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preventing and treating osteoporosis ReviewsReviews

Benefits and risks of preventing and treating osteoporosisAmerican Pharmacists Association

advisory board: peter Koval, pharmd, BCps, Cpp, Clinical associate professor, eshelman school of pharmacy, University of north Carolina, Chapel Hill. Mary Beth o’Connell, pharmd, BCps, FasHp, FCCp, associate professor of pharmacy practice, eugene applebaum College of pharmacy and Health sciences, Wayne state Univer-sity, detroit, Mi.

development: this home-study continuing pharmacy education (Cpe) activity was de-veloped by the american pharmacists as-sociation.

Funding: this activity is supported by an ed-ucational donation provided by amgen.

this article is based on the education ses-sion Breaking News on Breaking Bones: Helping Patients Understand the Risks and Benefits of Preventing and Treating Osteo-porosis, presented by peter Koval, pharmd, BCps, Cpp, and Mary Beth o’Connell, phar-md, BCps, FasHp, FCCp, at apha2012, the american pharmacists association annual Meeting & exposition, on March 10, 2012, in new orleans, La.

this publication was prepared by Cynthia Knapp dlugosz, Bspharm, CKd associates, LLC, on behalf of the american pharmacists association.

Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a conse-quent increase in bone fragility and susceptibility to fracture.1 It is considered

a major public health threat for an estimated 44 million Americans or 55% of adults 50 years or older.2 Approximately 10 million Americans have osteoporosis, with women accounting for most (80%) of those cases.2 An additional 34 million Ameri-cans have low bone density (osteopenia), which increases their risk for developing osteoporosis.2 According to the National Osteoporosis Foundation (NOF), up to one in two women and one in four men older than 50 years will have an osteoporosis-related fracture in their remaining lifetime.2

Although the prevalence of osteoporosis is greatest among white and Asian women (20%), considerable risk has been reported in people of all ethnic back-grounds.2 Approximately 5% of black women and 10% of Hispanic women have os-teoporosis.2 Risk currently is increasing most rapidly among Hispanic women.2

The number of fractures caused by osteoporosis is predicted to increase from more than 2 million in 2005 (the most recent year for which data are available) to more than 3 million by 2025.2 These fractures exert a considerable toll on patient quality of life. For example, 20% of patients who were ambulatory before a hip frac-ture required long-term care afterward and only 15% could walk across a room un-aided 6 months later.2 Approximately 24% of patients 50 years or older die during the year following a hip fracture; the 1-year morality rate is nearly twice as high for men as it is for women.2

Appropriate testing and treatment of women and men at risk of osteoporosis-re-lated fractures can improve clinical outcomes and patient quality of life.3,4 This article emphasizes the most recent (previous 2 years) developments related to the evalua-tion, prevention, and treatment of osteoporosis, with special attention to emerging safety information. Readers are referred to the July 2011 Highlights Newsletter titled New and Emerging Treatments for Osteoporosis (available at www.pharmacist.com/education) for more detailed information about osteoporosis medications.

Learning objectivesAt the conclusion of this knowledge-based activity, the pharmacist will be able to:

■ Explain the current understanding of the bone remodeling process and the pathophysiology of osteoporosis, including the role of RANKL (recep-tor activator of nuclear factor kappa B ligand).

■ Name current recommended dietary allowances for calcium and vitamin D in adult women and men.

■ Discuss the role of the FRAX (Fracture Risk Assessment) tool in assessing pa-tients at risk for osteoporosis and guid-ing treatment decisions.

■ Identify recommended first-line phar-macologic therapies for osteoporosis, based on current clinical guidelines.

■ Summarize recent developments re-garding the safety of osteoporosis medications.

Accreditation InformationProvider: American Pharmacists AssociationTarget audience: PharmacistsRelease date: July 15, 2012Expiration date: March 10, 2015

Learning level: 2ACPE number: 0202-0000-12-153-H01-PCPE credit hours: 2 hours (0.2 CEUs)

Fee: There is no fee associated with this activity.The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned to this activity by the accredited provider is 0202-0000-12-153-H01-P.

Disclosure: Dr. O’Connell serves on the speaker’s bureau for Amgen. Dr. Koval, Ms. Knapp Dlugosz and APhA’s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria.If you participated in the live offering of this activity with the same ACPE number held on March 10, 2012, at APhA2012, the American Pharmacists Association Annual Meeting & Exposition, you are not eligible to receive credit for this activity.

www.pharmacytoday.org74 Pharmacy Today • july 2012

Reviews preventing and treating osteoporosis

Preassessment questions1. A 75-year-old woman wants to know if she should take a

vitamin D supplement. She has read about the benefits of vitamin D in magazines, but she doesn’t have a lot of money and doesn’t like to take unnecessary medications or supplements. How do you respond?a. A supplement is not necessary; she can get all of the vitamin D

she needs from her diet.b. No decisions about vitamin D supplements should be

made until her serum 25-hydroxyvitamin D concentration is measured.

c. A vitamin D supplement is likely to be helpful, but she should take it only during the winter months.

d. She should begin taking 800 IU of vitamin D daily and talk with her primary care provider about having her serum 25-hydroxyvitamin D concentration measured.

2. Based on the 2010 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis, which medication is not recommended as a first-line agent for osteoporosis treatment?a. Alendronateb. Denosumabc. Raloxifened. Zoledronic acid

3. You identify a woman who hasn’t refilled her alendronate prescription for the previous 3 months. She tells you that she is concerned about getting osteonecrosis of the jaw (ONJ). How do you respond?a. She should not worry; orally administered osteoporosis

medications carry no risk of ONJ.b. She should not worry; ONJ is a concern only in patients being

treated with high doses of antiresorptive agents for cancer treatment–induced bone loss.

c. Although some patients have developed ONJ, the risk is very small, especially compared with the risk of developing an osteoporosis-related fracture.

d. Her concern is justified. You will contact the prescriber to recommend switching to zoledronic acid.

proteinases (e.g., cathepsin K, tartrate-resistant acid phospha-tase, collagenase) that digest the protein matrix and hydrogen ions that dissolve the mineralized component. The net result is small cavities in the surface of the bone.

When the resorption cavity is large enough—generally within 2 to 4 weeks—a reversal phase commences to switch bone resorption to bone formation. Osteoclasts release ad-ditional cytokines and growth factors, some of which work through Wnt/β-catenin signaling pathways. Osteoclasts also produce ephrinB2, which binds with ephB4 receptors on os-teoblast precursor cells and mature osteoblasts. These various proteins secreted by osteoclasts stimulate differentiation of mesenchymal stem cells into osteoblasts and regulate osteo-blast maturation and activity. Binding of ephrinB2 to ephB4 on mature osteoblasts stimulates the production of osteoprote-gerin, a soluble, nonsignaling “decoy receptor” for RANKL. By blocking the RANKL–RANK interaction, osteoprotegerin sup-presses osteoclast formation, induces osteoclast apoptosis, and stops bone resorption.

Osteoblasts are responsible for producing the bone matrix constituents needed for bone formation. First, osteoblasts fill the resorption cavity with osteoid by rapidly depositing colla-gen and proteoglycans. The matrix then is mineralized with cal-cium (predominantly), magnesium, and phosphate. When bone formation is complete (usually within 4–6 months), the mature osteoblasts undergo apoptosis or become bone-lining cells or osteocytes.

Osteoporosis pathophysiologyWith the onset of menopause in women and advancing age in both sexes, the overall rate of bone remodeling increases and the balance shifts such that bone resorption outpaces bone formation.3 This altered balance results in net bone loss.3 In addition to decreasing bone density, the loss of bone tissue compromises the structural integrity of bone and weakens the skeletal architecture.3

Before menopause, estrogen helps to maintain a normal bone resorption rate in women through a number of mecha-nisms that include5:

■ Suppressing the proliferation, differentiation, and activa-tion of osteoclasts.

■ Inhibiting cytokines that stimulate osteoclasts. ■ Decreasing production of RANKL and increasing produc-

tion of osteoprotegerin.Loss of estrogen and other hormonal changes occurring

throughout menopause and during the early postmenopausal years bring an increase in the number of new osteoclasts, pro-longed survival of mature osteoclasts, more RANKL, and less osteoprotegerin. The net result is a mean rate of bone loss of approximately 1% per year.4 Trabecular bone, which is found mostly in the vertebrae and ends of long bones, is most likely to be affected by these changes, making postmenopausal women especially susceptible to fractures of the spine and wrist.5

Age-related bone loss begins in the sixth decade of life sub-sequent to deficiencies in hormones, calcium, and vitamin D.3–5 Both cortical bone (which makes up approximately 80% of the

Bone physiology reviewA healthy adult skeleton is maintained through a dynamic pro-cess by which old bone is removed (resorption) and replaced by new bone (formation).3,5,6 Bone remodeling begins when various triggers (e.g., physical stress, microfractures, biofeed-back systems, potentially certain diseases and medications) prompt bone-lining cells (protective cells on the bone surface) and osteocytes (located inside bone) to release signals in the form of cytokines, growth factors, interleukins, and hormones. These signals travel to osteoblast precursor cells (bone-form-ing cells) and stimulate the release of receptor activator of nuclear factor kappa B ligand (RANKL). RANKL binds to its receptor RANK on the surface of osteoclasts and osteoclast precursor cells; the RANKL–RANK interaction initiates the formation, activity, and survival of mature osteoclasts (bone-resorbing cells). The mature osteoclasts migrate and attach to the bone surface, where they form a tight seal with the help of integrins. After the seal is formed, the osteoclasts secrete


preventing and treating osteoporosis Reviews

skeleton) and trabecular bone are affected.5,7 Hip fractures are especially common among older adults; most result from a fall from standing height or less.3,5 Fall prevention strategies are an important component of comprehensive osteoporosis care.3,8

A number of medications, medical conditions, and other factors cause or contribute to osteoporosis and the risk of frac-ture.3,5 Glucocorticoid therapy is the most common secondary cause of osteoporosis.5,9

Determining calcium and vitamin D needsTheresa, a 75-year-old white woman with osteoporosis, asks whether she should be taking any calcium or vitamin D supple-ments. She has read about possible benefits of these supple-ments in magazines; however, she doesn’t have a lot of money and doesn’t like to take unnecessary medications. Accord-ing to your calculations, she consumes 750 mg calcium daily from dietary sources. Theresa had her vitamin D level (serum 25-hydroxyvitamin D) tested recently, and the results were in the normal range (>30 ng/mL). Which of the following options would you recommend?a. Calcium carbonate 600 mg daily and vitamin D 800 units

dailyb. Calcium citrate 1,500 mg, vitamin D 400 units, and a multi-

vitamin dailyc. Calcium carbonate 1,250 mg with vitamin D 400 units tab-

let twice dailyd. Add 6 oz yogurt (20% daily value of calcium) and a glass of

fortified orange juice (35% daily value of calcium) to diet each day and take vitamin D 800 units daily.Almost all of the calcium in the human body (>99%) is lo-

cated in the bones and teeth.7,10 Bone tissue serves as a res-ervoir for and source of calcium for other metabolic needs (e.g., vascular contraction and vasodilatation, muscle function, nerve transmission, intracellular signaling, hormonal secre-tion).7,11

Calcium homeostasis is maintained in large part by vita-min D and parathyroid hormone.5,7 If the serum calcium con-centration decreases even slightly below the narrow normal range, parathyroid hormone is secreted to stimulate the con-

version of vitamin D to its final active hormonal form, 1α,25-dihydroxyvitamin D (calcitriol), in the kidney. In turn, calcitriol acts on the intestine, bone, and kidney to elevate serum cal-cium levels. Specifically, calcitriol increases the absorption of calcium and phosphate from the small intestine, induces the formation and activation of osteoclasts, and stimulates calci-um reabsorption by the kidney.

When a person has an inadequate calcium intake or when calcium absorption is reduced subsequent to vitamin D insuf-ficiency or deficiency, secretion of parathyroid hormone in-creases in an attempt to compensate for low serum calcium levels.4,7 This secondary form of hyperparathyroidism results in increased bone resorption and suppression of bone formation.7

Because of the close interrelationship between calcium and vitamin D, the Institute of Medicine issued updated dietary reference intakes for both nutrients in November 2010.7 The new recommendations, which reflected data from nearly 1,000 published studies and testimony from scientists and stakehold-ers, focus on the amount of calcium and vitamin D needed to maintain bone health and lessen the degree of bone loss in older adults.

Current recommended dietary allowances (RDAs) and up-per intake levels for men and women 19 years or older are sum-marized in Table 1.7 The RDAs represent total daily intake from all sources: dietary sources plus supplements. The RDAs for vi-tamin D also incorporate contributions from sun exposure and cover the needs of adults who get little sun.

Note that the RDA for calcium is higher for women 51 to 70 years of age than it is for men in that age group. This recom-mendation takes into consideration the rapid and notable bone loss during early menopause, as well as decreased calcium ab-sorption and increased calcium excretion pursuant to the loss of estrogen.5,7 The RDA for calcium is the same for women and men older than 70 years because of the similar effects of aging on bone loss.7

Note also that the RDA for vitamin D is higher for adults older than 70 years than it is for younger adults. This recom-mendation reflects the many physiologic changes that affect the vitamin D status of aging adults; it especially seeks to en-sure that the needs of the most frail men and women are met.7 NOF continues to recommend a higher daily vitamin D intake of

Table 1. Dietary reference intakes for calcium and vitamin D in adults Calcium (mg/day) Vitamin D (IU/day)

Age (years) RDA (mg/day UL (mg/day RDA (IU/day) UL (IU/day)Men

19–50 1,000 2,500 600 4,00051–70 1,000 2,000 600 4,000>70 1,200 2,000 800 4,000

Women 19–50 1,000 2,500 600 4,00051–70 1,200 2,000 600 4,000>70 1,200 2,000 800 4,000

Abbreviations used: RDA, recommended dietary allowance; UL, upper intake level. Reprinted with permission from the National Academies Press, Copyright 2010, National Academy of Sciences.



800 to 1,000 IU for all adults 50 years or older.12

The upper intake levels for calcium and vitamin D shown in Table 1 are the maximum safe daily intakes, not the amounts people need or should strive to achieve.7 Widespread fortifica-tion of food and rising rates of supplement use have increased the possibility of consuming excessive amounts of calcium and vitamin D. Excess calcium intake increases the risk of kidney stones; excess vitamin D intake can damage cardiac and renal tissue.7 Evidence that calcium supplement use is associated with a modest but significant increased risk of cardiovascular events, especially myocardial infarction, also is accumulat-ing.13–16

In light of these risks, there is general consensus that food is the best source of calcium, with supplements indi-cated only when adequate dietary intake of calcium cannot be achieved.3,4,7,17,18 A simple method for estimating the calcium content of a patient’s diet is depicted in Table 2. The amount of calcium in fortified foods (e.g., cereals, breakfast bars) and beverages (e.g., juices, soy milk) can be determined easily from the nutrition facts label; the “percent daily value” is based on 1,000 mg calcium per day; therefore, adding a zero to the end of the stated percentage yields milligrams of calcium per serv-ing.18 For example, one serving of fortified orange juice that provides 35% of the daily value of calcium contains 350 mg calcium. A number of online calcium calculators also are avail-able; these calculators include information for a wider variety of food items and may provide a more precise estimate of cal-cium intake.

On average, adults 50 years or older consume approxi-mately 600 to 700 mg calcium per day (i.e., about one-half the RDA).4,7 The first-line approach to increasing calcium intake is to look for ways to boost dietary calcium.7 If this approach still falls short of the recommended intake, the supplement dosage would be determined by subtracting total daily dietary calcium intake from the RDA.18

Most calcium dietary supplements are available as calcium carbonate or calcium citrate.7,10 Because calcium carbonate requires gastric acid for absorption, it is absorbed most effi-ciently when taken with food (immediately after meals or with a glass of acidic juice).7,11 Calcium citrate is less dependent on gastric acid and thus may be taken on an empty stomach.7,11 Calcium citrate is useful for patients with achlorhydria, inflam-matory bowel disease, or absorption disorders and for patients who use histamine H2-receptor antagonists or proton pump in-hibitors.7,11

The RDAs for calcium are based on elemental calcium, not the calcium salt.10 Calcium carbonate generally provides 40% elemental calcium, while calcium citrate provides 21% elemental calcium.7,11 In practical terms, fewer tablets of cal-cium carbonate typically are needed to achieve a given dose of elemental calcium, so the overall cost of therapy may be low-er.4,7 (The amount of elemental calcium provided by a product is stated on its supplement facts panel.11)

Few naturally occurring food sources of vitamin D exist.7,19 Most of the vitamin D in the American diet comes from forti-fied foods. For example, milk typically is fortified with 100 IU

vitamin D per 8 oz.19 However, average vitamin D intake from food alone is less than 300 IU for both men and women.19 Most adults need supplementary vitamin D to meet the cur-rent RDAs, especially during the winter months in northern latitudes.4,7 Supplementary vitamin D may be consumed as a single-ingredient supplement, as a component of a calcium supplement, or as a component of a multivitamin (or a com-bination of these sources). Adults with vitamin D insufficiency (i.e., serum 25-hydroxyvitamin D 21–29 ng/mL) may require at least 1,500 to 2,000 IU/day supplemental vitamin D to raise the blood concentration above 30 ng/mL; adults with vitamin D deficiency (i.e., serum 25-hydroxyvitamin D 20 ng/mL) require much larger doses (50,000 IU once a week or 6,000 IU daily for 8 weeks).20

As a 75-year-old woman, Theresa should be consuming 1,200 mg calcium and 800 IU vitamin D per day. As shown in Table 2, she currently consumes 750 mg calcium daily from dietary sources. The ideal strategy for Theresa to meet the rec-ommended RDAs would be to add 6 oz yogurt (20% daily value calcium, equal to 200 mg) and a glass of fortified orange juice (35% daily value calcium, equal to 350 mg) to her daily diet and take a daily vitamin D supplement containing 800 units daily. Although Theresa likely is getting some vitamin D from fortified foods, a supplement containing 800 IU would ensure that her needs are met while still falling well within the margin of safety (i.e., well below the 4,000 IU Upper intake level).

Pharmacists should be aware that calcium product la-

Table 2. Estimating daily dietary calcium intakeStep 1: Estimate calcium intake from calcium-rich foodsa

Product No. servings per day

Estimated calcium con-tent per serv-ing (mg)

Total calcium (mg)

Milk (8 oz) 300Yogurt (6 oz) 1 300 300Cheese (1 oz or 1 cubic in)

1 200 200

Fortified food and juices

80–1,000b

Step 2: Add 250 mg calcium to account for nondairy sources

250

Step 3: Determine total dietary calcium

750

aApproximately 75% to 80% of the calcium consumed in American diets is from dairy products. bCalcium content of fortified foods varies. Reprinted with permission from The Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010, p. 17, Table 6. National Osteoporosis Foundation, Washington, DC 20037. All rights reserved.



bels can be confusing for patients. Many patients assume that 1,250 mg calcium carbonate is the same as 1,250 mg calcium, though that amount of calcium carbonate actually contains 500 mg calcium. (Similarly, 1,500 mg calcium citrate contains 315 mg calcium.) Further, the serving size (dose) for calcium ci-trate generally is two tablets, not one tablet.

screening for osteoporosisGloria is a 63-year-old white woman who visits her primary care provider for her annual checkup. She has been postmeno-pausal for 8 years. She denies ever having “hot flushes.” She denies any personal history of fracture but reports that her mother had a hip fracture. She drinks alcohol socially (1–4 drinks per week), has never smoked, and has four healthy chil-dren. She exercises regularly and eats a well-balanced diet.

Gloria’s friend has just had a bone mineral density test, and she asks whether she should have one. Gloria is 5 ft, 9 in, weighs 133 lb, and has a body mass index (BMI) of 19.6 kg/m2.

Because osteoporosis is a symptomless condition, many at-risk women and men are not diagnosed in time to receive ef-fective therapy.3 Osteoporosis screening is an important strat-egy for detecting people with low bone mineral density and de-creasing the risk for subsequent fractures and fracture-related morbidity and mortality.21 Current NOF guidelines call for all postmenopausal women and men 50 years or older to be evalu-ated clinically for osteoporosis risk, in order to determine the need for bone mineral density testing.3

Bone mineral density measurement technologies encom-pass central and peripheral dual-energy x-ray absorptiometry (DXA), central and peripheral quantitative computed tomogra-phy, and quantitative ultrasound densitometry.3,21 Only central DXA of the hip and spine is used to establish a diagnosis of osteoporosis and guide treatment decisions.3,21 Central DXA devices typically measure bone density in the femoral neck and lumbar spine; the forearm is used when the hip and spine can-not be measured. Results are reported as the patient’s actual measured bone density value (g/cm2) and the patient’s value

in relation to two norms3,5: (1) mean bone mineral density of “young normal” adults of the same sex (T-score) and (2) ex-pected bone mineral density for the patient’s age and sex (Z-score).

For both the T-score and Z-score, the difference between the patient’s value and the norm is expressed as the number of SDs above or below the mean. Current World Health Orga-nization (WHO) diagnostic classifications for osteoporosis are based on the T-score, as shown in Table 3.3

Central DXA testing is relatively expensive, typically re-quires a prescription or referral from a health care provider, and exposes patients to a minimal amount of radiation.21,22 Consequently, universal bone mineral density testing is not considered practical or cost effective.4 Most current guidelines support testing in women 65 years or older and in younger postmenopausal women who have risk factors for osteoporo-sis.3,4,21 NOF also recommends testing all men 70 years or older and men 50 to 69 years who have risk factors for osteoporosis.3

The Fracture Risk Assessment (FRAX) tool, which was de-veloped by WHO, is gaining increasing popularity as a way to identify women and men 50 years or older who are most likely to benefit from bone mineral density testing and to guide treat-ment decisions in patients with low bone density or osteope-nia.4,21–23 It relies on readily available clinical information such as age, BMI, parental fracture history, and tobacco and alcohol use to estimate a person’s 10-year probability of both hip frac-ture and major osteoporotic fracture (defined as clinical ver-tebral, hip, forearm, or proximal humerus fracture). Although the FRAX tool includes questions about previous DXA results (bone mineral density at the femoral neck) and is considered most effective when it incorporates bone mineral density infor-mation, it does not require that information to estimate frac-ture risk.4,21

Online FRAX calculation tools are available at www.shef.ac.uk/FRAX. It is important to select the correct region and country (North America; United States) and to use the ver-sion appropriate for the patient’s race (white, black, Hispanic, Asian).23 Guidance on how to respond to each risk factor ques-tion is provided on the webpage.

The recently updated U.S. Preventive Services Task Force (USPSTF) recommendations on screening for osteoporosis support bone mineral density testing in women 50 to 64 years of age who have a fracture risk equal to or greater than that of a 65-year-old white woman who has no additional risk factors.21

Table 3. World Health Organization diagnostic classifications based on bone mineral density testinga

Classification Definition T-scoreNorma BMD within 1 SD of

a “young normal” adult

−1.0

Low bone mass (osteopenia)

BMD between 1.0 and 2.5 SD below that of a “young normal” adult

Between −1.0 and −2.5

Osteoporosis BMD 2.5 SD or more below that of a “young normal” adult

−2.5

Abbreviation used: BMD, bone mineral density. aThese classifications apply only to postmenopausal women and men 50 years of age. Source: References 3 and 4.

Table 4. Probability of major fracture before and after risk reclassification analysisFracture probability Without BMD

No. patients (%)With BMD No. patients (%)

Low risk (<10%) 22,599 (57.1) 23,137 (58.4)Moderate risk (10%–19%)

11,630 (29.4) 12,246 (30.9)

High risk (≥20%) 5,374 (13.6) 4,220 (10.7)Abbreviation used: BMD, bone mineral density. Source: Reference 24.



This corresponds to a FRAX score for 10-year probability of major osteoporotic fracture of 9.3% or greater.21

When Gloria’s information is entered into the appropri-ate FRAX questionnaire, her 10-year probability of a major osteoporotic fracture is estimated to be 17% and her 10-year probability of a hip fracture is estimated to be 2.4%. Gloria would be a candidate for bone mineral density testing based on current USPSTF screening recommendations. However, the USPSTF recommendations urge clinicians to consider each pa-tient’s values and preferences and use clinical judgment when discussing the possibility of bone mineral density testing in women 50 to 64 years of age.

initiating treatment for osteoporosisGloria undergoes central DXA testing, with the following re-sults: femoral neck left hip T-score = −2.1, lumbar spine T-score = −2.4. Her current medications are hydrochlorothiazide 12.5 mg once daily; a chewable calcium supplement daily with dinner, containing elemental calcium 500 mg plus vitamin D 500 IU; and a daily multivitamin that includes 220 mg calcium and 500 IU vitamin D. Is Gloria a candidate for treatment with an osteoporosis medication?

Current guidelines from NOF and the American Associa-tion of Clinical Endocrinologists (AACE) recommend consider-ing pharmacologic treatment of osteoporosis when any of the following are present in men or postmenopausal women 50 years or older3,4:

■ A hip or vertebral (clinical or morphometric) fracture

■ A T-score of −2.5 or lower at the femoral neck or spine, after appropriate evaluation to exclude secondary causes

■ A T-score between −1.0 and −2.5 at the femoral neck or spine in association with a FRAX 10-year probability of hip fracture of 3% or greater or 10-year probability of ma-jor osteoporosis-related fracture of 20% or greaterNeither of Gloria’s T-scores is −2.5 or lower, so it is neces-

sary to consider her FRAX scores as well. Note that Gloria’s FRAX scores need to be recalculated at this point to include the bone mineral density information. (Newer central DXA scanners incorporate the FRAX algorithm and report FRAX scores along with other results.3) When the femoral neck left hip T-score of −2.1 is added to the questionnaire, Gloria’s 10-year probability of major osteoporotic fracture is estimated at 18% and her 10-year probability of hip fracture is estimated at 1.6%.

Gloria does not have a 10-year probability of hip fracture of 3% or greater or a 10-year probability of major osteoporosis-related fracture of 20% or greater. Thus, treatment with osteo-porosis medication is not indicated at this time.

FRAX scores alone, without consideration of bone mineral density information, eventually may be sufficient for clinical decision making in many women and men categorized as low (<10%) or high (≥20%) fracture risk. Leslie et al.24 performed a risk reclassification analysis on a historical cohort of 36,730 women and 2,873 men 50 years or older in the Manitoba (Can-ada) Bone Density Program database, in order to determine how accurately FRAX scores without bone mineral density in-formation would identify individuals who would be designated

Table 5. Pharmacologic therapies for osteoporosisIndication and dosage

Postmenopausal osteoporosis

Drug (brand name) Drug class Route Prevention Treatment MenAntiresorption agents Alendronate (Fosamax)

Bisphosphonate Oral 5 mg daily, 35 mg weekly

10 mg daily, 70 mg weekly 10 mg daily, 70 mg weekly

Calcitonin (Fortical, Mia-calcin)

Synthetic polypeptide hormone

Intranasal, SC NAa 200 IU daily (intranasal), 100 IU every other day (SC)

NA

Denosumab (Prolia) RANKL inhibitor SC NAa 60 mg every 6 months NAIbandronate (Boniva) Bisphosphonate Oral, IV 2.5 mg daily,

150 mg monthly 2.5 mg daily (PO), 150 mg monthly (PO), 3 mg every 3 months (IV)

NA

Raloxifene (Evista) Estrogen agonist/antagonist

Oral 60 mg daily 60 mg daily NA

Risedronate (Actonel, Atelvia)

Bisphosphonate Oral 5 mg daily, 35 mg weekly, 150 mg monthly

5 mg daily, 35 mg weekly, 150 mg monthly

35 mg weekly, 150 mg monthly

Zoledronic acid (Reclast)

Bisphosphonate IV 5 mg every 2 years 5 mg yearly 5 mg yearly

Formation agents Teriparatide (Forteo)

Recombinant human parathyroid hormone

SC NAa 20 µg daily 20 µg daily

Abbreviation used: IV, intravenous; NA, not applicable; PO, oral (by mouth); RANKL = receptor activator of nuclear factor kappa B ligand; SC, subcutaneous. aNot approved for this indication. Source: Reference 4.



for intervention by current NOF guidelines. The 10-year prob-ability of major osteoporotic fracture for each participant was calculated using the Canadian FRAX tool with and without femoral neck bone mineral density, using information available from the database.

The results are presented in Table 4. Recalculating FRAX scores using bone mineral density information led to reclassi-fying 22.2% of the study cohort, including 6.3% of women and men who initially were designated as low risk, 10.2% initially designated as moderate risk, and 5.7% initially designated as high risk. In almost all cases, reclassification was to the adja-cent risk category; only 31 individuals (0.1%) were reclassified from low risk to high risk, and 72 (0.2%) were reclassified from high risk to low risk.

When FRAX scores were calculated without bone mineral density information, the vast majority (92.8%) of participants classified as high risk qualified for intervention under NOF guidelines. Conversely, the vast majority (80.5%) of partici-pants classified as low risk did not qualify for intervention. In-cluding bone mineral density information had the greatest im-pact (in terms of reclassification for intervention purposes) for participants classified as moderate risk; however, this group represented only one-third (29.4%) of the entire study cohort. The authors speculated that limiting bone mineral density test-ing to this subgroup—women and men whose initial FRAX scores place them at moderate risk—potentially could elimi-nate 70% of all central DXA testing.

Benefits and risks of pharmacologic therapy for osteoporosisHilda is a generally healthy, 77-year-old black female. She has hypertension that is well controlled with hydrochlorothiazide. Hilda is 5 ft, 5 in, weighs 119 lb, and has a BMI of 19.8 kg/m2. She consumes one glass of wine daily with dinner; she does not smoke.

Hilda’s current medications are hydrochlorothiazide 12.5 mg once daily (taken most days based on patient self-report); omeprazole 40 mg daily (taken most days); a chewable calcium supplement daily with dinner, containing elemental calcium 315 mg plus vitamin D 250 IU (taken approximately 6 days per week); and a daily multivitamin (taken approximately 3 days per week). Results of recent central DXA testing were as fol-lows: femoral neck left hip T-score = −2.6, lumbar spine T-score = −2.0.

Which of the following pharmacologic options would not be considered a first-line therapy for Hilda?a. Alendronate 70 mg weeklyb. Denosumab 60 mg s.c. every 6 monthsc. Raloxifene 60 mg dailyd. Zoledronic acid 5 mg i.v. yearly

Pharmacologic therapies for osteoporosis (Table 5) can be used for both prevention (i.e., preservation of bone mass in patients with low bone density) and treatment.21 They can be categorized broadly according to mechanism of action as antiresorption medications (which act by reducing bone re-sorption) and formation medications (which have anabolic

effects on bone).4,5

Current AACE guidelines dictate choosing pharmacologic agents for the treatment of osteoporosis on the basis of their proven efficacy in reducing fracture risk.4 All of the agents listed in Table 5 have been shown to be effective in reducing the risk of new vertebral fractures. Alendronate, denosumab, risedronate, teriparatide, and zoledronic acid have evidence of efficacy for reducing the risk of nonvertebral fractures; alen-dronate, denosumab, risedronate, and zoledronic acid also have been shown to reduce the risk of hip fracture. On the basis of this evidence, the AACE guidelines rank the available agents as follows4:

■ First-line agents: alendronate, denosumab, risedronate, zoledronic acid

■ Second-line agent: ibandronate ■ Second-line or third-line agent: raloxifene ■ Last-line agent: calcitonin

Teriparatide is recommended for patients with very high fracture risk or those in whom bisphosphonate therapy has been ineffective.

Hilda’s femoral neck T-score of −2.6 makes her a candidate for treatment. At Hilda’s age, hip fracture is a greater concern than spine fracture, so an agent with demonstrated ability to reduce the risk of hip fracture is preferred. Based on the rec-ommendations in the AACE guidelines, alendronate, denosum-ab, or zoledronic acid would be a good initial choice for Hilda. Raloxifene would not be considered a first-line choice.

Hilda also would benefit from an evaluation of her current calcium and vitamin D intake, with modification or supplemen-tation as needed to meet Institute of Medicine recommenda-tions.

Increasingly, the choice of initial therapy for osteoporosis needs to incorporate a thorough consideration of all known as-sociated risks. Some recent developments regarding the safety of osteoporosis medications are summarized below.

Bisphosphonate drug holidaysBisphosphonates bind strongly to and accumulate in bone, creating a reservoir of drug that is released back into the sys-temic circulation gradually over a period of months or years after treatment is stopped. Beneficial effects on bone miner-al density persist for some time after treatment is stopped, making it reasonable to consider periodic “drug holidays.”4,25 Speculation also exists that periodic drug holidays could miti-gate some of the risks associated with bisphosphonate therapy (discussed in greater detail in subsequent sections).25

The AACE guidelines state that a drug holiday may be con-sidered after 4 to 5 years of bisphosphonate therapy (10 years if fracture risk is high).4 Emerging evidence suggests that rec-ommendations for drug holidays should be drug specific and consider the benefits and risks of both continuation and dis-continuation of therapy.25,26 In a recent commentary, Compston and Bilezikian25 offered the following guidance:

■ For alendronate and risedronate, an initial 5-year treat-ment period seems reasonable, with assessment of the need for further treatment at the end of that time based on fracture history and bone mineral density. If a drug holiday



is advised, reassessment of risk should be performed after 1 to 2 years for alendronate and earlier (perhaps at 1 year) for risedronate.

■ In most patients treated with zoledronic acid, an initial treatment period of 3 years appears to be sufficient, with reassessment of the need for further treatment after 2 to 3 years.They also concluded that in the majority of patients, the

benefits of continued treatment outweigh the risks and that treatment should be continued long term in patients who re-main at high risk of fracture.

Osteonecrosis of the jawReports of osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy for osteoporosis began to appear in 2004.27 In recommendations published in 2011, an American Dental Association expert panel proposed replacing the term bisphosphonate-associated osteonecrosis of the jaw with the term antiresorptive agent–induced osteonecrosis of the jaw (ARONJ).28 This change recognizes the possibility that other antiresorptive agents, including denosumab and the investiga-tional cathepsin K inhibitors, may prove to be associated with ONJ.28

Based on a review of the available scientific literature, the panel concluded that the highest reliable estimate of ARONJ prevalence in patients being treated for osteoporosis is ap-proximately 0.1%.28 (The risk is greater in patients being treat-ed with higher doses of antiresorptive agents for cancer treat-ment–induced bone loss.) The panel further concluded that the benefit provided by antiresorptive therapy for osteoporosis far outweighs the very small risk of developing ONJ.

ARONJ is associated most commonly with invasive bone procedures such as tooth extractions. The panel recommended an oral health program consisting of excellent hygiene prac-tices and regular dental examinations as perhaps the optimal approach for lowering ARONJ risk in patients with osteoporo-sis.28

Although prolonged (>2 years) use of bisphosphonates ap-pears to increase the risk of developing ARONJ, discontinuing therapy does not necessarily eliminate the risk. Discontinuing therapy with antiresorptive agents could, however, have a pro-found negative impact on osteoporosis treatment outcomes. The panel concluded that major dental risks would need to be present for clinicians to consider stopping treatment and that all members of a patient’s health care team should be part of any discussions related to stopping treatment.28

Atypical fractures of the femurAtypical fractures of the femur occur anywhere along the fe-mur from just distal to the lesser trochanter to just proximal to the supracondylar flare.29 These rare fractures, accounting for fewer than 1% of all hip and femur fractures, have been re-ported mainly in patients taking bisphosphonates.30

Atypical femoral fractures sometimes are described as “chalk stick” fractures because of their radiologic appear-ance.4 The radiologic presentation also bears striking simi-larities to stress fractures.29 Experts have speculated that be-

cause bisphosphonates suppress bone remodeling, they might “freeze” the skeleton, allowing accumulation of microfractures that lead to stress fractures.31

A recent cohort analysis of 12,777 Swedish women 55 years or older yielded risk information characterized by the authors (Schilcher et al.31) as “reassuring” for bisphospho-nate users. All of the women in the cohort had sustained a fracture of the femur in 2008; 59 women had atypical frac-tures. The age-adjusted relative risk of atypical fracture with any bisphosphonate use was 47.3 (95% CI 25.6–87.3). The difference in the risk of atypical fracture between users and nonusers of bisphosphonates was five cases (95% CI 4–7) per 10,000 patient-years; the corresponding number of bisphos-phonate users needed for one case of fracture to occur was 2,000 per year of use.

Schilcher et al.31 also conducted a case–control analysis that compared the 59 women with atypical fractures with 263 control patients who had ordinary subtrochanteric or shaft fractures. The results revealed a higher risk of atypical frac-ture with increasing duration of bisphosphonate use (odds ra-tio 1.3 per 100 prescribed daily doses [95% CI 1.1–1.6]). After 2 years of bisphosphonate use, the risk was approximately 50 times as high as a normal level of risk. The risk diminished by 70% per year after bisphosphonate therapy was discontinued (0.28 [0.21–0.38]).

A task force assembled by the American Society for Bone and Mineral Research determined that although the associa-tion between bisphosphonate use and atypical femoral frac-tures is consistent with a role for bisphosphonates, causality has not been established definitively.29 Nevertheless, alterna-tive agents (e.g., raloxifene, teriparatide) could be considered for patients with low spine bone mineral density and normal or only moderately reduced femoral neck or total hip bone min-eral density.29 Because the median duration of bisphosphonate therapy in case reports of atypical femoral fracture is 7 years, the need for continued use of bisphosphonate therapy beyond 5 years should be reevaluated annually.29

Atypical femur fractures generally occur with no trauma or minimal trauma, such as falling from a standing height or less.29 They may be preceded by prodromal symptoms such as pain in the groin or thigh.4,29 Patients who complain of such pain should be referred to a primary care provider for evalu-ation.30

esophageal cancerThe first reports of a possible association between orally ad-ministered bisphosphonates and esophageal cancer were pub-lished in January 2009.32,33 Two epidemiologic studies evalu-ating the risk of esophageal cancer—using the same patient database (the U.K. General Practice Research Database)—yielded discrepant results.4,34,35 It is possible that differences in methodologies accounted for the conflicting findings.33

In a July 2011 drug safety communication, FDA stated that it was continuing to review data from published studies to evaluate whether use of oral bisphosphonate drugs was associated with an increased risk of esophageal cancer.33



Although the review is ongoing, FDA believes that the ben-efits of bisphosphonates in patients with osteoporosis con-tinue to outweigh their potential risks. Esophageal cancer is rare, especially in women.33

Patients who take oral bisphosphonates should be in-structed to follow the directions for use carefully to minimize any potential adverse events. Pharmacists should continue to emphasize the following information33:

■ All oral bisphosphonate drugs (except delayed-release risedronate) should be taken first thing in the morning af-ter awakening, with a full glass (6–8 oz) of plain water. (Delayed-release risedronate should be taken immediate-ly following breakfast.)

■ Patients should not lie down or eat or drink anything for at least 30 to 60 minutes after taking any oral bisphospho-nate drug.Patients also should consult a health professional if they

develop swallowing difficulties, chest pain, or new or worsen-ing heartburn or have trouble or pain when swallowing.

Renal insufficiencyIn January 2009, an FDA postmarketing safety review identi-fied five deaths from acute renal failure following infusions of zoledronic acid.36 A follow-up review in April 2011 showed an additional 11 cases of fatal acute renal failure and 9 cases of renal injury requiring dialysis.36 The risk of acute renal fail-ure appears to be higher in patients with underlying moder-ate to severe renal impairment or severe dehydration and in patients receiving concurrent therapy with nephrotoxic or di-uretic medications. The risk of developing renal failure also increases with age in patients with underlying renal impair-ment.

Pursuant to a September 2011 drug label revision, the use of zoledronic acid now is contraindicated in patients with cre-atinine clearance less than 35 mL/min or in patients with evi-dence of acute renal impairment.36 The label also recommends calculating creatinine clearance before each administration of zoledronic acid and screening patients before each adminis-tration to identify those with underlying acute or chronic renal impairment, advanced age, or dehydration.

The AACE guidelines note that no adverse effect on renal function has been observed when zoledronic acid was adminis-tered to patients with normal renal function in accordance with appropriate dosing instructions (i.e., infused during a mini-mum of 15 minutes).4 It is possible that the cases of acute renal failure were related to inappropriate medication administra-tion; rapid administration of nitrogen-containing bisphospho-nates such as zoledronic acid is known to interfere with kidney function.4

NonadherenceFormer U.S. Surgeon General C. Everett Koop, MD, is credited as saying, “Drugs don’t work in patients who don’t take them.” Adherence and persistence for osteoporosis therapies are known to be poor. For example, in a recently published analy-sis of pharmacy and medical claims data from 14 geographi-cally diverse health plans in the United States, the medication

possession ratio (a measure of adherence) among 45,939 members who had at least one pharmacy claim for alendro-nate, risedronate, or ibandronate corresponded to an adher-ence rate of approximately 58% at 12 months after therapy initiation.37 Adherence decreased each year thereafter, to ap-proximately 45% at 36 months.37

A claims database analysis by Wade et al.38 sheds new light on the association between bisphosphonate adherence in the first 12 months after therapy initiation and subsequent frac-ture risk. The 33,558 patients (94% women) included in the analysis were at least 45 years of age (59.5 ± 9.3 [mean ± SD) and new to bisphosphonate therapy. Patients were considered adherent at 12 months if they had an MPR(calculated as sum of days’ supply dispensed divided by 365 days) greater than 0.8. The follow-up period to assess incident fracture began at month 13.

The median MPR at 12 months was 0.61 for alendronate and risedronate and 0.58 for ibandronate. Proportionally few-er patients who experienced a fracture had an MPR greater than 0.8 compared with patients who did not experience a fracture (34.9% vs 39.3%, respectively; P < 0.001). Multi-variate analysis showed that patients who achieved an MPR greater than 0.8 had a 14% lower risk of subsequent fracture than patients with an MPR less than 0.5, after controlling for potential confounders that included demographics, previous fracture, concomitant medication use, and selected comor-bidities (P = 0.0459).

summaryOsteoporosis is a largely preventable condition that can be di-agnosed and treated before any fracture occurs. Pharmacists can help to improve osteoporosis outcomes by (1) encourag-ing evidence-based treatment for all appropriate patients, (2) educating patients about the benefits and risks of osteoporo-sis medications, (3) ensuring appropriate medication admin-istration and use, and (4) fostering adherence to osteoporosis therapy.

References1. Consensus development conference: diagnosis, prophylaxis,

and treatment of osteoporosis. am J Med. 1993;94:646–50.

2. national osteoporosis Foundation. Fast facts. accessed at www.nof.org/node/40, april 5, 2012.

3. national osteoporosis Foundation. Clinician’s guide to preven-tion and treatment of osteoporosis. accessed at www.nof.org/sites/default/files/pdfs/noF_Clinicianguide2009_v7.pdf, april 5, 2012.

4. Watts nB, Bilezikian Jp, Camacho pM, et al. american associa-tion of Clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal os-teoporosis. endocr pract. 2010;16(suppl 3):1–37.

5. o’Connell MB, vondracek sF. osteoporosis and other metabolic bone diseases. in: dipiro Jt, talbert rL, Yee gC, et al., eds. phar-macotherapy: a pathophysiologic approach. 8th ed. new York: Mcgraw-Hill Medical; 2011:1559–81.

6. Lewiecki eM. treatment of osteoporosis with denosumab. Ma-turitas. 2010;66:182–6.



7. institute of Medicine. dietary reference intakes: calcium and vitamin d. accessed at www.nap.edu/catalog.php?record_id=13050#toc, april 5, 2012.

8. panel on prevention of Falls in older persons, american geri-atrics society and British geriatrics society. summary of the updated american geriatrics society/British geriatrics society clinical practice guideline for prevention of falls in older person. J am geriatr soc. 2011;59:148–57.

9. Weinstein rs. glucocorticoid-induced bone disease. n engl J Med. 2011;365:62–70.

10. Huckleberry Y, rollins CJ. essential and conditionally essential nutrients. in: Krinsky dL, Berardi rr, Ferreri sp, et al., eds. Hand-book of nonprescription drugs: an interactive approach to self-care. 17th ed. Washington, dC: american pharmacists associa-tion; 2012:375–405.

11. national institutes of Health office of dietary supplements. di-etary supplement fact sheet: calcium. accessed at http://ods.od.nih.gov/factsheets/Calcium-Healthprofessional, april 5, 2012.

12. national osteoporosis Foundation. vitamin d and bone health. accessed at www.nof.org/node/173, april 5, 2012.

13. Bolland MJ, Barber pa, doughty rn, et al. vascular events in healthy older women receiving calcium supplementation: ran-domised controlled trial. BMJ. 2008;336:262–6.

14. Bolland MJ, avenell a, Baron Ja, et al. effect of calcium sup-plements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.

15. Bolland MJ, grey a, avenell a, et al. Calcium supplements with or without vitamin d and risk of cardiovascular events: reanaly-sis of the Women’s Health initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.

16. reid ir, Bolland MJ, sambrook pn, et al. Calcium supple-mentation: balancing the cardiovascular risks. Maturitas. 2011;69:289–95.

17. american society for Bone and Mineral research. american society for Bone and Mineral research statement on poten-tial cardiovascular risks associated with calcium supplements: august 12, 2010. accessed at www.asbmr.org/about/detail.aspx?cid=80efb4d9-d696-46c8-b83b-3e0940c9dddd, april 5, 2012.

18. national osteoporosis Foundation. Calcium: what you should know. accessed at www.nof.org/node/172, april 5, 2012.

19. national institutes of Health office of dietary supplements. di-etary supplement fact sheet: vitamin d. accessed at http://ods.od.nih.gov/factsheets/vitamind-Healthprofessional/, april 5, 2012.

20. Holick MF, Binkley nC, Bischoff-Ferrari Ha, et al. evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. J Clin endocrinol Metab. 2011;96:1911–30.

21. U.s. preventive services task Force. screening for osteoporo-sis: U.s. preventive services task Force recommendation state-ment. ann intern Med. 2011;154:356–64.

22. national osteoporosis Foundation. Bone basics alert: bone density testing. accessed at www.nof.org/sites/default/files/bonebasics/BoneBasicsalert_BMdtest.pdf, april 5, 2012.

23. World Health organization Collaborating Centre for Metabolic Bone diseases. FraX: WHo Fracture risk assessment tool. ac-cessed at www.shef.ac.uk/FraX/index.jsp, april 6, 2012.

24. Leslie Wd, Morin s, Lix LM, et al. Fracture risk assessment with-out bone density measurement in routine clinical practice. os-teoporosis int. 2012;23:75–85.

25. Compston Je, Bilezikian Jp. Bisphosphonate therapy for osteo-porosis: the long and short of it. J Bone Miner res. 2012;27:240–2.

26. Black dM, reid ir, Boonen s, et al. the effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HoriZon-pivotal Fracture trial (pFt). J Bone Miner res. 2012;27:243–54.

27. ruggiero sL, Mehrotra B, rosenberg tJ, et al. osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J oral Maxillofac surg. 2004;62:527–34.

28. Hellstein JW, adler ra, edwards B, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommen-dations from the american dental association Council on sci-entific affairs. J am dent assoc. 2011;142:1243–51.

29. shane e, Burr d, ebeling pr, et al. atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the ameri-can society for Bone and Mineral research. J Bone Miner res. 2010;25:2267–94.

30. Food and drug administration. Fda drug safety communica-tion: safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. accessed at www.fda.gov/drugs/drug-safety/ucm229009.htm#healthcare, april 11, 2012.

31. schilcher J, Michaëlsson K, aspenberg p. Bisphosphonate use and atypical fractures of the femoral shaft. n engl J Med. 2011;364:1728–37.

32. Wysowski dK. reports of esophageal cancer with oral bisphos-phonate use. n engl J Med. 2009;360:89–90.

33. Food and drug administration. Fda drug safety communication: ongoing safety review of oral osteoporosis drugs (bisphospho-nates) and potential increased risk of esophageal cancer. ac-cessed at www.fda.gov/drugs/drugsafety/ucm263320.htm#data, april 11, 2012.

34. Cardwell Cr, abnet CC, Cantwell MM, et al. exposure to oral bisphosphonates and risk of esophageal cancer. JaMa. 2010;304:657–63.

35. green J, Czanner g, reeves g, et al. oral bisphosphonates and risk of cancer of the oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ. 2010;341:c4444.

36. Food and drug administration. Fda drug safety communi-cation: new contraindication and updated warning on kid-ney impairment for reclast (zoledronic acid). accessed at www.fda.gov/drugs /drugsafety/ucm270199.htm?utm_campaign = google2& utm _ source = fdasearch & utm _medium=website&utm_term=zoledronic%20acid&utm_con-tent=3, april 11, 2012.

37. Martin Ke, Yu J, Campbell e, et al. analysis of the comparative effectiveness of 3 oral bisphosphonates in a large managed care organization: adherence, fracture rates, and all-cause cost. J Manag Care pharm. 2011;17:596–609.

38. Wade sW, Curtis Jr, Yu J, et al. Medication adherence and frac-ture risk among patients on bisphosphonate therapy in a large United states health plan. Bone. 2012;50:870–5.



CPe assessmentInstructions: This exam must be taken online; please see “CPE information” for further instructions. There is only one correct an-swer to each question. This CPE activity will be available online at www.pharmacist.com between July 15, 2012, and March 10, 2015.

1. The approximate number of Americans at possible risk for developing osteoporosis-related fractures is:a. 3 million.b. 10 million.c. 34 million.d. 44 million.

2. In the bone remodeling process, these cells are con-sidered bone forming and these cells are considered bone resorbing.a. Osteoblasts and osteoclasts, respectively.b. Osteoclasts and osteoblasts, respectively.c. Osteocytes and bone-lining cells, respectively.d. Osteocytes and osteoclasts, respectively.

3. Binding of receptor activator of nuclear factor kappa B ligand (RANKL) to its receptor RANK is primarily re-sponsible for which of the following?a. Formation of mature osteoclastsb. Inhibition of Wnt signalingc. Secretion of proteinases that digest the bone matrixd. Suppression of osteoclast formation

4. Which type of fracture is most likely to occur as a re-sult of age-related bone loss?a. Armb. Hipc. Spined. Wrist

5. Which of the following is the correct recommended dietary allowance (RDA) for calcium in a 65-year-old woman?a. 1,000 mg/dayb. 1,200 mg/dayc. 2,000 mg/dayd. 2,500 mg/day

6. Which of the following is the correct RDA for calcium in a 70-year-old man?a. 1,000 mg/dayb. 1,200 mg/dayc. 2,000 mg/dayd. 2,500 mg/day

7. A 73-year-old woman consumes one 8-oz glass of milk and one 6-oz carton of yogurt each day. She is not in-terested in adding any calcium-containing foods to her diet. Using the method described in this article for es-timating dietary calcium intake, how much additional calcium should this woman obtain from supplements?a. 150 mgb. 350 mgc. 400 mgd. 650 mg

8. A commercially available breakfast bar provides 20% of the daily value of calcium. How much calcium does this bar contain? a. 200 mgb. 240 mgc. 400 mgd. 500 mg

9. The RDA for vitamin D for men and women older than 70 years of age is:a. 600 IU.b. 800 IU.c. 1,200 IU.d. 1,500 IU.

10. At what dual-energy x-ray absorptiometry T-score is the diagnosis of osteopenia made?a. 0 to −1.5b. −1 to −2.5c. −1.5 to −2.5d. −1.5 to −3.0

CPE InformationTo obtain 2.0 contact hours of CPE credit (0.2 CEUs) for this activity, complete and submit the CPE exam online at www.pharmacist.com/education. A State-ment of Credit will be awarded for a passing grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before March 10, 2015, can receive credit.

Your Statement of Credit will be available online immediately upon successful completion of the CPE exam.CPE instructions: Get your documentation of credit now! Posttests can be completed at www.pharmacist.com/education using these steps:1. Go to Online CPE Quick List and click on the title of this activity.2. Log in. APhA members enter your user name and password. Not an APhA member? Just click “Create one now” to open an account.

No fee is required to register.3. Go to www.pharmacist.com/CPEMonitor to provide APhA with your required NABP e-Profile ID.4. Successfully complete the CPE exam and evaluation form to gain immediate access to your documentation of credit.

Live step-by-step assistance is available Monday through Friday 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742) or by e-mailing [email protected].



11. The U.S. Preventive Services Task Force recommends bone mineral density testing in women 50 to 64 years of age who have a FRAX score for 10-year probability of major osteoporotic fracture of:a. 3% or greater.b. 9.3% or greater.c. 14.5% or greater.d. 20% or greater.

12. A 58-year-old woman has T-scores of −1.9 at the lum-bar spine and −2.4 at the femoral neck left hip. Her FRAX (Fracture Risk Assessment) scores show a 3.7% 10-year probability of hip fracture and a 17% 10-year probability of major osteoporosis-related fracture. Which of the following statements about this woman is true?a. She is a candidate for osteoporosis medication based

on her T-score alone.b. She is a candidate for osteoporosis medication based

on her T-score in conjunction with her 10-year prob-ability of hip fracture.

c. She is a candidate for osteoporosis medication based on her T-score in conjunction with her 10-year prob-ability of major osteoporosis-related fracture.

d. She is not a candidate for osteoporosis medication.

13. Which medication decreases bone resorption by bind-ing to RANKL?a. Calcitoninb. Denosumabc. Raloxifened. Teriparatide

14. Based on the 2010 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Prac-tice for the Diagnosis and Treatment of Postmeno-pausal Osteoporosis, which medication is not recom-mended as a first-line agent for osteoporosis treat-ment?a. Alendronateb. Denosumabc. Raloxifened. Zoledronic acid

15. Recent guidance suggests that many patients treated with zoledronic acid may be considered for a drug holi-day after how many years of therapy?a. 3 yearsb. 4 yearsc. 5 yearsd. 10 years

16. You identify a woman who hasn’t refilled her alendro-nate prescription for the previous 3 months. She tells you that she is concerned about getting osteonecrosis of the jaw (ONJ). How do you respond?a. She should not worry; orally administered osteoporo-

sis medications carry no risk of ONJ.b. She should not worry; ONJ is a concern only in patients

being treated with high doses of antiresorptive agents for cancer treatment–induced bone loss.

c. Although some patients have developed ONJ, the risk is very small, especially compared with the risk of de-veloping an osteoporosis-related fracture.

d. Her concern is justified. You will contact the prescriber to recommend switching to zoledronic acid.

17. In a recent cohort analysis of Swedish women, the difference in the risk of atypical femoral fracture be-tween users and nonusers of bisphosphonates was how many cases per 10,000 patient-years?a. 5b. 59c. 263d. 2,000

18. What advice would you provide to a man who is tak-ing bisphosphonates and concerned about developing esophageal cancer?a. Esophageal cancer is a concern primarily for women.b. Esophageal cancer is a concern for patients taking

other types of osteoporosis medications (not bisphos-phonates).

c. The association between bisphosphonates and esopha-geal is unclear; any risk can be minimized by following the directions for use closely.

d. FDA has established a link between bisphosphonates and esophageal cancer, so he should talk with his pri-mary care provider about switching to a different medi-cation (i.e., from a different therapeutic class).

19. Which of the following medications is contraindicated in patients with a creatinine clearance less than 35 mL/min, pursuant to a recent drug label revision?a. Alendronateb. Ibandronatec. Risedronated. Zoledronic acid

20. The adherence estimate for oral bisphosphonate ther-apy 1 year after initiation is approximately:a. 40%.b. 50%.c. 60%.d. 70%.

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