Metabolic Bone Disease

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[edit] Metabolic Bone Disease

Michael F. Holick

Metabolic bone disease is a general term that includes diversity of bone diseases caused by a metabolic abnormality or pathology, such as renal failure, liver disease, endocrinopathies, vitamin D deficiency, estrogen deficiency, and Paget's disease. This chapter discusses osteoporosis, which affects four times as many women as men, and Paget's disease (see Chapter 100 ).^[1]

[edit] OSTEOPOROSIS

Osteoporosis is the most common metabolic bone disease and afflicts approximately 20 million women and 5 million men in the United States. The simplest definition of osteoporosis is porotic bone or holes in the bone (Fig. 45-1). This is an important distinction because porosity of bone does not cause bone pain. The consequence of osteoporosis (i.e., decrease in both bone matrix and bone mineral content), however, leads to compromised bone structure and strength, increasing the risk of fracture. Skeletal fracture in turn leads to acute and chronic bone and muscle pain.

Figure 45-1 Vertebral bodies from young woman (left) and elderly osteoporotic woman (right). Note marked loss of horizontal and vertical struts (trabeculae), wide spaces (holes), and severe compression of vertebral body on right.

[edit] Epidemiology and Risk Factors

Classically, osteoporosis is associated with a thin, white female who has been menopausal for 10 to 15 years. Both men and women of all races, however, are at risk of developing osteoporosis in their lifetime. The prevalence of osteoporosis increases progressively with age; by age 80, an estimated 25% of women and 15% of men have had a hip fracture. Although osteoporosis is often considered a benign disease of little consequence, osteoporotic fractures cause chronic debilitating pain, diminished quality of life, and even death. About 1.5 million skeletal fractures and 250,000 hip fractures occur annually because of this disease. Of patients with a hip fracture, 10% to 15% die within the first year from complications, 50% never regain their previous quality of life, and many require chronic care in a nursing home. Approximately $8 billion is spent annually for the acute care of patients with hip fractures. As the U.S. population grows older, by 2020 an estimated $120 billion dollars a year will be spent for the acute and chronic care of these patients.^[2]

Risk factors for osteoporosis include early age of onset for menopause, family history, history of amenorrhea or oligomenorrhea during the second and third decades, and poor lifetime intake of calcium (Box 45-1). Genetically, blacks have “stronger” bones (higher bone mineral density), but they are still at risk for osteoporosis because of poor calcium nutrition, often from lactase deficiency. Blacks also have decreased ability to make vitamin D₃ in their skin because of increased skin melanin, which leads to chronic vitamin D deficiency and secondary hyperparathyroidism.^[3]

[edit] Pathophysiology

Causes of osteoporosis include loss of ovarian function, calcium and vitamin D deficiency, and aging (Box 45-2). Osteoporosis is classified as two types: type I is caused by estrogen deficiency after menopause or ovariectomy (oophorectomy), and type II is associated with aging. These designations, however, are not particularly helpful in either diagnosis or treatment because osteoporosis is a multifactorial disease.^[4]

In women, estrogen plays an essential role in the bone-remodeling process. Osteoblasts, which lay down the collagen matrix for bone mineralization, have receptors for estrogen. Estrogen regulates bone mineralization and demineralization by coupling osteoblastic with osteoclastic activity. Without estrogen, this process uncouples, leading to decreased osteoblastic function and increased osteoclastic destruction of both the matrix and the mineral. This uncoupling can lead to rapid bone loss. As women enter menopause, they can lose 2% to 3% of their bone mass each year. This is usually unrelenting and continues for at least a decade, with up to a 30% to 50% reduction in skeletal density. Both men and women have an age-related decrease in bone of approximately ½% to 1% a year after age 50 years. Although the exact cause is unknown, this loss may result from the kidney's inability to produce an adequate amount of activated vitamin D₃ (1,25-dihydroxyvitamin D₃, [1,25(OH₂)D₃]), resulting in a decrease in intestinal calcium absorption. Steroids also can decrease the efficiency of intestinal calcium absorption and alter the bone-remodeling process, causing rapid loss of bone mineral content even in children and young adults.

Chronic calcium and vitamin D deficiency leads to an increase in serum levels of parathyroid hormone (PTH), which increases the mobilization of calcium stores from the bone, leading to or exacerbating osteoporosis. In addition, vitamin D deficiency causes a mineralization defect of the bone matrix (osteomalacia), resulting in decreased bone mineral content and increased risk of fracture. Primary hyperparathyroidism, which affects approximately 0.1% of the adult U.S. population, can lead to osteoporosis.^[5] Because hyperparathyroid disease enhances cortical bone loss more than trabecular bone loss, these patients are at increased risk of wrist and hip fractures.

[edit] Patient History

Although women are more likely to develop osteoporosis at an earlier age than men, it is important to document lifetime intake of calcium for both men and women. A low intake of calcium during the formative teenage and young adult years results in a decrease in attainable peak bone mass, which occurs between ages 20 and 30. An estimated 50% of the calcium in an adult skeleton is deposited during the formative ages of 13 to 17 years. To evaluate vitamin D status, the physician should ask about multivitamin use, sun exposure, and sunscreen use. A sunscreen with a sun protection factor (SPF) of 15 may reduce the cutaneous production of vitamin D₃ by more than 95%.^[6] Vitamin D₃ production is greatly reduced or halted in the winter at latitudes above Washington, D.C. A family history of osteoporosis, especially maternal grandmother, mother, and sister(s); heavy alcohol use; cigarette smoking; early menopause; and premature graying (i.e., 50% of hair has turned gray by age 40) are associated with increased risk of osteoporosis. Steroid treatment with doses greater than 5 mg of prednisone or 25 mg of hydrocortisone daily for only 3 to 6 months contributes to significant bone loss in some patients. Prolonged hyperthyroidism or suppressive doses of thyroxine for treating goiter or suppressing recurrence of thyroid cancer can increase bone turnover, leading to osteoporosis.^[1] Severe chronic liver disease and chronic renal failure can cause severe metabolic bone disease, which contains a component of osteoporosis. Prolonged anticoagulant therapy with heparin is associated with increasing risk of osteoporosis. Institutionalized patients taking multiple antiseizure medications are at risk for vitamin D deficiency, osteomalacia, and osteoporosis.

A useful tool to evaluate for osteoporosis is to ask patients how tall they are (verified by measuring their height) and how tall they were as a young adult. A loss of an inch or more in height suggests the possibility of one or more spinal fractures caused by osteoporosis. Increased flexibility of joints (double jointed) or increased skin elasticity may be consistent with genetic disorders of collagen cross-linking, such as osteogenesis imperfecta and Ehlers-Danlos syndrome, which are associated with a decrease in bone mineral content. Regional bone pain over the rib cage or spine may be caused by a new fracture. Isolated or more generalized, aching bone pain may be caused by osteomalacia. Osteoporosis does not cause bone pain unless there is an acute fracture.

[edit] Patient Evaluation

A careful measurement of a patient's height could be the first indication of osteoporosis. The body habitus is also helpful because multiple compression fractures of the spine result in the classic hunched-over appearance (dowager's hump) (Fig. 45-2). Exophthalmos may be an indicator of hyperthyroidism or previous Graves' disease. Blue sclera is a classic finding in patients with osteogenesis imperfecta. An increase in skin elasticity or a doughy skin texture and increased flexibility of finger joints are evidence of a collagen–cross-linking genetic disease. Warm, velvety, moist skin, brisk reflexes, or tachycardia are consistent with hyperthyroidism. Thin, transparent, frail skin is often caused by chronic estrogen deficiency or chronic topical or oral steroid use. Black and blue marks, centripetal obesity, and proximal muscle wasting and weakness are consistent with either excess exogenous or endogenous steroids. For males a testicular examination to rule out hypogonadism is warranted.

Figure 45-2 Elderly woman next to stadiometer used to measure her height accurately. She has severe osteoporosis with multiple vertebral compression fractures and classic dowager's hump.

Lower back pain with sciatic symptoms or a positive straight-leg test exacerbating sciatic symptoms may be consistent with lumbar and sacral spinal fractures and nerve compression (Fig. 45-3). Palpation of the vertebral bodies eliciting point tenderness may indicate a recent compression fracture, whereas point tenderness on the rib cage may be a rib fracture. Palpation with mild thumb pressure on the upper sternum or on periosteum of the radius or tibia that causes pain may indicate osteomalacia.

Figure 45-3 Lateral radiograph of 81-year-old female with lower back pain radiating down left leg to knee. Note severe osteopenia of thoracic and lumbar vertebral bodies with multiple wedge compression fractures. Marked osteopenia of trabecular bone with preservation of rim of cortical bone gives rise to classic fish-mouth appearance between two vertebral bodies, evidence of trabecular collapse and compression fractures.

[edit] Goals.

The major goals of the initial evaluation are to (1) document the patient's present height (see Fig. 45-2); (2) rule out endocrinopathies, including hyperthyroidism, hypogonadism, and hypercortisolism, or a genetic defect in collagen cross-linking; and (3) determine if bone pain is associated with osteomalacia.

[edit] Assessing Individual Risk.

Assessment of individual risk is necessary to optimize treatment decisions. For example, a white female with a strong family history of osteoporosis should consider hormonal replacement therapy (HRT) at the first signs of menopause. A premenopausal black woman who is genetically programmed to have a higher bone mineral density (BMD) would benefit from counseling to increase her calcium and vitamin D intake. Patients with asthma, collagen vascular disease, or an autoimmune disorder who will receive long-term steroid therapy should increase their calcium and vitamin D intake and may receive an antiresorptive agent (e.g., bisphosphonate).^[7]

The increased risk of skeletal fractures with decreased BMD must be evaluated in relation to the patient's gender, age, and other considerations. For example, a 30-year-old white female in her childbearing years who has a low BMD based on screening densitometry should not necessarily receive a bone-active drug such as a bisphosphonate. The half-life of these drugs in the skeleton is about ½ year. The physician should determine whether the patient has low bone mass because of genetics, environmental factors, premature graying, anorexia, or ovarian dysfunction in her second or third decade of life. Measurement of a urine bone resorption marker helps identify increased bone resorption. A repeat BMD test in 1 year may also be helpful. No significant change in 1 to 2 years indicates that the patient's low BMD, from whatever cause, is not becoming worse.

[edit] Determining Secondary Causes.

The most common cause of secondary osteoporosis in both men and women is steroid therapy (see Box 45-2). The second most common cause is an endocrinopathy, such as hyperthyroidism, primary hyperparathyroidism, and hypercortisolism. Chronic renal failure leads to severe secondary hyperparathyroidism, causing renal osteodystrophy, which can exacerbate osteoporosis. Severe parenchymal and cholestatic liver disease causes intestinal malabsorption of vitamin D and decreases the production of 25-hydroxyvitamin D [25(OH)D]. In addition, toxins not cleared by the liver likely decrease osteoblastic activity, which can lead to unrelenting osteoporosis, as typically seen in patients with chronic primary biliary cirrhosis.

[edit] Laboratory Evaluation and Diagnostic Procedures

Osteoporosis is usually asymptomatic unless a fracture (e.g., acute spinal) causes severe localized bone pain that gradually resolves over 2 to 4 weeks. An inch or more decrease from young adult height also suggests osteoporosis. Although a routine chest radiograph may reveal osteopenia and spinal fractures, at least 30% to 50% of skeletal mass has been lost by this time. Lumbar and sacral films evaluating patients with lower back pain often reveal compression fractures and a fish-mouth appearance of vertebral bodies, demonstrating severe wasting of tubercular bone with concave compression fractures and preservation of cortical bone (see Fig. 45-3).

The gold standard for determining the presence of osteoporosis is measuring BMD. A dual-energy x-ray absorptiometer (DXA) has a single x-ray beam that can determine with 1% to 2% precision the mineral content of various skeletal sites, including the lumbar spine, hip region, and wrist (Fig. 45-4). Other screening techniques use ultrasound or DXA to measure BMD in the wrist, finger, or heel. The T score helps interpret bone densitometry readings from different instruments and across gender, age, and race; it is the standard deviation (SD) from the peak bone mass of a person of the same race and gender. For example, a T score of −1.5 means that the individual has a BMD that is 1.5 SD below the mean for a person of the same race and gender at their peak bone mass. The World Health Organization (WHO) has defined a T score of −1 to −2.5 as decreased BMD (i.e., osteopenia). T scores greater than −2.5 indicate osteoporosis with increased risk of fracture.

Figure 45-4 Bone mineral density (BMD) printout of 55-year-old woman's lumbar spine showing density of vertebral bodies (left) and plot of BMD relative to age (right). Initial average BMD for L2-L4 (lower dot) showed patient had severe osteopenia. After 2 years of calcium and vitamin D therapy, BMD increased by 14.2% (upper dot).

Quantitative computed tomography (QCT) of the lumbar spine is another method to assess for osteoporosis. This procedure exposes the patient to a large amount of radiation, however, and therefore is no longer used for this purpose. The amount of radiation exposure from DXA is equal to about 10% of a chest radiograph (less than 5 mrem), whereas radiation exposure from QCT can be as much as a barium enema (300 mrem). Health maintenance organization (HMO) and Medicare guidelines for DXA reimbursement include (1) estrogen-deficient women at clinical risk for osteoporosis, (2) patients with radiographically demonstrable vertebral abnormalities indicative of low bone mass (osteopenia) or vertebral fracture, (3) patients receiving glucocorticoid (steroid) therapy equivalent to 7.5 mg of prednisone per day for more than 3 months or if the expected duration is greater than 3 months, (4) patients with primary hyperparathyroidism, and (5) those being monitored to assess response to or efficacy of Food and Drug Administration (FDA)–approved osteoporosis drug therapy. These groups often only reimburse for one skeletal site; the usual choice is a spinal bone density. Unfortunately, if the patient has had compression fractures, osteoarthritis, osteophytes, or sclerosis of the region being measured, the reading will be falsely evaluated (Fig. 45-5). If one site only will be reimbursed, the hip is a better choice because these artifacts are usually absent.

Figure 45-5 Bone mineral density (BMD) of 72-year-old woman who had lost 4 inches in height (right). T score of 1.2 suggests normal BMD, even increasing by 6.8% each year during subsequent 2 years. Examination of printout on left, however, shows white areas (signifying increased density) that are not uniform, indicative of osteoarthritis, osteophytes, or compression fractures. Patient was continuing to lose height, suggesting that BMD increase resulted from new compression fractures in lumbar spine.

Women approaching menopause should know their bone density. A follow-up measurement in 1 to 2 years can identify women losing 2% to 3% of their bone mass a year and at increased risk of osteoporosis. Bone density also documents the effectiveness of therapy and therefore can increase patient compliance (see Fig. 45-4).

The blood tests to evaluate a patient identified as having osteopenia or osteoporosis include calcium, phosphorus, albumin, alkaline phosphatase, liver function tests, creatinine, 25(OH)D (for determining vitamin D status), and TSH. 1,25(OH)D should not be measured because it can be low, normal, or even elevated depending on the patient's vitamin D status and the degree of secondary hyperparathyroidism. For males, free testosterone should be measured if hypogonadism is suspected. These tests will rule out more than 95% of the metabolic causes for osteoporosis. PTH is not routinely obtained. If the serum calcium is normal and serum PTH is elevated, it could falsely indicate that the patient has early primary hyperparathyroidism, when the patient more likely has secondary hyperparathyroidism caused by vitamin D deficiency. An intact PTH is worthwhile to obtain only when the serum calcium is elevated. This assists in the differential diagnosis of hypercalcemia, that is, primary hyperparathyroidism when it is inappropriately normal (when it should be suppressed) or elevated. The second most likely cause of hypercalcemia in menopausal women is malignancy. A thorough workup is needed, including a bone scan to evaluate for bone metastasis and PTH-related peptide, which is elevated in about 50% of patients with hypercalcemic malignancy, often caused by squamous cell tumors, especially of the lung.

It is especially important to measure 25(OH)D to rule out vitamin D deficiency; adults over age 50 are at risk.^[8] Vitamin D deficiency results in secondary hyperparathyroidism, which can cause and exacerbate osteoporosis. Normal serum calcium provides no information about the patient's vitamin D status; most patients with vitamin D deficiency have a normal serum calcium level. However, a fasting serum phosphorus level is often in the low-normal or low range because of secondary hyperparathyroidism. Serum alkaline phosphatase is elevated.

Measurement of a marker for bone collagen breakdown also helps to determine if increased bone remodeling is resulting in bone loss. The 24-hour urine hydroxyproline test has been replaced with assays that measure the hydroxylysine component of collagen, the pyridinium cross-links in the urine (N-telopeptide or Pyralinks assays). They are often found to be high normal or elevated in postmenopausal women not receiving HRT. These assays are also elevated in patients with vitamin D deficiency and secondary hyperparathyroidism, primary hyperparathyroidism, and other metabolic bone diseases (e.g., Paget's disease).

[edit] Management

[edit] Nonpharmacologic Therapy.

The aims of preventing and treating osteoporosis are to decrease rate of bone loss and increase bone mineral content (Box 45-3). Both men and women should increase their calcium and vitamin D intakes to the new recommended adequate intake (AI) levels recommended by the Institute of Medicine in 1997 (Table 45-1). In addition, weight-bearing exercise helps to maintain and may even increase BMD, as well as muscle mass and muscle tone, thereby decreasing their risk of falling and fracture. Once the exercise has stopped, however, any bone gain is lost. Osteoporosis cannot be addressed simply with exercise; every muscle cannot be exercised to influence the BMD of every bone in the body. The best recommendation for adults is to walk 3 to 5 miles a week. This helps to maintain and marginally increase BMD of the lumbar and sacral spine and hip regions.

Table 45-1 Recommended Adequate Intakes for Calcium and Vitamin D

• Courtesy Institute of Medicine, 1997.

  Age	Calcium (mg/day)	Vitamin D IU (μg/day)
  0-6 months	210	200 (5)
  6-12 months	270	200 (5)
  1-3 years	500	200 (5)
  4-8 years	800	200 (5)
  9-18 years	1300	200 (5)
  19-50 years	1000	200 (5)
  51-70 years	1200	400 (10)
  >70 years	1200	600 (15)
  Pregnancy
  ≤18 years	1300	200 (5)
  19-50 years	1000	200 (5)

[edit] Exercise.

Patients with spinal cord injury can lose 30% to 50% of the skeletal calcium content of the affected limbs within 6 months to 1 year after injury. Astronauts in a weightless environment have complete unloading of their skeleton in microgravity and lose an average 1% to 2% of their bone mass per month. Patients on strict bed rest can have a substantial increase of calcium mobilization from their skeletons, similar to what astronauts experience. The goal is to mobilize invalid patients as soon as possible so that gravity can interact with muscles and bone and thus maintain bone mass. Weightlifting or other exercises (e.g., volleyball, tennis) that involve a loading stress on the skeleton temporarily increase BMD as long as they are continued. Swimming is good for the cardiovascular system and for muscle tone; the buoyancy causes an unloading on the skeleton, however, and therefore swimming does not increase BMD. Again, the best and easiest exercise program to help maintain spinal and hip BMD is walking 3 to 5 miles a week.

[edit] Diet.

It is often stated that increasing calcium intake prevents and treats osteoporosis. After men and women have reached their peak bone mass, they can lose 0.25% to 0.5% of their bone mass a year if they are not receiving adequate calcium in their diet (see Table 45-1). Thus 20 years of inadequate calcium intake can lead to as much as a 5% to 15% reduction in BMD before age 50. The easiest method to obtain an AI of calcium is by drinking skim milk; since 8 ounces of skim milk has 300 mg of calcium, drinking one glass with each meal approaches the recommended AI for calcium in adults up to age 50.

When deciding which calcium supplement to recommend, cost and bioavailability are important (Table 45-2). Patients who have achlorhydria and chew or swallow their calcium carbonate supplement (e.g., Tums) with their meals are able to absorb the calcium adequately. If they swallow a calcium carbonate pill, however, they are often unable to dissolve it due to lack of stomach acid; therefore the tablet is not broken down or absorbed in the small intestine. Calcium citrate products have a small advantage by increasing the efficiency of calcium absorption by about 10% to 15%. When considering the cost, however, a cheaper chewable form of calcium carbonate may be better. If the patient shows no evidence of magnesium deficiency, magnesium supplementation or a magnesium-containing calcium product is unnecessary; magnesium does not enhance the bioavailability of calcium.

Table 45-2 Calcium Supplements

Most young and middle-aged adults have adequate exposure to sunlight and therefore no need for concern about vitamin D deficiency. Vitamin D deficiency is common in adults over age 50, however, especially those living in northern latitudes and not exposed to sunlight without a sunscreen. For adults up to age 50, 200 IU/day of vitamin D is recommended; for adults ages 50 to 70 and 71% years, however, the AI is 400 and 600 IU daily, respectively. The only foods that naturally contain vitamin D are fatty fish, but one must eat it two or three times a week to receive sufficient vitamin D. To treat vitamin D deficiency quickly, 50,000 IU of vitamin D₂ once a week for 8 weeks is effective.^[8] A daily multivitamin containing 400 IU of vitamin D provides AI for adults up to 70 years.

[edit] Pharmacologic Therapy

[edit] Prevention.

Women approaching or initiating menopause should be counseled about AI of 1000 to 1200 mg of calcium daily, weight-bearing exercise program such as walking, and exposure to some sunlight, along with a multivitamin containing 400 IU of vitamin D. This approach helps guarantee maximum bone health as estrogen deficiency ensues. Most women with decreased blood estrogen levels have a significant increase in bone calcium mobilization, resulting in 1% to 3% BMD loss per year. Intervention with HRT should be the first pharmacologic course of action to preserve bone health in women at risk for osteoporosis.

There are two approaches to therapy (Table 45-3). Cyclic therapy, which has lost favor because it causes a monthly menstrual cycle, includes Premarin (0.625 mg) on days 1 to 25 and Provera (5 or 10 mg) on days 14 to 25; the cycle is resumed on day 1. Combination therapy with Premarin (0.625 mg) and Provera (2.5 mg) daily benefits bone health as well as the cardiovascular system but causes cessation of the menstrual cycle. For women who develop breakthrough bleeding, Provera is increased to 5 to 10 mg a day for 6 to 12 months. Combination products are available for either cycling (Premphase) or combination therapy (Prempro containing 2.5 or 5 mg of Provera). Women entering menopause who no longer want to continue menstruating and still have an active endometrium should use Premphase (5 mg) since the higher daily dose of Provera (progestin) in the combined medication will shut down endometrial growth and result in less breakthrough bleeding. For women still bleeding an additional 5 mg of Provera is helpful to promote endometrial atrophy. Since women who have been menopausal for at least 10 years have an atrophied endometrium, Prempro (2.5 mg) provides the needed estrogen (Premarin) and the low-dose Provera (2.5 mg) to prevent endometrial hyperplasia that can lead to breakthrough bleeding. This is a convenient way for women to take these medications.

Table 45-3 Pharmacologic Management for Preventing and Treating Osteoporosis and Osteopenia

✢No evidence indicates that calcitonin prevents fractures.

For women with a history, strong family history, or fear of breast cancer who refuse to consider HRT, there are two alternative approaches. A selective estrogen receptor modulator (SERM) is a reasonable choice for women with a history or strong family history of breast cancer. Raloxifene is the newest SERM and is given at 60 mg a day. For women who want an alternative to HRT or SERM therapy, a low dose of alendronate (Fosamax, 5 mg a day) helps preserve bone mass to the same extent as HRT.

[edit] Treatment.

The major class of drugs that will increase BMD and decrease risk of skeletal fractures are known as antiresorptive agents (see Table 45-3). The bisphosphonates are prescribed most often and structurally resemble pyrophosphate. The oxygen between the two phosphoruses has been replaced with a carbon, however, making the compound essentially indestructible. The various attachments on this carbon give rise to a wide variety of bisphosphonates, which are used to treat hypercalcemia of malignancy and metabolic bone diseases, including osteoporosis and Paget's disease. Bisphosphonates are deposited on the surface of new bone, which decreases osteoclastic bone resorption, allowing osteoblasts to lay down new bone not only to replace what was lost but also to add a small amount, thus increasing bone matrix and mineral. Therefore patients receiving bisphosphonate therapy often have increased BMD of 2% to 5% per year over at least 5 years of therapy.

The most popular bisphosphonate prescribed worldwide for the treatment and prevention of osteoporosis is alendronate (Fosamax).^[9] This medication may increase BMD of both the hip and the spine by 2% to 5% a year and may decrease the risk for fractures of the hip and spine by 51% and 63%, respectively (Fig. 45-6). The advantage of alendronate over the first-generation bisphosphonate etidronate (Didronel) is that daily use will not cause the mineralization defect of osteomalacia. For patients unable to tolerate alendronate because of the strict dosing regimen (10 mg once a day or 70 mg once a week with 8 ounces of water and waiting ½ hour before eating) or the gastrointestinal (GI) discomfort, an alternative is etidronate, 400 mg at night for 2 weeks followed by a free period of 13 weeks. The 15-week cycle is repeated for up to 5 years. These drugs are effective only if the patient is vitamin D sufficient and receiving adequate calcium. Third-generation bisphosphonates being developed may have the same skeletal benefits and reduced risk of fracture but with fewer GI effects. If the patient cannot tolerate oral bisphosphonates, an alternative is pamidronate (Aredia), 30 mg intravenously over 4 hours once every 3 months.

Figure 45-6 Effect of alendronate therapy on bone mineral density (BMD) of lumbar spine (A) and hip (B) in 62-year-old woman with osteoporosis who received 1200 mg of calcium, 400 IU of vitamin D, and 10 mg of alendronate daily for 5 years. Annual increase in BMD of hip and spine averaged 3.4% and 1.9%, respectively.

Another class of antiresorptive drugs is the calcitonins (see Table 45-3). Calcitonin is a polypeptide made by the C cells in the thyroid gland that inhibits osteoclastic activity. Calcitonin is available by subcutaneous (50 IU every other day) and intranasal (200 IU/day) routes of administration. However, this drug has marginal, if any, long-term benefit for treatment or prevention of osteoporosis. Calcitonin may help decrease bone resorptive activity, especially in patients with high-turnover osteoporosis. Calcitonin may also marginally increase BMD by 1% to 2% for the first 12 to 24 months, but with little effect thereafter. Most patients develop tachyphylaxis to the medication in a relatively short time.

Box 45-4 lists specific drug therapy recommendations.

[edit] Adverse Effects.

The major side effects of alendronate therapy are esophagitis and gastritis, which can be minimized by ensuring the patient is taking the medication on an empty stomach with 8 ounces of water. The patient should not lie down or be in a reclining position for at least ½ hour to prevent the symptoms. Some evidence indicates that the aminobisphosphonates such as alendronate decrease esophageal motility and increase the transit time of the medication in the esophagus, causing lower esophageal irritation. Etidronate is not an aminobisphosphonate and usually does not cause GI distress. Taking the medication for only 2 weeks will not cause osteomalacia.

[edit] Estimating Benefits.

HRT prevents bone loss from estrogen deficiency, decreases risk of cardiovascular disease by about 44%, and may prevent or delay the onset of Alzheimer's disease. Alendronate therapy (10 mg/day or 70 mg once a week) is effective in increasing BMD in the hip and spine, decreasing the risk of height loss and new spinal and hip fractures. Cyclic etridonate therapy also increases BMD and decreases the risk of hip and spinal fractures. Calcitonin decreases bone resorptive activity and may marginally increase BMD for a short duration. No evidence indicates that bisphosphonate or calcitonin therapy alters the healing of hip or spinal fractures, and therefore therapy can continue when a patient sustains a bone fracture.

[edit] Special Issues.

Although nutritional and pharmacologic approaches can prevent and treat osteoporosis, it may continue to be a major health problem in the twenty-first century, with staggering health care costs to treat acute fractures and manage chronic lower back pain and hip fractures. Physicians should evaluate patients for dietary calcium and vitamin D intake, exposure to sunlight, exercise, and HRT and then institute appropriate pharmacologic osteoporosis treatment and prevention programs.

[edit] Poor Adherence to Drug Regimen.

Only about 30% of women prescribed HRT are taking the medication after 1 year. The physician should explain the consequences of HRT, including breakthrough bleeding and breast tenderness so that the patient is not surprised by the symptoms and does not stop the medication without further consultation with the physician. HRT is so important for women's health that every effort should be made to encourage women to consider this first line of preventive therapy as they are entering menopause. Less than 50% of patients who initiate alendronate therapy remain on therapy after 1 year, partly because of the rigorous regimen. To encourage compliance, the physician can show the patient the significant BMD benefit from the therapy.

[edit] Other Treatments.

The active form of vitamin D [1,25(OH)₂D₃] and its 25-deoxy analog [1α(OH)D₃] are routinely prescribed in Europe and Japan for the treatment of osteoporosis. This medication increases the efficiency of intestinal calcium absorption and stimulates osteoblastic activity to increase BMD. It is especially effective for women who are unable to tolerate, for whatever reason, the recommended AI for calcium. 1,25(OH₂)D₃ has not been approved to treat osteoporosis in the United States and has a very narrow window of therapeutic efficacy and safety. Active vitamin D can easily cause hypercalciuria and even hypercalcemia.

Another medication that greatly increases BMD is fluoride; however, high doses cause bone fluorosis, which increases the risk of skeletal fractures. Although new forms of slow-release fluoride are being developed, none is currently available or FDA approved for treatment or prevention of osteoporosis.

[edit] PAGET'S DISEASE

The first indication of Paget's disease is often a routine pelvic radiograph for ruling out spinal fractures that is found incidentally to have a mottled area in the pelvis consistent with the disease. Paget's disease is characterized by an increase in the bone-remodeling process and in both osteoblastic and osteoclastic activity. As a result, the collagen laid down by the osteoblasts is disorganized in a woven fashion, which causes the classic mottled appearance on radiographs (Fig. 45-7).

Figure 45-7 A, Radiograph of pelvis in 82-year-old black male complaining of left hip pain. Note mottled appearance of left and right hemipelves and left femoral head, which is classic for Paget's disease. B, Bone scan of pelvis and femur of same patient showing greatly increased uptake in left and right hemipelves and left femoral head.

[edit] Epidemiology and Pathophysiology

Paget's disease occurs with equal frequency in both men and women; 3% of patients over age 55 may have manifestations of the disease. The cause of Paget's disease is uncertain. Some suggest a viral infection similar to the measles virus, and others suggest a genetic disorder, but neither has been substantiated.

High turnover and haphazard formation result in a woven bone that has little architectural integrity or strength. Thus the pagetic bone is weaker and more susceptible to fracture. The bones most often affected, in order of frequency, are sacrum, spine, femur, skull, sternum, and pelvis. Involvement of the long bones is less common; however, the disease can occur at any skeletal site involving one or many bones. Patients with Paget's disease have an increased risk of osteogenic sarcoma associated with lytic lesions in the bone on radiographs and rapidly increasing alkaline phosphatase levels. Increased bone-remodeling activity causes increased vascularity in the affected area. When the disease is widespread, affecting more than 30% of the skeleton, it can substantially increase cardiac output, with up to 10% of output shunted to perfuse the pagetic bone. This can increase the risk of congestive heart failure (CHF) in compromised cardiac patients. Increased warmth in the area from the increased vascularity is often noted on physical examination, especially if the skull or long bones are involved. A decrease in warmth over the area after treatment is an effective way to evaluate therapeutic efficacy.

Although usually not painful, pagetic bone can cause chronic pain if a joint such as the hip is affected. Pagetic involvement of the spine can cause nerve impingement, leading to spinal stenosis, neuropathy, muscle wasting, and sciatica. Paget's disease of the skull, especially involving the small bones of the middle ear, can lead to deafness. Pagetic involvement of the auditory canal and surrounding areas can also lead to eighth cranial nerve dysfunction, including the vestibular manifestations of dizziness, vertigo, and tinnitus.

The increased remodeling process mobilizes calcium and may cause mild hypercalciuria. Significant hypercalciuria and hypercalcemia may occur, however, when patients are immobilized because of decreased bone formation from skeletal unloading. Hypercalcemia in patients with Paget's disease who are not immobilized suggests another cause for hypercalcemia, including malignancy, hyperparathyroidism, or diuretic (hydrochlorothiazide) therapy.

[edit] Patient Evaluation

As noted, Paget's disease is usually discovered as an incidental finding on a radiograph of the pelvis, chest, or skull. If the site (e.g., pelvis) does not put the patient at risk for complications, further therapeutic intervention is unnecessary. A bone scan can help determine whether the patient has pagetic involvement elsewhere in the skeleton. Increased uptake of the radioactive marker indicates increased bone turnover, as seen in Paget's disease (see Fig. 45-7).

[edit] Goals.

The two goals for the initial evaluation are to assess the patient's risk of (1) developing a complication from Paget's disease or (2) developing high-output CHF.

[edit] Assessing Individual Risk.

Patients who have pagetic involvement of their skull, long bones, and hip joint require aggressive antiresorptive therapy. Involvement of long bones can lead to bone deformation and may cause a bowing of the leg, increasing the risk of fracture and causing degenerative joint disease in the ipsilateral hip. Early intervention for Pagetic skull involvement can prevent serious hearing loss and vestibular abnormalities. Identification of hip joint involvement (femoral head or hip socket) reduces the risk of severe degenerative joint disease.

[edit] Clinical and Laboratory Evaluation

Most patients with Paget's disease are asymptomatic. Patients with skull involvement, however, may note an increase in hat size, increased frequency and intensity of headaches, tinnitus, hearing loss, dizziness, and vertigo. Involvement of the extremities can lead to bone deformities, especially of weight-bearing bones such as the femur and tibia (Fig. 45-8).

Figure 45-8 Classic appearance of bony deformities associated with pagetic involvement of left leg and skull. Note cap size (right) from same patient worn in 1844 and increased hat size (left) in 1867. (From Sir James Paget, before the Royal Medical Chirurgical Society of London, Nov. 14, 1876.)

Touching the affected area (e.g., skull, long bone) with the back of the hand may suggest pagetic involvement by increased warmth compared with surrounding areas. Full neurologic evaluation of the cranial nerves, especially the eighth nerve, is indicated for pagetic skull involvement. Spinal involvement requires an evaluation of sensory and motor neuron functions of the affected area.

Markers for osteoblastic and osteoclastic activity are used to assess disease activity. Serum alkaline phosphatase is a reliable indicator of Paget's disease, but not all patients with the disease have greatly elevated levels. A measure of increased bone remodeling is the 24-hour urine excretion of hydroxyproline or a spot urine test for determining pyridinium cross-links. To determine if more than one skeletal site are involved with Paget's disease, a radionuclide bone scan is valuable (see Fig. 45-7). Radiographs of suspected sites are useful for differentiating pagetic bone and metastatic bone disease. For patients with skull involvement, audiologic evaluation should be considered.

[edit] Management

Most patients with incidental Paget's disease of the pelvis do not require therapeutic intervention. If pain is associated with pagetic involvement, however, therapy should be considered. An alkaline phosphatase level more than two to three times the upper limit of normal; active disease of a long bone, the skull, or hip joints; or involvement of one or more vertebral bodies is often an indication for aggressive therapy to prevent potentially serious consequences. Surgical intervention is often required if nerve impingement is observed with sudden neurologic impairment, such as weakness of an extremity.

[edit] Bisphosphonate Therapy.

Bisphosphonates are effective in about 85% to 90% of patients with Paget's disease. Etidronate (Didronel), 200 to 400 mg/day (up to 20 mg/kg body weight), is usually given for 4 to 6 months, then stopped for 2 to 4 months, and reinstituted again. Because continual use causes osteomalacia and because of its low efficacy, etidronate is rarely used. Two second-generation bisphosphonates approved for treatment of Paget's disease are alendronate (40 mg/day) and risedronate (20 mg/day).^[10] These medications can be taken daily continuously and do not increase the risk of osteomalacia.

[edit] Pamidronate.

An effective alternative is intravenous (IV) pamidronate, with the advantage of therapy only once a week for 4 weeks. Pamidronate has been approved for treating hypercalcemia of malignancy. It is usually administered as an IV test dose of 30 mg over 4 hours in the physician's office. If the patient has no side effects, such as severe myalgias or arthralgias (flulike symptoms and fever may occur but usually resolve rapidly), the patient returns 1 week later to receive 60 mg over 2 to 4 hours. This is repeated once a week for an additional 3 weeks. An alternative is to give 30 mg/day for 3 successive days. In most patients the serum alkaline phosphatase level and urinary pyridinium cross-links will substantially decline within a few weeks and remain in the normal range. If Paget's disease recurs, however, a repeat of the IV regimen of 60 mg/week for 4 weeks often puts the patient into remission. This may be much easier for the patient than taking a medication every day.

[edit] Plicamycin.

Formerly called mithramycin, plicamycin is a cytotoxic antibiotic and potent inhibitor of osteoblastic activity. It is administered intravenously over 4 hours at 10 μg/kg body weight. Side effects include bone marrow toxicity and liver abnormalities, and thus this drug is no longer used for Paget's disease.

[edit] Calcitonin.

Once considered the treatment of choice for Paget's disease, calcitonin has been largely replaced by the second-generation bisphosphonates. The mode of administration, subcutaneous or intranasal, can be problematic, and only about 50% to 60% of patients respond to calcitonin therapy. Often they develop a resistance to therapy over time due to the development of antibodies or a down-regulation of the calcitonin receptor. The usual dose is 50 to 100 IU/day subcutaneously or 200 IU/day intranasally.

[edit] Nonsteroidal Antiinflammatory Drugs.

NSAIDs do not treat Paget's disease but may help relieve the pain associated with pagetic involvement of joint spaces (e.g., hip). Indomethacin, 25 mg three or four times daily, or NSAID such as Motrin may help relieve the pain.

[edit] REFERENCES