Beyond Bisphosphonates: Future Osteoporosis Therapies

Transcription

1 Beyond Bisphosphonates: Future Osteoporosis Therapies Clifford Rosen MD 1

2 No Conflicts of Interest 2

3 Outline What s the evidence for bisphosphonates and why not? Clinical trials with bisphosphonatesfracture efficacy Sub trochanteric fractures- Where do we go from here What s beyond bisphopshonates? CatK, Anabolics 3

4 Bisphosphonates: For Whom and For How Long? 4

5 Hip Fracture Rates are Leveling Off or Increasing while Dx and DXA testing has declined 5

6 Bisphosphonate Scripts in the US Over the last 2 decades have declined precipitously AFF first reports alendronate 6

7 How Do Bisphosphonates Work? 7

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9 Studies of Long Term Bisphosphonate Use (BMD primary endpoint) Study Drug Design N Follow-up years Notes FIT Long- Term Extension (FLEX) Alendronate (5 & 10 mg/day) Randomized, blinded trial =10 HORIZON- PFT Ext. Zoledronic acid (5 mg/year) Randomized blinded trial =6 Risedronate Risedronate weekly Observation al study =9 Small, nonrandomized, adherent only 9

10 Design of the FIT Long-Term Extension of Alendronate (FLEX)* FIT N = 6,459 Placebo N = 3,223 Alendronate N = 3,236 Primary endpoint: Change in hip BMD FIT (3 to 4.5 yrs) Post-FIT (1-2 yrs) Randomized in FLEX N = 1,099 FLEX (5 yrs) Placebo N = 437 Alendronate, 5 mg N = 329 Alendronate, 10 mg N = % 30% 30% * Black, et al, JAMA 12/

11 Total Hip BMD: Mean % Change from FIT Baseline Mean Percent Change FIT 3 to 4.5 yrs F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 FIT FLEX FIT/FLEX Recess 5 yrs 1 to 2 yrs Start of FLEX Year = Placebo = ALN (Pooled 5 mg and 10 mg groups) FLEX P<0.001 ALN vs PBO 2.8% 11

12 Fracture Incidence (Exploratory Endpoint) In FLEX Vertebral Clinical Clinical Any Non-vertebral PBO (N = 437) 5% Morphometric 11.3% 22% 20% ALN (N = 662) RR (95% CI) 2% 9.8% 21% 19% 0.45 (0.2, 0.8) 0.86 (0.6, 1.2) 0.93 (0.7, 1.2) 1.00 (0.8, 1.4) Hip 3% 3% 1.02 (0.5, 2.3) * Black, et al, JAMA 12/

13 Survival Curve for Time to First Nonvertebral Fracture in FLEX Cumulative Incidence, % Placebo ALN (pooled) Time to First Fracture, years RH=1.00 (0.76, 1.32) 5 F = FIT, FL = FLEX. Black DM et al. JAMA. 2006;296:

14 HORIZON Extension Study Design Similar to FLEX extension 3 years of annual ZOL, then randomized to either: 3 more years of ZOL (6 years, Z6) 3 years of PBO (Z3P3) 14 14

15 Fracture Results in HORIZON PFT Extension: 3 more years of ZOL Vertebral Clinical Morphometric 6% Non-vertebral Z3P3 (N = 616) 0.7% Z6 (N = 617) RR (95% CI) 1.2% 3% 1.8 (0.5, 6.2) 0.48 (0.3, 0.9) Non-vertebral 7.6% 8.2% 0.99 (0.7, 1.5) Hip 1.4% 1.3% 0.90 (0.3, 2.5) * Black, et al, JBMR

16 SUMMARY Long term effect of bisphosphonates before and after drug holiday. Alendronate Risedronate Zolendronate years years year 0-4 PL 21 % AL 11 % 0-3 PL 32% Ris 20% 0-3 PL 20% Z 10% 5-10 AL/AL 18 % Al/PL 17 % 4-5 R/R 19% PL 32% 4-6 Z/Z 9% clinical Z/P 12% ZZ 3% morph Z/P 6% 6-7 R/R 13% 0-9 Z/P 9% clin Z9 12% NNT Z/P 7% morph Z9 4% ns Sub group analysis! 16

17 Summary of Vertebral Fracture Reductions for FLEX and HORIZON Bisphosphonate benefit Relative Risk (Bis vs. PBO) 17

18 What are Atypical Femoral Fractures Most commonly observed in the proximal one-third of the femoral shaft Typically occur as a result of no or minimal trauma (fall from a standing height or less) May be incomplete, manifested by a transverse radiolucent line in the lateral cortex Complete AFFs are generally transverse Complete and incomplete fractures are commonly associated with a periosteal stress reaction and thickening of the lateral cortex at the fracture site Healing may be delayed On X-ray, presentation of an AFF appears similar to a stress fracture or a pseudofracture 18

19 Balancing Benefit vs Risk 19 19

20 Cortical Beaking pre- Sub Troch Frx 20

21 Signs and Symptoms of AFF Approximately 70% of patients with confirmed stress fracture report prodromal pain in the thigh or the groin several weeks prior to the diagnosis Pain can be anywhere from aching to sharp, generally in the thigh bone but occasionally in the groin Approximately 25% of patients with AFF have simultaneous or sequential bilateral fractures AFFs often occur in the setting of comorbid conditions with known adverse events on bone quality including glucocorticoid therapy or vitamin D deficiency Pain is exacerbated on weight bearing 21

22 AFF Incidence Rate The overall incidence of hip fracture is 103 per 10,000 person-years In the SOF (Study of Osteoporotic Fractures), the incidence of subtrochanteric fractures was very low at 3 per 10,000 personyears The highest incidence rate comes from preliminary estimates from a large US HMO survey indicating the incidence of AFF increases progressively from 2 per 100,000 cases per year with 2 years of BP use to 78 per 100,000 cases per year with 8 years of BP use In the SOF, predictors of subtrochanteric hip fracture are: Older age Lower total hip BMD A history of falls AFF can occur in the absence of BP exposure 22

23 Genetic Screening for AFFs 23

24 Prevention of fractures with bisphosphonates (3 years treatment) Type of fracture NNT Events prevented per 1000 pts Any non-vertebral fracture (Hip only) Vertebral fx Any fracture 100 Subtrochanteric/diaphyseal fractures Hypothetical RR for subtroch NNH Events associated with 1000 pts treated

25 Discontinuation of other Bisphosphonates Similar residual effects for Alendronate (>5 years) and Zoledronic Acid (>3 years) Limited data Risedronate suggests faster resolution of effect No data on ibandronate Results cannot be generalized to risedronate and ibandronate 25

26 Bottom Line: - After 5 years of alendronate: - Many women can discontinue with little loss of efficacy - Those at higher risk of vertebral fracture may benefit by continuation; these are: - Women with FN BMD below Women with existing vertebral fractures and somewhat higher BMD (up to -2.0) - Cannot generalize to risedronate or ibandronate - Need more info for efficacy (and risks) 26 26

27 Beyond Bisphosphonates Anti Catabolic Therapy -Odanticab Anabolic Therapy -PTHrp -PTH light -Sclerostin monoclonal Others 27

28 Bone Remodeling Goes Both Ways NTx D-Pyr CTx RANK RANK-L(OPGL) M-CSF Wnt 10b IGF-I IGFBPs OPG IL-1, PTH, IL-6, E2, IGF-I OC H + Collagen α v β 3 BMP,S1P Proteases Osteocyte COOH Osteocalcin Matrix Tgf-β Sclerostin - OB IGFs IGF-BPs TGFs LRP5,6 Osteocalcin BSAP PICP Resorption Formation 20 Days 100 Days 120 Days

29 WAYS TO TARGET THE OSTEOCLAST Cathepsin K is highly expressed in the osteoclast, where it is localized in the lysosomes and released during bone resorption. Rodan & Duong. BoneKey 2008 Odanacatib is a selective, non-basic inhibitor of Cathepsin K with minimal metabolism and an excellent pharmacokinetic profile

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31 Cathepsin K Deficiency Pycnodysostosis is a genetic disease associated with cathepsin K deficiency (Gelb,et al.,1996; Schilling et al 2007) Rare autosomal recessive skeletal dysplasia ~150 cases of pycnodysostosis reported worldwide Short stature, acrosteolysis of distal phalanges and large fontanelles High bone mass and increased fragility associated with high risk of fracture Normal intelligence, sexual development and lifespan Bone formation normal or high Cat K null mice have osteopetrotic phenotype, but otherwise healthy; bone formation is increased Frontal bossing Schilling et al 2007

32 Cathepsin K inhibitors Acid still dissolves hydroxyapetite Inhibition prevents loss of collagen Costa et al. Nat Rev Rheum 2012:73

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34 Blocking Cathepsin K produces shallow resorption pits OC Normal resorption leaves deep pits Normal P Blocking Cat K leaves shallow areas of resorption OC Cat K inhibited P Osteoclast number is increased Signals to the OB are not impaired

35 Odanacatib Normal Osteoclasts resorb less Osteoblasts form bone Greater gain in BMD Lotinun, Clin Invest. 2013

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39 Biochemical Markers at 18 Months Geometric Mean Percent Change from Baseline at Month Bone Resorption Bone Formation u-ntx s-ctx s-bsap s-p1np Placebo ODN 3 mg ODN 10 mg ODN 25 mg ODN 50 mg

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42 Continuous treatment with odanacatib for up to 8 years in postmenopausal women with low bone mineral density: a phase 2 study Rizzoli, OI 2016

43 The LOFT TRIAL:Odantacatib vs PBO 16,000 subjects enrolled in 3yr trial; finished 5 yr extension, PBO vs OD Spine BMD -2.7, FN BMD -2.7, 46% had vert frx OD: 52% reduction in vert frx, 48% reduction in hip fracture, 25% in non-vert frx, 67% reduction in clin vert frx BMD increase at year 5 for OD: 10.9% LS, 10.5% Total hip But AFF present in 0.3% of OD and only 0.1% for PBO; adjudication resulted in AFF in OD (10) and 0 in PBO Significantly greater risk of fatal stroke from TIMI adjudication

44 Antibodies to Sclerostin: The Next New Anabolic?

45 Two Recent Scientific Advances Wnt Signaling Pathway Osteocyte Biology 45

46 LRP5 signaling pathway for osteogeneiss: Canonical Pathway; SOST Blocks WNT-Lrp5 signaling SOST LRP5 Wnt Dkk1 Frizzled sfrp axin Frat1 dvl b-catenin TCF-LEF GSK-3b A P C nucleus Osteoblast differentiation Reduced Osteoclast

47 LRP5 signaling pathway: Inactivation by Dkk proteins LRP5 Kremen Dkk1 Dkk1 Frizzled Internalization Degradation P axin p b-catenin GSK-3b A P X C dvl

48 Sclerosteosis

49 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)

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

51 Monoclonal to Sclerostin vs Alendronate and PTH

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53 Romozsozumab Reduces Fractures

54 PTH1R Agonists That Activate the Anabolic Program

55 Phase 2 Results Show Continued Strong Improvement in Spine BMD at 48 Weeks Spine BMD: % Change from Baseline, Mean (SE), Extended Population (n=55)

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59 Summary: New treatments There are newer approaches to treating osteoporosis besides the bisphosphonates CatK inhibitors suppress bone resorption, increase BMD, and may reduce fracture risk There may be less inhibition of bone formation Monoclonal antibodies to sclerostin increase bone mass by enhancing bone formation This biologic therapy has the potential to be the second anabolic approach for osteoporosis; however safety has not been established yet Abaloparatide may soon enter the market as another anabolic

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61 Summary: Sclerostin Human genetics: Increased bone density, thick cortices in --Sclerosteosis: All null mutations in Sclerostin --Van Buchem: LRP5 mutation or a deletion with decreased Sclerostin expression (Brunkow et al, 2001;Balemans et al. 2002;Loots et al., 2005) -- Heterozygotes have high bone mass (Gardner et al.,2006) Mouse genetics: Targeted overexpression in osteoblasts: osteopenia (Van Bezooijen et al., 2004) Targeted overexpression in osteocytes: osteopenia (Winkler et al., 2006)

62 SCLEROSTIN Expression RESTRICTED to Osteocytes! Mechanism of action: *Binds to BMPs and/or to LRP5 and 6 (Li et al. 2005; Van Bezooijen et al., 2004) Pharmacology: *Sclerostin expression repressed by PTH (Keller and Kneissel, 2005; Bellido et al., 2005) *Neutralizing antibodies increase bone mass and cortex in rats (Winkler et al., 2005; Warmington et al, 2005)

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64 Wnts and their actions on bone

65 Wnt and Wnt Co-Receptors,LRP5-6 OB Receptors 1. Wnt canonical and noncanonical signaling pathways are important for mediating effects of Wnt in bone. 2. Lipoprotein-related receptors: LRP 5 and LRP 6 (~ 1,600 amino acids) are co-receptors for the frizzled family of Wnt transmembrane receptors that when activated, increase OB function 3.LRP s have an extracellular domain which is anchored to the plasma membrane which is attached to a cytoplasmic domain via strings of amino-acids. 3. LRP s regulated by a large number of extracellular proteins, especially sclerostin and the Dkk family that inhibit LRP signaling and OB function (myeloma cells secrete DKK1) and are activated by Wnt and/or PTH Williams BO and Insogna KL JBMR 2009; 24:

66 Inhibition of Cathepsin K: Odanacatib: Phase II- randomized, double-blind, placebo-controlled trial Extension of Phase 2 dosing study of Odanacatib, a Cathepsin K inhibitor Doses: Placebo, 3, 10, 25, 50 mg Primary Hypothesis: LS BMD after 18 and 24 months will be greater with drug than with placebo 320 women, mean age: 64 ± 7.8 Other end points: bone turnover markers Data from 18 month analysis and extension period McClung MR et al. Calcif Tissue Int 2008;82:S53.

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68 Odanacatib Protocol 031 Study Design Postmenopausal women age Odanacatib 50 mg + Vitamin D IU OW No previous hip fx at any time No previous non-hip clinical fragility fx within 24 months Not >1 prior clinical vertebral fx Screening period R Placebo + Vitamin D IU OW T-Score <-1.5 but >-3.5 at hip or spine, confirmed by DXA Month clinic visits (Screening & Months 0, 6, 12, 18, 23, 24) + follow up phone call 2. Efficacy measurements [abmd by DXA, vbmd by QCT (hip and spine) and HRpQCT (radius and tibia), FEA, BMx of bone turnover, subset of bone biopsies] 3. Safety measurements (AEs, safety labs, physical exam)

69 PN 031- Change in s-ctx (pg/ml): Bone Resorption Per-Protocol Population Geometric LS Mean Percent Change (±SE) = P<0.001 Baseline Month 6 Month 12 Month 18 Month 24 ODN 50 mg OW N=74 Placebo OW N=78 Time

70 Phase 2 Results Show Faster and Greater BMD Improvements Across Critical Vertebral and Non- Vertebral Sites Results Demonstrate BA058-SC Safety Profile and Robust Anabolic Effect at 24 Weeks Mean % Change BA058-SC 80 µg* FORTEO 20 µg* Spine BMD 6.7% 5.5% Hip BMD 2.6% 0.5% *n=221 Safe and well-tolerated 50% reduction in occurrence of hypercalcemia vs. Forteo at highest dose

71 PN 031- Change in s-p1np (ng/ml): Bone Formation Per-Protocol Population Geometric LS Mean Percent Change (±SE) = p=0.225 Baseline Month 6 Month 12 Month 18 Month 24 ODN 50 mg OW N=76 Placebo OW N=80 Time

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73 Protocol 004 Bone Biopsy Data at Year 2 Preliminary transilial biopsies (N=27) indicate no significant effect on bone remodeling at the 2-year biopsy time point. Placebo Odanacatib Variable units N=6 3mg N=7 10mg N=5 25mg N=6 50mg N=4 Bone Formation Rate (surface) Activation Frequency Osteoclast Surface/ Bone Surface Mineralizing /Osteoid surface Mineralization Lag Time mm 3 / mm 2 /d 0.037± ± ± ± ±0.014* /yr 0.50± ± ± ± ±0.17* % 0.62± ± ± ± ±0.20 % 63±18 82±22 54±11 63±11 43±25 days 27±8 18±3 19±5 15±2 32±12 All values are mean ± standard error; *N=3 for these endpoints in this group Bone et al, JBMR 25, May 2010

74 Odanacatib increased cortical thickness in the femoral neck and shaft Ovariectomized monkeys treated for 21 months Cortical thickness (mm) Vehicle ODN 30 mg Cusik et al. JBMR 2012;27:524

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76 PN004- Urinary N-Telopeptides/Creatinine Ratio at 5 years Per Protocol Population u-ntx/cr Ratio (nmol/mmol) % Change from Baseline (Geometric Mean ± SE) mg = odanacatib 50 mg OW PBO = placebo OW Month PBO/PBO 50 mg/50 mg/50 mg 50 mg/pbo/pbo ASBMR 2011 abstract 76

77 Serum N-Terminal Propeptides of Type 1 Collagen at 5 years Per Protocol Population 100 s-p1np (ng/ml) % Change from Baseline (Geometric Mean ± SE) mg = odanacatib 50 mg OW PBO = placebo OW Month PBO/PBO 50 mg/50 mg/50 mg mg/pbo/pbo ASBMR 2011 abstract 77

78 Effects of Anti-resorptive Agents on Bone Remodeling Not a head-to-head comparison % decrease from baseline of serum CTX and serum BSAP at 24 months Alendronate 1 Denosumab 1 Odanacatib 2 CTX-s BSAP-s 1. Lewiecki EM et al. J Bone Miner Res. 2007;22: McClung MR, et al. ASBMR 2008, Abstract

79 Protocol 031 Bone Biopsy Endpoints at Year 2 Full-Analysis-Set Population Mean (SD) Odanacatib 50 mg OW N = 109 Placebo OW N = 105 Bone Biopsy Endpoint n = 5 n = 5 Osteoid Thickness, micron 5.06 (1.07) 5.60 (0.85) Mineral Apposition Rate, micron/day 0.58 (0.05)* 0.56 (0.10) Mineralizing Surface, % 5.52 (5.88) 6.32 (4.22) Mineralization Lag Time, day (23.88)* (36.63) Bone Formation Rate, Total Volume Referent, %/yr (16.29)* (13.94) Bone Formation Rate, Total Surface Referent, micron 3 / micron 2 / day 0.04 (0.03)* 0.03 (0.02) Eroded Bone Surface, % 1.90 (1.32) 1.66 (1.13) Activation Frequency /yr 0.47 (0.38)* 0.50 (0.30) Mean Cortical Thickness, micron (183.69) (164.47) *n=4 Oral presentation- ECCEO

80 Putative mechanisms of action of strontium ranelate on bone cells. Hamdy N A T Rheumatology 2009;48:iv9-iv13 The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 80

81 Data from RPCTs: SR and Fractures Two Large RPCTs : TROPOS and SOTI SOTI: 1600 postmenopausal women- prevalent vertebral fractures and low BMD mean age 69: Primary efficacy- vertebral fractures; Risk Reduction: 38-41% for new morphometric or clinical fracture No risk reduction for hip or non-axial fractures TROPOS: 5091 postmenopausal women: mean age- 77 years: T- score <-2.5 in the femoral neck; 60% prevalent fracture: primary efficacy non-axial fractures Risk reduction:0.85 ( ) Secondary analysis T score <-2.5 and prevalent vert frx: Hip fracture RR: 0.64 ( ) 81

82 Proteolytic Pathways of Bone Collagen Degradation ICTP/CTx NTx 1-CTP is C-terminal peptide of Col I generated by MMPs 1-CTP is cleaved by Cat K to generated CTX-I Inhibition of Cathepsin K leads to accumulation of serum 1-CTP Garnero et al., J. Biol.Chem

83 BA058-SC (apthrp): Phase 2 Clinical Trial Design Randomized, parallel-group, placebo-controlled, comparator-controlled, Phase 2 Dose-finding study Statistically powered for the major efficacy outcomes of BMD change Study sites in USA, Argentina, India and UK All patients received concomitant Vitamin D and Calcium (4 weeks prior to treatment through treatment period) Treatment Regimen Study Medication Daily Dose (SC) Number of Patients 1 BA058-SC 20 µg 45 2 BA058-SC 40 µg 43 3 BA058-SC 80 µg 43 4 FORTEO 20 µg 45 5 Placebo 45 Total 221

84 The Wnt/β-catenin Signaling System Krishnan et al., J Clin Invest ; 2006

85 z Phase 1 Study of Sclerostin Antibody in Healthy Postmenopausal Women Objective: Design: Study population: Exclusion criteria: Dose groups: Endpoints: Follow-up: To determine the safety and tolerability and pharmacokinetics and pharmacodynamics (i.e., bone turnover markers, BMD) of sclerostin antibody in healthy postmenopausal women Randomized, double-blind, placebo-controlled, rising, single dose study 48 healthy postmenopausal women Not receiving estrogens, SERMS, calcitonin, PTH, > 1000 IU Vitamin D daily, anabolic steroids, glucocorticoids within 6 months; nor bisphosphonates or fluoride within 12 months; T score < to 10 mg/kg SC Scl-MAb Safety, pharmacokinetics, bone turnover markers, BMD Up to 85 days Padhi D, et al. J Bone Miner Res. 2007;22(suppl 1):S37. Abstract 1129 and oral presentation Amgen. All rights reserved. Amgen Confidential. Do not copy or distribute.

86 Phase 1 Study of Sclerostin Antibody in Healthy Postmenopausal Women: Changes in BMD of the Spine and Total Hip Mean % Change from Baseline Spine Time (day) Total Hip Time (day) Placebo (N=7) 1 mg/kg (N=6) 3 mg/kg N=6) 5 mg/kg (N=6) Placebo (N = 7) 1 mg/kg 10 mg/kg (N = (N=6) 6) 3 mg/kg (N = 6) 5 mg/kg (N = 6) 10 mg/kg (N = 6) I would skip this saying only that there are Phase 1 results Padhi D, et al. J Bone Miner Res. 2007;22(suppl 1):S37. Abstract 1129 and oral presentation Amgen. All rights reserved. Amgen Confidential. Do not copy or distribute.

87 Phase 1 Study of Sclerostin Antibody in Healthy Postmenopausal Women: Anabolic Window Following Single SC Doses of 5 and 10 mg/kg 5 mg/kg (N = 6) 10 mg/kg (N = 6) Percent Change from Baseline (Mean ± SEM) P1NP CTX Percent Change from Baseline (Mean ± SEM) Time (day) Time (day) I would skip this except to say very strong analbolic effects Padhi D, et al. J Bone Miner Res. 2007;22(suppl 1):S37. Abstract 1129 and oral presentation Amgen. All rights reserved. Amgen Confidential. Do not copy or distribute.

88 Odanacatib: 4 Year Data Primary Endpoint: Lumbar Spine BMD (L1 to L4) % Lumbar Spine BMD (gm/cm 2 ) % Change from Baseline (Mean ±SE) % 0.4% 50 mg/50 mg/50 mg 50 mg/pbo/pbo PBO/PBO/50 mg Month Data for all women who entered year 4 extension. Last Observation Carried Forward Binkley N et al ASBMR 2010

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90 Once Weekly PTH- BMD end point Telephone Screening N=348 Screening Visit 1 N=103 Screening Visit 2 N=52 Randomization N=50 Excluded=245 Excluded=51 Excluded=2 PTH N=25 Placebo N=25 Complete N=25 Complete N=24 Discon (AE) N=1 Black et al, 2008, JCEM

91 Mean change Spine abmd (%) PTH once Weekly Increases L-S BMD-2% POWR Placebo 2.1% Month Month POWR Placebo 3.8% Mean change Trabecular Spine vbmd (%) Mean change Hip abmd (%) POWR Placebo 0.04% Month Month POWR Placebo -0.4% Mean change Integral Femur vbmd (%)

92 Biochemical Markers of Bone Turnover with PTH once weekly Mean Change CTX (%) Month POWR Placebo Mean Change P1NP (%) Month POWR Placebo

93 PTH once weekly Fracture Trial-56ug: 1-34 Nakumara, 2012

94 Biological Roles of Mammalian Cysteine Cathepsins Epidermal Homeostasis L Pro-enzyme Activation B, C Apoptosis S, B Cysteine Cathepsins Cancer growth, metastases B, L, S, H Antigen Presentation L, S, V Bone Resorption K

95 Is osteoclast signaling to osteoblasts maintained during odanacatib exposure? PGE2 NO osteocytes Mineralized bone Morris Manolson, Toronto, ON ICOBR, 2008 Beijing, China, Oct. 23, 2008 osteoblast R. Schenk Osteoid (non-mineralized bone) Osteoclast

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97 Sclerostin binds LRP4,5,6 and blocks Wnt signaling Wnt signaling in bone More bone formation Blocks Wnt signaling in bone Less bone formation FZD Wnt LRP5 Wnt Scl LRP5 Scl = sclerostin FZD = frizzled receptor LRP5 = low-density lipoprotein receptor-related protein 5