Seminar 08-12-2007 - bisphosphonate mechanism of action
1. Werkingsmechanismen vanWerkingsmechanismen van
bestaande anti-osteoporosebestaande anti-osteoporose
medicatiesmedicaties
Zijn ze van belang in de keuze voor
de individuele patiënt?
Wat kunnen we in de nabije
toekomst verwachten?
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3. Mechanisms of action of drugs to prevent
fractures
Markers of
Bone
resorption
Bone
formation
Architecture Mineralization
Antiresorptives ïą ïą c ïĄ
Strontium ranelate ïą* ïĄ* ïĄ* c
Teriparatide, Preotact ïĄ ïĄïĄ ïĄ ïą
*demonstrated in animal studies
c: unchanged
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4. Routes and frequency of drug
administration and duration of studies
Drug Route Regimen Duration of studies
(years)
Alendronate po d,w 4.2/10
Risedronate po d,w 5/7
Ibandronate po m 3
IV shot 3m
Zoledronate IV 15â y 3
Calcitonin nasal d 3
Strontium ranelate po d 5
Teriparatide SC d 1.5
Preotact SC d 1.5
Po: oral intake; IV: intravenous administration; SC:
subcutaneous administration; nasal: nasal spray; D:
daily ; W: weekly; Y: yearlyazMaastricht
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5. Anti-Fracture Effects of Drugs
in primary analysis of RCTâs
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
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6. Anti-Fracture Effects of Drugs
in primary analysis of RCTâs 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
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7. Reduction of non-vertebral fractures in analyses atReduction of non-vertebral fractures in analyses at
the end of main anti-fracture studiesthe end of main anti-fracture studies
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8. Risico voor nieuwe fractuur
binnen het jaar na een wervelfractuur
0
5
10
15
20
25
30
Percent(%)ofPatients
25% nieuwe fractuur:
Niet-wervel: 5%
Wervel:
20%
Lindsay R, Geusens P et al, JAMA, 2001, 320azMaastricht
UHasselt
9. 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, 348
Van Geel, BMC Medicine, 2007
Center, JAMA, 2007
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YEARS OF FOLLOW-UP
302520151050
FRACTURE-FREEPROBABILITY
1,0
0,8
0,6
0,4
0,2
0,0
ï10% subsequent fracture 50% of subsequent fracture
within 2 years within 5 years after initial fracture
10. Anti-Fracture Effects of Drugs
Published 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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11. Anti-Fracture Effects of DrugsAnti-Fracture Effects of Drugs
Published 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, Abstract
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12. Comparisons between
anti-osteoporosis drugs
ïź Anti-fracture studies differed in
ïź patient selection and characteristics
ïź fracture endpoints [clinical, vertebral (clinical, morphometric),
non-vertebral (various definitions) or hip)
ïź doses of drugs
ïź statistical approaches (intention-to-treat or per-protocol)
ïź concomitant use of calcium and vitamin D
ïź trial duration
ïź proportion of patients lost to follow-up
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13. Comparisons between
anti-osteoporosis drugs
ïź Head-to-head RCTs with anti-fracture effects as primary endpoint
unlikely to become available
ïź need enormous numbers of patients
ïź would prove extremely costly to conduct
ïź No head-to-head RCTs with fracture prevention as primary
endpoint
ïź 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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17. Gastro-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)
â„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)
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18. Cumulative Hip Fracture Incidence
â43% *
at Month 12
*Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63%
Baseline Month 6 Month 12
%ofcohortwithahipfracture
0.00
0.10
0.20
0.30
0.40
0.50
0.58
alendronate
risedronate
Silverman et al. Osteoporos Int. January 2007
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19. Extra-skeletal benefits
ïź Raloxifene
ïź reduced the risk of invasive breast cancer in the CORE study by 66%
over 8 years
ïź recently been approved by the FDA for the prevention of ER positive
breast cancer in women at high risk
ïź Estrogens
ïź attenuate severe climacteric symptoms
ïź No first-line treatment of osteoporosis alone, because of side effects
(breast cancer, thromboembolisms, cardiovascular thrombotic events)
ïź Zoledronate, given yearly within 90 days of a hip fracture
ïź all-cause mortality -28% over 3 years when
ïź reason for the reduced mortality in this study is not clear
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20. Safety issues
ïź BP
ïź GI: adequate intake
ïź Osteonecrosis of the jaw: <1/10 000 to 100 000 in osteoporosis
ïź Atrial fibrillation: zoledronate in 1 of 3 studies, not with alendronare and
risedronate
ïź Flu-like symptoms at start (+/- 30% with zoledronate)
ïź Raloxifen
ïź Venous thrombosis
ïź Strontium ranelate
ïź Diarrhea; venous thrombosis; DRESS (<1/10 000)
ïź Teriparatide
ïź Cramps, dizziness
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21. Oplosbaarheid van alendronaat enOplosbaarheid van alendronaat en
generiekengenerieken
Epstein, J Appl Res, 2005, 1
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22. Therapietrouw
ï± Bisfosfonaten, na 1 jaar therapie:
ï± 40% met dagelijkse inname
ï± 50% met wekelijkse inname
ï± 60% met maandelijkse inname
ï± 70% met wekelijkse dosis in
fractuurpoli met osteoporose
verpleegkundige
ï± BarriĂšres bij artsen en patiĂ«nten
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23. Fundamental Components ofFundamental Components of
N-Bisphosphonate Anti-resorptive ActivityN-Bisphosphonate Anti-resorptive Activity
Availability, Distribution,Availability, Distribution,
Offset of ActionOffset of Action
Bone Mineral
Affinity
Bone Uptake and Release
PotencyPotency
FPPS Enzyme
Inhibition
Osteoclast Function
Ebetino FH, et al. J Bone Miner Res 2005;20(Suppl 1):S259
Kavanagh KL, et al. http://www.rcsb.org/pdb/explore.do?structureId=1YV5; Accessed 5-Dec-06
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24. Differential Binding toDifferential Binding to
Bone MineralBone Mineral
HAP Adsorption Affinity Constants at pH 7.4
0
1
2
3
4
KL/106
Lmol-1
ZOLALNIBNRIS
Adapted from Nancollas GH, et al. Bone 2006;38:617â627
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25. 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
IC50Final (nM)
0 5 10 15 20 25 30 100 200 300 400
ALN
IBN
RIS
ZOL
ALN
RIS
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27. QCT 12-Month Percent Changes from BLQCT 12-Month Percent Changes from BL
Completer 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
I nt egral Spine Trabecular Spine
PercentChangefromBL
Prior RI S (n= 112) Prior ALN (n= 119)
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28. PercentchangeinBMD
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
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29. Strategie na 5 jaar behandeling metStrategie 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 fracturenazMaastricht
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30. Botombouw na de menopauze
www.courses.washington.edu/ bonephys/opalgo.gif
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32. OB
RANKL OPG
Osteocyt
Resorption Formation Secondary
20 days 100 days mineralisation
OC
Proteases
IGF-1,2
IGF-BPs
Activation
PTH, PTHrP,1.25(OH)2D3
calcium deficiency
Inhibition
Oestrogens
RANK
Mechanic stimuli
TGFB
Bone turnoverBone turnover
LC
PG, NO
Sclerostin
DKK
OC = osteoclast
OB = osteoblast
LC = lining cell
Wnt
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33. ïĄ Replication
Pre-OB Pre-OC
ïĄ Bone formation
Osteoblasts
ïĄ Apoptosis
ïą Bone resorption
Osteoclasts
ïą Activity
ïĄ Bone Matrix
Synthesis
ïĄ OPG
RANKïą RANKL
Dual Effects of Strontium RanelateDual Effects of Strontium Ranelate
ïą Differentiation
CaSR
CaSR
+ Other?
Brennan, CTI, 2006 (ECTS 2006)
34. 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 placebo
P < 0.001 vs alendronate
P < 0.001 vs placebo
-100
-80
-60
-40
-20
0
20
0 2 4 6 8 10
Time (Months)
MeanPercentChange
fromBaseline
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
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35. Wnt signalling and osteoblasts
Baron, Endocrinology, 2007
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36. Disease and Therapy Mediated by theDisease and Therapy Mediated by the
Calcium-Sensing ReceptorCalcium-Sensing Receptor
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37. ConclusionsConclusions
ïź 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
ïź Anti-osteoporosis agents differ in:
ïź mechanisms of action between classes
ïź pharmacokinetics within classes
ïź extra-skeletal benefits
ïź side effects
ïź these differences can be helpful when deciding about treatment
ïź Future:
ïź Prevention of developing high risk
ïź Sequential treatment with anabolics followed by preservation with anti-resorptives
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38. Contributors to secondary osteoporosis inContributors 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
39. FRACTURE-FREE PROBABILITY OF WOMEN WITH ONEFRACTURE-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
FRACTURE-FREEPROBABILITY
1,0
0,8
0,6
0,4
0,2
0,0
Years of follow up
1 fracture2nd fracture
16%
54%
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40. Overall Initial and Subsequent Fracture RiskOverall 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%
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Alendronate significantly decreased both NTx (1 month) and PINP (3 months). The suppression of bone turnover with alendronate was maintained through month 12. Conversely, teriparatide significantly increased both markers of bone remodeling. The increases of the bone formation marker, PINP, were vigorous and rapid (113% above baseline at 1 month), peaking at 6 months of treatment (251% increase above baseline. The increases in the bone resorption marker, NTx, were of far smaller magnitude (58% at peak), reached significance only after 3 months of treatment, and lagged behind those of PINP. Thus, the different effects of the two drugs on bone remodeling were evident after 1 month of treatment, and there were significant differences (P<0.001) between the treatment groups in each marker at each time point (months 1,3,6,12). ___________________ McClung, et al. Differential effects of teriparatide and alendronate on markers of bone remodeling and areal and volumetric bone density in women with osteoporosis. J Bone Miner Res 2003:18(Suppl 2):S40.
Key points: After 12 months, the risedronate cohort had a 43% lower incidence of hip fracture than the alendronate cohort. This reduction is based upon an adjusted relative rate reduction. Adjustments were made based on baseline: Hip Age Estrogen use Number of medications History of hospitalizations The percent of cohort with fracture is very similar during the first 3 month (no separation) There is separation of the Kaplan-Meier curves from 3-12 months Background: The time to event plot is crude (unadjusted) fracture incidence, the 43% reduction is adjusted. Patients at risk at each time point (fracture events) BL 3 month 6 month 9 month 12 month Alendronate 21615 (0) 21590 (25) 12993 (54) 8677 (69) 5582 (80) Risedronate 12215 (0) 12202 (13) 6847 (19) 4319 (27) 2584 (29)
Key spoken message: â There are 2 fundamental components of how nitrogen containing bisphosphonates work and exhibit their anti-resorptive effects. These are how they bind to the bone and how they affect the enzyme which is essential for osteoclast activityâ Iâm going to start talking on the first one â Bone Mineral Affinity Background Terms âpotencyâ and âaffinityâ: Potency: The amount of drug needed to produce an effect Affinity: A chemical property (ie, force) that causes the drug to associate with a receptor, protein binding pocket, or other surface. Risedronate image used with permission of F.H. Ebetino, P&G Pharmaceuticals FPPS image: Kavanagh, K.L., Guo, K., Oppermann, U. Human farnesyl diphosphate synthase complexed with the clinical inhibitor risedronate To be Published (http://dx.doi.org/10.2210/pdb1yv5/pdb)
Key spoken message: â When comparing the mineral binding, we see differences between the bisphosphonates. However, the correlation between bone mineral binding and the clinical efficacy is not fully clear yetâ
Key spoken message: â This shows the amount of bisphosphonate needed to inhibit the enzyme by 50%. We see here heterocyclic bisphosphonates (ie zoledronate and risedronate) have a higher potency for enzyme inhibition than the alkly bisphosphonates (eg alendronate and ibandronate)â
2ef2143t; 13, 15
Protocol 054 - PBO patients Left: PBO patient with BV/TV of 22% - plates with holes Right - PBO patient with BV/TV of 8% - mostly rods Resolution 20 ï m- surface rendered images