102-1

BONE AND JOINT DISORDERS

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102
OSTEOPOROSIS
Bona Fide Treatment.................... Level II
Emily C. Farthing-Papineau, PharmD, BCPS

Optimal Plan IV zoledronic acid and ibandronate are preferred, since the patient does not tolerate an oral bisphosphonate. More information on teriparatide as an option is provided. Denosumab is identied as a therapeutic alternative if preferred therapy fails. Patient Education Information added on new dosages and routes of administration of bisphosphonates and nonpharmacologic treatment options. References Revised and updated to include recent information from major guidelines, new data on denosumab, and atypical femur fractures.

INSTRUCTORS GUIDE TO CHANGES IN THIS EDITION

CASEBOOK Patient Presentation New problem and chief complaint of intolerance to bisphosphonate therapy has been added. Additional laboratory result (calcium) has been added to aid in assessment of pharmacotherapeutic options. Additional risk factors for osteoporosis (cigarette smoking, maternal history of hip fracture) have been added. Medications for Stage II chronic obstructive pulmonary disease (COPD) modied to reect a commonly used, but potentially suboptimal regimen for this patient. New medication for osteoporosis (alendronate) has been added. INSTRUCTORS GUIDE Problem Identication Tiotropium is an alternative to adding an inhaled corticosteroid (recommended by the Global Initiatives for Chronic Obstructive Lung Disease [GOLD] guidelines for COPD) and avoids the potential for inhaled corticosteroids to decrease bone mineral density (BMD) in this patient. Use of the World Health Organization (WHO) FRAX score to quantify the patients risk for osteoporotic fracture has been added. Patient has high cardiovascular risk and therefore has a lower low-density lipoprotein (LDL) goal, which is not being met. Hypertriglyceridemia has been removed as a concurrent problem in this case. Added tobacco smoking as a problem to be addressed. Therapeutic Alternatives Updated recommendations on the daily recommended amounts of calcium and vitamin D. Risedronate dosages have been updated. Discussion of bisphosphonates and raloxifene has been updated. Discussion of denosumab has been added.

CASE SUMMARY
E.S., a 66-year-old woman, presents to a family medicine clinic for a routine follow-up visit for hypertension, dyslipidemia, and osteoporosis. Her complaints include heartburn and stomach pain with alendronate use. A recent dual-energy x-ray absorptiometry (DXA) scan reveals severe osteoporosis; the patient reports a 2-in loss in height since she was 35 years old, and has evidence of a vertebral compression fracture. The patient requires an osteoporosis therapy that is both efficacious and tolerable. Estrogen therapy should be withheld in this patient not only due to her history of breast cancer, but also because estrogen therapy is no longer recommended solely for the prevention of chronic diseases. Feasible treatment alternatives include IV ibandronate or zoledronic acid, oral raloxifene, subcutaneous or intranasal calcitonin, and subcutaneous teriparatide. The patient should also receive 1,500 mg of elemental calcium daily through diet and/or supplementation. Vitamin D (cholecalciferol) 8001,000 IU daily should be considered because many elderly patients are deficient in this vitamin. Nonpharmacologic interventions such as dietary modification, reduced caffeine and cola intake, and implementation of a weight-bearing exercise program play an important role in the management of osteoporossis.

QUESTIONS
Problem Identication
1.a. Create a list of the patients drug therapy problems. Suboptimal calcium supplementation. Calcium carbonate is not absorbed well in a patient on acid-suppressive therapy.1 Calcium citrates absorption is less dependent on gastric pH and is a better option for this patient. Osteoporosis therapy with alendronate is not being tolerated and needs to be altered.
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

102-2 Hypertension is uncontrolled. The patients blood pressure is currently not controlled on atenolol and ramipril (blood pressure 148/92 mm Hg). According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), -blockers are preferred in postmyocardial infarction patients and have been shown to reduce mortality and the incidence of myocardial infarction recurrence.2 However, -blockers can provoke bronchospasm, and such agents should be used with caution in patients with bronchospastic diseases such as COPD. This patient is taking a 1-selective -blocker (atenolol), but the risk of bronchospasm and current COPD control should be weighed against the benets of cardioprotection as indicated in the JNC 7 report.2 The case information does not depict intolerance related to COPD to be an issue for the patient. The dose of atenolol could also be increased to 100 mg daily. Angiotensin-converting enzyme (ACE) inhibitors (e.g., ramipril) are also a good choice in postmyocardial infarction patients, as they have been shown to prevent cardiac remodeling and improve long-term outcomes in such patients.2 This patient is already receiving the maximum dose of ramipril (20 mg per day). Thiazide diuretics have been shown to reduce morbidity and mortality in hypertension. According to JNC 7 guidelines and the ndings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), thiazide-type diuretics should be used either alone or in combination with drugs from other classes in the treatment of hypertension.2 In addition, there is some evidence that thiazide diuretics may improve bone density by reducing urinary calcium excretion and inhibiting bone resorption.3 A thiazide diuretic would be a reasonable addition. To increase adherence to the medication regimen, a combination product of thiazide diuretic and -blocker or ACE inhibitor may be useful. Examples of these combinations include Tenoretic (atenolol and chlorthalidone) and Zestoretic (lisinopril and hydrochlorothiazide). Dyslipidemia is inadequately treated. The patients triglycerides are at goal, but her LDL is not. Because this patient has known coronary artery disease, her goal LDL cholesterol is at least <100 mg/dL.4 Further lowering to <70 mg/dL may provide greater cardiovascular benet for those with a history of coronary heart disease.5 Her lipid levels are responding to therapy (as evidenced by reductions in total cholesterol, LDL cholesterol, and TGs and an increase in HDL over the past 3 months with no substantial increase in LFTs), but the lovastatin dose should be increased to at least 40 mg to provide an LDL below 100 mg/dL. Other statins, such as atorvastatin 10 mg or pravastatin 20 mg daily, could also achieve an LDL of <100 mg/dL in this patient. To achieve an LDL of <70 mg/dL, her baseline LDL should be lowered by 50%. The only statins capable of this percentage of LDL lowering are atorvastatin 40 mg and rosuvastatin 10 mg. The patient should also receive information on therapeutic lifestyle changes, specifying both diet and lifestyle changes, such as weight loss and increased physical activity.4 COPD therapy poses risks for adverse effects. Inhaled uticasone (the corticosteroid component of Advair) was added to the patients regimen 9 months ago following a COPD exacerbation. The guidelines from the GOLD suggest that inhaled corticosteroids may be useful in patients with severe or very
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

severe (Stage III or IV) COPD or who have experienced three or more exacerbations in the previous 3 years.6 The GOLD guidelines also highlight the current debate as to whether chronic administration of inhaled corticosteroids in COPD may lower BMD.6 Inhaled corticosteroids are preferred to systemic treatment because they have less osteoporosis risk. This patient currently has Stage II COPD and has not had multiple COPD exacerbations. Since an inhaled corticosteroid is not yet indicated in this patient according to the GOLD guidelines, the clinician may switch therapy from uticasone/salmeterol to a long-acting -agonist in addition to tiotropium, which will also avoid the potential for inhaled corticosteroids to adversely affect bone health. Furthermore, tiotropium therapy has also been shown to decrease COPD exacerbations. Smoking cessation should be encouraged, as this would help to lower her blood pressure and cholesterol, decrease the rate of decline of her lung function, and decrease the risk of osteoporotic fracture.2,4,69 Use the 5 As to guide this process, and discuss the various options to help minimize nicotine withdrawal, including nicotine replacement products, bupropion, and varenicline.10 Hypothyroidism is presently controlled. The thyroid-stimulating hormone (TSH) level is normal, indicating that the levothyroxine therapy is adequate. The patients TSH level should be routinely monitored because overtreatment of hypothyroidism that induces hyperthyroidism can contribute to further loss of BMD.7 1.b. What information (signs, symptoms, laboratory values, FRAX score) indicates the presence or severity of the patients osteoporosis? What are the patients risk factors for developing osteoporosis? The DXA scan results indicate severe osteoporosis. The WHO classies bone mass based on T scores, which represent the number of standard deviations (SDs) away from the mean BMD for the young normal adult population. Criteria for interpreting the results of a DXA scan are79: Normal: T score within 1.0 SD of young adult mean value. Osteopenia: T score between 1.0 and 2.5 SD below the mean. Osteoporosis: T score 2.5 SD below the young adult mean value. This patients worst T score is >3 SD from the young adult mean value, and she has one or more fragility fractures (loss of height of >1.5 in).7 The WHO FRAX score can be calculated to estimate the likelihood of the occurrence of a hip fracture or major osteoporotic fracture (dened as hip, spine, forearm, or shoulder fracture) within the next 10 years in a patient not on osteoporosis treatment. Since this patient has only taken two doses of alendronate, it is acceptable to perform a FRAX score calculation. The calculation can be performed at the Web site http://www.shef.ac.uk/ FRAX/ and takes into account many risk factors for osteoporosis. For E.S., her osteoporosis risk factors include her Caucasian ethnicity, age (and postmenopausal status), low body weight evidenced by BMI less than 21 kg/m2, history of previous fracture, cigarette smoking, history of maternal hip fracture, and femoral neck T score. E.S. has a 38% chance of experiencing a major osteoporotic fracture and a 13% chance of hip fracture in the next 10 years if her osteoporosis remains untreated. Even if this patients DXA scores were not osteoporotic, the National Osteoporosis Foundation (NOF) guidelines and the North American Menopause Society (NAMS) guidelines state

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Bone and Joint Disorders

102-3 that treatment is pharmacoeconomically benecial if the risk of hip fracture is at least 3% or if the risk of major osteoporotic fracture is at least 20%.7,9 Note: The clinical role of serum or urinary biochemical markers of bone remodeling (e.g., serum osteocalcin, bone-specic alkaline phosphatase, and urine pyridinoline) is not well established, as no clear relationship has been identied between levels of biochemical markers and fracture risk. Neither the NAMS nor the NOF recommends routine testing of biochemical markers, and they are not commonly obtained in clinical practice.7,9 Based on the information presented in the case, there is no reason to suspect a secondary cause of osteoporosis; however, both the NAMS and the NOF recommend checking various laboratory values such as a parathyroid hormone level, vitamin D level, and TSH (normal in this patient) when clinically appropriate.7,9 increasing dietary calcium or taking calcium supplements will be necessary for most women with osteoporosis. The recommended daily intake varies slightly among the NOF, National Institute of Health, and National Academy of Sciences; however, it should be at least 1,2001,500 mg per day of elemental calcium in postmenopausal women not taking estrogen and 1,0001,200 mg per day in postmenopausal women taking estrogen.7,9 (Refer to textbook chapter on osteoporosis for the content of elemental calcium in oral calcium supplementation products.) Doses greater than 1,500 mg of elemental calcium are not thought to offer any additional benet, and doses greater than 2,500 mg can increase the risk of developing kidney stones. Because calcium absorption is rate-limited, calcium supplements should be given in divided doses of approximately 500 mg of elemental calcium.7,12 Calcium carbonate should be taken with food not only to minimize GI side effects but also to increase calcium absorption.7 It is important to note that this patient is on acid-suppressive therapy for GERD and that long-term proton pump inhibitor use has been associated with increased risk of hip fractures.1 Although calcium citrate contains less elemental calcium than calcium carbonate, it is not dependent on gastric pH for absorption and, therefore, is a good choice for older adults who may have achlorhydria and those on acid-suppressive therapy.7,8 It may be taken independent of meals.7,8 Side effects of constipation and gas are more common with calcium carbonate than with calcium citrate.8 Therapy typically should be lifelong. Vitamin D enhances calcium absorption in the small intestine, and when combined with calcium, it has been shown to reduce the incidence of nonvertebral fractures in the elderly. It is not necessary for vitamin D and calcium to be administered concurrently for vitamin D to enhance the absorption of calcium because of the long half-life of vitamin D.7 Both the NAMS and NOF osteoporosis guidelines recommend that postmenopausal women take 8001,000 IU of vitamin D daily.7,9 This is because most individuals are thought to be vitamin D decient, and elderly patients are even more at risk for vitamin D deciency as a result of inadequate or limited exposure to sunlight.7 The American College of Rheumatology (ACR) also recommends 800 IU of vitamin D daily or calcitriol 0.5 mcg daily in those taking systemic glucocorticoids or who plan to be on systemic glucocorticoids for 3 months.13 Dairy products are the most common dietary source of vitamin D, although adequate amounts of vitamin D can be obtained through other vitamin Dfortied foods as well. Vitamin Dcontaining supplements have one of the two forms of vitamin D, namely, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Cholecalciferol is the form of vitamin D synthesized in the skin from sun exposure. It is better at increasing and sustaining vitamin D levels than ergocalciferol.14 This form of vitamin D can be found in many common supplements, such as Caltrate +D, Os-Cal 500 +D, and Cal-Citrate with vitamin D. Cholecalciferol is also the form of vitamin D in Fosamax Plus D. Use of vitamin D has also been associated with decreased risk of falls, and improvement in muscle strength.7 Calcitriol (oral Rocaltrol; injectable Calcijex) is a synthetic vitamin D analog. It is not approved by the FDA for the treatment of osteoporosis and is generally used only in patients who have had vertebral fractures or those who
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CHAPTER 102
Osteoporosis

Desired Outcome
2. What are the goals of pharmacotherapy for osteoporosis in this case? Prevent or decrease the incidence of fractures with a medication the patient can tolerate. Replenish bone mass and/or prevent further bone loss and loss of height. Prevent falls that can result in debilitating fractures and negatively impact quality of life. Provide optimal calcium and vitamin D supplementation, in addition to prescription drug therapy.

Therapeutic Alternatives
3.a. What nondrug therapies might be useful for this patients osteoporosis? Ensure adequate calcium and vitamin D intake through diet and/ or supplementation.79 (Refer to the textbook chapter on osteoporosis for the calcium content of various foods.) Perform regular weight-bearing and muscle-strengthening exercises, such as walking, jogging, dancing, and weightlifting.7,9 Encourage smoking cessation because postmenopausal women who smoke are more likely to experience fractures.7,9 Avoid caffeine intake. Caffeine can increase the excretion of calcium to a small extent and may contribute to low BMD.9 Cola beverages containing phosphorus can also decrease BMD. This is thought to be due to the increased acid environment caused by the phosphorus and subsequently neutralized by calcium.11 Reduce the risk of falls by removing throw rugs and extension cords, adding handrails to the bathtub and other areas, and obtaining nonskid mats for slippery surfaces such as bathtubs. Clarify the quantity and frequency of alcohol consumed, as excessive drinking, particularly >3 drinks per day, could contribute to fall risk.9 3.b. What feasible pharmacotherapeutic alternatives are available for treatment of the osteoporosis? Adequate calcium ingestion should be recommended for all patients with osteoporosis. Adequate calcium intake is not only essential for achieving peak bone mass and reducing the rate of bone loss but also vital for achieving adequate response to other osteoporosis therapies. Since most individuals over the age of 50 consume 600700 mg of elemental calcium per day,

102-4 have renal disease and cannot activate vitamin D. According to the ACR, calcitriol is better at preventing bone loss in patients taking oral glucocorticoids than those taking calcium and vitamin D alone.13 The recommended dose is 0.52.0 mcg per day orally or 0.5 mcg injected three times per week. Monitoring for hypercalcemia and hypercalciuria is recommended if calcitriol is initiated.13 Vitamin D or calcitriol replacement will most likely be given for the rest of the patients life. Neither the NOF, NAMS, nor the American Association of Clinical Endocrinologists (AACE) recommends one particular vitamin D supplement over another.79 Bisphosphonates are considered drugs of choice for the treatment of osteoporosis. They block osteoclast resorptive activity with no effect on osteoblasts. Alendronate, risedronate, and zoledronic acid are the only FDA-approved agents that can decrease the risk of vertebral and nonvertebral fractures, including hip fractures. A casecontrol study also found that bisphosphonate use reduced the risk of breast cancer in nonobese women (Br J Cancer, 2010;102(5):799802). While further investigation is needed in this area, this could be a potential added benet for the patient. Alendronate (Fosamax) is approved by the FDA for both treatment and prevention of osteoporosis, and is commonly selected for osteoporosis therapy due to its availability as a lower-cost generic medication. It reduces vertebral fractures and increases BMD in the spine, femoral neck, trochanter, and total body. Specically, it decreases the risk of fractures in women with established osteoporosis and prevents bone loss in nonosteoporotic women. Alendronate (either alone or in combination with hormone replacement therapy) was shown to be superior to hormone replacement therapy alone for preventing bone loss in elderly women.7 Alendronate has poor oral absorption (0.78%) and must be taken on an empty stomach, which increases side effects. The most common adverse effects are abdominal pain, acid reux, constipation, diarrhea, musculoskeletal pain, headache, and esophagitis. Unfortunately, the patient is currently experiencing heartburn and abdominal pain from taking the medication in the once-weekly 70-mg dose. Alendronate is also available in a once-daily dose of 10 mg, but that may cause more frequent GI irritation for the patient. Other forms of alendronate, including the liquid dosage form and Fosamax Plus D, which contains 70 mg of alendronate and either 2,800 or 5,600 IU of cholecalciferol in a once-weekly tablet, would also be expected to cause similar undesirable GI side effects for this patient. Risedronate (Actonel), which is also approved by the FDA for both treatment and prevention of osteoporosis, signicantly reduces the rate of vertebral and nonvertebral fractures.7,8 Like alendronate, risedronate has poor oral absorption and must be administered on an empty stomach. The side-effect prole is similar to that of alendronate and would be expected to cause similar GI side effects in this patient. The dose of risedronate is the same (5 mg once daily) for both treatment and prevention of osteoporosis. Alternative regimens include 35 mg once-weekly or 150 mg once-monthly dose. Actonel plus calcium is also available as a monthly package containing 4 tablets of risedronate 35 mg and 24 tablets of calcium carbonate 500 mg. The calcium is intended to be taken on the days of the week when the risedronate is not taken. Ibandronate (Boniva), a bisphosphonate similar to risedronate and alendronate, is also approved by the FDA for
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

the treatment and prevention of osteoporosis. In patients with established osteoporosis, ibandronate has been shown to increase BMD and reduce the incidence of vertebral fractures. With a T score below 3, ibandronate has been shown to decrease nonvertebral fractures as well.7 Like alendronate and risedronate, ibandronates oral absorption is signicantly reduced by the presence of food, and the drug must therefore be administered on an empty stomach, 60 minutes prior to eating or drinking. The oral form also has similar GI side effects as the other oral bisphosphonates. The dose of ibandronate for the prevention and treatment of osteoporosis is 2.5 mg once daily; a dose of 150 mg monthly may be used for the treatment of osteoporosis. Ibandronate is also available as a 3-mg IV injection administered every 3 months by a health care professional for the treatment of osteoporosis. This dosage form has been shown to increase BMD to a greater degree than daily oral ibandronate. Because it also has less GI side effects associated with its use, this product may be a treatment option for this patient. Zoledronic acid (Reclast) is the rst bisphosphonate FDA approved for IV once-yearly treatment of osteoporosis and once every 2 years for osteopenia. The once-yearly injection for the treatment of postmenopausal osteoporosis was found to decrease the risk of vertebral fractures by 70%, hip fractures by 41%, and other fractures by 25% over a 3-year period.7 It is also the rst bisphosphonate to receive FDA approval to reduce the incidence of new clinical fractures in patients with low-trauma hip fracture. The most common side effects of this treatment include an acute phase reaction of ulike symptoms, such as fever (44%), athralgia, and myalgia. These side effects typically resolve within 3 days after drug infusion and can be minimized with the use of acetaminophen prior to and for 3 days following zoledronic acid administration. Subsequent administration of the zoledronic acid tends to cause less ulike reactions. There was concern about zoledronic acid being associated with a statistically signicant increase in the incidence of arrhythmia (6.9% zoledronic acid group compared to 5.3% in the placebo group) in the HORIZON trial. Of these arrhythmias, 1.3% of patients given zoledronic acid experienced serious atrial brillation, compared to 0.4% of patients given placebo, and most episodes of atrial brillation occurred more than 1 month postinfusion. The FDA reviewed all the data surrounding atrial brillation with all bisphosphonates and determined that a causal relationship between the use of these medications, including zoledronic acid, and the onset of atrial brillation was unclear. The FDA recommends against changing prescribing habits for this class of medications at this time and will continue to monitor postmarketing reports.15 Use of zoledronic acid has also been associated with osteonecrosis of the jaw (ONJ) predominately when used in much higher doses for the treatment of malignancy and in patients who were also receiving chemotherapy and corticosteroids.7 This medication would be an excellent choice for the patient, as it has excellent fracture prevention data, would avoid GI toxicity, and is conveniently administered once yearly, which may help improve patient adherence to the treatment. Estrogen therapy was once considered the treatment of choice for osteoporosis in postmenopausal women. Estrogen preserves BMD and inhibits bone resorption by decreasing the rate of the bone activation cycle. This results in a lower incidence of hip fractures. Estrogen also provides relief from conditions associated with menopause, such as hot ashes. The U.S. Preventive

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102-5 Services Task Force now recommends against the routine use of estrogen or estrogen and progestogen for the prevention of chronic conditions, such as osteoporosis, due to the potential for risks associated with its use.16 This recommendation is due to ndings from the Womens Health Initiative (WHI) study and the Heart and Estrogen/Progestin Replacement Study (HERS) follow-up.16 According to these studies, women receiving hormone therapy were at a higher risk for coronary heart disease, invasive breast cancer, pulmonary embolism, stroke, and biliary tract surgery.16 For the treatment of postmenopausal symptoms, hormone therapy (estrogen alone, or the combination of an estrogen and progestogen for women with an intact uterus) can be very effective. If used for the treatment of postmenopausal symptoms, however, hormone therapy should be prescribed in the smallest effective dose(s) for the shortest possible time. It should no longer be recommended for osteoporosis prevention alone.16 Selective estrogen receptor modulators (also known as estrogen agonist/antagonists) have estrogenlike effects on cortical bone and antiestrogenlike effects on breast tissue and the endometrium. Raloxifene (Evista) increases BMD but to a lesser extent than estrogen. It has also been demonstrated to reduce the incidence of vertebral fractures in postmenopausal women with osteoporosis.7,8 It is indicated for both the prevention and treatment of osteoporosis, as well as decreasing the risk of invasive breast cancer in postmenopausal women. Raloxifene decreases serum total and LDL cholesterol concentrations with no effect on HDL or TGs. The 4-year results from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial revealed that raloxifene did not signicantly affect overall risk for cardiovascular events in the overall cohort of postmenopausal women, although a reduction in risk was noted in a subset of high-risk women and women with established CHD. The MORE-CORE trial looked specically at women with increased cardiovascular risk and found that raloxifene neither increased nor decreased cardiovascular outcomes.7,9 Raloxifene is safe in patients with breast cancer or a history of breast cancer because it is an estrogen antagonist in uterine and breast tissues. There is an increased risk of thromboembolic events similar to estrogen; the risk is greatest during the rst 4 months of treatment. The most common side effects are hot ashes and leg cramps. The usual dose of raloxifene is 60 mg per day. It should be combined with calcium supplementation. Calcitonin-salmon (Fortical, Miacalcin) inhibits bone resorption by inhibiting osteoclast function and is only indicated for the treatment of postmenopausal osteoporosis. It signicantly increases BMD and reduces vertebral fracture rates in women with established osteoporosis. It has not been shown to decrease nonvertebral or hip fractures.79 It also has an analgesic effect and may provide some pain relief in patients with acute vertebral fractures.7 Calcitonin-salmon is available as a nasal spray or subcutaneous injection. Its effect tends to be dose related, and the usual dose is 100 IU SC or 200 IU intranasally per day. When using the nasal spray, the patient should alternate nostrils daily. The nasal spray can cause rhinitis, epistaxis, and headache. Calcitonin-salmon is an expensive agent and is less potent than the bisphosphonates, but it is a viable option for patients who cannot tolerate other antiosteoporotic agents or for patients who experience back pain as a result of vertebral fractures. Teriparatide (Forteo) is a recombinant human parathyroid hormone with a unique mechanism of action of increasing osteoblast lifespan and function. When administered once daily, it leads to increased bone formation and improved bone quality. Teriparatide is indicated in postmenopausal women who are at high risk for fractures. In postmenopausal women with osteoporosis and a history of prior vertebral fractures, teriparatide significantly improves BMD and reduces the incidence of subsequent fractures.79 Teriparatide is administered subcutaneously daily into the abdomen or thigh with a prelled injectable device. It is very expensive relative to other agents used for treating osteoporosis and often requires special approval from insurance companies before it is available at a reduced price to the patient. Side effects, although uncommon, include dizziness, leg cramps, and arthralgias. The patient should sit or lie down on the initial administration of teriparatide to prevent orthostatic hypotension with the rst dose. The product also carries a black box warning due to an increased incidence of the development of osteosarcoma in rats. Teriparatide is contraindicated in patients with a history of Pagets disease, unexplained elevations in alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton. Use of teriparatide for more than 2 years is not recommended due to a lack of safety data. Denosumab (Prolia) is a newer FDA-approved option for the treatment of postmenopausal osteoporosis for those at high risk of fracture, including those with a history of osteoporotic fracture or multiple risk factors for fracture, or those who have failed or are intolerant to other available osteoporosis therapies. It is a human monoclonal antibody that inhibits nuclear factor-kappa ligand (RANKL) activity. RANKL is a protein that essentially promotes osteoclast formation. The FREEDOM trial demonstrated that denosumab increased BMD in the lumbar spine and hip and decreased the risk of vertebral, hip, and nonvertebral fractures by 68%, 40%, and 20%, respectively.17 One head-to-head trial comparing denosumab to once-weekly 70-mg alendronate showed that denosumab increased BMD at the total hip to a greater degree after 1 year, at 3.5% versus 2.6% with alendronate (P < .0001).18 Denosumab also increased BMD to a greater degree than alendronate at all tested sites and lowered markers of bone turnover more effectively than alendronate. The study was not powered to detect a difference in osteoporotic fractures.18 Denosumab is administered as 60 mg subcutaneously every 6 months by a health care professional and costs approximately $825 per injection. It has few reported side effects, such as back and musculoskeletal pain, hypercholesterolemia, cystitis, and dermatologic conditions like eczema.17 RANKL is also located on activated T and B lymphocytes and in lymph nodes, so its inhibition may explain the small increased risk of serious infection, such as cellulitis and endocarditis. Because it is an antiresorptive medication, reports of ONJ have occurred. A medication guide discussing the risks of therapy is to be distributed to patients. Denosumab is contraindicated in pregnancy and hypocalcemia. The package insert species patients should take 1,000 mg of calcium daily and at least 400 IU of vitamin D daily. Denosumabs place in osteoporotic therapy remains to be determined. Combination therapy: There is some evidence that alendronate or risedronate may increase BMD to a greater extent when used in combination with estrogen therapy or raloxifene than when used alone. Alendronate and teriparatide appear to be antagonistic when
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

CHAPTER 102
Osteoporosis

102-6 used in combination. Yet, when alendronate is added after the completion of therapy with teriparatide, alendronate appears to maintain or further increase BMD. This strategy is often employed after teriparatide use. However, due to a lack of data on the long-term safety or effect on fracture rates, the AACE, the NAMS, and the NOF do not recommend using concomitant therapy for the treatment of osteoporosis.79 elemental calcium per day, she needs a calcium supplement to provide the remaining calcium needed. An example of an appropriate product is Citracal Regular taken as two tablets twice daily. The serving size of two tablets contains 500 mg of elemental calcium (from calcium citrate) and 400 IU of vitamin D (as cholecalciferol). Because of her age, the patient should take 8001,000 IU of vitamin D daily. This could be taken in the form of a combination product with calcium, as mentioned above. The importance of ingesting calcium and vitamin D via dietary sources should be stressed to the patient and could reduce the amount of calcium and vitamin D supplements needed. Smoking cessation should be encouraged. Caffeine and phosphate-containing cola intake should be minimized. After receiving medical clearance, the patient should be instructed to begin an appropriate weight-bearing exercise program for 30 minutes three to ve times weekly. 4.b. What alternatives would be appropriate if the initial therapy fails or cannot be used? If the patient cannot tolerate IV bisphosphonate therapy, raloxifene could be initiated instead. Conversely, if the patient was initiated on raloxifene (rather than an IV bisphosphonate), an IV bisphosphonate could be used if intolerance occurs. If the patient does not respond to either bisphosphonates or raloxifene or sustains further fractures while taking those medications, teriparatide may be considered. Due to its high cost, teriparatide should be reserved for patients who fail to respond to less expensive therapies. Its daily subcutaneous route of administration is also considered less than ideal by patients, although the Forteo pen device has been redesigned for much easier administration. Giving a bisphosphonate after the completion of teriparatide therapy may help to retain the increases in BMD achieved with teriparatide use. Denosumab could also be considered as an alternative if the patient fails or cannot tolerate IV therapy with a bisphosphonate or oral therapy with raloxifene. Calcitriol (0.51 mcg po once daily or Calcijex 0.5 mcg injected thrice weekly) could be added to either a bisphosphonate or raloxifene, instead of a traditional vitamin D supplement. However, calcitriol is not FDA-approved for the prevention or treatment of osteoporosis and should be used only when standard therapy fails or is contraindicated. The combination of ibandronate or zoledronic acid plus raloxifene could be given. However, combination therapy has not been well studied and should not be attempted unless maximal therapy with either agent individually is unsatisfactory.79 There are other SERMS currently in drug development, such as bazedoxifene, lasofoxifene, and ospemifene. These drugs may have clinical differences relative to raloxifene, namely, differences in fracture reduction, lipid effects, and hot ushes. These products cannot be recommended until further information is known.

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Bone and Joint Disorders

Optimal Plan
4.a. What drug, dosage form, dose, schedule, and duration of therapy are best for treating this patients osteoporosis? A nonoral bisphosphonate (ibandronate or zoledronic acid) is an appropriate choice given that this patient experienced GI side effects from an oral bisphosphonate and is unwilling to experience these side effects again. Zoledronic acid is preferred over ibandronate due to zoledronic acids demonstrated efcacy in decreasing nonvertebral fractures in addition to vertebral fractures and in preventing recurrent osteoporotic fractures. The convenience of a once-yearly infusion of zoledronic acid compared to a quarterly infusion of ibandronate may make zoledronic acid a preferred choice for patients, as well. If the patient lacks insurance, zoledronic acid and ibandronate are expensive; however, most patients have coverage for this medication through Medicare Part B. As a practical tip, patients and clinicians can nd individualized information on insurance coverage for IV ibandronate and zoledronic acid via the Boniva and Reclast reimbursement hotlines accessed through their respective Web sites. The Reclast & You program will also locate a nearby infusion center for zoledronic acid administration. Zoledronic acid given as 5 mg IV every 12 months. Ibandronate given as 3 mg IV every 3 months. The optimal duration of bisphosphonate therapy remains unclear and has been recently debated due to cases of atypical subtrochanteric femur fractures in patients receiving bisphosphonate therapy.7 It remains to be determined whether or not these patients were predisposed to these types of fractures due to their underlying condition of osteoporosis or by bisphosphonates suppressing bone remodeling and affecting the bone architecture. Cases of these atypical femur fractures have also been reported in patients not taking bisphosphonate therapy. The FDA does not recommend altering prescribing patterns for these medications until more information conrms or refutes this concern. In general, bisphosphonate therapy has not been studied beyond 10 years for alendronate and beyond 3 years with ibandronate or zoledronic acid.7 Despite the long half-life of bisphosphonates, after discontinuation of therapy, eventual decreases in BMD and fracture prevention have been observed.7 Raloxifene 60 mg po daily is another potential option for this patient. It may be particularly useful because of its benecial lipid-lowering effects and safety in light of the patients breast cancer history. Bisphosphonates have greater efcacy data, but raloxifene may be benecial in this patient because of its positive effects on the lipid prole and its lack of GI side effects. Because of the severity of her osteoporosis, a bisphosphonate would be preferred. A different calcium salt should be used in this patient to increase calcium absorption, since she is elderly and on a proton pump inhibitor. Sufcient calcium intake is essential to increasing bone density. The patient should obtain a total of ~1,500 mg of calcium daily via diet and/or a supplement. Assuming the patient has a typical diet and ingests approximately 600 mg of
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

Outcome Evaluation
5. What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse effects?

Efcacy parameters:
The NOF and NAMS recommend repeating the DXA scan in 2 years.7,9 With bisphosphonate therapy, increases in BMD

102-7 can typically be observed after 1 year in the spine and after 2 years in the hip.7,8 A DXA scan could therefore be performed after 1 year of therapy; however, Medicare generally only covers DXA scans every 2 years. The optimal therapeutic goal is a signicant improvement in lumbar spine and/or femoral neck density, but given her severity of osteoporosis, stabilization of her BMD would also be acceptable. A stable or improved BMD indicates successful treatment, and a reduction in fracture risk is expected.7 In fact, fracture risk reduction is thought to occur even before increases in BMD can be measured.7 The patient should not experience more fractures or any additional loss of height. Question the patient at each subsequent visit, and evaluate any sudden onset of bone pain radiologically. Measure the patients height at this appointment and at each subsequent visit. This injection is given every 3 months. Be sure to keep all follow-up appointments with your primary care provider. A routine blood test to check your kidneys and calcium level is also done every 3 months while you are getting this medication. Some patients experience ulike symptoms, such as fever and muscles aches and pains for about 2 days after receiving this medication. You can often prevent this from occurring by taking acetaminophen just before and for a couple of days after getting your medication. These side effects often diminish with future doses of the medication. Let your primary care provider know if you experience severe muscle or bone pain. It is important to get enough calcium by eating foods rich in calcium such as yogurt, milk, and cheese, or by taking calcium supplementation. Continue to take your vitamin D supplement, as well. Adequate calcium and vitamin D help this medication to work properly. Ibandronate does not take the place of these supplements.

CHAPTER 102
Osteoporosis

Toxicity parameters:
For both intravenous ibandronate and zoledronic acid, the manufacturer recommends checking a serum creatinine level prior to each dose. If the creatinine clearance is <30 mL/min in a patient scheduled to receive ibandronate or <35 mL/min in a patient scheduled to receive zoledronic acid, then the medications should not be administered due to lack of clinical experience and renal safety data. Since E.S.s CrCL is approximately 46 mL/min, this is not currently an issue for her. The patient should also have serum calcium levels checked prior to subsequent infusions to rule out hypocalcemia, which is a contraindication with bisphosphonate use. This is also not currently an issue for E.S., since her calcium level is normal. E.S. should be questioned about the occurrence of any side effects such as ulike symptoms, abdominal pain, nausea, vomiting, diarrhea, or bone/muscle pain at each subsequent ofce visit. Encourage the patient to have good oral hygiene and get any necessary invasive dental procedures done prior to medication administration, because rare reports of ONJ have been described in patients taking bisphosphonates for osteoporosis.7 Increased risks for developing ONJ include poor oral hygiene, invasive dental procedures, and concomitant treatment with chemotherapeutic agents and/or highdose systemic corticosteroids.7 Raloxifene: Question the patient about side effects such as pain in the legs, lower extremity swelling, or hot ashes at each ofce visit.

Zoledronic acid (Reclast) intravenous administration:

Your primary care provider has recommended zoledronic acid to help strengthen your bones and to prevent any bone fractures in your hips or spine. This injection is given once every year. Be sure to keep all follow-up appointments with your primary care provider. A routine blood test to check your kidneys and calcium level is also done every year prior to your injection while you are getting this medication. Be sure to drink at least two glasses of water a few hours before you receive this medication. Some patients experience ulike symptoms, such as fever and muscles aches and pains for about 3 days after receiving this medication. Patients may experience these symptoms for 1 or 2 weeks after getting this medication, although this is uncommon. You can often prevent these symptoms from occurring by taking acetaminophen just before and for 3 or 4 days after you receive your medication. These side effects often diminish with future doses of the medication. Let your primary care provider know if you experience severe muscle or bone pain. It is important to get enough calcium by eating foods rich in calcium such as yogurt, milk, and cheese, or by taking calcium supplementation. Continue to take your vitamin D supplement, as well. Adequate calcium and vitamin D help this medication to work properly. Zoledronic acid does not take the place of these supplements.

Patient Education
6. What information should be provided to the patient to enhance adherence, ensure successful therapy, and minimize adverse effects?

Raloxifene (Evista):
Raloxifene (Evista) is a medication prescribed to prevent further weakening of your bones. This medication acts like estrogen on your bones but does not act like estrogen on the breast or uterus and is therefore safe for you to use, even though you have had breast cancer. In fact, it has been shown to reduce the chance of invasive breast cancer. It will not cause you to have menstrual periods like estrogen could. Take one 60-mg raloxifene tablet each day, preferably at the same time each day. You may take it with or without food. If you miss a dose, take the medicine as soon as you remember. If you do not think of it until the next day, skip the missed dose and just resume taking it once a day. Raloxifene may cause leg cramps and hot ashes. Tell your prescriber if these side effects become troublesome. A rare but serious side effect of raloxifene is blood clots in the veins. If you have pain in your calves, leg swelling, sudden chest pain, shortness of breath, coughing of blood, or change in your vision, contact your primary care provider immediately.
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

General information:
Educate the patient on her risk of osteoporotic fractures if her osteoporosis remains untreated. Encourage adherence to the medication regimen because typical adherence to medications for osteoporosis ranges from approximately 25% to 81%.7,9 Educate the patient on nonpharmacologic interventions to improve bone health, such as smoking cessation, avoidance of excessive alcohol, caffeine, or colas, and regular weight-bearing exercise.7

Ibandronate (Boniva) intravenous administration:

Your primary care provider has prescribed ibandronate (Boniva) to help strengthen your bones and to prevent any further bone fractures in your spine.

102-8

REFERENCES
10. 1. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:29472953. 2. National Institutes of Health. JNC 7 express; seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD, National Heart, Lung, and Blood Institute; 2003. NIH Publication No. 03-5233. 3. Feskanich D, Willett WC, Stampfer MJ, Colditz GA. A prospective study of thiazide use and fractures in women. Osteoporos Int 1997;7:7984. 4. National Cholesterol Education Program Expert Panel. Final report of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, MD, National Heart, Lung, and Blood Institute. National Institutes of Health; 2002. NIH Publication No. 02-5215. 5. Grundy SM, Cleeman JI, Merz CN, et al, for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227239. 6. Global strategy for diagnosis, management and prevention of COPD (updated 2009). The Global Initiative for Chronic Obstructive Lung Disease Web site. Available at: http://www.goldcopd.org/Guidelineitem. asp?l1=2&l2=1&intId=2003. Updated December 2009. Accessed April 20, 2010. 7. The North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17(1):2554. 8. American Association of Clinical Endocrinologists Osteoporosis Task Force. AACE medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 2003;9:544564. 9. National Osteoporosis Foundation. Clinicians guide to prevention and treatment of osteoporosis. National Osteoporosis Foundation Web

11.

12. 13.

14. 15.

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site. Available at: http://www.nof.org/professionals/Clinicians_Guide. htm. Updated January 2010. Accessed April 20, 2010. Treating tobacco use and dependence: 2008 update. U.S. Department of Health and Human Services Web site. Available at: http://www. surgeongeneral.gov/tobacco/index.html. Published May 2008. Accessed April 20, 2010. Tucker KL, Morita K, Qiao N, Hannan MT, Cupples A, Kiel DP. Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: the Framingham Osteoporosis Study. Am J Clin Nutr 2006;84:936942. Levenson DI, Bockman RS. A review of calcium preparations. Nutr Rev 1994;52:221232. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis, 2001 update. Arthritis Rheum 2001;44:14961503. Houghton LA, Veith R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006;84:694697. Update of safety review follow-up to the October 1, 2007, early communication about the ongoing safety review of bisphosphonates. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm . Published November 11, 2008. Accessed April 20, 2010. U.S. Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med 2005;142:855860. FDA drug safety communication: ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ ucm203891.htm. Published March 10, 2010. Accessed April 20, 2010. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756765.

SECTION 12
Bone and Joint Disorders

Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.