Verslag ASBMR 2011, deel 2. Presentatie van Prof Dr Willem F Lems op 5 oktober 2011 voor de Stichting IWO.

1. Verslag ASBMR 2011,
IWO, deel II
m s
(5 October, Utrecht)
L e
F
le m
W il
r
Prof Dr Willem F Lems
D
f
Vrije Universiteit medisch centrum,
r o afdeling reumatologie,
P
Amsterdam

2. ASBMR 2011
m s
L e
• Posters: 1481;
F
• Plenary Oral Posters: 24;
le m
• Oral abstracts: 264;
W il
•
r
Meet the Professors: 29;
D
•
r o f
Working Groups (including Working Group on Reumatic
Diseases): 11.
P

3. ASBMR 2011:
Trends and Special Emphasis
m s
L e
• Circulating Biomarkers;
F
• Vitamin D and Calcium;
le m
•
W il
Fracture Liaison Service;
•
D r
Outcome research, including mortality;
•
r o f
Clinical Trial Results, including new drugs;
• P
Osteoporosis in Men;
• Epidemiology: “fine tuning” of FRAX.

4. ASBMR 2011:
Trends and Special Emphasis
m s
L e
F
• Fracture Repair;
•
le
High Resolution Imaging; m
•
W il
Musculo-skeletal biology: Frailty
•
D r
Diabetes, Fat and Bone
• r o f
The Osteocyte.
P

5. The Osteocyte: the Great Communicator
m s
L e
F
le m
W il
D r
r o f
P

6. Inflammatory Biomarkers and
Hip-Fracture Risk, Mr Os (1)
m s
Q1 Q2 Q3 Q4
L e p voor trend
TNF ref 3.33 2.41
F 2.60 0.022
CRP ref ns
le m
ns ns 0.94
IL-6 ref 1.26
W il 1.63 2.22 0.019
r
(0.5-3.2) (0.7-4.0) (0.9-5.6)
IL-6SR ref
f D ns ns ns 0.95
IL-10
r
ref
o 1.24 0.68 0.59 0.026
P (0.6-2.8) (0.3-1.6) (0.2-1.5)
538 men with fractures and 980 healthy male controls
without fractures; average follow-up 6.96 years.
Cauley et al, ASBMR 2011, 1019

7. Inflammatory Biomarkers and
Clinical Spine Fracture Risk, Mr Os (2)
m s
Q1 Q2 Q3 Q4
L e p voor trend
TNF ref ns 2.25
F 2.33 0.004
CRP ref ns
le
ns
m ns 0.94
IL-6 ref 1.37
W il 1.52 1.94 0.037
r
(0.7-2.9) (0.7-3.2) (0.9-4.1)
IL-6SR ref
f D ns ns ns 0.60
IL-10
r
ref
o 0.5 0.33 0.28 <0.001
P
538 men with fractures and 980 healthy male controls
without fractures; average follow-up 6.96 years.
Cauley et al, ASBMR 2011, 1019

8. High Sensitive CRP and Fracture Risk: Mr Os Sweden
First Tertile Second Tertile
m s
Third Tertile
e
(<1.81 mg/l) (1.81-2.76 mg/l) (>2.76 mg/l)
Any Fracture ref ns
F L1.54 (1.25-1.89)
m
FN- BMD ref ns ns
Fracture, after ref
ille
ns 1.45 (1.7-1.79)
W
correction BMD
Vertebral Fracture ref
D r ns 1.73 (1.20-2.48)
r o f
P
N=2910 males, mean age 75 years, follow-up 5.4 years;
Fracture incidence 23.7/1000 years.
Skrtic, ASBMR 2011: 1021

9. Serum OPG and sRANKL Levels and
Incident Hip Fracture Levels in the Women s
Health Initiative
m s
L e
F
Quartile Odds ratio P value for trend
m
1 <4.0 pmol/l Reference 0.005
il le
2 4.0-5.0 pmol/l 1.40 (0.89-2.1)
W
3 5.0-6.0 pmol/l 1.24 (0.78-1.96)
r
4 >6.0 pmol/l 2.11 (1.30-3.37)
f D
r o
PCase-control, 400 hip fracture patients.
No association sRANKL and hipfracture risk;
OPG: see table.
La Croix, JBMR. 2011, 1020

10. Acute Decline in Serum Sclerostin in Response to
PTH-infusion in Healthy Men.
m s
L e
F
le m
W il
D r
ro f
P
53 gezonde mannen kregen een 18-uur durend infuus
met hPTH (1-34): 0.55 U/kg.hour
Yu et al, Moo120

11. Inhibition of sclerostin by monoclonal antibody
enhances bone healing in a rat osteotomy model
m s
L e
F
le m
W il
D r
r o f
P
He, ASMMR 2011, Su 464

12. Hoeveel calcium schrijft U voor aan uw patient met
osteoporose?
m s
• 500 mg per dag?
L e
F
• 1000 mg per dag?
• Suppletie afhankelijk van inname calcium met de voeding?
•
le m
Niets, is eigen verantwoordelijkheid van de patient.
W il
D r
r o f
P
12

13. m s
L e
F
le m
W il
D r
r o f
P

14. m s
L e
F
le m
W il
D r
r o f
P
JBMR 2011

15. Risico op botbreuken bij RA verhoogd
m s
L e
F
• Orstavik, Arch Int Med 2004;164:420-5
le m
il
30
25
W
20
r
RA
D
15
Ctr
f
10
r o
5
P
0
Any deformity >=2 deformities >=3 deformities

16. Fracture risk is particularly increased in
young women with RA
m s
Vrouwen Elke leeftijd < 50 jaar
L e
> 50 jaar
Osteoporotische 1.7 (1.4 2.2) 4.3 (2.4- 7.8)
F 1.4 (1.1-1.8)
Fractuuren
le m
Alle fracturen
W
1.6 (1.3 1.9)
il
2.4 (1.6- 3.5) 1.4 (1.1- 1.7)
Mannen
D r
Ost. fracturen
r o f
1.6 (1.1-2.4) niet verhoogd 1.8 (1.1-2.8)
Alle fracturen
P 1.4 (1.02-1.9) niet verhoogd niet verhoogd
Amin, JBMR 2011, Mo 354

17. Heart failure is a Independent and Novel Risk factor
for Major Osteoporotic Fractures
m s
L e
- population based cohort,
F
n=45.509; 1841 met heart failure.
le m - 2703 fractures (5 years
il
observation)
r W - RR 1.64, (95% c.i. 1.45-1.86)
f D - After adjustment for osteoporosis
o
risk factors, comorbidities and
P r BMD: RR 1.28, (95% c.i.:
1.06-1.53)
Majumdar JBMR 2011, 1031

18. m s
L e
F
le m
W il
D r
r o f
P

19. Is 2 cm lengte-verlies klinisch relevant?
m s
•
L e
2498 subjects (47-91 jaar), Japan (Hiroshima)
• Observatie van 1994-2003; F
le m
il
• 302 overleden;
•
W
2 cm height loss: algehele mortaliteit: 1.76 (95%
r
D
c.i. 1.32- 2.38), na correctie voor leeftijd, geslacht,
f
r o
life-style factors en “atoombomexposure”.
P
• Idem, cardiovasculaire mortaliteit: 3.35
(95% c.i.: 1.63-6.86).

20. Falling rates of fractures in US
m s
L e
F
• Study of Osteoporotic Fractures: 9704 women,
started in 1986-1988;
le m Radiology of
• Follow up each 5 years:lDXA and
W i
the Spine;
D r 4 months.
f fractures.
• Fall assessment each
ro
P
• Self-reported
Cummings ASBMR 2011, 1263

21. Falling Rates of Fractures in US
m s
L e
F
1992-1997 2000-2007 % Predicted
Reduction Change by
le m BMD
il
Hip 15.4 11.8 23.9 17.9
W
Wrist 9.9 6.9 20.2 12.3
Humerus 6.5
D r 4.4 23.5 9.4
Nonvert
r o f
45.8 38.7 15.6 9.6
P
Vertebral 32.6 24.4 25.0 12.5
Cummings ASBMR 2011, 1263

22. m s
L e
F
le m
W il
D r
r o f
P

23. m s
L e
F
le m
W il
D r
r o f
P

24. Clinical Characteristics of women who fracture
despite anti-osteoporotic therapy: Global
Longitudinal study of Osteoporosis in Women (1)
m s
• 46.443 participants, 6584 with L
e
F anti-
osteoporosis medication; m
le (340 fractures)
il
W observation.
• 338 women with a fracture
D r
in first two years of
•
r o f
P
Diez Perez et al; ASBMR 2011; 1024

25. Clinical Characteristics of women who fracture
despite anti-osteoporotic therapy: GLOW (2)
m s
Odds ratio
L
p value
e
F
Age (10 years) 1.16 (1.03-1.36) 0.018
m
Stroke 1.67 (1.05-2.66) 0.031
ille
Parkinson 2.66 (1.06-7.74) 0.038
W
Diabetes 2.74 (1.61-4.66) <0.001
Wrist fracture
D r
1.46 (1.09-1.95) 0.011
f
Spine 2.00 (1.38-2.88) <0.001
ro
Rib 2.08 (1.49-2.90) <0.0001
Past
P
Current Prednisone Use 1.94 (1.29-2.92)
1.15 (0.87-1.51)
0.002
ns
Alcohol 8.02 (2.81-22.85) <0.0001
Diez Perez et al; ASBMR 2011; 1024

26. En de Therapietrouw????
Odds ratio p value
Age (10 years) 1.16 (1.03-1.36) 0.018
m s
Stroke 1.67 (1.05-2.66) 0.031
L e
Parkinson 2.66 (1.06-7.74) 0.038
F
Diabetes 2.74 (1.61-4.66)
le m
<0.001
il
Wrist fracture 1.46 (1.09-1.95) 0.011
Spine
r W
2.00 (1.38-2.88) <0.001
Rib
f D
2.08 (1.49-2.90) <0.0001
ro
Current Prednisone 1.94 (1.29-2.92) 0.002
Use
Past P 1.15 (0.87-1.51) ns
Alcohol 8.02 (2.81-22.85) <0.0001
Diez Perez et al; ASBMR 2011; 1024

27. Zoledronate in Hip Fracture Patients: Reduction of Fractures and
Reduction in Mortality
m s
L e
F
le m
W il
D r
ro f
P
Lyles KW et al. N Engl J Med 2007;357:1799-1809

28. Is er verschil in fracturen en mortaliteit tussen anti-
osteoporose medicatie? Een vergelijking met
zoledronaat.
m s
Fracturen
L e
Mortaliteit
Ibandronaat iv 1.41 (1.03-1.93)
F 0.84 (0.59-1.20)
le m
il
Oral bisfosfonaat 1.33 (1.06-1.66) 0.94 (0.76-1.18)
W
Calcitonine 1.47 (1.16-1.86) 1.47 (1.17-1.85)
Raloxifen
D r
1.27 (0.97-1.67) 0.99 (0.75 1.31)
PTH
r o f 1.05 (0.78-1.42) 1.31 (0.98-1.75)
P
Bisfofonaten (oraal): n=24537; iv ibandronaat
n=750; Zol: n=1962; Calcitonin: n=7231;
Raloxifen: n=2222; PTH: n= 986
H Yun, JBMR 2011, 1247

29. ASBMR 2011:
Trends and Special Emphasis
m s
• Circulating Biomarkers; L e
F
• Vitamin D and Calcium;
le m
• il
Fracture Liaison Service;
W
•
D r
Outcome research, including mortality
•
r o f
Clinical Trial Results, including new drugs
• P
Osteoporosis in Men;
• Epidemiology: “fine tuning” of FRAX;

30. Bisfosfonaten, FDA en Drug-holydays
m s
L e
• Bisfosfonaten: aseptische necrose van de kaak,
F
spontane femurfracturen, oesophagus-
le m
problematiek, atriumfibrilleren (laatste 2 niet
bewezen)
W il
r
• FLEX: reductie klinische wervelfracturen (5.3%
D
r o f
versus 2.4%), geen reductie radiologische
P
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

31. CBO, na 5 jaar therapie: herevaluatie
(expert-opinion)
m s
L e
F
m
le
W il
D r
r o f
P
31

32. Welke patienten hebben het hoogste risico op
fracturen, na 3 jaar behandeling met Zol (Horizon)
(1)
m s
L e
vrouwen: placebo of nog 3 jaar Zol. F
• Extension-studie, na 3 jaar Zol nog 1233 postmenopauzale
m
le (versus Zol);
il
• Black 2010: botverlies, hogere botturnover en meer
W
wervelfracturen in placebogroep
r van therapie.
D
• Nu binnen de groep van 6 jaar Zol: wie hebben meeste
o f
baat van continueren
r
P
Cosman, JBMR 2011: 1248

33. Welke patienten hebben het hoogste risico op fracturen, na 3
jaar behandeling met Zol (Horizon) (2)
m s
Z3P3 Z6 Rel risk
L e NNT
Fem Neck <-2.5 9,2% 3,5%
F
0.36 (0.15-0.77) 18
Fem Neck >-2.5 3.0% 2.4%
le m 0.79 (0.23-2.53) 173
Incident 4/16 (25%)
W
0/11
il ?
r
Vertebral
D
fracture
r o f
P
No Inc 26/464 (5,6%) 12/451 (2,7%) 0.46 (0.22-0.9) 34
Vertebral Fr
Cosman, JBMR 2011: 1248

34. “No longer the forgotten gender
with regard to osteoporosis”
m s
L e
• Significant proportion (about 25%) of all osteoporotic
fractures; F
le m
il
• Guidelines are being developed by several organisations
(IOF, Endocrine Society)
r W
• In modern trials the need to include more than a paltry
f D
number of male individuals.
r o
P
Belizikian, ASBMR 2011.

35. Reductie in wervelfracturen bij mannen:
zoledronaat versus placebo
m s
10
L e
F
9
8
m
7
le
6
il
5 Placebo:4,9%
4 Zol: 1,6%
W
3
r
2
Rel risk: 0.32 (95% c.i.: 0.14-0.66)
D
1
f
0
o
% wervelfracturen
P r
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”
Boonen et al, JBMR 2011, 1066

36. Denosumab versus placebo:
initially Freedom (3 years), nonvertebral fractures
m s
4
L e
F
Rr: 0.22
(ns) (95%c.i: 0.14-0,34)
3
le m
il
(ns) year 1 , pl
W
year 1, dmab
r
2 year 2, pl
D
year 2, dmab
1
r o f year 3, pl
P
year 3, dmab
0
incidence nonvertfractures
Cummings, ASBMR 2011, 1063

37. 4 and 5 years extension of Denosumab versus placebo:
non-vertebral fractures, with Dmab data year 4 and 5
m s
4
L e
3,5 ns Rel risk: 0.72
F
m
(95%c.i: 0.54-0.97)
le
3 year 1 , pl
il
ns
2,5 year 1, dmab
W
year 2, pl
r
2
D
year 2, dmab
f
1,5 year 3, pl
1
r o year 3, dmab
0,5
0
P year 4-5, d
incidence nonvertfractures
Extension: n=2343
(3902 at baseline) Cummings, ASBMR 2011, 1063

38. 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 ).
m s
4
L e
3,5 ns Rel risk: 0.72
F
m
(95%c.i: 0.54-0.97) Rel.risk 0.49 year 1 , pl
le
3 (0.35-0.65)
il
ns year 1, dmab
2,5
W
year 2, pl
r
2 year 2, dmab
D
year 3, pl
f
1,5
o
year 3, dmab
r
1
P
year 4-5, d
0,5 year 4-5, pl
0
incidence nonvertfractures
Cummings, ASBMR 2011, 1063

39. Denosumab versus placebo:
initially Freedom (3 years), vertebral fractures
m s
4 Rr: 0.39
L e
F
Rr: 0.22
(0.26-0.58) (95%c.i: 0.14-0,34)
3
le m
Rr: 0.35 (0.24-0.51)
il
year 1 , pl
W
year 1, dmab
r
2 year 2, pl
D
year 2, dmab
1
r o f year 3, pl
P
year 3, dmab
0
incidence vertebral fractures
Cummings, ASBMR 2011, 1063

40. 4 and 5 years extension of Denosumab versus placebo:
initially Freedom (3 years), plus 4-5 year extension
( virtual twin method for placebo)
m s
4
L e
F
m
year 1 , pl
le
3
il
year 1, dmab
Rr 0.44 (0.43-0.93)
W
year 2, pl
r
2 year 2, dmab
D
year 3, pl
1
r o f year 3, dmab
P
year 4-5, d
year 4-5, pl
0
incidence vertebral fractures
Extension: n=2343
(3902 at baseline) Cummings, ASBMR 2011, 1063

41. Effect of denosumab on bone mineral density: 8 year
results of a phase 2 clinical trial.
m s
L e
F
le m
W il
D r
r o f
P
M Clung, JBMR 2011, 1061

42. PTH 1-84 accelerates fracture healing in
Pubic Bones of Elderly Osteoporotic Women
m s
•
L e
65 vrouwen met een pubis fractuur (gem. 82.8 jaar);
• F
21 dagelijkse PTH injecties, versus control (?);
le m
il
• Allen: 1000 mg calcium/800 IE vitamine D;
W
• Fractuur geheeld na 7.8 weken (PTH 1-84) versus 12.6
r
weken bij controls: (p<0.001)
D
o f
• Na 8 weken: 100% herstel versus 9% herstel
r
P
Holzer ASBMR 2011, 1199

43. Once weekly PTH (teriparatide)
m s
e
• 200 U (56.5 ugr) in 578 Japanese women (65-69 years
F L
old), 1-5 prevalent fractures, and low BMD;
• RCT, 72 weeks; (all 610 mg Calcium and 400 IU Vitamin
D)
le m
W il
• Primairy Endpoint: new vertebral fractures: 3.1% versus
r
14.5% (p<0.0001);
D
r o f
• BMD Lumbar Spine: 6.7% versus 0.3%;
P
• 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

44. Study Design
Protocol 004-02 Protocol 004-11 Protocol 004-22
s
(Years 1 & 2) (Year 3) (Year 4 & 5)
e m
PBO 50 mg Group 1
50 mg 50 mg
F L
Group 2
m
Group 3
le
PBO 50 mg
il
3 mg
50 mg 50 mg Group 4
r
PBO
W PBO Group 5
D
10 mg
ro f 50 mg 50 mg Group 6
25 mg P PBO
50 mg
PBO
50 mg
Group 7
Group 8
PBO PBO Group 9
50 mg
50 mg 50 mg Group 10

45. Baseline† Patient Characteristics
Patients Treated in the Fourth/Fifth Year Extension
Included in Included in
s
Baseline
Year 3 Year 4 & 5
e m
L
N 399 189 141
F
Age (years), mean 64.2 64.0 63.1
Race, %
le m
il
White 77 73 74
Years since menopause, mean
r W 17.2 17.6 16.5
T-score, mean
f D
ro
Lumbar Spine -2.2 -2.2 -2.3
Total Hip
Femoral Neck P -1.6
-1.9
-1.5
-1.8
-1.5
-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

46. Primary Endpoint
Lumbar Spine BMD
Full-Analysis-Set Population / LOCF
s
15
14
m
Lumbar Spine BMD (g/cm2)
13
e
% Change from Baseline
12 11.9%
L
11
F
10
(Mean ± SE)
9
m
8
le
7
il
6
5
W
4
r
3
D
2
f
1
ro
0
-1
P
-2
0 3 12 24 36 48 60
1 6 18 30 42 54
50 mg = odanacatib 50 mg OW
PBO = placebo OW Month
PBO/PBO 50 mg/50 mg/50 mg 50 mg/PBO/PBO

47. Femoral Neck BMD
Full-Analysis-Set Population / LOCF
12
s
Femoral Neck BMD (g/cm2) 11
m
% Change from Baseline 10 9.8%
e
9
L
8
F
(Mean ± SE)
7
m
6
le
5
il
4
3
2
r W
D
1
f
0
ro
-1
-2
P 0 3
1 6
12
18
24
30
36
42
48
54
60
50 mg = odanacatib 50 mg OW
PBO = placebo OW Month
PBO/PBO 50 mg/ 50 mg/ 50 mg 50 mg/PBO/PBO

48. 1/3 Distal Forearm BMD
Full-Analysis-Set Population / LOCF
3
s
1/3 Distal Forearm BMD (g/cm2) 2
e m
% Change from Baseline 1
L
0
F
-1.0%
(Mean ± SE)
-1
le m
-2
il
-3
W
-4
r
-5
f
-6
D
ro
-7
P 0 3
1 6
12
18
24
30
36
42
48
54
60
50 mg = odanacatib 50 mg OW
PBO = placebo OW
Month
PBO/PBO 50 mg/ 50 mg/ 50 mg 50 mg/PBO/PBO

49. Biochemical Markers of Bone Turnover
m s
e
Urinary N-Telopeptides/Creatinine Ratio Serum N-Terminal Propeptides of Type 1 Collagen
L
Per Protocol Population Per Protocol Population
F
100
100
75
80
u-NTx/Cr Ratio (nmol/mmol)
% Change from Baseline
m
(Geometric Mean SE)
% Change from Baseline
(Geometric Mean SE)
50
60
le
s-P1NP (ng/mL)
25
il
40
0 20
W
-25 0
r
-50 -20
D
-75 -40
f
-60
-100
o
0 6 18 27 33 42 54 0 18 27 33 54
6 42
r
3 12 24 30 36 48 60
50 mg = odanac atib 50 mg OW 50 mg = odanac atib 50 mg OW 3 12 24 30 36 48 60
PBO = placebo OW Month PBO = placebo OW Month
P
PBO/PBO 50 mg/50 mg/50 mg 50 mg/PBO/PBO
PBO/PBO 50 mg/50 mg/50 mg 50 mg/PBO/PBO
15 16

50. Clinical AE Summary
All-Patients-as-Treated, Years 4 & 5 Only
m s
L e
Combination Group
Odanacatib 50
Placebo or Odanacatib 3 Placebo †
mg
F
mg /Odanacatib 50 mg (N = 41)
(N = 73)
(N = 27)
Patients with 1 or more
le m
n (%) n (%) n (%)
il
AEs 65 (89.0) 23 (85.2) 33 (80.5)
W
Serious AEs 16 (21.9) 2 (7.4) 8 (19.5)
AEs that led to discontinuation
D r 2 (2.7) 1 (3.7) 0 (0.0)
f
Skin disorder 13 (17.8) 8 (29.6) 11 (26.8)
r o
Urinary tract infection 10 (13.7) 4 (14.8) 2 (4.9)
P
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.

51. Dank voor Uw aandacht!
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52. Biochemical Markers of Bone
Turnover
m s
e
Urinary N-Telopeptides/Creatinine Ratio Serum N-Terminal Propeptides of Type 1 Collagen
L
Per Protocol Population Per Protocol Population
F
100
100
75
80
u-NTx/Cr Ratio (nmol/mmol)
% Change from Baseline
m
(Geometric Mean SE)
% Change from Baseline
(Geometric Mean SE)
50
60
le
s-P1NP (ng/mL)
25
il
40
0 20
W
-25 0
r
-50 -20
D
-75 -40
f
-60
-100
o
0 6 18 27 33 42 54 0 18 27 33 54
6 42
r
3 12 24 30 36 48 60
50 mg = odanac atib 50 mg OW 50 mg = odanac atib 50 mg OW 3 12 24 30 36 48 60
PBO = placebo OW Month PBO = placebo OW Month
P
PBO/PBO 50 mg/50 mg/50 mg 50 mg/PBO/PBO
PBO/PBO 50 mg/50 mg/50 mg 50 mg/PBO/PBO
15 16