Osteoporosis: From Theory to Management

1
Osteoporosis From Theory to Management
2
New Definition of Osteoporosis

• It is a systemic skeletal disorder
  characterized by low bone mass Micro
  architecture deterioration of bone tissue with a
  consequent increase in bone fragility and
  susceptibility to fracture.
• International osteoporosis foundation, 2003
  

3
Relationships Between BMD, Age, and 10-Year
Fracture Risk
40
Age
80
30
70
Osteoporotic Fracture Risk ( per 10 Years)
60
20
50
10
0
?3
?2.5
?2
?1.5
?1
?0.5
0
0.5
1
BMD T-Score
Kanis JA, et al. Osteoporos Int. 200112989-995.
4
Osteoporotic Fractures in Women Comparison with
Other Diseases

• Riggs BL, Melton LJ. Bone 1995
• Heart and Stroke Facts, 1996, American Heart
  Association
• Cancer Facts Figures, 1996, American Cancer
  Society

5
Osteoporosis Accounts for More Disability and
Direct Hospital Costs
600
548,615
500
400
353,654
352,062
Number of hospital bed days (thousands)
300
200,669
200
131,331
100
0
Osteoporosis
COPD
Stroke
Breast
MI
carcinoma
Lippuner K, et al. Osteoporos Int 19977414425
6
The Incidence of Osteoporosis Is Sharply Rising
as Populations Age Around the World
This growing epidemic will have major
implications for our society
Sources Bulletin of the World Health
Organization 200381827-830. The Journal of Bone
and Joint Surgery. 200486958-961.
7
Life expectancy in men and women
Age (in years) Expectation of life (in years)
in 1999 Male Female
At birth (0) 75.4 80.2 5 71.0 75.7
20 56.2 60.8 30 46.7 51.0 50
27.9 32.0 60 19.4 23.0 70 12.2
15.1 80 7.0 8.7
and life expectancy is increasing
Data from the UK
8
What Is Osteoporosis and How Many People Are
Affected?
Osteoporosis is a progressive skeletal disease
characterized by low bone mass and
micro-architectural deterioration, with a
consequent increase in bone fragility and
susceptibility to fracture.
The Numbers

• Currently affects gt75 million people in Europe,
  Japan, and the U.S.

• The number of osteoporotic hip fractures has
  quadrupled in the past decade
• Will continue to rise as older population doubles
  by 2050

Sources Bulletin of the World Health
Organization 200381827-830. The Journal of
Bone and Joint Surgery. 200486958-961.
9
Projected Number of Osteoporotic Hip Fractures
Worldwide
742
Total number ofhip fractures1950 1.66
million 2050 6.26 million
378
Adapted from C. Cooper et al, Osteoporos Int.
1992 2285-9
10
The Risk Factors for Osteoporosis Are Well Known
Modifiable risk Factors
Non Modifiable risk Factors

• Alcohol
• Smoking
• Low BMI (leanness)
• Poor nutrition
• Insufficient exercises
• Repeated falls

• Age
• Being a Female gender
• Family History
• Previous fracture history
• Menopause (Hysterectomy)
• Long term use of Corticosteroid
• Rheumatoid Arthritis

11
Fragility Fracture Patients Are Rarely Evaluated
for Osteoporosis

• 90 - 95 of patients go home without a bone
  density test

Orthopedic surgeons are missing a major
opportunity to prevent future fractures by not
providing appropriate investigation of fragility
fracture patients themselves or initiating
appropriate protocols of care to be provided by
their colleagues.
International Osteoporosis Foundation. The
Journal of Bone and Joint Surgery.
200486958-961.
12
Osteoporosis Is Manageable and Fractures Are
Avoidable
By age 20, 98 of a womans skeletal mass is
established

• Early
• Proper nutrition calcium and vitamin D
• Weight-bearing exercise
• Middle-age
• Exercise
• No smoking
• Proper nutrition calcium and vitamin D
• Older adult with risk factors
• Bone density scan
• With fracture, get osteoporosis evaluation

More awareness and education is essential
Source National Osteoporosis Foundation Oct.
7, 2004.
13
NOF guideline for Diagnosis treatment
Postmenopausal below the age of 50
Assess risk of osteoporosis Check secondary
reasons
Calcium 1200 mg VIT D 400 IU
Calcium 1200 mg VIT D 400 IU
no
Postmenopausal between 50-65
Assess risk of osteoporosis
DEXA
Yes
Post menopausal Above 65 years
DEXA
Any postmenopausal With fracture
DEXA
National Osteoporosis Foundation February 2008
14
NOF guideline for Diagnosis treatment

• Initiate treatment with any DEXA score lt -2.5 T
  score with appropriate antiresorptive.
• Initiate treatment for osteopenic cases with a T
  score -1 to -2.5 in case that the patients FRAX
  (10 years fracture probability) score hip
  fracture gt3

National Osteoporosis Foundation February 2008
15
Frax-WHO (10 years fracture risk assessment)

• This is a tool developed by Prof. Kanis with
  association of Shifeld university and WHO
  organization, it calculate on a patients
  individual basis the risk of hip, vertebral and
  non vertebral fracture in the coming 10 years.
• The algorithm of the calculation is built upon 13
  inputs

16
Frax-WHO (10 years fracture risk assessment)

• Age
• Sex Male Female
• Weight
• Height
• Previous fractures
• Parent Fractures
• Glucocorticoid
• Current smoking
• Rheumatoid Arthritis
• Secondary osteoporosis
• Alcohol more than 3 units/day
• Femoral neck BMD T score

NO
YES
YES
NO
YES
NO
YES
NO
YES
NO
NO
YES
YES
NO
Calculate
http//www.shef.ac.uk/FRAX/tool.jsp?locationValue
9
17
Frax-WHO (10 years fracture risk assessment)

• Results

BMI 22 The ten year probability of fracture
() With BMD -1.8
Major osteoporotic fracture
33
Hip Fracture
2.1
18
Osteoporosis A Ticking Time Bomb
19
If pharmacologic therapy is indicated

• FDA-approved options are

• Estrogens (prevention only) according FDA new
  statement.
• Bisphosphonates and Selective estrogen-receptor
  modulators (prevention and treatment)
• Calcitonin (treatment only).
• PTH (treatment)
• Zoledronic Acid (Prevention Treatment)

20
Bone RemodelingRole of Bisphosphonate
21
Osteoclast Activation

• Due to the central role of osteoclast in bone
  remodeling, the osteoclast is an important
  pharmacological target in drug therapy for
  osteoporosis.

22
Osteoclast Activation

• Normal function of osteoclast is dependent on
  production of key lipid (G Prenylated Protein)
  intermediate in the osteoclast itself.
• The enzyme Farnesyl PyroPhosphate Synthase (FPP
  Synthase) mediate the production of these lipids.
  

23
Osteoclast Activation
Mevalonate
Statin
Geranyl pyrophosphate
(GPP)
Isopentenyl pyrophosphate
(IPP)
FPP synthase
Farnesyl pyrophosphate (FPP)
Cholesterol
Geranylgeranyl pyrophosphate (GGPP)
Prenylated G proteins
24
Osteoclast Activation

• The prenylated G proteins attach to the
  osteoclast lipid bilayers. Which activate
  Osteoclast for bone resorption.

• Formation of ruffled border.
• Attachment to bone.
• Trafficking of vacuoles.
• Inhibition of osteoclast apoptosis.

25
Action of Bisphosphonates Depends on Mineral
Binding to the bone surface
BP Bind to bone mineral
Concentrate at sites of bone resorption
Release and intracellular uptake during
resorption
Loss of resorptive function
BP bisphosphonates Courtesy of Professor M.
Rogers.
26
Bisphosphonates

• Following administration, nitrogen containing
  bisphosphonate binds to the hydroxyapatite
  crystals in the bone matrix.

27
Bisphosphonates

• Bisphosphonate is taken up into the osteoclasts.

28
Bisphosphonates
Prenylated G proteins
29
ACLASTA Key Pharmacological Characteristics
4
Binding to Hydroxyapatite1

• High binding affinity for bone in vitro
• Maximizes attachment
• Minimizes detachment
• Potent FPP synthase inhibition
• Maximizes antiresorptive potential
• Minimizes total amount of drug required
• Allow single administration of total annual dose

3
KL (L/mol x 106)
2
1
0
CLO ETD RIS IBA ALN ZOL
rhFPP synthase Activity2
IC50 (mM)
ALN IBA RIS ZOL

• Nancollas GH, et al. Bone. 2006, in press.
• Dunford JE, et al. J Pharmacol Exp Ther.
  2001296235-242.

30
Bisphosphonates

• Bisphosphonate block the Pharensyl pyrophosphate
  enzyme and hence
• Prevent the formation of osteoclasts ruffle
  border.
• Prevent osteoclast attachment to bone.
• Altered vesicular trafficking.
• Accelerate osteoclasts apoptosis and diminish the
  number of osteocalsts.

Inhibition of bone resorption
31
Bisphosphonate Osteoporosis

• Bisphosphonates are the standard of care for the
  treatment but

• Oral Bisphosphonate has poor bioavailability
• Oral therapy can result in GI adverse event
• Those are the reasons for patient non
  compliance.

32
Poor patient compliance
P NS
Data from Downey TW, et al. South Med J. In
press.
33
Poor Compliance and Persistence Lead to
Compromised Fracture Risk Reduction
1. Caro JJ, et al. Osteoporos Int.
2004151003-1008. 2. Siris E, et al. Poster
presented at NOF Sixth International Symposium on
Osteoporosis April 6-10, 2005 Washington, DC.
34
Persistence as a Main Determinant of Antifracture
Efficacy
2-year data in 35,537 patients
Persistent
Odds ratio using logistic regression to adjust
for baseline covariates PersistenceRefill gap
30 days non persistencerefill gap gt30
days Siris E, et al. Mayo Clin Proc.
20068110131022.
35
Bisphosphonate comparative bioavailability
Bioavailability
Systemic concentration
Year intake
Alendronate
0.43
3360 mg
14 mg/year
10.3 mg/year
1680 mg
0.62
Residronate
5 mg
5 mg/year
100
Zoledronic
Oral Bisphosphonate poor compliance, oblige the
patients to follow a rigid Instruction of taking
the medication on an empty stomach and refrain
for any food for 2 hrs
36
Rationale for Once-Yearly IV Bisphosphonate
Therapy

• Poor adherence to daily and weekly oral
  bisphosphonates results in compromised
  effectiveness.
• The new generation of i.v. administration of
  bisphosphonates is generally safe and well
  tolerated with long-term use
• The IV Bisphosphonates has greatly improved the
  GIT safety and patients convenience.

• The new generation of i.v. administration of
  bisphosphonates is generally safe and well
  tolerated with long-term use
• The IV Bisphosphonates has greatly improved the
  GIT safety and patients convenience.

37
Bisphosphonate
O
Both phosphonate groups act as a bone hook and
are essential both for binding to hydroxyapatite
and biochemical mechanism of action
OH
R1
P
OH
C
OH
P
R2
OH
O
R1 OH, R2 (CH2)2NH2 pamidronate R1
OH, R2 (CH2)3NH2 alendronate R1 OH, R2
(CH2)6(CH3)2N ibandronate
R1 OH, R2 CH2 risedronate
N
R1 OH, R2 CH2 zoledronic acid
N
38
Health Outcomes and Reduced Incidence With
Zoledronic Acid Once Yearly Pivotal Fracture Trial
Black DM, et al. N Engl J Med. 20073561809-1822.
39
Zoledronic Acid Reduced 3-Year Risk of
Morphometric Vertebral Fractures (Stratum I) by
70
70(62, 76)
15
71(62, 78)
10.9(310/2853)
10
7.7(220/2853)
60(43, 72)
Patients With New Vertebral Fractures
3.7(106/2853)
3.3(92/2822)
5
2.2(63/2822)
1.5(42/2822)
0
01
02
03
Years
P lt .0001, relative risk reduction vs placebo
(95 confidence interval) Adapted from Black DM,
et al. N Engl J Med. 20073561809-1822.
40
Zoledronic Acid Reduced Cumulative 3-Year Risk of
Clinical Fractures (Hip, Clinical Vertebral,
Non-vertebral)
25(13, 36)
15
10.7(388/3861)
77(63, 86)
10
41(17, 58)
8.0(292/3875)
Cumulative Incidence () of New Clinical
Fractures Over 3 Years
5
2.6(84/3861)
2.5(88/3861)
1.4(52/3875)
0.5(19/3875)
0
Clinical Vertebral Fracture
HipFracture
Non-vertebral Fracture
Values above bars are 3-year cumulative event
rates based on Kaplan-Meier estimates. P
.0024 P lt .0001 P .0002 relative risk
reduction vs placebo Hip fracture was not
excluded from analysis of non-vertebral
fracture. Black DM, et al. N Engl J Med.
20073561809-1822.
41

Aclasta Uniquely Maintains Protection Against
Vertebral Fractures
Data not from comparative trials
Aclasta1
Alendronate (FIT)4
Risedronate (VERT-NA)2,3
Strontium Ranelate5
Relative Risk Reduction ()
Years
Years
Years
Years
0-1
0-3
0-2
0-1
0-3
0-1
0-3
0-1
0-3
0
10
20
30
40
41
41
50
48
49
60
59
60
65
70
70
71
1. Black DM, et al. N Engl J Med.
20073561809-1822. 2. Harris ST, et al. JAMA.
19992821344. 3. Actonel Prescribing
Information. 4. Black D, et al. J Clin Endocrinol
Metab. 2000854118-4124. 5. Meunier PJ et al.
The effects of strontium ranelate on the risk of
vertebral fracture PMO. New Engl J Med
2004350459-68
42
Fracture Risk Reduction by Bisphosphonates
Data not from comparative trials
NS non-significant, Data not from comparative
trials, Includes wrist and hip fracture results
1. Stevenson M, et al (2006) Analyses of the
cost-effectiveness of pooled alendronate and
risedronate, compared with strontium ranelate,
raloxifene, etidronate and teriparatide.
Sheffield School of Health and Related Research
(ScHARR)) 2. Chesnut CH, et al. Curr Med Res
Opin. 200521(3)391401. 3. Black DM, et al. N
Engl J Med. 20073561809-1822.
43
Zoledronic Acid Produced Significant Increase in
Lumbar Spine BMD Over 3 Years vs Placebo
ZOL 5 mg
Placebo
5.90
3.66
2.39
6.71
Change From Baseline
0
6
12
18
24
30
36
Months
ZOL n PBO n
Bracketed values are least square mean
difference, ZOL vs placeboP lt .0001, P-value
computed from 3-way ANOVA with treatment, stratum
and center as explanatory variables.Adapted from
Black DM, et al. N Engl J Med. 20073561809-1822.
44
Zoledronic Acid Produced Significant Increase in
Femoral Neck BMD Over 3 Years vs Placebo
ZOL 5 mg
Placebo
3.89
2.17
1.58
5.06
Change From Baseline
0
6
12
18
24
30
36
Months
ZOL n PBO n
Bracketed values are least square mean
difference, ZOL vs placeboP lt .0001, P-value
computed from 3-way ANOVA with treatment, stratum
and region as explanatory variables.Adapted from
Black DM, et al. N Engl J Med. 20073561809-1822.
45
Bone Remodeling Parameters (Median)Significantly
Improved at 3 Years
The mineral apposition rate (MAR), which reflects
the bone-forming capacity of individual
osteoblasts, was increased in patients treated
with ZOL (P .0002)
n 59 ZOL, n 52 placebo.
Recker R, et al. Presented at 34th European
Symposium on Calcified Tissues May 5-9, 2007
Copenhagen, Denmark. Abstract PO21-M.
46
Studies 2304, 2305 Significantly More Patients
Achieved Therapeutic Response With ACLASTA vs
Risedronate
96
ACLASTA
Therapeutic response defined as normalization
of serum alkaline phosphatase OR 75
reduction in excess alkaline phosphatase
93
90
Risedronate
74
68
Patients With Therapeutic Response ()
47
20
1
10
28
63
91
182
Days
Core studies 2 identical, 6-month, randomised,
double-blind, active-controlled trials in 357
male and female patients with Pagets
disease. Extension study 267 patients who
experienced therapeutic response in the core
studies re-examined 24 months after treatment. P
lt .001. Reid IR, et al. N Engl J Med.
2005353898-908.
47
Study 2313 Mean Serum ß-CTX by Treatment
ZOL 5 mg IV
ALN 70 mg PO
0.4
0.3
Mean Serum ß-CTX (ng/mL)
0.2


0.1

0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months
1-year, double blind, double dummy study in 225
postmenopausal women aged 45 to 79 years, who had
been treated with alendronate for at least 1 year
immediately prior to randomisation. All had
documented lumbar spine or femoral neck T-scores
of -2.0 before beginning alendronate
therapy. P lt .0001.ALN alendronate ß-CTx
beta C-telopeptide of type 1 collagen ZOL
zoledronic acid. McClung M, et al. Poster
presented at ASBMR 28th Annual Meeting
September 15-19, 2006 Philadelphia, Pa. Poster
F354 SA354.
48
Study 2315 At Week 1, Significantly Greater
Decrease in Urine NTx From Baseline With ACLASTA
P lt .0001
46.1
45.8
50
35.5
40
ACLASTA(n 69)
alendronate 70 mg(n 59)
30
Mean ( SE) Urine NTX (nmol BCE/mmol creatinine)
20
15.2
10
0
Baseline
Week 1
Baseline
Week 1
24-week, multicenter, randomised, double-blind,
double-dummy, active-controlled trial in 128
postmenopausal women aged 45 to 79 years with
T-score of -2.0 at the lumbar spine or femoral
neck on dual energy x-ray absorptiometry
scans. P lt .0001 for relative change from
baseline for ZOL vs ALN. NTx N-telopeptide of
type 1 collagen. Saag K, et al. Bone.
2007401238-1243.
49
Aclasta Reduced Mean Serum ß-CTX
1.0
0.9
Annual dose
0.8
0.7
0.6
Mean Serum ß-CTX (ng/mL)
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
Months
Adapted from Black DM, et al. N Engl J Med.
20073561809-1822.
? C-telopeptide (?-CTX)
50
Aclasta Reduced Mean Serum Bone-Specific
Alkaline Phosphatase (Bone ALP)
Annual dose
Mean Serum Bone ALP (ng/mL)
0
6
12
18
24
30
36
Months
Adapted from Black DM, et al. N Engl J Med.
20073561809-1822.
51
Biopsy From a Patient Confirming Ongoing Bone
Remodelling After Aclasta

• 6 months after Aclasta administration

Doxycycline fluorescent double label at
Remodeling sites
Biopsy of Normal Bone From Iliac Crest
Data on file, Novartis.
52
HORIZON Recurrent Fracture Trial (2310) Overview

• Event-driven, randomized, double-blind,
  placebo-controlled clinical trial
• 2127 men and women, 148 clinical centers, 23
  countries
• Treatment
• Annual infusion of either ZOL 5 mg or placebo
• Loading dose of vitamin D 75,000125,000 IU/d
• Calcium 10001500 mg/d vitamin D 4001200 IU/d
• Follow-up visits at 6, 12, 24, and 36 months
• Telephone interviews every 3 months starting at
  month 9

53
Primary and Secondary Efficacy End Points

• Primary Objective
• Reduce the risk of subsequent clinical fractures
  after surgical treatment for low-trauma hip
  fracture
• Secondary Objectives
• Reduce the risk of clinical vertebral,
  non-vertebral, and hip fracture
• Increase BMD at the total hip and femoral neck of
  the non-fracture hip at months 12 and 24

54
2310 Study Population

• Inclusion
• Male or female patients aged 50 years and older
• Randomized up to 90 days following surgical
  treatment for low-trauma hip fracture
• Ambulatory prior to hip fracture
• Unwilling or unable to take oral bisphosphonates
• Exclusion
• Use of oral bisphosphonates (or any use of IV
  within 2 years)
• Any prior use of parathyroid hormone and analogs
  for gt1 week
• Calculated creatinine clearance 30 mL/min
• Hypercalcemia or hypocalcemia
• Other metabolic bone diseases

55
2310 Baseline Characteristics
56
Cumulative Risk of Clinical Fracturesin 2310 -
Primary Endpoint
35
Hazard ratio, 0.65 (95 CI, 0.500.84) P .0012
Absolute risk reduction 5.3
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1065 1013 950 895 762 628 473 316 212 12
9 Placebo 1062 1010 947 884 742 611 443 305 190 11
9
Lyles KW, et al. N Engl J Med. 2007.
e-publication 10.1056/NEJMoa074941 at
www.nejm.org
57
Cumulative Risk of Clinical Vertebral
Fracturesin 2310
Hazard ratio, 0.54 (95 CI, 0.320.92) P .0210
46
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1065 1027 978 931 794 664 499 339 229 14
0 Placebo 1062 1025 981 927 787 664 492 347 223 13
9
Lyles KW, et al. N Engl J Med. 2007.
e-publication 10.1056/NEJMoa074941 at
www.nejm.org
58
Cumulative Risk of Non-Vertebral Fractures in
2310
27
Hazard ratio, 0.73 (95 CI, 0.550.98) P .0338
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1065 1015 957 903 770 636 478 321 217 13
0 Placebo 1062 1014 961 902 758 626 458 320 201 12
9
Lyles KW, et al. N Engl J Med. 2007.
e-publication 10.1056/NEJMoa074941 at
www.nejm.org
59
Zoledronic Acid 5 mg and Subsequent Fracture Risk
Over Time in 2310
27 (2, 45)
35 (16, 50)
46 (8, 68)
30NS (-2, 59)
20
18
16
13.9(139/1062)
14
10.7(107/1062)
Event Rate ()
12
8.6(92/1065)
10
7.6(79/1065)
8
6
3.8(39/1062)
3.5(33/1062)
4
2.0(23/1065)
1.7(21/1065)
2
0
Non-VertebralFractures
ClinicalVertebralFractures
ClinicalFractures
HipFractures
P .0012 P .0338 P .0210, relative risk
reduction vs placebo NS not significant.
Values above bars are cumulative event rates
based on Kaplan-Meier estimates at Month 24.
Lyles KW, et al. N Engl J Med. 2007.
e-publication 10.1056/NEJMoa074941 at
www.nejm.org
60
Effect on All-Cause Mortality Over Time
28
Hazard ratio, 0.72 (95 CI, 0.560.93) P .0117
Absolute Risk Reduction 3.7
Cumulative Incidence ()
Month
No. at Risk
ZOL 5 mg 1054 1029 987 943 806 674 507 348 237 14
4 Placebo 1057 1028 993 945 804 681 511 364 236 14
9
61
Overall Safety in 2310 Deaths, SAEs, and
Safety-Related Discontinuations
62
Adjudicated Results for Targeted Eventsin 2310
Lyles KW, et al. Presented at 29th ASBMR
September 16-19, 2007 Honolulu, Hawaii. Abstract
1055.
63
Reduction in Clinical Fractures by Timing of
First Infusion
3
2
HR of Zoledronic Acid Relative to Placebo for
Clinical Fxs
1





0
lt2
gt24
gt46
gt68
gt810
gt1012
gt12
Time (Weeks)
Plt0.05 Eriksen, FE. Oral presentation, ECCEO
2008, April 11, Istanbul, Turkey
64
Zoledronic acid Pharmacokinetics
61
24 hours
39

• Rapid plasma half-life.
• Redistributed to bone or
• excreted by kidney.
• No circulating metabolites.

Papapoulos SE, 2005.
65
Zoledronic Acid Renal Safety Non-Oncology
Experience

• No clinically significant increases in mean serum
  creatinine were seen after 15-min infusions of
  ZOL 5 mg in patients with Pagets disease1.
• Not recommended for patients with severe renal
  impairment (creatinine clearance lt30 mL/min) due
  to lack of adequate clinical experience in this
  population2.
• Ensure patients are appropriately hydrated prior
  to infusion 2

ZOL zoledronic acid 1. Reid IR, et al. N Engl
J Med. 2005353898-908. 2. Aclasta summary of
product charactreristics. Available at
http//www.emea.eu.int/humandocs/Humans/EPAR/aclas
ta/aclasta.htm.
66
Common (5 in ZOL) Post-Dose Symptoms Occurring
Within 3 Days After Infusion
SE
15
16
14
12
Flu-like illness
10
8
Myalgia
Incidence ()
Pyrixia
8
Headache
7
5
6
6
4
2
2
2
2
1
1
2
1
1
1
1
0
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
Annual Infusion
Data from Black DM, et al. N Engl J Med.
20073561809-1822.
67
Conclusions
68
Efficacy Safety Analyses in 2301 - Conclusions

• In women with postmenopausal osteoporosis,
  once-yearly infusion of zoledronic acid 5 mg
  over 3 years significantly reduces vertebral
  fractures, hip fractures, and non-vertebral
  fractures
• Zoledronic acid annually as a 5 mg infusion is
  generally safe and well tolerated
• Annual infusions ensure that patients will have
  the full effect of treatment for at least one year

69
Efficacy Safety Analyses in 2310 - Conclusions

• ZOL 5 mg within 90 days of hip fracture treatment
  
• Reduced risk of overall clinical fractures by 35
• Multiple clinical fractures by 33
• Clinical vertebral fractures by 46
• Non-vertebral fracture by 27
• Reduced overall mortality by 28
• No adverse effects on ONJ, fracture healing,
  cardiovascular safety or renal function
• ZOL 5 mg is the first osteoporosis treatment to
  show significant anti-fracture efficacy and
  mortality benefit in a post-hip fracture
  population

70
400,000 patients got Aclasta in Y 08
71
Thank You