The medical letter on drugs and therapeutics september 29 2014

The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 September 29, 2014 Volume 56 ISSUE ISSUE No 1433 1452 IN THIS ISSUE Drugs for Postmenopausal Osteoporosis p 91 Volume 56 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No September 29, 2014 Take CME Exams IN THIS ISSUE 1433 1452 Drugs for Postmenopausal Osteoporosis Volume 56 RECOMMENDATIONS Postmenopausal women with osteoporosis who have an inadequate dietary intake of calcium and vitamin D should take calcium and vitamin D supplements to reduce their risk of fractures There is no evidence that women with an adequate dietary intake of calcium and vitamin D benefit from taking supplements, but an adequate intake of vitamin D may be difficult to achieve by diet alone For women taking antiresorptive drugs (all those below except teriparatide), achieving an adequate intake of both calcium and vitamin D will often require taking a supplement Bisphosphonates can prevent vertebral and nonvertebral fractures in postmenopausal women with osteoporosis Weekly or monthly doses of oral bisphosphonates are as effective as daily doses in increasing bone mineral density and are better tolerated IV administration of ibandronate (Boniva, and generics) every months or zoledronic acid (Reclast, and generics) once a year are other alternatives Ibandronate has not been shown to reduce the risk of nonvertebral fractures Denosumab (Prolia) injected subcutaneously once every months can reduce the risk of vertebral and nonvertebral fractures in women with postmenopausal osteoporosis It may be an effective alternative for patients who have not responded to bisphosphonates or cannot tolerate them Teriparatide (Forteo), the 1-34 sequence of parathyroid hormone, has been shown to reduce the risk of vertebral and nonvertebral fractures, but it must be injected daily and it is expensive Estrogen receptor agonists can increase bone mineral density and reduce the risk of vertebral fractures They have not been shown to reduce the risk of nonvertebral fractures US guidelines for the treatment of osteoporosis have been published.1,2 The diagnosis of osteoporosis has traditionally been established by the occurrence of fragility fractures or by bone densitometry, which is generally reported in terms of standard deviations (SD) from mean values in young adults (T-score) The World Health Organization (WHO) has defined normal bone mineral density (BMD) for women as a value within one SD of the young adult mean Values 2.5 SD or more below the mean (T-score -2.5 or below) at the spine, femoral neck, or total hip are defined as osteoporosis The WHO has developed a computerized model (FRAX) that predicts the 10-year probability of a hip fracture or other major osteoporotic fracture based on clinical risk factors and BMD at the femoral neck.3 CALCIUM AND VITAMIN D Evidence for the efficacy of calcium and vitamin D supplements in preventing osteoporotic fractures is mixed, perhaps because most studies did not recruit patients with low dietary intakes of calcium and vitamin D.4 A meta-analysis of 16 placebo-controlled trials conducted mostly in women ≥65 years old, including the Women’s Health Initiative, found that a combination of vitamin D (300-1000 IU/day) and calcium (5001200 mg/day), but not vitamin D alone, decreased fracture risk by 12% in older adults The benefit was greatest in institutionalized patients, who often have a low calcium intake and may be def icient in vitamin D.5 A meta-analysis of 11 double-blind, randomized controlled trials of vitamin D supplementation, with or without calcium, in persons  ≥65 years old (91% women) found that women who took ≥800 IU of vitamin D daily (most of whom also took calcium) had a 30% lower risk of hip fractures and a 14% lower risk of other nonvertebral fractures.6 91 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 56 (1452) ® Table Calcium Content of Some Foods1 Table Some Calcium Supplements Food Serving size Calcium content (mg)* Provolone cheese Mozzarella cheese, part-skim Tofu, raw, firm Milk, skim Swiss cheese Collards, boiled Yogurt, fruit, lowfat Spinach, boiled Cheddar cheese, reduced fat Breakfast cereals, Cheerios2 Cottage cheese, creamed Kale, boiled Parmesan cheese, shredded Broccoli, raw Oatmeal, instant (regular) cup cup 0.5 cup cup slice cup oz cup slice cup oz cup tbsp cup packet 998 945 861 299 269 268 258 245 160 112 94 94 63 43 21 * Content per serving US Department of Agriculture USDA national nutrient database for standard reference, release 27 Available at http://www.ars.usda.gov/ba/ bhnrc/ndl Accessed September 18, 2014 Calcium content of cereal varies; Total Whole Grain cereal (General Mills) contains 1000 mg of calcium per ¾ cup serving A recent review found that postmenopausal women and older men taking vitamin D plus calcium had fewer hip fractures (1 less hip fracture per 1000 older adults per year in low-risk patients; less per 1000 per year in institutionalized patients) and other nonvertebral fractures.7 REQUIREMENTS — The Institute of Medicine (IOM) recommends a total daily elemental calcium intake of 1000 mg for all adults 19-50 years old, including pregnant and lactating women, 1000 mg for men 51-70 years old, and 1200 mg for women >50 years old and men >70 years old.8 The IOM recommends a daily vitamin D intake of 600 IU for men and women up to 70 years old and 800 IU for those >70 years old Intakes of 600 IU or higher of vitamin D are difficult to achieve by diet alone Many experts recommend a daily intake of 800-2000 IU of vitamin D and target serum levels of Table Vitamin D Content of Some Foods1 Food2 Serving size Vitamin D content (IU)* Salmon, sockeye, cooked Tuna, light, canned Sardines, canned Halibut, cooked (Atlantic and Pacific) Herring, pickled (Atlantic) Milk, whole (fortified) Milk, skim (fortified) Milk, soy (fortified) Egg, whole large oz cup cup oz 447 393 288 196 cup cup cup oz egg 158 124 115 105 41 * Content per serving US Department of Agriculture USDA national nutrient database for standard reference, release 27 Available at http://www.ars.usda.gov/ba/ bhnrc/ndl Accessed September 18, 2014 Breakfast cereals, margarine, and many other products are often fortified with vitamin D 92 September 29, 2014 Drug Calcium Carbonate Ca* (mg) D3* (IU) Tabs/d1 333 600 500 300 500 267 800 600 — 500 2 315 250 200 250 4-6 600 500 2 Calcimate Plus 1000 3 (GNC) Caltrate 600+D3 (Pfizer) Os-Cal Extra D3 (GSK) Tums Extra 750 (GSK) Viactiv (Viactiv Lifestyle)4 Calcium Citrate2 Citracal Maximum (Bayer) Calcium Complex (carbonate, lactate) Calcet Petites (Mission) Calcium Phosphate Posture-D (Inverness)5 * Elemental calcium and vitamin D content per tablet Needed to provide about 1000 mg elemental calcium daily Available generically Also contains about 167 mg of magnesium Content of milk chocolate and caramel flavors; also contains 40 mcg vitamin K Also contains 280 mg phosphorus and 50 mg magnesium 25-OH-D between 30 and 60 ng/mL for postmenopausal women Some patients may require 2000 IU of vitamin D daily to reach desirable serum levels Postmenopausal women being treated for osteoporosis with a bisphosphonate or another antiresorptive drug generally require supplementation with both calcium and vitamin D PRODUCTS — Calcium supplements are available in a variety of salts Calcium citrate does not require acid for absorption and can be taken with or without food It is preferred for patients taking a proton pump inhibitor (PPI) or an H2-receptor antagonist Calcium carbonate should be taken with food to enhance calcium absorption Vitamin D supplements are available in the form of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3), often in combination with calcium ADVERSE EFFECTS — Calcium supplements are generally well tolerated Constipation, intestinal bloating, and excess gas can occur A slightly higher risk of kidney stones has been reported.9 Some reports have suggested that calcium supplementation could increase the risk of myocardial infarction,10,11 but in the Women’s Health Initiative, among 36,282 postmenopausal women randomized to either calcium (1000 mg/day) plus vitamin D (400 IU/day) or to placebo, years of calcium plus vitamin D supplementation did not increase the incidence of coronary heart disease, myocardial infarction, or stroke; it did increase the risk of nephrolithiasis by 13%.12 Hypercalciuria and hypercalcemia are manifestations of vitamin D toxicity The Medical Letter ® Indications for Treatment1 ▶ A hip or spine fracture ▶ A T-score of -2.5 or below at the spine, femoral neck, or total hip ▶ A T-score between -1.0 and -2.5 and a 10-year FRAX risk of ≥3% for hip fracture or  ≥20% for humerus, forearm, hip, or clinical vertebral fracture NB Watts et al Endocr Pract 2010; suppl 3:1 BISPHOSPHONATES These nonhormonal agents decrease bone resorption by binding to active sites of bone remodeling and inhibiting osteoclasts Alendronate, risedronate, and zoledronic acid have been shown to reduce the risk of vertebral and nonvertebral fractures in postmenopausal women, while ibandronate has only been shown to lower the risk of vertebral fractures.1 In most clinical trials of these drugs, patients were also taking calcium and vitamin D supplements ALENDRONATE — Alendronate (Fosamax, and others) is an oral bisphosphonate approved by the FDA for daily or once-weekly use for prevention and treatment of osteoporosis in postmenopausal women Weekly dosing appears to be as effective as daily dosing in increasing BMD and may be better tolerated RISEDRONATE — The second oral bisphosphonate approved by the FDA for prevention and treatment of osteoporosis in postmenopausal women, risedronate (Actonel, Atelvia) can be administered daily, onceweekly, or once-monthly; all of these regimens appear to have equivalent effects on BMD IBANDRONATE — Oral ibandronate (Boniva, and generics) is approved by the FDA for both prevention and treatment of postmenopausal osteoporosis Monthly dosing of oral ibandronate appears to be at least as effective as daily dosing in increasing BMD Intravenous (IV) ibandronate given every three months is also approved for treatment of postmenopausal osteoporosis and appears to be more effective than the oral formulation in increasing BMD.13 Ibandronate has not been shown to decrease the risk of nonvertebral fractures ZOLEDRONIC ACID — Zoledronic acid (Reclast, and generics) is approved by the FDA for IV administration once-yearly to treat postmenopausal osteoporosis and once every two years to prevent it.14 Studies in postmenopausal women with osteoporosis indicate that a single annual 5-mg IV dose of zoledronic acid can reduce bone turnover, increase BMD, and reduce the risk of vertebral fractures for up to years In patients at high fracture risk, treatment for an Vol 56 (1452) September 29, 2014 additional years continued to decrease the incidence of vertebral fractures.15 Zoledronic acid has also been shown to reduce the incidence of hip fractures.16 ORAL ADMINISTRATION — Food, calcium supplements, antacids, and other medications containing polyvalent cations, such as iron, interfere with the absorption of bisphosphonates from the gastrointestinal (GI) tract To ensure adequate absorption and prevent esophageal injury, they must be taken after an overnight fast, while in an upright position, along with 6-8 ounces of plain (not mineral) water After taking the drug, the patient must take nothing by mouth except plain water for at least 30 minutes (60 minutes for ibandronate) and avoid lying down The entericcoated, delayed-release, once-weekly formulation of risedronate (Atelvia) can be taken immediately after breakfast with at least ounces of water, but the patient must still remain upright for at least 30 minutes ADVERSE EFFECTS — GI – Oral bisphosphonates can cause heartburn, esophageal irritation, esophagitis, abdominal pain, diarrhea, and other adverse GI effects Severe bone, joint, and muscle pain have occurred infrequently with bisphosphonates.17 Ocular inflammation has also been reported.18 Hypocalcemia can occur, typically in patients with vitamin D deficiency IV bisphosphonates have been associated with acute phase reactions (low-grade fevers, myalgias, and arthralgias) within 1-3 days of the infusion, most frequently after the first infusion; NSAIDs or acetaminophen can decrease these symptoms Acute phase reactions have also been reported with monthly formulations of oral bisphosphonates Osteonecrosis of the jaw has occurred rarely with chronic use of oral bisphosphonates.19 The incidence has been higher in cancer patients and in immunocompromised patients given IV bisphosphonates Renal failure and death have occurred in patients with decreased renal function (creatinine clearance 52,000 93 The Medical Letter Vol 56 (1452) ® September 29, 2014 Table Some Drugs for Postmenopausal Osteoporosis Some Available Formulations Drug Usual Dosage1 Cost2 Prevention: mg once/d or 35 mg once/wk Treatment: 10 mg once/d or 70 mg once/wk Treatment: 70 mg + 2800 IU D3 once/wk or 70 mg + 5600 IU D3 once/wk Treatment: 70 mg once/wk5 Prevention: 150 mg once/month Treatment: 150 mg once/month Prevention: mg once/d or 35 mg once/wk Treatment: mg once/d, 35 mg once/wk, 75 mg consecutive days/month, or 150 mg once/month Prevention: mg once/d or 35 mg once/wk Treatment: 35 mg once/wk $53.80 107.60 140.60 mg/3 mL prefilled syringe Treatment: mg IV once every months 477.709 mg/100 mL soln Prevention: mg IV once every years Treatment: mg IV once/yr 60 mg tabs Prevention: 60 mg PO once/d Treatment: 60 mg PO once/d 198.00 198.00 0.45 mg/20 mg tabs Prevention: 0.45 mg/20 mg PO once/d 111.40 Denosumab – Prolia (Amgen)12 60 mg/mL prefilled syringe Treatment: 60 mg SC once every months 881.6013 Calcitonin Miacalcin Injection (Novartis) 200 IU/mL vial Treatment: 100 IU SC or IM once/d or every other day 3692.70 600 mcg/2.4 mL prefilled pen Treatment: 20 mcg SC once/d 1545.00 Oral Bisphosphonates Alendronate3,4 – Fosamax (Merck) 70 mg tabs Binosto (Mission Pharma) Ibandronate6 – Boniva (Genentech) 70 mg/2800 IU D3, 70 mg/5600 IU D3 tabs 70 mg effervescent tabs 150 mg tabs Risedronate7 – Actonel (Actavis)8 5, 35, 150 mg tabs Fosamax Plus D delayed-release – Atelvia (Actavis) 35 mg delayed-release tabs 140.00 153.10 153.10 199.50 216.10 168.60 168.60 Intravenous (IV) Bisphosphonates Ibandronate6 – Boniva (Genentech) Zoledronic acid6,10 – Reclast (Novartis) 1083.8011 1083.8011 Selective Estrogen Receptor Modulator Raloxifene6 – Evista (Lilly) Conjugated Estrogens and Selective Estrogen Receptor Modulator Conjugated estrogens and bazedoxifene – Duavee (Pfizer) Anti-RANK Ligand Antibody 14 Parathyroid Hormone Teriparatide – Forteo (Lilly) 10 11 12 13 14 Dosage adjustment may be needed for renal or hepatic impairment Approximate wholesale acquisition cost (WAC) for 30 days' with the lowest dosage and frequency Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) September 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Alendronate is available generically in 5, 10, 35, 40, 70-mg tablets Alendronate is available in a 40-mg tablet for treatment of Paget's disease of bone Effervescent tablet should be dissolved in oz of water Also available in generic formulations Risedronate is only available generically in 150-mg tablets Actonel is also available in a 30-mg tablet for treatment of Paget's disease Cost of one mg/3 mL syringe Zoledronic acid is also available in a 4-mg formulation (Zometa) for treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors Cost of one mg/100 mL infusion bottle Denosumab is also available in a 120 mg/1.7 mL formulation (Xgeva) for prevention of skeletal-related events in patients with bone metastases from solid tumors Cost of one 60 mg/mL syringe Due to the limited evidence of efficacy and concerns about its safety, many experts no longer recommend use of salmon calcitonin women with at least years of bisphosphonate use, a subtrochanteric or femoral shaft fracture occurred during the subsequent year in 0.13% of women and within years in 0.22%.23 The risk may increase with longer treatment duration (8-9 years).24 DURATION OF TREATMENT — The optimal duration of treatment with bisphosphonates is unclear Among 1099 postmenopausal women who had received alendronate for years and were randomized to an additional years of alendronate or to placebo, those 94 who received the additional years of alendronate had a significantly lower risk of clinically recognized vertebral fractures (2.4% vs 5.3%), but not nonvertebral fractures.25 Because of the association with atypical femur fractures, some experts discontinue bisphosphonates temporarily after years of oral use or after years of IV administration in patients at low risk of fracture (stable bone density, femoral neck T-score ˃2.5, no history of hip or spine fracture).26 How long to wait before restarting the drugs is unclear The Medical Letter ® DENOSUMAB Denosumab (Prolia) has been approved by the FDA for treatment of postmenopausal osteoporosis in women at high risk of fracture.27 It is a fully human monoclonal antibody against RANK ligand that inhibits osteoclast formation and reduces bone resorption Injected subcutaneously every months, denosumab has been shown to increase BMD and reduce the incidence of new vertebral, hip, and other nonvertebral fractures in postmenopausal women.28 No studies are available directly comparing the efficacy of denosumab and bisphosphonates in preventing fractures Denosumab’s effects on BMD and bone turnover are reversible with discontinuation of the drug After a 24-month course, bone turnover increased within months after the drug was discontinued and BMD declined to pre-treatment values at years after treatment cessation.29 The optimal duration of treatment is unknown ADVERSE EFFECTS — Denosumab can cause hypocalcemia; it is not contraindicated for use in patients with impaired renal function, but special care may be required to optimize intake of calcium and vitamin D In clinical trials, rash, eczema, and dermatitis occurred more commonly with denosumab than with placebo Denosumab is a potent antiresorptive agent; osteonecrosis of the jaw and atypical femur fractures, which can occur with bisphosphonates, have also been reported with denosumab PARATHYROID HORMONE Unlike other drugs available for osteoporosis, which act by decreasing bone turnover, low-dose intermittent subcutaneous injection of parathyroid hormone (PTH) increases bone density by stimulating bone formation Teriparatide (Forteo), the 1-34 sequence of PTH, is approved by the FDA for treatment of osteoporosis for up to years (in the patient’s lifetime) in postmenopausal women at high risk for fractures Once-daily injections of teriparatide have been shown to increase BMD and decrease the incidence of vertebral and nonvertebral fractures by 50% or more, but the effect of the drug on hip fractures is unknown BMD decreases after the drug is stopped, but retreatment after a drug-free period has been shown to produce further small gains in BMD.30 Most experts recommend starting a bisphosphonate or another antiresorptive drug after stopping teriparatide Vol 56 (1452) September 29, 2014 Adverse Effects – Adverse effects of teriparatide have included nausea, headache, dizziness, and muscle cramps Hypotension and tachycardia may occur with the first few doses Hypercalcemia and hypercalciuria can occur; they can generally be corrected by decreasing calcium or vitamin D supplementation The FDA has included a boxed warning in the labeling regarding a risk of osteosarcoma, based on animal data, but a postmarketing surveillance study found that among 1448 cases of osteosarcoma identified in the US in a 7-year period, none were associated with prior use of teriparatide.31 ESTROGEN AGONISTS RALOXIFENE — Raloxifene (Evista, and generics) is a selective estrogen receptor modulator (SERM) with estrogen-like effects on bone and antiestrogen effects on the uterus and breast It can reduce the risk of invasive breast cancer Approved by the FDA for both prevention and treatment of postmenopausal osteoporosis, it has reduced the risk of vertebral fractures, but not nonvertebral fractures.32 Raloxifene would be a reasonable alternative for younger postmenopausal women at high risk for invasive breast cancer Adverse Effects – Hot flashes, leg cramps, and peripheral edema can occur with raloxifene Like estrogens, raloxifene increases the risk of venous thromboembolic events CONJUGATED ESTROGENS/BAZEDOXIFENE — A fixeddose combination (Duavee) of conjugated estrogens and the new selective estrogen receptor modulator (SERM) bazedoxifene is approved by the FDA for prevention of osteoporosis in postmenopausal women with an intact uterus Like raloxifene, bazedoxifene inhibits the stimulating effect of estrogen on the endometrium and breast, but the combination has not been shown to reduce the risk of breast cancer It has been shown to increase BMD in postmenopausal women, and bazedoxifene alone has been shown to decrease the risk of vertebral fractures.33 Adverse Effects – In short-term clinical trials of conjugated estrogens/bazedoxifene, the combination did not increase the incidence of breast cancer, endometrial cancer, ovarian cancer, venous thromboembolism, stroke, myocardial infarction, or death from any cause In the long term, this combination would be expected to increase the risk of deep vein thrombosis and thromboembolism 95 The Medical Letter ® CALCITONIN Salmon calcitonin, a peptide hormone given intranasally, subcutaneously, or intramuscularly, is approved by the FDA for treatment of osteoporosis in women >5 years after menopause It decreases bone resorption by inhibiting osteoclast function A 5-year trial in 1200 women with osteoporosis found new vertebral fractures in 51 of 287 (18%) receiving a 200-IU dose of calcitonin nasal spray once daily and in 70 of 270 (26%) receiving a placebo, a statistically significant difference.34 Adverse Effects – Serious allergic reactions, including anaphylaxis, have occurred An increased risk of malignancy has been reported with use of calcitonin nasal spray.35 Given the limited evidence of efficacy, the FDA's warning about its safety, and the availability of many other options, many experts no longer recommend calcitonin It has been removed from the market in Canada and in Europe ■ NB Watts et al American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis Endocr Pract 2010; suppl 3:1 National Osteoporosis Foundation Clinician's guide to prevention and treatment of osteoporosis; 2014 issue, version Available at: http://nof.org/hcp/clinicians-guide Accessed September 18, 2014 FRAX WHO Fracture Risk Assessment Tool Available at www shef.ac.uk/FRAX/tool Accessed September 18, 2014 DC Bauer Calcium supplements and fracture prevention N Engl J Med 2013; 369:1537 M Chung et al Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated metaanalysis for the U.S Preventive Services Task Force Ann Intern Med 2011; 155:827 HA Bischoff-Ferrari et al A pooled analysis of vitamin D dose requirements for fracture prevention N Engl J Med 2012; 367:40 A Avenell et al Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men Cochrane Database Syst Rev 2014 April 14; 4:CD000227 Institute of Medicine of the National Academies Dietary reference intakes for calcium and vitamin D Available at http:// www.iom.edu/Reports/2010/Dietary-Reference-Intakes-forCalcium-and-Vitamin-D.aspx Accessed September 18, 2014 RB Wallace et al Urinary tract stone occurrence in the Women’s Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements Am J Clin Nutr 2011; 94:270 10 K Li et al Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg) Heart 2012; 98:920 11 IR Reid Cardiovascular effects of calcium supplements Nutrients 2013; 5:2522 12 RL Prentice et al Health risks and benefits from calcium and vitamin D supplementation: Women’s Health Initiative clinical trial and cohort study Osteoporosis Int 2013; 24:567 96 Vol 56 (1452) September 29, 2014 13 JA Eisman et al Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study J Rheumatol 2008; 35:488 14 A once-yearly IV bisphosphonate for osteoporosis Med Lett Drugs Ther 2007; 49:89 15 DM Black et al The effect of versus years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT) J Bone Min Res 2012; 27:243 16 DM Black et al Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis N Engl J Med 2007; 356:1809 17 DK Wysowski and JT Chang Alendronate and risedronate: reports of severe bone, joint, and muscle pain Arch Intern Med 2005; 165:346 18 M Pazianas et al Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database J Bone Miner Res 2013; 28:455 19 S Fedele et al Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series Am J Med 2010; 123:1060 20 FDA drug safety communication: new contraindication and updated warning on kidney impairment for Reclast (zoledronic acid) Available at www.fda.gov/Drugs/DrugSafety/ ucm270199.htm Accessed September 18, 2014 21 Y Vinogradova et al Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data BMJ 2013; 346:f114 22 J Schilcher et al Bisphosphonate use and atypical fractures of the femoral shaft N Engl J Med 2011; 364:1728 23 LY Park-Wyllie et al Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women JAMA 2011; 305:783 24 RM Dell et al Incidence of atypical nontraumatic diaphyseal fractures of the femur J Bone Miner Res 2012; 27:2544 25 DM Black et al Effects of continuing or stopping alendronate after years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial JAMA 2006; 296:2927 26 J Compston et al Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013; Maturitas 2013; 75:392 27 Denosumab (Prolia) for postmenopausal osteoporosis Med Lett Drugs Ther 2010; 52:81 28 SR Cummings et al Denosumab for prevention of fractures in postmenopausal women with osteoporosis N Engl J Med 2009; 361:756 29 HG Bone et al Effects of denosumab treatment and discontinuation on bone mineral density and bone tumor markers in postmenopausal women with low bone mass J Clin Endocrinol Metab 2011; 96:972 30 JS Finkelstein et al Effects of teriparatide retreatment in osteoporotic men and women J Clin Endocrinol Metab 2009; 94:2495 31 EB Andrews et al The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first years Bone Miner Res 2012; 27:2429 32 KE Ensrud et al Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial J Bone Miner Res 2008; 23:112 33 Conjugated estrogens/bazedoxifene (Duavee) for menopausal symptoms and prevention of osteoporosis Med Lett Drugs Ther 2014; 56:33 34 JA Knopp-Sihota et al Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systematic review and meta-analysis Osteoporos Int 2012; 23:17 35 In brief: cancer risk with salmon calcitonin Med Lett Drugs Ther 2013; 55:29 The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 78 question test enables you to earn 13 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or office Comprehensive tests are offered every January and July enabling you to earn up to 26 credits per year Starting with our January 2015 comprehensive exam, there will be 130 questions, enabling you to earn 26 credits upon successful completion of the test 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Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1452 Questions (Correspond to questions #61-70 in Comprehensive Exam #71, available January 2015) Osteoporosis is defined as bone mineral density: a 2.5 or more standard deviations below the mean value at the spine, femoral neck, or total hip in young adults b standard deviation below the mean value at the spine, femoral neck, or total hip in young adults c standard deviation below the mean value at the spine, femoral neck, or total hip in adults of the same age d lower than the mean value in adults of the same age A 60-year-old woman with postmenopausal osteoporosis who does not want to take oral bisphosphonates asks about the effectiveness of the once-yearly IV injection of zoledronic acid You could tell her that it has been shown to: a increase bone mineral density b decrease the risk of vertebral fractures for up to years c reduce bone turnover d all of the above A 55-year-old woman being treated with a bisphosphonate for postmenopausal osteoporosis asks if she should also take a supplement that contains calcium and vitamin D You should tell her that: a supplements are only recommended for women >65 years old b women being treated with a bisphosphonate usually will need to take a supplement c she does not need to take a supplement d supplements are not recommended for women who are also taking a bisphosphonate Denosumab: a stimulates bone formation b can be taken orally c remains effective for up to years after treatment is stopped d none of the above Which of the following bisphosphonates has not been shown to decrease the risk of nonvertebral fractures? a alendronate b risedronate c ibandronate d zoledronic acid Pharmacologic treatment for postmenopausal osteoporosis should be considered for women with: a a hip or spine fracture b a T-score of -2.5 or below at the spine, femoral neck, or total hip c a T-score between -1.0 and -2.5 and a 10-year FRAX risk of >3% for hip fracture or >20% for humerus, forearm, hip, or clinical vertebral fracture d all of the above Which of the following drugs increases bone mineral density by stimulating bone formation? a teriparatide b alendronate c raloxifene d ibandronate Osteonecrosis of the jaw has been reported with: a raloxifene b calcitonin c denosumab d all of the above 10 Raloxifene: a has been shown to decrease the risk of nonvertebral fractures b has estrogen-like effects on bone and antiestrogen effects on the uterus and breast c should be taken once every months for treatment of postmenopausal osteoporosis d has been associated with an increased incidence of esophageal cancer Oral bisphosphonates should be taken: a on a full stomach b with 6-8 ounces of plain water c for at least 10 years d all of the above ACPE UPN: Per Issue Exam: 0379-0000-14-452-H01-P; Release: September 29, 2014, Expire: September 29, 2015 Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016 EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission Subscription Services Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2014 ISSN 1523-2859 Subscriptions (US): year - $98; 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