New Dimensions and Landmark Advances in Osteoporosis Management Felicia Cosman, MD Professor of...

New Dimensions and Landmark Advances New Dimensions and Landmark Advances in Osteoporosis Managementin Osteoporosis Management

New Dimensions and Landmark Advances New Dimensions and Landmark Advances in Osteoporosis Managementin Osteoporosis Management

Felicia Cosman, MDFelicia Cosman, MDProfessor of Clinical MedicineProfessor of Clinical Medicine

Columbia UniversityColumbia UniversityNew York, NYNew York, NY

Osteoporosis Specialist/EndocrinologistOsteoporosis Specialist/EndocrinologistHelen Hayes Hospital, West Haverstraw, NYHelen Hayes Hospital, West Haverstraw, NY

Clinical DirectorClinical DirectorNational Osteoporosis FoundationNational Osteoporosis Foundation

Washington, DCWashington, DC

Felicia Cosman, MDFelicia Cosman, MDProfessor of Clinical MedicineProfessor of Clinical Medicine

Columbia UniversityColumbia UniversityNew York, NYNew York, NY

Osteoporosis Specialist/EndocrinologistOsteoporosis Specialist/EndocrinologistHelen Hayes Hospital, West Haverstraw, NYHelen Hayes Hospital, West Haverstraw, NY

Clinical DirectorClinical DirectorNational Osteoporosis FoundationNational Osteoporosis Foundation

Washington, DCWashington, DC

The Internal Medicine PerspectiveThe Internal Medicine Perspective

Universal Management MeasuresUniversal Management Measures

► Risk factor reductionRisk factor reduction• Bone massBone mass

• Medications- stop or reduce dose if possibleMedications- stop or reduce dose if possible• Smoking cessation programsSmoking cessation programs

• Fall Prevention Fall Prevention • MedicationsMedications• EnvironmentEnvironment• Balance trainingBalance training

► Physical Activity/ ExercisePhysical Activity/ Exercise

► Optimal NutritionOptimal Nutrition• CalciumCalcium• Vitamin DVitamin D

► BMD Testing When AppropriateBMD Testing When Appropriate

► Risk factor reductionRisk factor reduction• Bone massBone mass

• Medications- stop or reduce dose if possibleMedications- stop or reduce dose if possible• Smoking cessation programsSmoking cessation programs

• Fall Prevention Fall Prevention • MedicationsMedications• EnvironmentEnvironment• Balance trainingBalance training

► Physical Activity/ ExercisePhysical Activity/ Exercise

► Optimal NutritionOptimal Nutrition• CalciumCalcium• Vitamin DVitamin D

► BMD Testing When AppropriateBMD Testing When Appropriate

FDA Approved Osteoporosis TreatmentsFDA Approved Osteoporosis Treatments

Antiresorptive AgentsAntiresorptive Agents► Bisphosphonates Bisphosphonates

• Alendronate (Fosamax®)Alendronate (Fosamax®)• Risedronate (Actonel®)Risedronate (Actonel®)• Ibandronate (Boniva®: Oral and IV)Ibandronate (Boniva®: Oral and IV)• Zoledronic Acid (Reclast® IV)Zoledronic Acid (Reclast® IV)

► Estrogen Agonist/AntagonistsEstrogen Agonist/Antagonists• Raloxifene (Evista®)Raloxifene (Evista®)

► Estrogen/Estrogen-Progestin CombinationsEstrogen/Estrogen-Progestin Combinations► CalcitoninsCalcitonins (Miacalcin, Fortical) (Miacalcin, Fortical)

Anabolic TherapiesAnabolic Therapies► Teriparatide (Forteo)Teriparatide (Forteo)

Antiresorptive AgentsAntiresorptive Agents► Bisphosphonates Bisphosphonates

• Alendronate (Fosamax®)Alendronate (Fosamax®)• Risedronate (Actonel®)Risedronate (Actonel®)• Ibandronate (Boniva®: Oral and IV)Ibandronate (Boniva®: Oral and IV)• Zoledronic Acid (Reclast® IV)Zoledronic Acid (Reclast® IV)

► Estrogen Agonist/AntagonistsEstrogen Agonist/Antagonists• Raloxifene (Evista®)Raloxifene (Evista®)

► Estrogen/Estrogen-Progestin CombinationsEstrogen/Estrogen-Progestin Combinations► CalcitoninsCalcitonins (Miacalcin, Fortical) (Miacalcin, Fortical)

Anabolic TherapiesAnabolic Therapies► Teriparatide (Forteo)Teriparatide (Forteo)

Treating Patients Across the LifespanTreating Patients Across the Lifespan

► Try to take advantage of greatest potentialTry to take advantage of greatest potential

benefits of specific medications and avoid risks:benefits of specific medications and avoid risks:

• Age is a key determinant Age is a key determinant • HT greatest benefit and least risk early after menopause HT greatest benefit and least risk early after menopause

and for <5 years and for <5 years • ET alone: Perhaps can use for longerET alone: Perhaps can use for longer• Raloxifene during 50s to mid to late 60sRaloxifene during 50s to mid to late 60s• Bisphosphonates: 60s and beyondBisphosphonates: 60s and beyond• Teriparatide can be used at any point along this continuum Teriparatide can be used at any point along this continuum

for more severe patients, but needs to be followed by an for more severe patients, but needs to be followed by an

antiresorptive treatment to maximize and maintain gainsantiresorptive treatment to maximize and maintain gains

► Try to take advantage of greatest potentialTry to take advantage of greatest potential

benefits of specific medications and avoid risks:benefits of specific medications and avoid risks:

• Age is a key determinant Age is a key determinant • HT greatest benefit and least risk early after menopause HT greatest benefit and least risk early after menopause

and for <5 years and for <5 years • ET alone: Perhaps can use for longerET alone: Perhaps can use for longer• Raloxifene during 50s to mid to late 60sRaloxifene during 50s to mid to late 60s• Bisphosphonates: 60s and beyondBisphosphonates: 60s and beyond• Teriparatide can be used at any point along this continuum Teriparatide can be used at any point along this continuum

for more severe patients, but needs to be followed by an for more severe patients, but needs to be followed by an

antiresorptive treatment to maximize and maintain gainsantiresorptive treatment to maximize and maintain gains

Major Problem with all Current Osteoporosis Major Problem with all Current Osteoporosis Therapies: Adherence and PersistenceTherapies: Adherence and Persistence

► Fewer than 50% of people remain on any of Fewer than 50% of people remain on any of these therapies beyond one yearthese therapies beyond one year

► Patients who are not adherent and persistent do Patients who are not adherent and persistent do not have fracture benefitsnot have fracture benefits

► Once yearly zoledronic acid has the potential to Once yearly zoledronic acid has the potential to dramatically improve adherence and persistence dramatically improve adherence and persistence to therapy and thus translate clinical trial to therapy and thus translate clinical trial benefits into real clinical benefits for patientsbenefits into real clinical benefits for patients

► Denosumab (twice yearly subcutaneously) offers Denosumab (twice yearly subcutaneously) offers potential improvement in persistence and real potential improvement in persistence and real clinical benefitsclinical benefits

► Fewer than 50% of people remain on any of Fewer than 50% of people remain on any of these therapies beyond one yearthese therapies beyond one year

► Patients who are not adherent and persistent do Patients who are not adherent and persistent do not have fracture benefitsnot have fracture benefits

► Once yearly zoledronic acid has the potential to Once yearly zoledronic acid has the potential to dramatically improve adherence and persistence dramatically improve adherence and persistence to therapy and thus translate clinical trial to therapy and thus translate clinical trial benefits into real clinical benefits for patientsbenefits into real clinical benefits for patients

► Denosumab (twice yearly subcutaneously) offers Denosumab (twice yearly subcutaneously) offers potential improvement in persistence and real potential improvement in persistence and real clinical benefitsclinical benefits

Objectives of PresentationObjectives of Presentation

► Review Zoledronic Acid Pivotal TrialsReview Zoledronic Acid Pivotal Trials• Initial study: Pivotal Fracture Trial (PFT)Initial study: Pivotal Fracture Trial (PFT)• Most recent study: Recurrent Fracture Trial Most recent study: Recurrent Fracture Trial

(RFT)(RFT)

► Denosumab OverviewDenosumab Overview

► Review Zoledronic Acid Pivotal TrialsReview Zoledronic Acid Pivotal Trials• Initial study: Pivotal Fracture Trial (PFT)Initial study: Pivotal Fracture Trial (PFT)• Most recent study: Recurrent Fracture Trial Most recent study: Recurrent Fracture Trial

(RFT)(RFT)

► Denosumab OverviewDenosumab Overview

HORIZON Pivotal Fracture Trial (PFT) HORIZON Pivotal Fracture Trial (PFT) OverviewOverview

► Objective:Objective: To evaluate the potential of once yearly To evaluate the potential of once yearly zoledronic acid 5 mg to decrease fracture risk in zoledronic acid 5 mg to decrease fracture risk in postmenopausal women with osteoporosispostmenopausal women with osteoporosis

► 3-year, randomized, double-blind, placebo-controlled 3-year, randomized, double-blind, placebo-controlled clinical trial clinical trial ● 7736 women from 240 clinical centers in 27 countries7736 women from 240 clinical centers in 27 countries

► TreatmentTreatment● Annual infusion of either zoledronic acid 5 mg or placeboAnnual infusion of either zoledronic acid 5 mg or placebo● Calcium 1000Calcium 1000––1500 mg/d; vitamin D 4001500 mg/d; vitamin D 400––1200 IU/d1200 IU/d

► Follow-up visits at 6, 12, 24 and 36 monthsFollow-up visits at 6, 12, 24 and 36 months● Telephone interviews every 3 months Telephone interviews every 3 months

► Objective:Objective: To evaluate the potential of once yearly To evaluate the potential of once yearly zoledronic acid 5 mg to decrease fracture risk in zoledronic acid 5 mg to decrease fracture risk in postmenopausal women with osteoporosispostmenopausal women with osteoporosis

► 3-year, randomized, double-blind, placebo-controlled 3-year, randomized, double-blind, placebo-controlled clinical trial clinical trial ● 7736 women from 240 clinical centers in 27 countries7736 women from 240 clinical centers in 27 countries

► TreatmentTreatment● Annual infusion of either zoledronic acid 5 mg or placeboAnnual infusion of either zoledronic acid 5 mg or placebo● Calcium 1000Calcium 1000––1500 mg/d; vitamin D 4001500 mg/d; vitamin D 400––1200 IU/d1200 IU/d

► Follow-up visits at 6, 12, 24 and 36 monthsFollow-up visits at 6, 12, 24 and 36 months● Telephone interviews every 3 months Telephone interviews every 3 months

Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al.

N Eng J Med 2007; 356:1809

Study Population: HORIZONStudy Population: HORIZON

► InclusionInclusion● Women 65 to 89 years of age Women 65 to 89 years of age

● Femoral neck T-score ≤–2.5 Femoral neck T-score ≤–2.5 oror ≤–1.5 with two mild or one≤–1.5 with two mild or one

moderatemoderate prevalent vertebral fractureprevalent vertebral fracture

► ExclusionExclusion ● Current use of bisphosphonates, PTH, or strontium ranelateCurrent use of bisphosphonates, PTH, or strontium ranelate● Failure to meet specified washout periods for previous BP useFailure to meet specified washout periods for previous BP use

► Two strataTwo strata● Stratum I: No current osteoporosis therapy (80% of total Stratum I: No current osteoporosis therapy (80% of total

population)population)● Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline

(20% of total population)(20% of total population)

► InclusionInclusion● Women 65 to 89 years of age Women 65 to 89 years of age

● Femoral neck T-score ≤–2.5 Femoral neck T-score ≤–2.5 oror ≤–1.5 with two mild or one≤–1.5 with two mild or one

moderatemoderate prevalent vertebral fractureprevalent vertebral fracture

► ExclusionExclusion ● Current use of bisphosphonates, PTH, or strontium ranelateCurrent use of bisphosphonates, PTH, or strontium ranelate● Failure to meet specified washout periods for previous BP useFailure to meet specified washout periods for previous BP use

► Two strataTwo strata● Stratum I: No current osteoporosis therapy (80% of total Stratum I: No current osteoporosis therapy (80% of total

population)population)● Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline

(20% of total population)(20% of total population)Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al.

N Eng J Med 2007; 356:1809

Baseline Characteristics Baseline Characteristics

ZOL 5 mg ZOL 5 mg

(n = 3875)(n = 3875)Placebo Placebo (n = 3861)(n = 3861)

Stratum I, n (%)Stratum I, n (%) 3045 (79)3045 (79) 3039 (79)3039 (79)

Stratum II, n (%)Stratum II, n (%) 830 (21)830 (21) 822 (21)822 (21)

Mean (SD) age, yearsMean (SD) age, years 73.1 (5)73.1 (5) 73.0 (5)73.0 (5)

Region, n (%)Region, n (%)

Western/Eastern EuropeWestern/Eastern Europe 1934 (50)1934 (50) 1934 (50)1934 (50)

North/South America/OceaniaNorth/South America/Oceania 1391 (36)1391 (36) 1387 (36)1387 (36)

AsiaAsia 550 (14)550 (14) 540 (14)540 (14)

Femoral neck T-score, n (%)Femoral neck T-score, n (%)

≤–≤–2.52.5 2814 (73)2814 (73) 2734 (71)2734 (71)

Prevalent vertebral fracture, n (%)Prevalent vertebral fracture, n (%)

≥≥11 2416 (62)2416 (62) 2477 (64)2477 (64)

Prior bisphosphonate use, n (%)Prior bisphosphonate use, n (%) 565 (15)565 (15) 557 (14)557 (14)

Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al.

N Eng J Med 2007; 356:1809N Eng J Med 2007; 356:1809

Morphometric Vertebral Fracture Results Morphometric Vertebral Fracture Results (Stratum I)(Stratum I)

Relative risk reductions (95% confidence intervals) vs placeboRelative risk reductions (95% confidence intervals) vs placebo**PP < .0001, based on logistic regression with treatment and baseline fracture status in the model using log-likelihood < .0001, based on logistic regression with treatment and baseline fracture status in the model using log-likelihood type approachtype approach



Zoledronic acid 5 mg Zoledronic acid 5 mg PlaceboPlacebo

% P

atie

nts

With

New

%

Pat

ient

s W

ith N

ew

Ver

tebr

al F

ract

ure

Ver

tebr

al F

ract

ure

60%*60%*(43%, 72%)(43%, 72%)

71%*71%*(62%, 78%)(62%, 78%)

00

1010

0–10–1 0–20–2 0–30–3

YearsYears

55

1515

1.5%1.5%

3.7%3.7%

2.2%2.2%

7.7%7.7%

3.3%3.3%

10.9%10.9%

70%*70%*(62%, 76%)(62%, 76%)

Cumulative Risk of Hip Fracture Cumulative Risk of Hip Fracture (Strata I + II)(Strata I + II)

Relative risk reduction ( 95% confidence interval) vs placeboRelative risk reduction ( 95% confidence interval) vs placeboBlack DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al.


PP = .0024 = .0024

11

22

33

00

Placebo (n = 3861) Placebo (n = 3861) ZOL 5 mg (n = 3875)ZOL 5 mg (n = 3875)

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

Time to First Hip Fracture (months)Time to First Hip Fracture (months)

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

41%*41%*(17%, 58%)(17%, 58%)

Cumulative Risk of Clinical Vertebral FractureCumulative Risk of Clinical Vertebral Fracture(Strata I & II)(Strata I & II)

Relative risk reduction (95% confidence interval) vs placeboRelative risk reduction (95% confidence interval) vs placebo



PP < .0001 < .0001

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

Time to First Clinical Vertebral Fracture (months)Time to First Clinical Vertebral Fracture (months)

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

77%77%(63%, 86%)(63%, 86%)


11

22

33

00

Cumulative Risk of Clinical Non-vertebral Cumulative Risk of Clinical Non-vertebral Fracture Fracture (Strata I & II)(Strata I & II)

Relative risk reduction (95% confidence interval) vs placeboRelative risk reduction (95% confidence interval) vs placebo



PP = .0002 = .0002

Time to First Clinical Non-vertebral Fracture (months)Time to First Clinical Non-vertebral Fracture (months)

22

44

66

88

1010

1212

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

25%25%(13%, 36%)(13%, 36%)


00

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

Zoledronic Acid Produced Significant Zoledronic Acid Produced Significant Increases in BMD Over 3 YearsIncreases in BMD Over 3 Years

Bracketed values are least square mean difference, zoledronic acid vs placebo*P < .0001, P-value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables.Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.

-3-2-1012345678

Total HipTotal Hip Femoral NeckFemoral Neck Lumbar SpineLumbar Spine

Mea

n %

Cha

nge

Mea

n %

Cha

nge

Fro

m B

asel

ine

Fro

m B

asel

ine

6.0%*6.0%* 5.1%*5.1%*

6.7%*6.7%*

Zoledronic Acid Placebo

Please see full prescribing information.

Placebo (n = 305)Zoledronic acid 5 mg (n = 300)

Premenopausal reference range

Mean S

eru

m β

-CTX

(ng/m

L)

0.2

0.0

0.6

0.7

0.8

1.0

0.9

0.5

0.1

0.3

0.4

Months

0 6 12 18 24 30 36

Mean Serum CTX Over TimeMean Serum CTX Over Time


N Eng J Med 2007; 356:1809

= annual dose

Mean Serum BSAP Over TimeMean Serum BSAP Over Time


N Eng J Med 2007; 356:1809

Mean S

eru

m B

SA

P (

ng/m

L)

4

0

16

18

20

12

2

8

10

6

14

Months

0 6 12 18 24 30 36

Placebo (n = 305) Zoledronic acid 5 mg (n = 300)

= annual dose

Premenopausal reference range

Other Secondary End PointsOther Secondary End Points

► Disability: Significant reductions in limited activity Disability: Significant reductions in limited activity days due to:days due to:● Back pain (61 days zoledronic acid vs 72 days placebo, Back pain (61 days zoledronic acid vs 72 days placebo, P P

=.0076)=.0076)

● Fracture (6 days zoledronic acid vs 10 days placebo, Fracture (6 days zoledronic acid vs 10 days placebo, PP < .001) < .001)

► Height lossHeight loss● Significantly reduced in zoledronic Significantly reduced in zoledronic ● acid 5 mg group acid 5 mg group

––4 4 mm zoledronic acid vs 7 mm mm zoledronic acid vs 7 mm

placebo (placebo (PP < .0001) < .0001)

► Disability: Significant reductions in limited activity Disability: Significant reductions in limited activity days due to:days due to:● Back pain (61 days zoledronic acid vs 72 days placebo, Back pain (61 days zoledronic acid vs 72 days placebo, P P

=.0076)=.0076)

● Fracture (6 days zoledronic acid vs 10 days placebo, Fracture (6 days zoledronic acid vs 10 days placebo, PP < .001) < .001)

► Height lossHeight loss● Significantly reduced in zoledronic Significantly reduced in zoledronic ● acid 5 mg group acid 5 mg group

––4 4 mm zoledronic acid vs 7 mm mm zoledronic acid vs 7 mm

placebo (placebo (PP < .0001) < .0001) Months

ZOL 5 mgPlacebo

Heig

ht

Ch

an

ge

(mm

)

–8

–6

–4

–2

0

0 12 24 36


N Eng J Med 2007; 356:1809

Common (≥5% in ZOL) Post-Dose Symptoms Common (≥5% in ZOL) Post-Dose Symptoms Occurring Within 3 Days After InfusionOccurring Within 3 Days After Infusion

0

2

4

6

8

10

12

14

16

Annual Infusion

Pyrexia

Myalgia

Flu-like illnessHeadache Arthralgia

1 2 3 1 2 3 1 2 3 1 2 3 1 2 3

Inci

dence

(%

)

15%

2%

1%2%

1%1%

1%2%

1%2%

1%

8%

7%6% 5%

Placebo values cross-hatched



Systemic Safety ParametersSystemic Safety Parameters

► Renal safetyRenal safety● Short term: 9-11 day post-dose monitoring in >4000 patientsShort term: 9-11 day post-dose monitoring in >4000 patients● Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo) Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo)

with resolution and all patients redosed with resolution and all patients redosed ● Overall, no cumulative impact on renal functionOverall, no cumulative impact on renal function

► HypocalcemiaHypocalcemia (serum calcium < 2.075 mmol/L)(serum calcium < 2.075 mmol/L)● 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after

2nd (0.1%) or 3rd (0.3%)2nd (0.1%) or 3rd (0.3%)● All asymptomatic and transientAll asymptomatic and transient

► Cardiac safetyCardiac safety● Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo)Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo)● Atrial fibrillation SAEs more common in ZOLAtrial fibrillation SAEs more common in ZOL

• n = 50 (1.3%) ZOL 5 mg n = 50 (1.3%) ZOL 5 mg • n = 20 (0.5%) placebon = 20 (0.5%) placebo

● ECG study (n = 559) 9-11 days after 3rd infusion: ECG study (n = 559) 9-11 days after 3rd infusion: No differences observed between ZOL 5 mg and placeboNo differences observed between ZOL 5 mg and placebo

► Renal safetyRenal safety● Short term: 9-11 day post-dose monitoring in >4000 patientsShort term: 9-11 day post-dose monitoring in >4000 patients● Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo) Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo)

with resolution and all patients redosed with resolution and all patients redosed ● Overall, no cumulative impact on renal functionOverall, no cumulative impact on renal function

► HypocalcemiaHypocalcemia (serum calcium < 2.075 mmol/L)(serum calcium < 2.075 mmol/L)● 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after

2nd (0.1%) or 3rd (0.3%)2nd (0.1%) or 3rd (0.3%)● All asymptomatic and transientAll asymptomatic and transient

► Cardiac safetyCardiac safety● Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo)Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo)● Atrial fibrillation SAEs more common in ZOLAtrial fibrillation SAEs more common in ZOL

• n = 50 (1.3%) ZOL 5 mg n = 50 (1.3%) ZOL 5 mg • n = 20 (0.5%) placebon = 20 (0.5%) placebo

● ECG study (n = 559) 9-11 days after 3rd infusion: ECG study (n = 559) 9-11 days after 3rd infusion: No differences observed between ZOL 5 mg and placeboNo differences observed between ZOL 5 mg and placebo


N Eng J Med 2007; 356:1809

Bone Safety ParametersBone Safety Parameters

► Histomorphometry evaluable in 93 bone biopsiesHistomorphometry evaluable in 93 bone biopsies1,21,2

● Label seen in all specimensLabel seen in all specimens

► Fracture healingFracture healing22

● Non-union: 1 in ZOL 5 mg, 1 in placeboNon-union: 1 in ZOL 5 mg, 1 in placebo

► Avascular necrosis (hip or knee)Avascular necrosis (hip or knee)22

● 4 in ZOL 5 mg, 3 in placebo4 in ZOL 5 mg, 3 in placebo

► Osteonecrosis of the jawOsteonecrosis of the jaw22

● No spontaneous AE reportsNo spontaneous AE reports● AE database search of 50 MedDRA terms, with adjudicationAE database search of 50 MedDRA terms, with adjudication● Case definition: exposed bone in the mouth > 6 weeksCase definition: exposed bone in the mouth > 6 weeks● 1 in ZOL 5 mg, 1 in placebo1 in ZOL 5 mg, 1 in placebo● Both cases healed with antibiotic therapy and/or debridementBoth cases healed with antibiotic therapy and/or debridement

► Histomorphometry evaluable in 93 bone biopsiesHistomorphometry evaluable in 93 bone biopsies1,21,2

● Label seen in all specimensLabel seen in all specimens

► Fracture healingFracture healing22

● Non-union: 1 in ZOL 5 mg, 1 in placeboNon-union: 1 in ZOL 5 mg, 1 in placebo

► Avascular necrosis (hip or knee)Avascular necrosis (hip or knee)22

● 4 in ZOL 5 mg, 3 in placebo4 in ZOL 5 mg, 3 in placebo

► Osteonecrosis of the jawOsteonecrosis of the jaw22

● No spontaneous AE reportsNo spontaneous AE reports● AE database search of 50 MedDRA terms, with adjudicationAE database search of 50 MedDRA terms, with adjudication● Case definition: exposed bone in the mouth > 6 weeksCase definition: exposed bone in the mouth > 6 weeks● 1 in ZOL 5 mg, 1 in placebo1 in ZOL 5 mg, 1 in placebo● Both cases healed with antibiotic therapy and/or debridementBoth cases healed with antibiotic therapy and/or debridement

1. Recker RR, et al. JBMR 2007 or 20081. Recker RR, et al. JBMR 2007 or 2008

2. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. 2. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al.


The Effect of Once Yearly The Effect of Once Yearly Zoledronic Acid 5 mg on New Fractures Zoledronic Acid 5 mg on New Fractures

and Mortality After Hip Fracture: The and Mortality After Hip Fracture: The HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture Trial

The Effect of Once Yearly The Effect of Once Yearly Zoledronic Acid 5 mg on New Fractures Zoledronic Acid 5 mg on New Fractures

and Mortality After Hip Fracture: The and Mortality After Hip Fracture: The HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture Trial

Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J MedN Engl J Med. 2007;357:1799-. 2007;357:1799-18091809Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J MedN Engl J Med. 2007;357:1799-. 2007;357:1799-18091809

Landmark Advances in Osteoporosis TherapyLandmark Advances in Osteoporosis Therapy

HORIZON-Recurrent Fracture Trial (RFT)HORIZON-Recurrent Fracture Trial (RFT)Primary and Secondary Efficacy End PointsPrimary and Secondary Efficacy End Points

► Primary ObjectivePrimary Objective● Reduce the rate of new clinical fractures after Reduce the rate of new clinical fractures after

surgical procedure for low-trauma hip fracturesurgical procedure for low-trauma hip fracture

● ► Secondary ObjectivesSecondary Objectives

● Reduce the risk of clinical vertebral, hip, and non-Reduce the risk of clinical vertebral, hip, and non-vertebral fracturesvertebral fractures

● Increase BMD at the total hip and femoral neck of Increase BMD at the total hip and femoral neck of the non-fractured hip at months 12 and 24the non-fractured hip at months 12 and 24

► Primary ObjectivePrimary Objective● Reduce the rate of new clinical fractures after Reduce the rate of new clinical fractures after

surgical procedure for low-trauma hip fracturesurgical procedure for low-trauma hip fracture

● ► Secondary ObjectivesSecondary Objectives

● Reduce the risk of clinical vertebral, hip, and non-Reduce the risk of clinical vertebral, hip, and non-vertebral fracturesvertebral fractures

● Increase BMD at the total hip and femoral neck of Increase BMD at the total hip and femoral neck of the non-fractured hip at months 12 and 24the non-fractured hip at months 12 and 24


HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture TrialOverviewOverview

► Double-blind, placebo-controlled RCTDouble-blind, placebo-controlled RCT ● 2127 men and women, 148 clinical centers, 2127 men and women, 148 clinical centers,

23 countries23 countries

► TreatmentTreatment● Annual infusion of either zoledronic acid 5 mg or placeboAnnual infusion of either zoledronic acid 5 mg or placebo● Loading dose of vitamin D 50,000–125,000 IULoading dose of vitamin D 50,000–125,000 IU● Calcium 1000–1500 mg/d; vitamin D Calcium 1000–1500 mg/d; vitamin D

800–1200 IU/d800–1200 IU/d

► Follow-up visits at 6, 12, 24, and 36 monthsFollow-up visits at 6, 12, 24, and 36 months● Telephone interviews every 3 months starting at month 9Telephone interviews every 3 months starting at month 9

► Double-blind, placebo-controlled RCTDouble-blind, placebo-controlled RCT ● 2127 men and women, 148 clinical centers, 2127 men and women, 148 clinical centers,

23 countries23 countries

► TreatmentTreatment● Annual infusion of either zoledronic acid 5 mg or placeboAnnual infusion of either zoledronic acid 5 mg or placebo● Loading dose of vitamin D 50,000–125,000 IULoading dose of vitamin D 50,000–125,000 IU● Calcium 1000–1500 mg/d; vitamin D Calcium 1000–1500 mg/d; vitamin D

800–1200 IU/d800–1200 IU/d

► Follow-up visits at 6, 12, 24, and 36 monthsFollow-up visits at 6, 12, 24, and 36 months● Telephone interviews every 3 months starting at month 9Telephone interviews every 3 months starting at month 9


HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture TrialStudy PopulationStudy Population

► InclusionInclusion● Male or female patients aged 50 years and older Male or female patients aged 50 years and older ● Randomized up to 90 days following surgical procedure for a Randomized up to 90 days following surgical procedure for a

low-trauma hip fracturelow-trauma hip fracture● Ambulatory prior to hip fracture Ambulatory prior to hip fracture ● Unwilling or unable to take oral bisphosphonatesUnwilling or unable to take oral bisphosphonates

► ExclusionExclusion ● Use of oral bisphosphonates (or any use of IV within 2 years)Use of oral bisphosphonates (or any use of IV within 2 years)● Calculated creatinine clearance <30 mL/minCalculated creatinine clearance <30 mL/min● Hypercalcemia or hypocalcemiaHypercalcemia or hypocalcemia● Other metabolic bone diseasesOther metabolic bone diseases● Any prior use of parathyroid hormone or its analogs for >1 Any prior use of parathyroid hormone or its analogs for >1

week, any use of fluoride or strontiumweek, any use of fluoride or strontium

► InclusionInclusion● Male or female patients aged 50 years and older Male or female patients aged 50 years and older ● Randomized up to 90 days following surgical procedure for a Randomized up to 90 days following surgical procedure for a

low-trauma hip fracturelow-trauma hip fracture● Ambulatory prior to hip fracture Ambulatory prior to hip fracture ● Unwilling or unable to take oral bisphosphonatesUnwilling or unable to take oral bisphosphonates

► ExclusionExclusion ● Use of oral bisphosphonates (or any use of IV within 2 years)Use of oral bisphosphonates (or any use of IV within 2 years)● Calculated creatinine clearance <30 mL/minCalculated creatinine clearance <30 mL/min● Hypercalcemia or hypocalcemiaHypercalcemia or hypocalcemia● Other metabolic bone diseasesOther metabolic bone diseases● Any prior use of parathyroid hormone or its analogs for >1 Any prior use of parathyroid hormone or its analogs for >1

week, any use of fluoride or strontiumweek, any use of fluoride or strontium


Zoledronic acid 5 mgZoledronic acid 5 mg(n = 1065)(n = 1065)

PlaceboPlacebo(n = 1062)(n = 1062)

Sex, n (%)Sex, n (%)

MaleMale 248 (23.3)248 (23.3) 260 (24.5)260 (24.5)

FemaleFemale 817 (76.7)817 (76.7) 802 (75.5)802 (75.5)

Region, n (%)Region, n (%)

North AmericaNorth America 305 (28.6)305 (28.6) 318 (29.9)318 (29.9)

Latin AmericaLatin America 132 (12.4)132 (12.4) 131 (12.3)131 (12.3)

Western EuropeWestern Europe 359 (33.7)359 (33.7) 353 (33.2)353 (33.2)

Eastern EuropeEastern Europe 269 (25.3)269 (25.3) 260 (24.5)260 (24.5)

HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture TrialBaseline DemographicsBaseline Demographics


Zoledronic acid 5 mgZoledronic acid 5 mg(n = 1065)(n = 1065)


Age group (year), n (%)Age group (year), n (%)

<65<65 172 (16.2)172 (16.2) 192 (18.1)192 (18.1)

65-7465-74 307 (28.8)307 (28.8) 269 (25.3)269 (25.3)

75-8475-84 446 (41.9)446 (41.9) 449 (42.3)449 (42.3)

≥ ≥8585 140 (13.1)140 (13.1) 152 (14.3)152 (14.3)

Age (year)Age (year)

Mean (SD)Mean (SD) 74.4 (9.48)74.4 (9.48) 74.6 (9.86)74.6 (9.86)

Min, Median, MaxMin, Median, Max 50.0, 76.0, 95.050.0, 76.0, 95.0 50.0, 76.0, 98.050.0, 76.0, 98.0

HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture TrialBaseline Demographics (continued)Baseline Demographics (continued)


00

22

44

66

88

1010

1212

1414

1616

1818

2020

ClinicalClinicalFracturesFractures

Non-VertebralNon-VertebralFracturesFractures

ClinicalClinicalVertebralVertebralFracturesFractures

HipHipFracturesFractures

10.7%10.7%(107/1062)(107/1062)

8.6%8.6%(92/1065)(92/1065)

13.9%13.9%(139/1062)(139/1062)

7.6%7.6%(79/1065)(79/1065)

3.8%3.8%(39/1062)(39/1062)

1.7%1.7%(21/1065)(21/1065)

3.5%3.5%(33/1062)(33/1062)

2.0%2.0%(23/1065)(23/1065)

35%*35%*(16%, 50%)(16%, 50%)

27%†27%†(2%, 45%)(2%, 45%)

46%‡46%‡(8%, 68%)(8%, 68%)

30%30%NSNS

(-2%, 59%)(-2%, 59%)

**P P = .0012; †= .0012; †P P = .0338; ‡= .0338; ‡P P = .0210, relative risk reduction vs placebo; NS = not significant. = .0210, relative risk reduction vs placebo; NS = not significant. Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24. Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24.

Eve

nt R

ate

(%)

Eve

nt R

ate

(%)

Zoledronic acid 5 mg Zoledronic acid 5 mg PlaceboPlacebo

Zoledronic Acid 5 mg Reduced Subsequent Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk Over TimeFracture Risk Over Time


Zoledronic Acid 5 mg Reduced Risk of Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over TimeAll-Cause Mortality by 28% Over Time

MonthMonth

00

22

44

66

88

1010

1212

1414

1616

1818 Hazard Ratio, 0.72 (95% CI, 0.56–0.93)Hazard Ratio, 0.72 (95% CI, 0.56–0.93)PP = .0117 = .0117

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

00 44 88 1212 1616 2020 2424 2828 3232 3636

No. at RiskNo. at RiskZOL 5 mg ZOL 5 mg 10541054 10291029 987987 943943 806806 674674 507507 348348 237237 144144

PlaceboPlacebo 10571057 10281028 993993 945945 804804 681681 511511 364364 236236 149149

Zoledronic acid 5 mg (n = 1054)Zoledronic acid 5 mg (n = 1054)Placebo (n = 1057)Placebo (n = 1057)

28%28%

Absolute Risk Reduction, 3.7%Absolute Risk Reduction, 3.7%


Adjudicated Results for Targeted EventsAdjudicated Results for Targeted Events

Zoledronic acidZoledronic acid 5 mg 5 mg (n = 1054)(n = 1054)

n (%) n (%)


n (%)n (%)

Atrial fibrillation SAEsAtrial fibrillation SAEs 11 (1.0) 11 (1.0) 13 (1.2)13 (1.2)

Ocular Ocular 21 (2.0) 21 (2.0) 16 (1.5)16 (1.5)

Delayed union/nonunion Delayed union/nonunion 3 (0.3) 3 (0.3) 3 (0.3)3 (0.3)

Delayed hip fracture healing Delayed hip fracture healing 34 (3.2)34 (3.2) 29 (2.7) 29 (2.7)

Avascular necrosis Avascular necrosis 6 (0.6) 6 (0.6) 3 (0.3)3 (0.3)

HypocalcemiaHypocalcemia 3 (0.3) 3 (0.3) 0 (0.0)0 (0.0)

Osteonecrosis of the jawOsteonecrosis of the jaw 0 (0.0) 0 (0.0) 0 (0.0)0 (0.0)

RenalRenal 87 (8.3) 87 (8.3) 90 (8.5)90 (8.5)

Lyles KW, et al. Presented at: 29th ASBMR; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.

Where does Zoledronic Acid Fit into the Where does Zoledronic Acid Fit into the Armamentarium Against OsteoporosisArmamentarium Against Osteoporosis

► First line for all patients with hip fractureFirst line for all patients with hip fracture● Data show dismal diagnostic and treatment rates for these Data show dismal diagnostic and treatment rates for these

patients right nowpatients right now● An easily administered, well tolerated, agent, given only once An easily administered, well tolerated, agent, given only once

yearly, has dramatic efficacy in reducing subsequent fracture yearly, has dramatic efficacy in reducing subsequent fracture risk and even reducing mortalityrisk and even reducing mortality

► Consider as first line treatment for patients in whom a Consider as first line treatment for patients in whom a bisphosphonate is the chosen type of therapybisphosphonate is the chosen type of therapy● Why not offer all patients a choice?Why not offer all patients a choice?

• Many prefer this optionMany prefer this option• Efficacy is unequalledEfficacy is unequalled

► Certainly offer to all patients who have difficulty taking weekly Certainly offer to all patients who have difficulty taking weekly or monthly bisphosphonates due to upper GI symptoms or or monthly bisphosphonates due to upper GI symptoms or difficulty with adherence or persistence to regimendifficulty with adherence or persistence to regimen

► First line for all patients with hip fractureFirst line for all patients with hip fracture● Data show dismal diagnostic and treatment rates for these Data show dismal diagnostic and treatment rates for these

patients right nowpatients right now● An easily administered, well tolerated, agent, given only once An easily administered, well tolerated, agent, given only once

yearly, has dramatic efficacy in reducing subsequent fracture yearly, has dramatic efficacy in reducing subsequent fracture risk and even reducing mortalityrisk and even reducing mortality

► Consider as first line treatment for patients in whom a Consider as first line treatment for patients in whom a bisphosphonate is the chosen type of therapybisphosphonate is the chosen type of therapy● Why not offer all patients a choice?Why not offer all patients a choice?

• Many prefer this optionMany prefer this option• Efficacy is unequalledEfficacy is unequalled

► Certainly offer to all patients who have difficulty taking weekly Certainly offer to all patients who have difficulty taking weekly or monthly bisphosphonates due to upper GI symptoms or or monthly bisphosphonates due to upper GI symptoms or difficulty with adherence or persistence to regimendifficulty with adherence or persistence to regimen

Once Yearly TherapyOnce Yearly TherapySummary and ConclusionsSummary and Conclusions

► Infusion Therapy Required:Infusion Therapy Required: Overcoming barriers Overcoming barriers and directing patients to IV administration sitesand directing patients to IV administration sites

- - Infusion centersInfusion centers

- Rheumatologists- Rheumatologists

- Endocrinologists- Endocrinologists

- Other specialists skilled in infusion therapy- Other specialists skilled in infusion therapy

► Infusion Therapy Required:Infusion Therapy Required: Overcoming barriers Overcoming barriers and directing patients to IV administration sitesand directing patients to IV administration sites

- - Infusion centersInfusion centers

- Rheumatologists- Rheumatologists

- Endocrinologists- Endocrinologists

- Other specialists skilled in infusion therapy- Other specialists skilled in infusion therapy

Practical Issues in Placing Patients on an Annual Zoledronic Acid Regimen


Once Yearly TherapyOnce Yearly TherapySummary and ConclusionsSummary and Conclusions

► Most managed care health systems have designated Most managed care health systems have designated infusion servicesinfusion services

► Initiating therapy in the hospital following hip or Initiating therapy in the hospital following hip or osteoporosis-related fracture is an optionosteoporosis-related fracture is an option

► Most managed care health systems have designated Most managed care health systems have designated infusion servicesinfusion services

► Initiating therapy in the hospital following hip or Initiating therapy in the hospital following hip or osteoporosis-related fracture is an optionosteoporosis-related fracture is an option



Denosumab: OverviewDenosumab: Overview

► Fully human monoclonal antibody-IgGFully human monoclonal antibody-IgG22 isotype isotype

► High affinity and specificity for human RANK LigandHigh affinity and specificity for human RANK Ligand► Pharmacokinetics (SC): similar to other fully human Pharmacokinetics (SC): similar to other fully human

IgGIgG22 monoclonal antibodies monoclonal antibodies ● Absorption is rapid and prolonged (CAbsorption is rapid and prolonged (Cmaxmax ≈1-4 wks postdose) ≈1-4 wks postdose)● Long half-life ≈34 days with max doseLong half-life ≈34 days with max dose● Distribution ≈ intravascular volumeDistribution ≈ intravascular volume● Clearance ≈ reticuloendothelial systemClearance ≈ reticuloendothelial system● No kidney filtration or excretion of intact molecule No kidney filtration or excretion of intact molecule

► Phase 3 should be completed by midyear 2008Phase 3 should be completed by midyear 2008● NDA should be in by end 2008NDA should be in by end 2008

► Fully human monoclonal antibody-IgGFully human monoclonal antibody-IgG22 isotype isotype

► High affinity and specificity for human RANK LigandHigh affinity and specificity for human RANK Ligand► Pharmacokinetics (SC): similar to other fully human Pharmacokinetics (SC): similar to other fully human

IgGIgG22 monoclonal antibodies monoclonal antibodies ● Absorption is rapid and prolonged (CAbsorption is rapid and prolonged (Cmaxmax ≈1-4 wks postdose) ≈1-4 wks postdose)● Long half-life ≈34 days with max doseLong half-life ≈34 days with max dose● Distribution ≈ intravascular volumeDistribution ≈ intravascular volume● Clearance ≈ reticuloendothelial systemClearance ≈ reticuloendothelial system● No kidney filtration or excretion of intact molecule No kidney filtration or excretion of intact molecule

► Phase 3 should be completed by midyear 2008Phase 3 should be completed by midyear 2008● NDA should be in by end 2008NDA should be in by end 2008

Bekker PJ et al. J Bone Miner Res. 2004;19:1059-1066.Boyle WJ et al. Nature. 2003;423:337-342.

Mechanism of Action for DenosumabMechanism of Action for Denosumab

Growth Factors Growth Factors HormonesHormonesCytokinesCytokines

BoneBoneCFU-M = colony CFU-M = colony forming unit forming unit macrophagemacrophage

Osteoblast Osteoblast LineageLineage

OsteoclastOsteoclast

CFU-MCFU-M

Pre-Fusion Pre-Fusion OsteoclastOsteoclast

MultinucleatedMultinucleatedOsteoclastOsteoclast

RANKRANKRANKLRANKL

OPGOPG

denosumabdenosumab

Denosumab Phase 2 StudyDenosumab Phase 2 Study

► 1-year data: N Engl J Med 2006 1-year data: N Engl J Med 2006 McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. Denosumab in postmenopausal women with low bone mineral density. N Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831.Engl J Med. 2006;354:821-831.

► 2-year data: J Bone Miner Res 20072-year data: J Bone Miner Res 2007Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. postmenopausal women with low bone mineral density. J Bone Miner Res. 2007 Dec;22(12):1832-41.

► 4-year data: ASBMR Oral Presentation 20074-year data: ASBMR Oral Presentation 2007Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of denosumab on bone mineral density and bone turnover markers: 48-denosumab on bone mineral density and bone turnover markers: 48-month results. ASBMR 2007. Abstract 1205. month results. ASBMR 2007. Abstract 1205.

► 1-year data: N Engl J Med 2006 1-year data: N Engl J Med 2006 McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. Denosumab in postmenopausal women with low bone mineral density. N Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831.Engl J Med. 2006;354:821-831.

► 2-year data: J Bone Miner Res 20072-year data: J Bone Miner Res 2007Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. postmenopausal women with low bone mineral density. J Bone Miner Res. 2007 Dec;22(12):1832-41.

► 4-year data: ASBMR Oral Presentation 20074-year data: ASBMR Oral Presentation 2007Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of denosumab on bone mineral density and bone turnover markers: 48-denosumab on bone mineral density and bone turnover markers: 48-month results. ASBMR 2007. Abstract 1205. month results. ASBMR 2007. Abstract 1205.

Denosumab Phase 2 StudyDenosumab Phase 2 Study

► Randomized, placebo-controlled, dose-ranging studyRandomized, placebo-controlled, dose-ranging study

► Postmenopausal women (n = 412) with low BMD or OPPostmenopausal women (n = 412) with low BMD or OP● Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5)Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5)● Mean Spine T-Score -2.1Mean Spine T-Score -2.1

► Treatment Assignments:Treatment Assignments:● 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100, 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100,

or 210 mg Q6M SQ), or 210 mg Q6M SQ), ● 1 open label 70 mg weekly alendronate group1 open label 70 mg weekly alendronate group● Placebo groupPlacebo group

► All subjects received 1000 mg Ca and 400 IU D dailyAll subjects received 1000 mg Ca and 400 IU D daily

► Primary end point: Spine BMD at 12 monthsPrimary end point: Spine BMD at 12 months

► Prespecified exploratory analysis: BMD, BTMs, safety at 24 Prespecified exploratory analysis: BMD, BTMs, safety at 24 and 48and 48 monthsmonths

► Randomized, placebo-controlled, dose-ranging studyRandomized, placebo-controlled, dose-ranging study

► Postmenopausal women (n = 412) with low BMD or OPPostmenopausal women (n = 412) with low BMD or OP● Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5)Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5)● Mean Spine T-Score -2.1Mean Spine T-Score -2.1

► Treatment Assignments:Treatment Assignments:● 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100, 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100,

or 210 mg Q6M SQ), or 210 mg Q6M SQ), ● 1 open label 70 mg weekly alendronate group1 open label 70 mg weekly alendronate group● Placebo groupPlacebo group

► All subjects received 1000 mg Ca and 400 IU D dailyAll subjects received 1000 mg Ca and 400 IU D daily

► Primary end point: Spine BMD at 12 monthsPrimary end point: Spine BMD at 12 months

► Prespecified exploratory analysis: BMD, BTMs, safety at 24 Prespecified exploratory analysis: BMD, BTMs, safety at 24 and 48and 48 monthsmonths

Lewiecki EM et al. Lewiecki EM et al. JJ Bone Miner ResBone Miner Res. 2007 Dec;22(12):1832-41.. 2007 Dec;22(12):1832-41.

Spine BMDSpine BMD

MonthMonth

-2-2

BB 66 1212 1818 2424

Lum

bar

spin

e B

MD

Lu

mba

r sp

ine

BM

D

perc

ent

chan

ge (

%)

perc

ent

chan

ge (

%)

aaPP < 0.001 vs pbo < 0.001 vs pbo

Aln (a)Aln (a)

Den 60 (a)Den 60 (a)

PboPbo-1-100112233445566778899

1010


Total Hip BMDTotal Hip BMDT

otal

hip

BM

D

Tot

al h

ip B

MD

(per

cent

cha

nge

(%)

(per

cent

cha

nge

(%)

MonthMonthBLBL 66 1212 1818 2424

Aln (a)Aln (a)

Den 60 (a, b)Den 60 (a, b)

PboPboaaPP < 0.001 vs pbo < 0.001 vs pbobbPP < 0.05 vs aln < 0.05 vs aln

-3-3

-2-2

-1-1

00

11

22

33

44

55

66


1/3 Radius BMD1/3 Radius BMD

MonthMonth

-4-4

-3-3

-2-2

-1-1

00

11

22

33

BLBL 66 1212 1818 2424

Dis

tal 1

/3 r

adiu

s B

MD

D

ista

l 1/3

rad

ius

BM

D

perc

ent c

hang

e (%

) pe

rcen

t cha

nge

(%)

Aln (a)Aln (a)

Den 60 (a, b)Den 60 (a, b)

PboPboaaPP < 0.05 vs pbo < 0.05 vs pbobbPP < 0.05 vs aln < 0.05 vs aln


Serum CTXSerum CTXS

erum

CT

X p

erce

nt c

hang

e (%

)S

erum

CT

X p

erce

nt c

hang

e (%

)(m

edia

n)

(med

ian)

MonthMonth

-90-90-80-80-70-70-60-60-50-50-40-40-30-30-20-20-10-10

0010102020

BL BL D3 D3

6 6 D3 D3

1212 1818 2424

AlendronateAlendronate60 mg60 mg

PlaceboPlacebo


Serum BSAPSerum BSAP

MonthMonth

Bon

e-sp

ecifi

c al

kalin

e ph

osph

atas

e B

one-

spec

ific

alka

line

phos

phat

ase

perc

ent

chan

ge (

%)

(med

ian)

perc

ent

chan

ge (

%)

(med

ian)

BLBL 66 1212 1818 2424

AlendronateAlendronate60 mg60 mg

PlaceboPlacebo

-80-80

-70-70

-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

1010

2020


Medications Under DevelopmentMedications Under Development

► Medications Currently Under Development or FDA Medications Currently Under Development or FDA Review:Review:● New Estrogen Agonist/Antagonist AgentsNew Estrogen Agonist/Antagonist Agents

• Bazedoxifene (Wyeth) and CEE/Bazedoxifene comboBazedoxifene (Wyeth) and CEE/Bazedoxifene combo• Lasofoxifene (Pfizer)Lasofoxifene (Pfizer)• Arzoxifene (Lilly)Arzoxifene (Lilly)

● New PTH Compounds: Cyclic 1-31PTH (Zelos)New PTH Compounds: Cyclic 1-31PTH (Zelos)● New PTH Delivery Systems (Patch, Oral, Nasal)New PTH Delivery Systems (Patch, Oral, Nasal)● Cathepsin K Inhibitor (Merck)Cathepsin K Inhibitor (Merck)● PTH Receptor Antagonist (GSK)PTH Receptor Antagonist (GSK)● Antisclerostin Antibody (Amgen)Antisclerostin Antibody (Amgen)● Glucagon-Like PeptideGlucagon-Like Peptide

► Medications Currently Under Development or FDA Medications Currently Under Development or FDA Review:Review:● New Estrogen Agonist/Antagonist AgentsNew Estrogen Agonist/Antagonist Agents

• Bazedoxifene (Wyeth) and CEE/Bazedoxifene comboBazedoxifene (Wyeth) and CEE/Bazedoxifene combo• Lasofoxifene (Pfizer)Lasofoxifene (Pfizer)• Arzoxifene (Lilly)Arzoxifene (Lilly)

● New PTH Compounds: Cyclic 1-31PTH (Zelos)New PTH Compounds: Cyclic 1-31PTH (Zelos)● New PTH Delivery Systems (Patch, Oral, Nasal)New PTH Delivery Systems (Patch, Oral, Nasal)● Cathepsin K Inhibitor (Merck)Cathepsin K Inhibitor (Merck)● PTH Receptor Antagonist (GSK)PTH Receptor Antagonist (GSK)● Antisclerostin Antibody (Amgen)Antisclerostin Antibody (Amgen)● Glucagon-Like PeptideGlucagon-Like Peptide

SummarySummaryLandmark Advances and Emerging TherapiesLandmark Advances and Emerging Therapies

► New therapies are evolvingNew therapies are evolving

► Persistence must be consideredPersistence must be considered

► All approved bisphosphonates are effective if All approved bisphosphonates are effective if they are takenthey are taken

► Two landmark trials demonstrate zoledronic Two landmark trials demonstrate zoledronic acid reduces vertebral and non-vertebral acid reduces vertebral and non-vertebral (including hip) fracture risk; and one study (including hip) fracture risk; and one study demonstrates mortality reductiondemonstrates mortality reduction

► New therapies are evolvingNew therapies are evolving

► Persistence must be consideredPersistence must be considered

► All approved bisphosphonates are effective if All approved bisphosphonates are effective if they are takenthey are taken

► Two landmark trials demonstrate zoledronic Two landmark trials demonstrate zoledronic acid reduces vertebral and non-vertebral acid reduces vertebral and non-vertebral (including hip) fracture risk; and one study (including hip) fracture risk; and one study demonstrates mortality reductiondemonstrates mortality reduction

SummarySummary Landmark Advances and Emerging TherapiesLandmark Advances and Emerging Therapies

► Mononclonal antibodies are in late stage III Mononclonal antibodies are in late stage III development; initial studies promisingdevelopment; initial studies promising

► New Estrogen Agonist/Antagonist Agents might New Estrogen Agonist/Antagonist Agents might have greater potency than current one have greater potency than current one (raloxifene) and might provide additional (raloxifene) and might provide additional rationale for userationale for use

► Mononclonal antibodies are in late stage III Mononclonal antibodies are in late stage III development; initial studies promisingdevelopment; initial studies promising

► New Estrogen Agonist/Antagonist Agents might New Estrogen Agonist/Antagonist Agents might have greater potency than current one have greater potency than current one (raloxifene) and might provide additional (raloxifene) and might provide additional rationale for userationale for use

New Dimensions and Landmark Advances in Osteoporosis Management Felicia Cosman, MD Professor of...

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