Combination and Sequential Therapy for the …

Combination and Sequential Therapy for the Treatment of Osteoporosis

Felicia Cosman

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1


Prof. Felicia Cosman

Professor of Medicine, Columbia University, New York, NY

Medical Director, Clinical Research Center

Helen Hayes Hospital, West Haverstraw, NY

2

Disclosures/acknowledgements

• Speakers Bureaus: Eli Lilly, Amgen

• Advisory Boards: Amgen, Merck, Eli Lilly, Radius

• Consultant: Eli Lilly, Amgen, Merck, Novartis, Radius,

GSK, Unigene, Tarsa, Zosano, Enteris

• Research Grants/Research Medication:

Amgen, Novartis, Eli Lilly, Merck

3

Current pharmacologic management of osteoporosis

• Anabolic agents:

Parathyroid hormone analogs

– PTH 1-84

– Teriparatide (PTH 1-34)

• Antiresorptive agents:

Hormone/estrogen therapy

Selective estrogen

receptor modulators

Conjugated estrogen/

bazedoxifene complex

Oral bisphosphonates

– Alendronate, risedronate, ibandronate

Intravenous zoledronic acid

Subcutaneous denosumab


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Choosing anabolic vs. antiresorptive therapy

• As first-line therapy

No consensus or guidelines

Use in highest risk patients:

– Patient with recent fracture (within the year)

– Patients with history of multiple fractures

• As second-line therapy

Sometimes mandated by reimbursement

Response to anabolic medication different in patients

who have already been treated with potent antiresorptive therapy

(bisphosphonates and denosumab)

No fracture data in this group

5

Combination therapy rarely used

• Cost and potential for additional side effects/adverse events

• Belief that combination therapy provides no benefit

and might even be inferior to TPTD monotherapy

In part based on results of the PaTH trial1

– Women randomized to receive PTH monotherapy, alendronate

monotherapy or PTH plus alendronate combination therapy

1 Black et al., NEJM 2003; 349: 1207-1215

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PaTH 12 month changes with PTH1-84 in DXA BMD

Black et al., NEJM 2003; 349: 1207-15

• PTH-alendronate combination group showed no greater

improvement in spine BMD – a disappointment

• The combination therapy did produce a superior effect

on hip and radius BMD


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Caveats in generalizability of PaTH trial

• Daily not weekly alendronate

Small uptake into osteoblasts with each dose

• Alendronate is different from other bisphosphonates

and other antiresorptives

• PaTH utilized PTH 1-84 (not 1-34)

Possible differences in skeletal response1

• Study performed in treatment naïve women

Results may not apply to treatment experienced women,

particularly those on the most potent antiresorptive therapies

1Hansen S et al., JBMR 2013

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Response to TPTD different in treatment naïve and treatment experienced

• Much larger active bone surface in treatment naïve individuals

• In treatment naïve, with acute administration

of potent antiresoptive agents

Increase in endogenous PTH for up to 12 months

Might produce a different response

to exogenously administered PTH

• Perhaps unique effects on osteoclasts and/or osteoblasts

in treatment experienced individuals

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Alendronate treated Treatment naive

Inactive osteoclast Normal osteoclast

50 μm 50 μm

< 22 nuclei/cell profile < 8 nuclei/cell profile

Images used with permission by Dr. Dempster 31 May 2013

Dempster, et al., ASBMR 2007


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Re-evaluating the potential role for combination and sequential therapy

• In treatment naïve women

Concomitant treatment with intravenous zoledronic acid

and TPTD1

Concomitant treatment with subcutaneous denosumab

and TPTD2-3

1. Cosman, et al., JBMR 2011; 26(3): 503–511

2. Tsai et al., Lancet 2013

3. Leder et al., JCEM 2014

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Treatment naïve: IV zoledronic acidand daily TPTD study overview

• 412 treatment-naïve postmenopausal women

T score ≤−2.5 at any site or T score ≤−2.0 plus ≥1 op-related fracture

Age range 45-87 years, mean 65

Mean spine T-score spine -2.9, Hip -1.9

• Randomized to one of 3 active treatment groups

IV ZOL 5 mg

IV ZOL 5 mg + Subcut TPTD 20 μg/day

IV PBO + TPTD 20 μg/day

• One-year follow-up

Cosman, et al., JBMR 2011; 26(3): 503–511

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ZOL + TPTD

TPTD alone

ZOL alone

Treatment naïve women: IV Zol and daily TPTD changes in serum β–CTx and PINP

Weeks

Seru

m β

-CTx

(n

g/m

L)

Serum β-CTx

0 4 8 12 16 20 24 28 32 36 40 44 48 520

0.2

0.8

1

0.4

0.6

Weeks

Seru

m P

INP

(n

g/m

L)

Serum PINP

0 4 8 12 16 20 24 28 32 36 40 44 48 520

50

100

150

200

Cosman, et al., JBMR 2011; 26(3): 503–511


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Treatment naïve women: IV Zol and daily TPTDpercent changes in lumbar spine BMD

Weeks

‡Least-squares mean (LSM) % changes

0 13 26 39 52

Me

an %

ch

ange

in B

MD

‡

0

1

3

4

6

7

9

2

5

8

*

*

†

*P<0.001 vs. TPTD alone and vs. ZOL alone

†P<0.001 vs. ZOL alone

†

Cosman, et al., JBMR 2011; 26(3): 503–511

ZOL + TPTD

TPTD alone

ZOL alone

14

0

0.5

1

1.5

2

2.5

3

0 13 26 39 52

Weeks

Me

an %

ch

ange

in B

MD

‡

Total hip BMD

0 13 26 52

Weeks

Me

an %

ch

ange

in B

MD

‡

Femoral neck BMD

-1

0

2

3

1

39

*

*†*

**

*P<0.05 vs. TPTD alone

†P<0.05 vs. ZOL alone

*

*

*

*

**

*

ZOL + TPTD

TPTD alone

ZOL aloneCosman, et al., JBMR 2011; 26(3): 503–511

‡Least-squares mean (LSM) % changes

Treatment naïve women: IV Zol and daily TPTD percent changes in lumbar spine BMD (2)

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Treatment naïve women: IV Zol and daily TPTD - summary

.

• With combination (ZOL+TPTD) therapy:

Spine BMD increase similar to TPTD alone

– Combination >ZOL alone but not greater than TPTD alone

Hip BMD increase similar to ZOL alone

– Combination >TPTD alone

• Considering hip and spine BMD outcomes together,

combination therapy provided the overall largest

and fastest BMD outcome

Cosman, et al., JBMR 2011; 26(3): 503–511


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DATA trial: teriparatide or Dmab monotherapy vs. combination

• 94 postmenopausal women at high risk of fracture

(age 51-91)

• 12 month open label randomized controlled trial

with three treatment groups:

Teriparatide (TPTD) 20 μg SC daily (n=31)

Denosumab (DMAB) 60 mg SC Q6 mo (n=33)

Both medications (n=30)

Tsai JN Lancet 2013

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Teriparatide or Denosumab monotherapy vs. combination therapy

Tsai JN Lancet 2013

18Tsai Lancet 2013

Teriparatide or Denosumab monotherapy vs. combination therapy (2)


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Gray bars: BMD gain year 1

Yellow bars: BMD gain year 2

Leder et al., JCEM 2014

Teriparatide or Denosumab monotherapy vs. combination therapy (3)

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Summary: combination therapyin treatment naïve women

• Combination therapy: all studies consistent with superior

BMD gain in the hip compared to TPTD/PTH monotherapy

Teriparatide with zoledronic acid

Teriparatide with denosumab

PTH with alendronate

• Combination therapy superior for BOTH spine

and hip BMD gain

Teriparatide with denosumab

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Teriparatide in the treatment experienced woman: teriparatide monotherapy or combination therapy?


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Teriparatide after prior bisphosphonate treatment

• ADD vs. Switch Studies

Spine BMD may not be affected substantially when switching

to teriparatide monotherapy compared to adding teriparatide

to ongoing antiresorptive

Hip BMD routinely declines in Switch Studies over 6-12 months1-3

Hip BMD does not decline when TPTD is added to ongoing BP4

References:

1.Ettinger JBMR 2004; 19(5): 745–751

2.Miller, et al., JCEM 2008; 93: 3785–3793

3.Boonen, et al., JCEM 2008; 93: 852-860

4.Cosman, et al., NEJM 2005; 353: 566-75

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0 3 6 12 18

-2

0

2

4

6

8

10

12

*

TPTD after raloxifene or alendronate:effect on total hip BMD

Mean %change

Months

*P<0.05 vs. from baseline

†P<0.05 between groups

Raloxifene-TPTD

Alendronate-TPTD

0.3

1.8

*†

Ettinger JBMR 2004; 19(5): 745–751

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Total hip BMD percent changes from baselineCompleter population

Miller, et al. JCEM 2008; 93: 3785–3793

• Hip bone density declined substantially within the first

six months, and was still below baseline at the end

of the year-long study (residronate or alendronate

switch to PTH monotherapy)


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Adjusted mean BMD changes from baselineTotal hip

Boonen, et al., JCEM 2008; 93: 852-860

• When women were switched to teriparatide:

hip bone density declined significantly in both groups

within the first six months

It remained below baseline for the entire first whole year

of treatment

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Total hip BMD

Tota

l Hip

% C

han

ge in

BM

D

Cosman, et al., NEJM 2005; 353: 566-75

u ALN Only

l

n Daily PTH+ALN

Cyclic PTH+ALN

n

nn

nn

n

l l

ll

u

u uu

u

u

0 3 6 9 12 15-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Time (months)

l

l

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Switch to teriparatide in patients experienced on prior denosumab treatment

• Patients randomized to denosumab arm in DATA trial

After 2 years of denosumab alone, switched to teriparatide

Leder et al., ASBMR 2014


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Data trial 1 year extension

Leder et al., ASBMR 2014

PA Spine

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Switch to teriparatide in patients experienced on prior antiresorptive treatment

• Hip BMD declines consistently in all studies in patients

on potent antiresorptive agents (alendronate,

risedronate, denosumab)

Magnitude of BMD decline might be related to potency

of antiresorptive effect

• No fracture data available to determine if this decline

is associated with a detrimental effect on fracture occurrence

Studies small

An approach to prevent this BMD decline would be preferable

in patients at high risk for hip and other cortical bone fractures

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Teriparatide in treatment experienced: monotherapy vs. combination therapy

• Objective: to compare the effect of adding vs. switching

to TPTD in women on prior aln or rlx in a randomized trial

• Subjects: postmenopausal women ≥ 50 years of age

on weekly aln (n=102) or daily rlx (n=96) for > 18 months

Average treatment duration >4 years

Mean age 68

• Protocol: randomize to

Continue Aln/Rlx and add TPTD (combination therapy)

Stop Aln/Rlx and switch to TPTD (monotherapy)

Cosman F, et al., JCEM 2009; 94: 3772–3780


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Switch

Add

TPTD in treatment experienced switch vs. add: bone turnover markers: PINP

P < 0.05; §, P < 0.01; and †, P < 0.001 for percentage change difference

between groups within the alendronate or raloxifene stratum


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TPTD in treatment experienced switch vs. add: bone turnover markers: CTX

P < 0.05; §, P < 0.01; and †, P < 0.001 for percentage change difference

between groups within the alendronate or raloxifene stratum

Switch

Add


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Teriparatide in treatment experienced switch vs. add: BMD at 6 months

*P<0.05 within group from baseline

+P<0.05 between treatment groups within each treatment stratum

ALN RLX

(Switch) (Switch)(Add) (Add)



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Teriparatide in treatment experienced switch vs. add: BMD at 18 months

***P < 0.001, **P < 0.01 within group from baseline

++P < 0.01, +P< 0.05 between treatment groups within each treatment stratum

ALN RLX


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Spine volumetric BMD

*P<0.01 vs. baseline

p values for differences between add vs. switch groups are shown above each pair of bars

Add group

Switch group

Values are medians

(IQ range)

Cosman, et al., JBMR 2013 Jun; 28(6): 1328-36

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Estimated spine strength




Add group

Switch group

Values are medians

(IQ range)


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Hip volumetric BMD

Add group

Switch group

Values are medians

(IQ range)




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Estimated hip strength

*P<0.01 vs. baseline; †P<0.05 vs. baseline

p values for differences between add vs .switch groups are shown above each pair of bars

Add group

Switch group

Values are medians

(IQ range)


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Alendronate stratumHip volumetric BMD, month 18



ALN Add

ALN Switch


Values are medians

(IQ range)


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Alendronate stratumEstimated hip strength, month 18




Values are medians

(IQ range)

ALN Add

ALN Switch

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CONFORS trial: TPTD alone for 9 months followed by combination

• 125 women

90% had history of prior AR therapy

– 70% history of alendronate exposure

• All women received TPTD alone for 9 months

• After 9 months TPTD, randomized to:

Continued TPTD alone (n=47)

Continued TPTD + ALN 70 mg/wk (n=41)

Continued TPTD + RLX 60 mg/day (n=37)

for 9 additional months

Muschitz, et al., JMBR 2013; 28(1): 196–205

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Bone turnover



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BMD


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Summary Combination therapy studies

In both treatment naïve as well as in women

who have been on prior bisphosphonates,

hip BMD increments are superior with combination treatment

compared to teriparatide/PTH monotherapy

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Possible role of combination Rx

• Treatment naïve patients:

In general, anabolic therapy should be used alone followed

by potent AR

Limited role for combining anabolic and AR agents in patients

at highest risk for fractures

– Patients with acute hip or spine fractures

– Patients with multiple fractures

• Bisphosphonate/denosumab treated patients:

Bigger role for combination Rx esp in pts with acute hip fracture

or very low hip BMD

– Add TPTD to ongoing AR (possibly switch to most potent AR)

– Switch to TPTD for 6-9 months followed by re-addition of potent AR


Felicia Cosman


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