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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