52% 34% 5. Both 1) and 3) Start calcium... Both 1) and 3) Start alendron... Start raloxife... Page 1

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1 New Developments in Osteoporosis Mary S. Beattie, MD, MAS, UCSF Women s Health Thanks to Douglas C. Bauer, MD What s New in Osteoporosis Absolute risk - FRAX Under recognition Poor compliance When to stop bisphosphonates New treatments Case 1: Mrs. P 66 grandmother without previous fracture. Sister with breast cancer, 3 drinks/d, otherwise healthy. No meds About 5 7 and weighs 130 Hip BMD T-score -2.2 No contraindication to treatment Will follow your advice but wants no mistakes What Would You Do? 1. Start calcium 1000 mg + vitamin D 800 iu per day 2. Start alendronate 70 mg or risedronate 35 mg per week 3. Start raloxifene 60 mg/d 52% 4. Both 1) and 2) 5. Both 1) and 3) Start calcium... Start alendron... 5% Start raloxife... 0% Both 1) and 2) 34% 9% Both 1) and 3) Page 1

2 Treating Osteopenia (low bone mass) 1994 WHO definitions - Measurements define dz - Densitometry is widespread T < -2.5 = osteoporosis T between -1.0 and -2.5 = osteopenia (now called low bone mass ) T > -1.0 = normal Risk Factors in FRAX WHO Fracture Risk Assessment Tool In addition to age, gender, and race Prior adult osteoporotic fracture*: 20% risk of new fx in year following a fracture Parent fractured hip Height, weight (low BMI increases risk) Current smoker Steroid use (5 mg/d prednisone x 3 months) Rheumatoid arthritis & secondary osteoporosis Alcohol over 3 drinks/day Treatment Threshold Concept 10-Year Fracture Probability (%) AGE Current treatment threshold based on T-score Treatment threshold concept based on WHO Absolute Fracture Risk BMD T-score Adapted from JA Kanis et al, Osteoporos Int. 2001;12: Page 2

3 Age Relative and Absolute Risk Total Hip T score Relative Risk* % % Probability of Hip Fracture in 10 yrs *Compared to age-matched women with normal BMD Bottom line Mrs. P: Continued After discussing low bone mass and absolute risks, you and Mrs. P decide on calcium and Vitamin D. She read about a recent controversy regarding calcium and Vitamin D are they safe? When should she be re- scanned? News Flash!!! Calcium Kills and Vitamin D is Worthless! Meta-analysis analysis of 15 calcium RCTs found CHD increased 30% Not 1 endpoint, trials with vitamin D excluded Dairy calcium not implicated IOM Report on vitamin D Non-skeletal benefits not established, harms minimized Recommends daily intake IU/d, no more than 4,000/d Recommends serum levels ng/ml Bolland, BMJ, 2010 Calcium and Vitamin D Chapuy, 1992 Elderly women in long- term care 30% decrease in hip fracture Porthouse, 2005: Women >70 with 1+ risk factor Placebo Calcium + D 6 12 Months No benefit on hip, nonspine (RR=1.01, CI: 0.71, 1.43) Chapuy, NEJM, 1992 Meta-analysis: analysis: 15-20% reduction in fracture 18 Page 3

4 When would you rescan her? 1. In a year 2. In 2 years 3. In 4-5 years (age 70 or 71) 4. Never 5. None of the above In a year 11% In 2 years 51% In 4-5 years (... 31% 5% 2% Never None of the ab... When to repeat BMD? Rate of bone loss ~ 0.1 T-score per year DXA precisely measures BMD, but random error can occur Study of Osteoporotic Fractures cohort Mean age 72, DXA at BL and 8 years later Initial BMD was most predictive of fracture 2nd BMD did not add much to 1 st prediction Change in BMD modestly predicted fracture Probably most cost-effective to wait til age 70 to rescan Case 2: Mr. M Would you order a DXA for Mr. M? 74 year old active man presents for routine physical exam History of melanoma Quit smoking over 20 years ago 1. Yes 2. No 3. Don t know 42% 52% No known family history of fracture 6% Yes No Don t know Page 4

5 DXA results for Mr. M What is your next step for Mr. M? Femoral neck: T = -2.9 Spine: T = Calculate 10 year fracture risk 2. Medical work-up for osteoporosis 3. Recommend Calcium and Vitamin D 4. All of the above 84% 5% 2% 9% Calculate 10 y... Medical work-u... Recommend Calc... All of the abo... Medical Work-up Very little data, lots of opinions A reasonable start: Vitamin D (25-OH, not 1,25-OH) Serum calcium, Cr, TSH Additional tests that may be helpful: Sprue serology, SPEP, UEP Unlikely to be helpful: PTH, urine calcium Jamal et al, Osteo Inter, 2005 Mr. M s prescription treatment options For and For For Bisphosphonates PTH Testosterone (if ) Estrogen Raloxifene Calcitonin Page 5

6 Alendronate in Osteoporotic Men Two 2-yr studies in 241 and 134 men showed similar results BMD outcomes Spine: placebo 1.8%, alendronate 7.1% Hip: placebo 0.1%, alendronate 2.5% Vertebral fracture outcomes placebo 7.1%, alendronate 0.8% (p = 0.02) Orwoll NEJM 2000 and Ringe JCEM 2001 Effect of Alendronate on Non-spine Fracture Depends on Baseline BMD Baseline hip BMD T T T < -2.5 Overall Cummings, Jama, (0.77, 1.46) 0.97 (0.72, 1.29) 0.69 (0.53, 0.88) 0.86 (0.73, 1.01) Relative Hazard (± 95% CI) Poor Compliance with Oral Bisphosphonates Burdensome oral administration (fasting, remain upright for 30 minutes) % persistence after one year with daily dosing Similar to other preventative tx Multiple practice settings Does dosing interval matter? Daily to weekly may improve compliance Weekly to monthly may not Yearly dosing now available: zolendronate Which of Following Improves Compliance Most with Osteoporosis Treatments? 1. Less frequent dosing interval 2. Follow-up visits and adherence counseling 3. Monitoring with BMD 4. Monitoring with biochemical markers Less frequent... 38% Follow-up visi... 57% Monitoring wit... 6% 0% Monitoring wit... Page 6

7 RCT of Nurse Visits to Discuss Medication Compliance Nurse visits q3 mo. improved adherence by 59% Mr. M: Continued Mr. M starts weekly alendronate and remains adherent for 5 years No fractures Repeat hip BMD T = -2.4 Can he stop alendronate? Clowes, JCEM, 2004 What Would You Do? How Long to Use Bisphosphonates? 1. Assess compliance and continue current oral bisphosphonate 2. Switch to IV bisphosphonate 3. Switch to raloxifene 60 mg/day 4. Stop bisphosphonate, continue calcium/d, repeat BMD in 3-5 years Assess complia... 22% Switch to IV b... 10% Switch to ralo... 0% 68% Stop bisphosph... Long half-life life suggests that life-long long treatment may not be necessary Concerns about excessive suppression of bone resorption FIT Long-term Extension (FLEX) study 1099 ALN-treated FIT subjects Randomized to ALN or PBO for 5 yr. Black; Jama, 2006 Page 7

8 FLEX Change in Femoral Neck BMD: % Change from FIT Baseline Cumulative Incidence of Fractures During FLEX Mean Percent Change = Placebo = ALN (Pooled 5 mg and 10 mg groups) Start of FLEX 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 P<0.001 ALN vs PBO 2% Non-spine Non-vertebral Hip Vertebral Morphometric Clinical 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) Mr. M s conclusion.and his mother Mr. M makes the informed decision to stop alendronate But, his mother is in her mid-90 s and has never been checked for osteoporosis. She s been on estrogen since her TAH/BSO at 50 y/o and is wondering if she should stop estrogen What is your next step for Mr. M s mother? 1. Order a DXA now 2. Start a bisphosphonate now 3. Stop estrogen and order a DXA in 6 months 4. Switch from estrogen to a bisphosphonate 5. None of the above Order a DXA no... 48% Start a bispho... 2% Stop estrogen... 6% Switch from es... 4% 40% None of the ab... Page 8

9 BMD declines within months of stopping post- menopausal HT Mr. M s mother: Continued DXA hip T = -2.2 But, because she has a dowager s hump, you check an XRay She has no pain, and she wonders if she needs treatment since she s not osteoporotic by DXA Treatment options for Mr. M s mother Bisphosphonates Raloxifene PTH Denosumab (antibody to RANKL) Estrogen Calcitonin Bisphosphonates Four approved agents: alendronate, risedronate, ibandronate, and zolendronic acid No head-to-head fracture studies Oral bisphosphonates: fracture risk reduced 30-50% if Existing vertebral fracture OR Low BMD (T-score < -2.5) IV bisphosphonate: zolendronic acid Reduces vertebral fracture risk 60-70% Yearly IV administration, 20% initial acute phase rxn Page 9

10 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? 1/100K person-years of treatment Dental exam before Rx? Recommended, but unclear utility Stopping for dental procedures not likely to help Woo et al; Ann Intern Med, 2006 Other Things to Worry About (Maybe) Subtrochantic fracture (with atypical features) Case series only, risk factors unknown (Prolonged use? Steroid use? Active?) Probably real but very rare Prodromal pain and bone scan abnormalites in some Esophageal cancer Case series (FDA author) and two conflicting cohorts, Might be spurious Atrial fibrillation (zolendronate and alendronate RCTs) No association in other trials Likely spurious New vertebral fractures, MORE Placebo 60 mg 120 mg no prior fx prior fx Page 10

11 PTH: FDA approved Anabolic Agent RANK Ligand Mediates Osteoclast Formation, Function, and Survival Most treatments for osteoporosis inhibit bone resorption (and formation) Anabolic agents (anabolic steroids, fluoride, intermittent PTH) stimulate formation Daily SQ PTH (1-34) for 18 mo. vertebral fracture 65% and non-spine fracture 54%. No hip fracture data. Should be followed by bisphosphonate therapy CFU-M Hormones Growth Factors Cytokines Pre-fusion Osteoclast Osteoblasts Multinucleated Osteoclast RANKL RANK Activated Osteoclast Very expensive, daily self-administered injections... Use with severe OP, when other agents have failed? Bone Formation Neer, NEJM, 2001 Adapted from: Boyle WJ, et al. Nature. 2003;423: Bone Resorption Rank Ligand Inhibition: Denosumab Human monoclonal antibody against RANKL Extremely potent inhibition of osteoclast activity FREEDOM trial: 60 mg SQ every 6 months, 3 yrs No osteonecrosis of jaw, no impaired fx healing, no increase in CVD events, infection, cancer cellulitis (requiring hospital care) 3/1000 atopic dermatitis, about 1% more than placebo Cummings, et al. NEJM 2009 FREEDOM Fracture Endpoints Fracture Outcome Dmab vs. PBO RR (95% CI) Vertebral 0.32 ( ) 0.41) Hip 0.60 ( ) 0.97) Any Non-spine 0.80 ( ) 0.95) FDA approved for osteoporosis treatment in women in July, 2010 Cummings et al, NEJM 2009 Page 11

12 Mr. M s Mother.Case Conslusion Ms. M decides to stop estrogen and switch to a weekly oral bisphosphonate She has a normal dental exam beforehand, no need for tooth extraction Normal chem 20, vitamin D = mg calcium/day and IU Vitamin D/day 2011 Update and Conclusions Absolute risk estimates help clinicians and pts FRAX treatment threshold 10 year risk of 20% for any fracture and 3% for hip fracture Aggressive screening and rx = fewer fractures ID those who have already have the disease! Bisphosphonates: treatment of choice Use for spine/hip fracture, T<-2.5, or FRAX > threshold Adherence counseling. Intermittent dosing. Duration of therapy? 5 years then holiday? Denosumab, PTH effects impressive, but expensive and unclear when to use Thanks For Listening. Questions Welcome! Page 12

13 Age and BMD are independent risks for fracture Hip BMD and Fracture Risk at Age 70 T-score Hip fracture risk 5 year Lifetime > -1 1% 4% -1 to -2 1% 8% -2 to -3 4% 16% < -3 9% 29% 10 year probability of any fracture in women by age and T-score Age Page 13

14 Major osteoporotic fractures include hip, clinical vertebral, proximal humerus, and distal forearm. Highlighted risks equal or exceed the reference case (woman aged 65 years with no risk factors: 9.3% for osteoporotic fracture; 1.2% for hip fracture). BMI body mass index. * Normal BMI 25.0 kg/m2 based on average height of 163 cm (64.17 in) and weight of 66.5 kg ( lb). Low BMI 21.2 kg/m2 based on average height of 163 cm (64.17 in) and weight of 56.7 kg (125 lb). Daily alcohol use of 3 or more units/d (approximately 3 oz each). More on Calcium/Vitamin D NOF: 1200 mg calcium/day for all post-meno IU of Vitamin D3/day for all adults over 50 WHI: RPCT sub-study study ~ 36,000 women 1000 mg calcium carbonate IU Vit D* 7 year F/U for fractures, BMD BMD increased in all women, but no difference in fractures (HR 0.88 in hip and 0.74 in spine, p = NS) Increased renal calculi in treatment (HR 1.17) Hip fx in adherent women (HR 0.71, p < 0.05) NNT = 5045 to prevent one hip fx (all women) *Supplements were allowed, so some placebo women on Calcium/Vit D NNT = 1945 to prevent one hip fx in women > 60 Vit D + Ca Page 14

15 Medications & Osteoporosis Glucocorticoids Aromatase inhibitors Anticonvulsants Heparin (long term) Lithium Vit D vs. PBO/no rx Proton pump inhibitors Thyroid over-replacementreplacement Endocrine Medical conditions & osteoporosis Endocrine- hyperthyroid, hyperparathyroid, Cushing s, DM, hyperprolactinemia, hypercalciuria, hypogonadism Renal- CRF, ESRD, RTA, renal osteodystrophy Rheumatologic- RA, Ankylosing spondylitis, Marfan s GI/Liver GI/Liver- gastrectomy/bariatric surgery, celiac disease, cirrhosis, malabsorption of calcium Infiltrative- multiple myeloma, leukemia Nutritional/Metabolic Nutritional/Metabolic- eating disorders, B12 deficiency, vitamin D deficiency, elevated homocysteine More common in older and non-white populations Not significantly affected by latitude Page 15

16 Bisphosphonates Most commonly prescribed therapy for osteoporosis All indicated for prevention and treatment of osteoporosis Poor oral absorption Adverse Events: esophageal irritation or erosion (PO), hypocalcemia, bone pain Contraindications: esophageal dysmotility (PO), significant renal dysfunction, Ca Warning: Osteonecrosis of jaw (1/100K person yrs) Under Recognition of Osteoporosis Among women with fracture or BMD<-2.5 only 20-30% are evaluated and treated! Ask about fracture history, note vertebral fractures, use chart reminders for DXA Be aggressive about screening and, when indicated, appropriate treatment Soloman, Mayo Clin Proc, 2005 Non-pharmacologic Interventions Little new data Smoking cessation, avoid alcohol abuse Physical activity: modest transient effect on BMD; may reduce fracture risk Conflicting data on hip protector pads (compliance is big issue) Does Dosing Interval Matter? 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 IV zolendronate (5mg IV once/yr) vs. placebo Black et al, NEJM, 2007 Page 16

17 Risedronate HIP Study: Two Groups Group age <80; hip BMD T-score < % decreased hip fracture risk Group age >80; risk factors for hip fx No significant effect on hip fracture risk McClung, NEJM, 2001 Page 17