Disclosures Anabolic therapy, alone and in Research support from - PowerPoint PPT Presentation

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 Epidemiology & Biostatistics Treatment of Osteoporosis Outline  Antiresorptive agents  Overview of anabolic therapy  Bisphosphonates (oral or IV) - Currently FDA-approved:  Denosumab - Teriparatide (PTH)  Calcitonin - Abaloparatide (PTHrP)  Raloxifene  Combining anabolic and antiresorptive  Estrogen therapies  Anabolic agents  Teriparatide (PTH)  Abaloparatide (PTHrP) Page 1

Anabolic therapy increases bone PTH increases bone formation before remodeling bone resorption 400 Formation (P1NP) 300 Resorption (CTX) Median Change (%) 300 200 PTH(1-84) PTH(1-84) 200 100 100 ALN ALN 0 0 -100 -100 0 3 6 9 12 0 3 6 9 12 Month Month Black, NEJM 2003 Canalis, NEJM 2007 Parathyroid Hormone (PTH) PTH-related peptide (PTHrP)  84 amino acid sequence  PTHrP (1-34) (abaloparatide) approved @ 80 mcg/day  Most of bone activity in first 34 amino acids  Requires daily injection  PTH (1-34) (teriparatide) approved @ 20 mcg/day  Subcutaneous, abdomen  Requires daily injection  Approved for up to 2 years of cumulative use of  Subcutaneous, abdomen teriparatide + abaloparatide  Approved for up to 2 years of use Page 2

PTH(1-34) (Teriparatide) Effect of teriparatide on spine BMD Fracture Prevention Trial  1637 postmenopausal women 16 *** PTH 40 mcg 14 % Change ( ± SE)  Randomized to placebo, PTH (1-34) 20 ug, or *** 12 PTH (1-34) 40 ug PTH 20 mcg 10 *** *** 8  Fracture was primary endpoint *** 6 *** ~ 9% ***  3-year study, halted after 21 months (median) 4 *** 2  Safety problem with high doses in rodents Placebo 0 0 3 6 12 18 *** p < 0.001 vs. Placebo Months Neer, NEJM 2001 Neer, NEJM 2001 Effect of teriparatide on incident vertebral Effect of teriparatide on total hip BMD fracture risk 5 RR 0.35 (95% CI, 0.22 to 0.55)* *** 4 14 PTH 40 mcg % Change ( ± SE) 12 3 * P < 0.001 *** % of Women PTH 20 mcg 10 2 *** 8 6 1 *** 4 ~ 3% 0 2 64 22 19 0 -1 Placebo Placebo rhPTH 20mg -2 (n=448) (n=444) No. of women who had > 1 fracture 0 6 12 18 24 *** p < 0.001 vs. Placebo Months Neer, NEJM 2001 Neer, NEJM 2001 Page 3

Effect of teriparatide on non-vertebral PTHrP (Abaloparatide) fracture risk ACTIVE Trial  2463 postmenopausal women  Randomized to placebo, PTHrP 80 ug/day, or 20 mcg vs. placebo: RR=0.47 (0.25,0.88) open-label teriparatide 20 ug/day  18-month study Miller, JAMA 2016 Neer, NEJM 2001 Effect of abaloparatide on incident Effect of abaloparatide on incident vertebral fracture risk nonvertebral fracture risk RR 0.14 RR 0.20 Miller, JAMA 2016 Miller, JAMA 2016 Page 4

Teriparatide and abaloparatide in Teriparatide and abaloparatide in clinical practice clinical practice  High risk for future fracture  Approved for up to 2 years duration (cumulative use)  Prevalent vertebral compression fx  Very low BMD ( e.g., spine T-score <-3.0)  Barriers for adoption in clinical practice  Failed antiresorptive therapy  Cost ($1600-$2900/month  Incident fx or active bone loss wholesale price)  Need for daily injections  Glucocorticoid-induced osteoporosis Combination anabolic + antiresorptive? Combination anabolic + antiresorptive?  Anabolic increases formation then 3 distinct possibilities resorption 1.  Antiresorptives decrease resorption Antiresorptive Anabolic  Combine anabolic with antiresorptives to increase formation with smaller increase Antiresorptive 2. + Anabolic in resorption?  Could be synergistic: 1 + 1 = 3 3. Anabolic Antiresorptive  Or cancel each other: 1 - 1 = 0 Page 5

Combination #1 PTH following antiresorptives Patient taking bisphosphonate who switches to anabolic: anabolic effect still evident and strong Antiresorptive Anabolic •Magnitude somewhat delayed and/or blunted compared to treatment-naïve pts  Antiresorptive followed by anabolic Patient on denosumab who switches to anabolic • Key clinical question may have transient or sustained loss of BMD • Many patients on bisphosphonates •Long-term (after the 2-year PTH course) unclear and denosumab Leder, Lancet 2015 Combination #2 PTH and Alendronate (PaTH) Study • 238 postmenopausal women with osteoporosis Antiresorptive – Treatment naive + Anabolic • Randomized to four treatment groups x 2 years • Combination of PTH (1-84) + daily alendronate  Concurrent initiation of PTH plus antiresorptive in treatment naïve women N Year 1 Year 2 PLB • PTH+alendronate 59 PTH(1–84) PTH(1–84) 60 ALN • PTH+zoledronic acid 59 PTH(1–84) + ALN ALN • PTH+denosumab 60 ALN ALN Black, NEJM 2003 Black, et al. New Engl J Med 2003;349:1207–15 Page 6

Changes in Trabecular Volumetric Concurrent use of PTH+ALN in PaTH: BMD by QCT (g/cm 3 ) Summary 40 • No advantage to 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 Trial of once yearly zoledronic acid + Changes in BMD at spine (DXA) teriparatide PTH(1–34) • 412 patients PTH(1–34) + Zol. • Follow-up one year Zoledronic acid Cosman, J Bone Miner Res 2011 Page 7

Changes in BMD at the hip Fractures (Only assessed as AEs) Total Hip BMD Femoral Neck BMD 3 3 ZOL + TPTD TPTD alone ZOL alone * † Mean % Change in BMD ‡ * * n (%) n (%) n (%) Mean % Change in BMD ‡ * * Category * (n=137) (n=137) (n=137) 2.5 2 2 Clinical fractures * * (assessed as AEs 4 (2.9%) 8 (5.8%) 13 (9.5%)* * 1.5 1 * only) * * 1 0 Spine fractures 0 1 6 0.5 0 -1 0 13 26 39 52 0 13 26 39 52 * p=0.04 vs combination (post-hoc) Weeks Weeks ZOL+ TPTD TPTD alone ZOL alone * P <0.05 vs TPTD alone Cosman, J Bone Miner Res 2011 † P <0.05 vs ZOL alone Denosumab and Teriparatide trial PTH + Zoledronic acid (DATA) • BMD change: similar to individual agents • Fracture results intriguing PTH(1–34) – But not an official study endpoint • 100 patients • Missing pieces: PTH(1–34) + DMAB – QCT vBMD (trabecular vs. cortical) • Follow-up 2 years – Adjudication of fractures DMAB – Longer-term follow-up Tsai, Lancet 2013 Page 8

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? Potency? –Frequency? (q 6 months) • $$$ combo, but could be considered • What happens after the combo course? Leder, J Clin Endocrinol Metab 2014 PaTH: Change in spine BMD (DXA) Combination #3 over 24 months 20 Anabolic Antiresorptive Mean Change (%) 24 month change 15 PTH discontinued  Use of antiresorptive after Anabolic +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 60 PTH(1–84) ALN 0 12 24 59 PTH(1–84) + ALN ALN Month 60 ALN ALN Black, NEJM 2005 Black, NEJM 2005 Page 9

PaTH: Change in spine BMD (DXA) PaTH: Change in trabecular spine over 24 months BMD (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) 16 PTH (1–84) 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 DATA-Switch: Change in BMD (DXA) What to do following anabolic therapy? • 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 Leder, Lancet 2015 Page 10

Abaloparatide followed by (open- Combining antiresorptive and anabolic label) bisphosphonate agents: Conclusions • 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 Cosman, Mayo Clinic Proc 2017 Future of anabolic therapy • 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?) Page 11