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Disclosures Anabolic therapy, alone and in Research support from Bariatric Advantage and Tate & Lyle (supplements donated for research sequence with antiresorptive s study) Anne Schafer, MD Associate Professor of Medicine and of

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Anabolic therapy, alone and in sequence with antiresorptives

Anne Schafer, MD

Associate Professor of Medicine and of Epidemiology & Biostatistics

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

Disclosures Outline

 Overview of anabolic therapy

  • Currently FDA-approved:
  • Teriparatide (PTH)
  • Abaloparatide (PTHrP)

 Combining anabolic and antiresorptive

therapies

Treatment of Osteoporosis

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

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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(1-84) ALN PTH(1-84) ALN

Black, NEJM 2003

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 injection  Subcutaneous, abdomen  Approved for up to 2 years of use

PTH-related peptide (PTHrP)

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

mcg/day

 Requires daily injection  Subcutaneous, abdomen  Approved for up to 2 years of cumulative use of

teriparatide + abaloparatide

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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

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

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

Neer, NEJM 2001

Effect of teriparatide on non-vertebral fracture risk

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

Effect of abaloparatide on incident nonvertebral fracture risk

Miller, JAMA 2016

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 Approved for up to 2 years duration

(cumulative use)

 Barriers for adoption

in clinical practice

Cost ($1600-$2900/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

 Anabolic increases formation then

resorption

 Antiresorptives decrease resorption

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?

3 distinct possibilities

Anabolic Antiresorptive Antiresorptive + Anabolic Antiresorptive Anabolic

1. 2. 3.

Combination anabolic + antiresorptive?

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Antiresorptive Anabolic

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

and denosumab

Combination #1

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

  • Magnitude somewhat delayed and/or blunted

compared to treatment-naïve pts

Patient on denosumab who switches to anabolic may have transient or sustained loss of BMD

  • Long-term (after the 2-year PTH course) unclear

PTH following antiresorptives

Leder, Lancet 2015

  • Concurrent initiation of PTH plus

antiresorptive in treatment naïve women

  • 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

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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 to 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

  • 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

Changes in BMD at spine (DXA)

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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
  • Fracture results intriguing

– But not an official study endpoint

  • Missing pieces:

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

PTH + Zoledronic acid

  • 100 patients
  • Follow-up 2 years

PTH(1–34) PTH(1–34) + DMAB DMAB

Tsai, Lancet 2013

Denosumab and Teriparatide trial (DATA)

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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
  • What happens after the combo course?

PTH + Denosumab

  • Use of antiresorptive after Anabolic
  • 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

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

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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

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%

PaTH: Change in trabecular spine BMD (QCT) over 24 months

Black, NEJM 2005

DATA-Switch: Change in BMD (DXA)

Leder, Lancet 2015

  • PTH followed by nothing will result in

some loss of BMD gains

  • Bisphosphonates and denosumab seem

to add to BMD gains

  • Follow anabolic with some sort of

antiresorptive therapy

What to do following anabolic therapy?

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Abaloparatide followed by (open- label) bisphosphonate

Cosman, Mayo Clinic Proc 2017

  • Substantial literature about combination

therapy, but (almost) no fracture outcomes

  • Sequential bisphosphonate then PTH: Still

see increases in formation, BMD with PTH

–Denosumab: Concerns/questions

  • If using anabolic, best to use alone

–Or with concurrent DMAB ($$$)

  • Anabolic followed by antiresorptive seems to

maximize BMD gains

Combining antiresorptive and anabolic agents: Conclusions

  • Learning more about anabolics + DMAB
  • Combo therapy with other anabolics
  • Abaloparatide (PTHrP), anti-sclerostin Ab
  • Other forms of and delivery methods for

anabolic agents (e.g., transdermal)

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

Future of anabolic therapy