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Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008

Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008. 2008. Symposia Series 2. 1. Osteoporosis Update: Prevention, Diagnosis, and Treatment. Mary D. Knudtson, DNSc, NP Clinical Professor Department of Family Medicine University of California, Irvine Irvine, California.

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Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008

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  1. Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008 2008 Symposia Series 2 1

  2. Osteoporosis Update: Prevention, Diagnosis, and Treatment Mary D. Knudtson, DNSc, NP Clinical Professor Department of Family Medicine University of California, Irvine Irvine, California

  3. Faculty Disclosure • Dr Knudtson: consultant/speakers bureau: Procter & Gamble

  4. 0 How confident are you addressing modifiable risk factors for osteoporosis with your patients? • Very confident • Somewhat confident • Not at all confident Use your keypad to vote now!

  5. Learning Objectives • Assess the risk factors associated with osteoporosis • Manage osteoporosis in the context of comorbidities • Evaluate nonpharmacologic preventive approaches as well as the efficacy and safety of pharmacologic management

  6. Osteoporosis Defined • Osteoporosis, primary or secondary, is characterized by compromised bone strength predisposing to an increased risk of fracture • Osteoporosis = bone mineral density (BMD) ≤2.5 SD below young normal mean at hip or spine [WHO] Bone density=grams of mineral/area, volume Bone quality=architecture, turnover, damage accumulation, mineralization Bone strength = density + quality SD = standard deviation; WHO = World Health Organization. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008; NIH Consensus Statement. 2000;17:1-45

  7. Prevalence of Osteoporosis* *Estimates based on 2000 census data. Ebeling PR. N Engl J Med. 2008;358:1474-1482; National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008. • Osteoporosis is a major health threat in the United States • 10 million Americans have osteoporosis, 34 million are at risk • Osteoporosis disproportionately affects Caucasian and Asian women; other races/ethnicities are also significantly affected • Under-recognized problem in men • In men, involvement of all races and ethnicities is significant • In the United States, women and men aged ≥50 years • 55% have low bone mass • 8 million women and 2 million men have osteoporosis • 1 of 2 white women, 1 of 5 men will suffer an osteoporosis-related fracture • Asian Americans with osteoporosis have same fracture risk as white persons

  8. 0 Which of the following best characterizes the burden of osteoporosis? • Osteoporotic fractures are more common than MI, stroke, and breast cancer combined • Only MIs are more prevalent than osteoporotic fractures • Incidence of osteoporotic fractures is equal to that of MIs • None of the above Use your keypad to vote now! MI = myocardial infarction.

  9. 2,000,000 1,500,000* 1,500,000 250,000hip 250,000forearm Annual incidence of Common Diseases 1,000,000 250,000 other sites 513,000† 500,000 228,000** 750,000 vertebral 184,300 0 Osteoporotic MI Stroke Breast Cancer Fractures Osteoporotic Fractures Are More Common Than MI, Stroke, and Breast Cancer Combined *Annual incidence all ages; †annual estimate women 29+; **annual estimate women 30+. American Cancer Society. Cancer Facts and Figures: 2003. Available at: www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf. Accessed April 15, 2008; American Heart Association. Heart and Stroke Statistics: 2003 Update. Available at: www.americanheart.org/downloadable/heart/10590179711482003HDSStatsBookREV7-03.pdf. Accessed April 15, 2008; Riggs BL, Melton LJ III. Bone. 1995;17(5 Suppl):505S-511S.

  10. 0 Which of the following is a common causeof secondary osteoporosis? • Proton pump inhibitors (PPIs) • Treatment for ulcerative colitis • Glucocorticoids • TNF-α receptor blockers and IL-1 receptor antagonists for the treatment of rheumatoid arthritis Use your keypad to vote now!

  11. Factors Contributing to Secondary Osteoporosis CHF = congestive heart failure; ESRD = end-stage renal disease; GI = gastrointestinal; MS = multiple sclerosis. AACE Osteoporosis Task Force. Endocr Prac. 2001;7:293-312; National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 30, 2008.

  12. Glucocorticoid Use and Fracture Risk 6 All nonvertebral 5.18 Forearm 5 Hip Vertebral 4 Relative Risk of Fracture Compared With Control 3 2.59 2.27 1.77 2 1.64 1.55 1.36 1.19 1.17 1.1 1.04 0.99 1 0 n = 2192 531 236 191 2486 526 494 440 1665 273 328 400 Low Dose Medium Dose High Dose (<2.5 mg/d) (2.5-7.5 mg/d) (>7.5 mg/d) Van Staa TP, et al. J Bone Miner Res. 2000;15:993-1000.

  13. Mineralization Osteoid Pathophysiology of Osteoporosis Bone Remodeling Activation Resting Resorption Osteoclasts Bone Bone Reversal Formation Osteoblasts Bone Bone

  14. Pathophysiology of Osteoporosis Early menopausal bone loss Inadequate peak bone mass Low bone mass/ impaired bone quality Decrease in bone mass/bone quality Fractures Calcium/ vitamin D deficiency Trauma Other factors

  15. Changes in Trabecular Architecture • Decrease in trabecular thickness, more pronounced for non load-bearing horizontal trabeculae • Decrease in connections between horizontal trabeculae • Decrease in trabecular strength and increased susceptibility to fracture 20 years 50 years 80 years Mosekilde L. Calcified Tissue Inter. 1993;53(Suppl 1):S121-S126.

  16. Location of Corticaland Trabecular Bone Trabecular Bone 20% of skeletal mass 80% of bone turnover Thoracic andLumbar Spine 75% trabecular25% cortical Distal Radius 25% trabecular75% cortical Cortical Bone 80% of skeletal mass 20% of bone turnover Femoral Neck 25% trabecular75% cortical Hip: Intertrochanteric Region 50% trabecular50% cortical Favus MJ, ed. Primer on the Metabolic Bone Disease and Disorders of the Mineral Metabolism. 4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 1999:30-32.

  17. Fracture Patterns By Age Vertebrae 4000 3000 Hip Annual Fracture Incidence /100,000 2000 1000 Colles' 0 35 45 55 65 75 85+ Age (years) Riggs B. N Engl J Med 1986;314:1676.

  18. Behavioral/Lifestyle Measures to Prevent Osteoporosis • Adequate intake of dietary calcium, vitamin D, and protein throughout life • Regular physical activity; load-bearing exercise • Minimal alcohol intake • Stop smoking • Take measures to prevent falls • Use of hip protectors by patients prone to falling Ebeling PR. N Engl J Med. 2008;358:1474-1482; National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008.

  19. 0 Which of the following is true with regard to vitamin D and bone health? • Oral vitamin D reduces the risk of hip fractures by 26% • Oral vitamin D has no benefit in preventing falls in osteoporotic patients • Only vitamin D absorbed through the skin is effective in preventing osteoporosis • Vitamin D supplementation has no effect on nonvertebral fractures Use your keypad to vote now!

  20. Vitamin D Protects Against Osteoporosis • Oral vitamin D supplementation 700-800 IU/d reduces risk of • Hip fracture by 26% • Nonvertebral fracture by 23% • Falls by 22% (↑ muscle strength, better balance) • Optimal fracture prevention achieved with 25-hydroxyvitamin D mean serum level 100 nmol/L • Best sources • Milk, salmon, canned tuna, sardines, eggs, liver, sunlight Bischoff-Ferrari HA , et al. JAMA. 2005;293:2257-2264.

  21. National Osteoporosis Foundation Clinical Recommendations 2008 • National Osteoporosis Foundation Clinical Recommendations February 2008 are based on the newly developed WHO 10-year fracture risk model (FRAX®) adapted to different population groups • The FRAX algorithm • Estimates the likelihood of a person breaking a bone due to osteoporosis during the next 10 years • Provides a useful way to ensure that people at risk of fracture receive treatment • Takes into account 9 clinical risk factors in addition to bone mineral density • Available online at http://www.shef.ac.uk/FRAX National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008.

  22. Risk Factors Used to Calculate WHO 10-Year Fracture Risk Femoral neck T-score Age Sex Secondary osteoporosis Previous low-trauma fracture *1 unit = 8 g alcohol ~ ½ pt beer ~ 1 glass wine. BMI = body mass index. Kanis JA, et al. Bone. 2002;30:251-258; Kanis JA, et al. Osteoporos Int. 2005;16:581-589; National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008. Low BMI Steroid exposure Family history of hip fracture Current cigarette smoking Alcohol intake >2 units/day*

  23. 10-Year Fracture Risk: Age and BMD • For a given BMD, risk increases with age Age 20 80 15 70 Hip Fracture Risk (% /10 Years) 10 60 5 50 0 -3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 BMD T-Score Kanis JA, et al. Osteoporos Int. 2001;12:989-995.

  24. Clinical Evaluation of Risk Factors for Osteoporosis • Medical history • Risk factors • Signs and symptoms • Physical examination • Height assessment (with stadiometer) • BMD testing • Laboratory tests

  25. Central Dual Energy X-Ray Absorptiometry (DEXA): Test of Choice for Diagnosing Osteoporosis • Benefits • Highly accurate and precise • Profiles all skeletal areas • Requires little time • Emits low dose of radiation • Limitations • AP spine measurement affected by vascular calcifications and spinal osteoarthritis • Trabecular and cortical bone measured together • AP = anteroposterior.

  26. Who Should Have a Bone Density Test? Patient Category USPSTF NOF AACE ISCD Women  65 years of age Yes Yes Yes Yes Women 60 – 64 with risk factor Yes Yes Yes Yes All women  65 with risk factor Yes Yes Yes All women with a fragility fracture Yes Yes Yes Diseases/conditions/drugs causing osteoporosis Yes Yes Yes Anyone receiving treatment for osteoporosis Yes Yes Anyone considering therapy for osteoporosis Yes Yes Men aged  70 years Yes All men with a fragility fracture Yes USPTF. Ann Intern Med 2002 137:526-8; Leib, E. S., et al. J Clin Densitom 1998 7:1-6; Endocr Pract 7:293-312

  27. T-Score • Number of SDs above or below sex-matched mean reference value of young adults • T-score = (BMD patient – BMD young normal reference) SD young normal reference • Comparison to peak bone mass • Peak adult bone mass follows a normal distribution (bell curve). Low bone mass on initial DEXA does not necessarily mean bone loss. Person may be at low end of bell curve • Used for adult diagnosis • Each SD decrease = doubling of fracture risk NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Treatment. JAMA. 2000;285:785-795.

  28. 0 Which of the following applies to the WHO/NOF criteria for diagnosis of osteoporosis? • T-score > -1.0 • T-score between -1 and -2.3 • T-score is not a WHO/NOF criterion for diagnosing osteoporosis • T-score ≤ -2.5 Use your keypad to vote now!

  29. WHO/NOF Criteria for Diagnosis of Bone Status *Measured in T-scores. T-score indicates the number of standard deviations below or above the average peak bone mass in young adults. Ebeling PR. N Engl J Med. 2008;358:1474-1482; National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008.

  30. Fracture Rates Correlate With T-Scores: National Osteoporosis Risk Assessment (NORA) Study Data From More Than 163,000 Women Fracture Rate/100 Person-Years Siris ES, et al. JAMA. 2001;286:2815-2822.

  31. National Osteoporosis Foundation:Treatment Recommendations • Postmenopausal women and men aged >50 years with either of the following • Low bone mass (T-score -1 to -2.5, osteopenia) at femoral neck, total hip, or spine and 10-year hip fracture risk >3% • 10-year all major osteoporosis-related fracture risk >20% based on US-adapted WHO FRAX model National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008.

  32. ACR Recommendations: Bisphosphonate Use in GIO • Prevention of bone loss in patients initiating long-term (3 months) glucocorticoid therapy • Patients with low BMD (T-score ≤1) receiving long-term glucocorticoid therapy • Patients receiving long-term glucocorticoid therapy who cannot tolerate HRT or had fractures during HRT ACR = American College of Rheumatology; GIO = glucocorticoid-induced osteoporosis; HRT = hormone replacement therapy. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis.Arthritis Rheum. 2001;44:1496-1503.

  33. 0 Randomized, controlled trials with the bisphosphonate alendronate demonstrated reductions in risk of hip fracture at month 18 by: • <10% • 15%-25% • 30%-40% • >60% Use your keypad to vote now!

  34. Effects of Alendronate on Cumulative Incidence of Symptomatic Vertebral and Hip Fractures (FIT 1 and 2 Trials) Vertebral Hip 3 5 -59% -63% 4 PBO PBO 2 P <.014 3 P <.001 Cumulative Incidence Cumulative Incidence ALN 2 ALN 1 * * * * * * 1 * * * 0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months *P <.05 ALN = alendronate; FIT = Fracture Intervention Trial; PBO = placebo. Black DM, et al. J Clin Endocrinol Metab. 2000;85:4118-4124.

  35. Risedronate Reduces Risk of VertebralFracture in High-Risk Subjects in 1 Year Placebo 68% (51%, 80%) P <.001 Risedronate 5 mg 60% (33%, 77%) P <.001 14 62% (36%, 77%) P <.001 12 62% (44%, 75%) P <.001 10 48% (7%, 71%) P = .029 8 Percent of Subjects With New Vertebral Fractures 6 4 2 0 Aged 70 Years 2 Prevalent Fractures Low FN BMD Low LS BMD Overall FN = femoral neck; LS = lumbar spine. Watts NB, et al. J Clin Endocrinol Metab. 2003;88:542-549.

  36. Zoledronic Acid • HORIZON study • 3-year study to decrease fracture risk in postmenopausal women with osteoporosis • Pivotal Fracture Trial (PFT) • 3-year study to decrease fracture risk in postmenopausal women with osteoporosis • Efficacy 70% ↓vertebral fractures, 40% ↓hip fractures, 25% ↓nonvertebral fractures Black DM, et al. N Engl J Med. 2007;356:1809-1822.

  37. Placebo (n = 3861) Zoledronic acid (n = 3875) Zoledronic Acid Reduced Cumulative 3-Year Risk of Hip Fractures (Strata I + II) 3 41%* 2 Cumulative Incidence (%) 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time to First Hip Fracture (months) *P = .0024, relative risk reduction vs placebo (95% CI) CI = confidence interval. Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.

  38. Women’s Health Initiative: Effects of HRT in Women Aged 50-79 6700 Women With 5.2 Years of Follow-up Disadvantages Vertebral fracture Intestinal cancer Hip fracture Difference (%) vs Placebo Stroke Cardiovasculardiseases Breast cancer Thromb. venous Advantages Manson JE, at al. N Engl J Med. 2003;349:523-534.

  39. MORE: Increase in BMD With Long-term Raloxifene Treatment BMD Lumbar Spine BMD Femoral Neck Placebo (n = 1512) Raloxifene 60 mg (n = 1490) 3 3 2 2 1 1 Mean % Change From Baseline 0 0 -1 -1 -2 -2 0 12 24 36 0 12 24 36 Months Months P <.001 for all comparisons. MORE = Multiple Outcomes of Raloxifene Evaluation. Ettinger B, et al. JAMA. 1999;282:637-645.

  40. MORE: Reduction in New Vertebral Fractures Among Women Who Completed the Study Placebo Raloxifene hydrochloride 60 mg/d Raloxifene hydrochloride 120 mg/d 25 RR 0.5 (95% CI, 0.4-0.6) RR 0.5 (95% CI, 0.6-0.9) 20 % of Patients With Incident Vertebral Fracture 15 10 5 0 N = 6828 RR = relative risk.Ettinger B, et al. JAMA. 1999;282:637-645.

  41. Calcitonin Nasal Spray: PROOF Study (Analysis at 5 Years) Reduction in % of New Vertebral Fractures vs Placebo No. of Hip Fractures Per Group 25 0 10 20 20 100 IU 18% (NS) 30 400 IU 23% (NS) 15 40 200 IU 33% (P = .03) 50 7 (NS) 10 8 60 4 (NS) 70 2 (NS) 5 80 90 0 100 Placebo 100 IU 200 IU 400 IU N = 511 NS = nonsignificant IU = international units; PROOF = Prevent Recurrence of Osteoporotic Fractures. Chesnut CH III, et al. Am J Med. 2000;109:267-276.

  42. Effect of Parathyroid Hormone on BMD Over 18 Months 1637 Postmenopausal Women With Prior Vertebral Fracture 14 Lumbar spine 12 Femoral neck 10 8 Change From Baseline in BMD (%) 6 4 2 0 -2 PTH 20 µg Placebo PTH = parathyroid hormone. Neer RM, et al. N Engl J Med. 2001;344:1434-1441.

  43. Summary: FDA-Approved Osteoporosis Therapies PMO = postmenopausal. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Available at: www.nof.org/professionals/Clinicians_Guide.htm. Accessed April 22, 2008.

  44. 0 What percent of patients will stop their medications within 6-12 months of initiation? • <10% • 10%-15% • 20%-30% • 40%-50% Use your keypad to vote now!

  45. Adherence and Persistence • 20%-30% of patients taking oral osteoporosis medications suspend their medications within 6-12 months of initiation due to • Side effects • Lack of knowledge • Reluctance to take regular medications Papaioannou A. Drugs Aging. 2007;24:37-55.

  46. FLEX Study: Persistence • FLEX • Compared effects of discontinuing alendronate treatment after 5 years vs continuing treatment for 10 years • Women who discontinued treatment after 5 years experienced a moderate decline in BMD, increase in biochemical markers, no higher fracture risk except clinical vertebral fractures FLEX = Fracture Intervention Trial Long-Term Extension. Black DM, et al. JAMA. 2006;296:2927-2938.

  47. Osteonecrosis of Jaw • Osteonecrosis of jaw • Potential complication of bisphosphonate • Rare • 60% occur after dental extraction • Most cases occur in cancer patients • Most cases associated with high-dose IV bisphosphonate treatment in metastatic cancer patients

  48. Case Study

  49. Postmenopausal Asian Woman With Possible Osteoporosis • At annual physical examination for 57-year-old Asian woman • Height: 5 ft 2 in; weight: 101 lb; BMI: 18.5 kg/m2 • Postmenopausal for 5 years • No HRT • Medications: mesalamine for ulcerative colitis • No known drug allergies • Family history: mother had a hip fracture at age 76 years

  50. Postmenopausal Asian Woman With Possible Osteoporosis • Medical history: GERD, used PPIs daily for 5 years; ulcerative colitis, uses mesalamine; has used systemic steroids orally 3 or 4 times for limited periods of time • Diet: balanced, except does not include dairy (lactose intolerant) • Exercise: walks 20 minutes a day • Smokes ½ pack a day GERD = gastroesophageal reflux disease.

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