[PDF] - Bisphosphonates: Efficacy (Controversies/safety later) Dennis M. PDF Document

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Bisphosphonates: Efficacy (Controversies/safety later)

Dennis M. Black, PhD

Dept. of Epidemiology and Biostatistics

UC San Francisco

2

Financial Disclosures

*

Consulting or advisory boards:

Radius, Asahi-Kasei

Research agreements:

Alexion

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A bit of background
A quick summary of a very large

literature of RCTs

Bisphosphonates Efficacy: Outline

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Structure of Bisphosphonates Structure of Bisphosphonates Structure of Bisphosphonates

When R1 is an OH group binding to hydroxyapatite is enhanced R2 = -CH2-3-pyridine = Risedronate R2 = -CH2CH2CH2NH2 = Alendronate R2 = -CH2CH2NH2 = Pamidronate R2 = -CH3 = Etidronate The R2 side chain determines potency P-C-P is essential for binding to hydroxyapatite

OH R1 OH O O P P C OH OH R2

Russell, R., et al.,OI I999;Suppl 2:S68-80

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Bind to hydroxyapatite crystals in bone
Inhibit bone resorption

– Impact on osteoclasts

Results in increased bone density
Some can reduce fracture risk
Several approved for oral use, 2 for

injection/IV

Quickly summarize a very extensive

literature

Bisphosphonates: Overview

Bisphosphonates Available in U.S.

Name Administration Year Etidronate Oral 1977 Alendronate Oral (1/wk) 1995 Risedronate Oral (1/wk or 1/mo) 2000 Ibandronate Oral (1/mo) 2004 Zoledronic acid IV (1/yr) 2007

Bisphosphonates (alendronate>80%) represent vast majority of osteoporosis treatment

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Large set of placebo-controlled clinical trials

with fracture endpoints starting in 1996

Trials also show BMD gains and reductions

in bone turnover Evidence base supporting bisphosphonates

Summary of Bisphosphonate Fracture Reductions (up to 5 Years)*

*Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012

Also reductions ~25% in non-vertebral fractures

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Alendronate: Fracture Intervention Trial (FIT)

First large fracture trial (1992-97)

– Designed/managed by UCSF – Details: ALN most used and FIT a model for later studies

6,459 women aged 55-80

–Femoral neck BMD <0.68 g/cm2 (T<-1.6)

Randomized to daily alendronate vs. placebo

–5 mg for 2 years –10 mg for 3rd & 4th year

Black, et. al, Lancet, 1996; Cummings,

et. al. JAMA 1998

Alendronate: Fracture Intervention Trial (FIT)

Two separate studies

1. Women with existing vertebral fracture*

– Vertebral Fracture arm – Main endpoint: new vertebral fractures – Goal: n=2000 – 3 years of follow-up

2. Women without existing vertebral fracture**

– Clinical Fracture Arm – Main endpoint: new clinical fracture – Goal: n=4000 – 4.2 years of follow-up

* Black, et. al, Lancet, 1996; **Cummings, et. al. JAMA 1998

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Fracture Intervention Trial: Baseline characteristics

Vert Fx Arm Clinical Fx Arm (w/ vert. fx) (w/o vert fx) n = 2027 n = 4436

Vert. Fx

100% 0% Age 71 68 BMD (FN) 0.57 0.59 Prior Clin. Fx 58% 36%

Change in Bone Turnover Markers Over Three Years with Alendronate

PBO ALN ALN

B J

% Reduction

Years

1 2 3

70
60
50
40
30
20
10

0 J J 1 2 3

% Reduction

70
60
50
40
30
20
10

Resorption (NTX) Formation (BSAP)

Black, et. al, Lancet, 1996

PBO ALN ALN

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Effect of Alendronate on Spine BMD (5 mg/day 2 yrs then 10mg/day)*

6 12 18 24 30 36

Months

2

2 4 6 8

6.2% PA Spine * ~ 8% increase with 3 years of 10 mg daily (70 mg/wk) ALN ALN PBO

Alendronate and Vertebral Fracture Risk (women w/ existing VFx)

4 8 12 16 PBO Alendronate Incidence (%) 1 or more

Black, et al, Lancet, 1996. 47% reduction P<.001 15% 8%

New Vertebral Fractures

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Alendronate and Vertebral Fracture Risk (women w/ existing VFx)

4 8 12 16 PBO Alendronate Incidence (%) 1 or more 2 or more

Black, et al, Lancet, 1996. 47% reduction P<.001 15% 8% 5% 0.5% 90% reduction P<0.0001

New Vertebral Fractures

Hip Fractures: (Women with existing vertebral

fractures)

Months of Follow-up % of women with any clinical fracture Placebo Alendronate Relative hazard: 0.49 (0.23, 0.99) 2 4 12 24 36 2.2% 1.1%

Black, et. al, Lancet, 1996

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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

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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)

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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)

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Risedronate and Hip Fracture Risk (“HIP” study)

9497 women age > 70y (Mean = 78y)
Primary endpoint: hip fractures
Women 70 - 79 had T-score < -3.0 and one or

more risk factors

Women > 80 y had one or more risk factors

(not necessarily low BMD)

Risedronate/PBO, plus 1 g Ca, daily for 3 yr

– McClung, NEJM, 2001

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

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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 Fracture Study

2946 post-menopausal women for 3 years
Existing vertebral fracture and low BMD
2.5 mg/day vs. placebo

– Chesnut, et. al. JBMR 8/2004

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Oral Ibandronate Fracture Study: Results for Daily vs. PBO

Vertebral fractures: 50% reductions
Non-vertebral fractures: no overall

reduction

– In women with lowest BMD?? –Evidence of reduction among those with very low BMD at baseline (T < -3 at fn hip)

Chesnut, et. al. JBMR 8/2004

Less Frequent Dosing of Bisphosphonates

All fracture studies of Alendronate,

Risedronate and Ibandronate used daily dosing

Bisphosphonate dosing inconvenient
Less frequent dose is desirable

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Less Frequent Dosing of Bisphosphonates via “Bridging Studies”

“Bridge” to less frequent dose via BMD

and marker studies starting in 2000

Weekly: Alendronate and Risedronate (7x

daily dose)

Similar BMD, markers.

– No increase in upper GI effects.

Monthly: Ibandronate (60 x daily),

Risedronate (30 x daily)

No oral drugs tested for fracture effects

for less frequent than daily dosing

Example: Bridging from daily to weekly Alendronate: BMD Changes at Spine

Month 6 12 Mean Percent Change 1 2 3 4 5 6 ALN 10 mg Daily ALN 70 mg Once Weekly

Mean Percent Change from Baseline  SE

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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?
Ibandronate (quarterly injections) and

zoledronic acid (annual infusions) both available

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

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Effect of Zoledronic acid on Morphom etric Vertebral Fracture Effect of Zoledronic acid on Morphom etric Vertebral Fracture

ZOL 5 m g Placebo

% Patients W ith New Vertebral Fracture 1 0 Years 5 1 5

3 .3 %

0 –3

1 0 .9 %

7 0 % Reduction P< .0 0 0 1

9 0 % reduction in those w ith > 2 new Vfx ( 6 6 vs 7 ) P< .0 0 0 0 1

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

Cum ulative I ncidence ( % ) Tim e to First Hip Fracture ( m onths) 1 2 3 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6 P = .0 0 2 4 Placebo ( n = 3 8 6 1 ) ZOL 5 m g ( n = 3 8 7 5 )

* Relative risk reduction vs placebo

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

RH= 0 .5 9 ( 0 .4 2 , 0 .8 3 )

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

Recurrent Fracture Trial (only post hip-

fracture trial)

 ZOL given <12 weeks after hip fracture  2127 men/women, 23 countries, 1-3 years of FU  ZOL 5 mg annual or placebo  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=.01)

Zoledronic Acid after a Hip Fracture:

Recurrent Fracture Trial (only post hip-

fracture trial)

 ZOL given <12 weeks after hip fracture  2127 men/women, 23 countries, 1-3 years of FU  ZOL 5 mg annual or placebo  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=.01)

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

Summary of Bisphosphonate Fracture Reductions (up to 5 Years)*

*Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012

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Use of Bisphosphonates Longer than 5 years?

Controversial ..Talk to Dr. Rosen later!

Summary: Bisphosphonate Efficacy

Many large trials show that bisphosphonates

reduce fracture risk (up to 5 years)

– Most definitive in women but likely similar effect in men – Most effective in those with lowest BMD and those with history of fracture

Approved as oral in weekly and monthly dosages

– Alendronate, Risedronate and Ibandronate – All now generic

Annual IV also available

– Zoledronic acid (now generic)

Used by millions around the world
Benefits far outweigh risks (later)

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Thanks to great colleagues at UCSF

Cummings Bauer A Schwartz And many wonderful staff

1994 FIT Newsletter (10 yrs)

*Jarvinen, et al. BMJ, 5/15