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Osteoporosis - Diagnosis and Treatment Dr. Sophia Ish-Shalom Osteoporosis - definition “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture” Consensus Development Conference Osteoporosis Int 1997;7:1-6 S Ish-Shalom Osteoporosis • Important cause of mortality and morbidity • A disease that causes bones to lose mass, weaken and fracture • progression is slow, silent, painless Rickets Fish Oil Bone Effects of Vitamin D Deficiency • Ca X P insufficient insufficient mineralisation • Osreoblasts continue bone deposition • Endoosteal surface • Periosteal surface Rubbery matrix with insufficient support • Hydrates and expands under periosteal covering outward pressure on periosteal covering innervated with sensory nerves Vitamin D Metabolism Food: Salmon, Mackerel Cod liver oil, Yeasts, Plants, Fortified Foods Prostate, Placenta Breast; Colon Osteoblasts Keratynocytes Immune cells 1,25(OH)2D3 Regulation of cell growth (cancer prevention) Regulation ofRegulation immune of immune function function 1/100 active used to determine vitamin D status Dietary Reference Intake (DRI) of Vitamin D • < 50 years – 200 IU/day • > 51years - 400 – 600 IU/day • In absence of sunlight for adults 600 – 1000 IU/day • In Vitamin D deficiency state we absorb • < 10 – 15% of dietary calcium • < 60% of dietary phosphorus • With adequate Vitamin D • 30 % - 80% of dietary calcium • 70 – 80 % of dietary phosphorus Food IU per serving Percent DRI 1,360 340 Salmon, cooked, 3½ ounces 360 90 Mackerel, cooked, 3½ ounces 345 90 Tuna fish, canned in oil, 3 ounces 200 50 Sardines, canned in oil, drained, 1¾ ounces 250 70 Milk, nonfat, reduced fat, and whole, vitamin D fortified, 1 cup 98 25 Margarine, fortified, 1 Tablespoon 60 15 Pudding, prepared from mix and made with vitamin D fortified milk, ½ cup 50 10 Ready-to-eat cereals fortified with 10% of the DV for vitamin D, ¾ )cup to 1 cup servings (servings vary according to the brand 40 10 )Egg, 1 whole (vitamin D is found in egg yolk 20 6 Liver, beef, cooked, 3½ ounces 15 4 Cheese, Swiss, 1 ounce 12 4 Cod liver oil, 1 Tablespoon Vitamin D Production • Sun exposure in a bathing suit 1 minimal erythema dose = ingestion of 20 000 IU Use of sunscreen 100% in vitamin D production • Exposure of arms and legs 25% minimal erythema dose (5 –15 min) 11 am – 2 pm x 3/w 25(OH)D3 Serum Level in Hip Fracture Patients 94 (98 %) patients had inadequate 25(OH)D3 serum level 35 37% 36 37% 23 24% 2 (2%) < ng/ml - ng/ml - ng/ml > ng/ml E Segal, S. Ish-Shalom, JAGS 2004 Osteoporosis • Important cause of mortality and morbidity • A disease that causes bones to lose mass, weaken and fracture • 1:3 women and 1:8 men are affected • progression is slow, silent, painless מי סובל/ת מאוסטיאופורוזיס? אישה אחת מכל 3 מעל גיל ...50 גבר אחד מכל 7 ...60 מעל גיל שברים אוסטאופורוטיים שברים בחוליות עמוד השדרה: Only 33% of Osteoporotic Vertebral Fractures are Clinically Diagnosed! 100 % Patients with vertebral fractures that are visible on X-rays 50 % Symptomatic (dorsalgia) 33 % Clinically diagnosed 8% Hospitalized 2% Requiring long term care 2/3 of patients with vertebral fractures that are visible on X-rays are not diagnosed Adapted from ROSS PD: Clinical Consequences of Vertebral Fractures: AM J Med 1997;103 (2A): 30S-43S Grading Scheme for a Semiquantitative Assessment of Vertebral Deformities after Genant 0 no deformity 1 20-25% vertebral height 10-20% projected area 2 25- 40% vertebral height 20%- 40% projected area 3 40% vertebral height 40% projected area שברים אוסטאופורוטיים Colle’s Fracture שברים אוסטאופורוטיים שבר בצוואר הירך: Bone remodelling Quiescence Lining cells Activation Resorption Formation Osteoclasts Osteoblasts Mineralization Mineralized bone Quiescence Bone structural unit Adapted from Compston 1996 1.8 BMD (g/cm2) 1.6 1.4 400 Mineral density 1.2 1 0.8 0.6 + 2SD Fracture threshold 0.4 0.2 Fractures 0 300 Mean 200 – 2SD 100 0 10 20 30 40 50 60 70 80 Fractures/10,000 patient years Bone Mineral Density and Fractures 90 Age (years) Birdwood 1996 Osteoporosis - Causes • Menstral status – early menopause (before the age of 45 years) – previous amenorrhea (e.g., due to anorexia nervosa, hyperprolactinemia) • Drug therapy – glucocorticoids ( 7.5 mg/day for > 6 months) – antiepileptic drugs (e.g., phenytoin) – excessive substitution therapy (e.g., thyroxine) – anticoagulant drugs (e.g., heparin, warfarin) Osteoporosis - Causes • Endocrine disease – primary hyperparathryroidism – thyrotoxicosis – Cushing’s syndrome Rheumatologic diseases – rheumatoid arthritis – ankylosing spondylitis Osteoporosis - Causes • Hematologic disease – myltiple myeloma – systemic mastocytosis – lymphoma, leukemia – pernicious anemia • Gastrointestinal diseases – malabsorption syndromes (e.g., celiac disease, Crohn’s disease, surgery for peptic ulcer) – chronic liver disease (primary biliary cirrhosis) Glucocorticoid Induced Osteoporosis GI Calcium Absorption PTH Urinary Calcium Excretion LH, FSH, Testosteron, Estrogen Osteoprotegerin Bone Resorption Muscle Srength Bone Formation Oseoblast Apoptosis Growth Factors Traumarelated factors Fracture risk Bone strength Bone density Geometry Bone quality •Microarchitecture •Turnover •Microdamage •Mineralization 10 y probability of hip fracture in women by age and femoral neck T-score BMD- and age-associated risks are gradient functions; fractures occur in osteopenic postmenopausal women Kanis, Osteoporos Int 2001;12:989 Vertebral Fracture Dual-energy X-ray Absorptiometry - Case # 1: interpretation failure: a “non-osteoporotic” 89 y old lady with a fractured right femoral neck Case # 2: a 27 y old women with T-score -4.9 at L4; hardware failure Case # 2: a 27 y old women with T-score -4.9 at L4 Case # 2: hardware failure resolved Definition of Osteoporosis in Women According to WHO (diagnostic criteria) Definition Normal Osteopenia Osteoporosis Bone Strategy T-Score > - 1 SD Prevention -1 SD > T-Score > - 2.5 SD T-Score - 2.5 SD Treatment Severe Osteoporosis Osteoporosis with fracture(s) Kanis et al Osteoporos Int (1997)7:390-406 Management of Osteoporosis: Pharmacological Therapy • Calcium • Vitamin D • HT (not recommended for osteoporosis, but • • • • if used for menopausal symptoms, efficient for osteoporosis) SERMs ( Raloxifen, EVISTA) Bisphosphonates Calcitonin PTH analogues Management of osteoporosis: pharmacological therapy • Calcium • Vitamin D • HRT • SERMs • Bisphosphonates • Calcitonin • PTH Antiresorptive Drugs • antiresorptive drugs (estrogen, SERMS, bisphosphonates, calcitonin) both the rates of bone resorption (in weeks) and formation (in months) • bone mineral density is by 3 - 8 % for the first 2-3 years then plateaus; this reduces the risk of fracture by 30 - 50% in various skeletal sites Therapeutic Agents in Osteoporosis Decrease in Fracture Risk Risedron Alendron Raloxif Calciton Estrog in Fracture Risk ++ ++ + + + LS + ++ NS NS + Pr. Hip in BMD Risedron Alendron ++ ++ + ++ ++ הוכחה בשני מחקרים או יותר Raloxif Calciton + + Estrog + BMD LS Pr. Hip הוכחה במחקר + לא חד משמעי + אין הוכחהNS משמעותית אין נתונים ND Ref.: Hochberg M et al. Drug & Aging 2000 Oct: 17(4) :317-330 Bisphosphonates: Pharmacology • Bone-seeking • Effective orally or IV OH R1 OH O = P—C —P = O OH R2 OH • Poor absorption orally • Not metabolized, excreted by the kidney • Long skeletal retention • Side chain determines potency and side effects Bisphosphonates: Mechanisms of Action OH R1 OH O = P—C —P = O OH R2 OH Reduce activity of individual osteoclasts • inhibit lysosomal enzymes • inhibit lactate production Reduce activation frequency • inhibit recruitment of osteoclast precursors • inhibit differentiation of osteoclast precursors Increase osteoclast apoptosis Bisphosphonates: Indications and Contraindications Indications • Prevention of bone loss in recently menopausal women • Treatment of established osteoporosis • May have benefits in many conditions characterized by increased bone remodeling (eg, Paget’s disease, hypercalcemia of malignancy) Contraindications • Active upper GI disease (some bisphosphonates cause esophageal irritation) • Hypocalcemia • Renal insufficiency Fracture Intervention Trial (FIT) 2,027 women with low femoral neck BMD and one or more vertebral fracture 6 Placebo 5 5.0 Alendronate 4 Percent of patients 4.1 3 ** 2 2.3 * 2.2 2.2 * 1 1.1 0 Clinically apparent vertebral fractures % reduction 55% Hip fractures Wrist fractures 51% 48% **P< 0.001; *P< 0.05 Black DM et al, Lancet 1996;348:1535. © by The Lancet Ltd 1996. Reprinted with permission. Estradiol and Raloxifene Occupy the Same Ligand Binding Site Kd= 86 pM Kd= 54 pM Adapted from Brzozowski AM et al., Nature 1997;389:753-58 Evista - Mode of Action of Raloxifen • Blocks the effect of estrogen in the brain hot flaches • Blocks the effect of estrogen in the mammary gland breast cancer • Blocks the effect of estrogen in the uterus no vaginal bleeding • Acts as estrogen in bone – approved for the treatment of osteoporosis Bone Formation Drugs Biosynthetic PTH – stimulate bone formation – overfill resorption cavities – the increase in bone density continues beyond two years Effects of Treatments on Lumbar-spine Bone Mineral Density 1.2 Bone Formation drug 1.1 Antiresorptive drug 1.0 Placebo 0.9 -1 0 1 2 Year 3 4 Antiresorptive versus Anabolic Treatment Teriparatide Improves Skeletal Architecture Baseline Patient treated with teriparatide 20µg Data from Jiang et al. JBMR 2003 (in press) Follow up Female, age 65 Duration of therapy: 637 days (approx 21 mos) BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) Jiang UCSF Therapeutic Management of Postmenopausal Osteoporosis Osteoporosis prevention T-score >–2.5 Osteoporosis treatment with or without previous fracture Osteoporosis treatment with multiple fractures and at risk for hip fracture PTH HRT Bisphosphonates Raloxifene 50 55 60 65 70 HRT=hormone replacement therapy Age (years) 75 80 85 90 Comparison of BMD Changes During Treatment with PTH 1-34 or Fosalan Measurement Site PTH Fosalan Lumbar spine 12.2±9.4* 5.6±5.0 Total hip 4.0±5.7* 2.5±3.2 Femoral neck 4.8±6.5* 1.7±4.3 Ultradistal radius 0.2±6.6 1.4±5.1 Paget Disease of Bone Affected Sites