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Anabolic Therapy and in Combination with Antiresorptives

Dennis Black, PhD

Dept. of Epidemiology and Biostatistics University of California, San Francisco

2

Financial Disclosures

*

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

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Outline - Overview of anabolic therapy

- Currently FDA-approved: Teriparatide

- Combining anabolic and antiresorptive therapies

Treatment of Osteoporosis

• Antiresorptive agents – Bisphosphonates – Denosumab – Raloxifene and estrogen

• Anabolic agents – Teriparatide (injectable PTH) – Others in development

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Parathyroid Hormone (PTH)

•  84 amino acid sequence •  Most of bone activity in first 34 amino acids

– PTH (1-34) (teriparatide) approved @ 20 mcg/day

•  Requires (currently) daily injection – Patches and other forms being investigated

Anabolics and antiresorptives have opposite effects on bone remodeling

from Black, et al. New Engl J Med 2003;349:1207–15

Med

ian

Cha

nge

(%)

-100

0

100

200

300

400

0 3 6 9 12Month

Anabolic

ALN

-100

0

100

200

300

0 3 6 9 12Month

Resorption (CTX)Bone Formation

(P1NP)

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•  1637 postmenopausal women •  Randomized to placebo, PTH (1-34) 20 ug, or

PTH (1-34) 40 ug •  Fracture was primary endpoint •  3-year study planned, halted after 21 months

(median) –  Safety problem with high doses in rodents

Neer RM, et al. NEJM, 2001

PTH (1-34) (Teriparatide) Fracture Prevention Trial

Effect of PTH (1-34) on lumbar spine BMD

Placebo

PTH 20 mcg

PTH 40 mcg

Months

% C

hang

e (±

SE

)

0 2 4 6 8

10 12 14 16

0 3 6 12 18

***

***

***

***

***

***

***

***

*** p < 0.001 vs. Placebo

~ 7%

Neer et al. N Engl J Med. 2001;344:1434-1441

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Effect of PTH (1-34) on total hip BMD

Placebo

PTH 20 mcg

PTH 40 mcg

-2

-1

0

1

2

3

4

5

0 6 12 18 24

Months

***

***

***

***

% C

hang

e (±

SE

)

~ 2%

*** p < 0.001 vs. Placebo Neer et al. N Engl J Med. 2001;344:1434-1441

Effect of Teriparatide (20 ug) on risk of new vertebral fractures

*P < 0.001

Placebo (n=448)

rhPTH 20 ug (n=444)

64 22 19

% o

f Wom

en

RR 0.35 (95% CI, 0.22 to 0.55)*

No. of women who had > 1 fracture

Neer et al. N Engl J Med. 2001;344:1434-1441

8

0 2 4 6

10 12 14

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Adapted from Neer et al. N Engl J Med. 2001;344:1434-1441

Teriparatide and reduction in non-vertebral fragility fractures

20 mcg vs. placebo: RR=0.47 (0.25,0.88)

Histomorphometry: PTH (1-34) in a 64 y.o. woman

Dempster DW et al. J Bone Miner Res. 2001;16:1846-1853.

Before CtTh: 0.32 mm CD: 2.9 mm3

After CtTh: 0.42 mm CD: 4.6 mm3

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Teriparatide in clinical practice

§  Approved for up to 2 years duration §  Limited adoption in clinical practice

•  Cost (>$10,000/course) •  Need for daily injections

§  High risk for future fracture •  Prevalent vertebral compression fx •  Other osteoporotic fx + low BMD •  Very low BMD (e.g., T-score <-3.0)

§  Failed antiresorptive therapy •  Incident fx or active bone loss

§  Glucocorticoid-induced osteoporosis

Teriparatide in clinical practice

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Combination PTH + antiresorptive?

§  PTH increases formation then resorption §  Antiresorptives decrease resorption then

formation •  Combine PTH with antiresorptives to

increase formation with smaller increase in resorption?

§  Could be synergistic: 1 + 1 = 3 §  Or cancel each other: 1 - 1 = 0

Combination PTH + antiresorptive?

3 distinct possibilities

PTH Antiresorptives

Antiresorptives + PTH

Antiresorptives PTH1.

2.

3.

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Combination #1

Antiresorptives PTH

§  Pre-treatment with antiresorptives followed by PTH • Key clinical question • Many patients on bisphosphonates

and other antiresorptives

Summary: PTH following bisphosphonates

Anabolic effect still evident and strong if patient had been taking an antiresorptive before switching to PTH

•  Magnitude somewhat delayed and/or blunted compared to treatment-naïve pts

- 

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Combination #2

§  Concurrent initiation of PTH plus antiresorptive in treatment naïve women • PTH+alendronate • PTH+zoledronic acid • PTH+denosumab

Antiresorptives + PTH

N Year 1 Year 2 59 PTH(1–84)

ALN 60 PTH(1–84) + ALN

ALN 59

ALN 60

PTH(1–84) ALN

PLB

Black, et al. New Engl J Med 2003;349:1207–15

•  238 postmenopausal women with osteoporosis –  Treatment naive

•  Randomized to four treatment groups x 2 years •  Combination of PTH (1-84) + daily alendronate

PTH and Alendronate (PaTH) study

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Hypothesis: PTH + alendronate will increase BMD much more than either alone

Synergistic effect

PTH0

5%

10%

15%Sp

ine

BM

D:

Mea

n C

hang

e (%

)

ALN

Additive effect

PTH/ ALN

Changes in Trabecular Volumetric BMD by QCT (g/cm3)

Spine Total Hip0

10

20

30

40

PTH PTH/ALN ALN

Mea

n C

hang

e (%

) **

** p<.01 Black, et al. New Engl J Med 2003;349:1207–15

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•  No advantage of concurrent PTH + (daily) alendronate compared to monotherapy with PTH alone

•  Anabolic effect of PTH, particularly on trabecular bone, is blunted by concurrent use of alendronate

Concurrent use of PTH + ALN in PaTH: Summary

•  TPTD with IV ZOL (1 year trial, BMD trial)* - BMD effects similar to combination with alendronate (PaTH)

•  TPTD with denosumab (1 year BMD trial)** - Larger increases in BMD than with combination with alendronate - Very expensive, no fracture data

•  More details in “bonus slides”

What about teriparatide with other antiresorptives?

* Cosman, et al. JBMR, 2011 ** Tsai, Lancet, 2013

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Combination #3

§  Use of antiresorptive after PTH •  PaTH: 1 yr of PTH then 1 yr ALN or placebo

PTH Antiresorptives

Black DM et al. N Engl J Med 2005;353:555–65

N Year 1 Year 2 59 PTH(1–84)

ALN 60 PTH(1–84) + ALN

ALN 59

ALN 60

PTH(1–84) ALN

PLB

Change in spine BMD (DXA) over 24 months

Black DM et al. N Engl J Med 2005;353:555–65

Mea

n C

hang

e (%

)

0

5

10

15

20

0 12 24 Month

PLB

ALN

PTH discontinued

PTH (1–84)

24 month change

+12%

+ 4%

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Change in spine BMD (DXA) over 24 months

Black DM et al. N Engl J Med 2005;353:555–65

Mea

n ch

ange

(%)

0

5

10

15

20

0 12 24 Month

PLB

ALN

PTH discontinued

PTH (1–84)

24 month change

+12%

+ 4%

+ 8%

ALN only, 24 months

Change in trabecular spine BMD (QCT) over 24 months

Black DM et al. N Engl J Med 2005;353:555–65

0

8

16

24

32

40

0 12 24Month

Mea

n ch

ange

(%)

PTH discontinued

PLB

ALN

PTH (1–84)

24 month change

+30%

+13%

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• PTH followed by nothing will result in loss of most, if not all, BMD gains

• Bisphosphonates add to BMD gains •  In general for clinical use: Follow

PTH with some sort of antiresorptive therapy

What to do following PTH therapy?

•  Substantial literature about combination therapy, but no fracture outcomes

•  Sequential antiresorptive then PTH: Still see increases in formation, BMD with PTH – May be slightly delayed/blunted

• Concurrent use: - If using PTH, probably best to use alone – Or with DMAB ($$$)

•  PTH followed by antiresorptive will maximize/maintain BMD gains

Combination therapy with teriparatide: Summary

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• Other forms of and delivery methods for PTH (e.g., PTHrP, transdermal PTH) in development

• Anabolics with other mechanisms of action – Anti-sclerostin Ab – PTHrp

• Cyclic PTH? (e.g,, 3- or 6-mo at a time?)

Future of anabolic therapy (hear

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Bonus slides: Extra data from anabolic combination studies

Trial of once yearly zoledronic acid + teriparatide

•  360 patients •  Follow-up one year

PTH(1–34)

PTH(1–34) + Zol.

Zoledronic acid

Cosman, et al. J Bone Miner Res 2011

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Changes in total hip and femoral neck BMD

0

0.5

1

1.5

2

2.5

3

0 13 26 39 52

Weeks

Mea

n %

Ch

ang

e in

BM

D‡

Total Hip BMD

ZOL+ TPTD TPTD alone ZOL alone

0 13 26 52 Weeks

Mea

n %

Ch

ang

e in

BM

D‡

Femoral Neck BMD

-1

0

2

3

1

39

*

*† *

* *

*P<0.05 vs TPTD alone †P<0.05 vs ZOL alone

*

* *

*

* *

*

Changes in P1NP over 1 year: Zoledronic acid vs. alendronate

PTH PTH/BIS BIS

Weeks

Mea

n PI

NP

(ng/

mL)

PTH + ZOL

0 4 8 12 16 20 24 28 32 36 40 44 48 52 0

50

100

150

200

Black, NEJM 2003; Cosman, JBMR 2011

Med

ian

Cha

nge

P1N

P (%

)

-100

0

100

200

300

400

0 3 6 9 12Month

Formation (P1NP)

PTH + ALN

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Fractures (assessed as AEs only)

Category

ZOL + TPTD n (%)

(n=137)

TPTD alone n (%)

(n=137)

ZOL alone n (%)

(n=137)

Clinical fractures (assessed as AEs only)

4 (2.9%) 8 (5.8%) 13 (9.5%)*

Spine fractures 0 1 6

* p=0.04 vs combination (post-hoc)

PTH + Zoledronic acid

• BMD results similar to PTH+ALN in PaTH •  Pattern of marker changes is different

– Although not clear that it’s better •  Fracture results intriguing

– But not an official study endpoint • Missing pieces:

– QCT vBMD (trabecular vs. cortical) – Adjudication of fractures – Longer-term follow-up

•  Denosumab similar to zoledronic acid with respect to rapid onset

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Denosumab and Teriparatide trial (DATA)

•  100 patients •  Follow-up one year

PTH(1–34)

PTH(1–34) + DMAB

DMAB

Tsai, Lancet, 2013

Denosumab and Teriparatide trial (DATA)

Tsai, et al., Lancet, 2013

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•  First combo to increase BMD more at spine and hip than either agent alone

• Why does DMAB seem to interfere less with formation than bisphosphonates? – Mechanism of action? – Frequency? (q 6 months)

•  $$$ combo, but could be considered – Particularly if short-term (1-2 years)

PTH + Denosumab

Cyclic PTH: PTH – Ibandronate – PTH - Ibandronate

Schafer et al, J Clin Endocrinol Metab 2012

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Cyclic PTH: PTH – Ibandronate – PTH - Ibandronate

Schafer et al, J Clin Endocrinol Metab 2012

Bone Formation Increases with a Second Course of PTH(1-84)

0"

20"

40"

60"

80"

100"

120"

140"

160"

180"

0" 3" 6" 9" 12" 15" 18"

P1NP"(ng/mL)"

*

**

* *

Month

PTH PTH Ibandronate Ibandronate

*p≤0.01 compared to baseline

Sequential

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Anabolics and antiresorptives have opposite effects on bone remodeling

from Black, et al. New Engl J Med 2003;349:1207–15

Med

ian

Cha

nge

(%)

-100

0

100

200

300

400

0 3 6 9 12Month

Anabolic

ALN

-100

0

100

200

300

0 3 6 9 12Month

Resorption (CTX)Bone Formation

(P1NP)

The Holy Grail for combination therapy

Med

ian

Cha

nge

(%)

-100

0

100

200

300

400

0 3 6 9 12Month

Formation

Resorption

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Finite element modeling of femoral strength in PaTH

Keaveny et al. JBMR 2008 * p<0.05 within group from baseline

-4

-2

0

2

4

6

8

10

12

12 24CH

AN

GE

IN F

EM

OR

AL

STR

EN

GTH

FRO

M B

AS

ELI

NE

(%)

YEAR 1 YEAR 2

ALN-ALN

PTH-ALNCMB-ALN

TREATMENTYR1– YR2PTH-PLB

* * ***

Mean ± 95% CI