Osteoporosis treatment strategy using bisphosphonate once a year

Osteoporosis management
Efficacy and safety of yearly bisphosphonate

Osteoporosis
Increase morbidity and mortality

Who to treat ?
Prior h/o hip/vertebral #
or
T Score < -2.5
or
T Score -1 to -2.5 &
10 yr risk (FRAX) :
HIP # > 3 % or
major osteoporotic # > 20 %
Postmenopausal women /men > 50 yrs
with

Bone marrow precursors
Osteoblasts
Osteoclast
Lining cells
Stimulators of
Bone Formation
Fluoride
PTH analogs
Sr Ranelate (?)
Inhibitors of
Bone Resorption
Estrogen, SERMs
Bisphosphonates
Calcitonin
Inhibitors of
RANKL
Cathepsin K
Therapeutic strategies

Treatments & Efficacy
Vertebral Fx Non-vertebral Fx
Other Fx Hip Fx
Oral
HRT Yes Yes Yes
Etidronate* Yes
Alendronate* Yes Yes Yes
Risedronate* Yes Yes Yes
Ibandronate* Yes [Yes]
Raloxifene* Yes
Calcitriol* Yes
Strontium Ranelate* Yes Yes [Yes]

Vertebral Fx Non-vertebral Fx
Other 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
can halve the incidence of fractures
* plus calcium + vitaminD

Mainstay of treatment :
Bisphosphonates
Approval in US for osteoporosis
• Alendronate : 1995
• Risedronate : 2000
• Ibandronate : 2005
• Zoledronate : 2007.

HIP FRACTURE – Female Age 75 and over
Give single oral dose 100,000 IU vitaminD @ as soon as feasible post hip fracture & start 1000mg
CaCO3+800IU vitaminD asap, (if on this already – continue)
Already on a BP(bisphosphonate)?
No
Yes
Good prognosis & eGFR 30 or over
Duration of treatment?Yes No
1. Patient or resident carer understand
concepts of osteoporosis, fracture risk
reduction & protocol for ingesting oral BP
AND
2. No contraindications to oral BPs
[dysphagia / oesophageal stricture /
achalasia /hypocalcaemia].
Yes
Oral ALN 70mg / wk
No
Patient suitable for IV BP
& eGFR 35 or over
Yes No
Arrange IV zoledronic acid 5mg
infusion (over at least 15min),
4-6/52 after hip fracture
Consider oral BP or, if at risk
equivalent to that of fracture
plus T-score -2.4 or less,
consider strontium ranelate.
Continue b.d. calcium + vitaminD
Continue b.d.
oral calcium + vitaminD
More than 2yr 2yr or less
Optimal compliance with / adherence
to BP & BP well tolerated
YesNo
Continue oral BP
IF eGFR is 30 or more
Otherwise continue
b.d. calcium + vitaminD
GREATER GLASGOW & CLYDE PROTOCOL FOR FRACTURE SECONDARY PREVENTION AFTER HIP FRACTURE IN WOMEN AGE 75+

Zoledronic acid 5 mg IV
once a year

Once Yearly Zoledronic Acid Reduces
Fractures
 HORIZON Pivotal Fracture Trial
 Multi-national, multi-center, RCT
 7,736 women age 65-89 with T-score <
-2.5 or fracture plus T-score < -1.5
 Calcium 1000-1500 mg/day vit D (400-
1200 IU/day)
 Zoledronic acid IV infusion 5 mg
Black et al. NEJM 356:1809-1822, 2007

ZOL reduces hip fracture
*Relative risk reduction (95% confidence interval) vs placebo
Black et al. NEJM 356:1809-1822, 2007
P = .0024
1
2
3
0
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
CumulativeIncidence(%)
Time to First Hip Fracture (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
41%*
(17%, 58%)

P < .0001
CumulativeIncidence(%)
Time to First Clinical Vertebral Fracture (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
77%
(63%, 86%)
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
1
2
3
0
ZOL reduces vertebral fx
Black et al. NEJM 356:1809-1822, 2007

P = .0002
Time to First Clinical Non-vertebral Fracture (months)
2
4
6
8
10
12
0 3 6 9 12 15 18 21 24 27 30 33 36
25%
(13%, 36%)
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
0
CumulativeIncidence(%) ZOL reduces non-vertebral fx
Black et al. NEJM 356:1809-1822, 2007

Zoledronic Acid will Improve Patient Compliance as Once-
Yearly IV Therapy is Preferred
Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.
16.4
18.9
Both Are Equal
Once-Yearly IV
Once-Weekly Pill
More convenient
More willing to
take long term
Overall
preference
N = 122
66.4
59.8
0 20 40 60 80 100
68.0
66.4
15.6
18.0
20.5
15.6
19.7
13.9
% of Patients
More
satisfying

24
J Bone Miner Res. 2012;27:240–242
HORIZON-PFT 3-years data:
Black DM, et al. N Engl J Med. 2007;356:1809-1822
(HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly)
HORIZON-Pivotal Fracture Trial Extention

25
• 3-year, randomized, double-blind, placebo-controlled extension trial
• 2456 postmenopausal women
• 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: Study Overview
Black DM, et al. J Bone Miner Res. 2012;27:240–242

26
Primary Endpoint:
% Change of ZOL 5 mg Treatment in Femoral Neck BMD
at Years 6 VS Years 3
*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.
MITT = modified intention to treat
1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black 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= 3851
PBO n= 3845

27
ZOL n= 268 262 236 228
PBO n= 265 258 226 212
Z6 n= 101 100
Z3P3 n= 102 84
ZOL 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
Secondary Endpoint:
% Change of ZOL 5 mg Treatment in Lumbar Spine BMD
at Years 6 VS Years 3

28
Secondary Endpoint:
6 years of annual ZOL 5 mg infusions provides continued
fracture protection
Discontinuation of ZOL 5 mg treatment after 3
years still giving residual effect on prevention
nonvertebral fractures
Continuation of ZOL 5 mg treatment for 6 years
significantly reduced New 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 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 study
*P = 0.0348
*P < 0.001

29
A single infusion of ZOL 5 mg reduced bone resorption
marker rapidly than weekly oral ALN 70 mg
(Urine NTX) (Serum β-CTX )
* P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-CTX: Serum β-C-telopeptide of
type I collagen
Saag, et al. Bone 2007;40:1238-1243

30
Safety:
Overall No Increase in Risk of AEs or SAEs With Long-term
(6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment
Category
Z6 (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

31
Safety:
Five most common Post-Dose Symptoms (≤ 3 Days After Infusion)
and declined markedly with subsequent infusions
0
2
4
6
8
10
12
14
16
Annual Infusion
Pyrexia
Myalgia
Flu-like illness
Headache Arthralgia
1 2 3 1 2 3 1 2 3 1 2 3 1 2 3
Incidence(%)
15%
2%
1%
1%
2%
1%
2%
1%
2%
1%
8%
7%
6% 5%
Placebo values cross-hatched
1%
Treatment with antipyretic analgesics appeared to mitigate these symptoms2
Acetaminophen four times/day for 3 days significantly reduced the incidence and
severity of post-dose symptoms following ZOL infusion3
1Black DM, et al. N Engl J Med. 2007;356:1809-1822

32
ZOL= 3595 3574 3284 2989
PBO= 3624 3615 3338 3031
Z6= 613 572 517 459
Z3P3= 616 584 537 475
Renal Safety:
6 Years of ZOL Therapy Has No Cumulative Impact on Creatinine
Clearance

HORIZON-PFT Extension Study:
Summary
• Long-term efficacy - 6 years of ZOL therapy led to:
– Significantly greater increases from baseline in FN, TH
and trochanter BMD than stopping treatment at 3 years
– Significant risk reduction in vertebral morphometric
fracture risk vs stopping treatment at 3 years
– Maintenance of bone turnover markers within
reference range
– Losses in BMD and BTMs in discontinuation group were
modest
33
Black DM, et al. J Bone Miner Res. 2012;27:240–242

Long-term safety
•No new safety concerns identified in women with PMO
•No statistical difference in AF SAEs vs discontinuation of
ZOL
•No long-term effect on renal function vs discontinuation of
ZOL
•No increase in risk for ONJ events vs discontinuation of ZOL
•No cases of atypical fractures

Summary
• Reduce frequent dosing with bisphosphonates may
improve compliance as an important thing for the
success of osteoporosis treatment.
• Six years of annual ZOL 5 mg infusion preserves bone
mass and discontinuation after 3 years still provided
residual benefit of fracture protection.
• It may be beneficial for some women, particularly
those at high vertebral fracture risk, to continue ZOL
for an additional 3 years

Summary
• A single infusion of zoledronic acid 5 mg compared to weekly
oral alendronate produced More rapid effect on tone turn over
marker
• In both HORIZON-PFT ZOL 5 mg and extension were
generally safe and well tolerated
• Clinical experience with more than 1 million infusions
worldwide
• Once-yearly IV zoledronic acid 5 mg may be the answer of
unmet need of current osteoporosis treatments

Thank you
Keep your bone healthy

Osteoporosis treatment strategy using bisphosphonate once a year

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