A Patient s Journey with Osteoporosis: From Diagnosis through Treatment

A Patient s Journey with Osteoporosis: From Diagnosis through Treatment May 1, 2013 Anaheim, California Educational Partner:

Session 2: A Patient s Journey with Osteoporosis: From Diagnosis through Treatment Learning Objectives 1. Implement osteoporosis assessment guidelines regarding diagnosis and fracture prevention. 2. Initiate treatment of osteoporosis according to risk assessment scores and bone mineral density measurements. 3. Choose an appropriate treatment option for patients with osteoporosis and consider the benefit:risk ratio of short-term and longterm therapy across all classes of medications. Faculty E. Michael Lewiecki, MD, FACP, FACE Osteoporosis Director New Mexico Clinical Research & Osteoporosis Center Albuquerque, New Mexico E. Michael Lewiecki, MD, FACP, FACE, is clinical assistant professor of medicine at University of New Mexico School of Medicine and director of New Mexico Clinical Research & Osteoporosis Center. He is a consultant in osteoporosis and metabolic bone disease, supervisor and interpreter of bone density studies at the Center, and an educator with a special interest in the management of osteoporosis and metabolic bone disease. He is principal investigator for the Center s osteoporosis clinical trials and author of many scientific publications on osteoporosis and bone densitometry. Dr Lewiecki is past president of the International Society for Clinical Densitometry (ISCD). He is a faculty member for the ISCD educational programs in bone densitometry, vertebral fracture assessment, and management of osteoporosis. Dr Lewiecki is senior editor of the Journal of Clinical Investigation, associate editor of the Journal of Clinical Densitometry, and an editorial board member of Osteoporosis International and other peer-reviewed journals. He has received national and international awards, including Physician of the Year by the ISCD in 2002, the ISCD Paul D. Miller Service Award in 2006, and the Laureate Award of the New Mexico Chapter of the American College of Physicians in 2006. He is a fellow of the American College of Physicians and the American College of Endocrinology. Dr Lewiecki is president and founder of the Osteoporosis Foundation of New Mexico and director of its educational activities. He established and is program director of the annual Santa Fe Bone Symposium. Dr Lewiecki, who was raised in the Boston, Massachusetts, area, is a graduate of Amherst College in Amherst, Massachusetts, and Northwestern University Medical School in Chicago, Illinois. He completed postgraduate medical training at University of New Mexico Health Sciences Center and now resides in Albuquerque, New Mexico. Michael Maricic, MD Clinical Associate Professor of Medicine University of Arizona School of Medicine Tucson, Arizona Michael Maricic, MD, is director of Catalina Pointe Clinical Research and clinical associate professor of medicine at the University of Arizona School of Medicine in Tucson. While at the University of Arizona, Dr Maricic has served as head of the section of rheumatology and as program director for both the internal medicine residency and the rheumatology fellowship programs. He has chaired both the curriculum committee and the graduate medical education advisory committee. Dr Maricic has received the Dean s Teaching Award for Excellence and the Virginia Furrow Award for Excellence in Graduate Medical Education and was elected Alpha Omega Alpha by the medical student class. The internal medicine house staff named him the Outstanding Attending in both 2003 and 2004. Dr Maricic is a fellow of the American College of Rheumatology and past chairman of its educational materials and audiovisual aids committees. He is a member of the American Society for Bone and Mineral Research, a past member of the National Osteoporosis Foundation Newsletter Editorial Board, and past associate editor of the Journal of Clinical Densitometry, currently serving on its editorial board. Session 2

He has authored 40 peer-reviewed articles and numerous chapters on osteoporosis and rheumatology and has coedited the textbooks Decision Making in Internal Medicine, Clinical Care in the Rheumatic Disease, and Bone Disease in Rheumatology. Faculty Financial Disclosure Statements The presenting faculty reports the following: E. Michael Lewiecki, MD, FACP, FACE, receives grant/research support (principal investigator, funding to New Mexico Clinical Research & Osteoporosis Center) from Amgen, Eli Lilly and Company, GlaxoSmithKline, and Merck. He is on the scientific advisory board of Amgen, Eli Lilly and Company, and Merck. He is on the speaker bureaus for Eli Lilly and Company, Novartis, and Warner Chilcott. He is a consultant for GlaxoSmithKline. Michael Maricic, MD, serves on the speaker bureau for, is a consultant for, or receives clinical research grant support from Amgen, Eli Lilly and Company, Novartis, and Roche. Education Partner Financial Disclosure Statement The content collaborators at CME Incite have reported the following: Rose O Connor, PhD, and Monique Pond, PhD, have no financial relationships to disclose. Suggested Reading List Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis for whom and for how long? N Engl J Med. 2012;366(22):2051-2053. FRAX. WHO Fracture Risk Assessment Tool. Available at: http://www.shef.ac.uk/frax/. Accessed March 28, 2013. Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62(11):1515-1526. Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19(4):385-397. Lewiecki EM. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis. Drug Healthc Patient Saf. 2011;3:79-91. Maricic M. Update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 2011;37:415-431. National Osteoporosis Foundation. Clinician s guide to prevention and treatment of osteoporosis. 2010. Available at: http://www.nof.org/files/nof/public/content/file/344/upload/159.pdf. Accessed March 28, 2013. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6):785-795. Schilcher J, Michaёlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728-1737. U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. preventive services task force recommendation statement. Ann Intern Med. 2011;154(5):356-364. Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis: executive summary of recommendations. Endocr Pract. 2010;16(6):1016-1019. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 2010;95(4):1555-1565. Session 2

SESSION 2 9:45 AM 11:00 AM A Patient s Journey With Osteoporosis: From Diagnosis Through Treatment SPEAKERS E. Michael Lewiecki, MD, FACP, FACE Michael Maricic, MD Presenter Disclosure Information The following relationships exist related to this presentation: Dr Lewiecki receives grant/research support (principal investigator, funding to New Mexico Clinical Research & Osteoporosis Center) from Amgen, Eli Lilly and Company, GlaxoSmithKline, and Merck. He is on the scientific advisory board of Amgen, Eli Lilly and Company, and Merck. He is on the speaker bureaus for Eli Lilly and Company, Novartis, and Warner Chilcott. He is a consultant for GlaxoSmithKline. Dr Maricic serves on the speaker bureau for, is a consultant for, or receives clinical research grant support from Amgen, Eli Lilly and Company, Novartis, and Roche. Presenter Disclosure Information 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. A Patient s Journey With Osteoporosis: From Diagnosis Through Treatment Michael Maricic, MD Clinical Associate Professor of Medicine University of Arizona Tucson, AZ E. Michael Lewiecki, MD Clinical Assistant Professor of Medicine University of New Mexico School of Medicine Albuquerque, NM Drug List Learning Objectives Estrogen Alendronate Risedronate Ibandronate Zoledronate Calcitonin Raloxifene Denosumab Teriparatide Estrogen Fosamax Actonel, Atelvia Boniva Reclast Miacalcin, Fortical Evista Prolia Forteo Implement osteoporosis assessment guidelines regarding diagnosis and fracture prevention Initiate treatment of osteoporosis according to risk assessment scores and bone mineral density (BMD) measurements Choose an appropriate treatment option for patients with osteoporosis and consider the benefit:risk ratio of short- and long-term therapy across all classes of medications 1

Demographic Question? Outcomes Question 1? Approximately how many patients have you seen in the last 60 days with osteoporosis? 1. None 2. 1-5 3. 6-10 4. 11-20 5. Over 20 A 56-year-old postmenopausal woman has a T-score of -2.3 at the FN. She meets NOF guidelines for pharmacologic treatment to reduce fracture risk in which one of the following cases? 1. Wrist fracture at 49 years 2. Mother had hip fracture at 82 years 3. FRAX 10-year probability of major osteoporotic fracture is 22% 4. FRAX 10-year probability of hip fracture is 2% FN, femoral neck; NOF, National Osteoporosis Foundation. Outcomes Question 2? Outcomes Question 3? Which one of the following is a clinical risk factor for input with FRAX? 1. Diabetes mellitus 2. Rheumatoid arthritis 3. Proton pump inhibitor therapy 4. Long-term anticonvulsant therapy Which one of the following is FDA approved for the treatment of osteoporosis in both men and women? 1. Ibandronate 2. Calcitonin 3. Raloxifene 4. Denosumab Outcomes Question 4? A 72-year-old woman was diagnosed with osteoporosis at 67 years, with a femoral neck T-score of -3.2. After 5 years of oral bisphosphonate therapy, her T-score has stabilized at -2.8. What should be your next course of action? Osteoporosis: Diagnosis and Screening 1. Stop treatment, since there is no benefit beyond 5 years 2. Add salmon calcitonin to further reduce fracture risk 3. Continue alendronate, since benefits probably outweigh risks 4. Switch to another bisphosphonate, so that she continues to achieve an adequate response to therapy Michael Maricic, MD Clinical Associate Professor of Medicine University of Arizona Tucson, AZ 2

Katherine s Story 65-year-old grandmother in relatively good health Presents for a routine check-up Menopause commenced at 48 years, but she never accepted hormone therapy Has never taken oral glucocorticoids She is 5 ft 2 in, but says that she used to be 5 ft 3 in Is Katherine at risk for developing osteoporosis? Osteoporosis NIH Consensus Statement 2000 a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture Bone strength primarily reflects integration of bone quality and bone density Normal Osteoporosis Bone mass + bone quality = bone strength NIH Consensus Development Panel. JAMA. 2001;285:785-795. Normal Bone Remodeling Postmenopausal Bone Loss 1 2 1 2 Osteoclast Resorption Osteoblast Recruitment Increased Osteoclast Resorption Increased Osteoblast Recruitment 3 4 3 4 New Bone Formation Osteoblast Apoptosis/ Osteocyte Transition Inadequate Osteoblast Osteoid Production Net Bone Loss Osteocyte Transition Impact of Osteoporosis Distribution of Osteoporotic Fractures: Combined Total for Men and Women 44 million Americans have low bone mass 12 million have osteoporosis Estimated to increase to >14 million by end of 2020 50% of women and 25% of men >50 years will suffer 1 osteoporotic fracture in their lifetimes Prevalence of osteoporosis will rise with increases in elderly population US Preventive Services Task Force. Ann Intern Med. 2011;154:356-364. NOF. http://www.nof.org/articles/4. Accessed March 21, 2013. Burge R, et al. J Bone Miner Res. 2007;22:465-475. Burge R, et al. J Bone Miner Res. 2007;22:465-475. Watts NB, et al. Endocr Pract. 2010;16(suppl 3):1-37. 3

Consequences of Fractures Vertebral Fractures Increased risk of future fractures Chronic pain Loss of height Impaired pulmonary function Medical expenses/lost income Hospitalization Surgery Need for rehabilitation Nursing home care Loss of self-esteem Depression Loss of independence Disability Death Most common fractures Only 1/3 of VFs are clinically apparent Progressive Associated with Deformity, height loss, back pain Morbidity and mortality Predict future VFs and non-vfs US Preventive Services Task Force. Ann Intern Med. 2011;154:356-364. Melton LJ III. J Bone Miner Res. 2003;18:1139-1141. Lindsay R, et al. JAMA. 2001;285:320-323. Melton LJ III. J Bone Miner Res. 2003;18:1139-1141. VFs, vertebral fractures. Incident VF Rapidly Increases Risk of Next VF Prevalent VF Predicts Risk of Future Hip Fracture Patients, % 24 20 16 12 8 4 0 6.6 Incidence During Study Year 0-1 (n=2570) Lindsay R, et al. JAMA. 2001;285:320-323. 19.2 Incidence Within 1 Year Following 1st Fracture (n=381) Presence of 1 VF at baseline increased risk of additional VF 5-fold during Study Year 1 N=2725 postmenopausal women, mean age 74 years. Cumulative Incidence of Hip Fracture in Men and Women, % 25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 Years After VF Melton LJ III, et al. Osteoporos Int. 1999;10:214-221. Observed Expected Relative Risk of Death Following Clinical Fractures Fracture Intervention Trial (FIT) N=6459 postmenopausal women Aged 55-81 years Followed for average of 3.8 years Any Symptomatic Cauley JA, et al. Osteoporos Int. 2000;11:556-561. Non-spine Hip Spine Forearm Other 6.7 8.6 0.3 1.0 2.0 5.0 10.0 16.0 Age-Adjusted Relative Risk (95% CI) CI, confidence interval. Hip Fractures Are Associated With Increased Morbidity and Mortality Of patients who experience a hip fracture 80% are unable to carry out at least 1 independent activity of daily living 40% are unable to walk independently 30% become permanently disabled 20% die within 1 year Hip fractures account for 14% of incident fractures but 72% of fracture costs Cooper C. Am J Med. 1997;103:12S-17S. Burge R, et al. J Bone Miner Res. 2007;22:465-475. 4

Clinical Evaluation Clinical Risk Factors History Assessment of risk factors for low bone mass, falls, and fractures Physical exam Laboratory tests and measurement of BMD Age Previous low trauma fracture Current cigarette smoking Rheumatoid arthritis High alcohol intake (>2 units/d) Parental history of hip fracture Prior or current glucocorticoid use Watts NB, et al. Endocr Pract. 2010;16(suppl 3):1-37. BMD, bone mineral density. Adapted from Kanis JA, et al. Osteoporos Int. 2005;16:581-589. Is BMD testing for Katherine indicated? 1. Yes 2. No ARS Question? Bone Density Measurement: DXA Is the Gold Standard Widely used in epidemiologic studies from which prevalence data are derived WHO criteria based on BMD measured by DXA Correlation with fracture risk Low radiation Excellent precision DXA, dual-energy X-ray absorptiometry; WHO, World Health Organization. WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser. 1994;843:1-129. US Preventive Services Task Force. Ann Intern Med. 2011;154:356-364. 2013 NOF Guidelines Indications for BMD Testing Women 65 years and men 70 years, regardless of clinical risk factors Younger postmenopausal women, women in the menopausal transition, and men aged 50-69 years with clinical risk factors for fracture Adults with fracture after age 50 years Adults with conditions such as rheumatoid arthritis or taking medications (such as glucocorticoids 5 mg/d 3 months) associated with low bone mass or bone loss NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. http://www.nof.org/hcp/clinicians-guide. Accessed April 9, 2013. Bone Mass Measurement Act July 1, 1998 5 Categories of Medicare-Covered Services Estrogen-deficient women at clinical risk for osteoporosis Individuals with vertebral abnormalities Individuals receiving long-term glucocorticoid therapy Individuals with primary hyperparathyroidism Individuals being monitored to assess response to or efficacy of an FDA-approved osteoporosis drug therapy Federal Register, Volume 63, Number 121. June 24, 1998. 5

WHO Diagnostic Categories Diagnosis in Postmenopausal Women and in Men Aged 50 Normal Classification Low bone mass (osteopenia) Osteoporosis Severe osteoporosis T-score -1.0 or greater Between -1.0 and -2.5-2.5 and below -2.5 with history of fragility fracture Osteoporosis may be diagnosed in postmenopausal women and in men aged 50 years and older if the T-score of the lumbar spine, total hip, or femoral neck is -2.5 or less * In certain circumstances, the 33% radius (also called 1/3 radius) may be utilized * Note: Other hip regions of interest, including Ward s area and the greater trochanter, should not be used for diagnosis. Application of recommendation may vary according to local requirements. WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser. 1994;843:1-129. ISCD Official Positions. http://www.iscd.org/official-positions/2007-iscd-official-positions-adult/. Accessed April 10, 2013. Katherine s lowest T-score is -2.3 at the FN. What is her diagnosis? 1. Normal 2. Osteopenia 3. Osteoporosis 4. Severe osteoporosis ARS Question? Use Clinical Judgment T-score -2.5 does not always mean that osteoporosis is present Primary disease may be something else (eg, hyperparathyroidism, osteomalacia, or multiple myeloma) T-score >-2.5 does not eliminate the possibility of osteoporosis Clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture Perform FRAX in patients with osteopenia Diagnosis of Osteoporosis Densitometric diagnosis DXA WHO criteria Clinical diagnosis Fragility fracture Vertebral Fracture (VF) Assessment Recognition of VF may Change diagnostic classification Change estimate of fracture risk Change treatment decisions Normal VF 6

Combined Effect of Bone Density and Prevalent Fractures Problem: Most Women With Fracture Have T-score >-2.5 prevalent fracture prevalent fracture Study of Osteoporotic Fractures in 243 Women With Hip Fractures 1 National Osteoporosis Research Assessment 2259 Women With Osteoporotic Fractures 2 Rate Ratio 46% 54% 18% 82% Bone Mass (mg/cm 2 ) Bone Density T-score > -2.5 T-score -2.5 T-score > -2.5 T-score -2.5 Ross PD, et al. Ann Intern Med. 1991;114:919-923. 1. Wainwright SA, et al. J Clin Endocrinol Metab. 2005;90:2787-2793. 2. Siris ES, et al. Arch Intern Med. 2004;164:1108-1112. Clinical Evaluation of Katherine ARS Question? History Menopause commenced at age 48 years but she never accepted hormone therapy Never taken oral glucocorticoids Physical exam She is 5 ft 2in, but says that she used to be 5 3 in Weight: 120 lb Laboratory tests What tests should be done to assess skeletal health and fracture risk? What laboratory tests should be done in the evaluation for secondary causes of osteoporosis? 1. Serum creatinine, calcium, phosphorus, and alkaline phosphatase 2. Serum 25(OH)D 3. 24-hour urinary calcium 4. All of the above 25(OH)D, 25-hydroxyvitamin D. Clinical Evaluation: Laboratory Tests Serum calcium, phosphorus, and alkaline phosphatase Creatinine Serum 25(OH)D 24-hour urine calcium TSH (in women receiving thyroid supplementation) The above tests identify 92% of patients with secondary causes Unmet Needs Underdiagnosis Undertreatment Poor adherence to treatment Adapted from Tannenbaum C, et al. J Clin Endocrinol Metab. 2002;87:4431-4437. TSH, thyroid-stimulating hormone. 7

Undertreatment of Osteoporosis in Men and Women Who Have Experienced a Hip Fracture Real-World Persistence to Daily and Weekly Bisphosphonate Therapies Taking Treatment, % 60 50 40 30 20 P<0.001 Hospital admission Hospital discharge 1-5 year follow-up 10 * * * 0 Men Women n=110 n=253 *P 0.001 for % of men taking treatment Kiebzak GM, et al. Arch Intern Med. 2002;162:2217-2222. vs % of women taking treatment Patients, % 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 Months of Continuous Persistence Data from Downey TW, et al. South Med J. 2006;99:570-575. Daily Weekly P=NS Low Adherence and Nonpersistence Lead to Compromised Fracture Risk Reduction N=11,249 Fracture Risk Hazard Ratio 1 1.0 0.8 0.6 0.4 0.2 1.000 *16% Risk Reduction 0.843 N=35,537 0 0 Low Adherence High Adherence Nonpersistent Persistent Low adherence = filled prescriptions to treat osteoporosis <80% of the time; *P<0.001 high adherence = filled prescriptions to treat osteoporosis 80% of the time. 1. Caro JJ, et al. Osteoporos Int. 2004;15:1003-1008. 2. Siris E, et al. Mayo Clin Proc. 2006;81:1013-1022. 3. Medstat MarketScan Research Databases over 24 months (1999-2003). 24-Month Fracture Risk, 2,3 % 14 12 10 8 6 4 2 12.6 *29% Risk Reduction 9.4 Summary Osteoporosis results in great cost, morbidity, and mortality to both men and women Prevalence of osteoporosis and fractures is rising worldwide Only 1/3 of VFs are clinically apparent Presence of 1 VF increases risk of subsequent VFs and non-vfs Combination of BMD testing and presence of clinical risk factors is a better predictor of fracture risk than BMD or CRF alone CRF, clinical risk factor. Fracture Risk Assessment and Treatment of Osteoporosis Fracture Risk Assessment: Fracture BMD, Risk CRFs, Assessment FRAX Intervention Thresholds E. Michael Lewiecki, MD Clinical Assistant Professor of Medicine University of New Mexico School of Medicine Albuquerque, NM Treatment Follow-up 8

Age Is an Independent Risk Factor for Osteoporotic Fractures Prior Fracture Increases Relative Risk of Subsequent Fractures Probability of Major Osteoporotic Fracture 10-Year Fracture Probability, % Age in Years 80 70 60 50 Site of Subsequent Fracture (Relative Risk) Site of Prior Fracture Wrist Vertebra Hip Wrist 3.3 1.7 1.9 Vertebra 1.4 4.4 2.3 Hip NA 2.5 2.3 Adapted from Kanis JA, et al. Osteoporosis Int. 2001;12:989-995. Klotzbuecher CM, et al. J Bone Miner Res. 2000;15:721-739. ARS Question? Do the NOF guidelines recommend using FRAX for making treatment decisions with Katherine? 1. Yes, because she has osteopenia and no prior hip fracture or VF 2. Yes, because she is a Caucasian postmenopausal woman 3. No, because it makes no difference for treatment decisions 4. No, because she is <70 years FRAX: Assess Fracture Risk in Untreated Patients From 40-90 Years Access: http://www.shef.ac.uk/frax Input: BMD + CRFs Rationale: BMD + CRFs predict fracture risk better than either alone Output: 10-year fracture probability Kanis JA, et al. Osteoporos Int. 2008;19:385-397. CRF, clinical risk factor. Woman, Caucasian, 0.578, no CRFs: 11%, 2.2% Fracture Risk Assessment Intervention Thresholds: NOF Treatment Follow-up 9

NOF Treatment Guidelines Postmenopausal women and men 50 years with the following should be considered for treatment, after evaluation for secondary causes of osteoporosis: Osteoporosis T-score -2.5 at FN, TH, or LS, or Hip or vertebral (clinical or morphometric) fracture Osteopenia T-score between -1.0 and -2.5 at FN or LS, and FRAX 10-year probability of hip fracture 3% or major osteoporotic fracture 20% Fracture Risk Assessment Intervention Thresholds Treatment: Evidence + Clinical Judgment Follow-up NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. http://www.nof.org/hcp/clinicians-guide. Accessed April 9, 2013. Universal Recommendations Katherine s Story: 5 Years Later Regular weight-bearing and musclestrengthening exercise Fall prevention Avoid tobacco use and excess alcohol Calcium 1000-1200 mg/d IOM: RDA 1,000-1,200 mg, UL 2,000 mg Vitamin D 800-1,000 IU/d, target 30 ng/ml IOM: RDA 600-800 IU, target >20 ng/ml, UL 4,000 IU IOM, Institute of Medicine; RDA, recommended daily allowance; UL, tolerable upper intake level. NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. http://www.nof.org/hcp/clinicians-guide. Accessed April 9, 2013. IOM. Report on Dietary Reference Intakes. 2011. 70-year-old grandmother in relatively good health She is now 5 ft 1 in; lost 1 in in past 5 years; she used to be 5 ft 3 in BMD testing: FN T-score -2.3 FRAX 10-year probability 12% for major osteoporotic fractures 2.8% for hip fractures Diagnosis: osteopenia What would you do next? Katherine s VF Assessment Treatment Decisions Clinical Practice Guidelines: NOF, ACR, AACE, NAMS, etc Fracture T12 Individual patient factors Efficacy and safety for individual patient Nonskeletal risks and benefits Comorbidities Expected adherence to therapy Patient beliefs, concerns, preferences Insurance coverage/affordability Risk communication, shared decision making AACE, American College of Clinical Endocrinologists; ACR, American College of Rheumatology; NAMS, North American Menopause Society. NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. http://www.nof.org/hcp/clinicians-guide. Accessed April 9, 2013. Watts NB, et al. Endocr Pract. 2010;16(suppl 3):1-37. 10

FDA-Approved Medications: Indications Drug PMO GIO (Women and Men) Men Prevention Treatment Prevention Treatment Estrogen Alendronate PO Risedronate PO Risedronate Delayed-Release PO Ibandronate PO Ibandronate IV Zoledronate IV Calcitonin IN Raloxifene PO Denosumab SC Teriparatide SC GIO, glucocorticoid-induced osteoporosis; PMO, postmenopausal osteoporosis. FDA-Approved Medications: Efficacy Medication BMD BTM Fracture Risk Estrogen Alendronate Risedronate Ibandronate Zoledronate Calcitonin ~ Raloxifene Denosumab Teriparatide Boonen S, et al. J Bone Miner Res. 2012;27:963-974. Mulder JE, et al. Nat Clin Pract Endocrinol Metab. 2006;2:670-680. Sharif PS, et al. Rheumatol Int. 2001;31:289-300. BTM, bone turnover marker. FDA-Approved Medications: Efficacy Fracture Risk Reduction Drug Vertebral Nonvertebral Hip Raloxifene Yes No effect demonstrated a No effect demonstrated a Ibandronate Yes No effect demonstrated a No effect demonstrated a Alendronate Yes Yes Yes Risedronate Yes Yes Yes Zoledronic acid Yes Yes Yes Denosumab Yes Yes Yes Teriparatide Yes Yes No effect demonstrated a a Lack of demonstrable effect at these sites should be considered in the context that the studies may not have been adequately powered. Watts NB, et al. Endocr Pract. 2010;16(suppl 3):1-37. Non-Bisphosphonates: Safety Issues Estrogen/hormone therapy Increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis Estrogen agonist/antagonist: Raloxifene Increased risk of deep vein thrombosis Calcitonin FDA advisory committee voted that the risks outweigh the benefits for the treatment of postmenopausal osteoporosis (March 5, 2013) RANKL inhibitor: Denosumab Increased risk of skin infections and osteonecrosis of the jaw Parathyroid hormone: Teriparatide Treatment is not recommended for more than 2 years due to concerns of increased risk for osteosarcomas RANKL, receptor activator of nuclear factor kappa-b ligand. NOF. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. http://www.nof.org/hcp/clinicians-guide. Accessed April 10, 2013. Bisphosphonate Safety Issues: Balancing Benefits and Risks Combination therapy Oversuppression of bone turnover Osteonecrosis of the jaw Atypical femur fractures Atrial fibrillation Esophageal cancer Impaired fracture healing Drug holidays No guidelines Very little data http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021858s009medg.pdf. Accessed March 21, 2013. Black DM, et al. N Engl J Med. 2007;356:1809-1822. Sun K, et al. Osteoporos Int. 2013:24:279-286. Green J, et al. BMJ. 2010:341:c4444. Watts NB, et al. J Clin Endocrinol Metab. 2010;95:1555-1565. Ott S. Cleve Clin J Med. 2011;78:619-630. Odvina CV, et al. J Clin Endocrinol Metab. 2005;90:1294-1301. Drug Holiday Temporary withholding of bisphosphonate after at least 3-5 years in appropriate patients NOT drug retirement NOT stopping treatment ONLY applies to bisphosphonates Rationale: persistence of antifracture benefit while possibly reducing long-term risks Very little data, many opinions Periodic re-evaluation of balance of benefits and risks Consider for patients no longer at high fracture risk T-score >-2.0, no major fracture End drug holiday when fracture risk is again high T-score -2.5, fracture, FRAX, BTM Adapted from Whitaker M, et al. N Engl J Med. 2012;366:2048-2051. Black DM, et al. N Engl J Med. 2012;366:2051-2053. Bonnick SL. J Clin Densitom. 2011;14:377-383. Watts NB, et al. J Clin Endocrinol Metab. 2010;95:1555-1565. 11

Fracture Risk Assessment Intervention Thresholds Treatment Follow-up: Monitoring, Adherence Clinical Challenges After Beginning Treatment Motivating patient to fill prescription and take it correctly, regularly, and for a sufficient length of time to provide benefit Determining how (or if) to follow and monitor patient to assure that benefit is achieved Managing nonresponders/suboptimal responders Deciding when (if ever) to stop or change therapy Knowing when (if ever) to restart, if treatment is stopped Managing side effects, perceived side effects, and fear of side effects Improving Adherence to Therapy Risk communication Shared decision making Longer dosing intervals Less complex administration Injectable therapy Patient education Follow-up contact ARS Question? Which of the following is most correct in the setting of Katherine s low BMD and recent VF? 1. Fracture risk is high; treatment benefits outweigh treatment risks 2. Fracture risk is low; treatment risks outweigh treatment benefits 3. Fracture risk is not known; best approach is to repeat DXA in 1-2 years 4. Fracture risk is high, but risks of treatment are excessive Monitoring in Clinical Practice: Assess Long-term Benefit:Risk Ratio BMD (DXA) Measure 1-2 years after starting therapy Goal: stability or increase BTM (NTX, CTX, BSAP, P1NP, etc) Measure ~3 months after starting therapy or when BMD response is not as expected Goal: significant decrease with antiresorptive agent and increase with anabolic agent Cause for concern and further evaluation Significant loss of BMD Lack of expected change in BTM Fracture while receiving therapy BSAP, bone specific alkaline phosphatase; CTX, C-telopeptide of collagen type 1; NTX, N-telopeptide of collagen type 1; P1NP, N-terminal serum type 1 procollagen. Lewiecki EM, et al. Osteoporos Int. 2008;19:1363-1368. Summary FRAX used to assess fracture risk in untreated patients from age 40-90 years NOF recommends pharmacotherapy be considered in postmenopausal women and men 50 years of age in each scenario T-score -2.5 Presence of hip fracture or VF T-score between -1.0 and -2.5 at FN or LS and FRAX 10-year probability of hip fracture 3% or major osteoporotic fracture 20% Many therapeutic options available for women with PMO Treatment decisions must consider all available information and good clinical judgment 12

Martin Osteoporosis Case Study 71-year-old Caucasian man Weight: 175 lb Height: 5 ft 10 in Smoker Diagnosed with COPD Chest x-ray shows VF COPD, chronic obstructive pulmonary disease. ARS Question? Martin Is bone-density testing indicated? 1. No, because he is under age 75 years 2. No, because fracture risk is low 3. Yes, according to standard guidelines 4. Yes, because he is a smoker COPD was treated Evaluation for osteoporosis was not done No DXA No FRAX 2 years later, Martin has a hip fracture Could something have been done to prevent Martin s hip fracture? ARS Question? Outcomes Question 1? Which pharmacotherapies could have been considered for Martin to reduce his fracture risk? 1. Denosumab 2. Zoledronate 3. Alendronate and risedronate 4. All of the above A 56-year-old postmenopausal woman with a T-score of -2.3 at the FN meets NOF guidelines for pharmacologic treatment to reduce fracture risk in which one of the following cases? 1. Wrist fracture at age 49 years 2. Mother had hip fracture at age 82 years 3. FRAX 10-year probability of major osteoporotic fracture is 22% 4. FRAX 10-year probability of hip fracture is 2% 13

Outcomes Question 2? Outcomes Question 3? Which one of the following is a clinical risk factor for input with FRAX? 1. Diabetes mellitus 2. Rheumatoid arthritis 3. Proton pump inhibitor therapy 4. Long-term anticonvulsant therapy Which one of the following is FDA approved for the treatment of osteoporosis in both men and women? 1. Ibandronate 2. Calcitonin 3. Raloxifene 4. Denosumab Outcomes Question 4? A 72-year-old woman was diagnosed with osteoporosis at 67 years, with a femoral neck T-score of -3.2. After 5 years of oral bisphosphonate therapy, her T-score has stabilized at -2.8. What should be your next course of action? 1. Stop treatment, since there is no benefit beyond 5 years 2. Add salmon calcitonin to further reduce fracture risk 3. Continue alendronate, since benefits probably outweigh risks 4. Switch to another bisphosphonate, so that she continues to achieve an adequate response to therapy Questions? 14