopausal WomenIncrease in BMD in Healthy Postmenopausal Women

1.0 mg/kg (N = 6)3.0 mg/kg (N = 6)Placebo (N = 7) 10.0 mg/kg (N = 6)5.0 mg/kg (N = 6)

7

–3

0

3

6

–2

–1

1

2

4

5

–3

0

3

6

–2

–1

1

2

4

5

Padhi, et al. ASBMR. 2007.

Anabolic treatment of osteoporosis

PTH

LRP5WNT

RUNX/Osterix

Sclerostin(Mechanical sensing)

?

Teriparatide

Sclerostin mAb

”Treat to target?”

Osteoporosbehandling

i dagPTH 1-34PTH 1-84

AlendronateRisedronateDidronateZoledronateIbandronateRaloxifenSr-ranelate

Osteoporosbehandling

i dag i morgonPTH 1-34PTH 1-84

Alendronate DenusomabRisedronateDidronateZoledronateIbandronateRaloxifenSr-ranelate

Osteoporosbehandling

i dag i morgon övermorgonPTH 1-34PTH 1-84

Alendronate DenusomabRisedronate Kathepsin K inhibDidronate ev. Nya SERMZoledronateIbandronateRaloxifenSr-ranelate

Osteoporosbehandling

i dag i morgon övermorgon Till sist PTH 1-34 Sclerostin inhPTH 1-84

Alendronate DenusomabRisedronate Kathepsin K inhibDidronate ev. Nya SERMZoledronateIbandronateRaloxifenSr-ranelate

Is there a need for better treatment?Totalantalet frakturer I samhället?

71 årKotkompressionT score -2.8

Bisfosfonat i 6 år

Därefter?

Burden of Disease

Bone Cell Biology-RANK/RANKL-Sclerostin (LRP5-Wnt)

Treatment optionsAntiresorptiveAnabolic

Health Economy

Fracture Prediction

OsteoporosI kliniken