osteoporosis treatment strategy using bmd and clical risk factors (frax)
DESCRIPTION
This presentation give you the rationale as to how do we treat patients with Osteoporosis and prone to have a nontraumatic fractureTRANSCRIPT
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
61
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
62
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
63
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
64
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
65
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