Update on Management of Osteoporosis

1. Update on Management of Osteoporosis E. Michael Lewiecki, MD New Mexico Clinical Research & Osteoporosis Center University of New Mexico School of Medicine Albuquerque, NM

2. Faculty Disclosure It is the policy of the American Society for Bone and Mineral Research (ASBMR) and The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a faculty member with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The American Society for Bone and Mineral Research (ASBMR) and The France Foundation have identified and resolved any and all faculty conflicts of interest prior to the release of this activity.

3. Disclosure Grant / Research Support Amgen, Eli Lilly, Merck, Novartis, Warner Chilcott Consultant, Advisory Board, Speakers’ Bureau, or Sponsored Speaking Events Amgen, Eli Lilly, Merck, Novartis, Warner Chilcott

4. Learning Objectives • Improve the ability to assess risk factors for osteoporosis and apply evidence-based screening recommendations to these at-risk patients within one’s practice • Develop strategies to improve the treatment of patients with osteoporosis • Utilize the tools and other information provided within this initiative, including patient education tools and systems-based approaches to facilitate improving the assessment and care being provided to patients with osteoporosis

5. Postmenopausal Osteoporosis in the Primary Care Setting • What is osteoporosis? • Why you should care? • Whom to test and how? • Whom to treat and how?

6. Definition of Osteoporosis • A skeletal disorder characterized by • Compromised bone strength predisposing to • An increased risk of fracture • Bone strength reflects the integration of two main features: • Bone density • Bone quality Normal Bone Osteoporotic Bone 2000 NIH Consensus Development Conference

7. Osteoporosis Is a SeriousPublic Health Problem • At age 50, lifetime risk of fracture is • 1:2 women • 1:5 men • Affects 10 million Americans • 8 million women • 2 million men • Additional 34 million have low bone mass • 2 million fractures yearly* • Direct cost $17 billion* Distribution of Fractures *Based on figures from 2005. Cost does not include lost productivity, unpaid caregiver time, transportation and social services NOF Fast Facts. www.nof.org. Accessed February 2013. Burge R, et al. J Bone Miner Res. 2007;22:465-475. USDHHS. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD. 2004.

8. Identified Treatment GapNCQA HEDIS *2011 HMO Rates NCQA State of Healthcare 2012 - HMO Statistics (Commercial or Medicare data from 2011). http://www.ncqa.org/Portals/0/State%20of%20Health%20Care/2012/SOHC%20Report%20Web.pdf. Accessed February 2013.

9. National Osteoporosis Foundation 2013 Guidelines • Universal (risk, diet, vitamin D, exercise, smoking, monitoring) • Diagnosis (BMD, vertebral imaging, causes of secondary osteoporosis) • Monitoring (BMD) • Treatment (initiation criteria, options, duration) Major clinical recommendations http://www.nof.org/hcp/practice/tools. Accessed March 2013.

10. Who Should Have a Bone Density Test? AAFP1 and NOF2 • Women age 65 and older and men age 70 and older • Younger postmenopausal women and men ages 50–69 with clinical risk factors • Adults who have a fracture after age 50 • Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids) associated with low bone mass or bone loss 1. Sweet MG, et al. Am Fam Physician. 2009;79(3):193-200. 2. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. www.nof.org. Accessed February 2013.

11. Reimbursement for DXAFinal Rule Since 2006, Medicare covers bone densitometry for five indications • Estrogen-deficient women at clinical risk for osteoporosis • Patients with vertebral abnormalities • Patients receiving long-term glucocorticoids (prednisone ≥ 5 mg/d or equivalent for 3+ months) • Patients with primary hyperparathyroidism • Patients being monitored to assess the response to an approved drug Federal Register. 2006;71(231):67783-67784.

12. Category T-score Normal -1.0 and above Low bone mass (osteopenia) Between -1.0 to -2.5 Osteoporosis -2.5 and below Kanis JA, et al. J Bone Miner Res. 1994;9:1137-1141. WHO Criteria forPostmenopausal Osteoporosis The T-score compares an individual’s BMD with the mean value for young adults and expresses the difference as a standard deviation score.

13. NOF Treatment Guidelines 2013 Women ≥ 65 and men ≥ 70 (younger with risk factors) DXA T-score ≤ -2.5 in the lumbar spine, total hip, or femoral neck or Hip or spine (clinical or radiographic) fracture T-score between -1.0 and -2.5 and high fracture risk FRAX 10-y fracture risk YES ≥ 3% for hip fracture or ≥ 20% for major osteoporotic fracture YES Candidate for TREATMENT http://www.nof.org/hcp/practice/tools. Accessed March 2013.

14. Web Version 3.4

20. Clinical Benefits of FRAX • Derives 10-year probability of clinical event from measurable parameters • Internationally recognized and validated • Based on data from multiple cohorts • Easily accessible on the Internet or DXA software • Helps identify patients who need treatment

21. Limitations of FRAX™WHO Fracture Probability Tool • Not valid in patients on treatment • Only hip BMD is considered • Risk is “yes/no” – there is no consideration of “dose” (e.g., fractures, glucocorticoids, smoking, alcohol) • Not all risk factors are included (e.g., falls) • “Major osteoporotic fracture” is not the same as all osteoporotic fractures • Clinical judgment is required Watts NB, et al. J Bone Miner Res2009;24:975-979.

22. Patient Care Goals • Identify patients at risk of fractures • Reduce incidence of fractures • Maintain quality of life • Activity • Independence • Health

23. Counsel on the risk of fractures Calcium intake as follows, ideally through diet, with supplements if necessary 1000 mg per day for men 50-70 1200 mg per day for women ≥ 51 1200 mg per day for men ≥ 71 Vitamin D intake should be 800-1,000 IU per day, supplemented if necessary (age ≥50) Regular weight-bearing and muscle-strengthening exercise Fall prevention evaluation and training Universal Recommendations http://www.nof.org/hcp/practice/tools. Accessed March 2013.

24. FDA-approved MedicationsIndications *FDA advisory board found that evidence did not support calcitonin salmon for the treatment of osteoporosis (March 5, 2013)

25. Evidence for Fracture Reduction Adapted from Murad MH, et al. J Clin Endocrinol Metab. 2012;97(6):1871-1880.

26. BisphosphonatesSide Effects/Safety Concerns • May cause esophageal irritation (oral) • Can cause acute phase response (IV and high-dose oral) • Contraindicated in patients with hypocalcemia • Limited to patients with good kidney function (GFR > 30 or 35 mL/min) • Musculoskeletal pain? • Osteonecrosis of the jaw? • Atypical femur fractures?

27. Bisphosphonates“Side Benefits” • Decreased risk of breast cancer1-5 • Decreased risk of colorectal cancer6 • Decreased risk of stroke7 • Reduced risk of gastric cancer8 • Decreased overall mortality9,10 1. Chlebowski RT, et al. J Clin Oncol. 2010;28:3582-3590. 2. Dreyfuss JH. CA Cancer J Clin. 2010;60:343-344. 3. Newcomb PA, et al. Br J Cancer. 2010;102:799-802. 4. Rennert G, et al. J Clin Oncol. 2010;28:3577-3581. 5. Vestergaard P, et al. Calcif Tissue Int. 2011;88:255-262. 6. Rennert G, et al. J Clin Oncol. 2011;9:1146-1150. 7. Kang JH, et al. Osteoporos Int. 2012;23(10):2551-2557. 8. Abrahamsen B, et al. J Bone Miner Res. 2012;27:679-686. 9. Center JR, et al. J Clin Endocrinol Metab. 2011;96:1006-1014. 10. Sambrook PN, et al. OsteoporosInt. 2011;22:2551-2556.

28. Bisphosphonates have a long residence time in bone When long-term therapy is stopped, is sufficient drug available to exert a continuing benefit? Does long-term treatment create safety concerns that limit the duration of treatment? BisphosphonatesHow Long Should Treatment Last? Porras AG, et al. Clin Pharmacokinet. 1999;36(5):315-328. Watts NB, et al. J Clin Endocrinol Metab. 2010;95(4):1555-1565.

29. Long-term Experience with AlendronateFit Long-term Extension (FLEX) Study Patients who received ~5 years of alendronate in the Fracture Intervention Trial signed up for a second 5-year study Re-randomized to stay on alendronate (n = 662) or changed to placebo (n = 437) For those who had 10 years of alendronate compared with stopping after 5 years Clinical vertebral fractures were reduced by 55% overall Nonvertebral fractures were reduced by 50% in women with T-scores -2.5 or below at the start of FLEX Schwartz AV, et al. J Bone Miner Res. 2010;25:976-982.

30. Clinical Vertebral Fractures in the FLEX Study 6 5.3% ALN 5 years  Placebo 5 years 5 Alendronate 10 years 4 RR  55% P = 0.013 Cumulative Incidence of Fractures (%) 3 2.4% 2 1 0 0 1 2 3 4 5 Years Since FIT ALN/PLB 437 428 429 421 417 414 ALN/ALN 662 659 657 654 650 646 Black DM, et al. JAMA. 2006;296:2927-2938.

31. Suggestions for Bisphosphonate Duration • Long-term treatment (e.g., 5–10 years) appears to be safe for most patients • For lower risk patients, after 3–5 years of treatment, “drug holidays” can probably be taken without a major sacrifice of efficacy • Higher risk patients should probably continue treatment for at least 10 years • No evidence beyond 10 years Watts NB and Diab D. J Clin Endocrinol Metab. 2010;95(4):1555-1565.

32. Denosumab • Fully human monoclonal antibody to RANKL; decreases osteoclast differentiation, function and survival • Reduces risk of spine, hip and nonvertebral fractures • For treatment of osteoporosis, SQ dosing every 6 months • Does not require dose adjustment for decreased kidney function • Effect is reversible within 6–12 months of stopping Cummings SR, et al; FREEDOM Trial. N Engl J Med. 2009;361(8):756-765. Jiang X, et al. Menopause. 2013;20(2):117-119.

33. Differences Among Antiresorptive Agents • Pharmacology – mechanism of action, onset and offset of effect, skeletal retention • Route of administration – oral (fasting or with food) or parenteral • Frequency of administration – daily, weekly, monthly, quarterly, twice yearly, once yearly • Side effects/tolerability – depends on agent and patient • Non-skeletal effects – breast cancer reduction (raloxifene) • Cost/insurance coverage – generic oral; drugs “administered by health professional” covered by Medicare Part B

34. Teriparatide • Recombinant human PTH (rhPTH [1-34]) • Mechanism of action different from other agents (anabolic) • Daily SC injection • Indicated for patients at high risk for fracture • Postmenopausal women with osteoporosis • Men with primary or hypogonadal osteoporosis • Men and women with osteoporosis associated with sustained systemic glucocorticoid therapy • Treatment limited to 2 years, follow with antiresorptive agent Forteo PI. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021318s012lbl.pdf. Accessed Feb 2013. Han SL, Wan SL. Int J Clin Pract. 2012;66:199-209.

35. Monitoring • Monitor with DXA every 1–2 years • Do not "over-interpret" change • Be happy when BMD is stable OR increasing • Why do some patients lose BMD on treatment? • Poor adherence • Malabsorption • Underlying disorders that need to be addressed • Some patients may respond to therapy yet still have unacceptably high fracture risk – consider change in therapy

36. Fall Prevention • Improve lighting • Remove loose rugs • Add grab bars near bathtubs, toilets and stairways • Formal home safety evaluation • Physical therapy for core strength and balance • Eliminate medications that can affect alertness and balance • Assistive device evaluation and training Sweet MG, et al. Am Fam Physician. 2009;79(3):193-200.

37. Where Are We Now? The Good News • Improved awareness • Excellent diagnostic tools available • Fracture risk assessment using BMD and/or clinical risk factors • Safe and effective individualized treatment • Better understanding of pathogenesis • Federal initiatives to improve care

38. Where Are We Now? The Bad News • Declining numbers of patients on therapy • Under-recognition of patients at risk for fracture • Poor primary and secondary adherence • Poor patient understanding of risk/benefit • Decreasing access to DXA • Increasing patient concerns about side effects

39. Secondary Fracture Prevention A fracture is a sentinel event A fracture in a person over 50 is the most powerful risk factor for a future fracture Many high risk patients have the fracture successfully treated but do NOT receive subsequent medical assessment and treatment to prevent the next fracture

40. What can I Do as a PCP?Practical Steps • Patientdialog • Risk communication • Shared decision making • Decision aids • Handouts • Web resources • Brochures

41. What can I Do as a PCP?Practical Steps • Identify patients who are at high risk        • Use EHR decision tools • Flag patients with risk profile • Use checklist of risk factors • Identify patients who are not adherent • Pharmacy refill data if available • Ask questions • Patients who are nonadherent to one therapy are often nonadherent to others

42. Performance-improvement CME • and MOC Part IV Approved (ABFM) https://achsos.community360.net/default.aspx. Accessed April 2013.

43. What is osteoporosis? Decreased bone strength predisposing to an increased risk of fracture Why you should care Common, significant cost, morbidity and mortality Whom to test and how DXA for all women by age 65, higher risk women earlier; FRAX is a useful tool Whom to treat and how Individuals at high risk of fracture; approved agents are safe and effective; treatment decisions must be individualized Update on Management of Osteoporosis

44. Questions or Comments? WILL YOUR BONES LAST AS LONG AS YOU DO?