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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2. Veranderingen in botombouw met medicaties
Maanden
Resorptie
Formatie
Teriparatide
(PTH)
Bisfosfonaten
Oestrogenen
SERMs
% Verandering vs. baseline
Strontium Ranelaat
-100
-50
0
50
100
150
200
250
0 1 3 6 12
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3. Mechanisms of action of drugs to prevent
fractures
Markers of
Bone
resorption
Bone
formation
Architecture Mineralization
Antiresorptives   c 
Strontium ranelate * * * c
Teriparatide, Preotact    
*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 15’ 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 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
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6. Anti-Fracture Effects of Drugs
in 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
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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
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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
10% 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
 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
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13. Comparisons 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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14. Meta-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)

15. Bone resorption markers
–100
–80
–60
–40
–20
0
Baseline Month 6 Month 12
Mean%change
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 = 442 429 414 365 449 443 423 382
Risedronate 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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16. Hip 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
p≤0.001
3.4%
2.1%
Mean%change
p≤0.001
Treatment difference=1.4 %, p<0.001.
Alendronate (n=464)
Risedronate (n=481)
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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)
≥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
↓43% *
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
 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
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20. 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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21. Oplosbaarheid van alendronaat enOplosbaarheid van alendronaat en
generiekengenerieken
Epstein, J Appl Res, 2005, 1
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22. Therapietrouw
 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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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;38:617–627
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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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26. Pharmacokinetics of bisphosphonates
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Russell, Bone, 2006

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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31. En de toekomst?
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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.  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 Ranelate
 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
 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
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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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41. UHasselt
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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, 348
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