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Jan 07, 2023 •106 likes •220 views

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

  1. 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  Antiresorptive agents  Overview of anabolic therapy  Bisphosphonates (oral or IV) - Currently FDA-approved: Teriparatide  Raloxifene  Estrogen  Combining anabolic and antiresorptive  Calcitonin therapies  Denosumab  Anabolic agents  Teriparatide Page 1

  2. Anabolic therapy increases bone PTH increases bone formation before remodeling bone resorption 400 Formation (P1NP) 300 Resorption (CTX) Median Change (%) 300 200 PTH PTH 200 100 100 ALN ALN 0 0 -100 -100 0 3 6 9 12 0 3 6 9 12 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

  3. Effect of teriparatide on spine BMD Effect of teriparatide on total hip BMD 5 16 *** 4 *** PTH 40 mcg 14 PTH 40 mcg % Change ( ± SE) % Change ( ± SE) *** 3 *** 12 PTH 20 mcg PTH 20 mcg 10 2 *** *** *** 8 *** 1 *** 6 *** ~ 2% ~ 7% *** 4 0 *** 2 Placebo -1 Placebo 0 -2 0 3 6 12 18 0 6 12 18 24 *** p < 0.001 vs. Placebo Months *** p < 0.001 vs. Placebo Months Neer, NEJM, 2001 Neer, NEJM, 2001 Effect of teriparatide on non-vertebral Effect of teriparatide on incident 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) % of Women 10 8 6 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

  4. Histomorphometry: Teriparatide in clinical practice Teriparatide in a 64 y.o. woman Before After CtTh: 0.32 mm CtTh: 0.42 mm  Approved for up to 2 years duration CD: 2.9 mm 3 CD: 4.6 mm 3  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 formation  Other osteoporotic fx + low BMD  Combine PTH with antiresorptives to  Very low BMD (e.g., T-score <-3.0) 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

  5. Combination PTH + antiresorptive? Combination #1 3 distinct possibilities Antiresorptive PTH 1. Antiresorptive PTH  Pre-treatment with antiresorptives followed by PTH Antiresorptive 2. + PTH • Key clinical question • Many patients on bisphosphonates PTH Antiresorptive 3. 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  Concurrent initiation of PTH plus • Magnitude somewhat delayed and/or antiresorptive in treatment naïve women blunted compared to treatment-naïve pts • PTH+alendronate • PTH+zoledronic acid • PTH+denosumab - Page 5

  6. Hypothesis: PTH + alendronate will PTH and Alendronate (PaTH) Study increase BMD much more than either alone • 238 postmenopausal women with osteoporosis – Treatment naive 15% Synergistic effect • Randomized to four treatment groups x 2 years Mean Change (%) Spine BMD • Combination of PTH (1-84) + daily alendronate 10% Additive effect N Year 1 Year 2 5% PLB 59 PTH(1–84) 60 PTH(1–84) ALN 59 PTH(1–84) + ALN ALN 0 ALN PTH PTH/ 60 ALN ALN ALN Black, NEJM, 2003 Black, et al. New Engl J Med 2003;349:1207–15 Changes in Trabecular Volumetric Concurrent use of PTH+ALN in PaTH: BMD by QCT (g/cm 3 ) Summary 40 • No advantage of concurrent PTH + ** Mean Change (%) (daily) alendronate compared to 30 monotherapy with PTH alone 20 • Anabolic effect of PTH, particularly on trabecular bone, is blunted by 10 concurrent use of alendronate 0 Spine Total Hip PTH PTH/ALN ALN Black, NEJM, 2003 ** p<.01 Page 6

  7. Trial of once yearly zoledronic acid + Changes in BMD at spine and hip teriparatide PTH(1–34) • 360 patients PTH(1–34) + Zol. • 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 Fem oral Neck BMD PTH + ZOL 3 3 * † 200 Mean % Change in BMD ‡ * Mean % Change in BMD ‡ * * Mean P1NP ( ng /mL) * * 2.5 2 150 2 * * * 1.5 1 * 100 * * 1 0 50 0.5 0 -1 0 0 13 26 39 52 0 13 26 52 39 0 4 8 12 16 20 24 28 32 36 40 44 48 52 W eeks W eeks W eeks ZOL+ TPTD TPTD alone PTH PTH/BIS BIS ZOL alone * P < 0.05 vs TPTD alone † P < 0.05 vs ZOL alone Black, NEJM 2003; Cosman, JBMR 2011 Page 7

  8. Changes in P1NP over 1 year: Fractures (Only assessed as AEs) Alendronate vs. zoledronic acid PTH + ALN PTH + ZOL Median Change P1NP (%) ZOL + TPTD TPTD alone ZOL alone 200 400 Formation (P1NP) n ( % ) n ( % ) n ( % ) Mean P1NP ( ng /mL) Category ( n= 1 3 7 ) ( n= 1 3 7 ) ( n= 1 3 7 ) 300 150 Clinical fractures 200 ( assessed as AEs 4 ( 2 .9 % ) 8 ( 5 .8 % ) 1 3 ( 9 .5 % ) * 100 only) 100 50 Spine fractures 0 1 6 0 -100 0 0 3 6 9 12 0 4 8 12 16 20 24 28 32 36 40 44 48 52 * p=0.04 vs combination (post-hoc) W eeks Month PTH PTH/BIS BIS Cosman, J Bone Miner Res 2011 Black, NEJM 2003; Cosman, JBMR 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 • 100 patients • Fracture results intriguing PTH(1–34) + DMAB – 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

  9. Denosumab and Teriparatide trial PTH + Denosumab (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? –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 Mean Change (%) 24 month change 15 PTH discontinued  Use of antiresorptive after PTH +12% ALN 10 • PaTH: 1 yr of PTH then 1 yr ALN or placebo PTH (1–84) 5 + 4% N Year 1 Year 2 PLB PLB 59 PTH(1–84) 0 PTH(1–84) 60 ALN 0 12 24 59 PTH(1–84) + ALN ALN Month 60 ALN ALN Black, NEJM, 2005 Black, NEJM, 2005 Page 9

  10. Change in spine BMD (DXA) over 24 Change in trabecular spine BMD months (QCT) over 24 months 20 PTH discontinued Mean Change (%) 24 month 24 month change 40 15 change PTH discontinued Mean change (%) ALN +12% 32 ALN +30% 10 24 PLB PTH (1–84) PTH (1–84) 16 5 +13% + 4% PLB 8 0 0 0 12 24 0 12 24 ALN only, 24 months Month Month Black, NEJM, 2005 Black, NEJM, 2005 Combination therapy with teriparatide: What to do following PTH therapy? Conclusions • Substantial literature about combination • PTH followed by nothing will result in loss therapy, but no fracture outcomes of most, if not all, BMD gains • Sequential antiresorptive then PTH: Still see • Bisphosphonates seem to add to BMD increases in formation, BMD with PTH gains –May be slightly delayed/blunted • Follow PTH with some sort of • If using PTH, probably best to use alone antiresorptive therapy –Or with DMAB ($$$) • PTH followed by antiresorptive seems to maximize BMD gains Page 10

  11. 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 Page 11

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