UPDATE ON OSTEOARTHRITIS

Transcription

1 UPDATE ON OSTEOARTHRITIS Nancy E. Lane, MD Director of the Center for Musculoskeletal Health Endowed Professor of Medicine, Rheumatology, Aging University of California at Davis School of Medicine Sacramento, California Affiliated Faculty Department of Epidemiology and Biostatistics UCSF, San Francisco, California

2 Conflicts Consultant for Samumed, Regeneron, and Interhealth

3 Management of OA If there is an illness for which people offer many remedies, you may be sure that particular illness is incurable, Leonid Andreevich Gayev, The Cherry Orchard, Anton Checkov

4 Lecture Outline New Science of chondrocytes Translational studies of novel treatments and imaging Review Clinical papers over past year Some thoughts on future therapies

5 Molecular Mechanism of Mammalian Circadian Clock Molecular Mechanism of the Mammalian Circadian Clock Glossan et al, Biogenrotology 2015

6 Control of Tissue Circadian Rhythm is Through the SCN

7 Age Related Decline in Circadian Amplitude in Cartilage Tissue Explants Adampted fro Glossan et al 2013

8 Age-Related Imbalance of Chondrocyte Clock Function Adampted from Gossan Biogerontology 2015

9 Radiographic Knee OA

10 Time of acute knee Injury Anterior Cruciate Ligament Rupture

11 Post-traumatic Injury Model of OA After an ACL injury, longitudinal follow-up of patients reveals increased incidence of knee OA, yrs earlier than age similar controls Small animal models of ACL injury have been developed and ex-vivo histologic and imaging changes can be followed over time However, in vivo imaging of the joint tissues has been a challenge due to limitations of the imaging modalities.

12 Kartogenin Treatment Prevented Joint Degeneration in a Rodent Model of Osteoarthritis J Orthop Res Feb 19. doi: /jor [Epub ahead of print] Center for Musculoskeletal Health

13 Kartogenin Stimulates Mesenchymal Stem Cells to Differentiate into Chondrocytes Kartogeninwas identified By an image-based high-throughput screen. Kartogenin promotes Chondrocyte differentiation From MSCs in vivo and was Somewhat chondroprotective.,

14 KGN induces chondrocyte differentiation from hmscs and protects articular chondrocytes in vitro Kristen Johnson et al. Science. 2012;336:

15 KGN promotes cartilage repair in collagenase VII and surgeryinduced OA models in mice Kristen Johnson et al. Science. 2012;336:

16 Does Kartogenin prevent both cartilage and subchondral bone changes in an injury model of OA?

17 7T small animal MRI at UCSF

18 CARTILAGE COMPOSITION MR Relevant Hydration Collagen Proteoglycan Calcification MR measures T 2 Diffusion T 1ρ dgemric Sodium MR gagcest Source: Junqueira LC, et. Al. Basic Histology: Text and Atlas,

19 9.5mm 80

20 T2 vs. Histology (Toluidine Blue)

21 T1rho vs. Biochemistry and histology T1rho z score = (T1rho -Mean control )/SD control Cheng J, et al, OARSI 2007

22 Results T 1ρ and T 2 maps showed focal areas of proteoglycan loss in OA and KGN treated knee at 3 weeks after surgery.

23 Effect of KGN on cartilage T1ρ values T1ρ T1ρ OA vs control KGN vs OA

24 Effect of KGN on cartilage T2 values T2 T2 OA vs control KGN vs OA

25 Effect of KGN on COMP and CTX-I Increased cartilage and bone turnover in OA and KGN compared to control. Decreased cartilage and bone turnover in KGN compared to OA. * OA vs control # OA vs KGN + KGN vs control

26 Effect of KGN on Subchondral bone SCB sclerosis (white arrow), SCB plate breach (red arrow) and bone loss in OA. Intact SCB in KGN compared to OA.

27 Effect of KGN on Cartilage Histology section of tibia from a control, OA and KGN treated knee joint at 12 weeks. OA knee joint showed fibrillation, vertical fissures and delamination. The subchondral plate was fractured that lead to a cellular bone marrow, which was replaced by loosely arranged fibrous tissue surrounded by sclerotic bone as indicated by arrow. KGN treated knee joint showed intact articular cartilage and subchondral plate, without cysts or subchondral bone loss.

28 Conclusions KGN prevented cartilage degradation and also prevented subchondral trabecular bone loss. KGN decreased cartilage turnover and bone turnover rate. KGN is a potential disease modifying drug for OA. Further analyses are needed to determine the mechanisms through which KGN exerts its effects on MSCs.

29 What next? Jiang Y, Tuan RS. Nat Rev Rheumatol Apr;11(4): Does KGN prevent cartilage degradation by activating cartilage stem/progenitors cells (CPMCs) to differentiate into the cartilage?

30 Figure 1 Identification and stem-cell-like properties of CSPCs Jiang, Y. & Tuan, R. S. (2014) Origin and function of cartilage stem/progenitor cells in osteoarthritis Nat. Rev. Rheumatol. doi: /nrrheum

31 Osteoarthritis of the Hip As Cartilage deteriorates Bone Proliferates

32 Wnt Signaling Pathway Bone: B-catenin gets into nucleus bone formation Is stimulated Cartilage: B=cateinin gets into nucleus MMP13 production Is increased and cartilage breaks down Corr, Lane, Lories A & R, 2006

33 Proposed Therapy: SM04690 Inhibiting Wnt signaling may break the cycle and shift from cartilage degeneration to regeneration SM04690 is a small molecule Wnt inhibitor in development for the treatment of OA In preclinical models, SM04690 drug product has demonstrated the following properties: Low systemic PK and no observable local or systemic toxicity Decreased inflammation Decreased cartilage degradation Regenerated cartilage 44

34 In OA, cytokines induce cartilage catabolic enzymes 1 Dose dependent inhibition of protease expression demonstrated Cellular assay human chondrocytes: TNFα + Oncostatin M SMO4690 inhibited Protease Production in Chondrocytes in vitro Induce proteases Treat Measure SM04690 or Control qpcr: MMP 1, 3, & 13 Fold change (X/unstimulated) Fold change (X/unstimulated) Fold change (X/unstimulated) Control Control Control MMP1 *** nM nM MMP3 *** nM nM MMP13 * *** *** *** nM nM * p<0.05 *** p< Samumed Data on file 1 Glyn-Jones et al. Lancet 2015

35 SM04690 Increased Cartilage Thickness in a Rat Model of OA femur Control Knee 12 weeks tibia Treated Knee (0.3µg) 12 weeks Increased Cartilage Rat ACLT+pMMx model- Anterior cruciate ligament transection (ACLT) combined with partial medial meniscectomy Inject SM04690 single dose, intra-articular after 1 week Safranin O-stained sections from the rat knee analyzed 12 weeks post-surgery for OA cartilage pathology Increased cartilage thickness after injection of SM04690 knees after 1 injection

36 Study Demographics (mitt) 0.03 mg 0.07 mg 0.23 mg Placebo N Age at Consent (Years) [Mean (SD)] 63.2 (6.6) 60.5 (5.3) 63.1 (4.9) 64.1 (5.9) BMI (kg/m 2 ) [Mean (SD)] 31.4 (4.8) 30.6 (4.8) 28.7 (5.0) 31.1 (3.4) Female [N(%)] 10 (59%) 13 (77%) 12 (75%) 6 (55%) Race [N(%)] White 14 (82%) 14 (82%) 14 (88%) 9 (82%) African-American 2 (12%) 3 (18%) 1 (6%) 2 (18%) Asian 1 (6%) 0 1 (6%) 0 Kellgren-Lawrence Grade 3 [N(%)] 7 (41%) 8 (47%) 11 (69%) 5 (46%)

37 SM Efficacy Outcomes Mean Median (N=17) (N=17) 0.07 (N=17) 0.07 (N=17) Mean WOMAC Total Change from Baseline (mitt) (N=16) PBO (N=11) Median WOMAC Total Change from Baseline (mitt) (N=16) PBO (N=11) Time (Weeks) Time (Weeks) Exploratory analysis

38 SM Efficacy Outcomes OMERACT-OARSI strict response (mitt) 100 * p= * p=0.07 Strict OARSI Responders 12 W eeks (mitt) % * 76% 56% 44% % Weeks 24 Weeks Strict OARSI Responders 24 W eeks (mitt) * 73% 50% 25% 0 PBO PBO OMERACT-OARSI strict response: 50% improvement and corresponding ) improvement in either WOMAC pain or function subscale Post-hoc analysis

39 SM04690 Safety 0.03 mg 0.07 mg 0.23 mg Placebo SAE(s) Reported 0 1* 0 0 DLT(s) Reported 0 2* 0 0 AE(s) Reported All AE(s) Reported Target Knee Arthralgia Injection site bruising Injection site pain Joint injury Joint stiffness Joint swelling Meniscus injury *Increased target knee pain (DLT) and paroxysmal tachycardia (DLT and SAE) 0.03 mg 0.07 mg 0.23 mg Placebo Subjects Reporting AE(s) [N(%)] 9 (53%) 6 (35%) 7 (44%) 6 (55%) Subjects Reporting No AE(s) [N(%)] 8 (47%) 11 (65%) 9 (56%) 5 (45%) PK All subjects in all cohorts at all time points had plasma concentrations below quantifiable limit of detection (< 0.1 ng/ml) Per protocol, all AEs deemed related to drug.

40 Summary Intra-articular treatment with a Wnt inhibitor appears to improve pain and function in knee OA subjects The treatment also appears to be safe, without significant adverse events. Phase II studies are now underway for the signs and symptoms ot knee OA, eg pain Stay Tuned!!!!!!!

41 OSTEOARTHRITIS CLINICAL YEAR IN REVIEW Nancy E. Lane, MD Director, Center for Musculoskeletal Health Endowed Professor of Medicine, Rheumatology, Aging Barton L. Wise, MD, MSc; Kie Shidara, BSc U.C. Davis School of Medicine Sacramento, California, USA

42 Purpose: To Highlight Clinical Research in Osteoarthritis Epidemiology Non-pharmacologic treatment Pharmacologic treatment Systemic Intra-articular

43 Disclaimers Narrative review Small sub-sample in this presentation The articles presented peaked my interest

44 Methods Identified 627 articles, of which, 106 were considered relevant 106 articles were then scored by 2 reviewers (KS, BW) for: (A) importance/relevance and (B) methodology 1= strong in both 2= weak in one area 3= weak in both

45 Epidemiology of Knee OA and Pain Five clinical or radiographic phenotypes of knee OA that had been identified in the OAI cohort were replicated Amsterdam OA study : Minimal joint disease ; Strong muscle strength ; Severe radiographic OA ; Obese ; Depressive mood. Treatments could be personalized. Van der Esch M, Osteoarthritis Cartilage 2015 Meta-analysis of risk factors for incident knee pain included overweight, obesity, female gender, and previous knee injury with Odds ratios ranging from Smoking was not found to be protective factor. Obesity needs to be a major target for prevention for knee pain. Silverwood V, Osteoarthritis Cartilage 2015

46 Epidemiology of Incident Knee OA: WEIGHTY ISSUES Individuals born either with low body weight or premature (preterm) have an increased risk hip replacement, HR compared to normal weight or at term births. No effect on TKR Hussain SM, Arthritis Care Res 2015 Weight loss in obese subjects (BMI> 30 kg/m 2 ) reduced medial tibial cartilage loss and improved knee symptoms while weight gain increased both. [1% weight gain reduced 1.2 mm 3 medial tibial cartilage volume]. Teichtahl AJ, Ann Rheum Dis 2015

47 Epidemiology of Knee Replacement Retinal arteriolar narrowing was associated with increased risk of knee replacement with HR of 2.0 for narrowest 2/3s subjects. These data suggest a role for microcirculation in pathogenesis of OA. Hussain SM, Osteoarthritis Cartilage 2015

48 Statistical Shape Modeling and hip OA Statistical shape modeling identifies Independent proximal hip shapes (modes) are associated with either an increase risk or decreased risk of incident hip OA. However, to date all the shape modeling has only been done in individual cohorts so we do not know if the shapes that influence hip OA development are the similar across cohorts Lynch et al J. Rheum 2009

49 Epidemiology of Hip OA A number of hip shapes obtained by statistical shape modeling in two cohorts (Chingford and CHECK) One common Shape/ mode across both cohorts Shapes identified that predicted incident disease and others THR (CHECK n=5, and Chingford n=2) Agricola R, Rheumatology (Oxford) 2015 Prevalent hip OA in elderly white women (mean age 71 years) was associated with increase risk of all cause mortality over 16 yrs. [HR: 1.24] Barbour KE, Arthritis Rheumatology 2015

50 Non-Pharmacologic Therapies for Knee OA RCT of cognitive behavioral therapy for insomnia in knee OA subjects, improved sleep and clinical knee pain. Smith MT, Arthritis Rheumatology 2015 RCT with internet pain coach (pain coping skills training) versus assessment only for hip or knee OA found in women, 91% adherence and moderate reduction in joint pain with the intervention Rini C, Pain 2015

51 Pharmacologic Therapies Pharmacologic Therapies Systemic n=12 Intra-articular n=18 Topical n=2

52 NGF-mediated pain pathways NGF modulates pain signalling pathways, so there significant interest in analgesic potential of NGF inhibition

53 Baseline Characteristics Placebo Tanezumab (µg/kg) N = N = N = N = N = N = 74 Age, yr (SD) 58.1 (7.7) 58.3 (8.3) 59.9 (8.1) 60.4 (7.7) 57.1 (8.2) 58.4 (7.6) Female, % K/L grade 3-4, %* Walking knee pain, VAS mm SGA, VAS mm WOMAC pain, VAS mm Lane, NEJM 2010

54 - Tanezumab : Walking Pain in Index Knee Mean Change from Baseline Infusion Week mmvas(se) Lane N, et al. NEJM 2010 Placebo 10 ug/kg PF ug/kg PF ug/kg PF

55 WOMAC subscores (Mean change from baseline over Weeks 1-16 ± standard error) Placebo Tanezumab dose (µg/kg) 100 mm VAS N = N = N = N = N = N = 72 Pain 16.2 (2.4) 30.1 (2.3)* 36.0 (2.2)* 29.0 (2.4)* 39.6 (2.2)* 43.5 (2.3)* Physical function 15.2 (2.3) 30.1 (2.3)* 34.9 (2.2)* 30.8 (2.4)* 40.5 (2.2)* 43.8 (2.3)* Stiffness 16.3 (2.4) 33.5 (2.3)* 37.7 (2.2)* 34.5 (2.4)* 42.7 (2.2)* 47.8 (2.4)* *P<.0001 vs placebo Lane, NEJM 2010

56 Osteonecrosis of Femoral Head

57 Rapid Progression of Osteoarthritis Type 1 Significant loss of joint space width (>= 1mm) in less than approximately 1 year Type 2 Abnormal loss and/or destruction of bone that is not normally present in end-stage OA which, in its most severe form, was catastrophic bone failure and joint destruction

58 Mild to Moderate Radiographic hip OA

59 Rapidly Progressive OA, type 2

60 Dose-response relationship of reported cases of osteonecrosis Rate

61 Hochberg et al, Osteoarthritis and Cartilage 2015 Time to Total Joint Replacement by TZB Dose and Regimen tanezumab 2.5 mg tanezumab 5 mg tanezumab 10 mg tanezumab 2.5 mg + NSAID tanezumab 5 mg + NSAID vs. active comparator; p=0.012 tanezumab 10 mg + NSAID vs. active comparator; p=0.039 tanezumab 5 mg + NSAID tanezumab 10 mg + NSAID active comparator placebo At Risk: placebo tanezumab 2.5 mg tanezumab 5 mg tanezumab 10 mg active comparator tanezumab 2.5 mg + NSAID tanezumab 5 mg + NSAID tanezumab 10 mg + NSAID

62 Time to Rapidly Progression hip and knee OA Percent of Patients tanezumab 2.5 mg tanezumab 5 mg tanezumab 10 mg tanezumab 2.5 mg + NSAID tanezumab 10 mg vs. active comparator; p=0.032 tanezumab 2.5 mg + NSAID vs. active comparator; p=0.006 tanezumab 5 mg + NSAID vs. active comparator; p=0.004 tanezumab 10 mg + NSAID vs. active comparator; p=0.002 tanezumab 5 mg + NSAID tanezumab 10 mg + NSAID active comparator placebo At Risk: placebo Time (Days) tanezumab 2.5 mg tanezumab 5 mg tanezumab 10 mg active comparator tanezumab 2.5 mg + NSAID tanezumab 5 mg + NSAID tanezumab 10 mg + NSAID

63 Pharmacologic Interventions Anti-NGF Trial RCT of subjects (n=2700) with OA pain of knee and hip with partial symptomatic response to NSAIDs. Treatments were NSAID alone, Tenezumab (5mg or 10mg) alone, or the Combination. All tanezumab treated subjects had significant improvement in WOMAC pain and function over NSAID alone. All cause TJRs was higher in combination (tanezumab + NSAIDs) vs. either treatment alone RPOA was greater with tanezumab + NSAID vs. NSAID alone, and also vs. tanezumab 5mg dose Schnitzer TJ, Ann Rheum Dis 2015

64 Fasinumab-treated patients reported less pain at 16 weeks compared to placebo on the 10-point WOMAC subscale for pain. Press Release Regeneron May 2016

65 NGF and Trk A receptor on nociceptive neurons in peripheral nervous system

66 PLX7486 is a very selective kinase inhibitor Invitrogen screen ~ 250 human kinases PLX7486 FMS TRKC TRKB TRKA IC 50 s < 10nM TRK A, B, C; FMS 80nM-1µM MAP3K2, AURKB, MAP3K3, AURKA * > 1µM 240+ kinases

67 PLX7486 in NGF-induced pain model Dosing MA TH MA TH NGF 2h 0 h 0.5 h 1 h 2 h 3 h von Frey Measurement of Mechanical Allodynia (MA) Hot Plate Measurement of Thermal Hyperalgesia (TH) Von Frey (g) ## * **** ** * ** ** Hot plate (s) 20 G1=Vehicle G2=NGF+Vehicle 15 mg/kg ** mg/kg G5=PLX mg/kg mg/kg G7=PLX7486 mg/kg G1=Vehicle G2=NGF+Vehicle mg/kg mg/kg mg/kg mg/kg mg/kg 0 Baseline 0.5 h 2 h 0 Baseline 1 h 3 h

68 PLX7486 in CFA pain model PLX7486 (30mg/kg; PO-qd, AUC 0-24hr = 193,000 hr*ng/ml) was dosed 1 day-post CFA injection, when paw edema and thermal hyperalgesia were fully developed Paw Edema Thermal Hyperalgesia Avg Change in Paw Vol. (ml) ** ns DAY 1 vehicle indomethacin 7486 %Inhibition 100% 80% 60% 40% 20% 0% ** Indomethacin * PLX7486 Similar to anti-ngf monoclonal antibody PLX7486 has no effect on edema. But it has significant efficacy in thermal hypersensitivity EXP-11-AA2230 *: p < 0.05 **: p < 0.01 ns: p > 0.05

69 Summary The Trka/NGF pathway is an exciting pathway to target for inhibition of nociceptive pain Anti-NGF antibodies are effective, however adverse events may limit clinical use due to prolonged half-life The selective TrKa inhibitors with shorter T1/2 are currently in Phase II studies

70 Pharmacologic Interventions RCT of subjects with knee OA pain and mild radiographic disease treated with GS, CS or GS/CS or Placebo over 2 years had less JSN in GS/CS vs. Placebo but no differences between GS or CS and Placebo. Fransen M, Ann Rheum Dis 2015 RCTs (n=2) of oral salmon calcitonin vs. placebo in painful knee OA did not replicate benefits for x-ray or symptoms Karsdal MA, Osteoarthritis and Cartilage 2015

71 What Is UC-II? UC-II is a unique ingredient because it is an undenatured protein ~ 300 nm Collagen triple helix K. Kuhn, 1987, in R. Mayne and R. Burgeson, eds., Structure and Function of Collagen Types, Academic Press, p. 2 Vander Rest M et al. FASEB J., 1991, 5:2814.

72 Hypothesized Mechanism of Action of Undenatured Collagen II and Oral Tolerance UC-II IL-10 Von Boehmer et al. Exp Med 2007;204: Ramage, et al. Scand J Med Sci Sports. 2009;19: TGF-β Tregs, IL-10 and TGF-β helps repair and build new cartilage

73 Results of WOMAC, VAS Pain and LFI from Baseline to Day 180

74 Bone Marrow Lesions adjacent to the knee joint are associated with knee pain and loss of articular cartilage

75 Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial Laslett LL et al. Ann Rheum Dis

76 Knee Pain Scores over the 12 month study period. Laslett LL et al. Annals of Rheumatic Disease. 2012;71: s.

77 Change in Total Bone Marrow Lesion Area between ZA and Placebo Range in bone marrow lesion size between treatment groups (per protocol analysis) Baseline to 6 months Baseline to 12 months β Coefficient (95% CI) n=59 p Value β Coefficient (95% CI) n=59 * p Value Total area (mm 2 ) ( to 24.3) ( to +14.5) 0.07 Ordinal scale 0.63 ( 1.28 to +0.01) ( 1.6 to 0.1) Laslett LL et al. Annals of Rheumatic Disease. 2012;71:

78 Neridronate vs. Placebo: Change in Knee OA Pain with Bone Marrow Lesions -RCT of subjects with knee OA, recent knee pain and BMLs -Randomized to neridronate (BP) vs. Placebo - At day 60, Neidronate Treatment group had greater reduction in VAS knee pain, and reduction in BML size by MRI WORMs score Varenna M et al, Rheumatology 2015

79 Pharmacologic Therapies: Intra-articular Intra-articular Therapies Knee n=16 Hip n=1 Acromioclavicular n=1

80 Pharmacologic: Intra-articular RCT of single IA etanercept (soluble TNF inhibitor) vs. hyaluronic acid for painful knee OA found a significant reduction in knee pain by VAS at wk 1 and 2, and 4 wks by WOMAC with etanercept compared to HA. Ohtori S, Yonsei Med J 2015

81 Pharmacologic: Intra-articular Platelet Rich Plasma Meta-analysis of 10 RC or Non RC Trials for painful knee OA reported a significant reduction in pain with PRP compared to HA (moderate risk of bias), and PRP vs. Placebo (high risk of bias). N=1100 Laudy AB, Br J Sports Med 2015 RCT with PRP vs. HA with knee OA pain after 1 year found no difference in pain between the two treatments. Filardo G, Am J Sports Med 2015 RCT with PRP, 1 cycle vs. 2 cycles (3 injections/prp per cycle/yr) and found after 2 years, and found no differences in KOOS pain. Gobbi A, Knee Surg Sports Traumatol Arthrosc 2015

82 Pharmacologic: Intra-articular RCT of HA vs. Placebo in painful knee OA, no difference in pain or function between 0-6 months Van der Weegen W, J Arthroplasty 2015 HA (G-F 20) treatment reduced pain and WOMAC scores improved in subjects with and without effusions. Waddell BS, J Knee Surg 2015 RCT of Corticosteroid or Placebo injection before exercise in knee OA subjects did not reduce exercise induced pain. Henriksen M, JAMA Intern Med 2015 RCT of Extended release (ER) vs. Immediate Release Triamcinolone found more reduction in knee pain with ER medication duration of the pain reduction was not different Bodick N, J Bone Joint Surg Am 2015

83 Pharmacologic: Intra-articular and Growth factors for Knee OA - RCT of Chondrocytes expressing TGF-Beta 1 vs. Placebo injections in painful knee OA. - Both groups had within group reductions in pain at 24 weeks. -Significant reduction in VAS pain between groups ( TGFB1 > Placebo), but not WOMAC pain at 24 wks. Lee MC, Bone Joint J 2015

84 Pharmacologic: Intra-articular and Growth factors for Knee OA FGF18 signals through FGF3 to promote chondrogenesis. RCT of rhfgf18 (Sprifermin) found no significant differences between treatments for reduction in central medial FT compartment of cartilage thickness at 12 mths., however rhfgf18 related increases in lateral FT cartilage thickness, volume and JSW narrowing were observed. Lohmander et al, Arthritis & Rheumatology, 2014 POST-HOC analysis found an increase in Total cartilage thickening sum scores and decreased Total cartilage thinning sum scores vs PLACEBO These results suggest a need for both subject-specific and location independent analysis of both cartilage thickening and cartilage thinning for assessing effects of DMOADs in the future. Eckstein F, Arthritis Rheumatology 2015

85 Overview of Management of Pain in OA of the Knee Surgery Opioid analgesics NSAIDs, incl COX-2 SI Acetaminophen / OTC NSAIDs Nutritional Supplements Nonpharmacologic therapy Patient education Weight loss Occupational therapy Telephone support Physical therapy Aerobic exercise programs Adapted from ACR Recommendations for Management of Hip and Knee OA

86 Future Therapies 1. Treatment of Post-traumatic OA may begin at the time of injury with localized treatment that will be intermittent 2. Artificial Cartilage will probably be developed and 3D printed 3. Total joint replacement will improve with materials, also 3D printed that may be more personalized for each patient and be more physiologic 4. Medications 1. Focus on peripheral vs. Central pain and phenotype patients 2. Possibly everyone will take melatonin????? 3. Regenerative therapies

87 This work was supported by grants from the NIH 5U01AR , 5P01AI , 1R01AG05407, 1R01AR40431, P50-CORT, and P50-SCOR and Center for Musculoskeletal Health, Endowment for Aging Research at UC Davis,

88 ACKNOWLEDGMENTS Barton Wise, MD, MSc, UC Davis Kie Shidara, BSc, UC Davis OA Clinical Investigators for their research Rheumatologists for their insightful questions and continued commitment to improve the joint and function of their OA patients Any questions:

89 Current regenerative therapy for OA treatment. OA, osteoarthritis.