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OSTEOPOROSIS

OSTEOPOROSIS. Kristen M. Nebel, DO March 10, 2010. Objectives. Define Review Bone pathology Review risk factors, updated screening recommendations, evaluation Male Osteoporosis Skilled care and osteoporosis Prevention and Treatment Vertebral Fracture management. Osteoporosis.

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OSTEOPOROSIS

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  1. OSTEOPOROSIS Kristen M. Nebel, DOMarch 10, 2010

  2. Objectives • Define • Review Bone pathology • Review risk factors, updated screening recommendations, evaluation • Male Osteoporosis • Skilled care and osteoporosis • Prevention and Treatment • Vertebral Fracture management

  3. Osteoporosis • Definition: A disease characterized by low bone mass and microarchitechtural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture incidence. • WHO: BMD T-score of -2.5 or less

  4. Statistics • Effects approx. 8 million women in US • 22 million women with osteopenia • By 2020 14 million men and women • Risk of fragility fractures • 250,000 hip and 500,000 vertebral/ year in women • MORE trial: Risk of osteoporotic fracture > risk of CV event (MI or CVA) or breast CA • Risk of 2nd vertebral fracture within one year is 20%

  5. Statistics • Impact of osteoporosis-related fractures: • 2005 estimated Healthcare cost:$17 billion • 432,000 hospital admissions • 183,000 skilled care admissions (NOF.org)

  6. Bone Pathophysiology • Bone Strength • Related to bone mass (measured by BMD) and other factors, such as remodeling frequency (bone turnover), bone size and area, bone microarchitechture and degree of bone mineralization

  7. Bone Pathophysiology • Normal: Cyclic bone remodeling • Osteoclasts: The mineral content of matrix is first dissolved and the remaining protein components of the matrix (primarily collagen) are then degraded by proteolytic enzymes secreted into the resorption space.

  8. Bone Pathophysiology • Normal bone remodeling: • Osteoblasts: Synthesize new bone by first laying down a new protein matrix, principally composed of Type I collagen into the resorbed space. • Individual collagen molecules become interconnected by formation of pyridinoline cross-links to provide extra strength. • Bone mineralization occurs with deposition of hydroxyapatite.

  9. Bone Pathophysiology • Bone Turnover Markers • Formation: bone-specific alkaline phosphatase and osteocalcin • Resorption: carboxy terminal peptides of mature collaged (N-telopeptide and C-telopeptide) and deoxpyridinoline

  10. Something Somewhere Went Terribly Wrong

  11. Bone Pathophysiology • Abnormal: Imbalance of remodeling • High bone turnover rate leads to weakening due to weaker trabecular/ cancellous bone

  12. Bone Mass Changes • Peaks by mid-30’s • Bone loss begins several years prior to menopause • Risk of fracture increases with BMD loss • Compared to younger women: odds of having OP in 65-69 y/o is 5.9x higher and in 75-79 y/o is 14.3x higher • Genetic factors contribute 80% to a women’s risk of osteoporosis • BMD is likely to be lower in women with + FHX of osteoporosis than those without. • Risk of hip fx: • 50% greater if 1st degree relative had + fx • 127% greater if parent had hip fx

  13. Osteoporosis: Consequences • Reduced QOL • Increased mortality (20%) • Failure to return to baseline (50%) • Depression

  14. Risk Factors for Osteoporotic Falls: NOF • Body weight <70kg or BMI<21 • Corticosteroids • Personal history of fractures as adult • First-degree relative with fragility fracture • Current smoking • Early menopause • Nutrition • Decreased activity • ETOH • Impaired vision • Dementia • Poor health • Recent falls

  15. Fracture Risk Assessment (FRAX) • Introduced in 2008: • WHO’s new guide to identify an individual’s 10-yr risk of osteoporotic fracture • Goal: Ensure that those at high risk are treated • Accounts for nine clinical risk factors +/- hip BMD • Allows for calculation even if no BMD available • Designed to decide who and when to newly treat (not for those currently on treatment) • Therapy indicated if 10-yr. risk of hip fracture >/= 3% or other major fracture risk >/= 20% • Cut-off for therapy based on new cost-effective treatment thresholds (Tosteson et al. Osteop. Int. 2007)

  16. FRAX • FRAX • Does not apply to premenopausal women and men < 50 y/o

  17. BMD TestingRecommendations • USPSTF/ NOF • ALL women 65+ • MEN >/= 70 • Younger postmenopausal women and men 50-70 with clinical RF’s • Adults with fracture after age 50 • Adults with a condition or a medication a/w low bone mass • Perimenopausal women with high-risk risk factors (ie-meds, low BMI, h/o low-trauma fracture)

  18. Screening Methods • Dual-energy x-ray absorptiometry = preferred • Femoral neck BMD is best predictor of hip fx • Forearm BMD predicts non-hip fractures • Ultrasound densitometry (sahara screen)

  19. Screening and MedicareCoverage (ICD-9 codes) • Medicare covers BMD testing for the following individuals 65 and older • Estrogen deficient women at clinical risk for osteoporosis (627.2) • Individuals with vertebral anomalies (733.90) • Individuals receiving, or planning to receive, long-term glucocorticoid therapy of at least 5mg for 3 months (V58.69) • Individuals with primary HPTH (252.00) • Medicare permits repeat BMD testing every 2 years

  20. Osteoporosis Evaluation • “Silent fractures” • Check for loss of height (>5cm) • Up to 70% of vertebral fractures may be asymptomatic • In an evaluation of 2 primary care offices only 38% of patients with a history of vertebral fracture were evaluated for and treated for osteoporosis. (Neuner et al. JAGS 2003)

  21. Male Osteoporosis • Morbidity and mortality much higher in men than women with osteoporotic fracture • Secondary causes more common accounting for 50% • ETOH (15-20%), glucocorticoid (20%), and hypogonadism (15-20%) • Androgens may inhibit bone resorption • 3-6% of men in US (NHANES III study) • 28-47% with osteopenia • 1/3 of men 60+ are likely to have an osteoporotic fracture • Average onset is 10 yrs later than in women • Men often asymptomatic at onset

  22. Male Osteoporosis • Previously, no formal recommendations • Now, WHO recommends BMD for • ALL men >70 • Men 50-70 with risk factors • BMD should be compared to male references so that osteoporosis diagnoses are not missed • BMD of hip is most reliable indicator due to prevalence of spinal degenerative changes

  23. Osteoporosis Evaluation • When to suspect secondary causes: • Premenopausal women • Patient without risk factors • Men <70 • Multiple health problems • Worsening osteoporosis despite therapy

  24. Secondary Causes • Medications • Renal insufficiency  secondary HPTH • Cushing’s • Hyperthyroid • Multiple myeloma • Osteomalacia • Paget’s Dz • GI malabsorption / celiac • Mets to bone

  25. Osteoporosis Evaluation • Labs • CMP, phosphate, CBC, ESR, TSH/FT4 • Testosterone/ Estrogen • SPEP • 24 hour urine for calcium and creatinine • 25-OH Vit. D • Intact PTH • Biochemical markers of bone turnover • Imaging • X-rays not good for early detection: 20-40% of BMD must be lost to detect

  26. Osteoporosis and Skilled Care: To Treat or Not to Treat? • AMDA 2004 Quality Indicators: • Prevention: Within 1 month of admission all females to be offered Calcium, vitamin D, and weight-bearing exercises. • Mobilization: Attempted in bedfast individuals unless contraindicated • New Dx: Calcium and Vitamin D started within 1 month • New Dx: Therapy started within 3 months • Corticosteroid tx for > 1 month: start calcium • New Dx: Evaluate meds for secondary causes • New Osteoporotic fx in ambulatory resident: Physical therapy should be started within 1 month

  27. Osteoporosis and Skilled Care: To Treat or Not to Treat? • Osteoporosis present in up to 80% of residents • Most significant independent RFs for fracture • Low BMD and dependence for transfers (>3x fracture risk of those w/o low BMD) (Duque et al. JAMDA ’06) • Dx in LTC • BMD not always appropriate • Quebec Symposium for LTCI: Diagnosis based on patient risk factors, physical exam (kyphosis, fractures), x-ray and loss of height • Calcaneal BMD • Vitamin D level

  28. Osteoporosis and Skilled Care: To Treat or Not to Treat? • Studies estimate that therapy for osteoporosis, including calcium and vitamin D, is prescribed in only 9-20% of residents with documented disease. (Wright. JAMDA 2007) • Factors contributing to lack of prescribing • Compliance • Tolerance • Price • Risk vs. Benefit • Life expectancy, ambulation, time to efficacy

  29. General Treatment and Prevention Recommendations • Nutrition • Calcium • Dose increases with age due to decreased absorption • Decrease bone loss by 1%/ yr. • Greatest benefit in elderly, late-menopausal, and those with low baseline calcium intake • Vitamin D • Recommended intake 800-1000 IU • Meta-analysis (JAMA) showed reduced risk of hip and non-vertebral fractures with 700-800 IU/day • Natural sources: fatty fish, fish liver oils, and fortified foods (milk = 400 IU /qt.)

  30. General Treatment and Prevention Recommendations • Calcium and Vitamin D • Augmentation of other agents • Studies of etidronate in individuals with Vitamin D > 40 showed greater increase in BMD measured at L-S and femoral neck compared with levels < 40 (Boonen et al. JAGS 2004) • Given to all on osteoporosis therapy • Patients receiving corticosteroids • RA patients on prednisone lost 1-2% BMD/ yr. Those randomized to calcium (1000mg/d) and Vit. D (500IU/d) gained BMD at about 0.5%/yr. • Those with or at risk of deficiencies • Secondary HPTH due to hypovitamin D showed improved BMD on Alendronate and Vit. D compared with those only on Alendronate (Baron et al. JAGS 2005)

  31. General Treatment and Prevention Recommendations • Caffeine • Recommend < 4 cups/ d • May reduce calcium absorption • Some association with increased bone loss and fracture rates • Vitamin K • May help with bone metabolism and reducing urinary calcium excretion • No recommendations for supplementation • No association between Coumadin and fractures

  32. General Treatment and Prevention Recommendations • Vitamin A • RDA of 700 micrograms • High levels have been associated with increased risk of hip fracture in 2 out of 3 studies • Magnesium • Some epidemiologic studies showed correlation with increased BMD in elderly and females • Easily obtained in daily food intake • Deficiencies may exist in elderly and those with GI malabsorption • ETOH • Can suppress osteoblasts • Moderate intake (1-2 oz/week) in women 65+ is associated with higher BMD and decreased risk of hip fracture • Heavy intake (>7oz/week) increases risks of falls and hip fractures

  33. Non-pharmacologic Interventions • Rehabilitation • Exercise • Strengthening muscles: backs and legs • Prospective 10-year study showed decreased risk of vertebral fractures (Sinaki) • Orthotics • Gait training • Pain Management • Avoiding substances of abuse

  34. Pharmacologic Options • Who to treat (NOF Clinician’s Guideline 2008) • Treatment: Postmenopausal women and men 50+ with • BMD T-score of -2.5 or less • Any hip or vertebral fracture • BMD T-score of -1.0 to -2.5 AND prior fracture (new) • BMD T-score of -1.0 to -2.5 AND secondary causes a/w high risk of fracture • BMD T-score of -1.0 to -2.5 AND 10-yr prob. of hip fx >/= 3%, major fx >/= 20% • Prevention • Women with BMD hip T-score of -2.0 or less and no risk factors • Women with BMD hip T-score of -1.5 with one or more risk factors and does not meet FRAX criteria

  35. Pharmacologic Options • Antiresorptives • Estrogens/HRT • Selective-estrogen receptor modulators (SERMS) • Calcitonin • Bisphosphonates • Anabolic • PTH

  36. Estrogens/HRT • Recommended for prevention only • WHI: 5 years - 16K women ages 50-79 (mean 63) w/ uterus and no screening for osteoporosis • Increase in BMD • Decrease in hip, vertebral, and other osteoporotic fracture rates • Increased risk of CV events, VTE, and Breast CA; decrease in colon CA

  37. SERMS: Raloxifene (Evista) • Prevention and Treatment of postmenopausal OP Vertebral fracture risk • Daily oral dosing • Modest increase in BMD of spine and hip; decreases bone turnover • Multiple Outcomes of Raloxifene Evaluation (MORE): 3 year study of 7,700 women with OP • Postmenopausal OP +/- previous vertebral fracture • Insignificant results: 30% and 50% reduction in risk of vertebral fracture • Side effects: hot flashes, leg cramps, increased VTE

  38. Calcitonin (Miacalcin) • Treatment of postmenopausal OP (at least 5 yrs.) only • Patients unable to tolerate other agents • Daily dosing as nasal spray, SC injection, and oral • Minimally inhibits bone resorption; possible analgesic effect for acute vertebral fx • PROOF trial: At 5 yrs 33% reduced risk of new vertebral fx (200 mcg). After 5 yrs, increased dose (400 mcg) required to perpetuate BMD increase • Side effects: nasal irritation, nausea, local inflammation and flushing

  39. Bisphosphonates: Alendronate (Fosamax) • Prevention and Treatment of Male and Postmenopausal OP, Treatment of Glucocorticoid-induced OP • Daily or weekly dosing; oral form (tab or liquid) • Inhibits osteoclasts, Increases BMD • + h/o spine fx: Reduces risks of all osteoporotic fractures by 50% over 3 yrs. (NOF) • - h/o spine fx: Reduces incidence of spine fx by 46% over 3 yrs. • Side effects: Gastric irritation and ulcers, CrCl <35, hypocalcamia, ONJ

  40. Osteonecrosis of the Jaw • American College of Rheumatology position paper • Case review found 60% of cases to be following oral surgery or dental extraction. 94% of the cases occurred with IV bisphosphonates (Pamidronate or Zoledronic acid) and 85% had MM or metastatic breast CA to bone. • Non-cancer patients and oral meds not considered risk factors • Recommendations to avoid ONJ: treating infections and obtaining routine dental care prior to therapy • Appearance of intraoral lesion with exposed bone +/- painful ulcers, ragged

  41. Risedronate (Actonel) • Prevention and Treatment of Glucocorticoid-induced, male, and Postmenopausal OP • Daily, weekly, or monthly (75mg on 2 consecutive days) dosing, oral form only • + h/o spine fracture reduces risk of spine fracture by 41-49% and hip fractures by 36% over 3 yrs. (NOF) • Polled data of VERT and HIP trials for women 80+ with OP showed NNT = 12 to prevent 1 new vertebral fracture after 1 year of therapy. After 3 years of therapy NNT = 16

  42. Ibandronate (Boniva) • Prevention and Treatment of Postmenopausal OP • Dosing: IV q 3 months or orally daily or monthly • Decreases risk of vertebral (not hip) fracture by 50% over 3 yrs. • RCT by Delmas et al: Comparison of oral and IV dosing • 1400 women with OP of lumbar of lumber spine • At 1 year lumbar/ femur BMD greater in IV group greater than PO • Side effects: flu-like illness with 1st infusion, GI upset, arthralgias

  43. Zoledronate (Reclast) • Treatment of Postmenopausal OP • Dosing: 5mg IV yearly • Reduces incidence of spine fracture by 70%, hip fractures 41%, and non-vertebral fx 25% over 3 yrs. • Side-effects: Acute phase reactants (arthralgia, HA, myalgia, fever)- may pretreat with Tylenol • Risk of side effects tapers with subsequent dosing

  44. Bisphosphonates and Atrial Fibrillation • Conflicting reports from population-based case controlled studies • Reanalysis of several trials did not show increased risk of atrial fibrillation. • Current recommendations are not to withdraw therapy

  45. PTH (1-34): Teriperatide (Forteo) • Treatment of high risk postmenopausal and male OP • T-score of -3.5, fractures + T-score -2.5, and those who fail 2 yrs of bisphosphonate therapy • Daily SC injections (only approved for 2 years duration) • Anabolic: Stimulates osteoblast activity-> increased trabecular bone density

  46. PTH (1-34): Teriperatide (Forteo) • Side effects: dizziness, leg cramps, osteosarcoma seen in rat trials • Contraindications: Paget’s disease of bone, prior radiation therapy of the skeleton, bone metastases, hypercalcemia, or a h/o skeletal malignancy

  47. PTH (1-34): Teriperatide (Forteo) • “Fracture Prevention Trial”: 20mcg/d reduced vertebral and non-vertebral fractures by 65% and 53%, respectively • Review of FPT to assess safety and efficacy in women 75+ compared with younger women found that lumbar and femoral neck BMD both increased significantly and new vertebral fractures risk NNT =11 (Boonen et al. JAGS 2006) • Limitation of study: Subjects were ambulatory w/o significant comorbidities.

  48. Concurrent Therapy • Synergism: Teriperatide and Alendronate? • Small RCT 83 men: Spine and femoral neck BMD increased greatest in PTH only group • Alendronate impaired PTH anabolic activity (Finkelstein et al. NEJM 2003) • Recommended that bisphosphonate therapy follows PTH (Teriperatide). • Simultaneous use of bisphosphonate and other not generally recommended

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