Osteoporosis Puzzle: Next Steps Fractures with osteoporosis over - PDF document

Burden of Osteoporosis Osteoporosis Puzzle: Next Steps • Fractures with osteoporosis over the age 50? – 1 in 2 women Roger Long, MD – 1 in 4 men Normal • By 2020, Professor of Pediatrics (and Internal Medicine) – 12.3 million in US older than 50 are Division of Endocrinology expected to have osteoporosis (13.6 m by University of California, San Francisco 2030) Osteoporotic • Prevalence: – Highest: Mexican/American and non-Hispanic Disclosures: None white – Lowest: Non-Hispanic blacks NOF; USPSTF. JAMA 2018 319:2521 1 2 When to screen? Burden of Osteoporosis USPSTF 2018 • Women: Osteoporotic fractures, effects of – > 65 yo – ~40% unable to walk independently at 1 yr – < 65 yo, increased risk of fracture (using risk calculator tool) • FRAX MOF > 8.4% (65 yo white female, no risk factors) – ~60% require assistance for at least 1 ADL • Men: –Hip Fracture – No screening recommendation as primary fracture risk is low • 20-30% mortality at 1 year – Per FRAX, MOF risk in 80 yo male equal to 65 yo female NOF, ISCD, ACOG, Endocrine Society: • Women: Similar recommendations NOF, ISCD, Endocrine Society: • Men: – > 70 yo, < 70 yo with risk factors 3 4

Who is at risk for fracture? WHEN to treat? • Those with diagnosis of osteoporosis – DXA scan: T scores < -2.5 • Costs(risks) vs. benefits • Modifiers of fracture risk: – Previous fracture – Parent hip fracture • When is the risk of fracture high enough? – Female Sex – Age – Hip or vertebral fracture – Low BMI – T-score ≤ - 2.5 – Chronic illnesses – 10 year fracture risk (FRAX) – Glucocorticoids ≥ 3% hip fracture – Smoking ≥ 20% major osteoporosis-related – Alcohol fracture* – Falls * Generic bisphosphonate for cost-benefit analysis 5 6 Sample FRAX Calculation: WHY to treat? • To reduce risk of fracture » Can’t turn bones to steel, but can make them stronger Available at: www.shef.ac.uk/FRAX. 7 8

WHAT treatments? Calcium and Vitamin D Universal measures Risk factor reduction • Foundation for treatment regimens – Factors related to bone mass (meds, alcohol, • Presumed anti-fracture benefit smoking) – Factors related to falling (meds, environment) – When taken together Exercise • Calcium intake (~1200 mg/day) – – Weight bearing aerobic exercise (target 30 min 3x/wk) ideally from diet • Minimal skeletal loading is required to maintain skeletal mass – Muscle strengthening (large muscle groups) • Vitamin D (600-1000 units per day) Optimize nutritional status – Adequate protein and calories 9 10 Medication options Bisphosphonates Anti-resorptive agent • First line therapy for osteoporosis (without a high Reduce remodeling risk of fracture) - Bisphosphonate – Fracture Risk Reduction (vs placebo)*: Alendronate (approved 1995) Risedronate (approved 1998) • Vertebral: 33-52% Ibandronate (approved 2003) • Hip: 27-40% Zoledronate (Reclast) (approved 2007) • Nonvertebral: 16-22% - Denosumab (approved 2010) » Based on trials: Efficacy Anabolic agent » Alendronate: up to 10 years » Risedronate: 7 years Increase bone remodeling and modeling - Teriparatide (approved 2002) » Zoledronate: 6 years - Abaloparatide (approved 2017) - Romosozumab (approved 2019) *Barrioneuvo P, et al. JCEM 2019. 104:1623 11 12

Adverse effects: Bisphosphonate Effects Adapted from Endocrinology Advisor Atypical Femur Fracture (AFF) Osteonecrosis of the Jaw • First reported association with BPs • First reported association in 2003 in 2005 • Incidence 1/10,000-100,000 pt- • Likely duration response years relationship • Advise regular dental care, • Using previous figure (5yrs BP use): avoidance of invasive dental procedures – 2590 fractures averted for 16 AFF, Or 162 fractures/AFF • Risk likely higher in Asian • Prodromal thigh/groin pain populations • Risk likely higher in Asian populations Report from ASBMR Task Force: Managing osteoporosis in patients on long term bisphosphonate therapy. JBMR 2016 13 14 Long term treatment approach: When to restart? Post-menopausal women • No guidelines to date • Considerations: – Decreasing BMD – Increasing bone turnover markers • Suppression of BTM – Alendronate 2-3 yrs – Risedronate/Ibandronate 1-2 yrs – Zoledronate ~3 yrs When is there treatment failure? • Fracture greater than 1 year into treatment • BMD decrease > 5% or > LSC Report from ASBMR Task Force: Managing osteoporosis in patients on long term bisphosphonate therapy. JBMR 2016 15 16

Denosumab Alternative Therapies • Blocks osteoclast formation – Consider in bisphosphonate intolerance or failure or renal insufficiency • Fracture Risk Reduction (vs placebo)*: – Vertebral: 68% – Hip: 44% – Nonvertebral: 20% *Barrioneuvo P, et al. JCEM 2019. 104:1623 17 18 FREEDOM trial Rebound Vertebral Fractures Post-menopausal women, 60-90 yo, osteoporosis • Caution when doses missed or medication discontinued. Vertebral fractures within 6 mo. • Every 6 month 3 year RCT, 7 year injection extension/crossover Any Multiple • Uses immune system to block formation of cells that resorb bone • Similar concerns about ONJ/atypical • Higher rates in those with prevalent fractures femur fractures • No difference in nonvertebral fracture rates • Role of bisphosphonate to prevent Bone HG. Lancet 2017. 5:513 – Timing unclear Cummings SR. JBMR 2018. 33:190 19 20

High Fracture Risk Anabolics • Severe osteoporosis – T score < -3.5 • T score < -2.5 and fragility fracture – Fragility fracture significance • 1 in 5 will have another fracture in 2 years – Vertebral fracture significance • 5% with prevalent (date unknown) fracture and 20% with incidence (within 1 yr) will have another vertebral fracture in next year. • Argument for first line anabolic therapy 21 22 Anabolics • Treatment course – Teri/Abalo: 18-24 months – Romo: 1 year • Must follow treatment with antiresorptive therapy to preserve gains. Sclerostin secreted by osteocytes negatively regulates bone formation • Fracture Risk Reduction (vs placebo): Abalo Teri Romo Vertebral: 86% 73% 67% Hip: 76%* 36%* 56% Sclerosteosis – homozygous LOF mutation Romosozumab – Nonvertebral: 49% 38% 33% monoclonal Ab * not significant against sclerostin *Barrioneuvo P, et al. JCEM 2019. 104:1623 23 24

Teriparatide vs Risedronate VERO: Fracture Outcome VERO study • Post-menopausal women – high risk of fracture – T score <-1.5 AND at least 2 moderate or 1 severe vertebral fracture. • Randomized/double blind/double dummy • 2 year duration • 1366 enrolled. Kendler DL. Lancet 2018. 391:230. 25 26 Abaloparatide vs. Teriparatide ACTIVE: Outcomes ACTIVE study • Post-menopausal women – high risk of fracture – T score <-2.5 AND at least 2 mild or 1 moderate vertebral fracture or fragility fracture within past 5 years. Or, > 65 yo with Tscore < -3 without fracture. • Equal vertebral fracture risk reduction • Randomized to Abalo/Teri/Placebo versus placebo • 18 month duration – Abalo: 86% Teri: 80% • 2463 enrolled. 27 28

Romosozumab Anabolic AEs 3 trials: New vertebral fractures PTH/PTHrP – Hypercalcemia – Hyperuricemia – Hypothetical Osteosarcoma risk • Contraindicated in open growth plates, bone tumors, Paget Disease, skeletal irradiation Romosozumab – Potential increase CV risk • Do not use within 1 year of MI or stroke Langdahl BL. Lancet 2017. 390:1585; Cosman F . NEJM 2016. 375:1532; Saag KG. NEJM 2017. 377:1417. 29 30 Questions? Vitamin K • 2011: Japanese guidelines for prevention and treatment of osteoporosis – Included Vitamin K treatment • Largely based on studies that have been retracted 31 32

Vitamin K • Updated meta-analysis • In post-menopausal or osteoporotic patients • Vitamin K: – Clinical fracture: OR 0.72 (0.55-0.95) – BMD and Vertebral Fx: no difference Mott A, et al. Osteoporosis Int 2019. 30:1543 33