Osteoporosis Update PowerPoint Presentation

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Osteoporosis Review

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Osteoporosis “Silent disease” until complicated by fractures Most common bone disease in humans Characterized by: Low bone mass Microarchitectural deterioration Compromised bone strength Increased risk for fracture

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Failure To Diagnose and Treat Studies show failure to diagnosis and treat osteoporosis in older patients who have suffered a fracture In study of 4 Midwestern health systems: 1/8 – 1/4 of hip fracture pts received BMD testing < ¼ were given calcium/D supplements < 1/10 treated with antiresorptive medications US Department of Health and Human Services: Bone Health and Osteoporosis: A Report of the Surgeon General, Office of the Surgeon General, 2004.

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Risk Factors Major History of fracture as an adult Fragility fracture in first degree relative Caucasian/Asian postmenopausal woman Low body weight (< 127 lb) Current smoking Use of oral corticosteroids > 3 mo. Additional Impaired vision Estrogen deficiency at early age (< 45 YO) Dementia Poor health/frailty Recent falls Low calcium intake (lifelong) Low physical activity > 2 alcoholic drinks per day

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Factors Associated with Bone Loss in Men Genetics Smoking/alcohol Calcium intake Physical activity/strength Testosterone production Estrogen production

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Medical Conditions Associated with Increased Risk of Osteoporosis COPD Cushing’s syndrome Eating disorders Hyperparathyroidism Hypophosphatasia IBS RA, other autoimmune connective tissue disorders Insulin dependent diabetes Multiple sclerosis Multiple myeloma Stroke (CVA) Thyrotoxicosis Vitamin D deficiency Liver diseases Not an inclusive list

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Drugs Associated with Reduced Bone Mass Aluminum Anticonvulsants Cytotoxic drugs Glucocorticosteroids (oral/high dose inhaled) Immunosuppresants Gonadotropin-releasing hormone (e.g. Lupron) Lithium Heparin (chronic use) Supraphysiologic thyroxine doses Aromatase inhibitors Depo-Provera Not an inclusive list

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Risk Assessment/Diagnosis After menopause, all women should be evaluated clinically for osteoporosis risk to determine need for BMD testing 50-60% of men with osteoporosis have disorders known to reduce bone loss, such as hyperparathyroidism, intestinal disorders, malignancies, conditions resulting in immobilization BMD recommended in men with known risk factors and who have lost > 1.5 inches in height Diagnosis can be established in patients who have never had a fragility fracture by BMD measurement

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World Health Organization Diagnostic Criteria DIAGNOSIS BMD CRITERIA * Normal within 1 SD of a “young normal” adult (T-score at -1.0 and above) Osteopenia between 1 and 2.5 SD below that of a “young normal” adult (T-score between -1 and -2.5) Osteoporosis 2.5 SD or more below that of a “young normal” adult (T-score at or below -2.5) Severe Osteoporosis 2.5 SD or more below that of a “young normal” adult and fracture(s) T-score is the number of SDs above or below the average BMD value for young, normal adults of the same sex BMD = Bone mineral density SD = Standard deviation *Measured at the hip, spine, or wrist

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Who Should be Tested? Decision to test based on individual risk profile, never indicated unless results influence treatment decision BMD testing should be performed on: All women 65 YOA and older regardless of risk factors* Younger postmenopausal women with one or more risk factors (other than being white, postmenopausal and female) Postmenopausal women who present with fractures (confirm diagnosis, determine disease severity) *Medicare permits repeat BMD testing every 2 years.

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NOF – Clinician’s Guide to Prevention and Treatment of Osteoporosiswww.nof.org Released 2/21/08 (previous update in 2003) Guidelines expanded to include African-American, Asian, Latina and other postmenopausal women, also addresses men 50 years and older Dramatically alters approach to assessing fracture risk and treatment Will help identify people at high risk for developing osteoporosis/fractures and ensure appropriate treatment Uses absolute fracture risk methodology to enhance treatment decisions to individualize plan for each patient

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NOF’s Clinician’s Guide Applies the recently released algorithm on absolute fracture risk call FRAX® by the WHO Also called 10-year fracture risk model and 10-year fracture probability Estimates the likelihood of a person to break a bone due to low bone mass over a period of 10 years Most useful to determine if treatment needed for those with low bone mass or osteopenia http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=2

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Universal Recommendations Adequate intake of calcium, vitamin D Weight-bearing and muscle-strengthening exercises to reduce risk of falls/fracture Provide strategies for fall prevention Avoidance of tobacco use/excessive alcohol use Talk to your provider about bone health Have a bone density test and take medication when appropriate

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Adequate Intake of Calcium/Vitamin D Adequate intakes of dietary calcium and vitamin D, including supplements if necessary Elemental calcium per day (> 50 YOA) = at least 1200 -1500 mg Vitamin D3 per day (> 50 YOA) = 800 -1000 international units (IU) Vitamin D3 (cholecalciferol) plays major role in Ca absorption Controlled clinical trials have demonstrated the combination reduces fracture risk Inexpensive, well-tolerated

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Calcium/D Product Selection

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Vitamin D and Fall Risk In addition to its effect on BMD, may contribute to reduction in fracture risk Improved muscle function Reduction in risk for falls Meta-analyses of 5 clinical trials (> 60 YOA) showed significant reduction in risk for falling in those taking vitamin D plus calcium versus those taking placebo Vitamin D deficiency prevalent in older adult population Inadequate sun exposure, use of sunscreen Homebound, institutionalized Northern latitudes Maintain 25-hydroxyvitamin D3 at least > 40 ng/mL Treatment: 50,000 IU vitD weekly x 6-8 weeks, then assess need for chronic monthly therapy

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Regular Weight-Bearing Exercise Defined as those in which bones and muscles work against gravity as feet and legs bear the body’s weight Include walking, jogging, Tai-Chi, stair climbing, dancing, tennis, yoga Improve agility, strength, balance May increase bone density modestly, reduce fall risk, enhance muscle strength, improve balance

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Avoidance of Tobacco and Alcohol Tobacco products detrimental to skeleton, overall health NOF strongly encourages tobacco cessation programs as osteoporosis intervention Excessive alcohol intake also detrimental to bone health and requires treatment

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Who Should Be Treated?NOF Recommendations – 2008 Initiate therapy to reduce fractures in postmenopausal women/men > 50 with: BMD T-scores < -2.5 at hip or spine Prior vertebral or hip fracture Low bone mass (T-scores -1.0 to -2.5 at hip or spine) when: 10-year probability of hip fracture is > 3% 10-year probability of major osteoporosis-related fracture is > 20% Based on US-adapted WHO algorithm www.nof.org

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FDA-Approved Drugs for Osteoporosis Bisphosphonates Alendronate, Alendronate plus D (Fosamax®, Fosamax Plus D®) Risedronate, Risedronate with Calcium (Actonel®) Ibandronate (Boniva®) Selective Estrogen Receptor Modulators (SERMs) Raloxifene (Evista®) Calcitonin (Miacalcin®, Fortical®, Calcimar®) Parathyroid Hormone [PTH (1-34), teriparatide] Forteo® Estrogen/Hormone Therapy (ET/HT) Premarin®, Estrace®, Prempro®

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Bisphosphonates – Antiresorptive Agents Agents FDA-approved for: Prevention and treatment of osteoporosis in postmenopausal women Treatment to increase bone mass in men with osteoporosis Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids Treatment of Paget’s disease of bone in men and women Mechanism: inhibits bone resorption by attaching to bony surfaces undergoing active resorption and inhibiting action of osteoclasts Leads to increases in bone density and reduced fracture risk

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Bisphosphonates – Clinical Efficacy Controlled clinical trials indicate over 3-4 year period, alendronate ↑ bone mass and ↓ incidence of vertebral, hip, and all non-vertebral fractures by 50% Controlled clinical trials indicate risedronate ↑ bone mass and ↓ risk of vertebral fractures by 40% and non-vertebral fractures by 30% over 3-year period Ibandronate has been shown in controlled clinical trials to ↑ BMD and reduce the risk of vertebral fracture by 50% over 3-year period Alendronate appears to be well tolerated and effective for at least ten years

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Bisphosphonates – Dosing Alendronate* Prevention 5 mg PO daily 35 mg PO weekly Treatment 10 mg PO daily 70 mg PO weekly 70 mg/2,800 IU vitamin D PO weekly Risedronate Prevention/Treatment 5 mg PO daily 35 mg PO weekly Ibandronate Prevention/Treatment 2.5 mg PO daily 150 mg PO monthly Treatment 3 mg IV every 3 months *Alendronate also available in oral solution.

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Bisphosphonates – Administration Must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (1 hour prior for monthly ibandronate) Should only be taken upon arising for the day Tablet should be swallowed with a full glass of water (8 oz) and patients should remain upright, walking, standing, or sitting for at least 30 minutes (60 minutes for monthly ibandronate) Should supplement with calcium/vitamin D if dietary intake inadequate

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Bisphosphonates – Adverse Effects Hypocalcemia (18%) Hypophosphatemia (10%) Musculoskeletal pain, cramps – recent FDA warning Gastrointestinal Abdominal pain Acid reflux Dypepsia Esophageal ulcer Gastritis Osteonecrosis of the jaw (IV bisphosphonates) Visual disturbances (rare)

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Bisphosphonates Contraindications/Precautions Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia Inability to stand or sit upright for at least 30 minutes Patients at increased risk of aspiration Hypocalcemia Should be corrected prior to initiating therapy Renal insufficiency (Not recommended if CrCl < 30-35 ml/min)

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Bisphosphonates – Missed Dose Once weekly alendronate, risedronate Take on morning after remembering, then resume once weekly on regularly chosen day Once monthly ibandronate If next dose > 7 days away, take dose the morning following the date remembered Then return to original schedule If next dose < 7 days away, wait until next scheduled dose Must not take two 150 mg tablets within the same week

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Zolendronic Acid (Reclast®) Approved for treatment of osteoporosis in postmenopausal women in August 2007 Single 5 mg infusion given IV over > 15 minutes, once yearly Should still supplement with calcium/vitamin D May be ideal for those with GI contraindications to the oral formulations

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Price Comparison www.drugstore.com

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Bisphosphonates Very well tolerated in patients who adhere to proper administration techniques Proper patient counseling for correct administration is KEY to reduce risk of adverse effects and increase tolerability Place in Therapy: should be considered first-line for prevention/treatment of osteoporosis in patients with no contraindications

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SERMs – Raloxifene FDA-approved for: Prevention and treatment of osteoporosis in postmenopausal women Mechanism: tissue-selective activity, acts as an estrogen agonist on bone Estrogen antagonist on breast, uterus

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Raloxifene – Clinical Efficacy Reduces risk of vertebral fracture by 30% in patients with previous spinal fracture, 55% in patients without prior spinal fracture over 3 years Increases BMD at all skeletal sites and reduces total and LDL cholesterol Less potent antiresorptive agent than bisphosphonates, although direct comparison studies lacking

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Raloxifene – Dosing/Administration For prevention and treatment 60 mg PO once daily Can be taken any time of day without regard to meals Should supplement with calcium/vitamin D if dietary intake inadequate

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Raloxifene – Adverse Effects Frequency > 10% Hot flashes Arthralgias Sinusitis Frequency 1-10% Chest pain Insomnia Migraines Peripheral edema Diaphoresis **Has been associated with increased risk of thromboembolism (DVT, PE) and superficial thrombophlebitis; risk is similar to reported risk of HRT

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Raloxifene Contraindications/Precautions History of DVT/PE or at high risk Cardiovascular disease History of uterine/cervical carcinoma Discontinue at least 72 hours prior to and during prolonged immobilization Price 30-day supply = $86.99 No generic available

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Raloxifene Place in Therapy: considered first-line in women who cannot tolerate bisphosphonates and have no contraindications to therapy Combination therapy (usually a bisphosphonate with a non-bisphosphonate) can provide additional small increases in BMD when compared to monotherapy Impact of combination therapy on fracture rate unknown

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Estrogen/Hormone Therapy (ET/HT) FDA approved for: Prevent osteoporosis Treatment of moderate/severe vasomotor symptoms of menopause Treatment of moderate/severe symptoms of vulvar and vaginal atrophy associated with menopause Consider topical preparations to treat vaginal symptoms rather than oral ET/HT

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FDA Recommendations – ET/HT When prescribing medications for osteoporosis, physicians should consider all non-estrogen therapies first When prescribing ET/HT, use smallest dose for shortest amount of time to achieve treatment goals Prescribe ET/HT products only when benefits believed to outweigh risks for a specific patient

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Calcitonin FDA-approved for: Treatment of osteoporosis in women who are > 5 years postmenopausal Treatment of Paget’s disease of bone Adjunctive therapy for hypercalcemia Mechanism: Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorption Promotes the renal excretion of calcium, phosphate, sodium, magnesium and potassium by decreasing tubular reabsorption

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Calcitonin – Clinical Efficacy Has been shown to increase spinal bone mass and may decrease risk of vertebral fracture Conflicting data on efficacy of calcitonin at sites other than the spine Less effective than bisphosphonates in treatment of osteoporosis Beneficial, short-term effect on acute bone pain after osteoporotic fracture (vertebral)

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Calcitonin – Dosing/Administration Intranasal 200 units (1 spray) alternating nares daily Store unopened bottles in refrigerator, protect from freezing Can store open bottles at room temperature for up to 35 days Activate pump of new bottles until full spray produced (allow to reach room temperature before priming) Each bottle contains at least 30 doses IM/SQ 100 units/every other day (minimum effective dose not well-defined) Should perform skin test prior to initiating therapy Should supplement with calcium/vitamin D if dietary intake inadequate

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Calcitonin – Adverse Effects Most common: Nasal spray: rhinitis (12%), irritation of nasal mucosa (9%), epistaxis (3.5%), sinusitis (2.3%), back pain, arthralgia, headache Injection: nausea (10%), flushing (2-5%) Temporarily withdraw use of nasal spray if ulceration of nasal mucosa occurs Periodic nasal examinations recommended

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Calcitonin Contraindications Clinical allergy to calcitonin-salmon Precautions Nasal ulcerations Tachyphylaxis (parenteral dosage forms) Drug interactions No formal studies designed to evaluate DI Price per month 200 units/mL (2): $42.08 200 units/ACT (3.7): $81.59

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Calcitonin Valid option for treatment of established osteoporosis, especially when accompanied by fracture pain Place in therapy: because of cost, adverse effects, inconvenience of nasal administration, recommend using calcitonin until pain is no longer a problem and then switching to a bisphosphonate for long-term therapy

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Parathyroid Hormone [PTH (1-34)]Anabolic agent FDA-approved for: Treatment of osteoporosis in postmenopausal women at high risk for fracture previous osteoporotic fracture, multiple risk factors for fracture, extremely low BMD (< -2.5), or failed/intolerant to previous treatment Treatment of primary or hypogonadal osteoporosis in men at high risk of fracture Mechanism: recombinant formulation of endogenous parathyroid hormone (PTH) stimulates osteoblast function, increases gastrointestinal calcium absorption, increases renal tubular reabsorption of calcium Enhances bone turnover by initiating greater bone formation

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PTH (1-34) – Clinical Efficacy Shown to decrease the risk of new vertebral fractures by 65% and nonvertebral fractures by 53% versus placebo after median exposure of 19 months Increases lumbar spine BMD as well as at the femoral neck, total hip, and total body Safety, efficacy of PTH (1-34) has not been demonstrated beyond 2 years of treatment

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PTH (1-34) – Dosing/Administration 20 µg SQ once daily for treatment of osteoporosis Thigh or abdominal wall Forteo® prefilled pen contains 28 daily doses Important to read Medication Guide and User Manual before starting and each time medication refilled Should be administered initially under circumstances where the patient can immediately sit or lie down, in the event of orthostasis (dizziness, palpitations are transient)

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PTH (1-34) – Adverse Effects Most common Dizziness, rash, nausea, headache, leg cramps, arthralgia, rhinitis, transient hypercalcemia S/s of hypercalcemia: nausea, vomiting, constipation, low energy, or muscle weakness Most adverse effects in the clinical trials were mild and generally did not lead to the discontinuation of the drug Osteosarcoma risk in animals Lead to black box warning by FDA

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PTH (1-34) – Warnings/Precautions Increased risk of osteosarcoma (rats) – clinical relevance unknown (no excess reports in humans) Avoid in: Paget’s disease of bone Prior radiation therapy to skeleton Bone metastases Hypercalcemia History of skeletal malignancy Pregnant/nursing

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PTH (1-34) – Price One-month supply $539.99 Lilly offers Forteo® Patient Assistance Program for Medicare-eligible (LillyMedicareAnswers) and non-Medicare eligible patients LillyMedicareAnswers intended for patients who are enrolled in any Medicare Part D prescription drug plan and who meet certain eligibility requirements Expected to start early 2007 For non-Medicare patients, application process includes paper application and income restrictions Call 1-877-795-4559 or visit www.lilly.com for more details

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PTH (1-34) Due to safety concerns, PTH treatment should be limited to those most severely affected and for a maximum of two years Combination therapy with a bisphosphonate not recommended as effects do not appear additive Cost, daily SQ injection may be prohibitive for some patients

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PTH (1-34) Place in Therapy: Recommend PTH for women or men with severe osteoporosis (low bone mineral density [T-score < -2.5] and at least one fragility fracture) who are refractory to or unable to tolerate bisphosphonate therapy In patients considered to be bisphosphonate "failures," PTH may be started approximately 3 months after bisphosphonates are discontinued Antiresorptive therapy may be considered after discontinuation of PTH to maintain gains in BMD acquired with PTH alone in those at high risk for subsequent fracture

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Approaches to Monitoring Therapy Always important to ask patients about adherence, encourage continuation of therapies to reduce fracture risk Monitoring of therapy should be considered, as up to 1/6 of women taking effective therapies continue to lose bone, especially if they smoke May measure bone mineral density at a single site after one year of therapy, but results may be misleading; usually done every 2 years Drugs may decrease a patient’s risk for fracture even when there is no apparent increase in BMD

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ACR recommends the following interventions in patients taking prednisone doses of 5 mg/day or higher for more than 3 months Calcium/vitamin D (1500mg/day, 800 IU/day) Weekly formulations of bisphosphonate therapy Replacement of gonadal steroids in men, if deficient Calcitonin therapy, if bisphosphonates contraindicated or not tolerated Follow BMD to assess if bone loss continues Glucocorticoid-Induced Osteoporosis – Recommendations

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How Can Health Professionals Improve Bone Health? To help patients maintain strong, healthy bones, health care professionals should: Indentify and assist in recommending appropriate treatment for individuals at high risk for osteoporosis and other bone disorders Recognize risk factors that warrant osteoporosis screening Assess diet/lifestyle for effect on bone health Advise patients to take active steps to ensure bone health Be familiar with treatment of osteoporosis/low bone mass Actively look for other bone disease that can lead to bone loss/fractures

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References Actonel® Prescribing Information (www.actonel.com) Ann Intern Med 1990;112:352 Ann Intern Med 2006;144:753 Boniva® Prescribing Information (www.boniva.com) Clinical Reviews in Bone and Mineral Metabolism 2004;2(4):291 Evista® Prescribing Information (www.evista.com) Forteo® Prescribing Information (www.forteo.com) Fortical® Prescribing Information (www.fortical.com) Fosamax® Prescribing Information (www.fosamax.com)

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References JAMA 2004;291(16):1999 J Clin Densitom 2004;7(1):1-6 J Am Acad Orthop Surg 2006;14:347 Miacalcin® Prescribing Information (www.miacalcin.com) Reclast® Prescribing Information (www.reclast.com) National Osteoporosis Foundation (http://www.nof.org) NEJM 2003;348:1187 NEJM 2004;350(12):1189-99 Osteoporosis Int 1998;8:1