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


•  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


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


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


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.


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.


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


Inhibition of sclerostin by monoclonal antibody enhances bone healing in a rat osteotomy model

He, ASMMR 2011, Su 464


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


JBMR 2011


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


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


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

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).


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


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


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


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



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



Zoledronate in Hip Fracture Patients: Reduction of Fractures and Reduction in Mortality

Lyles KW et al. N Engl J Med 2007;357:1799-1809


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



•  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;


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


31

    

CBO, na 5 jaar therapie: herevaluatie (expert-opinion)


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


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


“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.


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)


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)


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


year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmabyear 4-5, d


Rel risk: 0.72 (95%c.i: 0.54-0.97) ns

ns

Extension: n=2343 (3902 at baseline)


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


year 1 , plyear 1, dmabyear 2, plyear 2, dmabyear 3, plyear 3, dmabyear 4-5, dyear 4-5, pl


Rel risk: 0.72 (95%c.i: 0.54-0.97) ns

ns

Rel.risk 0.49 (0.35-0.65)


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


Rr: 0.22 (95%c.i: 0.14-0,34)

Rr: 0.39

(0.26-0.58) Rr: 0.35 (0.24-0.51)


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


Rr 0.44 (0.43-0.93)

Extension: n=2343 (3902 at baseline)


Effect of denosumab on bone mineral density: 8 year

results of a phase 2 clinical trial.

M Clung, JBMR 2011, 1061


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


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


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


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


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%


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


9.8%


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


-1.0%


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)


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


s-P

1NP

(ng/

mL)

%

Cha

nge

from

Bas

elin

e (G

eom

etric

Mea

n SE

)


03

18 2736

546 12 42 48 6024 3033


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.


Dank voor Uw aandacht!


Biochemical Markers of Bone Turnover

15

Urinary N-Telopeptides/Creatinine RatioPer Protocol Population

Month

-100

-75

-50

-25

0

25

50

75

100


u-N

Tx/C

rRat

io (

nmol

/mm

ol)

% C

hang

e fro

m B

asel

ine

(Geo

met

ricM

ean

SE)


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


s-P

1NP

(ng/

mL)

%

Cha

nge

from

Bas

elin

e (G

eom

etric

Mea

n SE

)


03

18 2736

546 12 42 48 6024 3033


verslag asbmr 2011, san diego, deel 2

Health & Medicine