Tipping the Balance: Strategies for Enhanced Detection and Treatment of Osteoporosis in Primary Care

Transcription

1 Tipping the Balance: Strategies for Enhanced Detection and Treatment of Osteoporosis in Primary Care February 7, 2013 Fort Lauderdale, Florida Educational Partner:

2 Session 5: Tipping the Balance: Strategies for Enhanced Detection and Treatment of Osteoporosis in Primary Care Learning Objectives 1. Evaluate the risk of developing a fracture using currently available risk-assessment tools. 2. Initiate the treatment of osteoporosis from risk-assessment scores and bone mineral density measurements. 3. Assess treatment decisions over time based on the benefit-to-risk ratio of long-term therapy for individual patients. Faculty E. Michael Lewiecki, MD Clinical Assistant Professor of Medicine University of New Mexico School of Medicine Osteoporosis Director New Mexico Clinical Research & Osteoporosis Center Albuquerque, New Mexico Dr E. Michael Lewiecki is a clinical assistant professor of medicine at the University of New Mexico School of Medicine and director of the New Mexico Clinical Research & Osteoporosis Center in Albuquerque. His 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. Principal investigator for the center s osteoporosis clinical trials, Dr Lewiecki has authored many scientific publications on osteoporosis and bone densitometry. Dr Lewiecki is past president of the International Society for Clinical Densitometry (ISCD) and a faculty member for the ISCD s educational programs on bone densitometry, vertebral fracture assessment, and management of osteoporosis. He is senior editor of Clinical Investigation, associate editor of the Journal of Clinical Densitometry, and an editorial board member of Osteoporosis International and other peer-reviewed journals. Dr Lewiecki has received national and international accolades. In 2002, he was named Physician of the Year by the ISCD and, in 2006, was the recipient of both the ISCD Paul D. Miller Service Award and the Laureate Award of the New Mexico Chapter of the American College of Physicians (ACP). Dr Lewiecki is a fellow of the ACP and the American College of Endocrinology. He is president and founder of the Osteoporosis Foundation of New Mexico, as well as director of its educational activities. In addition, he established and is program director of the annual Santa Fe Bone Symposium. Dr Lewiecki, who was raised in the Boston area, is a graduate of Amherst College and Northwestern University Medical School. He completed postgraduate medical training at the University of New Mexico Health Sciences Center. He currently resides in Albuquerque. Michael Maricic, MD Clinical Associate Professor of Medicine University of Arizona School of Medicine Director Catalina Pointe Clinical Research Tucson, Arizona Dr Michael Maricic is a clinical associate professor of medicine at the University of Arizona School of Medicine and director of Catalina Pointe Clinical Research in Tucson. While at the University of Arizona, Dr Maricic served as head of the section of rheumatology and as program director of both the internal medicine residency and rheumatology fellowship programs. He has chaired both the Curriculum and the Graduate Medical Education Advisory committees. Dr Maricic is the recipient of 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 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 an editorial board member of the Journal of Clinical Densitometry, of which he was past associate editor. Session 5

3 Dr Maricic has authored 40 peer-reviewed articles and numerous chapters on osteoporosis and rheumatology and co-edited the textbooks Decision Making in Internal Medicine, Clinical Care in the Rheumatic Diseases, and Bone Disease in Rheumatology. Faculty Financial Disclosure Statements The presenting faculty reports the following: Dr Lewiecki receives grant/research support (as principal investigator, funding to New Mexico Clinical Research & Osteoporosis Center) from Amgen Inc., Eli Lilly and Company, GlaxoSmithKline, and Merck and Co., Inc.; is a scientific advisory board member for Amgen Inc., Eli Lilly and Company, and Merck and Co., Inc.; is a speaker for Amgen Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation, and Warner Chilcott; and is a consultant for GlaxoSmithKline. Dr Maricic receives grant/research support from, and/or is a speaker or consultant for Amgen Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation, and Roche. Education Partner Financial Disclosure Statement The content collaborators at CME Incite report the following: Rose O Connor, PhD, and Monique Pond, PhD, have no financial relationships to disclose. Suggested Reading List Banu J, Varela E, Fernandes G. Alternative therapies for the prevention and treatment of osteoporosis. Nutr Rev. 2012;70(1): World Health Organization Collaborating Centre for Metabolic Bone Diseases. FRAX. WHO Fracture Risk Assessment Tool. Available at: Accessed December 30, 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): 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): Lewiecki EM. Safety and tolerability of denosumab for the treatment of postmenopausal osteoporosis. Drug Healthc Patient Saf. 2011;3: Maricic M. Update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 2011;37(3): National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis Available at: Accessed December 30, NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6): Schilcher J, Michaёlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18): U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventative Services Task Force recommendation statement. Ann Intern Med. 2011;154(5): 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): Session 5

4 Tipping the Balance: Strategies for Enhanced Detection and Treatment of Osteoporosis in Primary Care 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 Estrogen Alendronate Risedronate Ibandronate Zoledronate Calcitonin Raloxifene Denosumab Teriparatide Drug List Estrogen Fosamax Actonel, Atelvia Boniva Reclast Miacalcin, Fortical Evista Prolia Forteo Learning Objectives Demographic Question? Evaluate the risk of developing a fracture using currently available risk assessment tools Initiate the treatment of osteoporosis from risk assessment scores and bone mineral density (BMD) measurements Assess treatment decisions over time based upon the benefit:risk ratio of long-term therapy for individual patients Approximately how many patients that you ve seen in the last 60 days have osteoporosis? 1. None Over 20 Pre-test Question 1? Pre-test Question 2? A 56-year-old postmenopausal woman with a T-score of -2.3 at the femoral neck meets the National Osteoporosis Foundation guidelines for pharmacologic treatment to reduce fracture risk in which one of the following cases? 1. Wrist fracture at age Mother had hip fracture at age FRAX 10-year probability of major osteoporotic fracture is 22% 4. FRAX 10-year probability of hip fracture is 2% Which one of the following is a clinical risk factor for input with FRAX to provide a quantitative estimate of the 10-year probability of fracture? 1. Diabetes mellitus 2. Rheumatoid arthritis 3. Proton pump inhibitor therapy 4. Long-term anticonvulsant therapy 1

5 Pre-test Question 3? Pre-test Question 4? 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 A 72-year-old woman with PMO was diagnosed with osteoporosis at age 67, with a femoral neck T-score of She has been taking an oral bisphosphonate for the last 5 years, and after an initial increase in BMD, femoral neck T-score has remained stable at -2.8 without any evidence of fracture. What should be your next course of action? 1. Since BMD is no longer improving, switch to teriparatide therapy 2. Since stable BMD on bisphosphonate therapy is associated with a reduction in fracture risk, and the current T-score of -2.8 suggests that fracture risk remains elevated, the benefit of continuing therapy is likely to outweigh the risks 3. Since there is no evidence of benefit after 5 years of therapy, start a drug holiday now 4. Switch the patient to another oral bisphosphonate so that she continues to achieve an adequate response to therapy Osteoporosis: Diagnosis and Screening Michael Maricic, MD Clinical Associate Professor of Medicine University of Arizona Tucson, AZ Case Study 1: Ms. BR 60-year-old asthmatic Caucasian woman Menopause commenced at age 48 but she never accepted hormone therapy She is 5 2, but says that she used to be 5 3 A recent CXR reported a vertebral deformity at T8 Never taken oral glucocorticoids What would you do next? 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 Bone Remodeling 1 2 Osteoclast Resorption Osteoblast Recruitment Normal Osteoporosis Bone mass + bone quality = Bone strength NIH Consensus Development Panel. JAMA. 2001;285: New Bone Formation Osteoblast Apoptosis/ Osteocyte Transition 2

6 Postmenopausal Bone Loss Impact of Osteoporosis 1 2 Increased Osteoclast Resorption 3 4 Inadequate Osteoblast Osteoid Production Increased Osteoblast Recruitment Net Bone Loss Osteocyte transition 44 million Americans have low bone mass 10 million have osteoporosis Increasing to 12 million by end of 2012 Increasing to >14 million by end of % of Caucasian women and 25% of men aged >50 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: ; National Osteoporosis Foundation. Washington, DC. 2003; Burge R. J Bone Miner Res. 2007;22: Prevalence of Health Conditions in US Women ( ) Distribution of Osteoporotic Fractures: Combined Total for Men and Women 2,000,000 Number of Women 1,500,000 1,000, , ,420,000 Osteoporotic Fractures 373, , ,000 Stroke Heart Attack Breast Cancer Vertebral (27%) Wrist (19%) Hip (14%) Pelvic (7%) Other (33%) Watts NB, et al. Endocr Pract. 2010;16(suppl 3):1-37. Burge R. J Bone Miner Res. 2007;22: ; Watts NB, et al. Endocr Pract. 2010;16(suppl 3):1-37. Consequences of Fractures High Economic Burden Increased risk of future fractures Chronic pain Loss of height Impaired pulmonary function Medical expenses/lost income Hospitalization Surgery Need for rehabilitation Nursing home Loss of self-esteem Depression Loss of independence Disability Death Estimated $17 billion/year spent related to osteoporosis in 2005 Inpatient care ($9.7 billion) 2.5 million office visits, ~200,000 nursing home admissions, ~400,000 hospitalizations annually Long-term care ($5.1 billion) Outpatient care ($2.2 billion) US Preventive Services Task Force. Ann Intern Med. 2011;154: ; Melton LJ III. J Bone Miner Res. 2003;18: Burge R. J Bone Miner Res. 2007;22:

7 Vertebral Fractures (VFs) Incident Vertebral Fracture Rapidly Increases Risk of Next Vertebral Fracture Most common fractures Only 1/3 of VFs are clinically apparent Progressive Associated with Deformity, height loss, back pain Morbidity and mortality Predict future vertebral and nonvertebral fractures Percentage of Patients % Incidence During Study Year 0-1 (n=2570) 19.2% Incidence Within 1 Year Following First Fracture (n=381) Presence of 1 VF at baseline increased risk of additional VF 5-fold during Study Year 1 Lindsay R, et al. JAMA. 2001;285: ; Melton LJ III. J Bone Miner Res. 2003;18: Lindsay R, et al. JAMA. 2001;285: N=2725 postmenopausal women, mean age 74 years Prevalent Vertebral Fracture Predicts Risk of Future Hip Fracture Relative Risk of Death Following Clinical Fractures Cumulative Incidence (%) of Hip Fracture in Men and Women Years After Vertebral Fracture Melton LJ III, et al. Osteoporos Int. 1999;10: Observed Expected Fracture Intervention Trial (FIT): N=6459 postmenopausal women Aged years Followed for average of 3.8 years Any Symptomatic Cauley JA, et al. Osteoporos Int. 2000;11: Non-spine Hip Spine Forearm Other Age-Adjusted Relative Risk (95% CI) 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 History Assessment of risk factors for low bone mass falls and fractures Physical exam Laboratory tests Clinical Evaluation Hip fractures account for 14% of incident fractures but 72% of fracture costs Measurement of bone density Cooper C. Am J Med. 1997;103:12S-17S; Burge R. J Bone Miner Res. 2007;22: Watts NB, et al. Endocr Pract. 2010;16(suppl 3):

8 Clinical Risk Factors Age Previous low trauma fracture Current cigarette smoking Rheumatoid arthritis High alcohol intake (>2 units/day) Parental history of hip fracture Prior or current glucocorticoid use Clinical Evaluation: Physical Exam Height loss >1.5 inches Kyphosis Adapted from Kanis JA, et al. Osteoporos Int. 2005;16: Clinical Evaluation: Laboratory Tests Serum calcium, phosphorus, and alkaline phosphatase Creatinine 25-OH Vitamin D 24 hour urine calcium TSH (in women receiving thyroid supplementation) Bone Density Measurement: DXA Is the Gold Standard Widely used in epidemiological studies from which prevalence data is derived WHO criteria based on BMD measured by DXA Correlation with fracture risk Low radiation Excellent precision The above tests identify 92% of patients with secondary causes Adapted from Tannenbaum C, et al. J Clin Endocrinol Metab. 2002;87: WHO=World Health Organization. DXA=Dual-energy X-ray absorptiometry NOF Guidelines Indications for BMD Testing Women 65, men 70 regardless of risk factors Younger postmenopausal women and men aged with risk factors Adults with fracture after age 50 Adults with conditions such as rheumatoid arthritis or taking medications (such as glucocorticoids 5 mg/day 3 months) associated with low bone mass or bone loss Anyone being treated or being considered for treatment for osteoporosis Postmenopausal women discontinuing estrogen therapy Should We Further Evaluate Ms. BR? Over age 50 Loss of only 1 inch in height Vertebral deformity noted on CXR No history of glucocorticoid use NOF=National Osteoporosis Foundation. National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis

9 Bone Mass Measurement Act July 1, Categories of Medicare-Covered Services WHO Classification of BMD 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 the response to or efficacy of an FDA-approved osteoporosis drug therapy Federal Register, Volume 63, Number 121. June 24, Normal WHO Study Group Classification Low Bone Mass (Osteopenia) Osteoporosis Severe Osteoporosis T-score -1.0 or greater Between -1.0 and and below -2.5 with history of fragility fracture Diagnosis in Postmenopausal Women and in Men Aged 50 Osteoporosis may be diagnosed in postmenopausal women and in men aged 50 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. Use Clinical Judgement 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 Consider FRAX Diagnosis of Osteoporosis Densitometric diagnosis DXA WHO criteria Clinical diagnosis Fragility fracture Vertebral Fracture Assessment (VFA) Recognition of vertebral fracture may... Change diagnostic classification Change estimate of fracture risk Change treatment decisions Normal Vertebral Fx 6

10 Combined Effect of Bone Density and Prevalent Fractures Problem: Most Women With Fracture Have T-score >-2.5 Rate Ratio None One Lowest Third Middle Third Highest Third Bone Mass (mg/cm 2 ) Bone Density 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 45% 54% T-score > -2.5 T-score % 82% T-score > -2.5 T-score -2.5 Ross PD, et al. Ann Intern Med. 1991;114: Wainwright SA, et al. J Clin Endocrinol Metab. 2005;90: ; 2. Siris ES, et al. Arch Intern Med. 2004;164: Current Status of Care Unmet Needs 3% of wrist fracture patients receive BMD testing Only 12% of vertebral fractures are diagnosed and 2% are treated Underdiagnosis Undertreatment Poor adherence to treatment Only 3% to 5% of hip fracture patients are diagnosed for osteoporosis and treated Freedman KB, et al. J Bone Joint Surg Am. 2000;82: ; Gehlbach SH, et al. Osteoporosis Int. 2000;11: ; Wiktorowicz ME. J Bone Miner Res. 1997;12:S252. 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 for % of men taking treatment Kiebzak GM, et al. Arch Intern Med. 2002;162: vs % of women taking treatment % of Patients Months of Continuous Persistence Data from Downey TW, et al. South Med J. 2006;99: Daily Weekly P=NS 7

11 Fracture Risk Hazard Ratio 1 Poor Adherence and Persistence Lead to Compromised Fracture Risk Reduction N=11, ***16% Risk Reduction N=35, % 9.4% 0 Low Adherence High Adherence 0 Non- Persistent Persistent ***P<0.001 Low adherence=filled prescriptions to treat osteoporosis <80% of the time; High adherence=filled prescriptions to treat osteoporosis 80% of the time. 1. Caro JJ, et al. Osteoporos Int. 2004;15: ; 2. Siris E, et al. Mayo Clin Proc. 2006;81: ; 3. Medstat MarketScan Research Databases over 24 months ( ). 24 Month Fracture Risk 2,3, (%) ***29% Risk Reduction 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 vertebral and non-vertebral fractures Combination of BMD testing and presence of clinical risk factors is better predictor of fracture risk than BMD or CRF alone Fracture Risk Assessment and Treatment of Osteoporosis Fracture Risk Assessment: Fracture BMD, VFA, 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 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 (%) Femoral Neck T-score Age Site of Subsequent Fracture (Relative Risk) Site of Prior Fracture Wrist Vertebra Hip Wrist Vertebra Hip NA Adapted from Kanis JA, et al. Osteoporosis Int. 2001;12: Klotzbuecher CM, et al. J Bone Miner Res. 2000;15:

12 FRAX: to Assess Fracture Risk in Untreated Patients From Age 40 to 90 Access: Input: BMD + clinical risk factors (CRF) Rationale: BMD + CRF predict fracture risk better than either alone Output: 10-year fracture probability Predicting Hip Fractures: Relative Risk vs Fracture Probability Age* (years) Hip T-score Relative Risk 1 (2.6) Year Fracture Probability % % Relative Risk = (RR per SD) T-score or Z-score Difference from 11 study populations including 90,000 person years of observation time 10-year probability from Swedish National Bureau of Statistics *Postmenopausal women. Kanis JA, et al. Osteoporos Int. 2008;19: Marshall D, et al. BMJ. 1996;32: ; 2. Kanis JA, et al. Osteoporos Int. 2001;12: Woman, Caucasian, 0.578, no CRFs: 11%, 2.2% Fracture Risk Assessment Intervention Thresholds: NOF Treatment Follow-up NOF Treatment Guidelines Postmenopausal women and men aged 50 with the following should be considered for treatment, after evaluation for secondary causes of osteoporosis: Osteoporosis T-score -2.5 at FN or LS after evaluation for secondary causes, 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% National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis

13 NOF Intervention Thresholds Benefits Provides objective criteria for making treatment decisions Directs limited healthcare resources to those most likely to benefit Limitations Based on cost-effectiveness analysis using obsolete assumptions Does not consider individual patient factors Not a substitute for good clinical judgment Fracture Risk Assessment Intervention Thresholds Treatment: Evidence + Clinical Judgment Follow-up National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis Universal Recommendations Regular weight-bearing exercise Fall prevention Avoid tobacco use and excess alcohol Identification and treatment of risk factors for fracture Elemental calcium at least 1200 mg/day IOM: RDA mg, UL 2000 mg Vitamin D IU/day, target 30 ng/ml IOM: RDA IU, target >20 ng/ml, UL 4000 IU National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. 2008; Institute of Medicine. Report on Dietary Reference Intakes Treatment Decisions Clinical Practice Guidelines: NOF, ACR, AACE, NAMS, etc 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 ACR=American College of Rheumatology. AACE=American College of Clinical Endocrinologists. NAMS=North American Menopause Society. FDA-Approved Medications: Indications Drug PMO GIO (Women & 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 PMO=post-menopausal osteoporosis. GIO=glucocorticoid-induced 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: Mulder JE, Kolatkar NS, LeBoff MS. Nat Clin Pract Endocrinol Metab. 2006;2: Sharif PS, Abdollahi M, Larijani B. Rheumatol Int. 2001;31: BTM=bone turnover marker. 10

14 Indications Injectable Osteoporosis Therapy Contraindications Ibandronate (Second-line agent) 1,2 Treatment of PMO Hypocalcemia, hypersensitivity, GFR <30 ml/min Zoledronate (First-line agent) 3,4 Prevention of PMO/GIO, treatment of PMO/GIO/men Hypocalcemia, hypersensitivity, GFR <35 ml/min Denosumab (First-line agent) 5,6 Treatment of men and PMO in women at high risk for fracture Hypocalcemia, pregnancy, hypersensitivity Teriparatide (Very high fracture risk) 7,8 Treatment of PMO/GIO/men at high risk for fracture Hypersensitivity Fracture Data Bridging study (DIVA) RCT (HORIZON) RCT (FREEDOM) RCT (Neer et al) Dosing 3 mg Q3M 5 mg IV Q12M 60 mg Q6M Administration Safety Concerns/ Side Effects Butterfly needle with syringe over sec Hypocalcemia, arthralgia, kidney problems, osteonecrosis, abnormal fractures Catheter with IV bottle over at least 15 min Hypocalcemia, arthralgia, kidney problems, osteonecrosis, abnormal fractures SC Hypocalcemia, serious infections, skin problems, osteonecrosis 20 µg daily (2-yr lifetime max) SC Osteosarcoma, arthralgia, pain, nausea Bianchi G, et al. Osteoporos Int. 2012;23: ; Black DM, et al. J Bone Minor Res. 2012;27: ; Papapoulos S, et al. J Bone Miner Res. 2012;27: ; Neer RM, et al. N Engl J Med. 2001;344: 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 Black DM, et al. N Engl J Med. 2007;356: ; Sun K, et al. Osteoporos Int. 2012:Epub; Green J, et al. BMJ. 2010:341:c4444; Watts NB, et al. J Clin Endocrinol Metab. 2010;95: ; Ott S. Cleve Clin J Med. 2011;78: ; Odvina CV, et al. J Clin Endocrinol Metab. 2005;90: Risk Communication [10-year probabilities] 80-year-old Woman With FN T-Score = -3.3 Fracture Risk Assessment Includes 0.01% Atypical Femur Fracture Risk Intervention Thresholds Includes 0.5% Atypical Femur Fracture Risk Treatment Untreated probability of major osteoporotic fracture calculated by FRAX. ONJ estimate is ~1/100,000 patienttreatment-years from ASBMR Task Force by Khosla S, et al. J Bone Miner Res. 2007;22: AFF estimate untreated is ~0.01/10,000 and treated is ~5/10,000 patient-years from Schilcher J, et al. N Engl J Med. 2011;364: Risk estimates assume long-term bisphosphonate therapy resulting in 50% reduction in fracture risk. MVA and murder data from the CDC at Image copyright 2011 Lewiecki EM. Slide version. 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 the 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 11

15 Monitoring in Clinical Practice: Assess Long-term Benefit:Risk Ratio BMD (DXA) Measure 1-2 years after starting therapy Goal is 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 NTX=N-telopeptide of collagen type 1. CTX=C-telopeptide of collagen type 1. BSAP=bone specific alkaline phosphatase. Lewiecki EM, Watts NB. Osteoporos Int. 2008;19: P1NP=N-terminal serum type 1 procollagen. Summary FRAX used to assess fracture risk in untreated patients from age 40 to 90 Inclusion of the following CRFs improves qualitative assessment Previous fracture, parental hip fracture, smoking status, glucocorticoid use, diagnosis of rheumatoid arthritis NOF recommends pharmacotherapy be considered in postmenopausal women and men 50 years of age in each scenario: T-score -2.5 Presence of hip or vertebral fracture 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 PMO women Alendronate, risedronate, zoledronate, denosumab, and teriparatide also indicated for osteoporosis treatment in men Treatment decisions must consider all available information and good clinical judgment Mrs. CS Osteoporosis Case Study 64-year-old Caucasian woman Healthy, active, feels fine Weight 116 lbs, height 5 2 Physical exam normal Takes no medications, vitamins, or supplements Only known fracture is to forearm falling off school jungle gym at age 10 Mother had hip fracture at age 87 ARS Question? Mrs. CS Is bone density testing indicated? 1. No, because she is under age No, because fracture risk is low 3. Yes, according to standard guidelines 4. Yes, because she takes no calcium supplements DXA shows femoral neck T-score = -2.3 and lumbar spine T-score = -2.1 Laboratory studies normal except for serum 25- OH-D = 18 ng/ml Further review of vital signs shows she had lost about 1¾ inches in height since historical maximum 12

16 ARS Question? ARS Question? What is the diagnosis? 1. Normal bone density 2. Osteopenia 3. Osteoporosis 4. Severe osteoporosis What is her fracture risk? 1. Normal 2. High 3. Low 4. Need more information ARS Question? Does she meet the NOF guidelines for pharmacological therapy to reduce fracture risk? 1. Yes 2. No Vertebral Fracture Assessment ARS Question? Does she meet the NOF guidelines for pharmacological therapy to reduce fracture risk now? L1 Grade 3 Wedge Fx 1. Yes 2. No 13

17 Post-test Question 1? Post-test Question 2? A 56-year-old postmenopausal woman with a T-score of -2.3 at the femoral neck meets the National Osteoporosis Foundation guidelines for pharmacologic treatment to reduce fracture risk in which one of the following cases? 1. Wrist fracture at age Mother had hip fracture at age FRAX 10-year probability of major osteoporotic fracture is 22% 4. FRAX 10-year probability of hip fracture is 2% Which one of the following is a clinical risk factor for input with FRAX to provide a quantitative estimate of the 10-year probability of fracture? 1. Diabetes mellitus 2. Rheumatoid arthritis 3. Proton pump inhibitor therapy 4. Long-term anticonvulsant therapy Post-test Question 3? Post-test Question 4? 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 A 72-year-old woman with PMO was diagnosed with osteoporosis at age 67, with a femoral neck T-score of She has been taking an oral bisphosphonate for the last 5 years, and after an initial increase in BMD, femoral neck T-score has remained stable at -2.8 without any evidence of fracture. What should be your next course of action? 1. Since BMD is no longer improving, switch to teriparatide therapy 2. Since stable BMD on bisphosphonate therapy is associated with a reduction in fracture risk, and the current T-score of -2.8 suggests that fracture risk remains elevated, the benefit of continuing therapy is likely to outweigh the risks 3. Since there is no evidence of benefit after 5 years of therapy, start a drug holiday now 4. Switch the patient to another oral bisphosphonate so that she continues to achieve an adequate response to therapy Questions & Answers? 14