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Chap ter V.

Chap ter V. Futures Directions. Futures Directions. 73. GLP-2 Significantly Increases Hip BMD in Postmenopausal Women: a 120-Day Study (1). Change in BMD Total Hip. Change in BMD Trochanter. 102.0. 102.0. *. 101.5. 101.5. *. Total hip BMD (% of baseline).

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Chap ter V.

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  1. Chapter V. Futures Directions

  2. Futures Directions 73 GLP-2 Significantly Increases Hip BMD in Postmenopausal Women: a 120-Day Study (1) Change in BMD Total Hip Change in BMD Trochanter 102.0 102.0 * 101.5 101.5 * Total hip BMD (% of baseline) TrochanterBMD (% of baseline) 101.0 101.0 100.5 100.5 100.0 100.0 0.4 mg 1.6 mg 3.2 mg 0.4 mg 1.6 mg 3.2 mg Placebo Placebo GLP-2 Dose GLP-2 Dose * p < 0.01 La Lettre du Rhumatologue ASBMR 2007 – From Henriksen D et al., Roedovre, Denmark, abstract 1127, updated

  3. Futures Directions 1.6 mg0.4 mg Placebo3.2 mg 74 GLP-2 Significantly Increases Hip BMD in Postmenopausal Women: a 120-Day Study (2) AUC from CTx Day 1 Day 1 160 0 140 * -50 120 100 * -100 ** 80 Placebo corrected AUC (% hour) Osteocalcin (% of baseline) mean (+ SEM) -150 60 * * 40 0.4 mg1.6 mg3.2 mg -200 * p < 0.001** p < 0.05 20 0 -250 Hours 0 2 4 6 8 10 Hours 0-3 0-6 0-10 La Lettre du Rhumatologue ASBMR 2007 – From Henriksen D et al., Roedovre, Denmark, abstract 1127, updated

  4. Futures Directions Calcimimetics(activators) Calcilytics(inhibitors) Calcium receptor Cellularproliferation Hyper-Ca Hypo-Ca Nucleus 84 1 84 1 PTH VDR PTHsynthesis Vitamin D Parathyroid cell 75 Calcium Receptor: Primary Regulator of Parathyroid Cell Functions La Lettre du Rhumatologue ASBMR 2007 – From Nemeth E, Toronto, Canada, Symposium D, updated

  5. Futures Directions 76 Calcium Receptor Antagonist SB-423557 used to Induce Bone Formation (1) Calcium sensing receptor Rat * 40 Ca++ 5 mg/kg * 15 mg/kg Ca++ AntagonistSB-423557 * 30 * 50 mg/kg * Vehicle PTH 1-84 (pM) 20 * * 10 PTH 0 30 60 90 120 360 0 [Ca2+]i Time (minutes) Bone forming * p < 0.05 versus vehicle Parathyroid cell La Lettre du Rhumatologue ASBMR 2007 – From Kumar S et al., Collegeville, USA, abstract O386, updated

  6. Futures Directions 77 Calcium Receptor Antagonist SB-423557 used to Induce Bone Formation (2) Spine 5th Lumbar vertebrae * 40 110 ** ** ** 30 105 * Ultimate strength(N/mm²) Lumbar BMD - % Week 6 20 * 100 10 95 90 0 PTH PTH Ovx Ovx Sham Sham SB-423557 SB-423557 * p < 0.1, ** p < 0.05 versus Ovx • Treatment with a CaR antagonist results in transient PTH release in multiple species and positive bone-forming effect in the rat La Lettre du Rhumatologue ASBMR 2007 – From Kumar S et al., Collegeville, USA, abstract O386, updated

  7. Futures Directions 78 Anabolic Effect of Sclerostin Antibody Treatment in Ovariectomized Rat: Tissue Level Mechanism Anti-sclerostin monoclonal antibody (Scl-mAb) turned quiescent surface into remodeling-based formation surface Sham Ovx Ovx+ScI-mAb 62.6% Quiescent surface (QS) 93.2% QS 78% QS 26% Model-Based Formation (MBF) Remodeling-Based Formation (RBF) Ovariectomized rats or sham with established osteopenia (5 months) Treated for 5 weeks, twice weekly by Scl-mAb (range dose 1-25 mg/kg, SC) Fluorescent labels to assess mineralization, bone formation and histomorphometric analysis La Lettre du Rhumatologue ASBMR 2007 – From Li X et al., Thousand Oaks, USA, abstract 1231, updated

  8. Futures Directions 79 Scl-mAb Increases Bone Mass by Stimulating Bone Formationbut not Bone Resorption in Aged Male Rats Anabolic effects in histomorphometry • Scl-mAb has not yet been evaluated in male • 16 months gonad-intact male SD rats treated by vehicle or Scl-mAb SC 2 x week (5 or 25 mg/kg) for 5 weeks 2.5 * * 2.0 1.5 Results Bone formation rate/bone surface BFR/BS (µm3/µm²/day) 1.0 • areal BMD at femur-tibia • trabecular bone volume and thickness • osteoblast but not osteoclast surface • cortical thickness,  endocortical perimeters • osteocalcin, but not CTx 0.5 0.0 Vehicle 5 25 Scl-mAb (mg/kg) * p < 0.001 vs vehicle • Scl-mAb increased bone formation without evidence of increased bone resorption La Lettre du Rhumatologue ASBMR 2007 – From LI X et al., Thousand Oaks, USA, abstract 1122, updated

  9. Futures Directions 250 200 P1NPCTX 150 100 50 0 -50 -100 0 7 14 21 28 35 42 49 56 63 70 77 84 Days 80 Anti-Sclerostin Antibody Increases Markers of Bone Formation in Healthy Postmenopausal Women (1) Large anabolic window following single SC doses of 5 and 10 mg/kg Scl-mAb to healthypostmenopausal women 5 mg/kg(n = 6) 10 mg/kg(n = 6) 250 200 150 100 % change from baseline(Mean + SEM) % change from baseline(Mean + SEM) 50 0 -50 -100 0 7 14 21 28 35 42 49 56 63 70 77 84 Days La Lettre du Rhumatologue ASBMR 2007 – From Padhi D et al., Thousand Oaks, USA, abstract 1129, updated

  10. Futures Directions 28 56 84 28 56 84 81 Anti-Sclerostin Antibody Increases Markers of Bone Formation in Healthy Postmenopausal Women (2) Single doses of Scl-mAb resulted in an increase in BMD in healthy postmenopausal women Spine Total Hip 7 6 5 4 3 2 Mean (%) change from baseline 1 0 -1 Placebo (n = 7) 5 mg/kg (n = 6) 1 mg/kg (n = 6) -2 10 mg/kg (n = 6) 3 mg/kg (n = 6) -3 Days Days La Lettre du Rhumatologue ASBMR 2007 – From Padhi D et al., Thousand Oaks, USA, abstract 1129, updated

  11. Futures Directions Pituitary Activin Inhibin FSH Ovary 82 ACE-011- A Soluble Activin Receptor Type IIA: a New Therapeutic Agent (1) • Activin A is a member of the TGFβ superfamily, highly expressed in bone • Its role in bone metabolism remains controversial • promotes osteoclastogenesis • inhibits bone matrix mineralization • overexpression of inhibin A (an activin antagonist) increases bone mass and strength • It was first identified by its ability to stimulate release of FSH by the pituitary ASBMR 2007 – From Ruckle J et al., Honolulu, USA, abstract 1132, Fajardo RJ et al., Boston, USA, abstract 1230, Rosen E et al., Boston, USA, abstract 1233, updated La Lettre du Rhumatologue

  12. Futures Directions 83 ACE-011- A Soluble Activin Receptor Type IIA: a New Therapeutic Agent (2) • ACE-011 is a soluble activin receptor type II fusion protein which inhibits activin • Biweekly dosing of 10 mg/kg SC in monkeys • increases total and distal femur BMD (DXA and QCT) • improves vertebral trabecular architecture and strength • has no action on cortical bone • doesn’t change bone remodeling markers • In ovariectomized mice • increases bone volume, trabecular number and bone formation rate without enhancing bone resorption • bone response differs from zoledronate and PTH RAP-011 Total body BMD(% change from tmt baseline) 14 ** PTH 10 * RAP-011 6 * ZOL SHAMVEH 2 -2 0 3 6 Weeks * p < 0.05 versus VEH; ** p < 0.05 versus ZOL ASBMR 2007 – From Ruckle J et al., Honolulu, USA, abstract 1132, Fajardo RJ et al., Boston, USA, abstract 1230, Rosen E et al., Boston, USA, abstract 1233, updated La Lettre du Rhumatologue

  13. Futures Directions 84 Effects of Cyclic and Daily PTH in Combination with OPG (1) • In humans: conflicting results regarding the association of PTH and bisphosphonates • Aim of the study: to test the association of PTH with another inhibitor of bone resorption, the OPG, on bone density or bone quality • C57 BL mice, 20 week-old, treated for 7 weeks by: – vehicle: daily injection SC – OPG: 10 mg/kg/day, 2 days/week – daily PTH (D-PTH): hPTH (1-34) 40 µg/kg/day, 7 days/week – cyclic PTH (C-PTH): daily PTH 7 days and daily vehicle 7 days alternatively – D-PTH + OPG: daily PTH + OPG 2 days/week – C-PTH + OPG: cyclic PTH + OPG 2 days/week 7 weeks : BMD, p-QCT, blood samples, bone strength La Lettre du Rhumatologue ASBMR 2007 – From Lida-Klein A et al., New York, USA, abstract 1125, updated

  14. Futures Directions 85 Effects of Cyclic and Daily PTH in Combination with OPG (2) OPG and PTH on Femoral Strength after 7 Weeks of Treatment (N) Maximun Load p < 0.05 50 40 30 Mean + SD 0 Control OPG D-PTH C-PTH DP + OPG CP + OPG La Lettre du Rhumatologue ASBMR 2007 – From Lida-Klein A et al., New York, USA, abstract 1125, updated

  15. Futures Directions 86 Barrier Site Metabolism of Vitamin D: A Mechanism for Protection Against Inflammatory Bowel Disease (1) • 1,25(OH)2D3 is known to be an immunomodulator • suppression of adaptative T-cell responses and induction of innate antibacterial activity in macrophages • both effects depend on localized synthesis of 1,25(OH)2D3 via theenzyme1-hydroxylase (CYP27b1) • in Crohn’s disease, 1,25(OH)2D3 variations have been reported in humans (Abreu et al. 2004) • Hypothesis: autocrine/paracrine 1,25(OH)2D3 is crucial to innate and adaptative immune responses at barrier sites (contact with pathogen-associated molecular pattern) • Mouse model of Crohn’s disease by injection of DSS BL6 mouse wild type or knockout for CYP27b1 Analysis of RNA, colonic tissue sections and vitamin D serum assay La Lettre du Rhumatologue ASBMR 2007 – From Wu S et al., Los Angeles, USA, abstract 1029, updated

  16. Futures Directions 12 *** Histology score 8 4 0 C DSS C DSS +/- -/- 87 Barrier Site Metabolism of Vitamin D: A Mechanism for Protection Against Inflammatory Bowel Disease (2) Dysregulated Vitamin D Metabolism with DSS-induced colitis: role of CYP27b1 • Vitamin D protects against the onset of inflammatory bowel disease Expression of CYP27b1 is crucial for this protective effect A B Serum 25 OHD3 Serum 1.25 (OH)2D3 80 Male Female 30 Male Female *** ** 60 20 Serum 1.25 (OH)2D3(ng/ml) Serum 25 OHD3(ng/ml) 40 10 20 0 0 C DSS C DSS C DSS C DSS C D CYP27b1 Disease histology *** p = 0.003 ** p = 0.01 6 *** 4 Fold change mRNA 2 0 C DSS DSS C Proximal colon Distal colon La Lettre du Rhumatologue ASBMR 2007 – From Wu S et al., Los Angeles, USA, abstract 1029, updated

  17. Futures Directions 88 Accelerated Bone Resorption due to Dietary Calcium Deficiency Promotes Tumor Growth in a Murine Model of Breast Cancer Bone Metastasis Low dietary calcium increases bone lytic lesion area • Increased bone turnover due to dietary calcium deficiency promotes tumor growth in bone, independent of the action of PTH X-ray Bone lytic lesion at 17 days Micro-CT Normal-Ca Low-Ca Normal-Ca OPG Low-Ca OPG La Lettre du Rhumatologue ASBMR 2007 – From Zheng Y et al., Sydney, Australia, abstract 1006, updated

  18. Futures Directions 89 Intermittent PTH Inhibits Development and Progression of Myeloma (1) • Multiple Myeloma (MM) is associated with suppression of osteoblastogenesis Increased osteoblast activity and bone formation inhibits MM growth (Yaccoby et al., Haematologica 2006) • Aim of the study • to investigate the effects of intermittent PTH on bone remodeling and MM growth • to study the consequences of PTH pre-treatment on MM development and progression • Myeloma SCID-rab mice ; PTH treatment at 0.3 mg/kg/d SC, 4-6 weeks La Lettre du Rhumatologue ASBMR 2007 – From Pennisi A et al., Little Rock, USA, abstract 1172, updated

  19. Futures Directions 1,500 1,000 Ig (% change) 500 0 400 Control PTH CONT 300 PTH 200 Ig (µg/ml) 100 0 -6 -4 -2 0 2 4 6 Weeks of Treatment 90 Intermittent PTH Inhibits Development and Progression of Myeloma (2) PTH Inhibits Myeloma Progression CONT p < 0.04 PTH • PTH has a bone anabolic effect in MM • the bone anabolic effect of PTH is associated • with reduced MM growth • Pre-treatment with PTH delays MM progression La Lettre du Rhumatologue ASBMR 2007 – From Pennisi A et al., Little Rock, USA, abstract 1172, updated

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