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

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

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

Postmenopausal women /men > 50 yrs

with

Anti-resorptive

Anabolic

‘Dual action’

Bone marrow precursors

OsteoblastsOsteoclast

Lining cells

Stimulators of Bone Formation

FluoridePTH analogs

Sr Ranelate (?)

Inhibitors ofBone Resorption Estrogen, SERMs

BisphosphonatesCalcitonin

Inhibitors ofRANKL

Cathepsin K

Therapeutic strategies

Treatments & Efficacy Vertebral Fx Non-vertebral Fx

Other Fx Hip FxOralHRT 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 can halve the incidence of fractures

* plus calcium + vitaminD

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

Contraindications

Duration of treatment

Hot topics

HIP FRACTURE – Female Age 75 and overGive 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

YesGood 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 BPAND2. 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 BPIF eGFR is 30 or moreOtherwise 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 placeboBlack et al. NEJM 356:1809-1822, 2007

P = .0024

1

2

3

0

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

Cu

mu

lati

ve I

nci

den

ce (

%)

Time to First Hip Fracture (months)0 3 6 9 12 15 18 21 24 27 30 33 36

41%*(17%, 58%)

P < .0001

Cu

mu

lati

ve I

nci

den

ce (

%)

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

*Relative risk reduction (95% confidence interval) vs placeboBlack 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

Cu

mu

lati

ve I

nci

den

ce (

%)

ZOL reduces non-vertebral fx

*Relative risk reduction (95% confidence interval) vs placeboBlack 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 EqualOnce-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

15.618.0

20.5

15.6

19.713.9

% 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 treat1Black 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 84ZOL n= 268 262 236 228

PBO n= 265 258 226 212

Z6 n= 101 100

Z3P3 n= 102 84

*P = 0.1910 **P < 0.00011Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242

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 study1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242

*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

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 < 0.00011Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242

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 illnessHeadache Arthralgia

1 2 3 1 2 3 1 2 3 1 2 3 1 2 3

Incid

en

ce (

%)

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

1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242

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

33Black 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

351Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242

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 youKeep your bone healthy