Seminar 08-12-2007 - bisphosphonate mechanism of action

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


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


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


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


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


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


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


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


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


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


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


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)


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)


Cumulative Hip Fracture IncidenceCumulative Hip Fracture Incidence

↓43% * at Month 12

*Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63%


% 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


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


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


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


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


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


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)


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


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


Botombouw na de menopauzeBotombouw na de menopauze

www.courses.washington.edu/ bonephys/opalgo.gif azMaastrichtUHasselt

En de toekomst?En de toekomst?


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


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




Alendronate 70 mg/wk, N = 46


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


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


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%


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%


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

Seminar 08-12-2007 - bisphosphonate mechanism of action

Health & Medicine

Transcript of Seminar 08-12-2007 - bisphosphonate mechanism of action