1. Osteoporosis Natasa Janicic M.D. Assistant Professor Georgetown University Hospital

2. Osteoporosis The most common metabolic bone disorderThe most common metabolic bone disorder Systemic skeletal disease characterized by:Systemic skeletal disease characterized by: –Low bone mass –Microarchitectural deterioration of bone tissue –Increased bone fragility and susceptibility to fracture

3. 3-D Micro CT: Healthy vs Osteoporotic Bone 52 year old Female 84 year old Female (w/ vertebral fracture ) Borah et al Anat. Rec.(2001)

4. Pathophysiology of Osteoporosis Bone remodeling occurs throughout an individual’s lifetimeBone remodeling occurs throughout an individual’s lifetime In normal adults, the activity of osteoclasts (bone resorption) is balanced by that of osteoblasts (bone formation)In normal adults, the activity of osteoclasts (bone resorption) is balanced by that of osteoblasts (bone formation) With the onset of menopause (mid-forties or fifties), diminishing estrogen levels lead to excessive bone resorption that is not fully compensated by an increase in bone formationWith the onset of menopause (mid-forties or fifties), diminishing estrogen levels lead to excessive bone resorption that is not fully compensated by an increase in bone formation

5. Bone Remodeling Hormones AcF BMU Balance Reversal Formation Bone Osteoid Mineralization BioMarkers Bon e BioMarkers Howship’s lacuna BMU Resting Activation Resorption Bone osteoclasts osteoblasts

6. Contributors to Bone Strength Bone size, BMD, and mineralization play a role Bone turnover rates affect the quality of bone Preservation of bone architecture plays a major role in determining bone strength

7. Why Recognize & Treat Osteoporosis? To Prevent Fractures 1.5 million fractures/yr1.5 million fractures/yr $10 billion direct costs$10 billion direct costs 300,000 hip fractures/yr300,000 hip fractures/yr –20% die –25% confined to long-term care facilities –50% long-term loss of mobility

8. Why Recognize & Treat Osteoporosis? Less than 5% of hip fractures are evaluated for osteoporosis! (NIH Health report, 2001) To Prevent Fractures

9. 9 Osteoporosis Osteoporosis

10. Osteoporotic Fractures in Women Compared With Other Diseases 1,200,000 1 513,000 2 228,000 2 184,300 3 0 500,000 1,000,000 1,500,000 2,000,000 Osteoporotic Fractures Heart Attack StrokeBreast Cancer Annual Incidence 1 National Osteoporosis Foundation, 2002. Available at: http://www.nof.org. 2 American Heart Association. Heart & Stroke Facts: 1999 Statistical Supplement. 3 American Cancer Society. Breast Cancer Facts & Figures 1999-2000.

11. *p<0.05, vs patients with no prevalent vertebral fractures (12-fold increased risk). Lindsay R, et al, JAMA. 2001;285:320-323. Overall,  20% fractured again within the year following a new fracture Risk of fracture increased with the number of baseline fractures % of Patients 0 5 10 15 20 25 30 Overall012+ Number of Baseline Vertebral Fractures * Risk of Another Vertebral Fracture Is Higher in the Year Following a New Fracture

12. Postmenopausal Osteoporosis Who to Treat When to Treat What Therapy For How Long

13. National Osteoporosis Foundation Guidelines for Bone Density Testing All women aged 65 or olderAll women aged 65 or older All postmenopausal women under age 65 who have one or more additional risk factorsAll postmenopausal women under age 65 who have one or more additional risk factors Postmenopausal women who present with fracturesPostmenopausal women who present with fractures USPSTF makes no recommendation for or against routine screening in women under age 60USPSTF makes no recommendation for or against routine screening in women under age 60 www.nof.org

14. Classification Normal Osteopenia (low bone mass) Osteoporosis Severe or established osteoporosis WHO Criteria for Diagnosis *T score indicates the # of SDs below or above the average peak bone mass in young adults T score* < –1 –1 to –2.5 –2.5 or greater –2.5 or greater + fx(s)

15. One-Minute Treatment Decision Therapy Decision Treat all patients with an existing fracture High Risk- Treat Moderate Risk - Treat if other risk factors Low Risk- Check again in 1-2 years T-Score * Below -2.0 -1.5 to -2.0 Above -1.5 National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998.

17. Combined Effect of Bone Density and Risk Factors Rate of Hip Fracture/ 1000 Woman-Years Bone Density Cummings SR et al. N Engl J Med. 1995;332:767-773. Number of Risk Factors 55 3-4 0-2

18. Center et al. Lancet 1999. Mortality Associated with Fracture Mortality (deaths/1,000 person-years)

19. Diseases Associated with Decreased Bone Mass Hypogonadism Hypercortisolemia Hyperthyroidism Hyperparathyroidism Anorexia Renal Failure Chronic Liver Disease Malabsorption –Celiac Sprue –Surgical Inflam. Bowel Dz Pregnancy Type 1 Diabetes HIV

20. Medications associated with Decreased Bone Mass Corticosteroids Heparin (high dose) Aluminum Anticonvulsants –phenobarbital, phenytoin Medroxyprogesterone acetate Cyclosporine Prograf Aromatase inhibitors Antiretroviral therapy Retinoids

21. Glucocorticoid-Induced Bone Loss Glucocorticoid tx at 7.5 mg/day for  3 months often results in rapid loss of trabecular bone Up to 50% of patients taking >7.5 mg/d of prednisone or equivalent will fracture

22. Management of Osteoporosis: Goals of Therapy Prevent first fragility fracture or future fractures if one has already occurredPrevent first fragility fracture or future fractures if one has already occurred Stabilize/increase bone massStabilize/increase bone mass Relieve symptoms of fractures and/or skeletal deformitiesRelieve symptoms of fractures and/or skeletal deformities Improve mobility and functional statusImprove mobility and functional status Initiate lifestyle changes to enhance prevention of fracturesInitiate lifestyle changes to enhance prevention of fractures

23. NOF Guidelines Public Health Recommendations 1-1.5 g of daily calcium 400-800 of vitamin D daily Weight-bearing exercise Discourage smoking

24. Drug therapy for osteoporosis Prevention Treatment HRT YesNo Raloxifene YesYes Calcitonin NoYes*? Alendronate YesYes Risedronate YesYes PTH NoYes

25. Bisphosphonates for Osteoporosis Benefit: reduction of fracture risk (alendronate, risedronate, ibandronate) Problem: poor adherence to therapy Cause: multifactorial, including issues of convenience (complexity of dosing) and tolerability (GI irritation in clinical experience) Possible solutions: larger doses given less frequently, parenteral administration

26. Bisphosphonates: Molecular Mechanisms of Action Interfere with the action of osteoclasts –Recruitment, differentiation, and action –Two mechanisms: Incorporated into cytotoxic ATP analogs (etidronate) –Affect cellular activity Interfere with the mevalonate pathway (nitrogen-containing BPs) –Cause apoptosis Russell R, et al. Osteoporos Int. 1999;(suppl 2):S68-S80.

27. *Significant difference vs placebo. VERT MN = Vertebral Efficacy With Risedronate Therapy Multinational study. VERT NA = Vertebral Efficacy With Risedronate Therapy North America study. Actonel ® (risedronate sodium) Tablets Prescribing Information. Procter & Gamble Pharmaceuticals; July 2004. Relative Risk Reduction of Vertebral Fractures in 3-Year Studies: Risedronate 5 mg/d vs Placebo VERT NA Study Type of FractureRelative Risk Reduction, % New vertebral fracture41* VERT MN Study Type of FractureRelative Risk Reduction, % New vertebral fracture49*

28. Baseline 3 Years VERT-NA: Placebo Patient Increased perforation Trabecular thinning Borah, et al, JBMR 16 (Suppl 1), 2001

29. Similar thickness of trabeculae and number of perforations Baseline 3 Years Borah, et al, JBMR 16 (Suppl 1), 2001 VERT-NA: Risedronate Patient

30. *p < 0.05 vs baseline † p < 0.05 vs baseline & control † p < 0.05 vs baseline & control North American Study Lumbar Spine BMD Multi-National Study † * * * * * ** † † † † † † † † † † 36 month diff. = 7.1% 5mg. vs. baseline 36 month diff. = 5.3% 5mg. vs. baseline Harris ST, et. al. JAMA. 1999;282(14):1344-52. Reginster JY, et al. Osteoporos Int. 2000;11:83-91.

31. Bisphosphonates: Contraindications and Warnings Contraindications –Hypocalcemia –Known hypersensitivity to any component of this product –Inability to stand or sit upright for at least 30 minutes Warnings –Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, and esophageal or gastric ulcer.

32. Monthly Cost of Osteoporosis Drugs (Data from www.drugstore.com)

33. Women’s Health Initiative Estrogen + Progestin arm – stopped 5/31/02 –Follow-up mean 5.2 years –Absolute excess risks per 10000 person years 7 more CHD 8 more CVA 8 more Pulmonary embolism 8 more invasive breast cancers –Absolute risk reduction per 10000 person years 6 fewer colorectal cancers 5 fewer hip fractures

34. HRT When prescribing solely for the prevention of postmenopausal osteoporosis HRT should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg/1.5 mg PREMPRO daily Dosage may be adjusted depending on individual clinical and bone mineral density responses

35. Combination Therapy Bisphosphonate + HRTBisphosphonate + HRT –Combination increases BMD > either agent alone Harris ST, et.al. J Clin Endocrin Metab. 2001;86:1888-1889Harris ST, et.al. J Clin Endocrin Metab. 2001;86:1888-1889 Lindsay R, et al. J Clin Endocrin Metab. 1999;84:3076-3081Lindsay R, et al. J Clin Endocrin Metab. 1999;84:3076-3081 Emkey R et al. Abstract from 63rd Annual ACR Scientific Meeting Nov 1999Emkey R et al. Abstract from 63rd Annual ACR Scientific Meeting Nov 1999 Bisphosphonate + RaloxifeneBisphosphonate + Raloxifene –Combination increases BMD > either agent alone Stock, Johnell, Scheele, et al. Presented at 63rd annual Scientific Meeting of ACRStock, Johnell, Scheele, et al. Presented at 63rd annual Scientific Meeting of ACR No fracture dataNo fracture data

36. Recently Approved Boniva – 150 mg monthly –2.5 mg daily approved May, 2003 –Vertebral fracture efficacy shown with daily –Based on 1 year BMD data, 150 mg monthly is superior to the 2.5 mg daily –60 minute post dose fast, not 30 minute Fosamax PLUS D – 70 mg/2800 IU weekly

37. Summary All postmenopausal women should be evaluated for osteoporosis risk factorsAll postmenopausal women should be evaluated for osteoporosis risk factors Bone density testing is the best predictor of fracture riskBone density testing is the best predictor of fracture risk Treatment should be initiated to prevent osteoporotic fractures and their subsequent morbidityTreatment should be initiated to prevent osteoporotic fractures and their subsequent morbidity