1. Number of hospital bed days (thousands) 0 100 200 300 400 500 600 OsteoporosisCOPDStrokeBreast carcinoma MI Lippuner K, et al. Osteoporos Int 1997;7:414–425.

Osteoporosis Management:

Translating Research Into Optimal

Fracture Protection

1

Num

ber

of

hosp

ital bed d

ays

(thousa

nds)

0

100

200

300

400

500

600

Osteoporosis COPD Stroke Breastcarcinoma

MI

Osteoporosis in Women Accounts for More Disability and Direct Hospital Costs Than Many Other Diseases

Lippuner K, et al. Osteoporos Int 1997;7:414–425

548,615

353,654 352,062

200,669

131,331

The Incidence of Osteoporotic Vertebral and Hip Fractures is Higher in Women Than in Men and Increases With Age

Data from Europe 1988–1998Sambrook P, Cooper C. Lancet 2006;367:2010–2018

Men Women400

300

200

100

0

HipRadiographic vertebralWrist

Rate

per

10

,00

0 p

er

Year

50–5

4

55–5

9

60–6

4

65–6

9

70–7

4

75–7

9

80–8

4>85

Age (Years)

400

300

200

100

0

50–5

4

55–5

9

60–6

4

65–6

9

70–7

4

75–7

9

80–8

4>85

Age (Years)

4

Risk Factors for Osteoporotic fractures

Genetic/Non-modifiable Age Female sex Asian or white ethnicity Previous fragility fracture Family history of

hip fracture or osteoporosis Small frame

Potentially Modifiable Menopause-related

estrogen deficiency Low body weight Calcium/vitamin D

deficiency Inadequate physical

activity Excessive alcohol intake Cigarette smoking Long-term steroid therapy

(secondary osteoporosis)

National Osteoporosis Foundation (NOF). Available at: http://www.nof.org/osteoporosis/diseasefacts.htm.Accessed August 31, 2007.

Diagnosis of Osteoporosis Patient history, for detection of etiology

and risk factors of osteoporosis. Initial physical examination, signs of

dorsal kyphosis could be the consequence of vertebral compression fractures.

X-rays or other medical imaging techniques to detect skeletal pathology and fractures.

Measurement of BMD to assess low bone mass

Laboratory tests measuring biochemical markers of bone turnover.

[NIAMS Osteoporosis Diagnosis, p1].

Recommendations for Bone Mineral DensityTesting

All women aged 65 years or older, regardless of other risk factors for osteoporosis.

Postmenopausal women younger than 65 years who have at least 1 risk factor for osteoporosis other than menopause, eg:Family history of osteoporosis.Personal history of low trauma fracture at age

>45.Current smoking.Low body weight (< 127 lb).

All postmenopausal women who have experienced a fragility fracture.According to NOF guidelines, Delaney 2006, pS13

7

Adapted from WHO Technical Report Series 921. Geneva: World Health Organization; 2003.

Normal

Low bone mass [osteopenia]

Osteoporosis

Severe osteoporosis

No lower than −1

Between −1 and −2.5

−2.5 or less

−2.5 or less with fragility fractures

WHO Bone Density Criteria for Osteoporosis

T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip.

Reduction by 1 SD equals a 10%–12% decrease in BMD.

1 SD change increases fracture risk by 1.5- to 2.5-fold.

BMD T-Score Diagnosis

Silent disease; some fractures may initially go unnoticed.

Insufficient rates of diagnosis and treatment.

Poor adherence to prescribed doses: Low persistence over time Lack of compliance with dosing instructions

Southern Medical Journal • Volume 99, Number 6, June 2006The Journal of Family Practice, Vol 59, No 6 | JUNE 2010

Real-World Obstacles in the Management of Osteoporosis

9

Compliance and persistence with Oral Bisphosphonates are poor and suboptimal in clinical practice1

1. Véronique Rabenda , Poor adherence to oral bisphosphonate treatment and its consequences: a review of the evidence, Expert Opin. Pharmacother. (2009) 10(14):2303-23152. Downey TW, et al. South Med J 2006;99:570-575.

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

Months of Continuous Persistence 2

DailyWeekly

% o

f Pa

tients

P = NS

10

Determinants of Poor Persistence

Poor persistence is particularly associated with complex administration and frequent dosing1,2

To improve persistence, eliminate the causes of poor persistence.

Poor persistence

Gastrointestinal intolerability3–5

Complexity of administration3–5

Frequency of dosing3–5

Burden of polypharmacy

(multiple medications)3

1. Emkey RD, Ettinger M. Am J Med. 2006;119:S18–S24. 2. Cramer JA, Silverman S. Am J Med. 2006. 3. Downey TW, et al. South Med J. 2006;99:570–575. 4. Gold DT, et al. Ann Pharmacother. 2006. 5. Sambrook P. Aust Fam Physician. 2006;35:135–137.

11

Rationale for Less-Frequent and Easier-to-Follow Dosing Regimens

Poor adherence to daily, weekly, and monthly regimens of oral bisphosphonates may result in compromised effectiveness. 1

A once-yearly IV bisphosphonate therapy can deliver real-world effectiveness by assuring adherence for the entire annual dosing interval 2

1-The Journal of Family Practice, Vol 59, No 6 | JUNE 20102- Black DM, et al. N Engl J Med. 2007;356:1809-1822

Summary of FDA Approved Indications for Osteoporotic Therapies

12

Supplement to Journal of Managed Care Pharmacy JMCP May 2012 Vol. 18, No. 4-b

14

1. Nancollas GH, et al. Bone. 2006;38:617-627. 2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242.

0

1

2

4

3

KL

(L/m

ol x 1

06)

CLO ETD RIS IBA ALN ZOL

ALN IBA RIS ZOL

IC5

0 (

mM

)

0.0

0.1

0.2

0.3

0.4

0.5

Zoledronic acid:Key Pharmacological Characteristics

High binding affinity for bone

in vitro Maximizes attachment

Minimizes detachment

Potent FPP synthase inhibition in vitro

Maximizes antiresorptive potential

Minimizes total amount of drug required

Allows single administration of total annual dose

Binding to Hydroxyapatite1

FPP synthase2

2007 2008

PUBLISHEDHORIZON

1.Glucocorticoid-induced

Osteoporosis (GIO) Trial

2.HORIZON PFT Trial (Subgroup Analysis)

2005–6

Zoledronic Acid Clinical Trials:Past, Present and Future

PUBLISHED1.HORIZON Pivotal

Fracture Trial (PFT)

2.HORIZON Recurrent

Fracture Trial (RFT)

PUBLISHEDHORIZON Pivotal

Fracture Trial (PFT):

Bone remodeling

PUBLISHEDZoledronic Acid

For Paget’s Disease

2009–10 2012

PUBLISHEDHORIZON

PFT extension study

15

LONG-TERM TREATMENT OF PATIENTS WITH OSTEOPOROSIS

16

Zoledronic Acid Extension Study

Journal of Bone and Mineral Research, 2012

HORIZON-PFT Extension:Objectives

A 3-year extension of the 3-year HORIZON-PFT study was performed to address whether increasing the duration of therapy beyond 3 years will:

Maintain BMD Provide additional fracture protection Reinforce the safety profile established

for 3 years of ZOL therapy

PFT = pivotal fracture trial, Dennis Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Core study N = 7,736

Placebo N = 3,876 ZOL N = 3,889

Randomized in extensionN = 1,233

HORIZON-PFT core study

(3 years)

Extension

(3 years)

1,221 assigned to ZOLto maintain blinding(follow up <3 years)

P3Z3

ZOLN = 617

Z6

Placebo N = 616

Z3P3

Patient Flow From Core Study to Extension

Dennis Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 19

*All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months. FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

HORIZON-PFT Extension: Study Overview

International, multicenter, double-blind, placebo controlled extension trial,

1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n.616) or placebo (Z3P3, n.617).

All patients received daily oral calcium (1000 to 1500 mg) and vitamin D (400 to 1200 IU).

*All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months. FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

HORIZON-PFT Extension: End Points

Primary endpoint: Percentage change in FN BMD at Year 6 vs.

Year 3. Secondary endpoints:

BMD at other sites, BTMs, fracture incidence & safety.

HORIZON-PFT Extension: Inclusion and Exclusion Criteria

Key inclusion criteria1

Postmenopausal women aged ≤ 93 years who received all 3 infusions of study drug in the Core study.

Randomized ≤ 13 weeks after completing the Core study.

Key exclusion criteria2

Pregnancy. Prior use of IV bisphosphonate, strontium, sodium

fluoride, PTH. Use of oral bisphosphonate, systemic corticosteroid,

anabolic steroid or growth hormone without sufficient washout.

Serum calcium < 2 or > 2.75 mmol/L at Core study last visit.

Renal insufficiency with CrCl < 30 mL/min or urine dipstick > 2+ protein.

CrCl = creatinine clearance; IV = intravenous; PTH = parathyroid hormone; SCr = serum creatinine.1. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 2. Black DM, et al. N Engl J Med. 2007;356:1809–1822.

Characteristics and Bone Parameters at Extension Study Baseline

Z6(n = 616)

Z3P3(n = 617)

Age, years

Mean 75.5 75.5

Femoral neck T-score, n (%)*

≤ –2.5 353 (57.3) 325 (52.7)

Prevalent vertebral fractures, n (%)

0 256 (41.6) 227 (36.8)

1 177 (28.7) 168 (27.2)

≥ 2 186 (29.7) 222 (36.0)

*Missing values: Z6, n = 2;Z3P3, n = 2.Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

On average, patients were 75.5 years old, with >50% having femoral neck BMD T-scores lower than 2.5 and approximately 60% with at least one vertebral fracture.

Baseline characteristics between the Z3P3 and Z6 groups were similar.

Efficacy Data from the HORIZON-PFT Extension Study

24

ITT = intention to treat.Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Time (Years from Core Study Baseline)

Z6 Z3P3

0 3 61 2 4 5

Ch

an

ge f

rom

Baselin

e (

%)

Core Study

1.36%

0

1

2

3

4

5

Start of extension

(0.58, 2.15)P = 0.0007

+4.5%

+3.1%

Extension Study

6 Years of Continuous ZOL Treatment Resulted in Significant Gains in Femoral Neck BMD

* ITT = intention to treat.Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

0

1

2

3

4

8

0 1 5 6

Time (Years)

1.47%P < 0.0001

2 3 4

7

6

5

Ch

an

ge f

rom

Baselin

e (

%)

Core Study Extension Study

Z6 Z3P3

27

Change in Total Hip BMD at Year 6 Relative to Core Baseline (ITT)*

Change in Lumbar Spine BMD at Year 6 Relative to Core Baseline (ITT)*

Ch

an

ge f

rom

Baselin

e (

%)

Time (Years from Core Study Baseline)

2.06%

0 1 2 3 4 5 6

0

–2

2

4

6

8

10

12

14

Start of extension


Z6 Z3P3

*ITT = intention to treat.Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254, P = 0.19 28

Core study:†P < 0.001 relative risk reduction vs. placebo (PBO).*P = 0.0348, relative risk reduction vs Z3P3; 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.1. Black DM, et al. N Engl J Med. 2007;356:1809–1822. 2. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

1233 randomized to Extension

49%*

Core Study1 Extension Study2

70%†

Z3P3 Z6ZOL Core Study (Yr 0–3)PBO

0

5

10

15

Significantly Fewer New Morphometric Vertebral Fractures in ZOL Continuation Than Discontinuation (ITT)**

Pati

en

ts w

ith

New

Vert

eb

ral

Fra

ctu

re (

%)

30

For fractures, we saw 49% lower risk for morphometric vertebral fractures but no significant difference in clinically evident vertebral fractures or nonvertebral fractures.

** ITT = intention to treat.

Taken together, these efficacy results show that continuing ZOL for 6 years maintains early gains in BMD and, by implication, bone strength, but discontinuation after 3 years also maintains substantial residual benefit.

Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Change in Serum PINP with 6 vs. 3 Years Zoledronic Acid (ITT)

PINP: Procollagen type I N-terminal propeptide, Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822) Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Mean values remained within the premenopausal reference range throughout

0

20

40

60

0 1 2 3 4 5 6Time (Years)

Mean

PIN

P (

ng

/mL)

Start of extension

Z6 Z3P3

* *

Time of infusion


28.8

25.8

Absolute difference at Year 63.0 ng/mL

(P = 0.0001)

32

Change in BSAP with 6 vs. 3 Years Zoledronic Acid (ITT)

BSAP: Bone specific alkaline phosphatase , Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822). Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

0

5

10

20

0 1 5 6

Z3P39.1%

2 3 4

15

Mean

level (n

g/m

L)

Z69.0%

Time of infusion

Time (Years)

Z6 Z3P3

33

Absolute difference

0.14 ng/mL

P =0.74(Y0-Y6)

Change in β-CTX with 6 vs. 3 Years Zoledronic Acid (ITT)

Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822) Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Mean values remained within the premenopausal reference range throughout.

Mean

β-C

TX

(n

g/m

L)

0

0.1

0.2

0.3

0.4

0.4

0.6

0 1 2 3 4 5 6Time (Years)

Z6 Z3P3Start of extension

Time of infusion


0.18

0.16

34

Absolute difference Year 0–6

0.03 ng/mL

(P = 0.45)

6 Years of ZOL Treatment Maintains Reduction in β-CTX at a Lower Level Than 3 Years of Treatment (ITT)

ß-CTX :Beta C-terminal type 1 collagen telopeptide, *P < 0.05. No significant difference at any other time point in the extension study. Horizontal dashed lines represent premenopausal reference range (Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822). Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

*

0

0.1

0.2

0.3

0.4

0.6

0.8

0 1 2 3 4 5 65.54.53.52.51.50.5

Mean

β-C

TX

(n

g/m

L)

Time (years)

Z6 Z3P3

Start of extension trial

Mean values remained within the premenopausal reference range throughout.

35

Safety Data from the HORIZON-PFT Extension Study

36

Overall Safety Results of the Extension Study

Category Z6, n = 613n (%)

Z3P3, n = 616n (%) P value

Total subjects with any AEs 552 (90.1) 552 (89.6) 0.85

Total subjects with any SAEs 191 (31.2) 168 (27.3) 0.15

Total deaths 26 (4.2) 18 (2.9) 0.22

Total discontinuations due to AEs

14 (2.3) 11 (1.8) 0.55

AE = adverse event; PMO = postmenopausal osteoporosis; SAE = serious adverse event.Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

No increase in risk of AEs or SAEs with long-term (6-Year) ZOL treatment compared with 3 years of treatment

37

Zoledronic Acid: Long-Term Safety

In general, safety was similar in those continuing ZOL compared with those who discontinued.

In the extension trail , rates of post dose

symptoms were much lower than active group rates in the core study and not significantly different between randomized groups.

Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 3838

There were significantly more short-term rises in serum creatinine 9 to 11 days after infusion in the Z6 versus the Z3P3 group, but these short-term increases quickly resolved;

There was no difference between treatment groups in mean change in creatinine clearance and there were no long-term differences in any aspect of renal function.

Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 39

Renal Safety

39

Selected Cardiovascular Events

TIA = transient ischaemic attack.Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

CategoryZ6, n = 613

n (%)Z3P3, n = 616

n (%)P value

Arrhythmia SAEs 20 (3.3) 11 (1.8) 0.11

Atrial fibrillation SAEs 12 (2.0) 7 (1.1) 0.26

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

Stroke SAEs 19 (3.1) 9 (1.5) 0.06

Stroke SAEs excluding TIA 13 (2.1) 7 (1.1) 0.18

Death from stroke 4 (0.7) 0 (0.0) 0.06

Myocardial infarction SAEs 5 (0.8) 4 (0.6) 0.75

Hypertension 48 (7.8) 93 (15.1) 0.0001

The difference in cardiovascular events in the Z6 (2.0%) versus Z3P3 (1.1%), was not statistically significant (P : 0.26).

40

Bone Safety

*Events were new events that occurred during the extension trial. †Results for the Pivotal Fracture Trial are from a secondary analysis that reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare and to assess atypical features.1. Grbic JT, et al. JADA. 2008;139:32–40; 2. Black DM, et al. N Engl J Med. 2010; 362:1761–1771. 3. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Pivotal Fracture Trial,1, 2

Events, nExtension Study,*3

New Events, n

Z3 (N = 3862)

PBO (N = 3852)

Z6 (N = 613)

Z3P3 (N = 616)

Osteonecrosis of the jaw (ONJ) 1 1 1 0

Subtrochanteric or diaphyseal femur fracture† 3 2 0 0

No cases of atypical femur fracture or hip or knee avascular necrosis.

One case of ONJ reported from a patient with risk factors in Z6 which was resolved with appropriate treatment.

In non-randomized group (P3Z3):• 1 ONJ case with several ONJ risk factors.

• 1 Subtrochanteric fracture with no atypical features.

Summary of HORIZON-PFT

Extension Study

42

HORIZON-PFT Extension Study: Efficacy Summary

Long-term efficacy results showed that 6 years of ZOL treatment led to: Significantly greater increases from baseline in

femoral neck and total hip BMD than discontinuation at 3 years.

Significant risk reduction in vertebral morphometric fracture risk vs. discontinuation at 3 years.

Maintenance of BTMs within reference range. Losses in BMD and BTMs in discontinuation

group were modest Residual benefits after discontinuation suggests

that some patients may discontinue infusions for up to 3 years.


HORIZON-PFT Extension Study: Safety Summary

Safety results were similar in those continuing ZOL vs. those who discontinued:

Rates of post-dose symptoms were similar and much lower than that in ZOL group in the Core study.

There is no significant increase in the risk of atrial fibrillation with ZOL treatment.

ZOL treatment for 6 years showed no overall impact on renal function:

Significantly more transient rises in SCr 9–11 days after infusion in patients who continued ZOL that quickly resolved.


Clinical Implications of the Extension Study: WHO SHOULD REMAIN ON TREATMENT? POST HOC ANALYSIS

45

Clinical Recommendation

6-year data support a positive benefit/risk for long-term ZOL therapy.

A post hoc analysis provides insights on which patients:May benefit most from continued treatment

beyond 3 years.May be considered for treatment discontinuation

for up to 3 years.

Decision to continue or interrupt ZOL therapy beyond 3 years should be made on an individual patient basis.

46

FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf 46

The existing data do not support a specific limitation on the duration of use of Aclasta for all osteoporosis patients.

However, based on the reduction in morphometric fractures, those who are at high fracture risk, ( existing vertebral fractures or with hip osteoporosis after an initial course of therapy), may benefit from continued annual infusions.

Clinical Recommendation

Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf

47

48

To avoid noncompliance problems and the associated increase in fracture risk, consider IV bisphosphonates for first-line therapy in women with postmenopausal osteoporosis.

The intermittent dosing regimens of IV bisphosphonates ensure 100% persistence throughout the dosing interval.

Adapted from The Journal of Family Practice, Vol 59, No 6 | JUNE 2010 , Postmenopausal osteoporosis: Another approach to management

Consider IV Bisphosphonates for First-line Therapy

Zoledronic Acid Efficacy In

Prevention Of Postmenopausal

Osteoporosis

49

NEW

PREVENTING FRAGILITY FRACTURES IS AN IMPORTANT PUBLIC HEALTH OBJECTIVE

Fragility fractures are associated with increased morbidity and mortality, so an effective fracture prevention strategy would have a major impact on morbidity and a smaller but important impact on mortality in older adults.1–3

In the United States, approximately 10 million women have osteoporosis and another 34 million have low bone mass (osteopenia).4

50

1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–95.2. Miller RG. Osteoporosis in postmenopausal women. Therapy options across a wide range of risk for fracture. Geriatrics 2006;61:24–30.3. Brown JP, Josse RG, 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada [published errata appear in CMAJ 2003;168:400, CMAJ 2003;168:676, and CMAJ 2003;168:544]. CMAJ. 2002;167 (10 Suppl): S1–34.4. National Osteoporosis Foundation 2008. Available at: http://www.nof.org/osteoporosis/diseasefacts.htm.Retrieved December06, 2009.References 1-4 are stated in McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.

Although women with low bone mass have a lower fracture risk compared with women of the same age with osteoporosis, they are at risk for developing osteoporosis unless bone loss is prevented.

Zoledronic acid has been evaluated for the prevention of PMO in a 2 year study.

The study compared a single ZOL acid infusion or two annual infusions with PBO (McClung 2009).

51

STUDY DESIGN

24 ‐ month, multicenter, randomised, double‐blind, placebo‐controlled, parallel group clinical trial in the prevention of bone loss in postmenopausal women with osteopenia.

52McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.

OBJECTIVES

To demonstrate that zoledronic acid given at randomization and at Month 12 or given at randomization only was superior to placebo in % change in lumbar spine BMD at Month 24 in women stratified by time since menopause(<5years or≥5years).


POPULATION AND METHODOLOGY

581 female patients aged over 45 years with osteopenia.

Stratum I patients : less than 5 years since menopause.

Stratum II patients : 5 or more years since menopause.


TREATMENT REGIMEN

Zol 5mg infusion at randomization and Month 12 or,

Zol 5mg infusion at randomization and placebo infusion at Month 12 or,

Placebo infusion at randomization and Month 12.

All patients received calcium 500–1200 mg/d; vitamin D400–800 IU/d.


RESULTS

Significantly, both Zoledronic acid regimens were superior to placebo in increasing lumbar spine, total hip, femoral neck, trochanter and distal radius BMD at Month 24 and Month 12 in both subpopulations (Stratum I and II) of postmenopausal women.


Zoledronic Acid Once per 2* Years Results in Significant Increase in BMD of Lumber Spine and Femoral Neck at Months 12 and 24 Relative to Baseline

Lumbar spine after 12 months

Hip after 12 months

Lumbar spine after 24 months

Hip after 24 months

-2

-1

0

1

2

3

4

5

2.33% 2.33%

4.42%

2.28%

-0.380000000

000001

-0.380000000

000001 -1.32 -1.45

Aclasta

Placebo

Per

cent

cha

nge

in B

MD

* fr

om b

asel

ine

in

wom

en r

ecei

ved

Zol

aci

d on

ce p

er 2

yea

rs

p ˂ 0.001

*The recommended regimen in prevention of postmenopausal osteoporosis is a single IV infusion of 5mg Aclasta administered once yearly. An annual assessment of patient’s risk of fracture and clinical response to treatment should guide the decision of when retreatment should occur, Aclasta BPIMcClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.

RESULTS (Cont’d)

Both once‐yearly ACLASTA and ACLASTA given at the start of the study significantly decreased levels of serumβ‐CTx, serum P1NP and serum BSAP compared with placebo at all time points over 24 months in both subpopulations of postmenopausal women.


Zoledronic Acid Once Per 2* Years Results in Significant Decrease in BTM** Levels Relative to Baseline at all Time Points

p ˂ 0.001

**Bone Turnover Markers.* The recommended regimen in prevention of postmenopausal osteoporosis is a single IV infusion of 5mg Aclasta administered once yearly. An annual assessment of patient’s risk of fracture and clinical response to treatment should guide the decision of when retreatment should occur. Aclasta BPI

McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.

Conclusion

Both once-yearly dosing and a single dose of intravenous

zoledronic acid 5 mg prevented bone loss for 2 years and were well-tolerated in postmenopausal

women with low bone mass.


THANK YOU

61

1. Number of hospital bed days (thousands) 0 100 200 300 400 500 600 OsteoporosisCOPDStrokeBreast carcinoma MI Lippuner K, et al. Osteoporos Int 1997;7:414–425.

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