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OSTEOPOROSIS OBJECTIVES Know and understand: • How to diagnose osteopenia and osteoporosis • The pathogenesis of osteoporosis • Common secondary causes of bone loss • Prevention and treatment strategies for osteoporosis • How to diagnose and treat osteomalacia Slide 2 TOPICS COVERED • Bone Remodeling and Changes in Bone Mass • Epidemiology of Osteoporotic Fractures • Pathogenesis of Osteoporosis • Evaluation for Osteoporosis • Prevention and Treatment of Osteoporosis • Management of Vertebral Fractures Slide 3 BONE REMODELING • Bone repairs itself by actively remodeling Bone resorption (osteoclasts) Bone formation (osteoblasts) • The remodeling cycle may become unbalanced After menopause; with aging in men & women Bone resorption increases more than bone formation, resulting in net bone loss Bone loss osteopenia, osteoporosis, fractures Slide 4 LIFETIME CHANGES IN BONE MASS Age Puberty to mid20s and 30s Women Men Bone mass increases rapidly, reaching peak bone mass Mid-30s to 40s A few years of stability, then slow bone loss No risk factors: bone loss 1%/year Mid-40s to 50s Menopause, then rapid bone loss 7%/year for 7 years With risk factors: bone loss 6%/year Mid-50s to late life Continuing bone loss of 1%–2%/year Risk factors: low calcium intake, smoking, alcoholism, certain drugs. Both men and women lose predominantly cancellous (vertebral) bone. Slide 5 EPIDEMIOLOGY OF OSTEOPOROTIC FRACTURES High prevalence • 1.5 million osteoporotic fractures in US annually • 250,000 hip & 500,000 vertebral fractures in US annually Serious consequences • quality of life, function, independence • morbidity & mortality (50% of women do not recover prior function after hip fracture; 20% excess mortality in year after hip fracture) Cost • • In 2005, estimated to be responsible for $19 billion in costs Experts predict that by 2025, costs will rise to $25.3 billion Slide 6 DEFINITIONS OF BONE LOSS DISORDERS Osteopenia • Low bone mass • T-score < –1 but –2.5 Osteoporosis • BMD measurement at any site >2.5 standard deviations below the young-adult standard, with or without previous fracture • T-score < –2.5 Slide 7 PATHOGENESIS OF OSTEOPOROSIS • Estrogen deficiency • Calcium deficiency & secondary hyperparathyroidism • Androgen deficiency • Changes in bone formation • Secondary causes and medications Slide 8 ESTROGEN DEFICIENCY • Factors that play a role in bone loss related to estrogen deficiency: Increased resorption Osteoclast activity • Fracture risk is inversely related to estrogen levels in post-menopausal women Slide 9 CALCIUM DEFICIENCY AND SECONDARY HYPERPARATHYROIDISM • Aging skin & sunlight exposure conversion of 7dehydrocholesterol to cholecalciferol (vitamin D3) by ultraviolet light vitamin D deficiency • Vitamin D insufficiency absorption of calcium • Older adults tend to ingest inadequate amounts of calcium and vitamin D • PTH in order to maintain serum levels of calcium • When chronically elevated, PTH is a potent stimulator of bone resorption Slide 10 ANDROGEN DEFICIENCY • Men with estrogen deficiency or resistance have bone mass and failure of epiphyseal closure • Severe male hypogonadism can cause osteoporosis • The effect of moderate decreases in testosterone levels in aging men on rate of bone loss is uncertain Slide 11 CHANGES IN BONE FORMATION With aging and menopause: • Osteoblast activity decreases • Bone resorption increases • Growth factors (eg, transforming growth factor B and insulin-like growth factor 1) may be impaired, resulting in decreased osteoblast function Slide 12 RISK FACTORS FOR OSTEOPOROSIS • Age (postmenopausal in women, >70 yr in men) • Glucocorticoids • Female sex • Previous fragility fracture as adult • Low body weight (BMI <20) • Androgen-deprivation therapy • 10% decline in weight (from usual adult body weight) • Current smoking • Physical inactivity • Low dietary calcium • Spinal cord injury • Alcoholism Slide 13 MODIFICATIONS TO REDUCE THE RISK OF OSTEOPOROSIS (1 of 2) Exercise: Encourage regular, weightbearing exercise at least 5 times per week for 30 minutes Nutrition: Encourage adequate intake of calcium (1,200–1,500 mg/d in divided doses) and vitamin D3 (800–1000 IU/d) Smoking cessation Slide 14 MODIFICATIONS TO REDUCE THE RISK OF OSTEOPOROSIS (2 of 2) Medications that can increase risk of osteoporosis—use with caution: • Glucocorticoids • Methotrexate • Anticonvulsants • GnRH agonists used for prostate cancer • Cyclosporine • Long-term heparin • Excess thyroid hormone replacement • Aromatase inhibitors (eg, anastrozole, letrozole, exemestane) used for breast cancer Slide 15 SECONDARY CAUSES OF BONE LOSS Women • Primary hyperparathyroidism • Glucocorticoid use Men • Hypogonadism • Malabsorption syndrome including gastrectomy Slide 16 EVALUATION • Measure Vitamin D level • Measure bone density • Assess for secondary causes of bone loss • Use of biochemical markers in clinical practice is controversial Slide 17 BMD MEASUREMENT Best predictor of fracture • Relative risk of fracture is 10 greater in women in the lowest quartile than in those in highest quartile Dual-energy x-ray absorptiometry (DEXA) • Preferred method of measurement • Can measure hip, anterior-posterior spine, lateral spine, and wrist • Cost = $200 to $300; covered by Medicare and Medicaid if indications for use are met Lateral vertebral assessment • Technology available for diagnosis of vertebral fractures as part of DEXA Slide 18 INDICATIONS FOR BMD TESTING (1 of 2) Disease Hyperparathyroidism Recommended Laboratory Tests Calcium, PTH level Hyperthyroidism TSH, thyroxine levels Hypogonadism (men only) Bioavailable testosterone or total testosterone, free testosterone with sex hormone-binding globulin Multiple myeloma CBC, serum protein electrophoresis, urine electrophoresis Gold font = recommended routinely Slide 19 INDICATIONS FOR BMD TESTING (2 of 2) Disease Osteomalacia Recommended Laboratory Tests Bone-specific alkaline phosphatase, 25(OH)D level Paget’s disease Bone-specific alkaline phosphatase, urine NTx Electrolytes, 24-h urinary free cortisol Cushing’s disease Slide 20 LATERAL VERTEBRAL ASSESSMENT • Vertebral fractures are highly associated with future fracture risk and morbidity • Can be present in patients with T-scores > ‒2.5 • Used as an adjunct to BMD testing Slide 21 BIOCHEMICAL MARKERS OF BONE TURNOVER • May be early indicator of treatment efficacy • Bone resorption markers Cross-linked C-telopeptides of type I collagen (serum CTX) Cross-linked N-telopeptides of type I collagen (NTx – urine or serum) • Bone formation marker Bone alkaline phosphatase Slide 22 LIMITATIONS ON THE USE OF BIOCHEMICAL MARKERS • Clinical use is controversial because of substantial overlap of values in women with high and low bone density or rate of bone loss • Few studies have compared the response of a particular marker and bone density with goals of therapy Slide 23 WHOM TO TREAT • Older men and women with osteoporosis diagnosed by DEXA or with history of fragility fracture • FRAX is an algorithm that uses clinical and BMD information to model the 10-year fracture probability in men and women (http://www.shef.ac.uk/FRAX/index.htm) Slide 24 PREVENTING AND TREATING OSTEOPOROSIS • Exercise • Calcium and vitamin D • Bisphosphonates • Selective estrogen receptor modulators • Calcitonin • Estrogen replacement • Investigational agents Slide 25 EXERCISE • Marked decrease in physical activity or immobilization decline in bone mass • Walking, a weight-bearing exercise, can be recommended for all adults • Start slowly and gradually increase the number of days and time spent walking each day Slide 26 CALCIUM & VITAMIN D RECOMMENDED REQUIREMENT • 1200 mg/day of calcium: men 65 years and older & postmenopausal women • 800-1000 IU/day of vitamin D Slide 27 BISPHOSPHONATES Rationale: Approved for osteoporosis prevention in postmenopausal women and treatment in men and women • bone density of spine & hip (alendronate and risedronate) • vertebral fracture rate (ibandronate) • Optimal duration of treatment unclear Side effects: GI (abdominal pain, dyspepsia, esophagitis, nausea, vomiting, diarrhea); musculoskeletal pain; osteonecrosis of the jaw (rare in patients being treated for osteoporosis); atypical fractures; there have been cases of atrial fibrillation after doses of zoledronate Slide 28 BISPHOSPHONATES COMPARED (1 of 2) Medication Dosage Special Considerations Observed Beneficial Treatment Outcomesa Bisphosphonates should not be used if CrCl <30 mL/min Alendronate 70 mg/wk; 35 mg/wk for prevention Adherence to dosing instructions required; used in men and women to prevent glucocorticoidinduced osteoporosis Vertebral fracture: absolute risk reduction (ARR)=7.1%, number needed to treat (NNT)=14 over 3 yr Hip fracture: ARR=1.1%, NNT=91 over 3 yr Risedronate 35 mg/wk or 150 mg/moh Adherence to dosing instructions required Vertebral fracture: ARR=5%, NNT=20 over 3 yr Nonvertebral fracture: ARR=4%, NNT=25 over 3 yr aPatient populations were not comparable, so direct comparisons of ARR and NNT may not be valid Slide 29 BISPHOSPHONATES COMPARED (2 of 2) Medication Dosage Special Considerations Observed Beneficial Treatment Outcomesa Bisphosphonates should not be used if CrCl <30 mL/min Ibandronate 150 mg/mo or 3 mg IV every 3 mo Adherence to dosing instructions required Vertebral fracture: ARR=4.9%, NNT=20 over 3 yr Zoledronic acid 5 mg/year IV Adherence to dosing instructions required Morphometric vertebral fracture: ARR=7.6%, NNT=13 over 3 yr Clinical vertebral fracture: ARR=2.1%, NNT=48 over 3 yr All nonvertebral fractures: ARR=2.7%, NNT=37 over 3 yr Hip fracture: ARR=1.1%, NNT=91 over 3 yr aPatient populations were not comparable, so direct comparisons of ARR and NNT may not be valid Slide 30 INSTRUCTIONS FOR TAKING BISPHOPHONATES • Take first thing in the morning before eating or drinking anything else • Take with at least 8 oz of plain tap water • Take while upright in a chair or standing, and remain upright for 30 minutes after ingestion • With alendronate and risedronate, do not eat or drink anything for 30 minutes after ingestion (60 minutes for ibandronate) Slide 31 SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) • Act as estrogen agonists in bone and heart • Act as estrogen antagonists in breast and uterine tissue • Potential for preventing osteoporosis or cardiovascular disease without the increased risk of breast or uterine cancer Slide 32 SERMs: RALOXIFENE • Approved for osteoporosis prevention & treatment in postmenopausal women • Dose: 60 mg/d • In comparison with placebo: vertebral fractures breast cancer (relative risk 0.24) bone turnover & maintains BMD • Side effects: Flu-like symptoms, hot flushes, leg cramps, peripheral edema Slide 33 CALCITONIN Rationale • Hormonal inhibitor of bone resorption • In comparison with placebo: vertebral fractures and spine bone density No in hip or nonvertebral fractures • Possible analgesic effect in women with painful vertebral compression fractures Dosing • Subcutaneous injection (50–100 IU 3–5 times/week • Nasal spray 200 IU/day, alternate nostrils (fewer reported side effects, greater patient acceptance, may be less effective) Slide 34 ESTROGEN REPLACEMENT • Prevents bone loss at hip & spine when initiated within 10 years of menopause • An option for osteoporosis prevention but not recommended as first-line choice • Women’s Health Initiative showed risk of hip fracture, vertebral fracture, and colon cancer but ↑ risk of breast cancer, heart disease, stroke, and venous thromboembolism • USPSTF Guidelines advise against routine use of estrogen plus progesterone for the prevention of chronic conditions in postmenopausal women Slide 35 PARATHYROID HORMONE • Increases bone formation and resorption • Reduces vertebral and nonvertebral fractures in postmenopausal women • Increases BMD at all sites • Typically reserved for those with severe osteoporosis and fracture history • Teriparatide dose 20 mcg/d SC for patients who cannot tolerate other treatment • FDA-approved for only 2 years of use Slide 36 DENOSUMAB • Human monoclonal antibody that inhibits RANKL (receptor activator for nuclear factor κB ligand) • ↓ bone turnover and ↑ BMD • Approved in US for postmenopausal women at high risk of fractures Slide 37 STRONTIUM RANELATE • Anabolic agent that ↑ bone formation and ↓ bone resorption • Not approved in US • Many patients are taking other forms of strontium bought OTC • No data available Slide 38 VERTEBRAL FRACTURES • Asymptomatic (the majority) Diagnosed by spinal radiographs kyphosis or height Chronic back pain due to spinal changes that occur with vertebral compression • Symptomatic Pain usually lasts 2 to 4 weeks Can be debilitating Slide 39 MANAGING VERTEBRAL FRACTURES (1 of 2) • Medications NSAIDs and calcitonin Narcotics commonly required for pain control • Physical therapy Important for both acute and chronic pain Postural exercises Alternative modalities for pain Slide 40 MANAGING VERTEBRAL FRACTURES (2 of 2) • Education, support groups • Vertebroplasty and kyphoplasty Surgical options for treatment of painful compression fractures Complications can occur (eg, emboli, infection) Limited randomized, controlled trials Slide 41 SUMMARY (1 of 2) • Osteoporosis is prevalent among older adults and is associated with high personal and financial costs as well as mortality • Osteopenia and osteoporosis can be diagnosed by measuring BMD using dual-energy x-ray absorptiometry • Evaluation of patients with osteoporosis should include assessment for secondary causes of bone loss Slide 42 SUMMARY (2 of 2) • Osteoporosis prevention and treatment combines risk reduction, exercise, calcium and vitamin D supplementation, hormones, and other pharmacotherapies • Pain of osteoporotic vertebral fractures can be treated with NSAIDs, calcitonin, and narcotics, as well as physical therapy with surgical options of vertebroplasty and kyphoplasty Slide 43 CASE 1 (1 of 3) • A 69-year-old man comes to the office to establish care. • His wife is being treated for osteoporosis. • She wants to know whether her husband should also undergo a screening assessment. Slide 44 CASE 1 (2 of 3) Which of the following is the strongest risk factor for osteoporosis in men? A. Androgen deprivation therapy B. Low dietary intake of vitamin D C. Respiratory disease D. Thyroid replacement therapy E. Type 2 diabetes mellitus Slide 45 CASE 1 (3 of 3) Which of the following is the strongest risk factor for osteoporosis in men? A. Androgen deprivation therapy B. Low dietary intake of vitamin D C. Respiratory disease D. Thyroid replacement therapy E. Type 2 diabetes mellitus Slide 46 CASE 2 (1 of 3) • A 75-year-old woman with established osteoporosis wishes to discuss advertisements she has seen for ibandronate and risedronate. • She currently takes alendronate and wonders whether she would benefit more from a different agent. • She has not had a fracture. Slide 47 CASE 2 (2 of 3) Which of the following is the best agent for preventing fracture? A. Alendronate B. Ibandronate C. Pamidronate D. Risedronate E. Data are not available to answer her question Slide 48 CASE 2 (3 of 3) Which of the following is the best agent for preventing fracture? A. Alendronate B. Ibandronate C. Pamidronate D. Risedronate E. Data are not available to answer her question Slide 49 CASE 3 (1 of 3) • An 80-year-old woman comes to the office for follow-up because a recent evaluation identified significant osteoporosis. • She agrees to begin oral bisphosphonate therapy. Slide 50 CASE 3 (2 of 3) What is the most common adverse effect of oral bisphosphonate therapy? A. Atrial fibrillation B. GI effects C. Osteogenic sarcoma D. Osteonecrosis of the jaw E. Thromboembolic disease Slide 51 CASE 3 (3 of 3) What is the most common adverse effect of oral bisphosphonate therapy? A. Atrial fibrillation B. GI effects C. Osteogenic sarcoma D. Osteonecrosis of the jaw E. Thromboembolic disease Slide 52 ACKNOWLEDGMENTS Editor: Annette Medina-Walpole, MD GRS7 Chapter Author: Pamela Taxel, MD Leen Bakkali, MD GRS7 Question Writer: C. Bree Johnston, MD, MPH Pharmacotherapy Editor: Judith L. Beizer, PharmD Medical Writers: Beverly A. Caley Faith Reidenbach Managing Editor: Andrea N. Sherman, MS Copyright © 2010 American Geriatrics Society Slide 53