Verslag ASBMR 2009, IWO

(14 October, Utrecht)

Prof Dr Willem F LemsVrije Universiteit medisch centrum,

afdeling reumatologie,Amsterdam

• Combinatietherapie;• Nieuwe middelen;• Therapietrouw;• Denosumab;• Vertebroplastiek;• Nederlandse Young Investigators Award Winners;

• FRAX : pro en contra.

• NB Soms korte terugblik op zeer recente literatuur!

Combinatietherapie met PTH en botresorptieremmer zinvol?

Black, D. M. et al. N Engl J Med 2003;349:1207-1215

Mean Percent Changes in Areal Bone Mineral Density on Dual-Energy X-Ray Absorptiometry

Black, D. M. et al. N Engl J Med 2003;349:1207-1215

Changes in Markers of Bone Formation (N-Propeptide of Type I Collagen, Panel A) and Bone Resorption (C-Terminal Telopeptide of Type I Collagen, Panel B)

Effects of Once-Yearly Zoledronic Acid 5mg in Combination with Teriparatide (PTH) on Postmenopausal Women with Osteoporosis

• In 412 postmenopausal, osteoporotic, women, the combination of ZOL and PTH increased BMD more than either alone.

• “Combination therapy could be considered for patients at high risk for hip fractures or those with very low BMD”

F Cosman et al; 1025

New Anti-Osteoporotic Drugs?

Disease and Therapy Mediated by the Calcium-Sensing Receptor

Ronacaleret, A Calcium-Sensing Receptor Antagonist: Results of a 1 Year Double-Blind, Placebo-Controlled, Dose-Ranging Phase II Study

• 569 postmenopausal women open-label teriparatide (TER) or placebo or one of 4 doses of ronacaleret (RON) (100, 200, 300 or 400mg daily), or alendronate (ALN) (70mg weekly).

• The primary endpoint was the % change in lumbar spine (LS) bone mineral density (BMD) at 12 months.

• The trial was terminated early due to lack of efficacy following an interim analysis of % change in LS BMD at 6 months.

• Ronacaleret (200, 300, 400mg) Spine BMD was significantly different from placebo (1.4-1.9%), while ALN and TER increased LS BMD 4.7% and 9.2%.

• At the total hip, RON caused small but statistically significant decreases in BMD at all dose ronacaleret levels, while ALN and TER showed modest gains (2.8%, 2.6%).

• RON (200, 300, 400mg) showed median increases in serum CTx >20% starting at month 6, reaching a maximum of 58% at month 10 as compared to TER

Over therapie-trouw

Netelenbos, ASBMR, Denver, 2009

?

Persistance of anti-osteoporotic drugs in daily practice

Most Non-Persistent Patients with Osteoporosis Do Not Switch to Other Drug Treatments: a 3,5 year market survey

of 240,000 patients in the Netherlands

• After stopping, follow-up of 18 month: only 20% (95% c.i.: 17-25%) switched to other drugs.

• “ major failure to adequately treat patients at high risk for fractures in real clinical practice”

Reasons for stopping anti-osteoporosis medications among postmenopausal women. (GLOW).

(Ch Roux, et al, M 352)

• Heel veel data over denosumab!

Denosumab Binds to RANK Ligand Inhibiting Osteoclast Development, Activation, and Survival

Osteoblasts

HormonesGrowth factorsCytokines

Bone Resorption Prevented and Inhibited

Osteoclast Precursor Osteoclast

Formation Inhibited

Osteoclast Function and Survival

Inhibited

Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.

RANK Ligand

RANK

Denosumab

OPG

Original Article

Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., Ethel S. Siris, M.D., Richard Eastell, M.D., Ian R. Reid, M.D., Pierre Delmas, M.D., Ph.D., Holly B. Zoog, Ph.D., Matt Austin, M.S., Andrea Wang, M.A., Stepan Kutilek, M.D., Silvano Adami, M.D., Ph.D., Jose Zanchetta, M.D., Cesar Libanati, M.D., Suresh

Siddhanti, Ph.D., Claus Christiansen, M.D., for the FREEDOM Trial

N Engl J MedVolume 361(8):756-765

August 20, 2009

17

FREEDOM Study Design• International, multicenter, randomized, double-blind, placebo-controlled study

Key Inclusion Criteria:

• Postmenopausal women aged 60 to 90 years• T-score < -2.5 and > -4.0 at the lumbar spine or total hip• No severe or > 2 moderate vertebral fractures

Primary Endpoint:• New vertebral fractures

Secondary Endpoints:• Nonvertebral fractures• Hip fractures

RANDOMIZATION

Placebon = 3906

Denosumab 60 mg Q6M SCn = 3902

Daily Calcium and Vitamin D Supplementation

N = 7808

SCREENING

Months: 0 6 12 18 24 30 36

END

OF

TREATMENT

Last dose

Cummings S, et al. N Engl J Med. 2009;361:756-765.

Primairy Endpoint: Vertebral Fractures

Cummings SR et al. N Engl J Med 2009;361:756-765

RR hip: 0.60; 95% c.i.: 0.37-0.97

RR 0.80; 95% c.i.: 0.67-0.95

Secondairy Outcomes: non-vertebral fractures and hipfractures

Percent Changes in Bone Mineral Density and Biochemical Markers of Bone Turnover

Cummings SR et al. N Engl J Med 2009;361:756-765

Cummings SR et al. N Engl J Med 2009;361:756-765Cummings SR et al. N Engl J Med 2009;361:756-765

Freedom-studie, subanalyse (pre-specified) bij high-risk patients:

>70 jaar, T<-3, prevalente wervelfractuur (tenminste 2 items)

0

2

4

6

8

10

12

vertebral hip nonvertebral

all placebo

high risk placebo

high risk denosumab-65%, p<0,0001

-48%, p=0,02

NS

Effects of denosumab on bone histology/histomorphometry:

FREEDOM and STAND studies

•

Reid et al; Saturday 1030 hour

Background

• Anti-resorptive therapies for postmenopausal osteoporosis reduce bone resorption, increase bone mineral density (BMD), and reduce the risk of fracture.

• Whether therapy-associated increases in BMD and reductions in fracture risk are related to the level of bone resorption at baseline is a topic of interest.

Subject Incidence of New Vertebral Fracture Through

Month 36 by Baseline CTX Quartiles

n = Number of subjects with spine x-ray at baseline and ≥ 1 postbaseline visit.

Baseline CTX Quartiles (ng/mL)

Incidence Through Month 36 (%)

0

2

4

6

8

10

12

14 Cochran-Armitage trend test among denosumab groups; P = 0.01

891 898 895 914n

< 0.381 0.381-0.536 0.537-0.717 0.718

Inci

de

nce

Th

rou

gh

Mo

nth

35

(%

)Placebo Denosumab

86%

884 917 937 887

3.1%

P = 0.0002

55%6.9%

1.4%

P < 0.0001

9.9%

4.9%

1.8%

P = 0.0002

64%

6.7%

3.2%

P = 0.0009

51%

Subject Incidence of New Vertebral Fracture Through Month 36 by Baseline TRACP5b Quartiles

n = Number of subjects with spine x-ray at baseline and ≥ 1 postbaseline visit.

Placebo Denosumab

Baseline TRACP5b Quartiles (IU/L)

< 3.424 3.424-4.352 4.353-5.478 5.4790

2

4

6

8

10

881 878 891 940n

Cochran-Armitage trend test among denosumab groups; P = 0.16

7.9%

3.2%

P < 0.0001

59%

906 919 918 871

6.7%

2.1%

P < 0.0001

70%

7.3%

1.7%

P < 0.0001

76%

6.5%

2.4%

P < 0.0001

62%

Inci

denc

e T

hrou

gh M

onth

35

(%)

Subject Incidence of Nonvertebral Fracture Through

Month 36 by Baseline CTX Quartiles

n = Number of randomized subjects.

Cochran-Armitage trend test among denosumab groups; P = 0.09

Baseline CTX Quartiles (ng/mL))

Incidence Through Month 36 (%)0

2

4

6

8

10

11

7.5%

P = 0.899.7%

P = 0.06

7.5% 7.2%

P = 0.37 P = 0.06

7.2% 7.3%6.7%

5.2%

2%

26%

15%

30%

937 944 950 951 938 972 966 936n

< 0.381 0.381-0.536 0.537-0.717 0.718

Inci

de

nce

Th

rou

gh

Mo

nth

36

(%

)

Placebo Denosumab

Subject Incidence of Nonvertebral Fracture Through

Month 36 by Baseline CTX Quartiles

n = Number of randomized subjects.

Cochran-Armitage trend test among denosumab groups; P = 0.09

Baseline CTX Quartiles (ng/mL))

Incidence Through Month 36 (%)0

2

4

6

8

10

11

7.5%

P = 0.899.7%

P = 0.06

7.5% 7.2%

P = 0.37 P = 0.06

7.2% 7.3%6.7%

5.2%

2%

26%

15%

30%

937 944 950 951 938 972 966 936n

< 0.381 0.381-0.536 0.537-0.717 0.718

Inci

de

nce

Th

rou

gh

Mo

nth

36

(%

)

Placebo Denosumab

Subject Incidence of Nonvertebral Fracture Through

Month 36 by Baseline TRACP5b Quartiles

n = Number of randomized subjects.

Cochran-Armitage trend test among denosumab groups; P = 0.43

Baseline TRACP5b Quartiles (IU/L)

Inci

de

nce

Th

rou

gh

Mo

nth

36

(%

)

0

2

4

6

8

10

11

7.4%

P = 0.22

8.1%

P = 0.62

6.8%

9.4%P = 0.16

P = 0.01

6.0%

8.9%

5.4%6.1%

20%

8%

24%

35%

934 959 926 968 939 955 984 910n

< 3.424 3.424-4.352 4.353-5.478 5.479

Placebo Denosumab

        Effects of Denosumab on Bone Mineral Density and Biochemical Markers of Bone Turnover: 6 Year Results of a Phase 2 Clinical Trial

P Miller

Was er echt nieuws over

vertebro-kyfoplastieken? (Sa -389)

• R. Pflugmacher•

Background: Excellent clinical and radiological results could be achieved in patients with osteoporotic fractures treated with Balloon-Kyphoplasty. Only a few articles report on the clinical and radiological outcome in comparison to a non surgical treatment.Purpose: To evaluate the long-term outcomes of 126 patients with 239 osteoporotic vertebral fractures, located in the thoracic and lumbar spine, treated with Balloon Kyphoplasty and compared with a conservatively treated control group.Study design: A prospective follow-up was performed in all patients. Patients who refused surgical treatment served as control.Patient sample: 90 patients (37 males and 53 females) with 187 osteoporotic vertebral fractures were treated with Balloon Kyphoplasty, 36 (12 males and 24 females) with 52 vertebral fractures served as controls. We were able to have a 2 year follow up in 78 patients with 168 vertebrae treated with Balloon Kyphoplasty and 32 patients with 45 vertebral fractures treated conservatively.Outcome measures:Clinical and radiological results were measured prospectively in all patients.Methods: Symptomatic levels were identified by correlating the clinical presentation with conventional radiographs, CT and / or MRI. During the 2 year follow-up reduction in pain was determined. The effects on pain symptoms were measured on a self-reported Visual analog Scale (VAS) and the Oswestry score was documented to assess disability. Radiographic scans were performed pre- and postoperatively and after 3, 6, 12 and 24 months. The vertebral height and kyphosis angle were measured to assess the restoration of the sagittal alignment.Results: The median pain scores (VAS) improved significantly from pre- to post-intervention as did the Oswestry Disability Score (p<0.001), in the conservative group no significant changes could be documented. Balloon Kyphoplasty led to a significantly vertebral height restoration and correction of kyphotic deformity in the long-term (p<0.05), in the conservative group significant further height loss and increase of kyphosis could be documented (p<0.001). There were significantly fewer patients with new vertebral fractures of the thoracic and lumbar spine, after 24-months, in the kyphoplasty group (15 patients, 4 male, 11 female, 19.2%) than in the control group (13 patients, 3 male, 9 female, 40.6%).Conclusion: Balloon Kyphoplasty as an addition to medical treatment leads to a statistically significant reduction of pain status and improvement of physical function. Further, Balloon Kyphoplasty reduces occurrence of new vertebral fractures and prevents a height loss and increase of kyphotic deformity in the long term.Disclosures: None

Original Article A Randomized Trial of Vertebroplasty for Painful

Osteoporotic Vertebral Fractures

Rachelle Buchbinder, Ph.D., Richard H. Osborne, Ph.D., Peter R. Ebeling, M.D., John D. Wark, Ph.D., Peter Mitchell, M.Med., Chris Wriedt, M.B., B.S., Stephen Graves, D.

Phil., Margaret P. Staples, Ph.D., and Bridie Murphy, B.Sc.

N Engl J MedVolume 361(6):557-568

August 6, 2009

Buchbinder R et al. N Engl J Med 2009;361:557-568

Original Article A Randomized Trial of Vertebroplasty for

Osteoporotic Spinal Fractures

David F. Kallmes, M.D., Bryan A. Comstock, M.S., Patrick J. Heagerty, Ph.D., Judith A. Turner, Ph.D., David J. Wilson, F.R.C.R., Terry H. Diamond, F.R.A.C.P., Richard

Edwards, F.R.C.R., Leigh A. Gray, M.S., Lydia Stout, B.S., Sara Owen, M.Sc., William Hollingworth, Ph.D., Basavaraj Ghdoke, M.D., Deborah J. Annesley-Williams,

F.R.C.R., Stuart H. Ralston, F.R.C.P., and Jeffrey G. Jarvik, M.D., M.P.H.

N Engl J MedVolume 361(6):569-579

August 6, 2009

Secondary Outcome Measures at 1 Month (Intention-to-Treat Analyses)

Kallmes DF et al. N Engl J Med 2009;361:569-579

Scores on Measures of Disability and Pain over a 3-Month Period

Kallmes DF et al. N Engl J Med 2009;361:569-579

397/23/03

EFOS participants

Enrolment8 European countries

AustriaDenmarkFranceGermanyGreeceIrelandNetherlandsSweden

Incident fractures during teriparatide treatment

40

n=72(4.6%)

n=45(3.5%)

n=33(2.8%)

n=138(8.8%)

OR 0.68 (95% CI 0.47, 0.98)a**

OR 0.53 (95% CI 0.35, 0.82)a*

a Adjusted model by age, prior bisphosphonate use, and a history of fracture in the last 12 months before starting teriparatide*p<0.05, **p<0.005

Langdahl et al. CTI [in press]

Frequency of back pain

41Langdahl et al. CTI [in press]

* ***

*p<0.001 compared to baseline (sign test)

Limitation of activities

42Langdahl et al. CTI [in press]

* ***

*p<0.001 compared to baseline (sign test)

Incidence of fractures during and after teriparatide treatment

51(3.5%)

76 (4.8%)

34 (2.7%)

41(3.0%)

18 (1.6%)

13 (1.3%)

OR 0.71 (95% CI: 0.50, 1.00; p=0.051)

OR 0.61 (95% CI: 0.41, 0.90; p=0.012)

OR 0.54 (95% CI: 0.36, 0.82; p=0.004)

OR 0.33 (95% CI: 0.19, 0.55; p<0.001)

OR 0.26 (95% CI: 0.14, 0.47; p<0.001)

43

About Fractures

Effects of antiresorptive treatment of various non-vertebral fracture outcomes (1242, Mackey D, Cummings S).

• Achtergrond: verschillende definities voor non-vertebral fractures in RCTs;

• Data van FIT (alendronaat), HORIZON (zoledronaat), PEARL (lasoxifen);

• 17.098 postmenopausal osteoporotic women, 1.892 non-vertebral fractures;

Effects of antiresorptive treatment of various non-vertebral fracture outcomes (1242, Mackey D, Cummings S).

• Treatment effect vergelijkbaar voor high-trauma versus low trauma: 0.70 (0.52-0.96) versus 0.76 (0.69-0.84);

• Non vertebral 6 versus all nonvertebral fractures: 0.69 (0.61-0.77) versus 0.78 (0.69-0.89);

• Excluding finger and toe fractures versus all nonvertebral fractures: 0.73 (0.67-0.81) versus 0.75 (0.68-0.82)

Effects of antiresorptive treatment of various non-vertebral fracture outcomes (1242, Mackey D, Cummings S).

Time Since Prior Fracture is a Risk Modifier for Ten Year Osteoporotic Fractures: The Manitoba Bone Density

Program(Leslie, 1093)

Risico voor nieuwe fractuur clusteren in de tijd

Maastricht UMC & UHasselt

--- First fracture Subsequent fracturefrom menopause on from 1st fracture on

Van Geel, ARD, 2009

• Twee Young Investigators Award!

• Tineke van Geel (Maastricht) en Lilian van Tuyl (Amsterdam)

5- EN 10-JAARS FRACTUURRISICO: EEN NOMOGRAM (1022, Van Geel)

• 2372 postmenopausal women, 3 years follow-up;

• 382 fractures (16,1%);• Age: 1,09 per 5 years;• Low BMD: 1,23 per SD; • Prior Fracture 3.27 for fracture within last 5

years;• Prior Fracture 1.97 for fracture > 5 years ago;

1 Lancet 1997

COBRA trial results: 1 year

Change in disease activity

Arthritis & Rheumatism 2004

COBRA trial results: 4.5 years

P =0.008

0

10

20

30

40

0 1 2 3 4 5

Damage progression (Sharp/van der Heijde)

Years

COBRACOBRA

SSZSSZ

Annals of Rheumatic Diseases 2009

COBRA trial results: 11 years

CTX-1 dataset CTX-2 dataset

RANKL:OPG RANKL:OPG

CTX1 CTX2 at 3 mo

ESR at 3 mo ESR at 3 mo

Baseline damage Baseline damage

RF

R2 = 42% R2 = 46%

Best prediction models based on baseline AND follow-up measurements

• Dank voor Uw aandacht!

About FRAX: case finding by the web

www.shef.ac.uk/FRAX/ Kanis, Osteoporosis Int, 2008

Doelstellingen van FRAX

• Berekening van het 10-jaars fractuurrisico – op basis van gewogen bijdragen van klinische risicofactoren

voor osteoporose en fracturen – met en zonder resultaten van botdichtheidmeting

• Bijdrage tot het bepalen van afkappunten voor:– indicatie voor botmeting– starten van medicamenteuze behandeling

– Wat is de plaatsbepaling in de dagelijkse praktijk?

Voordelen van FRAX

• Wereldwijd bruikbaar, en gratis beschikbaar via web

• Zinvol voor: –klinische opsporing van fractuurrisico–geeft patient en arts inzicht in absoluut

fractuurrisico;–kan belangrijk zijn bij beslissing omtrent

behandeling.

Beperkingen van FRAX (1)• Houdt geen rekening met dosiseffect van risico’s

– dosis glucocorticoïden– tijdstip van en aantal voorafgaande fracturen

• Wervelfracturen tellen niet mee;• Valrisico niet meegenomen;• Enkel toepasbaar bij onbehandelde patiënten;• BMD: enkel femurhals• Geen consensus/recommendation omtrent indicaties therapie

– wel beschikbaar via rechtstreekse link met NOGG (UK)

Beperkingen/aandachtspunten FRAX (2):

– vitamine D deficiëntie– lichamelijke (in)activiteit– botmarkers– medicatie zoals anti-epileptica, aromatase

remmers en androgeen deprivatie therapie

– Het lijkt logisch met betrouwbaarheidsintervallen te werken wanneer fractuurrisico wordt berekend op basis van risicofactoren, dit is echter niet in het model geïmplementeerd.

• Het is niet mogelijk om in het model meerdere secundaire risicofactoren in te voeren, terwijl soms ook sprake is van meer dan een oorzaken van secundaire osteoporose;

Bij de FRAX calculator veranderd het fractuurrisico niet wanneer secundaire osteoporose wordt aangevinkt, en ook een BMD waarde wordt ingevuld. “dit wordt verklaard doordat BMD het risico van secundaire osteoporose teniet doet”

• FRAX geeft alleen de mogelijkheid om heuphals BMD in te voeren, terwijl met name een lage BMD in de lumbale wervelkolom geassocieerd is met een verhoogd risico op wervelfracturen.

Enkele beperkingen/aandachtspunten FRAX (3):

UK: Strategie voor interventie in FRAX-NOGG

• (elderly) women with a prior fragility fracture should be considered for treatment without the need for further assessment

• In men with or without a fragility fracture and in women without a previous fragility fracture, management strategy should be based on the assessment of the ten year probability of a major osteoporotic fracture (clinical spine, hip, forearm or humerus).

NOF richtlijn (VS) interventie

– Postmenopauzale vrouwen en mannen van 50 jaar en ouder met de volgende criteria:• Zelf gerapporteerde heup of wervelfractuur na

het 20e levensjaar• Heuphals of wervel T-score ≤−2.5• Heuphals T-score tussen −1 en −2.5 SD met een

10-jaars heup fractuur risico ≥3% of 4-fractuur risico ≥20%

Dawson-Hughes B et al., Osteoporos Int 2009. webfirst

Case finding Risicoscore ≥ 4

DEXA (VFA)

T-score ≥ -1T-score tussen -1

en -2,5

T-score ≤ -2,5of

wervelinzakking

Geen behandelingBereken FRAX

risico indien geen VFA of Wervelfoto

VFA of

WervelfotoBehandelen

Wervelinzakking

Nee Ja

BehandelenBereken FRAX

risico

NOGG Geen behandeling

NOGGBehandelen

• Dank voor Uw aandacht!