1. Treatment

2. 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

3. 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

4. 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

5. 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

6. Estrogen & Bone Metabolism

7. 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

8. 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

9. 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

10. 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

11. 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.

12. 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

13. 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

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

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

16. 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

17. Calcium and Vitamin D Hip Fracture Incidence

18. 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

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

20. 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.

21. 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

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

23. 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,