1. ARTHRITIS Inflammation of the Joint (over 100 specific diseases) Rheumatoid Arthritis Gout Degenerative Joint Diseases Ankylosing spondylitis JRA Psoriatic Arthritis Bacterial Arthritis Systemic Lupus Erythematosus Scleroderma
2. ARTHRITIS: Inflammation of the Joint Pain Swelling Redness Warmth
3. IL-8 IL-6 GM-CSF IL-1 TNF- FGF Fibroblast/ type B synovial cells Metalloproteinases Prostaglandins Complement IL-6 IL-1 IL-6 IL-8 GM-CSF M-CSF Macrophage/ type A synovial cells IL-1 TNF- Adhesion molecule expression on blood vessels HLA-DR Complement metalloptoteinases CYTOKINE NETWORKS IN SYNOVITIS + FEEDBACK
4. IL-8 IL-6 GM-CSF IL-10 IL-1 TNF- FGF Fibroblast/ type B synovial cells Metalloproteinases Prostaglandins Complement IL-6 TGF- IL-4 IL-1 IL-6 IL-8 GM-CSF M-CSF Macrophage/ type A synovial cells IL-1 TNF- Adhesion molecule expression on blood vessels HLA-DR Complement metalloptoteinases CYTOKINE NETWORKS IN SYNOVITIS + FEEDBACK - FEEDBACK
5. Points to Remember Cells involved in Inflammation: - macrophage, fibroblast, T-cells Pro inflammatory cytokines: - IL-1, TNF alpha, IL-6 - IL-8, FGF, GM-CSF Anti inflammatory cytokine: - IL-10, TGF-B, IL-4
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12. Biochemical markers in Osteoarthritis Major tissue of origin Biochemical markers Synovium Hyaluran, type 2 collagen propeptide, proteases Subchondral bone Type 1 collagen crosslinks, osteocalcin, alk. phosphatase, Cart. oligomeric protein (COMP)
18. Mechanism of Action of NSAIDs – New hypothesis Arachidonic Acid Prostaglandins Prostaglandins Protection of gastric mucosa Homeostasis Mediates pain Inflammation and fever Conventional NSAIDs COX-1 COX-2 Coxibs
19. COX-1 COX-2 - produces PG from AA - produces PG from AA - constitutively expressed - inducible - governs PG production - governs PG production that mediate hemostatic that mediate inflammation function - essentially important in: gastric, bowel mucosa kidney, platelets
102. Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999, p 257 Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After Age 50 40 30 20 10 Slide Modified: Review: Reviewer Memo: Source: Memo: 50 60 70 80 Vertebrae Hip Wrist Age (Years) Annual incidence per 1000 women
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104. Unitary model for postmenopausal bone loss: role of oestrogen deficiency Indirect effects Directly increases osteoclast number and longevity Dietary calcium (decreased absorption) Secondary hyperparathyroidism Increased bone resorption Bone loss Decreased bone formation Remodelling imbalance ? Adapted from: Riggs BL, et al. J Bone Miner Res 1998;13:763–73 Oestrogen deficiency
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106. Glucocorticoid dose Dependent Effect on Fracture Risk 0.99 1.77 5.18 1.55 2.59 2.27 0 1 2 3 4 5 6 Hip Vertebral Type of Fracture Relative Risk of Fracture <2.5 mg 2.5 mg-7.5 mg >7.5 mg Dose* Van Staa TP, et al. J Bone Miner Res. 2000. *Prednisolone equivalent N = 488 470
107. Most rapid bone loss occurs in the first 6-12 months of Steroid therapy
115. Osteoporosis prevention T-score >–2.5 Osteopenia treatment with or without previous fracture Osteoporosis treatment with multiple fractures and at risk for hip fracture 50 55 60 65 70 75 80 85 Raloxifine Age (years) HRT Therapeutic Management of Postmenopausal Osteoporosis Teriparatide Bisphosphonates Adapted from Seeman & Eisman, MJA Vol 180 15 March 2004, p298-303
116. Optimal Daily Calcium Requirements 1300 mg 1000 mg 1200 mg Recommended Calcium Intake (Daily) Age 1997 Recommended Dietary Intakes 9-18 years 19-50 years 51 years or older National Academy Press. Available at: http://books.nap.edu/catalog/5776.html. 1999.
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118. Widespread Prevalence of Vitamin D Inadequacy* Regardless of Geographic Location *Vitamin D inadequacy was defined as serum 25(OH)D <30 ng/ml; **Interim results of ongoing study Study Design: Observational, cross-sectional study of 1285 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution. Adapted from Lim S-K et al. Poster presented at ISCD, February 16–19, 2005, New Orleans, Louisiana,USA; Heaney RP Osteoporos Int 2000;11:553–555. Prevalence (%) 0 10 30 40 60 80 90 Latin America 51% 63% Asia All 59% Australia 59% Europe 52% Regions N=1285 81% Middle East 50 70 20 In a cross-sectional observational international study in 1285 postmenopausal women with osteoporosis**
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120. Vitamin D Inadequacy* Has Important Consequences Appropriate neuromuscular function *Vitamin D inadequacy is defined as serum 25(OH)D <30 ng/ml. Adapted from Parfitt AM et al Am J Clin Nutr 1982;36:1014–1031; Allain TJ, Dhesi J Gerontology 2003;49:273–278; Holick MF Osteoporos Int 1998;8(suppl 2):S24–S29; DeLuca HF Metabolism 1990;39(suppl 1):3–9; Pfeifer M et al Trends Endocrinol Metab 1999;10:417 – 420; Lips P. In: Draper HH, ed. Advances in Nutritional Research . New York, Plenum Press, 1994:151–165. Bone mineral density Parathyroid hormone Calcium absorption Risk of fracture Artistic rendition
121. Bisphosphonate mechanism of action Adapted from: Bone H, et al. Clin Ther 2000;22:15–25 RESTING RESORPTION Osteoclast FORMATION Osteoblasts BISPHOSPHONATES INHIBIT OSTEOCLAST -MEDIATED BONE RESORPTION
122. PTH - Mechanism of Action PTH binds to cell surface G protein-coupled receptor Stimulates differentiation of bone lining cells and preosteoblasts to osteoblasts Decreases apoptosis of osteoblasts Net increase in number and action of bone forming osteoblasts
123. Osteoporosis has been thought of as a silent epidemic….this is not true anymore. At present, there is much noise in the field of research for its prevention, diagnosis and treatment. Ego Seeman ARCOS meeting, Feb 2002
124. One of the Many Faces of Osteoporosis “ You could have floored me when they told me. It’s very frightening, very frightening… I don’t want to end up in a nursing home incapacitated.”
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