Current and Emerging I have nothing to disclose. Strategies for - PDF document

Current and Emerging I have nothing to disclose. Strategies for Osteoporosis Anne Schafer, MD Assistant Professor of Medicine Division of Endocrinology & Metabolism December 12, 2014 Outline Osteoporosis Has Tremendous Medical and Economic Impact • Osteoporosis screening and diagnosis • Nonpharmacologic strategies • Mortality after hip fracture ~25% at 1 yr • Pharmacologic therapy ▫ Of survivors, only 50% recover pre- fracture functional status ▫ Whom to treat • 1.5 million fractures per year in US ▫ FDA-approved medications ▫ Common patient questions • Direct cost $18 billion ▫ Combination therapy Lu-Yao, Am J Pub Health, 1994; Magaziner, J Gerontol, 1990; Burge, JBMR, 2007

Osteoporosis Definition Risk Factors for Osteoporosis • A chronic, progressive disease Non Modifiable Modifiable characterized by • Increasing age • Low BMI ▫ low bone mass, • Female gender • Current smoking • White or Asian race • Alcohol ( ≥ 3/day) ▫ microarchitectural deterioration of bone, • Family history • Immobilization ▫ bone fragility and a consequent increase • Previous • Glucocorticoids in fracture risk osteoporotic fracture • Sex hormone deficiency • Decreased bone quality as well as • Falls quantity National Osteoporosis Foundation, 2008 Screening for Osteoporosis Screening for Osteoporosis US Preventive Services Task Force: National Osteoporosis Foundation: • Women age ≥ 65 • Women age ≥ 65 and men age ≥ 70 • Younger women whose risk is equal to that • Younger postmenopausal women, and men of a 65 y.o. white woman who has no age 50-69, with additional risk factors additional risk factors • Adults with a condition or taking a ▫ 9.3% ten-year risk for any osteoporotic medication associated with bone loss fracture, by the US FRAX algorithm • Adults who fracture after age 50 • Current evidence insufficient to assess benefits vs. harms in men National Osteoporosis Foundation, 2008 United States Preventive Services Task Force, 2011

DXA Scanning WHO Definitions - 1994 • Assesses 2-dimensional BMD • Normal ▫ Lumbar spine, total hip, femoral neck ▫ BMD within one SD of a “ young normal ” adult (T-score +1.0 to -1.0) • Same machine, by same operator, for • Low bone mass ( “ osteopenia ” ) optimal longitudinal assessment ▫ T-score -1.0 to -2.5 • Reports BMD (g/cm 2 ), T-scores, Z-scores • Osteoporosis ▫ T-scores: compared to sex-matched reference population of young adults ▫ T-score ≤ -2.5 ▫ Z-scores: age- and sex-matched For use in postmenopausal women and men age ≥ 50 WHO, 1994 What about premenopausal women Approach to Osteoporosis Treatment and men <50? 1) Evaluate for secondary causes of bone • Diagnosis more complicated loss/fracture • ISCD: ▫ “Low BMD for age” when Z-score ≤ -2.0 2) Institute nonpharmacologic strategies ▫ Don’t diagnose osteoporotic by BMD alone 3) Select pharmacologic therapy • Example of diagnostic challenge: Adolescent girl who has not attained peak bone mass Simonelli et al., J Clin Densitom, 2008

Secondary Causes of Osteoporosis How extensive a laboratory work- and/or Fracture up does a patient need? • Depends on degree of suspicion • Vitamin D deficiency • Rheumatoid arthritis • Medications ▫ Pre-menopausal women, men deserve more • Calcium deficiency ▫ Glucocorticoids ▫ Severe (e.g., multiple fractures, very low Z-scores) • Malabsorption (e.g., celiac ▫ Aromatase inhibitors disease, gastric bypass • Basic: Serum Ca, alb, Cr, 25(OH)D, TSH, surgery) ▫ Depo-Provera CBC, LFTs ▫ Thyroid hormone • Hypogonadism • Next level: PTH, testosterone in men excess • Thyrotoxicosis • Consider: 24h urinary Ca, SPEP/UPEP ▫ Thiazolidinediones • Primary hyperparathyroidism ▫ Phenytoin • As clinically indicated: Celiac Abs, 24h urinary • Anorexia nervosa ▫ Androgen deprivation free cortisol/dexamethasone suppression test • Multiple myeloma therapy Nonpharmacologic Strategies IOM Dietary Reference Intakes • Calcium CALCIUM CALCIUM VITAMIN D VITAMIN D AGE (mg) (RDA) (mg) (UL) (IU) (RDA) (IU) (UL) • Vitamin D • Weight-bearing & resistance exercise 19-50 1000 2500 600 4000 • Smoking cessation 1000 (men) 51-70 2000 600 4000 1200 (women) • Alcohol moderation • Fall prevention measures >70 1200 2000 800 4000 ▫ Home safety evaluation 19-50, ▫ Medication review pregnant/ 1200 2000 800 4000 lactating ▫ Hip protectors Institute of Medicine, 2010

Vitamin D: The Controversy Pharmacologic Therapy • IOM: 25(OH)D ≥ 20 ng/mL adequate NOF recommends osteoporosis medication for ▫ Based on rigorous RCT evidence postmenopausal women and men ≥ 50 with ▫ Population-based recommendation • An osteoporotic hip or vertebral fracture • Others insist ≥ 30 ng/mL optimizes Ca • T-score at the femoral neck or spine ≤ -2.5 absorption, suppresses PTH, protects after secondary causes excluded against fractures/falls • Low bone mass (T-score < -1.0 but > -2.5) • More than 600-800 IU daily may be and FRAX 10-year risk of needed to achieve ≥ 20 (or ≥ 30) ng/mL - major osteoporotic fracture ≥ 20%, or ▫ Malabsorption, obesity - hip fracture ≥ 3% Institute of Medicine, 2010; Endocrine Society, 2011 Tosteson, Osteoporos Int, 2008 FRAX FRAX • Estimates 10-year absolute fracture risk • Especially for those in low bone mass ( “ osteopenia ” ) range ▫ Example: 80 y.o. w/ prior fracture and taking prednisone, 52 y.o. with no risk factors, both with femoral neck T-score -2.0 • Applies to postmenopausal women and men ≥ 50 y.o., who are treatment naïve Kanis, Osteoporos Int, 2008 www.sheffield.ac.uk/FRAX/

Pharmacologic Therapy Bone Resorption • Antiresorptive agents ▫ Bisphosphonates (oral or IV) ▫ Raloxifene ▫ Estrogen therapy ▫ Calcitonin ▫ Denosumab • Anabolic agents ▫ Parathyroid hormone (PTH) Bisphosphonates cause osteoclast apoptosis From Bob Josse, HealthPlexus 2010 Oral Bisphosphonates IV Bisphosphonates • Zoledronic acid • Alendronate, risedronate, ibandronate ▫ Once yearly infusion ▫ Alendronate and risedronate: ↓ risk of spine, nonvertebral, hip fractures ▫ ↓ risk spine, nonvertebral, hip fxs ▫ Ibandronate: ↓ risk spine fracture ▫ Given w/in 90 days of hip frx: ↓ mortality • Side effect: esophagitis • Side effect: transient flu-like symptoms • Potential complication (of any antiresorptive): � Full glass of water, do not lie down osteonecrosis of the jaw • Inefficiently absorbed ▫ Risk 1-10/100 with IV therapy at cancer doses; � Take on empty stomach ~1/100,000 with oral therapy for osteoporosis Black, 1996; Cummings, 1998; Harris, 1999; McClung, 2001; Chesnut, 2004 Black, N Engl J Med, 2007; Lyles, N Engl J Med, 2007; Khosla, JBMR, 2007

Raloxifene, Estrogen, Calcitonin Bone Resorption Denosumab • Raloxifene ▫ ↓ risk spine fractures (not NVF) ▫ ↓ risk breast cancer ▫ ↑ risk venous thromboembolism • Estrogen or estrogen/progestin therapy ▫ ↓ risk spine, nonvertebral, hip fxs ▫ Other concerns • Calcitonin Denosumab binds to RANKL ▫ ↓ risk spine fracture (not NVF) and inhibits activation of ▫ Analgesic benefit in pts with vertebral fxs? RANK Bob Josse, HealthPlexus 2010 Ettinger, JAMA, 1999; Rossouw, JAMA, 2002; Anderson, JAMA, 2004; Chesnut, Am J Med, 2000 Denosumab Teriparatide (PTH Therapy) • Sole anabolic agent currently available • Monoclonal antibody to RANK-ligand ▫ ↑ bone formation • ↓ risk of spine, nonvertebral, hip fractures • ↓ risk of spine and nonvertebral fractures • SubQ injection q 6 months • Daily subQ injection • Expensive • Approved for 2 years of use • Can be used in renal failure • Consider in severe disease, especially ▫ But be careful that you are treating spine > hip osteoporosis, not CKD-MBD • Follow course with a bisphosphonate Cummings, N Engl J Med, 2009 Neer, N Engl J Med, 2001; Black, N Engl J Med, 2005

You start Ms. O, a 70 y.o. woman with osteoporosis, on alendronate. “ How long will I take this medication? ” Adapted from Canalis et al., NEJM, 2007) Duration of Bisphosphonate Therapy Duration of Bisphosphonate Therapy • FLEX: After 5 years of alendronate (ALN), • HORIZON-PFT extension trial: After 3 randomized to continued ALN vs. placebo years of zoledronic acid (ZOL), randomized to continued ZOL vs. placebo ▫ ALN group had continued reduction in ▫ Those with 3 years on, 3 years off had a clinical (but not radiographic) vertebral fx small but significant decline in BMD ▫ Those in ALN group with femoral neck T- ▫ Those with 6 years ZOL had fewer scores ≤ -2.5 had continued nonvertebral fx radiographic vertebral fractures (but no risk reduction difference in other fracture types) Black, JAMA, 2006; Schwartz, J Bone Miner Res, 2010 Black, JBMR, 2012