Seminar 14-10-09 - asbmr 2009
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Transcript of Seminar 14-10-09 - asbmr 2009
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!