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Teriparatide, alone and in I have nothing to disclose. combination - - PDF document

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Teriparatide, alone and in I have nothing to disclose. combination with antiresorptive s Anne Schafer, MD Assistant Professor Medicine - Endocrinology & Metabolism Epidemiology & Biostatistics Outline Treatment of Osteoporosis

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Teriparatide, alone and in combination with antiresorptives

Anne Schafer, MD

Assistant Professor

Medicine - Endocrinology & Metabolism Epidemiology & Biostatistics

I have nothing to disclose.

Outline

 Overview of anabolic therapy

  • Currently FDA-approved: Teriparatide

 Combining anabolic and antiresorptive

therapies

Treatment of Osteoporosis

 Antiresorptive agents Bisphosphonates (oral or IV) Raloxifene Estrogen Calcitonin Denosumab  Anabolic agents Teriparatide

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Page 2 Anabolic therapy increases bone remodeling

Median Change (%)

  • 100

100 200 300 3 6 9 12 Month

  • 100

100 200 300 400 3 6 9 12 Month Resorption (CTX) Formation (P1NP) PTH ALN PTH ALN

Black, NEJM, 2003

PTH increases bone formation before bone resorption

(adapted from Canalis, NEJM, 2007)

Parathyroid Hormone (PTH)

 84 amino acid sequence  Most of bone activity in first 34 amino acids  PTH (1-34) (teriparatide) approved @ 20 mcg/day  PTH (1-84) not approved in US for osteoporosis  Requires (currently) daily injection  Subcutaneous, abdomen

PTH(1-34) (Teriparatide)

Fracture Prevention Trial

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

PTH (1-34) 40 ug

 Fracture was primary endpoint  3-year study, halted after 21 months (median)  Safety problem with high doses in rodents

Neer, NEJM, 2001

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Effect of teriparatide on spine BMD

Placebo PTH 20 mcg PTH 40 mcg Months

% Change (±SE)

2 4 6 8 10 12 14 16 3 6 12 18

*** *** *** *** *** *** *** ***

*** p < 0.001 vs. Placebo

~ 7%

Neer, NEJM, 2001

Placebo PTH 20 mcg PTH 40 mcg

  • 2
  • 1

1 2 3 4 5 6 12 18 24

Months *** *** *** ***

% Change (±SE)

~ 2%

*** p < 0.001 vs. Placebo

Effect of teriparatide on total hip BMD

Neer, NEJM, 2001

*P < 0.001

Placebo

(n=448)

rhPTH 20mg

(n=444)

64 22 19

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

  • No. of women who had > 1 fracture

8 2 4 6 10 12 14

Effect of teriparatide on incident vertebral fracture risk

Neer, NEJM, 2001

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

(Adapted from Neer, NEJM, 2001)

Effect of teriparatide on non-vertebral fracture risk

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Before CtTh: 0.32 mm CD: 2.9 mm3 After CtTh: 0.42 mm CD: 4.6 mm3

Dempster, J Bone Miner Res, 2001

Histomorphometry: Teriparatide in a 64 y.o. woman

 Approved for up to 2 years duration  Limited adoption in clinical practice Cost (>$10,000/course) Need for daily injections

Teriparatide in clinical practice

 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

 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?

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3 distinct possibilities

PTH Antiresorptive Antiresorptive + PTH Antiresorptive PTH

1. 2. 3.

Combination PTH + antiresorptive?

Antiresorptive PTH

  • Pre-treatment with antiresorptives

followed by PTH

  • Key clinical question
  • Many patients on bisphosphonates

and other antiresorptives

Combination #1

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

  • PTH following bisphosphonates
  • Concurrent initiation of PTH plus

antiresorptive in treatment naïve women

  • PTH+alendronate
  • PTH+zoledronic acid
  • PTH+denosumab

Antiresorptive + PTH

Combination #2

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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

Black, NEJM, 2003

Synergistic effect

PTH 5% 10% 15%

Spine BMD Mean Change (%)

ALN

Additive effect

PTH/ ALN

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

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

Spine Total Hip 10 20 30 40 PTH PTH/ALN ALN

Mean Change (%)

**

** p<.01 Black, NEJM, 2003

  • 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

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  • 360 patients
  • Follow-up one year

PTH(1–34) PTH(1–34) + Zol. Zoledronic acid

Cosman, J Bone Miner Res 2011

Trial of once yearly zoledronic acid + teriparatide

Changes in BMD at spine and hip

0.5 1 1.5 2 2.5 3 13 26 39 52

W eeks Mean % Change in BMD‡

Total Hip BMD

ZOL+ TPTD TPTD alone ZOL alone

13 26 52

W eeks Mean % Change in BMD‡

Fem oral Neck BMD

  • 1

2 3 1 39

* * † * * *

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

* * * * * * *

Changes in BMD at the hip

PTH PTH/BIS BIS

Black, NEJM 2003; Cosman, JBMR 2011

Changes in P1NP over 1 year: Alendronate vs. zoledronic acid

W eeks

Mean P1NP (ng/mL) PTH + ZOL

4 8 12 16 20 24 28 32 36 40 44 48 52 50 100 150 200

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PTH PTH/BIS BIS

Black, NEJM 2003; Cosman, JBMR 2011

Median Change P1NP (%)

  • 100

100 200 300 400 3 6 9 12 Month Formation (P1NP)

PTH + ALN

Changes in P1NP over 1 year: Alendronate vs. zoledronic acid

W eeks

Mean P1NP (ng/mL) PTH + ZOL

4 8 12 16 20 24 28 32 36 40 44 48 52 50 100 150 200

* p=0.04 vs combination (post-hoc)

Category ZOL + TPTD n ( % ) ( n= 1 3 7 ) TPTD alone n ( % ) ( n= 1 3 7 ) ZOL alone n ( % ) ( n= 1 3 7 ) Clinical fractures ( assessed as AEs

  • nly)

4 ( 2 .9 % ) 8 ( 5 .8 % ) 1 3 ( 9 .5 % ) * Spine fractures 1 6

Cosman, J Bone Miner Res 2011

Fractures (Only assessed as AEs)

  • 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

PTH + Zoledronic acid

  • 100 patients
  • Follow-up one year

PTH(1–34) PTH(1–34) + DMAB DMAB

Tsai, Lancet 2013

Denosumab and Teriparatide trial (DATA)

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Page 9 Denosumab and Teriparatide trial (DATA)

Tsai, Lancet 2013

  • 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

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

PTH Antiresorptive

N Year 1 Year 2 59 PTH(1–84) ALN 60 PTH(1–84) + ALN ALN 59 ALN 60 PTH(1–84) ALN PLB

Combination #3

Black, NEJM, 2005

Mean Change (%)

5 10 15 20 12 24

Month PLB ALN

PTH discontinued PTH (1–84)

24 month change +12% + 4%

Change in spine BMD (DXA) over 24 months

Black, NEJM, 2005

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Mean Change (%)

5 10 15 20 12 24

Month PLB ALN

PTH discontinued PTH (1–84)

24 month change +12% + 4%

Change in spine BMD (DXA) over 24 months

Black, NEJM, 2005

ALN only, 24 months

8 16 24 32 40 12 24

Month Mean change (%)

PTH discontinued

PLB ALN

PTH (1–84)

24 month change +30% +13%

Change in trabecular spine BMD (QCT) over 24 months

Black, NEJM, 2005

  • PTH followed by nothing will result in loss
  • f most, if not all, BMD gains
  • Bisphosphonates seem to add to BMD

gains

  • 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

  • If using PTH, probably best to use alone

–Or with DMAB ($$$)

  • PTH followed by antiresorptive seems to

maximize BMD gains

Combination therapy with teriparatide: Conclusions

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  • Cyclic PTH? (e.g., 3- or 6-mo at a time?)
  • Other forms of and delivery methods for

PTH (e.g., PTHrP, transdermal PTH) in development

  • Anabolics with other mechanisms of

action

–Anti-sclerostin Ab

Future of anabolic therapy