Nitrogen-containing Bisphosphonates: Bisphosphonates: Differences in - - PowerPoint PPT Presentation

7/11/2019 1

1

Bisphosphonate Therapy for Fracture Risk Reduction: Efficacy (Short and Long Term) (Risks etc. tomorrow)

Dennis M. Black, PhD Professor Epidemiology and Biostatistics, UCSF

Financial Disclosures

• Consulting & talks: Zuellig pharma,
• Advisory Board: Roche Diagnostics
• DSMB (not bone): Eli Lilly

Bisphosphonates: We’ve come a LONG way

• 1990: No approved medications for osteoporosis

(U.S.)

– No real randomized fracture trial of any drug

• 1997-98: First amino-bisphosphonate approved

(alendronate)

• 2018: > 10 approved medications

– Bisphosphonates (~6)

• (+ other antiresorptives + PTHs)

– Large evidence base supporting efficacy 4 N P O O P OH OH OH OH OH C

Nitrogen-containing Bisphosphonates: Differences in R2 Side Chain Structure

Risedronate

N N P O O P OH OH OH OH HO C

Zoledronic Acid

H2N P O O P OH OH OH OH OH C

Ibandronate Alendronate

CH3 N P O O P OH OH OH OH OH C

Accounts for about 85% of

• steoporosis treatment

worldwide

7/11/2019 2 Summary of Design of Fracture Intervention Trial (FIT)

• First large fracture trial (1991–97) (alendronate vs.

placebo)

– Designed/managed by UCSF

• 6,459 women aged 55–80

– Low femoral neck BMD T-score < –1.6 – Two sub-studies:

• 1. Women with vertebral fx (‘Vertebral Fracture arm’ aka FIT I)

2. Women without vertebral fx (‘Clinical Frx arm’ aka FIT II)

• Alendronate 5 mg daily (2 years) then 10 mg daily (years

3-4)

Results: Effect of Alendronate on Lumbar spine BMD*

6 12 18 24 30 36 Months

• 2

2 4 6 8 6.2% PA Spine ~ 8% with 3 years of 10 mg

% Patients With New Vertebral Fracture 10 5 15 7.5% 15%

48% p < 0.001

Morphometric Vertebral Fractures in FIT I & II

Alendronate 10mg/daily Placebo 51% * p < 0.001

2% 4% Existing vertebral fractures (FIT I) No existing vertebral fractures (FIT II)

Black, Lancet 1996: Cummings JAMA 1998

5 10

Number of Women with Two or More New Vertebral Fractures: ALN vs. Placebo

FIT Vertebral Fracture Arm2

PBO

n=965

ALN

n=981

90%

reduction at Year 3 p0.001 % of patients with fracture

• 1. Liberman UA, et al. NEJM. 1995;333(22):1437–1443.
• 2. Black DM, et al. Lancet. 1996;348(9041):1535–1541.

7/11/2019 3 Fracture Reductions in in Women with Existing Vertebral Fractures

• Results for primary outcomes
• Vertebral fractures: 47% decrease (p<0.001)
• All clinical fractures: 28% decrease (p<0.01)
• Results for secondary fracture outcomes
• Wrist fractures: 48% decrease (p<0.001)
• Hip fractures: 51% decrease (p=0.047)

Black, et. al, Lancet, 1996

What About the Women Without Existing Vertebral Fractures at Start?

• 50% risk of vertebral fracture
• Overall, reductions in clinical

fractures were not significant

– Relative hazard: 0.86 (0.73, 1.01) –Reduction in hip and nonspine fracture more evident in those with hip BMD T-score <-2.5

Cummings, JAMA, 1997

Any Clinical Fracture Incidence (ALN v PBO)

in Women without Existing Vertebral Fractures

Overall 0.1 1 10 Relative Hazard (± 95% CI) 0.86 (0.73, 1.01) Baseline BMD T-score < - 2.5

• 2.0 – -2.5
• 1.6 – -2.0

~1/3 ~1/3 ~1/3

Cummings, JAMA, 1997

0.64 (0.50, 0.82) 1.03 (0.77, 1.39) 1.14 (0.82, 1.60)

Hip Fracture Reduction

in Women without Existing Vertebral Fracture

Baseline BMD T-score Overall < - 2.5

• 1.6 – -2.5

0.1 1 10 Relative Hazard (± 95% CI) 0.79 (0.43, 1.44) 0.44 (0.18, 0.97) 1.84 (0.7, 5.4)

7/11/2019 4

1 2 3 4 5

Alendronate Effect on Hip Fractures in FIT

1 2 3 4 5

Vertebral fracture arm1

All With Prior VFx=100% Hip T-score –1.6

PBO

n=1,005

ALN

n=1,022

PBO

n=812

ALN

n=819

51%

reduction at Year 3 p=0.047

56%

reduction at Year 4 p=0.044 % of patients with fracture % of patients with fracture

• 1. Black DM, et al. Lancet. 1996;348(9041):1535–1541.
• 2. Cummings SR, et al. JAMA. 1998;280(24):2077–2082.

Clinical Fracture Arm2,3

With Prior VFx=0% Subgroup with Hip T-score –2.5

Risedronate and Fracture Risk: The VERT Study

• 2458 women mean age 68,
• All with existing vertebral fracture
• Daily 5 mg (n=813) vs PBO (n = 815);
• Endpoints: new vertebral, nonvertebral fracture

Harris, et al, JAMA, 1999.

Risedronate and Fracture Risk

4 8 12 16 PBO 5 mg Incidence (%) New Vertebral Fractures New Nonvertebral Fractures*

* Osteoporotic fractures, Harris, et al, JAMA, 1999. RR = 0.59 (0.43-0.82) 16.3% 11.3% 8.4% 5.2% RR = 0.60 (0.39-0.94)

Risedronate and Hip Fracture Risk (“HIP” study)

• 9497 women age > 70y (Mean = 78y)
• Primary endpoint: hip fractures
• Women 70 – 79: T-score < -3.0 and >= 1 risk

factor

• Women > 80 y had >= 1 risk factor (not

necessarily low BMD)

• Risedronate (2.5 and 5 mg)/PBO, plus 1 g Ca,

daily for 3 yr

7/11/2019 5

Risedronate and Hip Fracture Risk: HIP Study Results

Overall Subgroup analysis Study

Group 1 Group 2 (age 70-79, (age >80, BMD T< -3) risk factor)

% redux. 30%

40% 16%

P 0.02

0.01 0.35 McClung, et. al. NEJM, 2001 Why no redux > 80?

Possible reasons 1. BMD not low enough 2. Older women don’t respond 3. Adherence low

Effect of Alendronate and Risedronate

• n Non-vertebral Fractures:

Conclusions

• Alendronate and Risedronate

–Spine fractures reduced in all women studied –Non-vertebral fracture reductions:

» Largest in those with lowest BMD (<-2.5) or with existing fractures (especially vertebral fracture)

• Suggests two groups with greatest clinical

benefit:

» Low BMD (T-score < –2.5) or » Existing vertebral fracture

Oral Ibandronate Trial

• Reduction in vertebral fractures
• No significant reductions in non-vertebral or hip

fractures in overall population

– (BMD T-score < -3…???)

• Dose too low?? (currently monthly dose twice

equivalent of daily dose used in study)

Chesnut, 2003

Less Frequent Dosing of Bisphosphonates via “Bridging Studies”

• All large phase III oral BPs tested in

fracture trials with daily dosing

• More convenient weekly and monthly

doses tested in “bridging studies”

– Equivalent effects of daily/weekly/monthly on BMD and bone markers

7/11/2019 6

IV Bisphosphonates

• Oral BP’s effective daily, weekly or

monthly

– Compliance low: < 30% still using after 1 year!!

• What about less frequent use via injection
• r IV?
• Zoledronic acid (annual infusions)

– Also Ibandronate (quarterly injections)

IV Zoledronic Acid Fracture Trial (HORIZON Pivotal Fracture Trial)

• 5 mg given once per year, 3 years

–15 minute infusion

• 7706 patients with osteoporosis
• Primary Endpoints: Vertebral and hip fracture

* Black, et. al, NEJM, 5/07

Effect of Zoledronic acid on Morphometric Vertebral Fracture Effect of Zoledronic acid on Morphometric Vertebral Fracture

ZOL 5 mg Placebo

% Patients With New Vertebral Fracture 10 Years 5 15

3.3%

0–3

10.9%

70% Reduction P<.0001

90% reduction in those with > 2 new Vfx (66 vs 7) P<.00001

* Black, et. al, NEJM, 5/07

Effect of Zoledronic Acid on Hip Fracture Risk Effect of Zoledronic Acid on Hip Fracture Risk

Cumulative Incidence (%) Time to First Hip Fracture (months) 1 2 3 3 6 9 12 15 18 21 24 27 30 33 36 P = .0024 Placebo (n = 3861) ZOL 5 mg (n = 3875)

*Relative risk reduction vs placebo

Also, 25% reduction in non- vertebral fractures (p<.01)

RH=0.59 (0.42, 0.83) * Black, et. al, NEJM, 5/07

7/11/2019 7

Are BP’s effective after a fracture? Are BP’s effective after a fracture? Zoledronic Acid after a Hip Fracture:

• Recurrent Fracture Trial (unique post hip-

fracture trial)

 ZOL given <12 wks after hip fracture  2127 men/women, 23 countries, 1-3 years of FU  ZOL or PBO  Primary Endpoint: new clinical fractures

 Results:

▬ New clinical fractures reduced 35% (RR=0.65, p=.001) ▬ Also reduction in total mortality 22% (RR=0.78, p=0.01)

Zoledronic Acid after a Hip Fracture:

• Recurrent Fracture Trial (unique post hip-

fracture trial)

 ZOL given <12 wks after hip fracture  2127 men/women, 23 countries, 1-3 years of FU  ZOL or PBO  Primary Endpoint: new clinical fractures

 Results:

▬ New clinical fractures reduced 35% (RR=0.65, p=.001) ▬ Also reduction in total mortality 22% (RR=0.78, p=0.01)

Lyles KW, et al. N Engl J Med. 2007.

ZoledronicAcid on Fractures in Elderly with Osteopenia (i.e. BMD T >=-2.5)

• Test effect of ZOL in elderly without osteoporosis by

BMD

• 2 unique aspects
• Treatment with ZOL every 18 months (not annually)
• 6 year RCT (longer than any other osteoporosis RCT)
• 2000 women (1000 each to Pbo and ZOL)
• Primary endpoint: “fragility fractures”
• Morphometric vertebral + any non-vertebral
• BMD > -2.5 at the hip
• Median FRAX 10 year risk: 12% for Osteo. Fx, 2.3% Hip Fx.

Reid NEJM, 2018

Reduction in Fracture of 6 Years of Zol (@ 18 mo intervals) in Elderly without Osteoporosis by Hip BMD

Also, significant reductions in vertebral fractures

Long Term Efficacy of Bisphosphonates

• Trials are 3-6 years but what about the

longer term effects?

• Remain effective? Safe?
• What is optimal duration of therapy?

7/11/2019 8 Osteoporosis Treatment Long-term Randomized Extension Studies for Alendronate and ZOL

2 4 6 8 10 Risedronate Alendronate Zoledronic acid

ALN = alendronate; DB = double-blind; EXT 1= extension 1; EXT 2= extension 2; FIT = Fracture Intervention Trial; FLEX = FIT Long-term EXtension; HORIZON-PFT = Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly Pivotal Fracture Trial; OL, Open-label; PBO = placebo; RCT = randomized controlled trial; RIS = risedronate; VERT-MN = Vertebral Efficacy with Risedronate Therapy MultiNational; Z3P3 = zoledronic acid treatment for 3 years followed by placebo for 3 years; Z6 = zoledronic acid treatment for 6 years; ZOL = zoledronic acid.

• 1. Black DM, et al. N Engl J Med. 2007;356:1809-1822. 2. Black DM, et al. J Bone Miner Res. 2012; 27:243-254. 3. The Effect of 6 versus 9 Years of Zoledronic

Acid Treatment in Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT).Presented at ASBMR 2013 (abstract no. SA0389). 4. Black DM, et al. Lancet. 1996;348:1535-1541. 5. Cummings SR, et al. JAMA. 1998;280:2077–2082.

• 6. Black DM, et al. JAMA. 2006;296:2927-2938. 7. Reginster J-Y, et al. Osteoporos Int. 2000;11:83–91. 8. Sorensen OH, et al. Bone. 2003;32:120-126. 9. Mellström DD, et al. Calif Tissue Int. 2004;75:462-468.

Time (Years)

FIT4,5

ALN (n = 3236) PBO (n = 3223)

RCT – FLEX6

ALN 5 mg (n = 329) or 10 mg (n = 333) PBO (n = 437)

HORIZON-PFT1

ZOL (n = 3889) PBO (n = 3876)

RCT – EXT12

Z6 (n = 616) Z3P3 (n = 617)

VERT-MN7

RIS 2.5 mg (n = 408) 5 mg (n = 407) PBO (n = 407)

RCT – EXT8

RIS (n=135) PBO (n=130)

OL-EXT9

RIS 7 yrs (n = 83) PBO 5 yrs/RIS 2yrs (n = 81)

RCT – EXT23

Z9 (n = 95) Z6P3 (n = 95)

Design of the FIT Long-Term Extension (to 10 years) of Alendronate (FLEX)*

FIT N = 6,459 Placebo N = 3,223 Alendronate N = 3,236 Randomized in FLEX N = 1,099 Alendronate, 5 or 10 mg N = 662 Placebo N = 437

Mean ALN use: 5 years FLEX (5 yrs)

* Black, et al, JAMA 12/2006

40% 60% BMD: Primary endpoint Fractures: Exploratory endpoint 10 years of ALN % yrs ALN/5 pbo

FLEX: Alendronate

Randomized, Double-blind Treatment 5 years of ALN followed by 5 more years or PBO

Fractures Placebo, No. (%) (n=437) Pooled Alendronate,

• No. (%)

(n=662) Relative Risk (95% Confidence Interval)*

Vertebral Clinical . Morphometric 23 (5.3) 46 (11.3) 16 (2.4) 60 (9.8) 0.45 (0.24–0.85) 0.86 (0.60–1.22) Clinical Nonspine Hip 83 (19.0) 13 (3.0) 125 (18.9) 20 (3.0) 1.00 (0.76–1.32) 1.02 (0.51–2.10)

FLEX: Incidence of Fracture by Treatment Group

Black DM, et al. JAMA. 2006;296:2927–2938.

0.1 1 10 Vertebral FX (clinical) Clinical Fracture Alendronate (FLEX: 5 yrs/5 yrs

1.00 (0.8, 1.3) 0.45 (0.2, 0.85) 0.99 (0.7, 1.5) 0.48 (0.3, 0.9)

Vertebral FX (morphometric) Clinical Fracture Zoledronic acid: HORIZON: 3yrs/3 yrs

Reductions (RR) for fractures for continuing bisphosphonates: Alendronate and ZOL

3 Relative Hazard (± 95% CI) Favors Bisphosphonate Favors Placebo

Black JAMA 2006;Black et a. JBMR 2012

7/11/2019 9 Fracture reductions with long-term continuation

• f bisphosphonates (2 RCTs)
• Fracture results for Alendronate and Zol
• Continuing lowers vertebral fractures risk vs discontinuing
• Continuing vs. discontinuing  no effect on non-vertebral

− Confidence intervals are wide and allow for possible benefit

• What about long term safety? Does AFF risk increase with

longer duration of treatment?

• Hold your horses til tomorrow…

Black JAMA 2006; Black et a. JBMR 2012

34

Bisphosphonate Efficacy: The Bottom Line

• BP’s are extremely effective drugs in osteoporotic

women over 3 to 5 years.

• > 50% reduction vertebral fractures
• 40 to 60% reduction in hip fractures
• 20-30% reduction in non-vertebral and all clinical fractures
• Compares positively to other preventive therapies (eg. Statins
• r antihypertensives)
• IV Zol also effective after hip fracture and in elderly without
• steoporosis (6 years)
• After 5 years,
• Continuation (vs. Discon) decreases vertebral fracture but

perhaps not non-vertebral fracture

• Residual effect for up to 5 years supports drug holiday
• Tomorrow: Lonisks (vs. benefits) and drug holidays

35

Thanks!