Beth Bryles Phillips
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the association between osteoporosis and morbidity and mortality.
2. Identify risk factors that predispose patients to osteoporosis.
3. Describe the pathogenesis of fractures.
4. List the criteria for diagnosis of osteoporosis.
5. Recommend appropriate lifestyle modifications to prevent bone loss.
6. Compare and contrast the effect of available treatment options on reduction of fracture risk.
7. Recommend an appropriate treatment regimen for a patient with osteoporosis and develop a monitoring plan for the selected regimen.
8. Educate patients on osteoporosis and drug treatment, including appropriate use, administration, and adverse effects.
KEY CONCEPTS
Major risk factors for osteoporotic fracture include low bone mineral density, personal history of adult fracture, age, family history of osteoporotic fracture, current cigarette smoking, low body mass index, excessive alcohol use, and chronic glucocorticoid use.
A standardized approach for diagnosing osteoporosis is recommended using central dual-energy x-ray absorptiometry (DXA) measurements.
Both pharmacologic and nonpharmacologic therapies for osteoporosis are aimed at preventing fractures and their complications, maintaining or increasing bone mineral density, preventing secondary causes of bone loss, and improving morbidity and mortality.
All men and women over age 50 be should be considered for pharmacologic treatment if they meet any of the following criteria: history of hip or vertebral fracture, T-score less than or equal to –2.5 at femoral neck or spine, or osteopenia and at least a 3% 10-year probability of hip fracture or at least a 20% 10-year probability of major osteoporosis-related fracture as determined by FRAX.
Adequate calcium and vitamin D intake is essential in prevention and treatment of osteoporosis. Calcium and vitamin D supplements to meet requirements should be added to all drug therapy regimens for osteoporosis.
Bisphosphonates are first-line therapy for postmenopausal osteoporosis due to established efficacy in preventing hip and vertebral fractures.
Alendronate should be considered first-line treatment for primary osteoporosis in men due to proven benefit in reducing fractures and relative safety.
For prevention of glucocorticoid-induced osteoporosis, bisphosphonate therapy is recommended in all patients who are starting treatment with glucocorticoids (prednisone 5 mg or more daily or equivalent) for at least 3 months. For patients receiving chronic glucocorticoids (prednisone 5 mg or more daily or equivalent), bisphosphonate therapy is also recommended if the bone mineral density is low or if there is a history of fracture.
INTRODUCTION
Osteoporosis is a common and often silent disorder causing significant morbidity and mortality and reduced quality of life. It is associated with increased risk and rate of bone fracture and is responsible for over 1.5 million fractures in the United States annually resulting in direct health care costs of over $17 billion.1 As the population ages, these numbers are expected to increase by two- to threefold. It is estimated that postmenopausal Caucasian women have a 50% lifetime chance of developing an osteoporosis-related fracture, whereas men have a 20% lifetime chance.1 Common sites of fracture include the spine, hip, and wrist, although almost all sites can be affected. Only a fraction of patients with osteoporosis receive optimal treatment.
The fractures associated with osteoporosis have an enormous impact on individual patients. In addition to the initial pain associated with a new fracture, several adverse long-term complications can occur, including chronic pain, loss of mobility, depression, nursing home placement, and death. Patients with vertebral fractures may experience chronic pain, height loss, kyphosis, and decreased mobility due to limitations in bending and reaching. Multiple vertebral fractures may lead to restrictive lung disease and alter abdominal anatomy. Patients with hip fractures have added risks associated with surgical intervention to repair the fracture. Some patients never fully recover or regain preinjury independence; mortality is common within one year of hip fracture.
Due to the widespread impact of osteoporosis on the population as a whole, several societies and governmental agencies have published clinical guidelines with recommendations for appropriate evaluation, screening, prevention and treatment of these patients. These groups include the American Association of Clinical Endocrinologists (AACE),2 American College of Physicians (ACP),3,4 International Society for Clinical Densitometry,5 National Osteoporosis Foundation (NOF),1 North American Menopause Society (NAMS),6 and United States Preventive Services Task Force (USPSTF).7 The most recent guidelines were published in 2008 by the National Osteoporosis Foundation. The recommendations of these groups are represented throughout the chapter.
EPIDEMIOLOGY AND ETIOLOGY
Osteoporosis is the most common skeletal disorder, affecting over 10 million Americans. Additionally, over 30 million Americans have low bone mass. The prevalence of vertebral fracture in postmenopausal women is greater than 20%.2 Only one in three patients with osteoporosis has been diagnosed, and only one in seven will receive treatment.2
Osteoporosis can be classified as either primary (no known cause) or secondary (caused by drugs or other diseases). Primary osteoporosis is most often found in postmenopausal women and aging men, but it can occur in other age groups as well.
The prevalence of osteoporosis varies by age, gender, and race/ethnicity. The risk of fracture increases exponentially with each decade in age over 50.8 Residents of nursing homes may be at an even higher risk of fracture. Both men and women lose bone as they age. However, women have accelerated bone loss surrounding menopause due to loss of estrogen. Men have some protection from osteoporosis due to their large bone mass and size and the absence of menopause. Fragility fractures of the hip and spine are common among men, especially as age increases. Men comprise 20% of the Americans with osteoporosis. Secondary causes of osteoporosis are found more commonly in men with fragility fractures.
Table 56–1 Risk Factors for Osteoporosis
Most hip fractures occur in postmenopausal Caucasian women; this group also has the highest incidence of fracture when adjusted for age.9 The incidence of osteoporosis and low bone mass is highest in Caucasian women, followed by Asian, Hispanic, and African American women, respectively9
Many of the risk factors for osteoporosis and osteoporotic fractures are predictors of low bone mineral density, such as age and ethnicity (see Table 56–1). Major risk factors for osteoporotic fracture include low bone mineral density, personal history of adult fracture, age, family history of osteoporotic fracture, current cigarette smoking, low body mass index, excessive alcohol use, and chronic glucocorticoid use.1 As bone mineral density decreases, the risk of fracture increases. However, the threshold at which individual patients develop a fracture varies, and other factors may play a role in fracture susceptibility. One such factor that can influence the development of fracture is falling.
Osteoporosis can also develop from secondary causes such as concurrent disease states and drugs (see Table 56–2). Approximately one-third to one-half of osteoporosis cases in men and half of all cases in perimenopausal women are due to secondary causes.9 Common secondary causes in men include hypogonadism, glucocorticoid use, and alcoholism. The most common cause of drug-induced osteoporosis is glucocorticoid use.
Table 56–2 Medical Conditions and Drugs Associated With Osteoporosis or Low Bone Mass
PATHOPHYSIOLOGY
The human skeleton is comprised of both cortical and trabecular bone. Cortical bone is dense and compact and is responsible for much of bone strength. It is the most common type of bone and accounts for approximately 80% of the skeleton. It is generally found on the surfaces of long and flat bones. Trabecular or cancellous bone has a spongelike appearance and is generally found along the inner surfaces of long bones and throughout the vertebrae, pelvis, and ribs.
Under normal circumstances, the skeleton undergoes a dynamic process of bone remodeling. Bone tissue responds to stress and injury through continuous replacement and repair. This process is completed by the basic multicellular unit, which includes both osteoblasts and osteoclasts. Osteoclasts are involved with resorption or breakdown of bone and continuously create microscopic cavities in bone tissue. Osteoblasts are involved in bone formation and continuously mineralize new bone in the cavities created by osteoclasts. Until peak bone mass is achieved between the ages of 25 and 35, bone formation exceeds bone resorption for an overall increase in bone mass. Trabecular bone is more susceptible to bone remodeling in part due to its larger surface area.
Patient Encounter 1, Part 1: Patient History
A 74-year-old Caucasian woman with a history of chronic obstructive pulmonary disease (COPD) and gastroesophageal reflux disease (GERD) presents to the clinic for follow-up. She reports intermittent daytime and nighttime sweating that comes on suddenly. She reports soaking her bed sheets when this occurs. She had a hysterectomy at age 20 and has never taken estrogen replacement. She reports good relief of reflux symptoms on her current regimen. She started taking a calcium supplement approximately 2 years ago on the suggestion of her friend because she has never gotten much calcium in her diet. She states she does not like milk and never drank it even as a child. She occasionally eats some dairy products such as cheese and ice cream approximately once a week.
PMH: COPD; GERD; S/P total abdominal hysterectomy and bilateral salpingoophorectomy at age 20; nicotine dependence
FH: Father died at age 85 with Alzheimer’s dementia; mother died at age 86 with history of colon cancer and osteoporotic fractures of the hip and spine; brother alive and well at age 71
SH: Retired elementary school teacher; smoked one pack per day for the last 50 years; does not drink alcohol
Meds: Albuterol/ipratropium inhaler two puffs as needed (note: albuterol is known as salbutamol outside the United States); formoterol inhaler 12 mcg twice daily; omeprazole 20 mg daily; calcium carbonate 500 mg daily; multivitamin daily
Do any symptoms suggest the presence of osteoporosis?
What risk factors for osteoporosis does this patient have?
What are her calcium and vitamin D requirements?
How could she incorporate more calcium into her diet?
In osteoporosis, an imbalance in bone remodeling occurs. Most commonly, osteoclastic activity is enhanced resulting in overall bone loss. However, a reduction in osteoblastic activity and reduced bone formation can also occur in certain types of osteoporosis. Due to a decrease in endogenous estrogen, bone remodeling accelerates during menopause and up to 15% of bone is lost during the first 5 years after menopause. After this initial decline, bone loss continues to occur but at a much slower rate of up to 1% per year. The resultant bone loss and change in bone quality predispose patients to low-impact or fragility fractures.
CLINICAL PRESENTATION AND DIAGNOSIS
Diagnosis
Osteoporosis has been defined by the WHO as a disease characterized by low bone density and weakening of bone tissue associated with an increase in fragility and vulnerability to fracture.10 Because bone strength cannot be measured directly, an assessment of bone mineral density is used, which represents 70% of bone strength. Low bone mineral density has been associated with an increased risk of fractures. X-rays are useful only in identifying patients suspected of sustaining a fracture and are not recommended for diagnosis of osteoporosis.
Measurement of Bone Mineral Density
Bone mineral density can be measured at various sites throughout the skeletal system and by various methods. The site of measurement can be either central (hip and/or spine) or peripheral (heel, forearm, or hand). Dual-energy x-ray absorptiometry (DXA) can be used to measure central and peripheral sites of bone mineral density. Quantitative ultrasound, peripheral quantitative computed tomography, radiographic absorptiometry, and single-energy x-ray absorptiometry are used to measure peripheral sites.
The WHO recommends a standardized approach to measuring bone mineral density for diagnosis of osteoporosis using central measurement of bone mineral density by DXA.9 Central DXA is recommended for diagnosis due to inconsistencies in T-scores measured between different sites and by different methods.1,2 Current standards of practice consist of measuring bone mineral density at the lumbar spine and hip, although the WHO suggests the hip is the preferred site for diagnosis.8,10
Peripheral bone mineral density measurements cannot be used for diagnosis because they do not correlate with central measurements. However, they are useful in identifying patients who are candidates for central DXA and who are at increased risk of fracture.6 They may also be useful in patients who have had multiple fractures or in low-risk patients. Additionally, peripheral measurement of bone mineral density is generally less expensive than central DXA and is easily accessible. Instruments used for peripheral bone densitometry are portable, which allows bone density to be measured in pharmacies and health-fair screening booths.
Clinical Presentation and Diagnosis of Osteoporosis
General
Many patients with osteoporosis are asymptomatic unless they experience a fragility fracture.
Symptoms
Symptoms of fragility fracture include pain at the site of the fracture or immobility.
Signs
Height loss (greater than 2 cm), spinal kyphosis (“dowager’s hump”), fragility fracture especially of the hip or spine.
Laboratory Tests
Lab tests are only useful to rule out secondary causes of osteoporosis.
Diagnostic Tests
Bone densitometry using DXA reveals a T-score at least -2.5 SD below the mean.
Once the bone mineral density report is available, T-scores and Z-scores are useful tools in interpreting the data. The T-score is the number of standard deviations from the mean bone mineral density in healthy young white women. Osteoporosis is defined as a T-score at least -2.5 standard deviations below the mean (Table 56–3). Osteopenia, or low bone mass that may eventually lead to osteoporosis, is defined as a T-score between -2.5 and -1.0 standard deviations below the mean. The International Society for Clinical Densitometry recommends use of the WHO definition and T-scores for diagnosis of osteoporosis in postmenopausal women and men over the age of 65, and in men between the ages of 50 and 65 if other risk factors are present.5
The Z-score is a similar measure that is corrected for age and gender of the patient. The Z-score is defined as the number of standard deviations from the mean bone mineral density of age- and sex-matched controls. In premenopausal women, men under the age of 50, and patients who may have secondary causes for low bone mineral density, Z-scores may be more clinically relevant in evaluating bone mineral density.
Screening and Risk Factor Assessment
Screening for low bone density is an effective way to identify individuals at risk for osteoporotic fracture. A number of published osteoporosis guidelines provide recommendations for screening based on age and risk factors.1–7Routine bone mineral density screening is generally recommended for all women over the age of 65 and men over the age of 70.1–3,6,7,11 Many guidelines also recommend screening in individuals under these ages but over the age of 50 with specific risk factors such as previous fragility fracture, glucocorticoid use or other high-risk medication, or secondary cause of osteoporosis.
An additional tool, FRAX, was developed by the WHO to evaluate an individual’s 10-year risk for hip and major osteoporotic fracture.1 This probability is calculated based on BMD T-score, age, and other risk factors. Its intended use is for men and women over the age of 50 and may be accessed at www.shef.ac.uk/FRAX. Although the T-score is helpful in calculating risk of fracture with FRAX, fracture risk may be calculated without it. Additionally, the NOF recommends adjusting the T-score prior to using it in the FRAX risk calculator. The patch is available at www.nof.org/frax_patch.htm.
Table 56–3 WHO Definition of Osteoporosis
Laboratory Evaluation
Laboratory assessment has little value in diagnosing osteoporosis, but it can be beneficial in identifying or excluding secondary causes of bone loss, such as hyperparathyroidism, low 25-hydroxyvitamin D levels, hyperthyroidism, hypogo-nadism, or cancer.8 Biochemical markers of bone turnover such as pyridinoline, deoxypyridinoline, N-telopeptides, and C-telopeptides of Type I collagen cross-links have been associated with an increased fracture risk in some trials. Variations in the normal ranges of these tests may be related to age, gender, food, and diurnal variation, making interpretation of these tests difficult.2 For these reasons, biochemical markers of bone turnover are not recommended for diagnosis of osteoporosis.
TREATMENT
Desired Outcomes
Pharmacologic and nonpharmacologic therapies are aimed at the following goals: (a) preventing fractures and their complications; (b) maintaining or increasing bone mineral density; (c) preventing secondary causes of bone loss; and (d) reducing morbidity and mortality associated with osteoporosis.
Nonpharmacologic Therapy
The primary goal of nonpharmacologic therapy for osteoporosis is to prevent fractures. Strategies include maximizing peak bone mass, reducing bone loss, and using precautions to prevent falls leading to fragility fractures (Fig. 56–1).
Modification of Risk Factors
Some osteoporosis risk factors (see Tables 56–1 and 56-2) are nonmodifiable, including family history, age, ethnicity, gender, and concomitant disease states. However, certain risk factors for bone loss may be minimized or prevented by early intervention, including smoking, low calcium intake, poor nutrition, inactivity, heavy alcohol use, and vitamin D deficiency. In order to avoid certain risk factors and maximize peak bone mass, efforts must be directed toward osteoporosis prevention at an early age.
Nutrition
Good nutrition is essential for intake of sufficient nutrients and maintenance of appropriate weight. Dietary calcium intake is important for achieving peak bone mass and maintaining bone density. Adequate dietary intake of vitamin D is essential for calcium absorption. Table 56–4 lists calcium and vitamin D requirements for different age groups. Good dietary sources of calcium include dairy products, fortified juice, cruciferous vegetables (e.g., broccoli, kale), salmon, and sardines (see Table 56–5). The most common source of vitamin D comes from exposure to sunlight. Ultraviolet rays from the sun promote synthesis of vitamin D3 (cholecalciferol) in the skin. This generally occurs within 15 minutes of sunlight exposure. It is recommended that individuals receive twice weekly sun exposure to ensure optimal synthesis. Vitamin D may also be found in some dietary sources, including fortified milk, egg yolks, salt-water fish, and liver.
Exercise
Exercise can be beneficial in preventing fragility fractures. Weight-bearing exercise such as walking, jogging, dancing, and climbing stairs can help build and maintain bone strength. Muscle-strengthening or resistance exercises can help improve and maintain strength, agility, and balance, which can reduce falls.1 It is important to develop and maintain a lifelong routine of weight-bearing and resistance exercise as the benefits on bone can be lost after cessation of the exercise program.1
Table 56–4 Recommended Daily Calcium and Vitamin D Intake
Table 56–5 Calcium-Rich Foodsa
1 cup skim milk
1 cup soy milk (calcium-fortified)
1 cup yogurt
1½ ounces cheddar cheese
1½ ounces jack cheese
1½ ounces Swiss cheese
1½ ounces part-skim mozzarella
4 tablespoonfuls grated Parmesan cheese
8 ounces tofu
1 cup greens (collards, kale)
2 cups broccoli
4 ounces almonds
2 cups low-fat cottage cheese
3 ounces sardines with bones
5 ounces canned salmon
1 cup orange juice (calcium-fortified)
a Foods containing approximately 300 mg of elemental calcium.
Falls Prevention
Another crucial step in avoiding fragility fractures is prevention of falls. Patients with frailty, poor vision, hearing loss, or those taking medications affecting balance are at higher risk for falling and subsequent fragility fractures.1,2
A number of medications have been associated with an increased risk of falling, including drugs affecting mental status such as antipsychotics, benzodiazepines, tricyclic anti-depressants, sedative/hypnotics, anticholinergics, and corticosteroids. Some cardiovascular and antihypertensive drugs can also contribute to falls, especially those causing orthostatic hypotension.1
Efforts to decrease the risk of falling include balance training, muscle strengthening, removal of hazards in the home, installation of fall reduction measures such as handrails in the home, and discontinuation of predisposing medications.1,2,14 Use of hip protectors also helps prevent hip fractures, although adherence to this measure may be problematic.14
Pharmacologic Treatment (Fig. 56–1)
The NOF recommends that all men and women over age 50 be considered for pharmacologic treatment if they meet any of the following criteria: history of hip or vertebral fracture, T-score less than or equal to –2.5 at femoral neck or spine, or osteopenia and at least a 3% 10-year probability of hip fracture or at least a 20% 10-year probability of major osteoporosis-related fracture as determined by FRAX.1
FIGURE 56–1. Algorithm for management of osteoporosis in postmenopausal women (A) and in men (B). (BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.) (Adapted from DiPiro JT, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1490–1491, Figure 93–3, with permission; updated with information from Ref.1.)
Calcium and Vitamin D
Adequate calcium and vitamin D intake are essential for preventing and treating osteoporosis. Calcium and vitamin D supplements to meet requirements should be added to all drug therapy regimens for osteoporosis. Calcium and vitamin D supplementation increases bone mineral density, and the combination decreases the risk of hip and vertebral fractures. Additionally, vitamin D supplementation decreases nonvertebral fractures in older men and women living independently.15
Calcium plays an important role in maximizing peak bone mass and decreasing bone turnover, thereby slowing bone loss. When the calcium supply is insufficient, calcium is taken from bone stores to maintain the serum calcium level. Adequate calcium consumption is essential to prevent this from occurring. Calcium supplementation may also correct hyperparathyroidism in elderly patients.
The highest daily elemental calcium requirements of 1,500 mg are recommended for postmenopausal women and elderly men over age 65. When these requirements cannot be achieved by diet alone, appropriate calcium supplementation is recommended.
Calcium supplements are available in a variety of calcium salts and dosage forms. Calcium requirements are listed in terms of elemental calcium. However, many product labels list calcium content in the salt form, so the percentage of elemental calcium must be known to calculate the elemental calcium content per tablet.
Some calcium products contain lead.16 While the clinical significance and long-term risks are unknown, it is best to use supplements without a high lead content. Due to the number of calcium supplements available, patients may find it overwhelming to choose a supplement. Health care providers can help patients find a suitable and tolerable supplement with good absorption and high elemental calcium content, necessitating fewer tablets per day. Table 56–6lists widely available supplements with elemental calcium and vitamin D content.
A number of factors can limit calcium absorption, and special consideration must be given to calcium dosing to maximize absorption. Large amounts of calcium taken at once cannot be absorbed. Supplement doses should be limited to 500 to 600 mg of elemental calcium per dose. Calcium intake greater than 2,500 mg/day should be avoided due to increased risk of toxicity, including hypercalciuria and hypercalcemia.6
Calcium carbonate should be taken with food to maximize absorption. Elderly patients or patients receiving proton pump inhibitors or H2-receptor antagonists may have added difficulty absorbing calcium supplements due to reduced stomach acidity. Better absorption may occur in this setting with calcium citrate because an acid environment is not needed for absorption; it may be taken with or without food.
Table 56–6 Calcium and Vitamin D Content of Common Supplementsa
Common adverse effects of calcium salts include constipation, bloating, cramps, and flatulence. Changing to a different salt form may alleviate symptoms for some patients. Calcium salts may reduce the absorption of iron and some antibiotics, such as tetracycline and fluoroquinolones.
Vitamin D is crucial for calcium absorption and maintenance of bone. The NOF recommends a daily vitamin D intake of 800 to 1,000 mg for all men and women age 50 and older (see Table 56–4).1 Some individuals are at risk for vitamin D deficiency, including elderly patients with malabsorption syndromes, chronic renal insufficiency, other chronic diseases and those with limited sun exposure.1 For example, most elderly patients living in nursing homes will not be able to meet vitamin D requirements and will need supplementation. Vitamin D deficiency is common in elderly patients due to decreased exposure to sunlight and subsequent decreased vitamin D synthesis in the skin, decreased GI absorption of vitamin D, and reduction in vitamin D3 synthesis. Individuals living in northern climates also have decreased exposure to sunlight and are less likely to achieve vitamin D requirements.
Patient Encounter 1, Part 2: Physical Exam and Diagnostic Tests
ROS: (+) hot flushes, 5-cm height loss since middle age; (-) back pain
PE:
Gen: Well developed Caucasian woman in no acute distress
VS: BP 122/66, P 77, RR 16, T 36.3°C (97.3°F), wt 55.4 kg (122 lb), ht 5’3½” (161 cm)
Chest: Decreased breath sounds bilaterally, air movement decreased; no rales or rhonchi
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
Abd: Soft, nontender, nondistended; normal bowel sounds, no hepatosplenomegaly
Ext: No clubbing, cyanosis, or edema Labs: Within normal limits
Bone Densitometry by DXA
• BMD of left hip: 0.544 g/cm2; T-score: -3.3
• BMD of lumbar spine: 0.683 g/cm2; T-score: -3.3
What additional risk factor and signs of osteoporosis are present in this patient?
What are the goals of pharmacologic and nonpharmacologic therapy?
List at least three nonpharmacologic interventions important in her treatment plan.
What factors support pharmacotherapy for osteoporosis in this patient?
What type of calcium supplement would you recommend for this patient? Why?
Vitamin D is often combined in varying amounts with calcium salts. A multiple vitamin is another good source of vitamin D. Most multivitamins contain 400 IU per tablet. Vitamin D is also available as a single entity. To avoid hypercalciuria and hypercalcemia, the maximum recommended dose for most patients is 2,000 IU/day. Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are available in higher doses and are generally reserved for patients with vitamin D deficiency.
Bisphosphonates
Bisphosphonates are first-line therapy for osteoporosis due to established efficacy in preventing hip and vertebral fractures. They are also the most commonly prescribed therapy for osteoporosis. They decrease bone resorption by binding to the bone matrix and inhibiting osteoclast activity. They remain in the bone for a prolonged period and are released very slowly. These effects increase bone mineral density. Although several bisphosphonates are currently available, only alendronate, ibandronate, risedronate, and zoledronic acid are currently approved by the FDA for use in osteoporosis. Table 56–7contains comparative dosing and cost information for these bisphosphonates.
In placebo-controlled clinical trials, bisphosphonates increased bone mineral density by up to 5% to 8% in the lumbar spine, and up to 3% to 6% in the hip.17–20 Additional data with oral bisphosphonates suggest that bone mineral density continues to increase with long-term therapy of 7 to 10 years.21,22 Although increases in bone mineral density have been reported at other sites, most of the clinically significant fractures occur in the hip or spine, and these sites have become clinically important measures in the trials. These increases in bone mineral density at the hip and spine are an important marker of treatment effects and are probably related to the decreases in fracture risk found in larger trials.
Table 56–7 Dosage Regimens and Cost of Prescription Agents for Osteoporosis
Large, well-designed trials have proven the benefits of bisphosphonate therapy in preventing vertebral and nonvertebral fractures. Several studies have found decreases in vertebral fracture risk by as much as 40% to 50% with oral bisphosphonates and up to 70% with zoledronic acid.1,17,23 Although data suggest a similar reduction on vertebral fractures with ibandronate, only alendronate, risedronate, and zoledronic acid have been shown to decrease the incidence of hip and nonvertebral fractures as well by as much as 25% to 40%.19,20,23,24 In addition to benefits in fracture reduction, the Horizon Recurrent Fracture Trial found a 28% decrease in mortality associated with hip fracture in patients treated with IV zoledronic acid.20
Several studies have evaluated the long-term efficacy and safety of bisphosphonates in postmenopausal women. One study evaluated the use of alendronate over a 10-year period and found no difference in adverse effects between women who received alendronate for 10 years compared to women who discontinued alendronate after 5 years. Women who discontinued alendronate after 5 years continued to experience sustained increases in bone mineral density compared to baseline values and reduction in fracture rates.21 Another study found sustained increases in bone mineral density after discontinuation of alendronate, albeit less than in those who continued longer-term alendronate therapy.25 A 7-year follow-up study with risedronate found continued increases in bone mineral density and no increase in adverse effects in women receiving risedronate for 7 years compared to women receiving risedronate for 2 years.22
The safety of long-term bisphosphonates observed in clinical trials has been challenged by a number of case reports. Concern exists over the use of chronic bisphosphonate therapy due to reports of nonvertebral atraumatic fractures and osteonecrosis of the jaw (ONJ).26–28 One report described nonvertebral atraumatic fractures in nine patients and delayed fracture healing in four of those patients while receiving alendronate therapy for 3 to 8 years. Bone biopsies in all patients revealed severely suppressed bone turnover, which may have caused bone weakening due to suppression of osteoclastic activity.26,27Another report described 63 cases of ONJ resistant to conservative measures and requiring surgical intervention in most cases.28 A majority of the cases were reported in cancer patients who had received an IV bisphosphonate and only a small number of cases were reported in women who had received oral bisphosphonates for osteoporosis.28 Risk factors for development of ONJ include chemotherapy, radiotherapy, corticosteroids, infection or pre-existing dental disease.
The most notable adverse effects associated with the bisphosphonates are GI, ranging from relatively mild nausea, vomiting, and diarrhea to more severe esophageal irritation, and esophagitis. However, the most common adverse reactions reported in clinical trials include dyspepsia, abdominal pain, nausea, and esophageal reflux. Clinically significant adverse events include esophageal ulceration, erosions with bleeding, perforation, stricture, and esophagitis. Upper GI adverse effects can occur in up to 20% of patients taking these medications and are often related to inappropriate administration. Other factors that increase risk for GI adverse events include advanced age, previous upper GI tract disease, and use of nonsteroidal anti-inflammatory drugs. Along with appropriate administration, once-weekly administration of oral bisphosphonates may decrease the risk of adverse GI effects.
In addition to the adverse effects associated with oral bisphosphonates, a number of adverse effects have been noted with injectable bisphosphonates, specifically zoledronic acid. Patients in osteoporosis clinical trials experienced a higher rate of atrial fibrillation, increases in serum creatinine, and infusion-related reactions. Pretreatment with acetaminophen may alleviate the influenza-like symptoms of headache, arthralgia, myalgia, and fever.1,20 Laboratory monitoring, including serum creatinine, alkaline phosphatase, phosphate, magnesium, and calcium, is recommended prior to administration of each dose.
Oral bisphosphonates are poorly absorbed (less than 5%). Taking them in the presence of food or calcium supplementation further reduces absorption. After absorption, bisphosphonate uptake to the primary site of action is rapid and sustained. Once attached to bone tissue, bisphosphonates are released very slowly. They are not recommended for use in patients with renal insufficiency as they are renally excreted and not metabolized.
Proper drug administration is important for optimal absorption and prevention of adverse effects. Oral bisphosphonates should be taken 30 to 60 minutes prior to the first meal or food in the morning after an overnight fast with 6 to 8 ounces (about 180–240 mL) of water (or 2 ounces [60 mL] with the oral solution). Patients should remain upright and refrain from lying down for 30 to 60 minutes after administration. The tablets should be swallowed whole without chewing or sucking. Administration should be with water only and not combined with other fluids. Bisphosphonates should not be taken with other medications or dietary supplements. Bisphosphonates are not recommended for use in patients with esophageal abnormalities, hypocalcemia, renal insufficiency or failure (creatinine clearance less than 30–35 mL/min). For patients unable to tolerate oral bisphosphonates, options exist for IV administration with ibandronate or zoledronic acid.
Selective Estrogen Receptor Modulators
Raloxifene is a selective estrogen receptor modulator (SERM) that has estrogen-like activity on bones and cholesterol metabolism and estrogen antagonist activity in breast and endometrium. These drugs reduce bone resorption and decrease overall bone turnover. The related SERMs tamoxifen and toremifene have partial agonist and antagonist activity at various estrogen receptors. However, the latter agents are limited to the treatment of breast cancer; potential adverse effects preclude further study for long-term use in osteoporosis.
Raloxifene increases bone mineral density and reduces fracture rates. In trials of 1 to 3 years, raloxifene increased vertebral and hip bone mineral density by 2% to 3% and 1% to 2%, respectively.29 In the Multiple Outcomes for Raloxifene Evaluation (MORE) trial, raloxifene decreased the risk of vertebral fractures by 30% in postmenopausal women with at least one prior fracture.29 No significant reduction in nonvertebral fractures was reported.
Additional beneficial effects of raloxifene relate to its antagonistic activity in breast tissue. The Raloxifene Use for the Heart (RUTH) study found a significant decrease in estrogen receptor positive invasive breast cancers in postmenopausal women who took raloxifene for more than 5 years.30 Raloxifene’s beneficial effects on the lipid profile prompted the RUTH trial, which sought to determine raloxifene’s impact on cardiovascular disease. This study did not find a difference in cardiovascular events but did reveal an increased risk of fatal stroke in women treated with raloxifene.30
Adverse effects of raloxifene include hot flushes, leg cramps, and increased risk of venous thromboembolism. Hot flushes are very common and may be intolerable in postmenopausal women who are already predisposed to experiencing them. A more serious adverse effect is the significantly increased risk of venous thromboembolism that has been found in clinical trials.30 A previous history of venous thromboembolism is a contraindication to therapy.
Hormone Therapy
Estrogen, either alone or in combination with a progestin as hormone replacement therapy (HRT), has a long history as an effective treatment of osteoporosis. The Women’s Health Initiative (WHI) trial found a 33% reduction in both vertebral and hip fractures and a 23% reduction in other fractures in postmenopausal women receiving conjugated estrogen and medroxyprogesterone.31 However, data from the WHI and another well-designed trial, the Hormone and Estrogen/progestin Replacement Study (HERS), found significant risks associated with HRT, including a higher incidence of breast cancer and venous thromboembolism.31,32 For these reasons, the AACE no longer recommends estrogen or hormone replacement therapy for the treatment of osteoporosis.
Calcitonin
Calcitonin is a naturally occurring mammalian hormone that plays a major role in regulation of calcium levels. It inhibits bone resorption by binding to osteoclast receptors. Compared to mammalian calcitonin, salmon calcitonin has high potency and extended duration of action. Although commercial formulations of calcitonin-salmon are actually synthetic and not derived from salmon, they contain the same amino acid sequence as calcitonin of salmon origin.
Calcitonin salmon is available in injectable and intranasal formulations. It cannot be administered orally due to inactivation by gastric fluids. The parenteral formulation must be administered either subcutaneously or intramuscularly every other day. It is associated with significant adverse effects including flushing, urinary frequency, nausea, vomiting, abdominal cramping, and irritation at the injection site. Additionally, the benefits of the parenteral formulation on bone may diminish over time due to the formation of neutralizing antibodies.
The intranasal formulation is the preferred route of administration due to ease of administration and fewer adverse effects, which are mainly local in nature. Adverse effects associated with the intranasal formulation include rhinitis, nasal irritation, and dryness. Hypersensitivity can develop with either formulation and should be considered before administering to patients with suspected risk of hypersensitivity.
Perhaps the most benefit of calcitonin salmon is in patients with or at risk for vertebral fractures. Nasal calcitonin increases vertebral bone mineral density by 1% to 3%.33 One 5-year study found a 30% decrease in the risk of vertebral fractures.33 However, increases in hip bone mineral density and reductions in nonvertebral fractures have not been demonstrated.33 Calcitonin may have analgesic effects in women with back pain from vertebral fractures. However, enthusiasm for using calcitonin in this setting has waned in favor of managing fracture risk and pain separately.12
Anabolic Agents
Teriparatide, recombinant human parathyroid hormone (1-34), is the first anabolic agent approved by the FDA for treatment of osteoporosis. It is generally reserved for patients with moderate to severe osteoporosis. This agent differs from antiresorptive therapies in that it stimulates osteoblastic activity to form new bone when administered once daily. Teriparatide also has many actions that are similar to endogenous parathyroid hormone, and continuous infusions actually stimulate osteoclastic activity and increase bone resorption. In one study, its bone-forming properties increased bone mineral density in the spine and hip by 9% and 3%, respectively. After 21 months of therapy, these increases led to 65% and 35% reductions in vertebral and nonvertebral fractures, respectively.34
The dose of teriparatide is 20 mcg given by subcutaneous injection once daily. It is available in a prefilled multiple-dose pen delivery system. Common adverse effects include nausea, headache, leg cramps, dizziness, injection site discomfort, and hypercalcemia. Patients may also experience orthostatic hypotension. For this reason, patients should be seated after the first several doses until drug response is predictable. Osteosarcoma has been observed in animal studies, but no cases have been reported in humans. However, this potential concern has led to the inclusion of a “black-box warning” in the product labeling. The warning states that teriparatide should not be used in patients at increased risk for osteosarcoma, including patients with Paget’s disease of bone, unexplained elevations of alkaline phosphatase, prior radiation therapy involving the skeleton, and/or children and young adults with open epiphyses. Additionally, teriparatide should not be used in patients with pre-existing hypercalcemia. Patient-related concerns regarding the use of teriparatide include cost of therapy and need for subcutaneous injections. The labeling recommends treatment for a maximum of 2 years because it has not been studied for longer periods.
Combination and Sequential Therapy
Interest in combination antiresorptive therapies developed from the hope that using two agents with differing mechanisms for inhibiting bone resorption would result in greater increases in bone mineral density and reductions in fracture rates. Studies have evaluated the combination of bisphosphonates plus estrogen or raloxifene, or estrogen plus calcitonin. Combination therapy produced greater increases in bone mineral density than single agents in some trials, but there was no further reduction in fracture risk. Combination therapy is also more expensive, and concern has been raised that significant reductions in bone turnover may promote bone that is more brittle.35 The AACE does not recommend combination antiresorptive therapy for treating osteoporosis.
The combination of a bisphosphonate with anabolic therapy (teriparatide) should not be used because a well-controlled trial showed that women receiving the combination actually had smaller increases in bone mineral density than women receiving teriparatide alone.36 However, sequential therapy with these agents may be more promising. In one study, women who received parathyroid hormone for 1 year followed by alendronate for 1 year had greater increases in bone mineral density than those receiving combination alendronate plus parathyroid hormone, alendronate monotherapy, or parathyroid hormone for one year followed by placebo for 1 year. Additionally, patients who received no therapy after 1 year of parathyroid hormone experienced decreases in bone mineral density.37 Whether sequential therapy leads to reductions in fracture risk remains to be seen.
Other Therapies
Investigational Agents
Several agents, including anabolic and antiresorptive therapies, are currently under investigation for treatment of osteoporosis. A number of SERMs (ospemifene, lasofoxifene, bazedoxifene, and arzoxifene) are undergoing phase 2 and 3 clinical trials for treatment of osteoporosis.38
Strontium ranelate is an oral agent possessing bone-forming and antiresorptive properties. Some data suggest significant reductions in vertebral fractures.39 However, the benefit in nonvertebral fractures is unclear.
Denosumab is a human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL) action. The resultant antiresorptive effects are fully reversible, which may be advantageous in patients who experience adverse events. In clinical trials, denosumab was administered subcutaneously at 3- and 6-month intervals.40
PTH (1-84) is an injectable parathyroid hormone that is currently being investigated for use in osteoporosis. It is an 84 amino acid peptide and is known as full-length parathyroid hormone. This is in contrast to teriparatide (PTH 1-34), which is an N-terminal parathyroid hormone analog. It is thought that the full-length parathyroid hormone has additional biologic functions on the bone.41 PTH (1-84) has shown mixed results in vertebral and hip fracture reduction.38
Alternative Therapies
Several studies have evaluated dietary supplements such as isoflavones, which are found in soy products and red clover. A well-controlled trial in more than 400 postmenopausal women evaluating a specific isoflavone, ipriflavone, found no benefits on bone mineral density or fracture rates after 3 years.42 Nevertheless, because these therapies are available without prescription and are not regulated by the FDA, patients may choose to self medicate with isoflavones. Lymphocytopenia appeared in several patients treated with ipriflavone in clinical trials. Additionally, ipriflavone should be used with caution in immunocompromised patients or those with renal disease. It may inhibit CYP 1A2 and 2C9 and may interact with drugs metabolized by those pathways, such as warfarin.
Treatment of Special Populations
Premenopausal Women
The NOF recommends measuring bone mineral density in premenopausal women with specific risk factors for osteoporosis, such as medical condition or medication, in whom treatment would be considered.1Premenopausal women at risk for osteoporosis should follow all nonpharmacologic recommendations for exercise and adequate calcium and vitamin D intake. Currently, no good data are available regarding pharmacologic therapy on fracture reduction in this population. Bisphosphonates should be used with caution in this population due to pregnancy risks and uncertain long-term effects.
Men
Compared to postmenopausal osteoporosis, few clinical trials have been conducted evaluating therapies in men. Although alendronate and calcitonin have both been studied, only alendronate reduces fracture rates in men. Teriparatide has also been studied, but no data are yet available on fracture rates. At this time, alendronate and teriparatide are FDA-approved for the treatment of osteoporosis in men. Due to proven benefit in reducing fractures and relative safety, alendronate should be considered first-line treatment for primary osteoporosis in men. Teriparatide should be reserved as alternate therapy in this population. Because secondary osteoporosis causes play a significant role in men, any secondary cause (e.g., hypogonadism) should be excluded or treated before considering other drug therapy.
Glucocorticoid-Induced Osteoporosis
Glucocorticoids play a significant role in bone remodeling. Exogenous glucocorticoid administration results in an increase in bone resorption, inhibition of bone formation, and change in bone quality. Glucocorticoids (e.g., prednisone, hydrocortisone, methylprednisolone, and dexamethasone) promote bone resorption through reduced calcium absorption from the GI tract and increased renal calcium excretion. Bone formation is reduced through inhibition of osteoblasts. They also decrease estrogen and testosterone production.
Patients receiving long-term glucocorticoids are at increased risk of fracture. This risk is greater with higher doses and longer-term therapy. Most bone is lost during the initial 6 to 12 months of therapy, and bone mass continues to decline thereafter. Due to the risk of bone loss and fractures, therapy is recommended for patients receiving long-term supraphysiologic doses of glucocorticoids.
In addition to nonpharmacologic measures, the American College of Rheumatology (ACR) has specific recommendations for preventing and treating patients receiving glucocorticoids.43 Recommendations for optimal calcium and vitamin D intake are higher for patients receiving glucocorticoids. These recommendations include 1,500 mg daily of elemental calcium and 800 IU daily of vitamin D for all adults receiving glucocorticoids. Patients should take a vitamin D–containing supplement to ensure these requirements are being met.
The ACR recommends bisphosphonate therapy for all patients who are starting treatment with glucocorticoids (prednisone 5 mg or more daily or equivalent) that will continue for 3 months or longer. For patients receiving chronic glucocorticoids (prednisone 5 mg or more daily or equivalent), bisphosphonate therapy is also recommended if the bone mineral density is low or there is a history of fracture.43Calcitonin may be used in patients who are intolerant of bisphosphonates.
GI Disease
Various GI disorders, including inflammatory bowel disease, celiac disease, and postgastrectomy states, are associated with osteoporosis due to impairment of calcium and vitamin D absorption, corticosteroid-induced bone changes, and chronic inflammatory states. The American Gastroenterological Association recommends bone mineral density measurement in high-risk patients and consideration of treatment for patients with a T-score below –2.5, history of vertebral compression fracture, or who are receiving long-term glucocorticoids.44
Patient Encounter 1, Part 3: Development of a Treatment Plan
Considering all of the information presented, develop a treatment plan for this patient. Include the following information:
(a) recommendations for patient-specific drug therapy including dose and frequency; (b) patient education about the chosen regimen; (c) monitoring plan for efficacy and adverse effects; and (d) consideration of alternative therapies if the initial therapy fails or is intolerable.
OUTCOME EVALUATION
• Evaluate patients for progression of osteoporosis, including signs and symptoms of new fragility fracture (e.g., localized pain), loss of height, and physical deformity (e.g., kyphosis). Assess patients on an annual basis or more often if new symptoms present.
Patient Care and Monitoring
1. Assess patient risk factors for osteoporosis, with special attention to age, menopausal status, previous history of osteoporotic fracture, smoking status, low body weight, family history of osteoporotic fracture in first-degree relatives, and presence of secondary causes of osteoporosis.
2. Perform a thorough medication history, including prescription, over-the-counter, and alternative therapies. Pay special attention to any vitamins and calcium and vitamin D supplements the patient is taking.
3. Assess nonpharmacologic interventions for preventing osteoporotic fractures, including nutrition, weight-bearing and muscle-strengthening exercise regimens, and fall risk.
4. Determine average calcium intake from diet (Table 56–5) and supplements (Table 56–6). Compare to age-adjusted recommendations (Table 56–4). Evaluate the patient’s sources of vitamin D. Recommend appropriate calcium and vitamin D supplementation.
5. Review bone densitometry (i.e., central DXA) for presence of low bone mass (i.e., T-score below -2.5 in the spine or hip. If T-score is between -1.0 and -2.5, use the FRAX risk calculator to estimate fracture risk.
6. Educate the patient about nonpharmacologic measures to prevent osteoporotic fractures.
7. If drug therapy is indicated, assess the patient for contraindications (e.g., esophageal disease or severe renal impairment for bisphosphonate therapy).
8. Educate the patient on the drug therapy selected, including drug name, dose, method of administration, common or serious adverse reactions, adherence and monitoring. Pay special attention to administration instructions and monitoring for adverse effects. Include a discussion about the therapeutic goals and expectations (e.g., changes in individual T-scores may not necessarily correlate with benefit in fracture risk reduction).
9. Develop a monitoring plan, including assessment of efficacy, adverse effects, nonpharmacologic measures to prevent fractures and appropriate drug administration.
• Monitor for beneficial effects on bone density. The NOF recommends a follow-up DXA scan every 2 years to monitor the effects of therapy.
• Assess patients for adverse effects of therapy:
• Bisphosphonates: Dyspepsia, esophageal reflux, esophageal pain, or burning
• Zoledronic acid: Influenza-type symptoms related to infusion, ONJ (rare)
• SERMs: Hot flushes, signs or symptoms of thromboembolic disease (e.g., pain, redness, or swelling in one extremity, chest pain, and shortness of breath)
• Calcitonin salmon: Nasal irritation or burning
• Teriparatide: Nausea, headache, leg cramps, hypercalcemia
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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