seminar 08-12-2007 - bisphosphonate mechanism of action
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Werkingsmechanismen van Werkingsmechanismen van bestaande anti-osteoporose bestaande anti-osteoporose
medicatiesmedicaties
Werkingsmechanismen van Werkingsmechanismen van bestaande anti-osteoporose bestaande anti-osteoporose
medicatiesmedicaties
Zijn ze van belang in de keuze voor de individuele patiënt?
Wat kunnen we in de nabije toekomst verwachten?
azMaastrichtUHasselt
Veranderingen in botombouw met medicatiesVeranderingen in botombouw met medicaties
Maanden
ResorptieFormatie
Teriparatide(PTH)
BisfosfonatenOestrogenen
SERMs
% Verandering vs. baseline
Strontium Ranelaat
-100
-50
0
50
100
150
200
250
0 1 3 6 12
azMaastrichtUHasselt
Mechanisms of action of drugs to prevent fractures
Mechanisms of action of drugs to prevent fractures
Markers of
Bone resorption
Bone formation
Architecture Mineralization
Antiresorptives c
Strontium ranelate * * * cTeriparatide, Preotact
*demonstrated in animal studiesc: unchanged
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Routes and frequency of drug administration and duration of studies
Routes and frequency of drug administration and duration of studies
Drug Route Regimen Duration of studies (years)
Alendronate po d,w 4.2/10Risedronate po d,w 5/7Ibandronate po m 3
IV shot 3mZoledronate IV 15’ y 3Calcitonin nasal d 3Strontium ranelate po d 5Teriparatide SC d 1.5Preotact SC d 1.5
Po: oral intake; IV: intravenous administration; SC: subcutaneous administration; nasal: nasal spray; D: daily ; W: weekly; Y: yearlyazMaastricht
UHasselt
Anti-Fracture Effects of Drugsin primary analysis of RCT’s Anti-Fracture Effects of Drugsin primary analysis of RCT’s
Fractures prevented:
Spine Non-spine Hip
Alendronate x x x
Risedronate x x x
Ibandronate x
Zoledronate x x x
Raloxifene x
Calcitonin x
Strontium ranelate x x
rhPTH 1-34 x x
1-84 x
azMaastrichtUHasselt
Anti-Fracture Effects of Drugsin primary analysis of RCT’s and post-hoc analyses (*)
Anti-Fracture Effects of Drugsin primary analysis of RCT’s and post-hoc analyses (*)
Fractures prevented:
Spine Non-spine Hip
Alendronate x x x
Risedronate x x x
Ibandronate x x*
Zoledronate x x x
Raloxifene x x*
Calcitonin x
Strontium ranelate x x x*
rhPTH 1-34 x x
1-84 x
azMaastrichtUHasselt
Reduction of non-vertebral fractures in analyses at Reduction of non-vertebral fractures in analyses at the end of main anti-fracture studiesthe end of main anti-fracture studies
Reduction of non-vertebral fractures in analyses at Reduction of non-vertebral fractures in analyses at the end of main anti-fracture studiesthe end of main anti-fracture studies
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Risico voor nieuwe fractuur binnen het jaar na een wervelfractuur
0
5
10
15
20
25
30
Perc
ent (
%) o
f Pat
ient
s
25% nieuwe fractuur:
Niet-wervel: 5%
Wervel: 20%
Lindsay R, Geusens P et al, JAMA, 2001, 320azMaastrichtUHasselt
0,0 4,0 8,0 12,0 16,0 20,0 24,0
maanden
0,00
0,03
0,06
0,09
0,12
0,15
%
>80
50-59
60-69
70-79
n=537
n=554
n=475
n=591
Refracture incidence in 50+ women and men
(all causes, all locations)
Van Helden, Osteoporosis Int, 2006, 348Van Geel, BMC Medicine, 2007Center, JAMA, 2007
azMaastrichtUHasselt
YEARS OF FOLLOW-UP
302520151050
FR
AC
TU
RE
-FR
EE
PR
OB
AB
ILIT
Y
1,0
0,8
0,6
0,4
0,2
0,0
10% subsequent fracture 50% of subsequent fracturewithin 2 years within 5 years after initial fracture
Anti-Fracture Effects of DrugsPublished data on speed of action (in months)
Anti-Fracture Effects of DrugsPublished data on speed of action (in months)
Fractures prevented: Spine
Alendronate 12
Risedronate 6
Ibandronate 12
Zoledronate 12
Raloxifene 12
Calcitonin 36
Strontium ranelate 12
rhPTH 1-34 18
1-84 18
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Anti-Fracture Effects of DrugsAnti-Fracture Effects of DrugsPublished data on speed of effect (in months)Published data on speed of effect (in months)
Anti-Fracture Effects of DrugsAnti-Fracture Effects of DrugsPublished data on speed of effect (in months)Published data on speed of effect (in months)
Fractures prevented: references
Spine Non-spine
Alendronate 12 12 Pols, Ost Int, 1999, 461
Risedronate 6 6 Roux, CMROpin, 2004, 433
Ibandronate 12 36*
Zoledronate 12 36
Raloxifene 12
Calcitonin 36
Strontium ranelate 12 12 if >80 yrs Seeman, JBMR, 2006, 1113
rhPTH 1-34 18 18
1-84 18
* Cranney, Adachi, EULAR, 2007, AbstractazMaastrichtUHasselt
Comparisons between anti-osteoporosis drugsComparisons between anti-osteoporosis drugs
Anti-fracture studies differed in
patient selection and characteristics
fracture endpoints [clinical, vertebral (clinical, morphometric), non-vertebral (various definitions) or hip)
doses of drugs
statistical approaches (intention-to-treat or per-protocol)
concomitant use of calcium and vitamin D
trial duration
proportion of patients lost to follow-up
azMaastrichtUHasselt
Comparisons between anti-osteoporosis drugsComparisons between anti-osteoporosis drugs
Head-to-head RCTs with anti-fracture effects as primary endpoint unlikely to become available
need enormous numbers of patients
would prove extremely costly to conduct
No head-to-head RCTs with fracture prevention as primary endpoint
Thus, rates of fracture reduction and speed of onset of anti-fracture effect compared to placebo should not be compared directly and no inferences should be made regarding superiority of one efficacious treatment over another
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Meta-analysesMeta-analyses
Highest level of evidence
But results depend on patient selection
RR non-vertebral fractures:
Boonen, 2006 Cranney, 2002
Alendronate 0.86 (CI: 0.76-0.97) 0.51 (CI: 0.43-0.65)
(including non-OP) (including only ≥10 mg/d)
Risedronate 0.81 (CI: 0.71-0.92) 0.73 (CI: 0.61-0.87)
(including 3 studies) (including 7 trials)
Bone resorption markers
–100
–80
–60
–40
–20
0
Baseline Month 6 Month 12
Mea
n %
ch
ang
e
Urine NTx Serum CTx
p<0.001
p<0.001 –40%
–53% –55%
–74%
p<0.001
p<0.001
Month 3
p<0.001
Treatment difference 13%
p<0.001
Treatment difference 19%
Alendronate n = 442 429 414 365 449 443 423 382Risedronate n = 457 449 426 375 459 455 433 387
Alendronate 70 mg OW Risedronate 35 mg
OW
–100
–80
–60
–40
–20
0
Baseline Month 6 Month 12Month 3
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Hip Trochanter BMDHip Trochanter BMD
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Baseline Month 6 Month 12
p0.001
3.4%
2.1%
Mea
n %
ch
ang
e
p0.001
Treatment difference=1.4 %, p<0.001.
Alendronate (n=464)
Risedronate (n=481)
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Gastro-intestinal side effectsGastro-intestinal side effectsGastro-intestinal side effectsGastro-intestinal side effects
No significant differences between treatment groups
Number (%) of patients
Alendronate 70 mg OW
(n=515)
Risedronate 35 mg OW
(n=527)
1 upper-GI adverse
experience 116 (22.5) 106 (20.1)
Discontinued due to upper-GI
adverse experience 13 (2.5) 16 (3.0)
Discontinued due to serious
upper-GI adverse experience 0 (0.0) 1 (0.2)
azMaastrichtUHasselt
Cumulative Hip Fracture IncidenceCumulative Hip Fracture Incidence
↓43% * at Month 12
*Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63%
Baseline Month 6 Month 12
% o
f c
oh
ort
wit
h a
hip
fra
ctu
re
0.00
0.10
0.20
0.30
0.40
0.50
0.58
alendronate
risedronate
Silverman et al. Osteoporos Int. January 2007
azMaastrichtUHasselt
Extra-skeletal benefitsExtra-skeletal benefits
Raloxifene
reduced the risk of invasive breast cancer in the CORE study by 66% over 8 years
recently been approved by the FDA for the prevention of ER positive breast cancer in women at high risk
Estrogens
attenuate severe climacteric symptoms
No first-line treatment of osteoporosis alone, because of side effects (breast cancer, thromboembolisms, cardiovascular thrombotic events)
Zoledronate, given yearly within 90 days of a hip fracture
all-cause mortality -28% over 3 years when
reason for the reduced mortality in this study is not clear
azMaastrichtUHasselt Geusens et al. Nature Osteoporosis Clin Pract, 2008, in press
Safety issues Safety issues
BP
GI: adequate intake
Osteonecrosis of the jaw: <1/10 000 to 100 000 in osteoporosis
Atrial fibrillation: zoledronate in 1 of 3 studies, not with alendronare and risedronate
Flu-like symptoms at start (+/- 30% with zoledronate)
Raloxifen
Venous thrombosis
Strontium ranelate Diarrhea; venous thrombosis; DRESS (<1/10 000)
Teriparatide Cramps, dizziness
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Oplosbaarheid van alendronaat en Oplosbaarheid van alendronaat en generiekengenerieken
Oplosbaarheid van alendronaat en Oplosbaarheid van alendronaat en generiekengenerieken
Epstein, J Appl Res, 2005, 1azMaastrichtUHasselt
TherapietrouwTherapietrouw
Bisfosfonaten, na 1 jaar therapie:
40% met dagelijkse inname
50% met wekelijkse inname
60% met maandelijkse inname
70% met wekelijkse dosis in fractuurpoli met osteoporose verpleegkundige
Barrières bij artsen en patiënten
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Fundamental Components ofFundamental Components ofN-Bisphosphonate Anti-resorptive ActivityN-Bisphosphonate Anti-resorptive Activity
Fundamental Components ofFundamental Components ofN-Bisphosphonate Anti-resorptive ActivityN-Bisphosphonate Anti-resorptive Activity
Availability, Distribution,Availability, Distribution,Offset of ActionOffset of Action
Bone MineralAffinity
Bone Uptake and Release
PotencyPotency
FPPS EnzymeInhibition
Osteoclast Function
Ebetino FH, et al. J Bone Miner Res 2005;20(Suppl 1):S259Kavanagh KL, et al. http://www.rcsb.org/pdb/explore.do?structureId=1YV5; Accessed 5-Dec-06
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Differential Binding to Differential Binding to Bone MineralBone Mineral
Differential Binding to Differential Binding to Bone MineralBone Mineral
HAP Adsorption Affinity Constants at pH 7.4
0
1
2
3
4
KL/1
06 L
mo
l-1
ZOLALNIBNRIS
Adapted from Nancollas GH, et al. Bone 2006;38:617–627
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FPPS Enzyme Inhibition Potency (ICFPPS Enzyme Inhibition Potency (IC5050))Amount of N-BP needed to inhibit 50% of max. enzyme activityAmount of N-BP needed to inhibit 50% of max. enzyme activity
FPPS Enzyme Inhibition Potency (ICFPPS Enzyme Inhibition Potency (IC5050))Amount of N-BP needed to inhibit 50% of max. enzyme activityAmount of N-BP needed to inhibit 50% of max. enzyme activity
1 Kavanagh KL, et al. PNAS 2006;103:7829-7834. 2 Dunford JE, et al. Unpublished data (2006)
FPP-S
FPP-S
IC50 Final (nM)
0 5 10 15 20 25 30 100 200 300 400
ALN
IBN
RIS
ZOL
ALN
RIS
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Pharmacokinetics of bisphosphonatesPharmacokinetics of bisphosphonates
azMaastrichtUHasselt Russell, Bone, 2006
QCT 12-Month Percent Changes from BLQCT 12-Month Percent Changes from BLCompleter Population: Spine BMDCompleter Population: Spine BMD
QCT 12-Month Percent Changes from BLQCT 12-Month Percent Changes from BLCompleter Population: Spine BMDCompleter Population: Spine BMD
r=0.3133 r=0.46703
(Average of L1 and L2 for entire vertebra excluding transverse process,
g/cm3)
(Average of L1 and L2 for vertebral trabecular BMD,
g/cm3)
P=0.0131
P=0.0194
0
5
10
15
20
25
30
Integral Spine Trabecular Spine
Perc
ent
Change fro
m B
L
Prior RIS (n=112) Prior ALN (n=119)
azMaastrichtUHasselt
Per
cen
t ch
ang
e in
BM
D
No OP drug use (n=144)
(+6 months) (+18 months) (+30 months)
Antiresorptive starting before 6 months and continued for at least 24 months (n = 65)
Antiresorptive starting after 6 months and continued for at least 18 months (n = 34)
Endpoint Visit 1 Visit 2 Visit 3
Lindsay et al. Program & Abstracts, Endocrine Society 84th Ann Mtg June 19-22, 2002; #OR35-6
Lumbar Spine BMD TPTD20 Followed with Antiresorptive Treatment
Fracture Prevention Trial Baseline through Follow-up Study
Lumbar Spine BMD TPTD20 Followed with Antiresorptive Treatment
Fracture Prevention Trial Baseline through Follow-up Study
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Strategie na 5 jaar behandeling met Strategie na 5 jaar behandeling met bisfosfonatenbisfosfonaten
Strategie na 5 jaar behandeling met Strategie na 5 jaar behandeling met bisfosfonatenbisfosfonaten
Start Fractuur T-score AR* Strategie
tijdens 5 jr F.U. na 5 jr
Geen fractuur
T<-2.5 neen T<-2.5 hoog continuren
neen T>-2.0 laag stop + opvolging
Fractuur
Wervel neen any hoog continueren
ja any hoog switch naar PTH
Niet-wervel neen T<-2.5 hoog continueren
T>-2.0 intermediair stop /continueren?
ja any hoog switch naar PTH
AR*: absoluut risico voor fracturen
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Botombouw na de menopauzeBotombouw na de menopauze
www.courses.washington.edu/ bonephys/opalgo.gif azMaastrichtUHasselt
En de toekomst?En de toekomst?
azMaastrichtUHasselt
OB
RANKL OPG
Osteocyt
Resorption Formation Secondary 20 days 100 days mineralisation
OC
Proteases
IGF-1,2IGF-BPs
ActivationPTH, PTHrP,1.25(OH)2D3
calcium deficiencyInhibition
Oestrogens
RANKMechanic stimuli
TGFB
Bone turnoverBone turnover
LC
PG, NOSclerostin
DKKOC = osteoclastOB = osteoblastLC = lining cell
Wnt
azMaastrichtUHasselt
Replication
Pre-OB Pre-OC
Bone formation
Osteoblasts
Apoptosis
Bone resorption
Osteoclasts
Activity Bone Matrix
Synthesis
OPG
RANK RANKL
Dual Effects of Strontium RanelateDual Effects of Strontium RanelateDual Effects of Strontium RanelateDual Effects of Strontium Ranelate
Differentiation
CaSR
CaSR
+ Other?
Brennan, CTI, 2006 (ECTS 2006)
Anti-RANKL: Effect op merker van botresorptie (CTX-I) met SC injectie om de 6 maanden
Phase 2: Postmenopausal Women with Low BMD
McClung MR, et al. N Engl J Med. 2006;354:821-831
12
NS vs placeboP < 0.001 vs alendronate
P < 0.001 vs placebo
-100
-80
-60
-40
-20
0
20
0 2 4 6 8 10Time (Months)
Mea
n P
erce
nt
Ch
ang
e fr
om
Bas
elin
e
Placebo, N = 46
Denosumab 14 mg, N = 53
Denosumab 60 mg, N = 47
Denosumab 100 mg, N = 41
Denosumab 210 mg, N = 46
Alendronate 70 mg/wk, N = 46
azMaastrichtUHasselt
Wnt signalling and osteoblastsWnt signalling and osteoblasts
Baron, Endocrinology, 2007azMaastrichtUHasselt
Disease and Therapy Mediated by the Disease and Therapy Mediated by the Calcium-Sensing ReceptorCalcium-Sensing Receptor
Disease and Therapy Mediated by the Disease and Therapy Mediated by the Calcium-Sensing ReceptorCalcium-Sensing Receptor
azMaastrichtUHasselt
ConclusionsConclusionsConclusionsConclusions
Anti-osteoporosis agents differ in size and speed of anti-fracture effects between agents, but these differences should be interpreted with caution in the absence of head-to-head RCTs
Anti-osteoporosis agents differ in:
mechanisms of action between classes
pharmacokinetics within classes
extra-skeletal benefits
side effects
these differences can be helpful when deciding about treatment
Future: Prevention of developing high risk
Sequential treatment with anabolics followed by preservation with anti-resorptives
azMaastrichtUHasselt
Contributors to secondary osteoporosis in Contributors to secondary osteoporosis in patients with osteoporosispatients with osteoporosis
Contributors to secondary osteoporosis in Contributors to secondary osteoporosis in patients with osteoporosispatients with osteoporosis
Postmenopausal women, sent to an osteoporosis clinic, with T-score <-2.5, n=664
33% had known contributors to secondary osteoporosis
33% of the other presumably healthy women had newly diagnosed contributors
Tannenbuam, JCEM, 2002, 4431
FRACTURE-FREE PROBABILITY OF WOMEN WITH ONE FRACTURE-FREE PROBABILITY OF WOMEN WITH ONE FRACTURE (N = 681) FRACTURE (N = 681)
AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)
FRACTURE-FREE PROBABILITY OF WOMEN WITH ONE FRACTURE-FREE PROBABILITY OF WOMEN WITH ONE FRACTURE (N = 681) FRACTURE (N = 681)
AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)
YEARS OF FOLLOW-UP
302520151050
FR
AC
TU
RE
-FR
EE
PR
OB
AB
ILIT
Y
1,0
0,8
0,6
0,4
0,2
0,0
Years of follow up
1 fracture2nd fracture
16%
54%
azMaastrichtUHasselt
Overall Initial and Subsequent Fracture Risk Overall Initial and Subsequent Fracture Risk by Gender (Dubbo study, mean follow up 15-by Gender (Dubbo study, mean follow up 15-
16 yrs)16 yrs)
Overall Initial and Subsequent Fracture Risk Overall Initial and Subsequent Fracture Risk by Gender (Dubbo study, mean follow up 15-by Gender (Dubbo study, mean follow up 15-
16 yrs)16 yrs)
Center, JAMA, 2007, 387Center, JAMA, 2007, 387
% of refractures within 5 years 41% 52%
azMaastrichtUHasselt
UHasseltazMaastricht
0,0 4,0 8,0 12,0 16,0 20,0 24,0
maanden
0,00
0,03
0,06
0,09
0,12
0,15
%
>80
50-59
60-69
70-79
n=537
n=554
n=475
n=591
Refracture incidence according to age
>80 (n=537)
70-79 (n=591)
60-69 (n=475)
50-59 (n=554)
Months Van Helden, Osteoporosis Int, 2006, 348azMaastrichtUHasselt
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