The Prevention and Treatment of Postmenopausal Osteoporosis

The Prevention and Treatment of Postmenopausal Osteoporosis Educational Partner: A Rockpointe Company

Session 3: The Prevention and Treatment of Postmenopausal Osteoporosis Learning Objectives Identify 3 risk factors for osteoporosis and osteoporotic fractures. Review at least 2 pharmacologic interventions available in the treatment of postmenopausal osteoporosis and the effect of therapeutic agents on bone density and fracture risk. Faculty M. Susan Burke, MD, FACP Clinical Assistant Professor of Medicine Thomas Jefferson University Medical School Philadelphia, Pennsylvania Director Lankenau Internal Medicine Clinical Care Center Wynnewood, Pennsylvania M. Susan Burke, MD, FACP, received her bachelor s degree in biology from Chestnut Hill College in Philadelphia, Pennsylvania. She graduated from the University of Pennsylvania School of Medicine in 1979 and completed a residency in internal medicine at Lankenau Hospital in Wynnewood, Pennsylvania in 1982. Since then, Dr Burke has been the director of the Lankenau Internal Medicine Clinical Care Center; she is clinical assistant professor of medicine at Thomas Jefferson University in Philadelphia and is board certified in internal medicine and geriatrics. Dr Burke is a Fellow of the American College of Physicians. Dr Burke is a two-time recipient of the Osler-Blockley Award from Thomas Jefferson University for excellence in teaching medicine at the bedside, and has also received the residents award for best teacher from the Lankenau Internal Medicine house staff. She was named Top Doctor for Women by Main Line Today magazine in 25, and Top Doctor again in 26. Dr Burke lectures nationally and has published chapters, articles and CD-ROMs on osteoporosis and other geriatric topics. Joseph M. Grisanti, MD Assistant Clinical Professor of Medicine State University of New York at Buffalo Chief of Rheumatology Mercy Hospital of Buffalo Medical Director Buffalo Rheumatology Associates Buffalo, New York Dr Joseph Grisanti is an assistant clinical professor of medicine in the Division of Rheumatology at the State University of New York (SUNY) at Buffalo and chief of rheumatology at the Mercy Hospital of Buffalo. He is the medical director of Buffalo Rheumatology Associates in Orchard Park, New York and President of the Buffalo Osteoporosis Institute. Dr Grisanti received a bachelor's degree in biology from Canisius College in 198, where he received the coveted 7ri-Bela Award for having the highest grade-point average in the sciences in his graduating class. He attended medical school at the University of Rochester graduating in 1984. Dr Grisanti completed a medical residency program at SUNY at Buffalo. He went on to complete a fellowship in rheumatology at the Cleveland Clinic Foundation in 1989. Board certified in both internal medicine and rheumatology, Dr. Grisanti also holds certification with the International Society for Clinical Densitometry. Dr Grisanti was voted Teacher of the Year by the medical staff at Millard Fillmore Hospitals in Buffalo, NY in 1987. Dr Grisanti has published extensively in such journals as the Journal of Rheumatology, the Journal of Clinical Densitometry, and the American Family Physician, and has a national reputation as a lecturer in both arthritis and metabolic bone diseases. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Burke is a speaker and member of the advisory board for Novartis Pharmaceuticals Corporation and Merck & Co., Inc. Session 3

Dr Grisanti has received honoraria for serving on the speakers bureau and as a consultant for Abbott; Amgen; Bristol- Myers Squibb; Centocor; Eli Lilly and Company; GlaxoSmithKline; Genentech; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Proctor and Gamble; Roche; sanofi-aventis U.S.; Wyeth; and E.C.B. (United Chemicals of Belgium). Education Partner Financial Disclosure Statements The content collaborators at Potomac Center for Medical Education, A Rockpointe Company have reported the following: Laurie Frueh, MD, medical science liaison, has no relationships to disclose. Kathy Merlo, medical writer, has no relationships to disclose. Donna Fucello, vice president, has no relationships to disclose. Debra Minnick, program coordinator, has no relationships to disclose. Drug List Generic amlodipine albuterol sertraline tiotropium salmon calcitonin raloxifene Trade Norvasc Proventil Zoloft Spiriva Miacalcin Evista Generic alendronate risedronate ibandronate zoledronic acid teriparatide clonidine Trade Fosamax Actonel Boniva Reclast (Aclasta outside US) Forteo Catapres, Duraclon Suggested Reading List Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA. 21;286(22):2815-2822. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. 26. National Osteoporosis Foundation. NOF physician s guide to prevention and treatment of osteoporosis. NOF Web site. 28. http://www.nof.org. Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 28;19:385 397. FRAX WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/frax/tool.jsp. Chestnut CH, Silverman S, Andriano K. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. Am J Med. 2;19:267-276. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-645. Hochberg M, Ross P, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. Arthritis Rheum. 1999;42:1246-1254. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344-1352. Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 24;19:1241-1249. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 27;356:189-1822. Lyles KW, Colon-Emeric CS, Magaziner JS et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 27. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 21;344:1434-1441. Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int. 24;15:13-18. Session 3

Notes TM

The Prevention and Treatment of Postmenopausal Osteoporosis The Prevention and Treatment of Postmenopausal Osteoporosis SUSAN BURKE, MD Identification and Evaluation of Postmenopausal Osteoporosis NIH Consensus Conference Defines Osteoporosis A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture Normal 2 Osteoporosis 2 Osteoporosis in the US Epidemiology 4-5% of women age 5 will suffer an osteoporosisrelated fracture within their lifetime 1 Approximately 7, vertebral fractures and 3, hip fractures occur annually 2 Fewer than half of hospitalized hip-fracture patients recover pre-fracture competence in activities 3 BONE STRENGTH = BONE DENSITY + BONE QUALITY 1 1. NIH Consensus Conference, 2. Available at: http://consensus.nih.gov/2/2osteoporosis111html.htm. Accessed 12-16-5. 2. Dempster DW et al. J Bone Miner Res. 1986;1:15-21. 1. Johnell O, Kanis J. Osteoporos Int. 25;16:S3-S7. 2. Surgeon General. Bone health and osteoporosis: a report of the Surgeon General. 24. 3. National Osteoporosis Foundation. NOF physician's guide to prevention and treatment of osteoporosis. 26. Available at: www.nof.org/professionals/clinicians_guide.htm. Hip Fractures Are Common Numbers Are Projected to Increase Increased Morbidity and Mortality 1 Year After Hip Fracture Hip Fractures Worldwide (million) 3.5 3. 2.5 2. 1.5 1..5 Projected Data Men Women % of Patients 2 3 4 8 199 2 21 22 23 24 25 Year Death Within 1 Year Permanent Disability Unable to Walk Independently Unable to Carry Out 1 Independent ADL Gullberg B et al. Osteoporos Int. 1997;7:47-413. ADL = activity of daily living Cooper C. Am J Med. 1997;13:12S-17S. 6 1

Case Study 1 History Mrs. Brown, a 7-year-old white female, presents for a physical exam HTN x 12 years Mild COPD (last exacerbation requiring oral steroids >1-year prior) Continues to smoke ½ ppd Depression x 2 years Medications Amlodipine Albuterol prn Sertraline Tiotropium Physical Exam/Study Findings 5 3, 118 pounds, healthy appearing Caucasian female BP 122/78, NAD T-scores: - 1.3 at lumbar spine (LS) and - 1.5 at the femoral neck (FN) Indications for BMD Testing Women age 65 and older and men age 7 and older, regardless of clinical risk factors Men age 5-7 and younger postmenopausal women about whom you have concern, based on their clinical risk factor profile National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. 28. Indications for BMD Testing, cont d: Risk Factor Profiles Perimenopausal women with a specific risk factor associated with increased fracture risk (e.g. smoking, family history) Fracture after age 5 Adults with a condition (e.g. rheumatoid arthritis) or taking a medication (e.g. glucocorticoids) associated with bone loss Individuals with primary hyperparathyroidism Anyone being considered for pharmacologic therapy for osteoporosis Anyone being treated for osteoporosis, to monitor treatment effect Postmenopausal women discontinuing estrogen What is Mrs. Brown s s chance of fracture in the next 1 years? 1. Pretty low because her T-scores are not osteoporotic 2. About the same as a 5-year-old who has the same T-scores 3. Higher than a 5-year-old who has a femoral neck T-score of -3. 4. The same as a 5-year-old with a femoral neck T-score of -3.? National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. 28. ARS 1-year Probability of Fracture in Women By Age and FN T-ScoreT Age (years) 5 55 6 65 7 75 T-Score 3.8 4.1 5.1 6.3 7.1 7. T-Score.5 4.7 5.3 6.5 8. 9. 9.1 Data from Kanis JA et al. Osteoporos Int. 21;12:989-995. T-Score 1. 5.9 6.7 8.2 1. 11.5 11.8 T-Score 1.5 7.4 8.5 1.4 12.6 14.6 15.2 T-Score 2. 9.2 1.7 13. 15.6 18.3 19.4 T-Score 2.5 11.3 13.4 16.2 19.3 22.8 24.5 T-Score 3. 14.1 16.8 2.2 23.9 28.4 3.8 Hip Fracture Age and BMD Are Independent Risk Factors 1-year Hip Fracture Probability (%) 2 1 3 Age (y) Kanis JA et al. Osteoporos Int. 24;15:2-26. 8 7 6 5 T-score that defines osteoporosis Absolute Fracture Risk will influence treatment decisions 3 2 1 1 T-Score (SD) 2

Fracture Risk Assessment The use of clinical factors can improve identification of people at higher fracture risk The WHO Fracture Probability approach will determine an individual s s 1-year hip and major osteoporotic fracture risk based on BMD and other important risk factors Risk Factors Included in the WHO Fracture Risk Assessment Model Current age Use of oral glucocorticoid therapy Gender Secondary osteoporosis (e.g. rheumatoid arthritis) Personal history of a fracture Parental history of hip fracture Femoral neck BMD Current smoking Low body mass index (kg/m2) Alcohol intake of 3 or more drinks/day FRAX WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/frax/tool.jsp. Accessed April 11, 28. WHO Risk Assessment Tool (FRAX) Summary of Mrs. Brown s s Fracture Risk 7-year-old postmenopausal female with a femoral neck T-score of -1.5 Based on other major risk factors her 1-year probability of: Hip fracture: 4.3% Major osteoporotic fracture: 22% Should she be treated? FRAX WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/frax/tool.jsp. Accessed April 11, 28. National Osteoporosis Foundation (NOF) 28 Additions to Treatment Guidelines Initiate treatment in postmenopausal women and in men age 5 and older with: Low bone mass (T-score -1 to -2.5, osteopenia) at the femoral neck, total hip, or spine and 1-year hip fracture probability 3% -----------------OR------------------- 1-yr all major osteoporosis-related fracture probability of 2%, based on the US-adapted WHO absolute fracture risk model. FRAX tool calculates probability for major osteoporotic fracture and hip fracture Take Home Messages BMD should be completed on all women over 65, or younger postmenopausal women with risk factors for osteoporosis T-scores don t tell the whole story Age and BMD are independent risks for fracture The WHO FRAX tool will help clinicians identify patients who should receive treatment by incorporating other risk factors into a 1-year fracture risk determinant National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. 28. FRAX WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/frax/tool.jsp. Accessed April 11, 28. 3

Risk Factors for Fracture Identifying Others at Risk for Osteoporotic Fractures Low BMD Advanced age History of fracture as an adult History of a low trauma fracture in a first-degree relative Low body weight ( 127 lbs) Smoker Use of oral corticosteroid therapy for >3 months Excessive alcohol intake (>2 drinks per day) Medications (narcotics, sedatives, diuretics) Impaired vision Weakness Estrogen deficiency at an early age (<45 yrs) or hypogonadism Discontinuation of estrogen therapy Dementia Poor health status/frailty/ low physical activity Recent falls Poor mobility Lifelong low calcium intake/low vitamin D National Osteoporosis Foundation. The State of Osteoporosis and Low Bone Mass in the US.. Washington, DC: National Osteoporosis Foundation; 25. Vondracek SF, Hansen LB. Am J Health Syst Pharm.. 24;61:181-1811. 1811. Risk Factors for Falls Prior falls age, female, white Low mobility or poor neuromuscular control, neurological disease or cognitive deficit Use of eye meds, impaired vision Use of psychotropic drugs, diuretics, laxatives Dependency in ADLs, chronic medical conditions, DJD, HBP Low systolic blood pressure Low BMI FALL EVALUATION Observe patient walking to exam room Have patient do get up and go test Assess vision If any of above are impaired, arrange for in-home evaluation to assess hazards/minimize risks Herndon JG, et al. Chronic Medical Conditions and Risk of Fall Injury Events at Home in Older Adults. JAGS 1997; 45:739-743. Campbell AJ, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: A randomized, controlled trial. JAGS 1999; 47: 85-853. Medical Conditions Contributing to Osteoporotic Fracture Risk Endocrine Diseases Hyperthyroidism Hyperparathyroidism Hypogonadism Diabetes Mellitus GI Diseases Malabsorption syndromes Chronic liver disease Gastric operations Organ Transplant Other Chronic Diseases Rheumatoid arthritis Chronic lung disease Malignancy Renal Insufficiency Dietary Disorders Vitamin D deficiency/ insufficiency Excess alcohol intake Anorexia nervosa Medications Contributing to Osteoporotic Fracture Risk Glucocorticoids Long-acting progestin Aromatase inhibitors Gonadotropin-releasing hormone agonists Anticonvulsants Cytotoxic drugs Long-term heparin Lithium Proton pump inhibitors Selective serotonin receptor inhibitors Glitazones 1. National Osteoporosis Foundation. The State of Osteoporosis and Low Bone Mass in the US. Washington, DC: National Osteoporosis Foundation; 25. 2. Yu-Xiao Yang et al. JAMA. 26; 296: 2947-2953. 3. Richards JB et al. Arch Int Med. 27;167:188-194. 4

How Often Do Healthy Women with Osteoporosis Have Underlying Disorders? 173 healthy women age 46-87 T-score < -2.5 No prior lab abnormalities Evaluated for secondary osteoporosis: CBC, chemistry, 24-hr urine for calcium, PTH, 25(OH) Vitamin D Most also had TSH, SPEP Result: 44% had at least one unexpected new diagnosis Data recalculated from Tannenbaum C et al. J Clin Endocrinol Metab. 22;87:4431-4437. 4437. All of the following should be considered in the routine evaluation of someone found to be osteoporotic EXCEPT 1. Complete blood cell count 2. Renal/liver function 3. Serum chemistries 4. TSH 5. 1,25(OH) 2 D 6. 24-hour urine for calcium and creatinine? ARS Laboratory Assessment Consider the following: Complete blood cell count Renal/liver function Serum chemistries TSH 25(OH)D 24-hour urine for calcium and creatinine Vondracek SF and Hansenm LB. Am J Health Syst Pharm. 24;61:181-1811. US Department of Health and Human Services, Office of the Surgeon General. Prevention and Treatment in Bone Health and Osteoporosis: A Report by the Surgeon General. Rockville, MD. 24;186-253. Laboratory Assessment Specialized Testing for Secondary Osteoporosis Intact PTH Urine-free cortisol or overnight dexamethasone suppression test (if considering Cushing s syndrome) SPEP, UPEP, and IEP (if anemia, high ESR, protein or calcium) Tissue transglutaminase AB IgA and small bowel Bx (if malabsorption, low iron, or low 25(OH) vitamin D with suggestive Hx) Serum iron and ferritin (if malabsorption or hemachromatosis) Transiliac bone biopsy (very selected cases) Stein E et al. Endocrinol Metab Clin North Am. 23;32:115-134. Take Home Messages Fracture risk includes both risk factors for osteoporosis and risk factors for fall When evaluating patients with osteoporosis, consider secondary causes Check calcium and vitamin D levels Case Study, continued: Mrs. Brown s lab work all came back within normal limits Her femoral neck BMD is 1.5 Based on other risk factors and using the WHO FRAX tool, her 1-year probability of: Hip fracture: 4.3% Major osteoporotic fracture: 22% 5

What treatment options should we consider for Mrs. Brown? 1. No need to treat, her BMD is not osteoporotic 2. Lifestyle modifications at this time; recheck BMD in 1-2 years 3. Pharmacotherapy only 4. Lifestyle modifications and pharmacotherapy? NOF 28 Updated Treatment Recommendations Postmenopausal women and men age 5 and older presenting with the following should be treated: Hip or vertebral fracture Other prior fractures and low bone mass (T-score between -1. and -2.5 at the femoral neck, total hip, or spine) T-score < -2.5 at the femoral neck, total hip, or spine after appropriate evaluation to exclude secondary causes Low bone mass and secondary causes associated with high risk of fracture (e.g. glucocorticoid use or total immobilization) Low bone mass + 1-yr probability of hip fracture 3% or 1-yr probability of any major osteoporosis related fracture 2% ARS National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. 28. The Prevention and Treatment of Postmenopausal Osteoporosis JOSEPH GRISANTI, MD Focus on Recent Advances in Treatment Prevention Measures Nonpharmacologic Fall prevention strategies Regular weight-bearing exercise Strength training maintains or increases BMD, improves muscle mass, strength, and balance Nurses Health Study: active women with 24 metabolic equivalent task (MET)-h/wk had 55% lower risk of hip fracture (linear relationship) Avoid tobacco & excessive use of alcohol Holick MF. Curr Opin Endocrinol Diabetes. 22;9:87-98. Feskanich D et al. JAMA. 22;288:23-236.. In Search of the Sun Recent Emphasis on Vitamin D Vitamin D Actually a hormone (not really a vitamin) UVB rays convert 7-dehydrocholesterol to vitamin D 3 in the skin By age 65, 75% reduction in vitamin D production in skin Few dietary sources Fat soluble Supplements differ in type and quantity - Ergocalciferol (vitamin D 2 ) - Cholecalciferol (vitamin D 3 ) Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997. 432. Grant WB et al Alternative Med Rev. 25;1:94-111. 6

25-OH Vitamin D Levels After 5, IU Bolus of D2 and D3 2 Vitamin D Supplementation Decreases Fall and Fracture Risk VITAMIN D SUPPLEMENTATION: 1, IU 4 MONTHS REDUCTION IN FRACTURE VITAMIN D (8 IU/DAY ) AND CA (12 MG/DAY) SUPPLEMENTATION: REDUCTION IN FALLS 25-OH Vitamin D Level 15 1 5-5 D2 D3 1 8 15 22 29 Fracture relative risk (hip, wrist, forearm, spine) 1.2 1..8.6.4.2 P =.2 33% Fall risk 1.2 1..8.6.4.2 P =.1 49% -1 Days. Untreated (n = 1341) Treated (n = 1345). Calcium only (n = 44) Calcium + vitamin D (n = 45) Heaney RP et al. J Clin Endocrinol Metab. 25;9:4417. Bischoff HA et al. J Bone Miner Res. 23;18:343-351. Trivedi D et al. BMJ. 23;326:469.. Manifestations of Vitamin D Deficiency Osteoporosis Muscular weakness, falls, myalgias Cancers Cardiovascular benefits Neurologic: Multiple Sclerosis Endocrinology: Type 1 Diabetes Rheumatologic: Rheumatoid Arthritis Dermatologic: Psoriasis Immunologic: Infections Death & Vitamin D Supplementation Meta-analysis of 18 randomized controlled clinical trials Vitamin D vs placebo 57,311 patients Death from all causes was higher in placebo group Grant WB et al Alternative Med Rev. 25;1:94-111.. Wachtowski-Wende J, NEJM, 26, 354: 684-6;98 Nursyam et al, Acta Med Indonesia, 26 Autier P, Gandini S. Arch Intern Med. 27;167:173-1737. Change in Vitamin D Recommendation Old Guideline Vitamin D 4 IU/d for women under age 7 Vitamin D 6 IU/d for women over age 7 28 Guideline Vitamin D 3 4-8 IU/d for all women under age 5 Vitamin D 3 8-1, IU/d for all women over age 5 Which calcium product contains the most elemental calcium? 1. 1 mg of calcium carbonate 2. 1 mg of calcium citrate 3. 1 mg of calcium phosphate 4. 1 mg of calcium gluconate? National Osteoporosis Position Statement. July 27, 27. www.nof.org. ARS 7

Recommendations for Calcium and Vitamin D Calcium 12-15 mg/day Vitamin D 8-1 IU/day May safely use up to 2 IU/day Aim for 25(OH) vitamin D level 3 ng/ml Toxicity rare unless chronic doses > 1, IU daily For deficient vitamin D levels 5, IU once/twice weekly for 8-12 doses After correction, use 1 IU/day or 5, IU 1-2x/mo How to Interpret Osteoporosis Clinical Trials Nomenclature Morphometric vertebral factures Clinical vertebral fractures Nonvertebral fractures Hip fractures History of previous fractures? Holick MF. Curr Opin Endocrinol Diabetes. 22;9:87-98. Vieth R. Am J Clin Nutr. 1999;69:842-856. EXAMPLE OF AN OSTEOPOROSIS CLINICAL TRIAL Alendronate: : The Fracture Intervention Trial Vertebral Fractures in Postmenopausal Women (FIT) WITH PRIOR VFx Hip T-score 1.6; Age range=55-81 yrs % of patients with fracture 2 15 1 5 PBO n=965 FIT = Fracture Intervention Trial 47% Reduction at year 3 p<.1 ALN n=981 Black DM et al. Lancet. 1996;348:1535-1541. Cummings SR et al. JAMA. 1998;28:277-282. WITHOUT PRIOR VFx Hip T-score 2.5; Age range=54-81 yrs % of patients with fracture 2 15 1 5 PBO n=812 5% Reduction at year 4 p=.6 ALN n=819 Alendronate Hip Fractures in Postmenopausal Women (FIT) WITH PRIOR VFx Hip T-score 1.6; Age range=55 81 y Patients with Fracture (%) 5 4 3 2 1 PBO n=15 FIT = Fracture Intervention Trial 51% Reduction at year 3 P=.47 ALN n=122 Black DM et al. Lancet. 1996;348:1535-1541. Cummings SR et al. JAMA. 1998;28:277-282. Black DM et al. J Clin Endrocinrol Metab. 2;85;4118-4124. WITHOUT PRIOR VFx Hip T-score 2.5; Age range=54 81 y Patients with Fracture (%) 5 4 3 2 1 PBO n=812 56% Reduction at year 4 P=.44 ALN n=819 FDA-Approved Approved Pharmacologic Options for Osteoporosis Treatment in Women Antiresorptive Agents Lower bone turnover, maintain/improve bone mass, stabilize bone architecture Hormone (salmon calcitonin) SERM (raloxifene) Bisphosphonates alendronate with/without vitamin D risedronate ibandronate zoledronic acid Anabolic Agent Increase bone turnover with bone formation, > bone resorption, increase bone mass, and improve bone architecture Teriparatide FDA-Approved Osteoporosis Indications Calcitonin Raloxifene Reduce Vertebral Fractures Reduce Hip Fractures Alendronate X X Ibandronate X X X Reduce Nonvertebral Fractures Risedronate X X Zoledronic Acid X X X Teriparatide X X 8

Raloxifene Update Osteoporosis indication: vertebral fracture reduction in women Adverse events: hot flashes, venous thromboembolic events, leg cramps 9/13/7: FDA-approved raloxifene for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for developing breast cancer. CASES OF INVASIVE BREAST CANCER OVER 4 YRS/1 WOMEN 2 15 1 5 Placebo Raloxifene Bisphosphonates Most commonly prescribed therapy for osteoporosis Oral bisphosphonates indicated for prevention and treatment of postmenopausal osteoporosis, IV formulation indicated for treatment only Adverse events: esophageal irritation or erosion (oral only), hypocalcemia, bone pain Contraindications: esophageal dysmotility (oral only), significant renal dysfunction, hypocalcemia Warnings: rare cases of osteonecrosis of the jaw (ONJ) Physician s Desk Reference 26. Montvale, NJ. Thomson PDR; 26:1735-1739. Ettinger B et al. JAMA. 1999;282:637-645. Physician s Desk Reference 26. Montvale, NJ. Thomson PDR; 26:1949-1962; 2679-2688; 2747-2751. Bisphosphonate Indications for Osteoporosis Post- Menopausal Prevention Post- Menopausal Treatment Prevention Steroid- Induced Treatment Steroid- Induced Approved in Men Alendronate X X X X Ibandronate X (Oral Only) X Risedronate X X X X X Zoledronic Acid X Risedronate Update FDA approves risedronate 15 mg once-monthly dosing on April 24, 28 Study shows similar improvement in BMD compared to 5 mg daily Additional indications Reduction of spine and nonvertebral fractures Prevention and treatment of steroid-induced osteoporosis Treatment of male osteoporosis US Food and Drug Administration. www.fda.gov. Ibandronate Update: Results from Meta-analysis analysis Estimated Key Nonvertebral Fracture Rate, % 8 6 4 2 Annual cumulative exposure 1.8 mg Placebo 5 1 15 2 25 3 35 4 45 5 55 6 65 7 75 Days P=.31 (log-rank) for time to fracture with ibandronate vs placebo Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo Kaplan-Meier plot (2-year data) Harris ST et al. Curr Med Res Opin. 28 Jan;24(1):237-245. Physician s Desk Reference 26. Montvale, NJ. Thomson PDR; 26:2747-2751. Relative Risk Reduction 34.4% P<.5 Zoledronic Acid Update FDA approves use of zoledronic acid for the treatment of postmenopausal osteoporosis on September 17, 27 Additional indications Reduction of spine, nonvertebral, and hip fractures Available as 5 mg IV infusion given 15 minutes once yearly Black DM et al. N Engl J Med. 27;356:189-1822. [Evidence Level A]. 9

Zoledronic Acid Cumulative Reduction in 3-Year 3 Risk of Clinical Fractures Black DM et al. N Engl J Med. 27;356:189-1822. [Evidence Level A]. Effect of Zoledronic Acid 5 mg on All-Cause Mortality Over Time Cumulative Incidence (%) No. at Risk 18 Hazard ratio,.72 (95% CI,.56.93) 16 P =.117 14 12 1 8 6 4 2 ZOL 5 mg (n = 165) Placebo (n = 162) 4 8 12 16 2 24 28 32 36 Months ZOL 5 mg 154 129 987 943 86 674 57 348 237 144 Placebo 157 128 993 945 84 681 511 364 236 149 Lyles KW et al. N Engl J Med. 27;357:1799-189. 28% Teriparatide (Parathyroid Hormone) ) Update Current indications: treatment of postmenopausal women and men with osteoporosis at high-risk of fracture Daily 2 mcg injection for a maximum of 2 years Recent studies in glucocorticoid-induced osteoporosis (GIOP): Among patients with osteoporosis at high risk for fracture, BMD increased more in patients receiving teriparatide than in those receiving alendronate Indication in EU label 4/28, request to FDA for supplemental indication filed 27 Assessing Therapeutic Response Follow-up BMD in the Treated Patient Repeat labs and BMD testing after two years in patients taking pharmacotherapy for osteoporosis BMD maintained or increased = satisfactory response BMD decline Assess technical issues (e.g. validity of DXA comparison) Assess compliance and dosing Consider and re-evaluate for secondary causes Patient may be a true non-responder Physician s Desk Reference 26. Montvale, NJ. Thomson PDR; 26:1739-1743. Saag KG et al. N Eng J Med. 27;357:228-239. Watts NB et al. J Clin Densitom. 24;7:255-261. Burke MS. Curr Opin Endocrinol Diabetes. 24;11:33-337. Long-Term Therapy Mrs. Smith has been treated for osteoporosis with an oral bisphosphonate for the past 7 years because of the following T-scores: Lumbar Spine: -2.6 Femoral Neck: -2.5 Her T-scores have improved to their current values: Lumbar Spine: -1.6 Femoral Neck: -1.5 Her previous doctor is suggesting she stop her medication in favor of a drug holiday; she has never had a fracture; she seeks a second opinion from you What do you tell her?? 1. I am opposed to a drug holiday. I recommend you continue your bisphosphonate as usual. 2. Let s determine your absolute fracture risk using the FRAX TM tool if your 1-yr all major osteoporosis-related fracture probability is 2%, we will stop treatment. 3. I recommend you stop your medicine for a year, then we will recheck your BMD. 4. Because these medicines are incorporated into bone, I am concerned about the potential for you developing frozen bone. I believe 7 years is enough. I suggest you stop this medicine and remain off it indefinitely. ARS 1

Total Hip BMD Change in FLEX Population From Beginning of FIT to Completion of FLEX Long-Term Data with Bisphosphonates Mean Percent Change From FIT Baseline, % 5 4 3 2 1 FIT: 3-4.5 years 1 F F 1 F 2 F 3 F 4 = ALN/placebo (n = 437) = ALN/ALN (pooled 5-mg and 1-mg groups: n = 662) F = FIT; FL = FLEX Black DM et al. JAMA. 26;296:2927 2938. Time between FIT and FLEX: 1-2 years FLEX: 5 years FL FL 1 FL 2 FL 3 FL 4 FL 5 Year 2.4% P<.1 Alendronate: efficacy and safety of 1 years treatment (FLEX study: FIT long-term extension) Clinical vertebral fractures 55% with 1 yr treatment vs 5 yr; other fractures not significantly different 1 Bone biopsies: normal bone histology 2 Clear evidence of ongoing bone remodeling (no frozen bone) Risedronate with safety/efficacy data through 7 years 3,4 Confirms safety of long-term bisphosphonate treatment 1. Black DM et al. JAMA. 26;296:2927-2938 2. Recker RR et al. J Bone Miner Res. 24;19:1173 3. Zoehrer R et al. J Bone Miner Res. 26;21:116-12. 4. Mellström DD et al. Calif Tissue Int. 24; 75:462-468. Mrs. Brown returns 8 years later, following a hip fracture She is now 78 She was initially prescribed a weekly bisphosphonate, but was lost to follow-up until now Evaluation in the hospital showed normal chemistries, TSH, and vitamin D level Further questioning reveals she has been taking her bisphosphonate 1-3 times a month, often with coffee; Recent refills were provided by another physician. Secondary Fracture Prevention In Bisphosphonate Non-responders Rule out secondary causes of osteoporosis Endocrine diseases Glucocorticoids Low calcium/vitamin D Evaluate for compliance issues Not following dosing instructions Simplify dosing regimen e.g. IV zoledronic acid or monthly ibandronate Consider anabolic agent Absorption and Tolerability of Oral Bisphosphonates Affected When Dosing Instructions Are Not Followed 1. Weycker D et al. Osteoporos Int. 26;17:1645-1652. 2. Seeman E et al. Osteoporos Int. 27;18:711-719. 3. Siris ES et al. Mayo Clin Proc. 26;81:113-122. 4. Downey TW et al. South Med J. 26;99:57-575. Persistence Increases With Weekly Bisphosphonates but Remains Suboptimal % of Patients Persistent on Therapy 1 9 8 7 6 5 4 3 2 1 Median Daily Median Weekly 133.5 269 365 Days of Follow-Up Adapted with permission from Cramer JA et al. Curr Med Res Opin. 25;21:1453-146. Weekly (N=731) Daily (N=21) 44.2% 31.7% 11

Poor Compliance and Persistence Lead to Compromised Fracture Risk Reduction Bisphosphonate Treatments Dosing Frequency N = 35,537 24 Month Fracture Risk (%) 14 12 1 8 6 4 2 1 Non- Persistent 29% Risk Reduction P <.1 7.7 Persistent Agent Alendronate Risedronate Ibandronate Zoledronic acid Weekly 35 or 7 mg oral Monthly 35 mg oral 15 mg oral 15 mg oral Quarterly 3 mg IV injection Annually 5 mg IV infusion Siris E et al. Mayo Clin Proc. 26;81:113-122. Individualizing Therapy Each Modality has its Clinical Place Exercise Alendronate Calcitonin Ibandronate Calcium and Vitamin D Fall Risk Evaluation TAILORED PHARMACOLOGIC MANAGEMENT Risedronate Teriparatide Zoledronic Acid Raloxifene Take Home Messages Treatment of Osteoporosis Osteoporosis is an important public health concern Fracture risk incorporates both BMD and other important risk factors and should be calculated to help determine need for therapy Consider secondary causes of bone loss Recommend lifestyle modifications in all patients with or at risk for osteoporosis Pharmacotherapy should be individualized to the patient Patients who have had fractures are at high risk for future fractures and should be targeted for pharmacologic intervention The Prevention and Treatment of Postmenopausal Osteoporosis 12