Moderne behandeling osteoporose
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Transcript of Moderne behandeling osteoporose
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Moderne behandeling van osteoporose
Prof P Geusens, MD, PhD Maastricht UMC & UHasselt
MUMC&UHasselt
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Fractuurpreven>e bij 50-‐plussers: een 5-‐stappenplan
MUMC&UHasselt
Case finding Risico evalua1e Differen1eel diagnose Therapie Follow up
1/ Recente fractuur 2/ Klinische risicofactoren zonder recente fractuur
DXA Beeldvorming van WK Klinische risicofactoren
Medische geschiedenis Klinisch onderzoek Laboratorium onderzoek
Overleg Leefs1jl Calcium en vitamine D Medica1es (PO, IV, SC) Valpreven1e
Compliance Toleran1e Efficiën1e Duur van therapie
www.CBO.Nl
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Fracture Rates, Popula>on BMD Distribu>on and Number of Fractures (in NORA)
Siris, E. S., et al. Arch Intern Med 2004 164:1108-‐12,
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UHasselt azMaastricht
Postmenopausal women with a clinical fracture (n=354) (%)
Osteoporosis: 41% Clinical risk factors: 61% Fall risk factors: 86%
Van Helden, JBJS, 2008
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Independent predictors of fracture risk at specific sites in women and men without osteoporosis at the femoral neck
Nguyen, JCEM, 2007, 955 MaastrichtUMC & UHasselt
Incorporated in the Garvan Fracture Risk Calculator http://www.garvan.org.au/bone-fracture-risk/
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Moderne behandeling voor fractuurpreven>e
Prof P Geusens, MD, PhD Maastricht UMC & UHasselt
MUMC&UHasselt
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Wie behandelen? 50-‐plussers
CBO NHG
2011 2012 • Medica>e
– Osteoporose (T<-‐2.5) x x
– Wervelfractuur, ona]ankelijk van BMD • ≥ 50 jaar x
• ≥ 60 jaar x
– Osteopenie met andere risicofactoren x – Ziekten/medica>es met fractuurrisico x x
• Valpreven>e – bij vallers x x
MUMC&UHasselt
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Wanneer starten?
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Mechanical loading influences mesenchymal stem cell (MSC) differen>a>on
MUMC & UHasselt Ozcivici, E. et al. Nat. Rev. Rheumatol. 6, 50–59
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Associa>on between altered physical ac>vity and bone development
n=833 men, 24 yrs old, 5 yr follow up
Nilson, JBMR, 2012, 1206
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Five-‐year changes in cor>cal CSA and trabecular volumetric BMD of the >bia according to changes in
physical ac>vity
Nilson, JBMR, 2012, 1206 CSA: cross-sectional area
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Case finding: 2 klinische uitgangssitua>es
1. Pa>ënt met recente fractuur • preven>e van volgende fractuur
2. Pa>ënt met risicofactoren zonder recente fractuur • preven>e van 1ste fractuur
MUMC&UHasselt
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Es>mated age-‐standardized distribu>on of incident low-‐trauma fractures by risk category (BMD and prior fracture) for men and
women 50–90 yr of age.
azMaastricht & UHasselt
Repeat fractures: 24% 40%
Langsetmo, JBMR, 2009, 1515
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DE FRACTUURPOLI
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Most subsequent fractures occur within short term amer a first fracture
azMaastricht & UHasselt
Repeat Repeat Post-hip fracture vertebral fractures non-vertebral
Lindsay, JAMA, 2001 Van Geel, ARD, 2008 Von Friedendorf, JBMR, 2008
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Number of past fractures: 0, 1, 2, >2 and 10 yr fracture risk
(women, 70 jr, 60 kg, 170 cm)
Van Geel et al. Maturitas 2010
GARVAN
10 yr fracture risk
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Eisman, JBMR, 2012, 2039
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Fracture Liaison Service
• A high propor>on of secondary fractures can be prevented by appropriate management
• An ini>al fracture in an at-‐risk person is sufficient grounds to require a full evalua>on – BMD
– fracture risk assessment
• If not contraindicated, ini>a>on of treatment for underlying bone fragility
Eisman, JBMR, 2012, 2039
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An>resorp>ve treatment effects (summary hazard ra>o [HR], 95% CI) for composite nonvertebral fracture outcomes
Mackey, JBMR, 2011, 2411
Six: hip, pelvis, leg, wrist, humerus, and clavicle
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HET BELANG VAN HET HERKENNEN VAN WERVELFRACTUREN
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Densitometric vertebral fracture assessment (VFA)
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Specificity and nega>ve predic>ve value of VFA vs X-‐rays
Chapurlat RD, et al. Osteoporos Int. 2006;17(8):1189-‐1195.
L5 L4 L3 L2 L1 T12 T11 T10 T9
Specificity Negative predictive value
0.30
T8 T7 T6 T5 T4
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Spec
ifici
ty a
nd n
egat
ive
pred
ictiv
e va
lue
Vertebral level
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jan
4
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bon
2
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Indica>e voor beeldvorming van de wervels VFA/RX
• Bij klinisch vermoeden van wervelfractuur – Anamnese
– Kliniek • Bij aanwezigheid van risicofactoren
– Recente niet-‐wervelfractuur – Risicofactoren
• Score >3 • Medica>es/ziekten
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Case finding: 2 klinische uitgangssitua>es
1. Pa>ënt met recente fractuur • preven>e van volgende fractuur
2. Pa>ënt met risicofactoren zonder recente fractuur • preven>e van 1ste fractuur
MUMC&UHasselt
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Es>mated age-‐standardized distribu>on of incident low-‐trauma fractures by risk category (BMD and prior fracture) for men and
women 50–90 yr of age (CaMos study, n= 2179 men and 5269 women, !yr follow up)
azMaastricht & UHasselt
First fractures: 76% 60%
Langsetmo, JBMR, 2009, 1515
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Risicofactoren voor het optreden van een fractuur, met risicoscore: bij een totaal van 4 punten of meer wordt een DXA geadviseerd
CBO vs. NHG (verschillen in geel)
Risicofactor Risicoscore Gewicht <60 kg en/of BMI < 20 kg/m2 1 Leeftijd > 60 jaar 1 Leeftijd > 70 jaar (>60 jaar niet extra meetellen) 2 Eerdere fractuur na het 50e levensjaar >2 jaar geleden 1, 2 als >1 fractuur Heupfractuur bij een ouder 1 Verminderde mobiliteit 1 Meer dan 1 keer vallen in het laatste jaar 1 Reumatoïde artritis 1 Aandoening/medicatie met secundaire osteoporose 1 Gebruik van glucocorticoïden (>3 maanden; ≥7,5 mg/dag) 4
MUMC&UHasselt
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WERKINGSMECHANISMEN VAN MEDICATIES
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MUMC & UHasselt
Maanden
Resorptie Formatie
Teriparatide/PTH Bisfosfonaten SERMs
Denosumab
% Verandering vs. baseline
Veranderingen in botombouw met medica>es
Strontium Ranelaat
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Effect of Denosumab and Bisphosphonates on Osteoclasts
RANKL = RANK ligand; OPG = osteoprotegerin
RANKL
RANK
OPG
Denosumab
Denosumab, a soluble inhibitor, blocks RANKL
Denosumab inhibits osteoclast forma1on, func1on, and survival
X Bone
Precursor osteoclast
BPs bind to bone mineral at sites of bone resorp1on
BP are engulfed (endocytosed) by osteoclasts during the process of bone resorp1on
BP BP BP BP
BP BP BP BP
BP
Bone
BPs cause loss of resorp1ve func1on (via inhibi1on of FPPS and prenyla1on of GTP-‐ases), but ‘disabled’ osteoclasts may persist
BP BP BP BP
BP BP
BP BP
BP
Bone BP BP BP BP
BP = bisphosphonate; FPPS = farnesyl pyrophosphate synthase; GTP = guanosine-‐5'-‐triphosphate Baron et al., Bone 2011; 48(4):677-‐692. Russell RG, et al. Osteoporos Int. 2008;19:733-‐759.
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Denosumab Binds RANK Ligand and Inhibits Osteoclast Forma>on, Func>on, and Survival
RANKL
RANK
OPG
Denosumab
Bone Forma1on Bone Resorp1on Inhibited
Osteoclast Forma1on, Func1on, and Survival Inhibited
CFU-‐GM Prefusion Osteoclast
Osteoblasts
Hormones Growth Factors Cytokines
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-‐342.
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*P ≤ 0.0001. Adapted from Brown JP, et al. J Bone Miner Res. 2009;24:153-‐161.
Effect of Treatment on Bone Turnover Markers Phase 3: The DECIDE Trial
Med
ian (Q1, Q3) Cha
nge
From
Baseline (%
)
Study Month
sP1NP sCTx-‐1
Study Month
Med
ian (Q1, Q3) Cha
nge
From
Baseline (%
) -‐100
-‐80
-‐60
-‐40
-‐20
0
20
0 1 3 6 9 12 -‐100
-‐80
-‐60
-‐40
-‐20
0
20
0 1 3 6 9 12
* * * *
Denosumab 60 mg Q6M Alendronate 70 mg QW
*
* * * *
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Denosumab Re-‐treatment and Changes to Serum CTx and BSAP Levels
Phase 2: Postmenopausal Women With Low BMD
Adapted from Miller PD, et al. Bone. 2008;43:222-229.
Re-treatment 60 mg Q6M
Discontinued Treatment
Placebo 30 mg Q3M
Serum CTx BSAP
Months
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
0 6 12 18 24 30 36 42 48
Med
ian
ng/m
L (Q
1, Q
3)
Months
0
5
10
15
20
25
0 6 12 18 24 30 36 42 48 M
edia
n m
cg/L
(Q1,
Q3)
Re-treatment 60 mg Q6M
Discontinued Treatment
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Denosumab Re-‐treatment and Changes in Lumbar Spine and Total Hip BMD
Phase 2: Postmenopausal Women With Low BMD
Adapted from Miller PD, et al. Bone. 2008;43:222-229.
Lumbar Spine Total Hip
Perc
ent C
hang
e (L
S M
ean
± SE
)
Months
-6
-4
-2
0
2
4
6
8
Months
0 6 12 18 24 36 48 -4 -2 0 2 4 6 8
10 12 14
0 6 12 18 24 36 48
Re-treatment 60 mg Q6M
Discontinued Treatment
Re-treatment 60 mg Q6M
Discontinued Treatment
Placebo 30 mg Q3M
Perc
ent C
hang
e (L
S M
ean
± SE
)
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MUMC&UHasselt 1. Kendler DL. Osteoporos Int 2010;21:837–846.
Van de pa1ënten die een voorkeur rapporteerden, vermeldden 65% van de Prolia® groep en 63% van de alendronaat groep dat ze de voorkeur gaven aan de injec1e eenmaal om de 6 maanden, wat neerkomt op gemiddeld 64% van de pa1ënten die de voorkeur gaven aan een injec1e om de 6 maanden. Globaal drukte 83% van de pa1ënten een voorkeur uit. Bijgevolg, van de pa1ënten die een voorkeur uitdrukten, verkoos 77% (64/83) de injec1e om de 6 maanden.
Subcutane injec1e eenmaal om de 6 maanden
De pa>ënten verkiezen een eenvoudige subcutane injec>e om de 6 maanden boven wekelijkse orale table|en
Percentage pa1ënten die een grotere voorkeur voor een schema rapporteerden1
Orale tablet eenmaal per week
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MUMC&UHasselt Freemantle, Osteoporos Int. 2012, 317
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Effect of teripara>de/PTH on bone
1. Stimulation of RANKL 2. Inhibition of sclerostin production in osteoblasts production by osteocytes
RANKL
RANK OPG
Multinucleated osteoclast
PTH
Osteoblast
Baron, JCEM, 2012
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‡p<0.001 Saag KG, et al. N Engl J Med. 2007;357(20):2028-2039.
Alendronate n= Teriparatide n=
Alendronate Teriparatide
195 198
184 183
173 178
159 170
148 156
0 3 6 12 18 Endpoint 0
2
4
6
8
10 C
hang
e in
BM
D, M
ean
± SD
(%)
Time (Months)
‡
‡
‡
‡
195 198
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‡p<0.001
CTX = C-terminal telopeptitde of type I collagen; IRQ = Interquartile range; PINP = Procollagen type I N-terminal propeptide. Saag KG, et al. N Engl J Med. 2007;357(20):2028-2039.
Alendronate
Teriparatide
Time (Months) Cha
nge
from
Bas
elin
e, M
edia
n ±
IRQ
(%)
0 1 6 18
0
-50
-100
50
100
150
200
Time (Months) 0 1 6 18
0
-50
-100
50
100
150
200
Serum PINP Serum CTX
‡
‡ ‡
‡ ‡
‡
Cha
nge
from
Bas
elin
e, M
edia
n ±
IRQ
(%)
ALN n=
TPTD n=
79
71
75
66
71
64
91
85
99
98
85
86
76
77
100
99
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Effect of stron>um ranelate on bone forma>on
MUMC&UHasselt Meunier, NEJM Rizzoli, Rheum Int, 2010, 1341 Rizzoli, OI, 2012, 305
+20%
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Effect of stron>um ranelate on bone resorp>on
MUMC&UHasselt Meunier, NEJM Rizzoli, Rheum Int, 2010, 1341 Rizzoli, OI, 2012, 305
-10%
+8%
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Posi>eve associa>es
• An>-‐resorp>va verminderde mortaliteit
• Denosumab preven>e van wervelfracturen bij mannen met aromatase remmers bij prostaatCa
• SERMs preven>e van borstkanker (US)
• Stron>um ralenlaat preven>e van knie artrose • Teripara>de verbetering van rugpijn
MUMC&UHasselt
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Kaplan-‐Meier survival curves according to osteoporosis medica>on for women with osteoporo>c fractures aged 60–74 yr (A), aged 75 yr (B). The P value refers to
differences between treatment groups.
MUMC&UHasselt Center, JCEM, 2011,1006
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NIEUWE THERAPIEËN
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Disease and Therapy Mediated by the Calcium-‐Sensing Receptor
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Ronacaleret (calcily>c)
MUMC&UHasselt
PTH
sCa
BSAP
CTX
BMD Spine
BMD Hip
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MUMC&UHasselt
S
S
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MUMC&UHasselt
S
S
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MUMC&UHasselt
CTR
RANK M-CSF
OSCAR IL-1R
TNFR
S
S
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MUMC&UHasselt
Odanaca>b
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Changes in bone markers in postmenopausal women treated with odanaca>b 50 mg weekly for 3 years
MUMC&UHasselt
uNTX sBSAP
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Osteopon>n (BSP)
MUMC&UHasselt Akeila Bellahcène, Nature Reviews Cancer 8, 212-226 (March 2008)
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SRC kinase inhibi>on
MUMC&UHasselt
placebo; 60 mg;125 mg;185 mg; and 250mg saracatinib
Hannon, JBMR, 2010, 463
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Maastricht UMC & UHasselt
Bone remodeling during life
Pre-meno
1 yr post-meno
13 yr post-meno
Osteo-porosis
Recker et al, JBMR 2004; 10 : 1628-1633
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The osteocyte, the mechanosensor of bone
MUMC&UHasselt Baron, JCEM, 2012
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29 Sept 2010
Wnt signalling and osteoblasts and osteocytes
MUMC & UHasselt Baron, Endocrinology, 2007
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Scleros>n inhibi>on in monkeys
MUMC&UHasselt
Increase in P1NP Increase Increase in Increase mineral apposi>on No change in CTX in trabecular bone endocor>cal rate and in bone forma>on
and periosteal rate bone apposi>on
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High resolu>on peripheral quan>ta>ve computer tomography (HRpQCT) in fracture healing
1 week post-‐fracture 4 weeks post-‐fracture 3D-‐model of distal radius one week post-‐fracture
Xtreme CT project, MaastrichtUMC
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10-‐yr fracture risk according to number of past fractures and recent falls
(women, 70 jr, 60 kg, 170 cm)
Van Geel et al. Maturitas 2010
GARVAN no fall
2 falls
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The fracture cascade in 834 consecu>ve fracture pa>ents in the Fracture
Liaison Service (Maastricht University)
Risk factors Only Bone Bone + Fall RFs Only Fall No RFs
RFs RFs Number 183 334 170 147 % 22% 40% 20% 18%
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Postmenopausal and senile sarco-‐osteopenia
Sarcopenia Bone fragility
Genetics, age, hormones, cytokines, physical activity, body composition, vitamin D status
Comorbidity
Falls, frailty disability, mortality, cost
Interaction Mechanostat
Physical activity
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MUMC & UHasselt Arras, France
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Only post-‐mortem fractures: a long way to go
MUMC & UHasselt Arras, France