Current and Emerging Strategies for Osteoporosis Jeffrey A. Tice, MD Professor of Medicine Division of General Internal Medicine, I have no conflicts of interest University of California, San Francisco 1 2 Overview • Under-diagnosis and under-treatment Under-diagnosis and under-treatment • Risk assessment and evaluation • Prevention • Pharmacologic treatment – Recommended therapies – Treatment harms – When to start and stop drug therapy • Summary 3 4 Page 1
How many women are treated for Risk for fractures osteoporosis within one year of hip fracture? 44% • Lifetime risk for osteoporotic fractures A. 15% – Women: 50% B. 25% – Men: 20% 24% C. 50% • US Hospitalizations for women ages ≥ 55 18% years between 2000 and 2011 D. 75% 11% – Osteoporotic fractures 4.9 million E. 90% – Stroke 3.0 million 2% – MI 2.9 million % % % % % 5 5 0 5 0 1 2 5 7 9 Harvey et al, 2008;Singer et al, Mayo CP, 2015 5 6 Under Recognition of Osteoporosis And it is getting worse… • Osteoporosis (like hypertension) is silent until fracture – Women with fracture or BMD<-2.5: only 20-30% are evaluated and treated! – 12 months after hip fracture: 2% had DXA, 15% treated with appropriate drug • Implications : Ask about fracture history, note vertebral fractures, use chart reminders for DXA Soloman, Mayo Clin Proc, 2005 Shibli-Rahhal, Osteo Internat, 2011 7 8 Page 2
Adherence with Treatment is Poor • 30-50% persistence after one year • Why? – Oral burdensome: fasting, remain upright for 30 minutes – Parenteral: daily injections; infusion at doctors office – Upset stomach and heartburn; infusion reactions – Asymptomatic until fracture Clowes, JCEM, 2004 9 10 What is osteoporosis? Adverse Publicity: Effect on Oral Bisphosphonate Use in USA A disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. World Health Organization (WHO), 1993 Normal bone Osteoporosis Jha S et al JBMR 2015 11 12 Page 3
Bone density measurement: Traditional Risk Factors for Fracture Dual energy x-ray absorptiometry (DXA) • The Big Three: • Absolute mineral (calcium) content using x-rays – Age – Not used clinically – Postmenopausal • T-score is the number of standard deviations above or below – Caucasian or Asian average 30 year old • Other important risk factors – T > -1.0 “ normal ” - Family history of fracture – -1.0 to -2.5 “ low bone mass ” (was called “ osteopenia ” ) - Low body weight (<127 pounds in women) – T < -2.5 “ osteoporosis ” - Smoker, >3 drinks/d • Z-score is the number of SDs above or below others of the - Certain drugs (steroids, AIs) and diseases (RA, celiac) same age - Previous fracture (especially hip or spine) • Bone mineral density (BMD) 13 14 Calculating Absolute Fracture Risk: FRAX http://www.shef.ac.uk/FRAX/tool.jsp Risk of Fractures Over 10 Years in Women AGE T-Score T-Score = -1.0 = -2.5 50 6 % 11 % 60 8 % 16 % 70 12 % 23 % 80 13 % 26 % BMD Does Not Fully Explain The Effect of Age on Fracture Risk 15 16 Page 4
Who Should Have a DXA? How Often to Screen? • Guidelines for general population • No evidence based guidelines available – All women > 65, men >70 (until ACP May 2017) – “Earlier” for postmenopausal women with • Study of Osteoporosis Fractures fracture, family history, smoker, weight<127, certain meds – 4597 women: BMD baseline, 2, 6, 10, 16 y – Estimate time for ≥10% to develop • Usually covered by insurance osteoporosis 2013 National Osteoporosis Foundation Guidelines 17 18 Risk of Osteoporosis Implications for Screening Interval by BMD Result at Age 65 • BMD results greater than –1.49 at age 65 Baseline BMD Result Time to 10% Femoral Neck BMD <–2.5 – Repeat screening at age 80 (15 years) Normal > –1.0 16.8 y • BMD results of–1.50 to –1.99 at age 65 – Repeat screening at age 70 (5 years) T = –1.01 to –1.49 17.3 y • BMD results –2.00 to –2.49 – Repeat screening at age 67 (2 years) T = –1.50 to –1.99 4.7 y T = –2.00 to –2.49 1.1 y NEJM 2012; 366: 225-33 Gourlay ML, et al. NEJM 2012; 366: 225-33 19 20 Page 5
Summary: Osteoporosis Medical Evaluation of Osteoporosis Risk Factors and Evaluation • History and physical to identify underlying • Osteoporosis (like hypertension) is silent until problems something bad happens. Under recognized. • Routine assessment of risk factors and screening • Basic lab tests: DXA at 65. Extensive lab testing wasteful. – Vitamin D level (25OH-D) – Serum calcium, creatinine • Everyone should receive lifestyle and nutritional counseling • Additional tests only if indicated • Calculation of absolute risk (FRAX) helps – TSH, PTH, SPEP/UPEP, anti-TTG IgA clinicians and patients Jamal et al, Osteo Inter, 2005; Maraka and Kennel BMJ 2015 21 22 Osteoporosis prevention Prevention for everyone • Lifestyle – Smoking cessation – Avoid excess alcohol intake – Physical activity: modest effect on BMD – but reduces fracture risk • Fall prevention: targeted PT, home evaluation, vision check, medications • Calcium and Vitamin D 23 24 Page 6
News Flash: Calcium Kills!!! Calcium and Vitamin D • Chapuy, 1992: 800 IU D; 1200 mg Ca • Pooled 15 calcium trials: cardiovascular events increased 30% – Older women in long-term care – Not 1 ° endpoint; trials with vitamin D excluded – Calcium + vitamin D in WHI did not increase risk – 30% decrease in hip fracture • Little supporting scientific data • Porthouse, 2005: 800 IU D; 1000 – No effect on other surrogates (coronary calcium on CT) mg Ca – Dairy calcium not implicated – Independent women >70 with • ASBMR Task Force: “ the weight of the evidence is insufficient 1+ risk factor to conclude that calcium supplements cause adverse CV events… ” – No benefit on hip or other Chapuy, NEJM, 1992 fractures • MA 25 studies: 14% fewer fractures together, no benefit alone Bolland, BMJ, 2010, 2011 Bockman, ASBMR, 2010 25 26 Recent Review Meta-analysis Annals IM 10/25/2016 • Calcium intake in RDA range is not associated with CVD in health adults • Editorial – Imperfect evidence – Diet is safer (fewer kidney stones) – Low fat dairy, tofu, canned fish with bones: 2- 3 servings/day 27 28 Page 7
Vitamin D and Bone Strength Rational use of Calcium and Vitamin D • RCT n = 311 • Vitamin D 600 - 1000 IU per day • Vitamin D3 400 vs. 4,000 vs 10,000 IU daily • Calcium • Follow-up: 3 years – Ensure adequate intake (1000-1200 mg) – Dietary intake preferred • Dose response: higher 25(OH)D, lower PTH – Small doses with meals if needed • Unexpected dose response: lower bone density, – Focus on adherence (calcium poorly tolerated) greater loss of bone Burt et al, JAMA, 2019 29 30 FDA-Approved Therapeutic Options in the USA Prevention Treatment Stops bone loss Reduces vertebral fractures Estrogen Calcitonin Alendronate Risedronate Ibandronate Pharmacologic therapy Zoledronic acid Teriparatide Raloxifene Abaloparatide Denosumab Romosuzumab 31 32 Page 8
Average wholesale price (AWP) for one year Bisphosphonate efficacy • Alendronate $82 • Bind to bone and prevent absorption and remodeling • Zoledronic acid: $270 – Resides in bone for decades • Denosumab: $2708 • Four approved agents: alendronate, risedronate, • Romosuzumab* $21,900 ibandronate, and zoledronic acid • Abaloparatide: $23,400 – First line therapy – No head-to-head fracture studies • Teriparatide: $47,444 • What we know: fracture risk reduced 30-50% if – Existing vertebral fracture OR – Low BMD (T-score < -2.5) * Not in article as not approved until 2019, so approximate comparison Tu, P&T, 2018 33 34 NNT and Fractures Prevented for BMD monitoring during treatment: FIT Trial 3 Years of Anti-resorptive Treatment 1 Among older women with prevalent VF or T-score<-2.5 • 1/5 women taking alendronate lost BMD g during first year – Still had 50% fracture reduction – 92% regained lost BMD by next measurement Compare to 3 years of statin to prevent one major cardiovascular event 2 : NNT= 95 Black, Rosen. NEJM 1/16; **Khosla, JBMR 9/16 1. Black NEJM 2016; 2. Khosla JCEM 2012 35 36 Page 9
DEXA to monitor bisphosphonate therapy • BMD after 1 year of therapy does not accurately predict what will happen over time or reflect fracture reduction • Effective treatment for osteoporosis Controversy should not be changed because of loss of DO WE TREAT LOW BONE MASS? BMD during the first year of use 37 38 New Study: Effect of Alendronate on Non-spine Effective treatment of low bone mass Fracture Depends on Baseline BMD Baseline hip BMD • RCT of 2000 women ages 65+ years T -1.5 – -2.0 1.06 (0.77, 1.46) • T-score -1.0 to -2.5 hip or femoral neck 0.97 (0.72, 1.29 ) T -2.0 – -2.5 • Mean age 71; mean T-score -1.6 T < -2.5 0.69 (0.53, 0.88) • Zoledronic acid 5 mg IV every 18 months or placebo infusion for 6 years Overall 0.86 (0.73, 1.01) 0.1 1 10 Relative Hazard ( ± 95% CI) Reid, NEJM, Dec 2018 Cummings, JAMA, 1998 39 40 Page 10
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