Mechanisms of Anabolic Therapies for Osteoporosis Clifford Rosen MD - PDF document

Mechanisms of Anabolic Therapies for Osteoporosis Clifford Rosen MD rosenc@mmc.org MMC: Portland Maine 1 Conflicts of Interest Associate Editor- UpToDate NEJM 2 1

Outline  -Anabolics – How do they work? • Work of the osteoblast? • Formation> Resorption • Increase osteoblast progenitors  PTH, PTHrp, Romosozumab – Drugs: • PTH • Abaloparatide-PTHrp • Romosozumab • Others???? 3 PTH1R Agonists That Activate the Anabolic Program PTHrp 2

PTH and Bone Remodeling PTH RANK-L(OPGL) D-Pyr OPG RANK NTx CTx M-CSF IGF-I Wnt 10b IGFBPs α v β 3 LRP5,6 COOH Osteocalcin BMP,S1P Osteocalcin OB OC Tgf- β BSAP - PICP Proteases Sclerostin H + IGFs Matrix IGF-BPs Osteocyte Collagen TGFs Resorption Formation 20 Days 100 Days 120 Days Effect of PTH (1-34) on lumbar spine BMD 16 *** PTH 40 mcg 14 % Change ( ± SE) *** 12 PTH 20 mcg 10 *** *** 8 *** 6 *** ~ 7% *** 4 2 *** Placebo 0 0 3 6 12 18 *** p < 0.001 vs. Placebo Months Neer et al. N Engl J Med. 2001;344:1434-1441 3

Effect of Teriparatide on Incidence of Vertebral and Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis New vertebral fracture Non-vertebral fractures 20 20 P< 0.01 P< 0.01 Patients (%) with fracture 18 18 Patients (%) with fracture 16 16 14 14 12 12 10 10 8 8 65% 6 6 53% 4 4 2 2 0 0 20  g PTH 20  g PTH Placebo Placebo Neer RM, et al. N Engl J Med. 2001;344:1434-41 How do Anabolic Agents Increase the Work of the Osteoblast? Baseline Follow-up Female, age 65 Patient 1124 Duration of therapy: 637 days (approx 21 mos) BMD Change: B3D-MC-GHAC  Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) UCSF - Jiang  Total Hip: +5.2% (group mean = 2.6 ± 4.9%) Jiang Y et al. J Bone Miner Res . 2003;18:1932–1941 4

Major Clinical Trials With Teriparatide • Reduction in vertebral (65% ) and non- vertebral (53% ) fractures (Neer et al. N Eng J Med . 2001) • As effective in women with mild or severe previous fragility fractures (Gallagher et al. 2004) • As effective in women with 1, 2 or more previous fragility fractures (Gallagher et al. 2004) • Reduced back pain (McClung et al. 2005; Miller et al. 2006) PTH Light!! Does once weekly PTH work? 5

PTH once Weekly Increases L-S BMD-2% Mean change Trabecular Spine vBMD (%) Mean change Spine aBMD (%) 4 4 POWR POWR 3 3 Placebo Placebo 2 2 1 1 3.8% 2.1% 0 0 -1 -1 -2 -2 0 3 6 9 12 0 3 6 9 12 Month Month Mean change Integral Femur vBMD (%) Mean change Hip aBMD (%) 4 4 POWR POWR 3 3 Placebo Placebo 2 2 1 1 0 0 0.04% -1 -1 -2 -2 0 3 6 9 12 -0.4% 0 3 6 9 12 Month Month Biochemical Markers of Bone Turnover with PTH once weekly 20 120 POW R Mean Change P1NP (%) Mean Change CTX (%) 10 POW R Placebo 80 0 Placebo -10 40 -20 -30 0 -40 -50 -40 0 3 6 9 12 0 3 6 9 12 M onth Month 6

PTH once weekly Fracture Trial-56ug: 1-34 Nakumara, 2012 PTH once weekly Reduces vert fractures by more than 50% 7

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Fracture Efficacy for Abaloparatide 9

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How Does PTH or PTHrp Work? Wein et al, Nature Communications , 2 PTH PPR Gs  cAMP, PKA SIK2 Silk inducible kinase pHDAC4/5 pCRTC2 HDAC4/5 CRTC2  bone formation  bone resorptio Mef2c CREB SOST RANKL 11

The Bone Marrow Niche: Mesenchymal and Hematopoietic Vitality Sost? Adipocytes HSCs Osteocyte OB Choices for Fuel Utilization AMPK Long et al, 2014 12

Aerobic glycolysis in bone: lactate production and gradients in calvaria- PTH induces glycolysis W. F. Neuman, M. W. Neuman, R. Brommage American Journal of Physiology - Cell Physiology Jan 1978 What happens if we reduce or prevent PTH1R activation? 13

A PTH1R fl/fl Prx1cre;PTH1R fl/fl 1.5 B Fold over control 5 PTH1R fl/fl Prx1Cre;PTH1R fl/fl 1.0 0 * * PTH1R deletion in pre- OBs * 0.5 5 *** *** *** 0.0 0 Runx2 Osx Alp Col1 α 1 Ocn PTH1R fl/fl Prx1cre;PTH1R fl/fl C D PTH1R fl/fl Prx1cre;PTH1R fl/fl Fan et al Cell Metabolism 2017 PTH Reduces Bone Marrow Adiposity Fan et al, Cell Metabolism, 2017 14

Hypoparathyroidism- High BMAT and Decreases with PTH MSC Fate in the Marrow Niche PTH in the Marrow Niche PTH - osteoblast Ocy Pre-OB ? ?? mesenchymal stromal cell (mMSC) PDGFR C/EBPs Zfp423 Zfp467 pre ‐ adipocyte Prx1 Pref ‐ 1 adipocyte 15

PTH Summary- Part 1 • PTH and PTHrp stimulate bone formation and resorption- Super- remodelers • Fracture efficacy established for both • PTH stimulates progenitor differentiation and glycolysis via actions on IGF-I, SOST, and Sik2 • PTH inhibits adipocyte differentiation Antibodies to Sclerostin: The Next New Anabolic? 16

Sclerosteosis Sclerostin (SOST) A member of Dan/Cerb family • Expressed in Bone…limited synthesis in non skeletal tissue – Osteocytes – Increased by BMP and during osteoblast differentiation • PTH down regulates • High affinity for BMP 6, 7 not 2 or 4 • A BMP and Wnt antagonist (binds LRP5) 17

Sclerostin Increased bone Wild Type Mouse Sclerosteosis / mass throughout van Buchem ’ s skeleton. Good quality, Normal fracture resistant bone. Photo: Janssens and Van Hul. Hum Mol Genet. 2002;11:2385 ‐ 93. Scl ‐ KO Mouse Osteocyte 18

LRP5 signaling pathway: Inactivation by Dkk proteins LRP5 Dkk1 Frizzled Dkk1 Kremen Internalization GSK-3b axin dvl A p P Degradation C b-catenin P X LRP5 signaling pathway for osteogeneiss: Canonical Pathway; SOST Blocks WNT-Lrp5 signaling SOST LRP5 Wnt Dkk1 sFRP Frizzled axin Frat1 dvl GSK-3b A P C b-catenin Osteoblast differentiation TCF-LEF nucleus Reduced Osteoclast 19

Monoclonal to Sclerostin vs Alendronate and PTH 20

Romozsozumab Reduces Fractures 21

Summary: New Anabolic Treatments • PTH builds bone by suppressing SOST, stimulating glycolysis and shifting progenitors towards OBs • Abaloparatide enters the market as a PTH like agent at lower cost and possibly greater benefit? • Monoclonal antibodies to sclerostin increase bone mass by enhancing the work of bone formation • Romosozumab works but safety has not been fully established due to potential cardiovascular risk 22