Osteoporosis treatment strategy using BMD and Clical Risk Factors (FRAX)

Rachmat Gunadi WachjudiRachmat Gunadi Wachjudi

Divisi ReumatologiDivisi ReumatologiDepartemen Ilmu Penyakit DalamDepartemen Ilmu Penyakit Dalam

Rumah Sakit Dr Hasan Sadikin BandungRumah Sakit Dr Hasan Sadikin Bandung

Critical Challenges in OsteoporosisCritical Challenges in Osteoporosis

What’s osteoporosis?What’s osteoporosis?

► Loss of bone mineral density and destruction of bone Loss of bone mineral density and destruction of bone matrix micro-architecture matrix micro-architecture

► Clinically important disease that increases risk of Clinically important disease that increases risk of fracturefracture

► What about “osteopenia”? What about “osteopenia”? – Old term for “low bone Old term for “low bone

mineral density”mineral density”– Not technically a diseaseNot technically a disease

Breaking news:Breaking news:

►We’re getting old!We’re getting old!– 1 in 2 white* women and 1 in 5 men will 1 in 2 white* women and 1 in 5 men will

have an osteoporotic fracturehave an osteoporotic fracture

► It costs a ton!It costs a ton!– 432,000 hospital admissions432,000 hospital admissions– 180,000 nursing home admissions180,000 nursing home admissions– $17 billion in cost$17 billion in cost

►We can prevent and treat it!We can prevent and treat it!

National Osteoporosis National Osteoporosis FoundationFoundation

Screen with DXA:Screen with DXA:

►Women 65 and older, men 70 and olderWomen 65 and older, men 70 and older►Anyone 50-69 whose profile increases Anyone 50-69 whose profile increases

riskrisk•Thanks, NOF!Thanks, NOF!

How are results reported?How are results reported?

Who needs treatment?Who needs treatment?

► Anyone with diagnosed osteoporosisAnyone with diagnosed osteoporosis– T-score at hip T-score at hip ≤ -2.5 (ignore Z score)≤ -2.5 (ignore Z score)– Fragility fracture (what’s this?!)Fragility fracture (what’s this?!)

► NOF recommends treating in LBMD if high NOF recommends treating in LBMD if high FRAX risk of fracture: FRAX risk of fracture: – 3% for hip 3% for hip

OR OR – 20% major osteoporosis-related fracture.*20% major osteoporosis-related fracture.*

FRAX tool

Clinical Risk FactorsClinical Risk Factors

Femoral neck T-scoreFemoral neck T-score + +

► AgeAge

► Previous low trauma fracturePrevious low trauma fracture

► Current cigarette smokingCurrent cigarette smoking

► Rheumatoid arthritisRheumatoid arthritis

► High alcohol intake (> 2 units/day)High alcohol intake (> 2 units/day)

► Parental history of hip fractureParental history of hip fracture

► Prior or current glucocorticoid usePrior or current glucocorticoid use

Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.

OSC Guideline, 2002

Major and Minor Risk FactorsMajor and Minor Risk Factors

MajorMajor MinorMinor

Age > 65Age > 65 Rheumatoid arthritisRheumatoid arthritis

Vertebral compression fracture Vertebral compression fracture History of hyperthyroidismHistory of hyperthyroidism

Fragility fracture after age 40Fragility fracture after age 40 Anticonvulsant therapyAnticonvulsant therapy

Family history of osteoporsis/ #Family history of osteoporsis/ # Low dietary calcium intakeLow dietary calcium intake

Steroids > 3 monthsSteroids > 3 months SmokingSmoking

MalabsorptionMalabsorption Excess caffeine intakeExcess caffeine intake

Primary hyperparathyroidismPrimary hyperparathyroidism Weight < 57 kgWeight < 57 kg

Propensity to fallPropensity to fall Weight loss > 10% Weight loss > 10%

Osteopenia on x-rayOsteopenia on x-ray Chronic heparin therapyChronic heparin therapy

HypogonadismHypogonadism

Early menopause (< age 45)Early menopause (< age 45)

Intervention ThresholdIntervention Threshold

►A fracture probability above which A fracture probability above which it is it is cost-effectivecost-effective to treat with to treat with pharmacological agentspharmacological agents

►Based on statistical modeling using Based on statistical modeling using many medical, social, and many medical, social, and economic assumptions economic assumptions

•Canadian Guidelines RecommendCanadian Guidelines Recommend

Who to treat ?Who to treat ?

•Prior h/o hip/vertebral #Prior h/o hip/vertebral #•Prior h/o hip/vertebral #Prior h/o hip/vertebral #

•oror•oror

•T Score < -2.5T Score < -2.5•T Score < -2.5T Score < -2.5

•oror•oror•T Score -1 to -2.5 &T Score -1 to -2.5 &•10 yr risk (FRAX) :10 yr risk (FRAX) :

•HIP # > 3 % or HIP # > 3 % or •major osteoporotic # > 20 %major osteoporotic # > 20 %

•T Score -1 to -2.5 &T Score -1 to -2.5 &•10 yr risk (FRAX) :10 yr risk (FRAX) :

•HIP # > 3 % or HIP # > 3 % or •major osteoporotic # > 20 %major osteoporotic # > 20 %

•Postmenopausal women /men > 50 yrsPostmenopausal women /men > 50 yrs

•witwithh

•

•Anti-resorptive

Anti-resorptive

•AnabolicAnabolic

•‘‘Dual action’

Dual action’

•Bone marrow precursorsBone marrow precursors

•OsteoblastsOsteoblasts•OsteoclastOsteoclast

•Lining cellsLining cells

Stimulators of Stimulators of Bone FormationBone Formation• FluorideFluoride• PTH analogsPTH analogs• Sr Ranelate (?)Sr Ranelate (?)

•Inhibitors ofInhibitors of•Bone ResorptionBone Resorption

• Estrogen, SERMsEstrogen, SERMs• BisphosphonatesBisphosphonates• CalcitoninCalcitonin

•Inhibitors ofInhibitors of•RANKLRANKL

•Cathepsin KCathepsin K

Therapeutic strategiesTherapeutic strategiesTherapeutic strategiesTherapeutic strategies

•Treatments & Efficacy Treatments & Efficacy

Vertebral Fx Non-vertebral FxOther Fx Hip Fx

OralHRT Yes Yes YesEtidronate* YesAlendronate* Yes Yes YesRisedronate* Yes Yes YesIbandronate* Yes [Yes]Raloxifene* Yes Calcitriol* YesStrontium Ranelate* Yes Yes [Yes]

Vertebral Fx Non-vertebral FxOther Fx Hip Fx

Subcutaneous Teriparatide* Yes Yes 1-84 PTH* Yes Denosumab* Yes Yes Yes Intravenous Pamidronate Ibandronate*

Zoledronate* Yes Yes Yes Intranasal or Subcutaneous Calcitonin* Yes

Vertebral Fx Nonvertebral Fx

Other Fx Hip Fx

Alendronate* Yes Yes Yes

Risedronate* Yes Yes Yes

Zoledronic acid* Yes Yes Yes

PTH* Yes Yes ???

Strontium ranelate* Yes Yes ???

Denosumab* Yes Yes Yes

Appropriate use of appropriate treatments Appropriate use of appropriate treatments can can halve halve the incidence of the incidence of fractures fractures

•* plus calcium + vitaminD* plus calcium + vitaminD

Mainstay of treatmentMainstay of treatment ::

BisphosphonatesBisphosphonatesApproval in US for osteoporosisApproval in US for osteoporosis►Alendronate : 1995Alendronate : 1995►Risedronate : 2000Risedronate : 2000► Ibandronate : 2005Ibandronate : 2005►Zoledronate : 2007Zoledronate : 2007

DefinitionsDefinitions

►   Initiation-Initiation- Getting the prescription filled. Getting the prescription filled. About 10% of prescriptions are never About 10% of prescriptions are never filled.    filled.    

► Adherence-Adherence- Taking the medicine. Taking the medicine. Often defined as taking more than  80% of Often defined as taking more than  80% of pills over a specified period of time.    pills over a specified period of time.    

► Compliance-Compliance- Taking the pills correctly. Taking the pills correctly. Important issue with bisphosphonates.    Important issue with bisphosphonates.    

► Persistence-Persistence- Still taking the pills. Still taking the pills. Often measured at the one year time point.Often measured at the one year time point.

Non-AdherenceNon-AdherenceHow Large is The Problem?How Large is The Problem?

Studies of patient behavior show that Studies of patient behavior show that LESS THAN 50%LESS THAN 50%

of the people who leave a doctor's of the people who leave a doctor's office with a prescriptionoffice with a prescription

adhere and comply with drug therapyadhere and comply with drug therapy

Simons, et al MJA 1996; 164:208.

n = 610

Persistence with Lipid-Lowering Persistence with Lipid-Lowering TherapyTherapy

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11

Months on lipid lowering therapy

% p

ersi

stin

g

The Effects of Non-AdherenceThe Effects of Non-Adherence

1) Poor patient outcomes due to1) Poor patient outcomes due to sub-optimal therapeutic responsesub-optimal therapeutic response

2) Increased cost burden to society2) Increased cost burden to society

Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97

Poor Patient OutcomesPoor Patient Outcomes

► Increased Morbidity due to disease Increased Morbidity due to disease “exacerbations” “exacerbations”

► More treatment “Failures” with potential for More treatment “Failures” with potential for addition or switching of medications due to addition or switching of medications due to perceived inefficacyperceived inefficacy

► More frequent Physician VisitsMore frequent Physician Visits► Increased HospitalizationsIncreased Hospitalizations► Excess MortalityExcess Mortality

Osterberg L,Blaschke T, N Engl J Med 2005;353:487-97

What Are the Possible Causes of What Are the Possible Causes of Poor Adherence?Poor Adherence?

Disruption to daily routine?

(need for frequent dosing)

Concern about side effects?

“Target disease" eclipsed by other

chronic conditions?

Lack of positive reinforcement?

Complex dosing

guidelines?

Poor patient education

(Health Illiteracy)

POORADHERENCE

Health Literacy

*(Selden et al. 2000; Healthy People 2010, HHS 2000; Ratzan & Parker 2000) **(Institute of Medicine report- 2004)

The degree to which individuals have the capacity to The degree to which individuals have the capacity to obtain, process, and understand basic information and obtain, process, and understand basic information and make appropriate decisions about their health*make appropriate decisions about their health*

90 million people in the United States, nearly half of all 90 million people in the United States, nearly half of all adults, have difficulty understanding and using health adults, have difficulty understanding and using health information**information**

Patient Beliefs Affect CompliancePatient Beliefs Affect Compliance

► Don’t believe diagnosis or the seriousness Don’t believe diagnosis or the seriousness of the diagnosisof the diagnosis

► Believe other diseases are more importantBelieve other diseases are more important

► Believe side effects outweigh benefitsBelieve side effects outweigh benefits

► Concerned about their ability to carry out Concerned about their ability to carry out recommended actionrecommended action

AARP Survey, 1985National Prescription Buyers’ Survey, USA 1985

Lack of CommunicationLack of Communication

► Study of 300 medical encounters: Study of 300 medical encounters: doctors spent doctors spent average 1.3 minutes giving informationaverage 1.3 minutes giving information11

► Study of 264 visits to family physicians.-during Study of 264 visits to family physicians.-during patient initial statement of the problem, patient initial statement of the problem, physician interrupted after average of 23 physician interrupted after average of 23 seconds.seconds.22

► 50% of 50% of patientspatients leave office visit leave office visit not not understandingunderstanding what the doctor said what the doctor said33

Clement, Diab Care 1995;18:1204. Waitzkin. JAMA 1984;252:24411

Kravitz et al. Arch Intern Med 1993;153:1869. 2

Roter and Hall. Ann Rev Public Health 1989;10:163. Marvel JAMA 1999;281:283. 3

Nonadherence to Nonadherence to Osteoporosis Medications: Osteoporosis Medications:

How Common Is It? How Common Is It?

Adherence With Osteoporosis Adherence With Osteoporosis Medications Is Sub-optimalMedications Is Sub-optimal

Tosteson ANA, et al. Am J Med. 2003;115:209-216.

20% to 25% of Patients Abandon Therapy Within 7 Months20% to 25% of Patients Abandon Therapy Within 7 Months

Pat

ien

ts A

ban

do

nin

gT

reat

men

t (%

)

30

25

20

15

10

5

0 Hormone Replacement Therapy(n=334)

Bisphosphonate(n=366)

Selective Estrogen Receptor Modulator

(n=256)

Telephone survey of 956 randomly selected women with postmenopausal osteopenia or osteoporosis who initiated therapy in 2000-2001. Mean follow-up was 7 months.

26%

19% 19%

Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325.

A HIPAA-compliant, longitudinal patient database of prescriptions dispensed from ~25% of US retail pharmacies was used to assess discontinuation of bisphosphonates over a 12-month period in women aged ≥50 years.*

* Primary usage in osteoporosis; however, data may include use in other indications.

Adherence With Oral Bisphosphonates Is Adherence With Oral Bisphosphonates Is Suboptimal, Regardless of DosingSuboptimal, Regardless of Dosing

Percentage of Patients on Therapy (defined as having at least 1 day of medication supply in the month)

P<0.001 vs daily therapy

10

20

30

40

50

60

70

80

90

100

Oct2002

Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct2003

Pat

ien

ts o

n T

her

apy

(%)

Daily Bisphosphonates (n=33,767)

Weekly Bisphosphonates (n=177,552)

54.6%

36.9%

Surgeon General’s Report Cites Need toSurgeon General’s Report Cites Need toImprove Adherence With Osteoporosis TherapiesImprove Adherence With Osteoporosis Therapies

► Long-term adherence rates with Long-term adherence rates with any medication are poor (~50%)any medication are poor (~50%)

► Follow-up strategies that Follow-up strategies that improve adherence to should be improve adherence to should be applied to osteoporosisapplied to osteoporosis– Simplifying the treatment Simplifying the treatment

regimenregimen– Counseling Counseling – Addressing patient concerns Addressing patient concerns

about side effectsabout side effects– Maintaining an encouraging Maintaining an encouraging

provider-patient relationshipprovider-patient relationship

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; 2004.

Non-Adherence to OsteoporosisNon-Adherence to OsteoporosisMedication Affects BMDMedication Affects BMD

0

0.5

1

1.5

2

2.5

3

3.5

4

Compliant

Non-compliant

Yood R, et al Osteoporosis int 14:2003. 965-68

Lumbar Lumbar BMDBMD

Non-Adherence to OsteoporosisNon-Adherence to OsteoporosisMedication Increases Fracture RiskMedication Increases Fracture Risk

3.4

3.6

3.8

4

4.2

4.4

4.6

Non-compliant

Compliant

11,249 women suffering from osteoporosis with a mean age of 68.4 years and average follow-up of 2 years

16% decrease

Caro JJ et al. Osteoporosis Int 14, 2003, Suppl 7

Fracture Rate %

* P<0.0001.† Compliant is defined as taking medication ≥80% of the time over a 24-month period.

Retrospective cohort study that used longitudinal medical and pharmacy claims data from Medstat MarketScan® Research Databases to assess adherence and fracture risk over 24 months (1999-2003).

Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC.

Better Long-term Compliance ReducesBetter Long-term Compliance Reducesthe Risk of Fracturethe Risk of Fracture

Compliance With Bisphosphonates and Fracture Risk Over 2 Years in Women ≥45 Years With Postmenopausal Osteoporosis

(n=6825)

% P

atie

nts

Wit

h F

ract

ure

0

2

4

6

8

10

12

14

Compliant Noncompliant

(n=3400) (n=3425)

*

†

9.4%

12.6%

How Can Adherence How Can Adherence Be Improved?Be Improved?

Improving Adherence byImproving Adherence byReinforcing Treatment EfficacyReinforcing Treatment Efficacy

►Patient monitoring may be helpful Patient monitoring may be helpful in in demonstrating effects of demonstrating effects of treatmenttreatment1-31-3

– BMDBMD– Biochemical markers of bone Biochemical markers of bone

turnoverturnover

►Frequent visits or calls from staffFrequent visits or calls from staff

1. Clowes et al. JCEM. 2004;89:1117-1123).2. Deal CL. Curr Rheumatol Rep. 2001;3:233-239.3. Chapurlat RD, Cummings SR. Osteoporos Int. 2002;13:738-744.

Improving Adherence Through Modifying Dosing Improving Adherence Through Modifying Dosing Interval: Focus on BisphosphonatesInterval: Focus on Bisphosphonates

►Survey data suggests that patients Survey data suggests that patients prefer more widely-spaced dosing prefer more widely-spaced dosing intervalsintervals

►Retrospective data suggest improved Retrospective data suggest improved adherence with once-weekly versus adherence with once-weekly versus daily bisphosphonatesdaily bisphosphonates

►To date, there are no prospective data To date, there are no prospective data demonstrating that extended dosing demonstrating that extended dosing regimens improve patient adherence regimens improve patient adherence and clinical outcomesand clinical outcomes

Women Preferred Weekly over DailyWomen Preferred Weekly over Daily

►288 postmenopausal women with osteoporosis 288 postmenopausal women with osteoporosis – 4 weeks of alendronate Weekly followed by 4 weeks alendronate Daily4 weeks of alendronate Weekly followed by 4 weeks alendronate Daily– 4 weeks of alendronate Daily followed by 4 weeks alendronate Weekly4 weeks of alendronate Daily followed by 4 weeks alendronate Weekly

►At the final visit, patients completed a preference study At the final visit, patients completed a preference study questionnaire: Which Treatment Routine…questionnaire: Which Treatment Routine…

AlendronateAlendronate

Simon JA et al Clin Ther 2002;24:1871-1886

86.4% 89.0% 87.5%

9.2% 7.7% 8.5%4.4% 3.3% 4.0%

0

20

40

60

80

100

Once weekly

Once daily

No preference

Do You Prefer?Do You Prefer?

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Is More Convenient?Is More Convenient? Would Be Easier toWould Be Easier toComply With For aComply With For a

Long Period of Time?Long Period of Time?

33%

Once a month Once a month

Once a week Once a week

Women Preferred Monthly over WeeklyWomen Preferred Monthly over Weekly

Dosing Schedule PreferenceDosing Schedule Preference(n = 367)*(n = 367)*

p <0.001p <0.001

** Among women expressing a preference, 67% prefer once-a-month dosing, Among women expressing a preference, 67% prefer once-a-month dosing, a statistically significantly higher proportion than the 33% who prefer once-a-week dosinga statistically significantly higher proportion than the 33% who prefer once-a-week dosing

Patients Say They Prefer a Once-a-month Patients Say They Prefer a Once-a-month Over a Once-a-week Dosing ScheduleOver a Once-a-week Dosing Schedule

67%

Simon JA et al Female Patient 2005;30:31-6

* p < 0.0001 vs alendronate* p < 0.0001 vs alendronate

Excludes those patients who did not express a preference for one treatment / m ITT populationExcludes those patients who did not express a preference for one treatment / m ITT population

Twenty-two patients did not express preferenceTwenty-two patients did not express preference

Patient Preference: Ibandronate MonthlyPatient Preference: Ibandronate Monthlyvs Alendronate Weeklyvs Alendronate Weekly

28.6%

71.4%*

0

10

20

30

40

50

60

70

80

Ibandronate Alendronate

Preferred TreatmentPreferred Treatment

Pat

ien

ts (

%)

Pat

ien

ts (

%)

n = 197 n = 79

Emkey R et al Curr Med Res Opin. 2005 Dec;21(12):1895-903

(Patients Expressing Preference)(Patients Expressing Preference)

* p < 0.0001 vs alendronate* p < 0.0001 vs alendronate

Excludes those patients who did not express a preference for treatmentExcludes those patients who did not express a preference for treatment

Thirty-two patients found both treatments equally convenientThirty-two patients found both treatments equally convenient

25.4%

74.6%*

0

10

20

30

40

50

60

70

80

Ibandronate AlendronateMore Convenient TherapyMore Convenient Therapy

Pat

ien

ts (

%)

Pat

ien

ts (

%)

n = 197 n = 67

Patient Preference: Ibandronate MonthlyPatient Preference: Ibandronate Monthlyvs Alendronate Weeklyvs Alendronate Weekly

(Those Expressing Convenience)(Those Expressing Convenience)

Emkey R et al Curr Med Res Opin. 2005 Dec;21(12):1895-903

Principles of Evidence-Based MedicinePrinciples of Evidence-Based Medicine

►AcquireAcquire the Evidence the Evidence

►Critically Critically AppraiseAppraise the Evidence the Evidence

►ApplyApply the Evidence to the Individual the Evidence to the Individual PatientPatient

Evidence-Based Medicine: Integrate Findings Evidence-Based Medicine: Integrate Findings With Clinical Expertise and Patient NeedsWith Clinical Expertise and Patient Needs

Clinical Expertise

Research Evidence

Patient Preferences

Rx

Adapted from: Sackett DL et al. Evidence-Based Medicine: How to Practice and Teach EBM. 2nd ed.

Churchill Livingstone; 2000

Bisphosphonate algorithmBisphosphonate algorithm

A cure for every ailmentsA cure for every ailments

Zoledronic acid 5 mg IV Zoledronic acid 5 mg IV once a yearonce a year

Once Yearly Zoledronic Acid Reduces Once Yearly Zoledronic Acid Reduces FracturesFractures

HORIZON Pivotal Fracture TrialHORIZON Pivotal Fracture Trial Multi-national, multi-center, RCTMulti-national, multi-center, RCT 7,736 women age 65-89 with T-score < -2.5 7,736 women age 65-89 with T-score < -2.5

or fracture plus T-score < -1.5or fracture plus T-score < -1.5 Calcium 1000-1500 mg/day vit D (400-1200 Calcium 1000-1500 mg/day vit D (400-1200

IU/day)IU/day) Zoledronic acid IV infusion 5 mgZoledronic acid IV infusion 5 mg

•Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007

ZOLZOL reduces reduces hiphip fracture fracture

•*Relative risk reduction (95% confidence interval) vs placebo*Relative risk reduction (95% confidence interval) vs placebo•Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007

•PP = .0024 = .0024

•11

•22

•33

•00

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

• Cu

mu

lati

ve I

nci

den

ce (

%)

Cu

mu

lati

ve I

nci

den

ce (

%)

•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%)

•PP < .0001 < .0001

• Cu

mu

lati

ve I

nci

den

ce (

%)

Cu

mu

lati

ve I

nci

den

ce (

%)

•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%)

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

•11

•22

•33

•00

ZOLZOL reduces reduces vertebral vertebral fxfx

•*Relative risk reduction (95% confidence interval) vs placebo*Relative risk reduction (95% confidence interval) vs placebo•Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007

•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%)•Placebo (n = 3861) Placebo (n = 3861)

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

•00

• Cu

mu

lati

ve I

nci

den

ce (

%)

Cu

mu

lati

ve I

nci

den

ce (

%)

ZOL ZOL reduces reduces non-vertebralnon-vertebral fx fx

•*Relative risk reduction (95% confidence interval) vs placebo*Relative risk reduction (95% confidence interval) vs placebo•Black et al. NEJM 356:1809-1822, 2007Black et al. NEJM 356:1809-1822, 2007

Zoledronic Acid will Zoledronic Acid will Improve Improve Patient Patient Compliance Compliance as as Once-Yearly IV Therapy is PreferredOnce-Yearly IV Therapy is Preferred

•Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.

•16.416.4

•18.918.9

•Both Are EqualBoth Are Equal•Once-Yearly IVOnce-Yearly IV

•Once-Weekly PillOnce-Weekly Pill

•More More convenientconvenient

•More willing More willing to take long to take long

termterm

•Overall Overall preferencepreference

•N = 122N = 122

•66.466.4

•59.859.8

•00 •2020 •4040 •6060 •8080 •100100

•68.068.0

•66.466.4

•15.615.6•18.018.0

•20.520.5

•15.615.6

•19.719.7•13.913.9

•% of Patients% of Patients

•More More satisfyingsatisfying

56

J Bone Miner Res. 2012;27:240–242J Bone Miner Res. 2012;27:240–242

•HORIZON-PFT 3-years data:HORIZON-PFT 3-years data:•Black DM, et al. Black DM, et al. N Engl J MedN Engl J Med. 2007;356:1809-1822. 2007;356:1809-1822

•(HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly)(HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly)

•HORIZON-Pivotal Fracture Trial ExtentionHORIZON-Pivotal Fracture Trial Extention

57

• 3-year, randomized, double-blind, placebo-controlled extension trial 3-year, randomized, double-blind, placebo-controlled extension trial • 2456 postmenopausal women2456 postmenopausal women• Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3• Secondary endpoints: BMD at other sites, BTMs, fracture incidence, Secondary endpoints: BMD at other sites, BTMs, fracture incidence,

safetysafety

•HORIZON-PFT Extension: Study HORIZON-PFT Extension: Study OverviewOverview

Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

58

•Primary Endpoint: Primary Endpoint: •% Change of ZOL 5 mg Treatment % Change of ZOL 5 mg Treatment in Femoral Neck BMD in Femoral Neck BMD •at Years 6 VS Years 3at Years 6 VS Years 3

*P < 0.0001, P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables*P < 0.0001, P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables

**P value computed from 2-way ANOVA with treatment and region as explanatory variables.**P value computed from 2-way ANOVA with treatment and region as explanatory variables.

MITT = modified intention to treatMITT = modified intention to treat11Black DM, et al. N Engl J Med. 2007;356:1809-1822 Black DM, et al. N Engl J Med. 2007;356:1809-1822 22Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

Z6 n= 589 609 608 600 524 450

Z3P3 n= 599 613 606 602 540 467

Z3 n= 3851Z3 n= 3851

PBO n= 3845PBO n= 3845

59

ZOL n= 268 262 236 228

PBO n= 265 258 226 212

Z6 n= 101 100

Z3P3 n= 102 84ZOL n= 268 262 236 228

PBO n= 265 258 226 212

Z6 n= 101 100

Z3P3 n= 102 84

*P = 0.1910 **P < 0.0001*P = 0.1910 **P < 0.000111Black DM, et al. N Engl J Med. 2007;356:1809-1822 Black DM, et al. N Engl J Med. 2007;356:1809-1822 22Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

•Secondary Endpoint: Secondary Endpoint: •% Change of ZOL 5 mg Treatment in % Change of ZOL 5 mg Treatment in Lumbar Spine Lumbar Spine BMD BMD at Years 6 VS Years 3at Years 6 VS Years 3

60

•Secondary Endpoint: Secondary Endpoint: •6 years of annual ZOL 5 mg infusions provides 6 years of annual ZOL 5 mg infusions provides continued fracture protectioncontinued fracture protection

•Discontinuation of ZOL 5 mg treatment after Discontinuation of ZOL 5 mg treatment after 3 years still giving residual effect on 3 years still giving residual effect on

prevention nonvertebral fracturesprevention nonvertebral fractures

•Continuation of ZOL 5 mg treatment for 6 Continuation of ZOL 5 mg treatment for 6 years significantly reduced New years significantly reduced New

Morphometric Vertebral Fractures Morphometric Vertebral Fractures

Core study:†P < 0.001 relative risk reduction vs placebo (PBO); n = the number of patients in the analysis population with X-rays at Year 3 and Core study:†P < 0.001 relative risk reduction vs placebo (PBO); n = the number of patients in the analysis population with X-rays at Year 3 and Year 6; ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. †The event rate is from Kaplan-Meier Year 6; ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. †The event rate is from Kaplan-Meier estimate at Month 36 in the extension studyestimate at Month 36 in the extension study11Black DM, et al. N Engl J Med. 2007;356:1809-1822 Black DM, et al. N Engl J Med. 2007;356:1809-1822 22Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

•*P = 0.0348*P = 0.0348

•**P P < 0.001< 0.001

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A single infusion of ZOL 5 mg reduced bone A single infusion of ZOL 5 mg reduced bone resorption marker rapidly than weekly oral ALN 70 mgresorption marker rapidly than weekly oral ALN 70 mg

(Urine NTX)(Urine NTX) (Serum (Serum β-β-CTX )CTX )

•* P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; * P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-β-CTX: Serum CTX: Serum β-β-C-C-telopeptide of type I collagentelopeptide of type I collagen

•Saag, et al. Saag, et al. BoneBone 2007;40:1238-1243 2007;40:1238-1243

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Safety: Safety: Overall No Increase in Risk of AEs or SAEs With Long-termOverall No Increase in Risk of AEs or SAEs With Long-term(6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment(6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment

CategoryZ6 (N=613)

n (%)Z3P3 (N=616)

n (%)P-value

Total no. of patients with an AE 552 (90) 552 (89) 0.85

Serious AEs 191 (31) 168 (27) 0.15

Deaths 26 (4) 18 (3) 0.22

Cardiovascular AE

Atrial fibrillation AEs 21 (3.4%) 13 (2.1%) 0.17

Atrial fibrillation SAEs* 11 (1.8%) 6 (1.0%) 0.23

Stroke related AEs 26 (4.2%) 19 (3.1%) 0.29

Stroke SAEs 19 (3.1%) 9 (1.5%) 0.06

Stroke deaths* 1 (0.2%) 0 (0%) 0.50

New hypertension AEs† 48 (7.8%) 94 (15.2%) <0.001

*P = 0.1910 **P < 0.0001*P = 0.1910 **P < 0.000111Black DM, et al. N Engl J Med. 2007;356:1809-1822 Black DM, et al. N Engl J Med. 2007;356:1809-1822 22Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

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Safety: Safety: Five most common Post-Dose Symptoms (≤ 3 Days After Infusion) Five most common Post-Dose Symptoms (≤ 3 Days After Infusion) and declined markedly with subsequent infusionsand declined markedly with subsequent infusions

•00

•22

•44

•66

•88

•1010

•1212

•1414

•1616

•Annual InfusionAnnual Infusion

•PyrexiaPyrexia

•MyalgiaMyalgia

•Flu-like illnessFlu-like illness•HeadacheHeadache •ArthralgiaArthralgia

•11 •22 •33 •11 •22 •33 •11 •22 •33 •11 •22 •33 •11 •22 •33

• In

cid

en

ce (

%)

Incid

en

ce (

%)

•15%15%

•2%2%

•1%1%•1%1%

•2%2%•1%1%

•2%2%•1%1%

•2%2%•1%1%

•8%8%

•7%7%•6%6% •5%5%

•Placebo values cross-hatchedPlacebo values cross-hatched

•1%1%

•Treatment with antipyretic analgesics appeared to mitigate these Treatment with antipyretic analgesics appeared to mitigate these symptomssymptoms22

•Acetaminophen four times/day for 3 days significantly reduced the Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusionincidence and severity of post-dose symptoms following ZOL infusion33

11Black DM, et al. N Engl J Med. 2007;356:1809-1822Black DM, et al. N Engl J Med. 2007;356:1809-1822

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ZOL= 3595 3574 3284 2989

PBO= 3624 3615 3338 3031

Z6= 613 572 517 459

Z3P3= 616 584 537 475

Renal Safety: Renal Safety: 6 Years of ZOL Therapy Has No 6 Years of ZOL Therapy Has No Cumulative Impact on Cumulative Impact on Creatinine ClearanceCreatinine Clearance

11Black DM, et al. N Engl J Med. 2007;356:1809-1822 Black DM, et al. N Engl J Med. 2007;356:1809-1822 22Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

HORIZON-PFT Extension Study: HORIZON-PFT Extension Study: SummarySummary

► Long-term efficacy - Long-term efficacy - 6 years of ZOL therapy6 years of ZOL therapy led led to:to:– Significantly greater increases from baseline in FN, TH Significantly greater increases from baseline in FN, TH

and trochanter BMD than stopping treatment at 3 years and trochanter BMD than stopping treatment at 3 years – Significant risk reduction in vertebral morphometric Significant risk reduction in vertebral morphometric

fracture risk vs stopping treatment at 3 yearsfracture risk vs stopping treatment at 3 years– Maintenance of bone turnover markers within reference Maintenance of bone turnover markers within reference

rangerange– Losses in BMD and BTMs in discontinuation group Losses in BMD and BTMs in discontinuation group

were modestwere modest

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Black DM, et al. J Bone Miner Res. 2012;27:240–242Black DM, et al. J Bone Miner Res. 2012;27:240–242

• No new safety concerns identified in women with PMONo new safety concerns identified in women with PMO

• No statistical difference in No statistical difference in AFAF SAEs vs SAEs vs discontinuationdiscontinuation of ZOLof ZOL

• No long-term effect on No long-term effect on renal renal function vs function vs discontinuation of ZOLdiscontinuation of ZOL

• No increase in risk for No increase in risk for ONJONJ events events vs discontinuation vs discontinuation of ZOLof ZOL

• No cases of No cases of atypical fracturesatypical fractures

Long-term safetyLong-term safety

SummarySummary

► Adherence Adherence to daily and weekly bisphosphonates to daily and weekly bisphosphonates is is suboptimalsuboptimal

► Poor adherence Poor adherence may compromise clinical outcomes may compromise clinical outcomes and may increase healthcare utilizationand may increase healthcare utilization

► Need to Need to improve communication and education improve communication and education of of patients utilizing all available resourcespatients utilizing all available resources

► Among other factors, Among other factors, dosing frequency dosing frequency may be may be an important determinant of adherence with an important determinant of adherence with bisphosphonatesbisphosphonates

““Drugs don’t work in people that Drugs don’t work in people that don’t take them”don’t take them”

C. Everett Koop, M.D.C. Everett Koop, M.D.

Thank youThank youKeep your bone Keep your bone

healthyhealthy