Structure of Bisphosphonates Structure of Bisphosphonates - - PowerPoint PPT Presentation

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Bisphosphonates: Efficacy (Controversies/safety later)

Dennis M. Black, PhD

• Dept. of Epidemiology and Biostatistics

University of California, San Francisco

2

Financial Disclosures

*

Research grants, speaking or consulting: Amgen, Lilly, Merck, Novartis, Radius

• 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

Bisphosphonates Available in U.S.

Name Administration Year Etidronate Oral 1977 Alendronate Oral 1995 Risedronate Oral 2000 Ibandronate Oral 2004 Zoledronic acid IV 2007

Bisphosphonates (especially generic ALN) represent vast majority of osteoporosis treatment

• 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

Alendronate: Fracture Intervention Trial (FIT)

• First large fracture trial (1992-97)

– Designed/managed by UCSF – Details: 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

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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

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

Effect of Alendronate on Spine BMD

6 12 18 24 30 36

Months

• 2

2 4 6 8

6.2% PA Spine * 5 mg 2 years/10 mg 3rd year/ ~ 8% increase with 3 years of 10 mg daily ALN ALN PBO

Page 4 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

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

What About the Women Without Existing Vertebral Fractures?

• 50% risk of vertebral fracture
• Overall, reductions in non-spine

fractures were not significant

– Relative hazard: 0.86 (0.73, 1.01) – Prevention of hip and of nonspine fracture depended on initial hip BMD

Cummings, JAMA, 1997

Page 5 Non-spine Fracture in Women without Existing Vertebral Fractures

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

• 2.0 – -2.5
• 1.6 – -2.0

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

Cummings, JAMA, 1997

Hip Fracture 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)

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

Effect of Alendronate and Risedronate

• n Non-vertebral Fractures:

Conclusions

• Alendronate and Risedronate

–Vertebral fracture reductions-all women studied –Non-vertebral fracture reductions:

» Largest in those with lowest BMD (<-2 to -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

Less Frequent Dosing of Bisphosphonates via “Bridging Studies”

• “Bridge” to less frequent dose via BMD

and marker studies

• 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

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

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)

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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

<12 weeks after hip fracture (first post-hip fxture

study)

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

<12 weeks after hip fracture (first post-hip fxture

study)

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

Use of Bisphosphonates Longer than 5 years?

• Bisphosphonates effective in reducing fractures

in 3-4 year trials vs. placebo

• What is optimal duration of treatment?

– Longer treatment may further decrease fracture risk – Or longer term treatment may compromise bone quality

• Long term placebo-controlled fracture trials not

feasible so must rely on extensions of shorter studies

Safety Concerns with Bisphosphonates

• Upper GI irritation

– Concerns with oral amino-bisphosphonates, esp. daily – Minimize if follow dosing instructions

• Atrial fibrillation

– Small increase in risk seen in some but not all trials with ZOL – Not seen with risedronate or ibandronate and probably not with alendronate

• Esophageal cancer

– Not borne out with careful studies

• Renal concerns

– Use BPs in patients with adequate renal function (CC>35ml/m) – Take care to infuse ZOL over >=15 minutes

• ONJ and atypical fractures, to be discussed later

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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
• Concerns about long term use to be discussed later