This document summarizes information presented at the 2008 ASBMR conference on new and emerging osteoporosis treatments. It discusses several drug classes and mechanisms of action, including SERMs, bisphosphonates, denosumab, cathepsin K inhibitors, calcilytics, sclerostin antibodies, PTH analogs, and strontium. It also summarizes clinical trial results for lasofoxifene, zoledronic acid after hip fracture, and the OPTAMISE study comparing teriparatide with prior bisphosphonate use. Odanacatib, a cathepsin K inhibitor, showed increases in bone mineral density in a phase II trial with once weekly dosing and no increased risk

1. J. Coen NetelenbosJ. Coen Netelenbos
8 oktober 2008, IWO, Utrecht8 oktober 2008, IWO, Utrecht
Klinische Highlights ASBMR
September 2008 Montreal
•SERMS
•Calcilytica
•Bisfosfonaten
•Cathepsine K remmer
•Ab RANKL
•Ab Scerostin

2. ““We Are Experiencing a Seismic Event inWe Are Experiencing a Seismic Event in
the Treatment of Osteoporosis”the Treatment of Osteoporosis”
Reuters 22 mei 2008Reuters 22 mei 2008
Bisphosphonates - Reclast/Aclasta (zoledronic acid; Novartis) - Fosamax (alendronate;Bisphosphonates - Reclast/Aclasta (zoledronic acid; Novartis) - Fosamax (alendronate;
Merck/Watson/Teva) - Fosavance (alendronate + Vitamin D; Merck) - BonivaMerck/Watson/Teva) - Fosavance (alendronate + Vitamin D; Merck) - Boniva
(ibandronate; Roche / GSK) - Actonel (risedronate; P&G/Sanofi-Aventis) MAb(ibandronate; Roche / GSK) - Actonel (risedronate; P&G/Sanofi-Aventis) MAb
Antiresorptives - Denosumab (Amgen) Cathepsin K Inhibitors - Odanacatib (MK-Antiresorptives - Denosumab (Amgen) Cathepsin K Inhibitors - Odanacatib (MK-
0822; Merck) - Balicatib (AAE-581; Novartis) SERMs - Evista (raloxifene; Lilly) -0822; Merck) - Balicatib (AAE-581; Novartis) SERMs - Evista (raloxifene; Lilly) -
Viviant (bazedoxifene; Wyeth) - Aprela (bazedoxifene + estrogen; Wyeth) - FablynViviant (bazedoxifene; Wyeth) - Aprela (bazedoxifene + estrogen; Wyeth) - Fablyn
(a.k.a Oporia; lasofoxifene; Pfizer/Ligand) - Arzoxifene (Lilly) Other Antiresorptives -(a.k.a Oporia; lasofoxifene; Pfizer/Ligand) - Arzoxifene (Lilly) Other Antiresorptives -
Protelos (Strontium; Servier) - SMC-021 (Oral Calcitonin; Novartis / NordicProtelos (Strontium; Servier) - SMC-021 (Oral Calcitonin; Novartis / Nordic
Biosciences / Unigene / Emisphere) Anabolics - Sclerostin / SOST / Wnt / Dkk1 -Biosciences / Unigene / Emisphere) Anabolics - Sclerostin / SOST / Wnt / Dkk1 -
AMG-785 (CDP-7851; Anti-Sclerostin MAb; Amgen / UCB) - BHQ880 (anti-Dkk1AMG-785 (CDP-7851; Anti-Sclerostin MAb; Amgen / UCB) - BHQ880 (anti-Dkk1
MAb Novartis/Galapagos) PTH - Forteo (teriparatide / sub-q PTH 1-34; Lilly) - PTHMAb Novartis/Galapagos) PTH - Forteo (teriparatide / sub-q PTH 1-34; Lilly) - PTH
Fc (1-34; Amgen) - Preos / Preotact (sub-q PTH 1-84; Nycomed/NPS) - Inhaled PTHFc (1-34; Amgen) - Preos / Preotact (sub-q PTH 1-84; Nycomed/NPS) - Inhaled PTH
1-34 (Lilly / Alkermes) - Nasal Transmucosal PTH (1-34); Nastech/P&G - Ostabolin-C1-34 (Lilly / Alkermes) - Nasal Transmucosal PTH (1-34); Nastech/P&G - Ostabolin-C
(PTH 1-31; Zelos/Nektar) - BA-058 (PTHrP Analog; Radius Pharmaceuticals / Teijen /(PTH 1-31; Zelos/Nektar) - BA-058 (PTHrP Analog; Radius Pharmaceuticals / Teijen /
Ipsen / Novartis) Prostaglandin Agonists - CP-533536 (Pfizer) Calcilytics - ronacaleretIpsen / Novartis) Prostaglandin Agonists - CP-533536 (Pfizer) Calcilytics - ronacaleret
(SB-751689; GSK / NPS Pharmaceuticals) Activin Receptor Agonists - ACE-011(SB-751689; GSK / NPS Pharmaceuticals) Activin Receptor Agonists - ACE-011

3. Effect of SERMEffect of SERM LasofoxifeneLasofoxifene through 3 yearsthrough 3 years
(PEARL) on fracture endpoints (1288)(PEARL) on fracture endpoints (1288)

4. Effect of SERMEffect of SERM Lasofoxifene through 5 yearsLasofoxifene through 5 years onon
Breast Cancer, VTE, Stroke and CHD (1288)Breast Cancer, VTE, Stroke and CHD (1288)
OutcomeOutcome Hazard RatioHazard Ratio
(95% CI)(95% CI)
ER+ Breast CancerER+ Breast Cancer 0.17 (0.05-0.57)0.17 (0.05-0.57)
VTEVTE 2.06 (1.17-3.61)2.06 (1.17-3.61)
StrokeStroke 0.64 (0.41-0.99)0.64 (0.41-0.99)
CHDCHD 0.68 (0.50-0.93)0.68 (0.50-0.93)
FDA Sept 8, 2008FDA Sept 8, 2008

5. Lasofoxifene effect on all cause mortality; FDALasofoxifene effect on all cause mortality; FDA
advisory committee sept 8, 2008advisory committee sept 8, 2008
Advies aan FDA:Advies aan FDA:
*Benefits outweigh the risks*Benefits outweigh the risks
*Restricted to patients with high risk of fracture*Restricted to patients with high risk of fracture
FDA beslist in oktober 2008FDA beslist in oktober 2008
NB regio 2NB regio 2
(Mexico, Centr. en Zuid Amerika)(Mexico, Centr. en Zuid Amerika)

6. Anabolic CalcilyticaAnabolic Calcilytica
(cinacalcet) (ronacalaret)

7. Ronacalaret (1174)Ronacalaret (1174)
GSK ends NPS's osteoporosis drug studyGSK ends NPS's osteoporosis drug study
Sep 26 2008 - 9:20amSep 26 2008 - 9:20am
Bad news for NPS Pharmaceuticals: the company announced lateBad news for NPS Pharmaceuticals: the company announced late
Thursday that its partner GlaxoSmithKline would abandon a Phase IIThursday that its partner GlaxoSmithKline would abandon a Phase II
study of Ronacalaret, an osteoporosis drug. According to SEC filingsstudy of Ronacalaret, an osteoporosis drug. According to SEC filings
cited by thecited by the AssociatedAssociated Press, GSK is halting the study becausePress, GSK is halting the study because
Ronacalaret is not effective.Ronacalaret is not effective.
NPS shares fall as Glaxo pulls out of drug studyNPS shares fall as Glaxo pulls out of drug study
15 september 200815 september 2008
Fase 1 studie: orale toediening: stijging PTH, BAP, PINP en OcFase 1 studie: orale toediening: stijging PTH, BAP, PINP en Oc
zonder stijging CTX!zonder stijging CTX!
Veel Belovend!!Veel Belovend!!

8. Biology of the Osteoclast in Bone MetabolismBiology of the Osteoclast in Bone Metabolism
Deftos LJ.Deftos LJ. NEJM 2005;353:872-5NEJM 2005;353:872-5
Denosumab
OdanaOdanacatib
Bisphosphonates

9. Significante reductie fracturen enSignificante reductie fracturen en
mortaliteit door jaarlijks zolendronaatmortaliteit door jaarlijks zolendronaat
infuus na heupfractuurinfuus na heupfractuur
www.nejm.orgwww.nejm.org on line September 17, 2007; NEJM 2007;357on line September 17, 2007; NEJM 2007;357

10. Reduction in mortality with ZoledronicReduction in mortality with Zoledronic
acid after hip fractureacid after hip fracture [25% (CI 3-42%)][25% (CI 3-42%)]
(1030)(1030)
• Kon niet verklaard worden uit lager aantal latere fracturenKon niet verklaard worden uit lager aantal latere fracturen
• Mannen hoger voordeel mbt mortaliteit (6.4 vs 2.8% vooral CHD)Mannen hoger voordeel mbt mortaliteit (6.4 vs 2.8% vooral CHD)
• Verpleeghuispatiënten hadden geen vermindering sterfteVerpleeghuispatiënten hadden geen vermindering sterfte
Zolendronaat heeft gunstig effect op :Zolendronaat heeft gunstig effect op :
““physiological reserve and ability to recover from acute illnessses”physiological reserve and ability to recover from acute illnessses”
vgl met placebo groep bleek minder sterfte door:vgl met placebo groep bleek minder sterfte door:
- pneumonie- pneumonie
- kanker- kanker
- cardiovasculaire ziekten- cardiovasculaire ziekten

11. OsteoNecrosis of the Jaw (ONJ); ExperienceOsteoNecrosis of the Jaw (ONJ); Experience
with Zoledronic Acid 5 mg yearly in a variety ofwith Zoledronic Acid 5 mg yearly in a variety of
osteoporosis indications (sept 2008 ASBMR)osteoporosis indications (sept 2008 ASBMR)
44 studies met 11 000 patienten - 7714 Horizon 1 (PMP osteoporose)studies met 11 000 patienten - 7714 Horizon 1 (PMP osteoporose)
- 2111 Horizon 2 (na heupfx)- 2111 Horizon 2 (na heupfx)
- 833 GIOP- 833 GIOP
- 302 Mannen met osteoporosis- 302 Mannen met osteoporosis
ONJ :ONJ :
• niet meer gevonden dan de twee eerder beschreven patienten (1 uitniet meer gevonden dan de twee eerder beschreven patienten (1 uit
placebo en 1 uit zolendronaat groep)placebo en 1 uit zolendronaat groep)
• geen verband ONJ met serum CTX spiegelgeen verband ONJ met serum CTX spiegel

12. Global Longitudinal study ofGlobal Longitudinal study of
Osteoporosis in Women (GLOWOsteoporosis in Women (GLOW))
• Scientific Advisory CommitteeScientific Advisory Committee
J. AdachiJ. Adachi A. LaCroixA. LaCroix S. AdamiS. Adami
R. LindsayR. Lindsay F. AndersonF. Anderson M. McClungM. McClung
S. BoonenS. Boonen J.C. NetelenbosJ.C. Netelenbos J. CompstonJ. Compston
J. PfeilschifterJ. Pfeilschifter C. CooperC. Cooper C. RouxC. Roux
P. DelmasP. Delmas K. SaagK. Saag A. Diez-PerezA. Diez-Perez
P. SambrookP. Sambrook S. GehlbachS. Gehlbach S. SilvermanS. Silverman
S. GreenspanS. Greenspan E. SirisE. Siris N. WattsN. Watts
• Center for Outcomes Research (COR) at the University ofCenter for Outcomes Research (COR) at the University of
MassachusettsMassachusetts
• The Alliance for Better Bone HealthThe Alliance for Better Bone Health
– Procter & Gamble Pharmaceuticals and sanofi-aventisProcter & Gamble Pharmaceuticals and sanofi-aventis
ASBMR 6 PostersASBMR 6 Posters
Onderzoek bij bijna 60 000 PMP vrouwenOnderzoek bij bijna 60 000 PMP vrouwen
in eerste lijn op drie continentenin eerste lijn op drie continenten

13. Why need to understand more aboutWhy need to understand more about
osteoporosis?osteoporosis?
Osteoporosis remains under-diagnosed andOsteoporosis remains under-diagnosed and
undertreatedundertreated
•Patients who fracture are not being treatedPatients who fracture are not being treated
•Patients at high risk of fracture (asymptomatic) are not beingPatients at high risk of fracture (asymptomatic) are not being
identified and treatedidentified and treated
•When interventions are initiated, adherence is suboptimalWhen interventions are initiated, adherence is suboptimal

14. Self-Perceived Fracture Risk Compared toSelf-Perceived Fracture Risk Compared to
Women of the Same AgeWomen of the Same Age

15. OPTAMISE Study; Doel en Design (OPTAMISE Study; Doel en Design (M349, F396M349, F396
en JCEM on lineen JCEM on line [Miller PD et al. doi:10.1210/jc.2008-0353][Miller PD et al. doi:10.1210/jc.2008-0353] ))
2-wk screening period2-wk screening period
PriorPrior
BisphosphonateBisphosphonate
Therapy ≥2 yearsTherapy ≥2 years
Daily TPTD for 12Daily TPTD for 12
monthsmonths
Prior Risedronate
5 mg/d or 30-35 mg/wk
Prior Alendronate
10 mg/d or 70 mg/wk
Teriparatide Only
20 μg/d SQ
Vraag: verstoort Risedronaat de effecten van Teriparatide inVraag: verstoort Risedronaat de effecten van Teriparatide in
dezelfde mate als Alendronaat?dezelfde mate als Alendronaat?

16. Comparison change P1NP bone markerComparison change P1NP bone marker
OPTAMISE study (M349, JCEM on line)OPTAMISE study (M349, JCEM on line)

17. Comparison change QCT Spine & HipComparison change QCT Spine & Hip
OPTAMISE study (M349, JCEM on line)OPTAMISE study (M349, JCEM on line)
QCT SPINEQCT SPINE
QCT HIPQCT HIP

18. Odanacatib (1291), Cathepsin-K inhibitorOdanacatib (1291), Cathepsin-K inhibitor
Odanacatib's phase lll trial is just getting under way
Fase II trial. PM osteoporose (T-score<-2)Fase II trial. PM osteoporose (T-score<-2)
Odanacatib oraal 1x per week gedurendeOdanacatib oraal 1x per week gedurende 2 jaar vs placebo2 jaar vs placebo
* 50mg dose -stijging LBMD 5.5% en BMDTHip 3.2%* 50mg dose -stijging LBMD 5.5% en BMDTHip 3.2%
-daling NTX 52% en BAP 13%-daling NTX 52% en BAP 13%
--huiduitslagenhuiduitslagen kwamen niet vaker voorkwamen niet vaker voor
zoals bij andere cathepsine-K remmerzoals bij andere cathepsine-K remmer
BalicatibBalicatib waarvan ontwikkeling is gestoptwaarvan ontwikkeling is gestopt

19. Werking
Denosumab
Botafbrekende celBotafbrekende cel
Botafbrekende stofantilichamenantilichamen

20. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial
BMD (1285 & JBMR Sept. on line)BMD (1285 & JBMR Sept. on line)
Lumbar Spine BMDLumbar Spine BMD Fem. Neck BMDFem. Neck BMD

21. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial
Bone Markers (1285 & JBMR Sept. on line)Bone Markers (1285 & JBMR Sept. on line)
CTXCTX P1NPP1NP

22. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial
baseline CTX and effect on Hip BMD (1285)baseline CTX and effect on Hip BMD (1285)

23. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial
Adverse events (1285 & JBMR Sept. on line )Adverse events (1285 & JBMR Sept. on line )

24. Denusomab FREEDOM Trial (1286)Denusomab FREEDOM Trial (1286)
3jaar bij 7868 PMP osteoporotische3jaar bij 7868 PMP osteoporotische
vrouwen (T-scorevrouwen (T-score ≤ -2.5 en ≥ -4)≤ -2.5 en ≥ -4)
wervelFx 68%wervelFx 68%
heupFx 40%heupFx 40%
nonVertFX 20%nonVertFX 20%

25. Denusomab (M372):Denusomab (M372): Preference and Satisfaction withPreference and Satisfaction with
a 6-monthly subcutaneous injection vs a weekly tableta 6-monthly subcutaneous injection vs a weekly tablet

26. Denusomab (1285):Denusomab (1285): Preference and Satisfaction with aPreference and Satisfaction with a
6-monthly subcutaneous injection vs a weekly tablet6-monthly subcutaneous injection vs a weekly tablet
Overall bother with treatment

27. Sclerostin and Wnt SignalingSclerostin and Wnt Signaling
Buchem diseaseBuchem disease &&
Sclerostosis metSclerostosis met
mutaties SOST gene,mutaties SOST gene,
waardoor tekort aanwaardoor tekort aan
sclerostinsclerostin
First Case (1955)First Case (1955)
Antilichamen tegenAntilichamen tegen
Sclerostin (Scl-Ab)Sclerostin (Scl-Ab)
Phase 1 studyPhase 1 study::
BMD , BFR , BRRBMD , BFR , BRR =

28. Weekly s.c. antibody to sclerostin elevates BMDWeekly s.c. antibody to sclerostin elevates BMD
reversibly in OVX rats (1211)reversibly in OVX rats (1211)

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