1. Osteoporosis

2. Introduction 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

3. Anatomy Compared to men, women have: Weaker bones: Smaller bone cross-sectional area 1,4 Less cortical bone thickness 4 Lower peak bone mass 1,2 Higher risk for osteoporosis: Less bone mineral density 2,4 Bone density that decreases more with age 1 Normal BoneOsteoporosis Cortical thickness

4. Physiology Osteoclast RANK Ligand RANK Receptor Osteoprotegerin Cells of bone remodeling: Osteoblasts build bone Osteoclasts resorb bone Proteins that regulate bone remodeling: RANK Ligand stimulates osteoclasts 1 Osteoprotegerin inhibits RANK Ligand 2 Osteoblasts Osteoclasts

5. Pathology Higher Peak Bone Mass 3,4 Age (in years) Bone Mass Menopause (rapid bone loss) 2

6. Estrogen Estrogen promotes bone formation 1 RANK LigandOsteoprotegerin After menopause, estrogen levels drop Women experience rapid bone loss after menopause due to estrogen deficiency 2

7. Testosterone Testosterone: Stimulates osteoblasts 3 Inhibits osteoclasts 3 Increases bone size and BMD 3 Mediated by an androgen receptor 3 Men with low testosterone are susceptible to osteoporosis 3

8. Epidemiology 80% 20% Will suffer an osteoporosis related fracture within their lifetimes 2 Reported Cases of Osteoporosis 1 - Total: about 6 million people 20% of Men 50% of Women

9. Fracture Incidence Estimated annual incidence 2 Total fractures: 9 million Hip fractures: 1.6 million Forearm fractures: 1.7 million Vertebral fractures: 1.4 million

10. Fracture Comparison

11. Treatment

12. Bisphosphonates Promotes bone formation and decreases bone resorption Mechanism of Action First line treatment for osteoporosis in both men and post- menopausal women 1 Application Approved in both sexes for the prevention and treatment of osteoporosis Aledronate 2, Risedronate 3 and Zoledronic Acid 4

13. Bisphosphonates Ibandronate (Boniva) Only FDA approved for treatment (not prevention) of osteoporosis in post- menopausal women Not FDA approved for males Paucity of studies 1 Similar pharmocokinetics in men and women 2 Similar efficacy in men and women probable 3

14. Bisphosphonates DrugVertebral Fracture RR Hip Fracture RR Non- vertebral RR Route/ Frequency Indicated for which gender AlendronatePO/QDay, QWeek Women Men RisedronatePO/QDay, QWeek, QMonth Women Men IbandronateNE PO/QMonth IV/Q3Mont h Women Zoledronic Acid IV/QYearWomen Men RR = Risk ReductionNE = No effect demonstrated

15. Other Agents DrugVertebral Fracture RR Hip Fracture RR Non- vertebral RR Route/ Frequency Indicated for which gender RaloxifeneNE PO QDayWomen CalcitoninNE Nasal QDay SQ QDay Women TeriparatideSQ QDayWomen Men DenosumabSQ Q6Months Women Men RR = Risk ReductionNE = No effect demonstrated

16. Estrogen & Bone Metabolism

17. Estrogen in Females Estrogen’s protective role in bone metabolism has long been appreciated 1 Decline of estrogen in postmenopausal females provides a ready example of estrogen’s protective role in bone metabolism 2 Estrogen HRT in postmenopausal women has been shown to: prevent bone loss (Maintain BMD) decrease bone remodeling and incidence of vertebral fracture 3 HRT- Hormone Replacement Therapy

18. Estrogen in Males Testosterone & estrogen decline with aging1 Estrogen has a greater role in preventing bone resorption in both males & females2 Testosterone’s influence on bone metabolsm is minimal in both sexes2

19. Raloxifene Mechanism of Action: selective estrogen-receptor modulator – Benefits Increases BMD of hip and spine in women 1 Females: approved for treatment and prevention of osteoporosis in women. Not approved in males 2 – Narrow study contexts 3,5 – Was not shown to significantly impact BMD in males 4

20. Tissue Selective Estrogen Complex 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

21. Tissue Selective Estrogen Complex Bazedoxifene/Conjugated Estrogen (Cont’d) – Approved in Women for 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.

22. Calcitonin-Salmon 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

23. Teriparatide (Forteo) Mechanism of Action: recombinant parathyroid hormone (PTH); stimulates bone formation. Approved for – Treatment & prevention of osteoporosis in men and postmenopausal women 1 – Especially those at high risk for vertebral fracture 2

24. Teriparatide Efficacy Extent of lumbar BMD increase similar in both males 1 and postmenopausal females 2 Significantly increased lumbar BMD from baseline levels 3

25. Calcium & Vitamin D NOF Recommended Daily Intake: CalciumMen: 1000 mg Women: 1200 mg Vitamin D Men & Women: 800 – 1000 units

26. Calcium and Vitamin D 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

27. Calcium and Vitamin D Hip Fracture Incidence

28. Calcium & Vitamin D 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 men 1 2007 Tang et al 2. Meta-Analysis included only 8% men 3

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

30. Denosumab (Prolia) Approved to increase BMD in 1,2 – 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.

31. Denosumab Increased: BMD at all skeletal sites (lumbar spine, femoral neck, trochanter, radius & total hip) Decreased : serum bone turnover markers, incidence of vertebral fracture in those with non-metastatic prostate cancer. Efficacy in Males

32. Denosumab Increased vertebral, hip and non-vertebral BMD 1. Decreased incidence of vertebral, hip and non- vertebral fractures 1,3 Efficacy in Females

33. Denosumab Research Disparities No data for fracture incidence in males without non- metastatic prostate cancer 1. Few phase III clinical trials have thoroughly investigated the efficacy of Denosumab in males, though it has been shown to be a beneficial treatment option. In Males, Major phase III clinical trials studied Denosumab efficacy in >2000 postmenopausal females2 – no equivalent in males. Examples: FREEDOM, DEFEND, DECIDE & STAND studies 3 In Females,

34. Fracture Prognosis

35. Fracture Morbidity Compared to men, Women: - Are almost twice as likely to survive - Are more likely to return to home - Are more likely to return to walking independently Compared to women, Men: - Have higher early post-operative mortality -Are less likely to return to independent living or mobility. WOMEN MEN

36. Fracture Mortality Men 197 out of 343 died Women 461 out of 952 died The Dubbo Osteoporosis Epidemiology Study 1

37. Osteoporosis Treatment after Hip Fracture 1 2

38. Risk Factors Cannot Change 1 Potential for Change 1 Menopause History of fracture in first-degree relative Caucasian race Advanced age Female Smoking Estrogen deficiency, including menopause onset <age 45 Low calcium intake (lifelong) Excessive Alcohol Vitamin D Insufficiency Specific Medications Specific Diseases Sedentary Female Athlete Triad Malnutrition

39. Screening Criterion 1 WomenMen Age-Based 65 years and older 70 years and older Based on Risk Factors Postmenopausal, < 65 with 1+ risk factor(s) Perimenopausal with specific high-risk factor associated with increased fracture risk Postmenopausal, discontinuing estrogen 50-70 years with 1+ risk factor(s) Regardless of Gender Fragility fracture (after age 50) High-risk condition or exposure to high-risk medication associated with low bone mass or bone loss Anyone being considered for pharmacologic therapy

40. DXA Scan The gold standard test for diagnosis 1 Measures 1 – Spine – Hip – Forearm Less radiation than in the environment 1 Provides the T Score 1

41. T-Score Definitions Diagnosis 1 T-Score 1 Normal BMDBMD is within 1 SD of a healthy young adult: T-score > -1.0 OsteopeniaBMD is between 1.0 and 2.5 SD below that of a healthy young adult: T-score between -1.0 and -2.5 OsteoporosisBMD is 2.5 SD or more below that of a healthy young adult: T-score < -2.5 Established Osteoporosis BMD representing a T-score ≤ –2.5 and the presence of one or more fragility fractures

42. Cost-Effectiveness Screening is Cost-Effective in Women >65 1 Screening is NOT Cost-Effective in Men >70 1

43. Gender Awareness Osteoporosis considered a “Woman’s Disease” 1 20% of men will suffer from osteoporosis 1 Research is biased towards women 2 Men have worse outcomes 3