Osteoporosis

1. Osteoporosis PATHOGENESIS DIAGNOSIS TREATMENT Robert D. Auerbach, M.D. FACOG Senior Vice President & Chief Medical Officer CooperSurgical, Inc. Associate Clinical Professor Yale University School of Medicine

2. Two Components of the Bone • Cortical Bone • Dense and compact • Runs the length of the long bones, forming a hollow cylinder • Trabecular bone • Has a light, honeycomb structure • Trabeculae are arranged in the directions of tension and compression • Occurs in the heads of the long bones • Also makes up most of the bone in the vertebrae

3. Osteons • Principal organizing feature of compact bone • Haversian canal – place for the nerve blood and lymphatic vessels • Lamellae – collagen deposition pattern • Lacunae – holes for osteocytes • Canaliculi – place of communication between osteocytes

4. Bone Cells • Osteocytes - derived from osteoprogenitor cells • Osteoblasts • Osteoclasts

5. Osteocytes • Trapped osteoblasts • In lacunae • Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase • Osteocytic osteolysis

6. Osteoblasts • Make collagen • Activate nucleation of hydroxyapatite crystallization onto the collagen matrix, forming new bone • As they become enveloped by the collagenous matrix they produce, they transform into osteocytes • Stimulate osteoclast resorptive activity

7. Osteoclasts • Resorb bone matrix from sites where it is deteriorating or not needed • Digest bone matrix components • Focal decalcification and extracellular digestion by acid hydrolases and uptake of digested material • Disappear after resorption • Assist with mineral homeostasis

8. Chemistry of the Bone • Matrix • Mineral

9. Matrix - Osteoid • Collagen type I and IV • Layers of various orientations (add to the strength of the matrix) • Other proteins 10% of the bone protein • Direct formation of fibers • Enhance mineralization • Provide signals for remodeling

10. Mineral • A calcium phosphate/carbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2 • Hydroxyapatite crystals • Imperfect • Contain Mg, Na, K

11. Mineralization of the Bone • Calcification occurs by extracellular deposition of hydroxyapatite crystals • Trapping of calcium and phosphate ions in concentrations that would initiate deposition of calcium phosphate in the solid phase, followed by its conversion to crystalline hydroxyapatite • Mechanisms exist to both initiate and inhibit calcification

12. Bone Remodeling Process • Proceeds in cycles – first resorption than bone formation • The calcium content of bone turns over with a half-life of 1-5 years

13. Bone Remodeling Process

14. Coordination of Resorption and Formation • Phase I • Signal from osteoblasts • Stimulation of osteoblastic precursor cells to become osteoclasts • Process takes 10 days

15. Coordination of Resorption and Formation • Phase II • Osteoclast resorb bone creating cavity • Macrophages clean up • Phase III • New bone laid down by osteoblasts • Takes 3 months

16. Pathways of Differentiation of Osteoclasts and Osteoblasts

17. Hormonal Influence • Vitamin D • Parathyroid Hormone • Calcitonin • Estrogen • Androgen

18. Vitamin D • Osteoblast have receptors for (1,25-(OH)2-D) • Increases activity of both osteoblasts and osteoclasts • Increases osteocytic osteolysis (remodeling) • Increases mineralization through increased intestinal calcium absorption • Feedback action of (1,25-(OH)2-D) represses gene for PTH synthesis

19. Parathyroid Hormone • Accelerates removal of calcium from bone to increase Ca levels in blood • PTH receptors present on both osteoblasts and osteoclasts • Osteoblasts respond to PTH by • Change of shape and cytoskeletal arrangement • Inhibition of collagen synthesis • Stimulation of IL-6, macrophage colony-stimulating factor secretion • Chronic stimulation of the PTH causes hypocalcemia and leads to resorptive effects of PTH on bone

20. Calcitonin • C cells of thyroid gland secrete calcitonin • Straight chain peptide - 32 aa • Synthesized from a large preprohormone • Rise in plasma calcium is major stimulus of calcitonin secretion • Plasma concentration is 10-20 pg/ml and half life is 5 min

21. Actions of Calcitonin • Osteoclasts are target cells for calcitonin • Major effect of clacitonin is rapid fall of plasma calcium concentration caused by inhibition of bone resorption • Magnitude of decrease is proportional to the baseline rate of bone turnover

22. Other Systemic Hormones • Estrogens • Increase bone remodeling • Androgens • Increase bone formation

23. Other Systemic Hormones • Growth hormone • Increases bone remodeling • Glucocorticoids • Inhibit bone formation • Thyroid hormones • Increase bone resorption • Increase bone formation

24. Local Regulators of Bone Remodeling • Cytokines • IL-6 • IL-1 • Prostaglandins • Growth factors • IGF-I • TGF-β

25. Osteoporosis A disease characterized by: • low bone mass • microarchitectural deterioration of the bone tissue Leading to: • enhanced bone fragility • increase in fracture risk

26. WHO Guidelines for Determining Osteoporosis • Normal: Not less than 1 SD below the avg. for young adults • Osteopenia: -1 to -2.5 SD below the mean • Osteoporosis: More than 2.5 SD below the young adult average • 70% of women over 80 with no estrogen replacement therapy qualify • Severe osteoporosis • More than 2.5 SD below with fractures

27. Osteoporosis - Epidemiology • Disorder of postmenopausal women of northern European descent • Increase in the incidence related to decreasing physical activity • Over 27 million or 1 of 3 women are affected with osteoporosis • Over 5 million or 1 of 5 men are affected with osteoporosis

29. Statistics

30. Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

31. Pathogenesis of Estrogen Deficiency and Bone Loss • Estrogen loss triggers increases in IL-1, IL-6, and TNF due to: • Reduced suppression of gene transcription of IL-6 and TNF • Increased number of monocytes • Increased cytokines lead to increased osteoclast development and lifespan

32. Osteoclast Differentiation and Activation in Estrogen Deficiency

33. Impact of Estrogen on Osteoclastic Differentiation and Activation

34. National Osteoporosis Risk Assessment (NORA): Factors Associated With Increased Risk of Osteoporosis

35. NORA: Factors Associated With Reduced Risk of Osteoporosis

36. NORA: BMD and Fracture Rate

37. Osteoporosis • Mechanisms causing osteoporosis • Imbalance between rate of resorption and formation • Failure to complete 3 stages of remodeling • Types of osteoporosis • Type I • Type II • Secondary

38. Osteoporosis - Types • Postmenopausal osteoporosis (type I) • Caused by lack of estrogen • Causes PTH to overstimulate osteoclasts • Excessive loss of trabecular bone • Age-associated osteoporosis (type II) • Bone loss due to increased bone turnover • Malabsorption • Mineral and vitamin deficiency

39. Secondary osteoporosis

40. Osteoporotic Vertebra

41. Normal vs. Osteoporotic Bone

43. When to Measure BMD in Postmenopausal Women • All women 65 years and older • Postmenopausal women <65 years of age: • If result might influence decisions about intervention • One or more risk factors • History of fracture

44. When Measurement of BMD Is Not Appropriate • Healthy premenopausal women • Healthy children and adolescents • Women initiating ET/HT for menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

45. Prediction of Fracture Risk • All techniques (DXA, QCT, QUS) predict fracture risk American Association of Clinical Endocrinologists Endocrin Prac 2001; 7: 283-312

46. Osteoporosis Can Be Assessed by DXA • DXA-assessed content is a proven effective method for assessing osteoporosis related fracture risk. • Population surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites. • Marshall, D, et al: Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. British Medical Journal. 312:1254-1259, 1996.

47. The McCue CUBA: Ultrasonometry Technology That Can Assess Osteoporosis

48. Heel BUA is Significantly Lower in Subjects With Future Hip Fracture. • Subjects who developed hip fracture showed significantly (p<0.001) lower heel BUA results in a two-year follow-up prospective study of 1,414 subjects. • Porter, RW, et al: Prediction of hip fracture in elderly women: a prospective study. British Medical Journal. 301:638-641, 1990.

49. Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis • When assessing vertebral osteoporosis, there was no statistically significant difference in the discriminating power of Heel BUA or Spine, Femur Neck or Trochanter BMD by DXA. • Ohishi, T, et al: Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture. Journal of Clinical Densitometry. 3:227-231, 2000.

50. Receiver Operator Characteristic Analysis of Hip Fracture Risk • Schott, AM, et al: Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density. • Journal of Bone and Mineral Research. 10:243-249, 1995.