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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