Seminar 08-10-2008 - klinische highlights asbmr september 2008 montreal
Verslag ASBMR 2011, San Diego, deel 2
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Transcript of Verslag ASBMR 2011, San Diego, deel 2
Verslag ASBMR 2011, IWO, deel II
(5 October, Utrecht)
Prof Dr Willem F Lems Vrije Universiteit medisch centrum,
afdeling reumatologie, Amsterdam Prof Dr W
illem F Lems
ASBMR 2011
• Posters: 1481; • Plenary Oral Posters: 24;
• Oral abstracts: 264;
• Meet the Professors: 29;
• Working Groups (including Working Group on Reumatic Diseases): 11.
Prof Dr Willem F Lems
ASBMR 2011: Trends and Special Emphasis
• Circulating Biomarkers;
• Vitamin D and Calcium;
• Fracture Liaison Service;
• Outcome research, including mortality;
• Clinical Trial Results, including new drugs;
• Osteoporosis in Men;
• Epidemiology: “fine tuning” of FRAX. Prof Dr W
illem F Lems
ASBMR 2011: Trends and Special Emphasis
• Fracture Repair;
• High Resolution Imaging;
• Musculo-skeletal biology: Frailty
• Diabetes, Fat and Bone
• The Osteocyte. Prof Dr Willem F Lems
The Osteocyte: the Great Communicator
Prof Dr Willem F Lems
Inflammatory Biomarkers and Hip-Fracture Risk, Mr Os (1)
Q1 Q2 Q3 Q4 p voor trend
TNF ref 3.33 2.41 2.60 0.022
CRP ref ns ns ns 0.94
IL-6 ref 1.26 (0.5-3.2)
1.63 (0.7-4.0)
2.22 (0.9-5.6)
0.019
IL-6SR ref ns ns ns 0.95
IL-10 ref 1.24 (0.6-2.8)
0.68 (0.3-1.6)
0.59 (0.2-1.5)
0.026
538 men with fractures and 980 healthy male controls without fractures; average follow-up 6.96 years.
Cauley et al, ASBMR 2011, 1019
Prof Dr Willem F Lems
Inflammatory Biomarkers and Clinical Spine Fracture Risk, Mr Os (2)
Q1 Q2 Q3 Q4 p voor trend
TNF ref ns 2.25 2.33 0.004
CRP ref ns ns ns 0.94
IL-6 ref 1.37 (0.7-2.9)
1.52 (0.7-3.2)
1.94 (0.9-4.1)
0.037
IL-6SR ref ns ns ns 0.60
IL-10 ref 0.5 0.33 0.28 <0.001
538 men with fractures and 980 healthy male controls without fractures; average follow-up 6.96 years.
Cauley et al, ASBMR 2011, 1019
Prof Dr Willem F Lems
High Sensitive CRP and Fracture Risk: Mr Os Sweden
First Tertile (<1.81 mg/l)
Second Tertile (1.81-2.76 mg/l)
Third Tertile (>2.76 mg/l)
Any Fracture ref ns 1.54 (1.25-1.89)
FN- BMD ref ns ns
Fracture, after correction BMD
ref ns 1.45 (1.7-1.79)
Vertebral Fracture ref ns 1.73 (1.20-2.48)
Skrtic, ASBMR 2011: 1021
N=2910 males, mean age 75 years, follow-up 5.4 years; Fracture incidence 23.7/1000 years.
Prof Dr Willem F Lems
Serum OPG and sRANKL Levels and Incident Hip Fracture Levels in the Women s
Health Initiative
Quartile Odds ratio P value for trend
1 <4.0 pmol/l Reference 0.005
2 4.0-5.0 pmol/l 1.40 (0.89-2.1)
3 5.0-6.0 pmol/l 1.24 (0.78-1.96)
4 >6.0 pmol/l 2.11 (1.30-3.37)
La Croix, JBMR. 2011, 1020
Case-control, 400 hip fracture patients. No association sRANKL and hipfracture risk; OPG: see table.
Prof Dr Willem F Lems
Acute Decline in Serum Sclerostin in Response to PTH-infusion in Healthy Men.
Yu et al, Moo120 53 gezonde mannen kregen een 18-uur durend infuus met hPTH (1-34): 0.55 U/kg.hour
Prof Dr Willem F Lems
Inhibition of sclerostin by monoclonal antibody enhances bone healing in a rat osteotomy model
He, ASMMR 2011, Su 464
Prof Dr Willem F Lems
Hoeveel calcium schrijft U voor aan uw patient met osteoporose?
• 500 mg per dag? • 1000 mg per dag?
• Suppletie afhankelijk van inname calcium met de voeding?
• Niets, is eigen verantwoordelijkheid van de patient.
12
Prof Dr Willem F Lems
Prof Dr Willem F Lems
JBMR 2011
Prof Dr Willem F Lems
Risico op botbreuken bij RA verhoogd
• Orstavik, Arch Int Med 2004;164:420-5
0
5
10
15
20
25
30
Any deformity >=2 deformities >=3 deformities
RACtr
Prof Dr Willem F Lems
Fracture risk is particularly increased in young women with RA
Vrouwen Elke leeftijd < 50 jaar > 50 jaar
Osteoporotische Fractuuren
1.7 (1.4 2.2) 4.3 (2.4- 7.8) 1.4 (1.1-1.8)
Alle fracturen 1.6 (1.3 1.9) 2.4 (1.6- 3.5) 1.4 (1.1- 1.7)
Mannen
Ost. fracturen 1.6 (1.1-2.4) niet verhoogd 1.8 (1.1-2.8)
Alle fracturen 1.4 (1.02-1.9) niet verhoogd niet verhoogd
Amin, JBMR 2011, Mo 354
Prof Dr Willem F Lems
Heart failure is a Independent and Novel Risk factor for Major Osteoporotic Fractures
Majumdar JBMR 2011, 1031
- population based cohort, n=45.509; 1841 met heart failure.
- 2703 fractures (5 years observation)
- RR 1.64, (95% c.i. 1.45-1.86)
- After adjustment for osteoporosis risk factors, comorbidities and BMD: RR 1.28, (95% c.i.: 1.06-1.53) Prof Dr W
illem F Lems
Prof Dr Willem F Lems
Is 2 cm lengte-verlies klinisch relevant?
• 2498 subjects (47-91 jaar), Japan (Hiroshima)
• Observatie van 1994-2003;
• 302 overleden;
• 2 cm height loss: algehele mortaliteit: 1.76 (95% c.i. 1.32- 2.38), na correctie voor leeftijd, geslacht, life-style factors en “atoombomexposure”.
• Idem, cardiovasculaire mortaliteit: 3.35 (95% c.i.: 1.63-6.86).
Prof Dr Willem F Lems
Falling rates of fractures in US
• Study of Osteoporotic Fractures: 9704 women, started in 1986-1988;
• Follow up each 5 years: DXA and Radiology of the Spine;
• Fall assessment each 4 months.
• Self-reported fractures.
Cummings ASBMR 2011, 1263
Prof Dr Willem F Lems
Falling Rates of Fractures in US
1992-1997 2000-2007 % Reduction
Predicted Change by BMD
Hip 15.4 11.8 23.9 17.9
Wrist 9.9 6.9 20.2 12.3
Humerus 6.5 4.4 23.5 9.4
Nonvert 45.8 38.7 15.6 9.6
Vertebral 32.6 24.4 25.0 12.5
Cummings ASBMR 2011, 1263
Prof Dr Willem F Lems
Prof Dr Willem F Lems
Prof Dr Willem F Lems
Clinical Characteristics of women who fracture despite anti-osteoporotic therapy: Global
Longitudinal study of Osteoporosis in Women (1)
• 46.443 participants, 6584 with anti-osteoporosis medication;
• 338 women with a fracture (340 fractures) in first two years of observation.
•
Diez Perez et al; ASBMR 2011; 1024
Prof Dr Willem F Lems
Clinical Characteristics of women who fracture despite anti-osteoporotic therapy: GLOW (2)
Odds ratio p value
Age (10 years) 1.16 (1.03-1.36) 0.018
Stroke 1.67 (1.05-2.66) 0.031
Parkinson 2.66 (1.06-7.74) 0.038
Diabetes 2.74 (1.61-4.66) <0.001
Wrist fracture 1.46 (1.09-1.95) 0.011
Spine 2.00 (1.38-2.88) <0.001
Rib 2.08 (1.49-2.90) <0.0001
Current Prednisone Use 1.94 (1.29-2.92) 0.002
Past 1.15 (0.87-1.51) ns
Alcohol 8.02 (2.81-22.85) <0.0001
Diez Perez et al; ASBMR 2011; 1024
Prof Dr Willem F Lems
En de Therapietrouw????
Odds ratio p value
Age (10 years) 1.16 (1.03-1.36) 0.018
Stroke 1.67 (1.05-2.66) 0.031
Parkinson 2.66 (1.06-7.74) 0.038
Diabetes 2.74 (1.61-4.66) <0.001
Wrist fracture 1.46 (1.09-1.95) 0.011
Spine 2.00 (1.38-2.88) <0.001
Rib 2.08 (1.49-2.90) <0.0001
Current Prednisone Use
1.94 (1.29-2.92) 0.002
Past 1.15 (0.87-1.51) ns
Alcohol 8.02 (2.81-22.85) <0.0001
Diez Perez et al; ASBMR 2011; 1024
Prof Dr Willem F Lems
Zoledronate in Hip Fracture Patients: Reduction of Fractures and Reduction in Mortality
Lyles KW et al. N Engl J Med 2007;357:1799-1809
Prof Dr Willem F Lems
Is er verschil in fracturen en mortaliteit tussen anti-osteoporose medicatie? Een vergelijking met
zoledronaat.
Fracturen Mortaliteit
Ibandronaat iv 1.41 (1.03-1.93) 0.84 (0.59-1.20)
Oral bisfosfonaat 1.33 (1.06-1.66) 0.94 (0.76-1.18)
Calcitonine 1.47 (1.16-1.86) 1.47 (1.17-1.85)
Raloxifen 1.27 (0.97-1.67) 0.99 (0.75 1.31)
PTH 1.05 (0.78-1.42) 1.31 (0.98-1.75)
H Yun, JBMR 2011, 1247
Bisfofonaten (oraal): n=24537; iv ibandronaat n=750; Zol: n=1962; Calcitonin: n=7231; Raloxifen: n=2222; PTH: n= 986
Prof Dr Willem F Lems
ASBMR 2011: Trends and Special Emphasis
• Circulating Biomarkers;
• Vitamin D and Calcium;
• Fracture Liaison Service;
• Outcome research, including mortality
• Clinical Trial Results, including new drugs
• Osteoporosis in Men;
• Epidemiology: “fine tuning” of FRAX;
Prof Dr Willem F Lems
Bisfosfonaten, FDA en Drug-holydays
• Bisfosfonaten: aseptische necrose van de kaak, spontane femurfracturen, oesophagus-problematiek, atriumfibrilleren (laatste 2 niet bewezen)
• FLEX: reductie klinische wervelfracturen (5.3% versus 2.4%), geen reductie radiologische fracturen. NB: reductie in fracturen vooral bij patienten met T<-2.5 in heup;
• Meer evidence nodig? voting: 17 versus 6.
J Lorenzo, ASBMR Communication
Prof Dr Willem F Lems
31
CBO, na 5 jaar therapie: herevaluatie (expert-opinion)
Prof Dr Willem F Lems
Welke patienten hebben het hoogste risico op fracturen, na 3 jaar behandeling met Zol (Horizon)
(1)
• Extension-studie, na 3 jaar Zol nog 1233 postmenopauzale vrouwen: placebo of nog 3 jaar Zol.
• Black 2010: botverlies, hogere botturnover en meer wervelfracturen in placebogroep (versus Zol);
• Nu binnen de groep van 6 jaar Zol: wie hebben meeste baat van continueren van therapie.
Cosman, JBMR 2011: 1248
Prof Dr Willem F Lems
Welke patienten hebben het hoogste risico op fracturen, na 3 jaar behandeling met Zol (Horizon) (2)
Z3P3 Z6 Rel risk NNT
Fem Neck <-2.5 9,2% 3,5% 0.36 (0.15-0.77) 18
Fem Neck >-2.5 3.0% 2.4% 0.79 (0.23-2.53) 173
Incident Vertebral fracture
4/16 (25%) 0/11 ?
No Inc Vertebral Fr
26/464 (5,6%) 12/451 (2,7%) 0.46 (0.22-0.9) 34
Cosman, JBMR 2011: 1248
Prof Dr Willem F Lems
“No longer the forgotten gender with regard to osteoporosis”
• Significant proportion (about 25%) of all osteoporotic fractures;
• Guidelines are being developed by several organisations (IOF, Endocrine Society)
• In modern trials the need to include more than a paltry number of male individuals.
Belizikian, ASBMR 2011.
Prof Dr Willem F Lems
Reductie in wervelfracturen bij mannen: zoledronaat versus placebo
0123456789
10
% wervelfracturen
Placebo:4,9%Zol: 1,6%
Boonen et al, JBMR 2011, 1066
1190 mannen met primaire of secundaire osteoporose, 32% met wervelinzakking at baseline. Follow-up 2 jaar. “first clear demonstration on the efficacy (and safety) of bisphosphonates for fracture risk reduction in men”
Rel risk: 0.32 (95% c.i.: 0.14-0.66)
Prof Dr Willem F Lems
Denosumab versus placebo: initially Freedom (3 years), nonvertebral fractures
0
1
2
3
4
incidence nonvertfractures
year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmab
Cummings, ASBMR 2011, 1063
Rr: 0.22 (95%c.i: 0.14-0,34)
(ns)
(ns)
Prof Dr Willem F Lems
4 and 5 years extension of Denosumab versus placebo: non-vertebral fractures, with Dmab data year 4 and 5
0
0,5
1
1,5
2
2,5
3
3,5
4
incidence nonvertfractures
year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmabyear 4-5, d
Cummings, ASBMR 2011, 1063
Rel risk: 0.72 (95%c.i: 0.54-0.97) ns
ns
Extension: n=2343 (3902 at baseline)
Prof Dr Willem F Lems
4 and 5 years extension of Denosumab versus placebo: non-vertebral fractures, with Dmab data year 4 and 5, and
estimated placebo fracture data ( virtual twin data ).
0
0,5
1
1,5
2
2,5
3
3,5
4
incidence nonvertfractures
year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmabyear 4-5, dyear 4-5, pl
Cummings, ASBMR 2011, 1063
Rel risk: 0.72 (95%c.i: 0.54-0.97) ns
ns
Rel.risk 0.49 (0.35-0.65)
Prof Dr Willem F Lems
Denosumab versus placebo: initially Freedom (3 years), vertebral fractures
0
1
2
3
4
incidence vertebral fractures
year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmab
Cummings, ASBMR 2011, 1063
Rr: 0.22 (95%c.i: 0.14-0,34)
Rr: 0.39
(0.26-0.58) Rr: 0.35 (0.24-0.51)
Prof Dr Willem F Lems
4 and 5 years extension of Denosumab versus placebo: initially Freedom (3 years), plus 4-5 year extension
( virtual twin method for placebo)
0
1
2
3
4
incidence vertebral fractures
year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmabyear 4-5, dyear 4-5, pl
Cummings, ASBMR 2011, 1063
Rr 0.44 (0.43-0.93)
Extension: n=2343 (3902 at baseline)
Prof Dr Willem F Lems
Effect of denosumab on bone mineral density: 8 year
results of a phase 2 clinical trial.
M Clung, JBMR 2011, 1061
Prof Dr Willem F Lems
PTH 1-84 accelerates fracture healing in Pubic Bones of Elderly Osteoporotic Women
• 65 vrouwen met een pubis fractuur (gem. 82.8 jaar); • 21 dagelijkse PTH injecties, versus control (?);
• Allen: 1000 mg calcium/800 IE vitamine D;
• Fractuur geheeld na 7.8 weken (PTH 1-84) versus 12.6 weken bij controls: (p<0.001)
• Na 8 weken: 100% herstel versus 9% herstel
Holzer ASBMR 2011, 1199
Prof Dr Willem F Lems
Once weekly PTH (teriparatide)
• 200 U (56.5 ugr) in 578 Japanese women (65-69 years old), 1-5 prevalent fractures, and low BMD;
• RCT, 72 weeks; (all 610 mg Calcium and 400 IU Vitamin D)
• Primairy Endpoint: new vertebral fractures: 3.1% versus 14.5% (p<0.0001);
• BMD Lumbar Spine: 6.7% versus 0.3%;
• Osteocalcin increased and urinary NTX decreased (?);
• Only mild side effects: headache and nuasea
• Conclusion (authors): once weekly teriparatide is safe and effective
Nakamura ASBMR 2011, 1201
Prof Dr Willem F Lems
Study Design
3 mg
10 mg
25 mg
50 mg
PBO 50 mg
50 mg 50 mg
PBO 50 mg
50 mg 50 mg
PBO PBO
50 mg 50 mg
PBO PBO
50 mg 50 mg
PBO PBO
50 mg 50 mg
Protocol 004-02 (Years 1 & 2)
Protocol 004-11 (Year 3)
Protocol 004-22 (Year 4 & 5)
Group 1
Group 2
Group 3
Group 4
Group 5
Group 6
Group 7
Group 8
Group 9
Group 10
Prof Dr Willem F Lems
Baseline† Patient Characteristics Patients Treated in the Fourth/Fifth Year Extension
Baseline Included in Year 3
Included in Year 4 & 5
N 399 189 141 Age (years), mean 64.2 64.0 63.1 Race, %
White 77 73 74
Years since menopause, mean 17.2 17.6 16.5 T-score, mean
Lumbar Spine -2.2 -2.2 -2.3 Total Hip -1.6 -1.5 -1.5 Femoral Neck -1.9 -1.8 -1.7 Trochanter -1.3 -1.2 -1.2 1/3 Distal Forearm N/A N/A -1.9
† At study start (Year 1) N/A= not available
Prof Dr Willem F Lems
Full-Analysis-Set Population / LOCF Lumbar Spine BMD
Month
Primary Endpoint
Lum
bar S
pine
BM
D (g
/cm
2 )
% C
hang
e fro
m B
asel
ine
(Mea
n ±
SE
)
PBO/PBO
0 1
3 6
12 18
24 30
36 42
48 54
60
-2 -1 0 1 2 3 4 5 6 7 8 9
10 11 12 13 14 15
50 mg/PBO/PBO 50 mg/50 mg/50 mg
50 mg = odanacatib 50 mg OW PBO = placebo OW
11.9%
Prof Dr Willem F Lems
Femoral Neck BMD Full-Analysis-Set Population / LOCF
Month
Fem
oral
Nec
k B
MD
(g/c
m2 )
%
Cha
nge
from
Bas
elin
e (M
ean
± S
E)
0 1
3 6
12 18
24 30
36 42
48 54
60
-2 -1 0 1 2 3 4 5 6 7 8 9
10 11 12
PBO/PBO 50 mg/PBO/PBO 50 mg/ 50 mg/ 50 mg
50 mg = odanacatib 50 mg OW PBO = placebo OW
9.8%
Prof Dr Willem F Lems
Full-Analysis-Set Population / LOCF 1/3 Distal Forearm BMD
Month
1/3
Dis
tal F
orea
rm B
MD
(g/c
m2 )
%
Cha
nge
from
Bas
elin
e (M
ean
± S
E)
0 1
3 6
12 18
24 30
36 42
48 54
60
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
PBO/PBO 50 mg/PBO/PBO 50 mg/ 50 mg/ 50 mg
50 mg = odanacatib 50 mg OW PBO = placebo OW
-1.0%
Prof Dr Willem F Lems
Biochemical Markers of Bone Turnover
15
Urinary N-Telopeptides/Creatinine RatioPer Protocol Population
Month
-100
-75
-50
-25
0
25
50
75
100
PBO/PBO 50 mg/PBO/PBO50 mg/50 mg/50 mg
u-N
Tx/C
rRat
io (
nmol
/mm
ol)
% C
hang
e fro
m B
asel
ine
(Geo
met
ricM
ean
SE)
50 mg = odanacatib 50 mg OW PBO = placebo OW
0 3 18 27 36 546 12 24 30 42 48 6033
16
Serum N-Terminal Propeptides of Type 1 CollagenPer Protocol Population
Month
-60
-40
-20
0
20
40
60
80
100
PBO/PBO 50 mg/PBO/PBO50 mg/50 mg/50 mg
s-P
1NP
(ng/
mL)
%
Cha
nge
from
Bas
elin
e (G
eom
etric
Mea
n SE
)
50 mg = odanacatib 50 mg OW PBO = placebo OW
03
18 2736
546 12 42 48 6024 3033
Prof Dr Willem F Lems
Clinical AE Summary
All-Patients-as-Treated, Years 4 & 5 Only
Patients with 1 or more
Odanacatib 50 mg
(N = 73)
Combination Group Placebo or Odanacatib 3 mg /Odanacatib 50 mg
(N = 27)
Placebo † (N = 41)
n (%) n (%) n (%)
AEs 65 (89.0) 23 (85.2) 33 (80.5)
Serious AEs 16 (21.9) 2 (7.4) 8 (19.5)
AEs that led to discontinuation 2 (2.7) 1 (3.7) 0 (0.0)
Skin disorder 13 (17.8) 8 (29.6) 11 (26.8)
Urinary tract infection 10 (13.7) 4 (14.8) 2 (4.9)
Back pain 8 (11.0) 5 (18.5) 1 (2.4)
Pain in extremity 12 (16.4) 4 (14.8) 2 (4.9)
Abdominal pain 1 (1.4) 0 (0.0) 3 (7.3)
† Patients in the placebo group received active ODN at either 10, 25 or 50 mg OW in years 1 and 2 ‡ Determined by the investigator to be possibly, probably or definitely drug related.
Prof Dr Willem F Lems
Dank voor Uw aandacht!
Prof Dr Willem F Lems
Biochemical Markers of Bone Turnover
15
Urinary N-Telopeptides/Creatinine RatioPer Protocol Population
Month
-100
-75
-50
-25
0
25
50
75
100
PBO/PBO 50 mg/PBO/PBO50 mg/50 mg/50 mg
u-N
Tx/C
rRat
io (
nmol
/mm
ol)
% C
hang
e fro
m B
asel
ine
(Geo
met
ricM
ean
SE)
50 mg = odanacatib 50 mg OW PBO = placebo OW
0 3 18 27 36 546 12 24 30 42 48 6033
16
Serum N-Terminal Propeptides of Type 1 CollagenPer Protocol Population
Month
-60
-40
-20
0
20
40
60
80
100
PBO/PBO 50 mg/PBO/PBO50 mg/50 mg/50 mg
s-P
1NP
(ng/
mL)
%
Cha
nge
from
Bas
elin
e (G
eom
etric
Mea
n SE
)
50 mg = odanacatib 50 mg OW PBO = placebo OW
03
18 2736
546 12 42 48 6024 3033
Prof Dr Willem F Lems