Disclosures PTH analogs, alone and in Research support from - - PowerPoint PPT Presentation

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Disclosures PTH analogs, alone and in Research support from - - PowerPoint PPT Presentation

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Disclosures PTH analogs, alone and in Research support from Bariatric Advantage and Tate & Lyle (supplements donated for research combination with antiresorptive s study) Anne Schafer, MD Associate Professor UCSF and the San Francisco VA

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PTH analogs, alone and in combination with antiresorptives

Anne Schafer, MD

Associate Professor UCSF and the San Francisco VA Health Care System July 11, 2019

Research support from Bariatric Advantage and Tate & Lyle (supplements donated for research study)

Disclosures Treatment of osteoporosis

 Antiresorptive agents  Bisphosphonates  Denosumab  Raloxifene  Calcitonin, estrogen  Anabolic agents  Teriparatide (PTH 1-34)  Abaloparatide (PTHrP)  Mixed anabolic and antiresorptive agent  Romosozumab

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

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Is PTH bad or good for the bone?

Captain Martell

Mode Effect Continuous (high dose) Catabolic Daily intermittent (low dose) Anabolic

PTH increases bone formation before bone resorption

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  Requires daily subQ injection  Thigh or abdomen  Approved for up to 2 years of use

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 Neer, NEJM 2001

~ 9% Placebo PTH 20 mcg PTH 40 mcg

  • 2
  • 1

1 2 3 4 5 6 12 18 24

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

% Change (±SE) *** p < 0.001 vs. Placebo

Effect of teriparatide on total hip BMD

Neer, NEJM 2001

~ 3% *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)

Neer, NEJM 2001

Effect of teriparatide on non-vertebral fracture risk

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R0 conformation of the PTH1R (Associated with more prolonged binding of the ligand)

[Ligand] Log M

125I-PTH(1-34) bound (%)

RG conformation of the PTH1R (Associated with a more transient binding of the ligand)

125I-M-PTH(1-15) bound (%)

Abaloparatide Teriparatide Abaloparatide Teriparatide

  • 11
  • 10
  • 9
  • 8
  • 7
  • 6
  • 5

100 75 50 25 100 75 50 25

  • 11
  • 10
  • 9
  • 8
  • 12

[Ligand] Log M

Can a PTH analog do better?

Donovan, Br J Clin Pharmacol 2018

PTH-related peptide (PTHrP)

 PTHrP (1-34) (abaloparatide) approved @ 80

mcg/day

 Requires daily subQ injection  Thigh or abdomen  Approved for up to 2 years of cumulative use of

teriparatide + abaloparatide

PTHrP (Abaloparatide)

ACTIVE Trial

 2463 postmenopausal women  Randomized to placebo, PTHrP 80 ug/day, or

  • pen-label teriparatide 20 ug/day

 18-month study

Miller, JAMA 2016

Effect of abaloparatide on incident vertebral fracture risk

Miller, JAMA 2016

RR 0.14 RR 0.20

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Effect of abaloparatide on incident nonvertebral fracture risk

Miller, JAMA 2016

 Approved for up to 2 yrs, cumulative  Barriers for adoption

in clinical practice

Cost ($1600-$3500/month

wholesale price)

Need for daily injections

Teriparatide and abaloparatide in clinical practice

 High risk for future fracture

Prevalent vertebral compression fx Very low BMD (e.g., spine T-score <-3.0)

 Failed antiresorptive therapy

Incident fx or active bone loss

 Glucocorticoid-induced osteoporosis

Teriparatide and abaloparatide in clinical practice

 Combine anabolic with antiresorptives

to increase formation with smaller increase in resorption?

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

Combination anabolic + antiresorptive?

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Page 6 3 distinct possibilities

Anabolic Antiresorptive Antiresorptive + Anabolic Antiresorptive Anabolic

1. 2. 3.

Combination anabolic + antiresorptive?

Antiresorptive Anabolic

  • Antiresorptive followed by anabolic
  • Key clinical question
  • Many patients on bisphosphonates

and denosumab

Combination #1

Patient taking bisphosphonate switches to PTH analog: anabolic effect still evident and strong

  • Magnitude somewhat delayed and/or

blunted compared to treatment-naïve pts

Bisphosphonate followed by PTH

Patient on DMAB switches to PTH analog: may have transient or sustained loss of BMD

Denosumab followed by PTH

Leder, Lancet 2015

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  • Concurrent initiation of PTH analog plus

antiresorptive in treatment naïve pt

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

Antiresorptive + Anabolic

Combination #2

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

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

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

  • 412 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

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Changes in BMD at spine (DXA)

0.5 1 1.5 2 2.5 3 13 26 39 52

Weeks Mean % Change in BMD‡

Total Hip BMD

ZOL+ TPTD TPTD alone ZOL alone

13 26 52

Weeks Mean % Change in BMD‡

Femoral 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

* p=0.04 vs combination (post-hoc)

Category ZOL + TPTD n (%) (n=137) TPTD alone n (%) (n=137) ZOL alone n (%) (n=137) Clinical fractures (assessed as AEs

  • nly)

4 (2.9%) 8 (5.8%) 13 (9.5%)* Spine fractures 1 6

Cosman, J Bone Miner Res 2011

Fractures (Only assessed as AEs)

  • BMD change: similar to individual agents
  • Pattern of marker changes is different

– Although not clear that it’s better

  • Fracture results intriguing

– But not an official study endpoint

PTH + Zoledronic acid

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  • 100 patients
  • Follow-up 2 years

PTH(1–34) PTH(1–34) + DMAB DMAB

Tsai, Lancet 2013

Denosumab and Teriparatide trial (DATA)

Leder, J Clin Endocrinol Metab 2014

Denosumab and Teriparatide trial (DATA)

  • 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? Potency? –Frequency? (q 6 months)

  • $$$ combo, but could be considered

PTH + Denosumab

  • Anabolic followed by antiresorptive
  • PaTH: 1 yr of PTH then 1 yr ALN or placebo

Anabolic 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

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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%

PaTH: Change in spine BMD (DXA)

  • ver 24 months

Black, NEJM 2005

DATA-Switch: Change in BMD (DXA)

Leder, Lancet 2015

ACTIVE-Extend: Change in BMD

Cosman, Mayo Clinic Proc 2017

  • PTH followed by nothing will result in

some loss of BMD gains

  • Bisphosphonates and denosumab seem

to add to BMD gains

Take-home point: Follow PTH analog with some antiresorptive

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  • Substantial literature about combination

therapy, but no fracture outcomes

  • Sequential antiresorptive then PTH analog:

–BP then PTH: OK -  in BMD –DMAB then PTH: ? - transient  in BMD

  • If using anabolic, best to use alone

–Or with concurrent DMAB (but $$$)

  • PTH analog followed by antiresorptive seems

to maximize BMD gains

Combination therapy: Conclusions

  • Combinations with abaloparatide
  • Other forms of and delivery methods for

PTH analogs (e.g., transdermal)

  • Cyclic anabolic therapy (e.g., 3- or 6-mo at a

time)

  • Role of anti-sclerostin Ab therapy

Future of anabolic therapy