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Emerging Trends in Osteoporosis Scioto County Medical Society Current Therapy Seminar 10/26/2007

Emerging Trends in Osteoporosis Scioto County Medical Society Current Therapy Seminar 10/26/2007. Steven Ing, MD, MSCE Division of Endocrinology, Diabetes, & Metabolism Ohio State University Medical Center. Objectives.

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Emerging Trends in Osteoporosis Scioto County Medical Society Current Therapy Seminar 10/26/2007

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  1. Emerging Trends in OsteoporosisScioto County Medical SocietyCurrent Therapy Seminar10/26/2007 Steven Ing, MD, MSCE Division of Endocrinology, Diabetes, & Metabolism Ohio State University Medical Center

  2. Objectives • Review nonpharmacologic and pharmacologic therapy in the management of osteoporosis • Review secondary causes of osteoporosis • Review risk factors for fracture From Mosekilde, LI, Bone 1988; 9:247

  3. Question #1: Can I just take Calcium and Vitamin D to treat osteoporosis? • 49 year-old woman without prior fracture • Menopause @ age 47 • 2003 DXA 2006 DXA Δ • Spine 1.107 (-0.6, -0.3)  1.016 (-1.4, -0.8) -8.2% • R Hip 0.720 (-2.3, -1.8)  0.694 (-2.5, -1.9) -5.2% • L Hip 0.804 (-1.6, -1.1)  0.762 (-2.0, -1.4) -3.6% • Felt “devastated” about falling BMD

  4. WHI: Ca + Vitamin D • Multicenter, placebo-controlled, randomized clinical trial of 36,282 healthy postmenopausal women, ages 50-79, follow up 7 years • Not recruited on basis of low BMD or fracture risk factors • 500 mg Ca-200 IU Vitamin D bid with meals vs. Placebo • Reduced bone loss at hip: • Hip BMD 1% higher in treated group • Hip fracture HR: (ITT): 0.88 (0.72-1.08) • Adherence (>80%): HR 0.71 (0.52 – 0.97) • Older age (60+): HR 0.79 (0.64-0.98) • Kidney stone HR: 1.17 (1.02-1.34) • 4 per 1000 women treated for 7 years • Baseline calcium intake > 1000 mg daily • Vitamin D dose may have been too low Jackson, RD et. al. NEJM 2006;543:669-683

  5. Ca (mg/day) Vit D (IU/day) AI* UL* AI UL** 0-6 months: 210 ND 200 1000 6-12 months: 270 ND 200 1000 1-3 years: 500 2500 200 2000 4-8 years: 800 2500 200 2000 9-18 years: 1300 2500 200 2000 19-50 years: 1000 2500 200 2000 51-70 years: 1200 2500 400 2000 >70 years: 1200 2500 600 2000 Institute of Medicine Dietary Recommendations (1997) *AI, Adequate Intake *UL, Tolerable Upper Intake Level **UL may change soon • Recommendations for healthy population • Optimal intake in disease is uncertain

  6. NOF Recommendations • Calcium • Age < 50 years: 1,000 mg calcium daily • Age ≥ 50 years: 1,200 mg calcium daily • Vitamin D • Age < 50 years: 400-800 IU vitamin D daily • Age ≥ 50 years: 800-1000 IU vitamin D daily http://www.nof.org/prevention/calcium_and_VitaminD.htm Accessed 7/27/2007

  7. Estimating Dietary Calcium • Start with 300 mg (from non-Ca rich foods) • Add 300 mg for each 8 oz serving milk or serving of other Ca-rich food (e.g. yogurt, cheese) • Ca-fortified juice: 300 mg per 8 oz • Need 3-4 servings of dairy to get to AI • Using “Nutrition Facts” panel on Food Label • % Daily Value assumes 100% DV = 1000 mg Ca

  8. Sources of Calcium • Milk (whole, low fat, nonfat): • 300 mg Ca-100 IU Vitamin D per 8 oz • Ca-fortified soy milk, fruit juices, cereals • Cheese • Fruit-flavored yogurt • Milk-based pudding & shakes • For lactose intolerant: • 15% Caucasian, 70% African American, 90% Asian American • Lactose-free products • Gradually increase lactose-containing foods (induce lactase enzyme?) • Yogurt with live active cultures (bacterial lactase) • Hard cheeses

  9. Calcium Supplements • Many patients will not get adequate Ca from diet  Need Ca supplement to achieve 1200-1500 mg elemental Ca daily • Read the fine print: • mg elemental calcium vs. mg calcium salt • How many tablets per serving size? • Maximum 500-600 mg elemental Ca at one time • Calcium carbonate • Most common form of Ca supplement, cheapest • Take with meal • Calcium citrate • Achlorhydria, e.g. PPI, H2 blocker • Mealtime administration not necessary • Separate from thyroid hormone & iron supplements

  10. Vitamin D • Food sources • Natural: oily fish (salmon, mackerel), fish liver oils • Fortified in milk: 100 IU per 8 ounces • Cutaneous synthesis is diminished in: • Sunscreen use: SPF 8 ↓ 97.5% vitamin D synthesis • Darker skin: melanin competes with vitamin D precursor for photons • High latitude regions: limited sunlight during winter • Age: ↓ efficiency of vitamin D synthesis in older persons

  11. Vitamin D • Increase in 25 OH Vit D inversely proportional to starting level • At low level, 400 IU ↑ 4.8 ng/ml • At higher level (28 ng/ml), 400 IU2.8 ng/ml • Rough rule of thumb: 100 IU qd  ↑ 1 ng/ml • US National Academy of Sciences • 800-1000 IU daily to reach 25 OH Vit D 30 ng/ml • “safe upper limit” = 2000 IU daily

  12. Vitamin D Dose-Response Heaney RP Am J Clin Nutr 2003(77):204-10

  13. Vitamin D Supplements Estimated dose needed to reach and maintain a serum 25 OH Vit D of 32 ng/ml Heaney R 2005 Steroid Biochem & Mol Biol

  14. Calcium & Vitamin D Supplements: $

  15. Question #2: What’s “ONJ”? You are considering oral bisphosphonate therapy in a 60 year-old woman with postmenopausal osteoporosis with hip T-score -2.6, spine T-score -2.5. She is seeing a dentist for a dental cavity and tooth extraction is recommended. She is fearful about “Osteonecrosis of the Jaw” which she read about in a magazine.

  16. Osteonecrosis of the Jaw (ONJ) • Chart review - 63 patients with ONJ • Risk factors: • IV bisphosphonate therapy in patient with metastatic disease to bone: myeloma, breast cancer • Usually at site of prior dental surgery • Usually longer treatment duration of bisphosphonate Ruggiero sl, J Oral Maxillofac Surg 2004;62:527-534 Nonhealing extraction sites with exposed alveolar bone Ruggiero SL, Oral and Maxillofacial Surgery 2006;102:433-441

  17. Signs & Symptoms of ONJ • Exposed bone • Pain • Swelling • Paresthesia • Supporation • Soft tissue ulceration • Intra or extraoral sinus tracks • Loosening of teeth • Case Definition: area of exposed bone in the mandible or maxilla that does not heal within 8 weeks after identification by a health care provider in a patient receiving bisphosphonate and without radiation therapy to the craniofacial region JBMR 2007;22(10):1479

  18. ONJ Incidence • True incidence is unknown, limited by case reporting • Literature review: 57 ONJ cases in PMO • alendronate: 52 cases • risedronate 2 cases • alendronate + risedronate: 1 case • IV pamidronate and/or zolendronate: 2 cases • Estimated incidence in PMO is low: 1/10,000 – 1/100,000 • In cancer patients, estimated incidence 1-10% JBMR 2007;22(10):1479

  19. ONJ Recommendations • Patient about to start or already on bisphosphonate: • Inform regarding low risk of ONJ: 1 in 10,000 to 100,000 • Patients expressing concern over ONJ should seek additional information from their dentist. • Optimize dental health: regular brushing and flossing, dental visits • Due to low risk and relation to duration of Tx, no recommendation to perform dental exam before starting or alter dental management • Patients on long-term bisphosphonate (>3 yrs) without ONJ: • Patients with periodontal disease should receive appropriate nonsurgical therapy • Current data suggests bisphosphonate therapy is not a contraindication for dental implants • Endodontic treatment preferable to extraction • ? Stopping bisphosphonate if an invasive dental procedure anticipated JBMR 2007;22(10):1479

  20. ONJ Recommendations • Patients with ONJ • Report case to manufacturer • (? Avoid tartar control toothpaste – Kalmar, OSU) • Managed by dentist and/or oral surgeon • Chlorhexidine 0.12% oral antimicrobial rinse • Oral antibiotics tailored to culture data from necrotic bone and wound exudate • Surgical treatment should be conservative or delayed since debridement of necrotic bone is not uniformly effective • Removal of sharp bone edges is recommended to prevent trauma to adjacent soft tissue • Loose bony segments should be removed without exposing uninvolved bone • Segmental jow resection may be required for symptomatic patients with large sements of necrotic bone or pathologic fracture • ? Stop IV bisphosphonate in cancer patients if situation permits (case by case basis) Ruggiero SL, Oral and Maxillofacial Surgery 2006;102:433-441

  21. Question #3: Can I stop Bisphosphonate Therapy? • A 65 year old woman with osteoporosis by DXA • Baseline DXA 8 years ago: LS T-score -2.5, TH -2.2 • Treated with alendronate x 7 years • 8% increase at spine, 5% increase at total hip • No prior fracture, no fracture on therapy • “I would like to come off the medicine. I’m having trouble paying for it. Do I need to stay on Fosamax?”

  22. To Continue or Stop Antiresorptive Treatment? FIT I & II: Alendronate therapy in postmenopausal women with: • Prior vertebral fracture  ↓ risk for vertebral and hip fractures (Lancet 1996;348:1535-1541) • T-score ≤ -2.5 without prior fracture  lowers vertebral and all clinical fractures (JAMA 1998;280:2077-2082) NEJM 2004;350(12):1172-1174

  23. Fracture Intervention Trial Long-term Extension (FLEX) • 1099 of FIT subjects on the alendronate arm (5 yrs) • Randomized to 5 more years: placebo vs. alendronate • Excluded: very low T-score (<-3.5), BMD lower than baseline FIT BMD • Primary outcome: total hip BMD (power to detect 0.9% difference) • Secondary outcome: BMD at other sites • Exploratory outcome: fracture incidence (detect ≥ 13.5% risk ↓) Black DM et. al., JAMA 2006;296:2927-2938

  24. Black DM et. al., JAMA 2006;296:2927-2938

  25. FLEX (cont’d) * Alendronate group pooled: 5 mg daily and 10 mg daily Black DM et. al., JAMA 2006;296:2927-2938

  26. FLEX (cont’d) Black DM et. al., JAMA 2006;296:2927-2938

  27. FLEX Conclusions • Stopping alendronate for 5 years after 5 years of therapy • did not increase risk of nonvertebral fracture • did not increase risk of x-ray detected vertebral fracture • did increase risk of clinically detected vertebral fracture • Women at high risk of vertebral fractures such as those with prevalent vertebral fracture or very low BMD(T-score <-3.5) may benefit from continuing alendronate beyond 5 years • Consider a “drug holiday” up to 5 years if there was a good response to 5 years of alendronate: 3-5% increase hip and 8-10% increase in spine BMD, T-score >-3.5, no new fractures • Monitor with DXA • Rapid hip BMD loss >8% at 1 year, >10% at 2 year, (or fractures)  resume bisphosphonate or switch to an alternative Black DM et. al., JAMA 2006;296:2927-2938

  28. Question #4: I can’t tolerate bisphosphonate pills • 60 year old postmenopausal woman • Fragility fractures: forearm, spine • Spine T-score -2.5 • Hip T-score -2.8 • Oral alendronate and risedronate not tolerated • Review oral bisphosphonate instructions and rechallenge  UGI symptoms

  29. iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) • Multicenter (73) clinical trial of 2946 postmenopausal ♀ • Inclusion: LS T-score ≤-2.0 & history of 1-4 vertebral fractures • Randomization: 3 years of • Ibandronate 2.5 mg daily • Cyclical Ibandronate - 20 mg every other day for 12 doses every three months • Placebo

  30. BONE Study Results Chestnut CH, et. al. JBMR 2004;19:1241-1249

  31. BONE: Fem Neck T-score <-3.0 PLA Intermittent Daily Chestnut CH, et. al. JBMR 2004;19:1241-1249

  32. Intermittent Oral Dosing

  33. Dosing Intravenous Administration Study (DIVA): IV Ibandronate • Randomized, double-blind, double-placebo, non-inferiority study • Inclusion: • ♀, age 55-80, ≥5 years postmenopausal • LS T-score <-2.5 • Primary endpoint: Δ LS BMD at 1 year • Secondary endpoint: Δ Hip BMD, CTX, safety Delmas PD, et. al. Arthritis & Rheum 2006

  34. Dosing Intravenous Administration Study (DIVA): IV Ibandronate Delmas PD, et. al. Arthritis & Rheum 2006

  35. IV Ibandronate: Adverse Effects Delmas PD, et. al. Arthritis & Rheum 2006

  36. IV Ibandronate: Summary • IV ibandronate is at least noninferior (actually superior) to oral ibandronate for increasing BMD • No fracture data on IV ibandronate • Well-tolerated and similar safety profile to oral • GSK receives FDA approval January 9, 2006

  37. IV Zolendronate • Health Outcomes and Reduced Incidence with Zoledronic Acid ONce Yearly (HORIZON): IV zolendronate 5 mg IV q 12 months vs. placebo • FN T-score ≤ -2.5 OR ≤ -1.5 with ≥ 2 mild or 1 moderate radiographic vertebral facture Black DM, NEJM 2007;356(18):1809-1822

  38. IV Zolendronate Black DM, NEJM 2007;356(18):1809-1822

  39. IV Zolendronate Black DM, NEJM 2007;356(18):1809-1822

  40. IV Zolendronate: Summary • Robust antifracture efficacy data for spine, hip, nonspine, and total fracture reduction • Annual IV administration • Novartis received FDA approval 8-17-2007

  41. IV Bisphosphonates

  42. Question #4: “I’m fracturing on osteoporosis meds, what now? • 66 ♀ started Fosamax after 1997 DXA shows osteoporosis • Menarche 11, menopause 55, on HRT, switched to Fosamax 1997 to present (3/2006) • Atraumatic back pain 2/2006  xrays compression fractures L1, L2, L3, T11 • PMH: Left hip replacement 1997 for arthritis, hypothyroidism, depression • Meds: Fosamax, Caltrate 600-200 AM, OsCal 500 PM, MVI, Synthroid, Paxil, Claritin, Flonase, Aleve, glucosamine • ROS: intermittent loose bowel movements

  43. Secondary Causes of Osteoporosis Endocrine Hypogonadism Hyperparathyroidism (10 and 20) Hyperthyroidism Hypercortisolism (endogenous and exogenous) Vitamin D deficiency/insufficiency Other Disorders Gastrointestinal: sprue, IBD, PBC, PSC, bariatric surgery Hematologic: myeloma, mastocytosis, leukemia, lymphoma Rheumatologic: RA, SLE, AS Renal: CKD Genetic: OI Medications/Lifestyle Glucocorticoid Cyclosporin Aromatase inhibitor GnRH agonist Anticonvulsant Heparin Methotrexate (high dose) Ethanol Cigarettes Immobilization Dietary calcium (lactose intolerance) Hypervitaminosis A Miscellaneous Hypercalciuria Transplantation

  44. Evaluation for 20 Causes • Chemistry panel (Ca, PO4, alkaline phosphatase, albumin, ALT, AST, Cr) • TSH (hyperthyroidism) • 25-OH vitamin D (hypovitaminosis D) • Testosterone (male hypogonadism) • 24 hour urinary Ca and Cr (hypercalciuria) • SPEP, UPEP (myeloma) • iPTH (10 or 2º hyperparathyroidism) • 24 hour urinary free cortisol (suspect Cushings’ syndrome) • Fe and ferritin (suspect malabsorption, hemochromatosis) • Antigliadin, antiendomysial Ab (suspect celiac disease) • Karotype analysis (Turner, Klinefelter)

  45. Lab Results • Ca 9.1 mg/dl (8.6-10.0) • Phos 3.6 mg/dl (2.7-4.5) • Intact PTH 32.7 pg/ml (14-72) • 25 OH Vitamin D 44 ng/ml (>30) • TSH 4.194 uIU/ml (0.35-5.50) • CBC: Hb 13.2 g/dl (11.7-15.5) • Urinary Ca 114 mg/24 hours (100-300) • SPEP/UPEP: no monoclonal gammopathy, albumin 3.4 g/dl • Transglutaminase IgA Ab 92.1 U (0-30)

  46. Conclusion • Small bowel biopsy: villous blunting, increased chronic inflammation, increased intraepithelial lymphocytes, • Tx: stop Fosamax, start gluten free diet • Lumbar spine: 0.836  0.917 (+9.7%, but confounded by fractures) • Total Hip: 0.676  0.718 (+6.2%) • Consider secondary causes of osteoporosis: • Low Z-score (cutoff ≤ -2.0 vs. ≤ -1.5 ?) • Fracturing on medication • Falling BMD on medication

  47. Question # 5: Does Osteopenia need Drug Treatment?

  48. BMD and Fracture Risk • 33.6 million in USA have osteopenia: 4:1 ♀:♂ • (10 million with osteoporosis) • Relationship between BMD and fracture is continuous • Normal T-score ≥ -1.0 • Osteopenia T-score -1.1 to -2.4 • Osteoporosis: T-score ≤ -2.5 • Severe osteoporosis: T-score ≤ -2.5 with fragility fracture • BMD predicts fracture better than BP predicts stroke: • 1 SD ↓ hip BMD  ↑ 2.6 RR hip fracture • History of fragility fracture = clinical osteoporosis

  49. Guidelines for Treatment of Osteopenia

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