New Developments in Osteoporosis Eliseo J. Pérez-Stable MD Professor of Medicine Division of General Internal Medicine Department of Medicine July 4, 2013 Declaration of full disclosure: No conflict of interest What s New in Osteoporosis Absolute risk Under-recognition Poor medication adherence When to stop bisphosphonates New treatments 55 year old woman for routine visit, what do you ask and do about bone health? A) Screening DxA of hip and spine B) Screening DxA of hip only C) Recommend calcium and vitamin D supplements D) Ask about family history, alcohol, smoking, get BMI and check Vitamin D E) Defer until age 60 or 65 What Would You Do? Mrs. C 66 WF recently moved to Switzerland. No previous fracture. Sister had breast cancer, 3 drinks/d, healthy. No meds. Exam normal. About 5 7 and weighs 130 Hip BMD T-score -2.2 No contraindication to treatment What tests would you order? How would you manage her? Page 1
Osteoporosis in a Nutshell What is it? Risk factors Evaluation Treatments Efficacy of available agents New side effects and clinical implications What is Osteoporosis? In adults, bone is constantly removed and replaced Osteoporosis is loss of mineral and structural integrity with resulting fragility Fractures common in older individuals What About Trauma? Even nonosteoporotic bone will fracture with extreme trauma There is no threshold for skeletal fragility The weaker the bone the less trauma required to fracture Traditional Risk Factors for Fracture The Big Three: Older age, Postmenopausal woman, and Caucasian/East Asian race Other important risk factors - Family history of fracture - Low body weight (<127 lbs. in women) - Smoker, >3 drinks/d - Certain drugs (steroids, PPIs) and diseases - Previous fracture (especially hip or spine) Measurement of bone mineral density (BMD) strongly predicts fracture Page 2
Bone Mineral Density (DXA) Interpretation of DXA Scans: Really Confusing Absolute mineral (calcium) content using x-rays Relative to young adult reference population T-score is the number of standard deviations above or below average 30 year old T greater than -1.0 = normal T between -1.0 and -2.5 = osteopenia (now called low bone mass ) T less than -2.5 = osteoporosis Large studies show low BMD increases fractures risk in both women and men BMD Tertile and Risk Factors Who Should Have a DXA? Cummings et al., NEJM 332(12):767-773, 1995 Guidelines for general population* All women > 65 y or older Postmenopausal with fracture, family history, smoker, weight <127 lbs, certain medications Women <65 y with fracture risk equal to 65 y old White woman Usually covered by insurance (Medicare: pays $128) Revised 2013 National Osteoporosis Foundation Guidelines Page 3
Hip BMD and Fracture Risk at Age 50 Hip fracture risk T-score 5 year Lifetime > -1 <1% 10% -1 to -2 1% 16% -2 to -3 1% 27% < -3 2% 41% Hip BMD and Fracture Risk at Age 70 Hip fracture risk T-score 5 year Lifetime > -1 1% 4% -1 to -2 1% 8% -2 to -3 4% 16% < -3 9% 29% Calculating Absolute Fracture Risk: FRAX http://www.shef.ac.uk/frax/tool.jsp Treatment Threshold Concept AGE 80 70 60 50 Current treatment threshold based on T-score Treatment threshold concept based on WHO Absolute Fracture Risk Adapted from JA Kanis et al, Osteoporos Int. 2001;12:989-995 Page 4
What About Interval Screening? Recommendations of q 2 y as interval to measure change No evidence based guidelines 4597 women in Study of Osteoporosis Fractures: BMD baseline, 2, 6, 10, 16 y Estimated interval to transition from normal to low bone mass, to osteoporosis Risk of Osteoporosis in 15 years by BMD Result at Age 65 (NEJM 2012; 366: 225-33) BMD Result Femoral Neck Risk of Osteoporosis Time to 10% BMD < 2.5 Normal 0.8% 16.8 y > 1.0 Mild Osteopenia T = 1.01 to 1.49 4.6% 17.3 y Moderate Osteopenia T = 1.50 to 1.99 Advanced Osteopenia T = 2.00 to 2.49 20.9% 4.7 y 62.3% 1.1 y Implications for Screening BMD results of more than 1.49 at age 65 can defer repeat screening to age 80 BMD results of 1.50 to 1.99 at age 65 can merits repeat screening BMD at 5 years BMD results 2.00 to 2.49 may need rescreening at 2 years Caution: 49% original SOF sample had osteoporosis Gourlay ML, et al. NEJM 2012; 366: 225-33 Under Recognition of Osteoporosis Among women with fracture or BMD T < 2.5 only 20-30% are evaluated and treated! 12 months after hip fracture at the VA: 2% had DXA, 15% treated with appropriate drug Implications for providers: Ask about fracture history, note vertebral fractures, use chart reminders for DXA Soloman, Mayo Clin Proc, 2005 Shibli-Rahhal, Osteo Internat, 2011 Page 5
Medical Work-up: Opinion, Little Data A reasonable start: Vitamin D (25-OH, not 1,25-OH) Serum calcium, kidney, TSH Additional tests to consider: Sprue serology, SPEP, UEP Unlikely to help: PTH, urine calcium Jamal et al, Osteo Inter, 2005 Summary: Osteoporosis Risk Factors and Evaluation Osteoporosis is silent until something bad happens: Under recognized Routine assessment of risk factors and screening DXA. Extensive lab testing wasteful. Everyone should receive lifestyle and nutritional counseling Calculation of absolute risk (FRAX) at www.nof.org helps clinicians/ patients Mrs. C Who Should Be Treated*? Preventive measures for everyone: adequate calcium and vitamin D in diet, exercise, no tobacco, limit alcohol When to offer pharmacologic therapy: Anyone with hip or vertebral fracture T-score 2.5 in femoral neck, hip, or spine Low bone mass and 10-year fracture risk 20% or hip fracture risk 3% *Revised 2013 National Osteoporosis Foundation Guidelines Page 6
What Can Be Done To Prevent Osteoporosis? Non-pharmacologic Interventions Smoking cessation, avoid alcohol abuse Physical activity: modest transient effect on BMD but reduces fracture risk Conflicting data on hip protector pads (adherence is big problem) Calcium and vitamin D Calcium and Vitamin D Chapuy, 1992 Elderly women in longterm care 30% decrease in hip fracture Porthouse, 2005: Independent women >70 with 1+ risk factor No benefit on hip or other fractures Chapuy, NEJM, 1992 Pooled studies: 12% fewer fractures together, little benefit alone News Flash: Calcium Kills!!! Pooled 15 calcium trials: cardiovascular events up 30% Not 1 endpoint; trials with vitamin D excluded Calcium + vitamin D in WHI did not increase risk Pool calcium + D trials? Similar but only after excluding those taking personal calcium supplements in WHI Little supporting scientific data No effect on other surrogates (coronary calcium on CT) Dietary calcium not implicated in German study The weight of the evidence is insufficient to conclude that calcium supplements cause adverse CV events Bolland, BMJ, 2010, 2011 Bockman, ASBMR, 2010 Page 7
How Much Is Enough for Skeletal Health? The Institute of Medicine Calcium 1200 mg/d for women >50, men >70 Vitamin D Recommends daily intake 600-800 IU/d, no more than 4,000/d Recommends serum levels 20-50 ng/ml Non-skeletal benefits not established, harms minimized IOM Report, 2010 US Preventive Task Force Recommendations Insufficient evidence to assess risks/benefits for daily supplementation with calcium >1000 mg/d and vitamin D3 400 IU Recommends against daily supplements of Vitamin D 400 IU or less and calcium 1000 mg or less to prevent fractures Vitamin D supplements effective in preventing fractures in 65 y at risk of falls Moyer VA, USPTF, Ann Intern Med 2013; 691-6 Bisphosphonates Bind to bone and prevent absorption and remodeling Resides in bone for decades Four approved agents: alendronate, risedronate, ibandronate, and zoledronic acid No head-to-head fracture studies What we know: fracture risk reduced 30-50% if Existing vertebral fracture OR Low BMD (T-score < -2.5) May not be as useful if higher BMD ( osteopenia ) Effect of Alendronate on Non-spine Fracture Depends on Baseline BMD Baseline hip BMD T -1.5-2.0 T -2.0-2.5 T < -2.5 Overall 1.06 (0.77, 1.46) 0.97 (0.72, 1.29) 0.69 (0.53, 0.88) 0.86 (0.73, 1.01) 0.1 1 10 Relative Hazard (± 95% CI) Cummings, Jama, 1998 Page 8
Risedronate HIP Study: Two Groups Group 1 5445 age <80; hip BMD T-score < -3.0 39% decreased hip fracture risk Group 2 3886 age >80; risk factors for hip fx No significant effect on hip fracture risk McClung, NEJM, 2001 Adherence with Bisphosphonates is Poor Burdensome oral administration (fasting, remain upright for 30 minutes) Upset stomach and heartburn can occur 50-60% persistence after one year with daily dosing Similar to other preventative tx Multiple practice settings Likely better with weekly, monthly and yearly (intravenous) administration Bisphosponates Once-a-week Does Dosing Interval Matter? Identical effects on BMD Possibly fewer effects on esophagus No fracture trials Alendronate: Daily vs. Weekly Schnitzer, Aging, 20 Poor quality data: Daily to weekly may improve compliance Weekly to monthly may not Yearly dosing now available: zolendronate Extremely potent bisphosphonate 3 year, multicenter controlled trial 7741 women 55-89, T-score <-2.5 or < -1 + vertebral fracture Zolendronate 5mg IV once/yr vs. placebo Black et al, NEJM, 2007 Page 9
A New Side Effect of Potent Bisphosphonates? Osteonecrosis of the Jaw Associated with potent bisphosphonate use: 94% treated with IV bisphosphonates 4% of cases have OP, most have cancer 60% caused by tooth extraction. Other risk factors unknown. Infection? Key points: extremely rare, early identification, conservative treatment Dental exam recommended before Rx, but no need to stop for dental procedures Atypical Subtrochanteric Fractures? Rare case reports in long-term bisphosphonate users (and others) Transverse not spiral, cortical thickening, minimal trauma Often bilateral, preceding pain, abnormal x-ray or bone scan ASBMR Task Force (2011) Causation not established Risk factors uncertain Mechanism unknown How Long to Use Bisphosphonates? Prolonged use (decades) common Long half-life suggests that life-long treatment is not always necessary What happens when you stop? FIT Long-term Extension (FLEX) study Women given ALN in FIT for 5 yr. Randomized to ALN or PBO for 5 yr. Black; Jama, 2006 Page 10
FLEX Change in Hip BMD: % Change from FIT Baseline New Fractures During FLEX Mean Percent Change 6 5 4 3 2 1 Start of FLEX 0 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 Year FIT FLEX = Placebo P<0.001 ALN vs PBO = ALN (Pooled 5 mg and 10 mg groups) 2% Non-spine Any Hip Vertebral Any Painful PBO (N = 437) 20% 3% 11% 5% ALN (N = 662) RR (95% CI) 19% 3% 2% 1.0 (0.8, 1.4) 1.1 (0.5, 2.3) 10% 0.9 (0.6, 1.2) 0.5 (0.2, 0.8) FDA View of Long-term Bisphosphonate Use (Sept. 2011) Independent review of epidemiologic studies to date and all bisphosphonate trial data After 5 years of treatment, fracture benefit less certain Regarding side effects Atypical fractures: conflicting results causality uncertain no agreement on effects of duration or cumulative dose ONJ: some evidence that risk increases after 4 yr. causality not established Discontinuation of Bisphosphonates After 3-5 Years? NOF recommendation for clinical reassessment after 3-5 years of use Driven by lack of non-spine fracture benefit after 5 yr and accumulating evidence of harm even if small risk No pharmacologic therapy should be considered indefinite Decisions need to be individualized Page 11
Implications of Bisphosphonate Trials Bisphosphonates reduce risk of spine, hip and nonspine fracture in women with existing spine fracture or low BMD (T-score < -2.5) May not reduce risk of non-spine fracture in women without spine fracture or BMD < -2.5, even if at high risk. Intermittent dosing, even yearly, effective Best data of any approved treatment After 5 years of treatment, some may stop BMD >-2.5 and no hip or vertebral fractures Other Anti-resorptive Agents Less effective than bisphosphonates Calcitonin (poor quality studies) Raloxifene (prevents vertebral fractures only; use for breast cancer prevention) Hormone replacement: WHI benefits Denosumab (antibody to RANKL) Women s Health Initiative RCT of ERT, PERT or PBO among women age 50-79, 10,739 with hysterectomy. Primary prevention PERT, ERT arms stopped after 5-7 years Follow-up 93% complete Fracture Endpoints: ERT vs. PBO Hip RR = 0.61 (0.41, 0.91) Non-spine RR = 0.70 (0.63, 0.79) CVD RR = 1.12 (1.01, 1.24 WHI Writing Group, Jama, 200 The Future: Anabolic Agents Neer, NEJM, 2001 Most treatments for osteoporosis inhibit bone resorption (and formation) Anabolic agents (anabolic steroids, fluoride, intermittent parathyroid hormone) stimulate formation Daily injections of PTH for 18 mo. reduces vertebral and non-spine fracture. No hip fracture data. Should be followed by bisphosphonate therapy Very expensive, daily self-administered injections... Use with severe OP, when other agents have failed? Page 12
Summary of Treatment Bisphosphonates: treatment of choice in selected individuals: Spine/hip fracture or T<-2.5. Benefit for others less clear. Duration of therapy? 3-5 years then off? Other agents available but expensive and unclear when to use New diagnostic tests and better treatments on the way Take Home Points Absolute risk estimates help with decisions Aggressive screening and treatment = fewer fractures; start for all women by 65 yrs Interval screening defined by baseline BMD Identify those who have already have the disease! Bisphosphonates: treatment of choice Use for spine/hip fracture or T< 2.5 Adherence counseling. Intermittent dosing. Duration of therapy? 5 years then off? Page 13