Osteoporosis

1. Osteoporosis

2. Introduction Osteoporosis

3. Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National Osteoporosis Foundation Currently, there are 6 million people diagnosed with osteoporosis in the United States Most of them are FEMALE But MEN have worse outcomes Introduction

4. Anatomy Osteoporosis

5. Compared to men, women have: • Weaker bones: • Smaller bone cross-sectional area1,4 • Less cortical bone thickness4 • Lower peak bone mass1,2 • Higher risk for osteoporosis: • Less bone mineral density2,4 • Bone density that decreases more with age1 Cortical thickness Anatomy Normal Bone Osteoporosis

6. Physiology Osteoporosis

7. Cells of bone remodeling: • Osteoblasts build bone • Osteoclasts resorb bone Osteoblasts Osteoclasts • Proteins that regulate bone remodeling: • RANK Ligand stimulates osteoclasts1 • Osteoprotegerininhibits RANK Ligand2 RANK Ligand RANK Receptor Osteoprotegerin Physiology Osteoclast

8. Pathology Osteoporosis

9. Higher Peak Bone Mass3,4 Bone Mass Menopause (rapid bone loss)2 Age (in years) Pathology

10. Estrogen promotes bone formation1 • After menopause, estrogen levels drop • Women experience rapid bone loss after menopause due to estrogen deficiency2 Osteoprotegerin RANK Ligand Estrogen

11. Testosterone: • Stimulates osteoblasts3 • Inhibits osteoclasts3 • Increases bone size and BMD3 • Mediated by an androgen receptor3 Men with low testosterone are susceptible to osteoporosis.3 Testosterone

12. Epidemiology Osteoporosis

13. 200 million women worldwide suffer from osteoporosis • Approximately 30% of all postmenopausal women in the U.S. and Europe have osteoporosis. • At least 40% of these women, and 15-30% of men, will sustain one or more fragility fractures in their remaining lifetime. Epidemiology

14. Estimated Annual Incidence:2 • Total fractures: 9 million • Hip fractures: 1.6 million • Forearm fractures: 1.7 million • Vertebral fractures: 1.4 million Fracture Incidence

15. Fracture Comparison

16. Treatment Osteoporosis

17. Treatment

18. Bisphosphonates

19. Bisphosphonates

20. Bisphosphonates RR = Risk Reduction NE = No effect demonstrated

21. Other Agents RR = Risk Reduction NE = No effect demonstrated

22. Estrogen & Bone Metabolism

23. HRT- Hormone Replacement Therapy Estrogen in Females

24. Estrogen in Males

25. Mechanism of Action: selective estrogen-receptor modulator • Benefits • Increases BMD of hip and spine in women1 • Females: approved for treatment and prevention of osteoporosis in women. • Not approved in males2 • Narrow study contexts3,5 • Was not shown to significantly impact BMD in males4 Raloxifene

26. Bazedoxifine/Conjugated Estrogen (Duavee) • Mechanism of Action: SERM that selectively stimulates lipid metabolism and bone, however, has no effect on the uterus and breast. • Benefits • FDA approved for • postmenopausal moderate/severe vasomotor symptoms • prevention of postmenopausal osteoporosis. • Increased hip and lumbar BMD Tissue Selective Estrogen Complex

27. Bazedoxifene/Conjugated Estrogen (Cont’d) • Approved in Womenfor:2 • prevention of osteoporosis • osteopenia • post menopausal vasomotor and sleep disturbances • Men: None of the three major clinical trials included men, despite that estrogen has been demonstrated to play a significant role in bone formation.3,4,5 Tissue Selective Estrogen Complex

28. Mechanism of Action • Analogous to endogenous calcitonin • Indications • Approved for the treatment (not prevention) of osteoporosis in women who are ≥5 years post-menopausal • Not utilized in men Calcitonin-Salmon

29. Mechanism of Action: • Recombinant parathyroid hormone (PTH) • Stimulates bone formation. • Approved for: • Treatment & prevention of osteoporosis in men and postmenopausal women1 • Especially those at high risk for vertebral fracture2 Teriparatide (Forteo)

30. Teriparatide Efficacy

31. Calcium & Vitamin D

32. Total Fracture Incidence • DIPART Group analysis of 7 major Vitamin D and Calcium trials in the US and Europe. • Analysis included 68,500+ patients • Only 14% of subjects were males Calcium and Vitamin D

33. Hip Fracture Incidence Calcium and Vitamin D

34. Efficacy: • Combination Calcium (1200 mg) and Vitamin D (800 mg) reduces the risk of hip, vertebral and total fractures in both men and women.1 • Study Demographics • Men were understudied • 2010 DIPART Group Meta-Analysis: only14% of 68,500 subjects studied were men1 • 2007 Tang et al.2 Meta-Analysis included only 8% men3 Calcium & Vitamin D

35. Mechanism of Action: monoclonal antibody; prevents osteoclast maturation. RANK-L Inhibitor (Denosumab) “RANK-L”, RANK-Ligand

36. Approved to increase BMD in1,2 • Women: • With non-metastatic breast cancer • post-menopausal women with osteoporosis at high risk for fracture. • Men:2 • With non-metastatic prostate cancer who are receiving Androgen Deprivation Therapy. • With osteoporosis who are at high risk for fracture. Denosumab (Prolia)

37. Efficacy in Males Denosumab

38. Efficacy in Females Denosumab

39. Denosumab Research Disparities

40. Prognosis Osteoporosis

41. Fracture Prognosis

42. Fracture Morbidity

43. The Dubbo Osteoporosis Epidemiology Study1 Men 197 out of 343 died Women 461 out of 952 died Fracture Mortality

44. 2 1 Osteoporosis Treatment after Hip Fracture

45. Risk Factors Osteoporosis

46. Smoking Menopause Low body weight (<127 lbs) History of fracture infirst-degree relative Estrogen deficiency, including menopause onset <age 45 Caucasian race Excessive Alcohol Advanced age Low calcium intake (lifelong) Female Cannot Change1 Potential for Change1 Vitamin D Insufficiency Specific Medications Specific Diseases Sedentary – lack of weigh-bearing exercise Female Athlete Triad Eating disorders Risk Factors

47. Screening Osteoporosis

48. Screening

49. The gold standard test for diagnosis1 • Measures1 • Spine • Hip • Forearm • Less radiation than in the environment1 • Provides theT Score1 DXA Scan

50. T-Score Definitions