1. Osteoporosis: pathophysiology Dr.noori Rheumatologist www.arrh.ir

2. osteoporosis

3. Osteoporosis Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Normal Bone Osteoporotic Bone

4. HEALTHY BONE Bone is living tissue, which is constantly being broken down and rebuilt, a process called remodeling Bone is renewed like skin, hair and nails

5. OSTEOPOROTIC BONE The loss of living bone tissue makes bones fragile and more likely to fracture Note: arrow points to micro - fracture

6. Support Protection Movement Mineral storage Blood cell formation (hemopoiesis) Triglyceride storage

7. BONE “REMODELING” Resorption- removes old bone Formation- replaces old bone with new bone

8. Why Bone Remodeling? Allows skeleton to Respond to mechanical loading Respond to mechanical loading Repair and prevent microdamage Repair and prevent microdamage Release growth factors and minerals (calcium and phosphate) stored in matrix into circulation Release growth factors and minerals (calcium and phosphate) stored in matrix into circulation

9. Pathophysiology Bone remodeling occurs throughout adulthood Bone remodeling occurs throughout adulthood Osteoporosis results from an imbalance between osteoclast and osteoblast activity Osteoporosis results from an imbalance between osteoclast and osteoblast activity

11. BMU Remodeling Sequence Activation Resorption Reversal Quiescence Formation & Mineralization www.ifcc.org/ejifcc/ vol13no4/130401004n.htm Osteocytes

12. Bone turnover What happens to bone………. What happens to bone………. –in youth? –Aged30-45? –postmenoposal?

13. BONE BANK DEPOSITS From birth through adolescence, new bone is built faster than old bone is removed In mid-life, depending on lifestyle and other factors, bone removal can achieve a balance with bone formation After menopause, bone removal may accelerate due to a decrease in estrogen

14. Bone Mass Age (years) Attainment of Peak Bone Mass Consolidation Age-related Bone Loss Men Women Menopause 0 10 20 30 40 50 60 Fracture Threshold Compston JE. Clin Endocrinol 1990; 33:653–682. Age Related Changes in Bone Mass

15. CHANGES IN BONE MASS After menopause, bone removal accelerates due to a decrease in estrogen

16. Controlling Factors Controlling Factors Hormones Hormones –Estrogen –Testosterone –Cytokines  Growth factors,  Interleukins (1, 6, and 11),  Transforming growth factor-b  Tumor necrosis factor-a of osteoclasts and osteoblasts

17. Bone Types Cortical- outer shell of bones Cortical- outer shell of bones Trabecular- spongy, internal support Trabecular- spongy, internal support

18. TYPES OF BONE (1) Cortical – is hard, compact, dense bone (example: mid- section of larger, long-bones of arms and legs) (2) Trabecular – is spongy, porous and flexible bone (example: end of the wrist, and the spine)

19. Bone Loss Bone mass peaks at age 30 Bone mass peaks at age 30 Then 0.4 % bone lost per year Then 0.4 % bone lost per year First 5-8 years after menopause, women lose 2% of cortical and 5% of trabecular bone per year First 5-8 years after menopause, women lose 2% of cortical and 5% of trabecular bone per year Early menopause- increased osteoclasts Early menopause- increased osteoclasts Later menopause- decreased osteoblasts Later menopause- decreased osteoblasts

20. BUILD YOUR BONE BANK You build bone until about age 30 Steps to building healthy bones include: Calcium & vitamin D Limit Caffeine & Alcohol Exercise Don’t Smoke

21. What is the composition of bone? What is the composition of bone? The matrix The matrix –40% organic Type 1 collagen (tensile strength) Type 1 collagen (tensile strength) Proteoglycans (compressive strength) Proteoglycans (compressive strength) Osteocalcin/Osteonectin Osteocalcin/Osteonectin Growth factors/Cytokines/Osteoid Growth factors/Cytokines/Osteoid –60% inorganic Calcium hydroxyapatite Calcium hydroxyapatite The cells The cells –osteo-clast/blast/cyte/progenitor

22. Abundant inorganic mineral salts: - Tricalcium phosphate in crystalline form called hydroxyapatite Ca 3 (PO 4 ) 2 (OH) 2 -Calcium Carbonate: CaCO 3 -Magnesium Hydroxide: Mg(OH) 2 -Fluoride and Sulfate

23. These salts are deposited on the collagen fiber framework (tensile strength) and crystallization occurs. - calcification or mineralization

24. Osteoblast Osteocyte Osteoclast Eats bone Builds new bone Mature bone cell

25. Osteoblasts Osteoblasts: - bone forming cells - found on surface of bone - collagen secretors

26. Osteocytes  Osteocytes: - mature bone cells - derived form osteoblasts - do not secrete matrix material

27. Osteoclasts Osteoclasts - bone resorbing cells - bone surface - growth, maintenance and bone repair

28. Bone is Dynamic! 1.Bone formation(by osteoblasts):3-4m. 2.Bone destruction/resorption (by osteoclasts):10- 14days Normal bone remodeling cycle in adult:4-6m. Normal bone remodeling cycle in adult:4-6m. All spongy bone replaced every 3-4 years. All spongy bone replaced every 3-4 years. All compact bone replaced every 10 years. All compact bone replaced every 10 years.

29. Bone turnover (increase osteoclast number and activity) Estrogen deficiency Estrogen deficiency Hyperparathyroidism Hyperparathyroidism Immobilization Immobilization Metabolic acidosis Metabolic acidosis Systemic and local inflammatory disease Systemic and local inflammatory disease

30. Remodeling Cycle Resting Resting Resorption Resorption Reversal Reversal Formation Formation

31. Bone Remodeling Cycle in Normal Bone Lining cells Resting Bone Resorption Osteoclasts digest bone within a sealed resorption vacuole Bone Reversal Apoptotic osteoclasts Preosteoblasts Bone Mature osteoblasts building osteoid tissue Mineralization Formation Bone

32. OTHER WAYS TO TARGET THE OSTEOCLAST Rodan & Duong. BoneKey 2008.

33. Bone Pathophysiology Normal bone remodeling: Normal bone remodeling: –Osteoblasts: Synthesize new bone by first laying down a new protein matrix, principally composed of Type I collagen into the resorbed space. Individual collagen molecules become interconnected by formation of pyridinoline cross-links to provide extra strength. Individual collagen molecules become interconnected by formation of pyridinoline cross-links to provide extra strength. Bone mineralization occurs with deposition of hydroxyapatite. Bone mineralization occurs with deposition of hydroxyapatite.

34. Osteoblast Growth Factors Hormones Cytokines RANK RANKL Mature Osteoclast CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast RANKL Stimulates Osteoclast-mediated Bone Resorption Adapted from Boyle WJ et al. Nature. 2003;423:337-42. RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival CFU-M = colony forming unit macrophage Bone

35. Bone Resorption Osteoclasts are related to macrophages: Osteoclasts are related to macrophages: –secrete lysosomal enzymes and HCl acid Move along surface of bone, dissolving grooves into bone with acid and enzymes Move along surface of bone, dissolving grooves into bone with acid and enzymes Dissolved material passed through osteoclasts and into bloodstream for reuse by the body Dissolved material passed through osteoclasts and into bloodstream for reuse by the body

36. Osteoclast Development Monocyte Macrophage Multipotent Progenitor Pro- monocyte Pu.1 GM-CSF NF-  B, c-Fos NFAT Mono- nuclear Osteoclast Precursor Mature Osteoclast RANK – RANK + RANKL

37. Stimulation of osteoclast Estrosen deficiency Estrosen deficiency RANKL RANKL Il-1 Il-1 Il-6 Il-6 TNF TNF

38. Life Cycle of Osteoblasts Stem Cell Stromal Mesenchymal Cell CBFA1 BMPs TGF  s Proliferation BMPs TGF-  s CBFA1 Msx-2 PTH TGF-  IGF-I, II Vitamin D 3 c-fos Proliferation CBFA1 Glucocorti- coids Vitamin D3 PGE 2 PTH TGF-  IGF-I, II Pre-Osteoblast Mature Osteoblast CBFA1 Dlx-5 fra-2/jun-D Mineralization Osteocyte Lian JB, et al. In Osteoporosis. 2nd ed. Marcus R, et al, eds. Stanford, CA: Academic Press, 2001. Commitment No Turning Back Osteoprogenitor

39. 1. Many Factors Stimulate Osteoblast Expression of RANK-Ligand 1,2 Activated Osteoclast RANKL RANK Osteoclast Precursor Colony-Forming Unit-Macrophage Multinucleated Osteoclast +mCSF Abbreviations: IL, interleukin; mCSF, macrophage colony-stimulating factor; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein.. 1. Boyle WJ, et al. Nature. 2003;423:337-342. 2. Hofbauer LC, et al. JAMA. 2004;292:490-495. PTH PGE 2 Glucocorticoids Vitamin D IL-11 IL-6 IL-1 PTHrP TNF-  Osteoblasts and Bone Marrow Stromal Cells

40. 2. RANK-Ligand Expression Mediates Osteoclast Formation, Function, and Survival Osteoblasts Activated Osteoclast Multinucleated Osteoclast Bone Resorption Boyle WJ, et al. Nature. 2003;423:337-342. RANKL RANK Osteoclast Precursor Hormones Growth Factors Cytokines Colony-Forming Unit-Macrophage Bone Formation

41. 3. Osteoprotegerin Prevents RANKL Binding to RANK and Inhibits Osteoclast Activity Activated Osteoclast Osteoclast Precursor Multinucleated Osteoclast Osteoblasts Bone Resorption RANKL RANK OPG X X Boyle WJ, et al. Nature. 2003;423:337-342. Colony-Forming Unit-Macrophage Hormones Growth Factors Cytokines X

42. Estrogen deficiency Increase osteoblast production of RANKL Increase osteoblast production of RANKL Decrease osteoblastic production OPG(osteoprotegerin) Decrease osteoblastic production OPG(osteoprotegerin)

43. Critical Checkpoint in Control of Bone Remodeling RANK/RANKL/OPG Pathway Regulation of osteoclast Formation Formation Number Number Activity Activity Lifespan Lifespan

44. 3. Osteoprotegerin Prevents RANKL Binding to RANK and Inhibits Osteoclast Activity Activated Osteoclast Osteoclast Precursor Multinucleated Osteoclast Osteoblasts Bone Resorption RANKL RANK OPG X X Boyle WJ, et al. Nature. 2003;423:337-342. Colony-Forming Unit-Macrophage Hormones Growth Factors Cytokines X

45. Resting Bone Reversal Bone Many Factors Regulate Bone Remodeling Formation Resorption GM-CSF IL-1 IL-6 Il-11 RANKL PGE 2 TNF-  Formation OPG TGF-  Estrogen Resorption Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; OPG, osteoprotegerin; RANKL, RANK-ligand, PGE 2, prostaglandin E 2 ; TGF, transforming growth factor; TNF, tumor necrosis factor. Illustration Copyright ©2009 Nucleus Medical Art, All rights reserved. www.nucleusinc.com

46. Bone Pathophysiology Bone Turnover Markers Bone Turnover Markers –Formation: bone-specific alkaline phosphatase and osteocalcin –Resorption: carboxy terminal peptides of mature collaged (N-telopeptide and C-telopeptide) and deoxpyridinoline

47. Risk factor osteoporosis Genetic Genetic Nutritional Nutritional Lifestyle Lifestyle Whites /asian Whites /asian Age Age Low body weight Low body weight Reduce gonadal H. Reduce gonadal H. Cigarette smoking Cigarette smoking Exessive alcohol intake Exessive alcohol intake

48. RISK FACTORS - CAN’T CONTROL Genetic:80% bone mass Gene collagen1A1:low bone density ss allele : lower bone density than SS group Menopause or several months without periods: bone loss begins to exceed bone formation, due to a decrease of estrogen

49. RISK FACTORS - CAN’T CONTROL Gender: Females are usually diagnosed with osteoporosis at four times the rate of males. Bone mass in males is approximately 15-20% higher than females Small Boned & Thin: may result in smaller bones with a lower bone density Activity - Risk Factor Worksheet

50. RISK FACTORS - CAN’T CONTROL Race/Ethnicity: Women, especially Caucasian and Asian women with thin frames are at greater risk African American women have a higher peak bone mass (10%) than Caucasian women.

51. RISK FACTORS – CAN CONTROL Caffeine: Recommendation- No more than 2-3 cups of caffeine beverages per day Cola, coffee and chocolate all contain caffeine

52. Alcohol: consuming more than one alcoholic drink per day is associated with risk of low bone mass RISK FACTORS – CAN CONTROL Eating Disorders: anorexia nervosa or bulimia can lead to malnutrition and bone loss

53. RISK FACTORS – CAN CONTROL Calcium Rich Diet: milk, cheese, yogurt Weight Bearing Exercise: walk, bike, run Vitamin D: sunshine, multivitamin, fortified food

54. Age: In your 45’s you start to lose bone faster than you build new bone. The accumulated loss of bone puts an older person at higher risk RISK FACTORS - CAN’T CONTROL

56. Smoking: causes lower bone density Immobility: extreme lack of exercise can lead to bone loss RISK FACTORS – CAN CONTROL

57. DRUGS-MAY CAUSE BONE LOSS Cortisone Isoniazid Seizure drugs Lithium Cyclosporine Heparin Methotrexate Some Hormones

58. Osteoclast Activity Vitamin D deficiency Vitamin D deficiency Estrogen deficiency Estrogen deficiency Parathyroid hormone excess Parathyroid hormone excess Hyperthyroidism Hyperthyroidism

59. Parathyroid Hormone Increases renal calcium reabsorption Increases renal calcium reabsorption Stimulates renal vitamin D production Stimulates renal vitamin D production Releases calcium from the bone Releases calcium from the bone

60. Calcium 98% stored in bones 98% stored in bones Regulated by intestinal, renal, and skeletal systems Regulated by intestinal, renal, and skeletal systems If inadequate dietary supply of calcium, will reabsorb skeletal stores to maintain plasma levels. If inadequate dietary supply of calcium, will reabsorb skeletal stores to maintain plasma levels.

61. Vitamin D 95% of vitamin D is from sunlight 95% of vitamin D is from sunlight Vit D  25(OH)D  1,25(OH) 2 D Vit D  25(OH)D  1,25(OH) 2 D Increases GI calcium absorption Increases GI calcium absorption Measure 25(OH)D to determine deficiency Measure 25(OH)D to determine deficiency

62. Vitamin D deficiency Vit D deficiency  secondary hyperparathyroidism (SH)  mobilize bone calcium stores  normal serum calcium Vit D deficiency  secondary hyperparathyroidism (SH)  mobilize bone calcium stores  normal serum calcium SH  decreases phosphorus levels  inadequate to mineralize skeleton SH  decreases phosphorus levels  inadequate to mineralize skeleton Kids = rickets Kids = rickets Adults = osteomalacia Adults = osteomalacia

63. Types of Osteoporosis Primary osteoporosis Primary osteoporosis –Related to aging and/or decreased gonadal function –Aging bone loss is slower than menopausal –Menopause related bone loss lasts about 10 yrs Secondary osteoporosis Secondary osteoporosis –Due to medications or chronic illnesses that accelerate bone loss –Consider secondary osteoporosis if Z-score is low

64. Cigarette smoker Impaired calcium absorption Impaired calcium absorption Lower estrogen level Lower estrogen level Earlier menopause Earlier menopause More fracture More fracture Exercise less Exercise less