Teriparatide, alone and in I have nothing to disclose. combination with antiresorptives
Anne Schafer, MD Assistant Professor Medicine - Endocrinology & Metabolism Epidemiology & Biostatistics
Outline Treatment of Osteoporosis
Antiresorptive agents Overview of anabolic therapy Bisphosphonates (oral or IV) - Currently FDA-approved: Teriparatide Raloxifene Combining anabolic and antiresorptive Estrogen therapies Calcitonin Denosumab
Anabolic agents Teriparatide
Page 1 Anabolic therapy increases bone PTH increases bone formation before remodeling bone resorption
400 Formation (P1NP) 300 Resorption (CTX) 300 200 PTH PTH 200 100 100 ALN ALN 0 0 Median Change (%) Change Median -100 -100 036912 036912 Month Month
Black, NEJM, 2003 (adapted from Canalis, NEJM, 2007)
PTH(1-34) (Teriparatide) Parathyroid Hormone (PTH) Fracture Prevention Trial
84 amino acid sequence 1637 postmenopausal women Most of bone activity in first 34 amino acids Randomized to placebo, PTH (1-34) 20 ug, or PTH (1-34) (teriparatide) approved @ 20 mcg/day PTH (1-34) 40 ug PTH (1-84) not approved in US for osteoporosis Fracture was primary endpoint Requires (currently) daily injection 3-year study, halted after 21 months (median) Subcutaneous, abdomen Safety problem with high doses in rodents
Neer, NEJM, 2001
Page 2 Effect of teriparatide on spine BMD Effect of teriparatide on total hip BMD
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16 *** 4 *** PTH 40 mcg 14 PTH 40 mcg *** 3 *** SE) 12 SE) PTH 20 mcg ± 10 PTH 20 mcg ± 2 *** *** 8 *** *** 1 *** 6 *** ~ 7% ~ 2% 4 *** 0 % Change (
2 *** % Change ( Placebo -1 0 Placebo -2 036 1218 0 6121824 *** p < 0.001 vs. Placebo Months *** p < 0.001 vs. Placebo Neer, NEJM, 2001 Months Neer, NEJM, 2001
Effect of teriparatide on incident vertebral Effect of teriparatide on non-vertebral fracture risk fracture risk
RR 0.35 (95% CI, 0.22 to 0.55)* 14 12 *P < 0.001 20 mcg vs. placebo: RR=0.47 (0.25,0.88) 10 8 6
% ofWomen 4 2 64 22 19 0 Placebo rhPTH 20mg (n=448) (n=444) No. of women who had > 1 fracture
Neer, NEJM, 2001 (Adapted from Neer, NEJM, 2001)
Page 3 Histomorphometry: Teriparatide in a 64 y.o. woman Teriparatide in clinical practice
Before After CtTh: 0.32 mm CtTh: 0.42 mm CD: 2.9 mm3 CD: 4.6 mm3 Approved for up to 2 years duration Limited adoption in clinical practice Cost (>$10,000/course) Need for daily injections
Dempster, J Bone Miner Res, 2001
Teriparatide in clinical practice Combination PTH + antiresorptive?
High risk for future fracture PTH increases formation then resorption
Prevalent vertebral compression fx Antiresorptives decrease resorption then Other osteoporotic fx + low BMD formation Very low BMD (e.g., T-score <-3.0) Combine PTH with antiresorptives to increase formation with smaller increase Failed antiresorptive therapy in resorption? Incident fx or active bone loss Could be synergistic: 1 + 1 = 3 Glucocorticoid-induced osteoporosis Or cancel each other: 1 - 1 = 0
Page 4 Combination PTH + antiresorptive? Combination #1
3 distinct possibilities Antiresorptive PTH 1. Antiresorptive PTH . Pre-treatment with antiresorptives 2. Antiresorptive followed by PTH + PTH • Key clinical question • Many patients on bisphosphonates 3. PTH Antiresorptive and other antiresorptives
PTH following bisphosphonates Combination #2
Anabolic effect still evident and strong if Antiresorptive patient had been taking an + PTH antiresorptive before switching to PTH • Magnitude somewhat delayed and/or . Concurrent initiation of PTH plus blunted compared to treatment-naïve pts antiresorptive in treatment naïve women • PTH+alendronate • PTH+zoledronic acid • PTH+denosumab
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Page 5 Hypothesis: PTH + alendronate will PTH and Alendronate (PaTH) Study increase BMD much more than either alone
• 238 postmenopausal women with osteoporosis – Treatment naive 15% • Randomized to four treatment groups x 2 years Synergistic effect • Combination of PTH (1-84) + daily alendronate 10% Additive effect
N Year 1 Year 2 5% 59 PTH(1–84) PLB Spine BMD
60 PTH(1–84) ALN Mean Change (%) 59 PTH(1–84) + ALN ALN 0 60 ALN ALN PTH PTH/ ALN ALN Black, et al. New Engl J MedBlack, 2003;349:1207–15 NEJM, 2003
Changes in Trabecular Volumetric Concurrent use of PTH+ALN in PaTH: BMD by QCT (g/cm3) Summary
40 ** • No advantage of concurrent PTH + 30 (daily) alendronate compared to monotherapy with PTH alone 20 • Anabolic effect of PTH, particularly on 10 trabecular bone, is blunted by Mean Change (%) concurrent use of alendronate 0 Spine Total Hip
PTH PTH/ALN ALN ** p<.01 Black, NEJM, 2003
Page 6 Trial of once yearly zoledronic acid + teriparatide Changes in BMD at spine and hip
PTH(1–34)
PTH(1–34) + Zol. • 360 patients • Follow-up one year Zoledronic acid
Cosman, J Bone Miner Res 2011
Changes in P1NP over 1 year: Changes in BMD at the hip Alendronate vs. zoledronic acid
Total Hip BMD Femoral Neck BMD PTH + ZOL 3 3 200 ‡ *† ‡ * * * * 2.5 *
2 /mL) 150
2 ng * * 1.5 1 * 100 * * * 1 0 50 0.5 Mean P1NP ( P1NP Mean Mean % Change in BMD in Change Mean % 0 Mean % Change in BMD -1 0 0 13263952 0132639 52 0 4 8 1216202428323640444852 Weeks Weeks ZOL+ TPTD Weeks TPTD alone ZOL alone *P<0.05 vs TPTD alone PTH PTH/BIS BIS †P<0.05 vs ZOL alone Black, NEJM 2003; Cosman, JBMR 2011
Page 7 Changes in P1NP over 1 year: Alendronate vs. zoledronic acid Fractures (Only assessed as AEs)
PTH + ALN PTH + ZOL 200 ZOL + TPTD TPTD alone ZOL alone 400 n (%) n (%) n (%) Formation (P1NP) Category (n=137) (n=137) (n=137)
300 /mL) 150
ng Clinical fractures 200 (assessed as AEs 4 (2.9%) 8 (5.8%) 13 (9.5%)* 100 only) 100
50 0 Spine fractures 0 1 6 Mean P1NP ( P1NP Mean Median Change P1NP (%) P1NP Change Median
-100 0 036912 0 4 8 1216202428323640444852 Month Weeks * p=0.04 vs combination (post-hoc) PTH PTH/BIS BIS Black, NEJM 2003; Cosman, JBMR 2011 Cosman, J Bone Miner Res 2011
Denosumab and Teriparatide trial PTH + Zoledronic acid (DATA) • BMD results similar to PTH+ALN in PaTH • Pattern of marker changes is different PTH(1–34) – Although not clear that it’s better • Fracture results intriguing PTH(1–34) + DMAB • 100 patients – But not an official study endpoint • Follow-up one year • Missing pieces: DMAB – QCT vBMD (trabecular vs. cortical) – Adjudication of fractures – Longer-term follow-up • Denosumab similar to zoledronic acid with respect to rapid onset Tsai, Lancet 2013
Page 8 Denosumab and Teriparatide trial (DATA) PTH + Denosumab
• 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) • $$$ combo, but could be considered –Particularly if short-term (1-2 years)
Tsai, Lancet 2013
Change in spine BMD (DXA) over 24 Combination #3 months
20 PTH Antiresorptive 15 24 month change PTH discontinued +12% . Use of antiresorptive after PTH ALN 10 • PaTH: 1 yr of PTH then 1 yr ALN or placebo
5 PTH (1–84) N Year 1 Year 2 PLB + 4% Mean Change (%) 59 PTH(1–84) PLB 0 60 PTH(1–84) ALN 01224 59 PTH(1–84) + ALN ALN Month 60 ALN ALN Black, NEJM, 2005 Black, NEJM, 2005
Page 9 Change in spine BMD (DXA) over 24 Change in trabecular spine BMD months (QCT) over 24 months
20 PTH discontinued
24 month 15 24 month change 40 PTH discontinued change ALN +12% 32 ALN +30% 10 24 PLB PTH (1–84) PTH (1–84) 16 5 +13% PLB + 4% Mean Change (%) 8
0 (%) Mean change 0 01224 01224 ALN only, 24 months Month Month
Black, NEJM, 2005 Black, NEJM, 2005
Combination therapy with teriparatide: What to do following PTH therapy? Conclusions
• PTH followed by nothing will result in loss • Substantial literature about combination of most, if not all, BMD gains therapy, but no fracture outcomes • Bisphosphonates seem to add to BMD • Sequential antiresorptive then PTH: Still see gains increases in formation, BMD with PTH –May be slightly delayed/blunted • Follow PTH with some sort of antiresorptive therapy • If using PTH, probably best to use alone –Or with DMAB ($$$) • PTH followed by antiresorptive seems to maximize BMD gains
Page 10 Future of anabolic therapy
• 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
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