Learning Objectives. Controversies in Osteoporosis Prevention and Management. Etiology. Presenter Disclosure Information. Epidemiology.

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1 12:45 1:30pm Controversies in Osteoporosis Prevention and Management SPEAKER Carolyn Crandall, MD, MS Presenter Disclosure Information The following relationships exist related to this presentation: Carolyn Crandall, MD, MS, has no financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning Objectives Controversies in Osteoporosis Prevention and Management Carolyn J. Crandall, MD, MS Professor of Medicine David Geffen School of Medicine at UCLA 1. Understand the guidelines and controversies regarding choice, benefits, and adverse effects of therapy 2. Understand the current controversies regarding duration of therapy and monitoring during therapy Epidemiology 1 in 2 postmenopausal women and 1 in 5 older men will have an osteoporosis-related fracture in their lifetimes!! (USPSTF, Ann Intern Med 3/1/2011) Etiology Disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture million Americans with osteoporosis million Americans low bone density (Wright et al JBMR 2014) (NIH Consensus Development Panel JAMA 2001; 285(6): )

2 Screening Guidelines: Women Women 65 years or older (USPSTF 2011, NOF 2014) Postmenopausal women aged 50-69: fracture during adulthood condition (e.g. rheumatoid arthritis) or medication associated with low bone mass or bone loss (NOF 2014) Women <65 y/o whose fracture risk is that of a 65- year-old white woman who has no additional risk factors (i.e. 9.3%) (USPSTF 2011) (USPSTF, Ann Intern Med 3/1/2011, National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 FRAX 2014 practical considerations (contd.) Not validated for spine bone mass If normal hip bone mass with low spine bone mass, FRAX underestimates fracture risk Not validated for: Patients treated with osteoporosis pharmacotherapy past 1-2 years FRAX underestimates fracture risk in patients with: Recent or multiple fractures Those at increased risk for falling Prevention and Treatment of Osteoporosis 2014 Screening guidelines: men 70 years-old, or fracture after age 50 or condition (e.g. rheumatoid arthritis)/medication (e.g. glucocorticoids) associated with low bone mass/bone loss (NOF 2014) Current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. (USPSTF 2011). (USPSTF Ann Intern Med 3/1/2011, National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 Screening guidelines: men Considerations: Potential preventable burden is increasing due to aging U.S. population Potential harms are likely to be small Men most likely to benefit from screening have a 10- year risk for osteoporotic fracture equal to or greater than that of a 65-year-old white women without risk factors (which is 9.3%). (USPSTF, Ann Intern Med 3/1/2011) Which test? Current diagnostic and treatment criteria rely on dualenergy x-ray absorptiometry (DXA) : Hip Lumbar spine. (USPSTF Ann Intern Med 3/1/2011, National Osteoporosis Foundation Clinician s Guide to Interpreting the DXA: 50 yrs old Classification BMD T-score Normal Within 1 SD of a young T-score at -1.0 and adult reference population above Low Bone Mass (Osteopenia) Osteoporosis Severe or Established Osteoporosis Between 1.0 and 2.5 SD below that of a youngadult reference population 2.5 SD or more below that of a young-adult reference population 2.5 SD or more below that of a young- adult reference population T-score between -1.0 and -2.5 T-score at or below -2.5 T-score at or below -2.5 with one or more fractures Prevention and Treatment of Osteoporosis 2014

3 Clinical Diagnosis: NOF Diagnosis is by either: Adulthood hip or vertebral fracture in the absence of major trauma (such as motor vehicle accident of multiple story fall) or BMD T-score -2.5 at lumbar spine or hip Diagnosis <50 y/o: Z-score (age-match reference) Z-score 2.0 below expected range for age Whom to treat: NOF 2014 Postmenopausal women and men age 50 if: Hip or vertebral (clinical or asymptomatic) fracture T-score -2.5 femoral neck, total hip, or lumbar spine Low bone mass (T-score between -1.0 and -2.5 at femoral neck, total hip, or spine) if: 10-yr probability of hip fracture 3% or 10-yr probability of any major osteoporosis-related fracture 20% based on U.S. WHO FRAX. New emphasis! Most fractures occur in patients with low bone mass rather than osteoporosis Because of large # of individuals with low bone mass Vertebral fractures detected incidentally by x-ray confer dx of osteoporosis. So. vertebral x-rays low bone mass or height loss: T-score -1.0 ( 70 y/o 80 y/o) T-score -1.5 ( 65-69, y/o) Height loss 1.5 vs. peak, 0.8 in clinic over time - yearly! Low-trauma fx, recent/chronic prednisone use Prevention and Treatment of Osteoporosis 2014) Funded by Agency for Healthcare Research and Quality and RAND Corporation (Crandall, et al, Annals of Internal Medicine 2014 Sept 9, doi: /M Epub ahead of print) Choice of therapy: systematic review efficacy High-strength evidence that the following drugs reduce fractures compared with placebo: Denosumab Teriparatide Risk reductions 40-64% for vertebral fractures, 20-40% for nonvertebral fractures However, raloxifene and teriparatide have not been demonstrated to decrease hip fractures. Demonstrated hip fracture reduction: bisphosphonates, denosumab (Crandall et al Annals of Internal Medicine 2014) Choice of therapy: systematic review adverse effects Mild upper GI symptoms: VTE, fatal stroke: raloxifene Denosumab Atypical subtrochanteric Teriparatide fracture: Influenza-like symptoms: Zoledronic acid per 100,000 women Serious infections: Osteonecrosis of the jaw: Denosumab (cellulitis, infectious arthritis, 0.03%-4.3% (pending endocarditis) new standardized case (Crandall et al Annals of definitions) Internal Medicine 2014)

4 Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Second Report of a Task Force of the American Society for Bone and Mineral Research Reported in patients taking BPs, and in patients on denosumab Occur in patients with no exposure to these drugs. Absolute risk with BPs is low, 3.2 to 50 cases per 100,000 person-years. Long-term use may be associated with higher risk (~100 per 100,000 person-years) (Shane et al JBMR 2013) Choice of therapy: Guidelines USPSTF The harms of bisphosphonates, the most commonly prescribed therapies, are no greater than small. (Ann Intern Med March ). What do I do? Balance with absolute risk of fracture if untreated: Likely benefits outweigh risks: Preexisting vertebral or hip fracture L-spine or hip BMD T-score -2.5 Unlikely benefits outweigh risks: Absolute 10-year risk of fracture 3% at hip or 20% for major osteoporotic fracture Calcium and Vit. D supplementation: USPSTF guideline is focused on 1 prevention of fractures! Group vit. D 400 IU/d + Ca 1000 mg/d Men Women Premenopausal Postmenopausal Against noninstitutionalized Dose Vit. D > 400 IU/d + Ca >1000 mg/d (summarized from Moyer et al, Ann Intern Med. 2013;158: ) Do not apply 1 prev. guideline to adults with osteoporosis. Instead, use the Institute of Medicine 2010 guidelines: Monitoring: Serial testing USPSTF Evidence is lacking about optimal intervals. Because of limitations in the precision of testing: minimum of 2 years to reliably measure a change in BMD longer intervals may be necessary to improve fracture prediction. (Ann Intern Med 3/1/2011) Monitoring: Serial testing in untreated women Study of Osteoporotic Fractures postmenopausal women 65 y/o If baseline T-score is. then the interval capturing 90% of women developing osteoporosis during f/u is to years to years to year (Gourlay et al NEJM 2012) Monitoring during therapy & treatment duration? Systematic review Duration: RCTs were not specifically designed to compare shorter with longer duration of therapy. (posthoc analyses) Optimal duration of therapy unknown. Monitoring: RCTs were not designed to show that monitoring BMD during therapy decreases hip fractures. For patients receiving antiresorptive therapy for whom serial BMD measurements have not shown an increase, or who have decreases in BMD, statistically significant benefits are still obtained in terms of fracture reduction (Crandall et al Annals of Internal Medicine 2014)

5 Duration of therapy: NOF Guidelines After the initial 3-5 year treatment check: interval fractures, new chronic diseases, new chronic meds Height measurement BMD testing Vertebral imaging if height loss during rx New innovations in monitoring untreated patients Population-based Framingham Osteoporosis Study, mean age 75 years. Median follow-up of 9.6 years In untreated older persons, a 2 nd BMD measure after 4 years did not meaningfully improve prediction of hip or major osteoporotic fracture. (Berry et al JAMA 2013) Prevention and Treatment of Osteoporosis 2013 Additional refs : Black et al NEJM 2012, Black et al JBMR 2012 New innovations in monitoring: treated patients Prospective Fracture Intervention Trial Long-term Extension (FLEX) study Among women who discontinue alendronate after 4-5 years: Age and hip BMD at discontinuation predict clinical fractures in the subsequent 5 years DXA and bone turnover markers 1 year after discontinuation do not. (Bauer et al JAMA Intern Med 2014) New medication in 2014: TSEC Tissue-selective Estrogen Complex: Conjugated estrogens (0.45mg) + bazedoxifene (20mg) daily Bazedoxifene is an estrogen agonist/antagonist Only for postmenopausal women who still have uterus, osteoporosis prevention (No fracture data available) (A few ) Gaps in knowledge What is optimal: Exercise type, intensity, duration, freq.? Optimal duration, long-term AEs meds Role of drug combinations/sequential meds? Screening/treatment in men? How to: Assess bone strength? Incorporate lumbar BMD into FRAX? Assess fracture risk during pharmacological rx? Maximize peak bone mass? Accurately/consistently diagnose vert. fx? Treat pts to a certain goal? Summary Screen women 65 years and older, younger women based on risk factors/frax Measure height in those reporting height loss and/or low bone density (alters rx decisions) Don t ignore incidentally-detected vertebral fx Use FRAX to aid treatment decisions in persons over age 50 with low bone density (not in osteoporotic range) Counsel about low absolute risk of serious AEs with bisphosphonates, balance against fx risk if no therapy Counsel to avoid excessive alcohol intake/smoking. Menopausal hormone therapy not appropriate 1 therapy in absence of vasomotor sx.

6 Only 2 in 10 fractures are followed up with testing or treatment! After hip fracture: Only 40% fully regain their pre-fracture level of independence. (NOF 2014) References Ruggiero et al, Medication-Related Osteonecrosis of the Jaw-2014 Update, American Association of Oral and Maxillofacial Surgeons Position Paper, 2014, available at Shane et al, Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Second Report of a Task Force of the American Society for Bone and Mineral Research, J Bone Miner Res Jan;29(1):1-23 Eisman et al, ASBMR Task Force on Secondary Fracture Prevention. J Bone Miner Res Oct;27(10):