Suzanne M. Jan de Beur
Bone is a dynamic organ that undergoes constant remodeling characterized by the sequential process of osteoblast-driven matrix production, maturation and mineralization of the matrix, and osteoclastic resorption. Metabolic bone disorders increase bone resorption or decrease bone formation, leading to decreased bone density and strength. The major metabolic bone diseases discussed in this chapter are hyperparathyroidism, osteomalacia, osteoporosis in males, and Paget disease of bone (female osteoporosis is discussed in Chapter 103). Because calcium and phosphorus are critical for appropriate bone formation and mineralization, disorders of metabolism of these minerals are also discussed.
HypocalcemiA
Causes
Hypocalcemia, although uncommonly encountered in ambulatory patients, has a broad differential diagnosis that ranges from a measurement artifact to a serious underlying disorder. Autoimmune hypoparathyroidism is classically associated with hypocalcemia, yet the most common cause is inadvertent surgical ablation of the parathyroids or as a result of a metabolic disturbance such as renal failure. Table 84.1 lists an extended differential diagnosis for hypocalcemia.
Clinical Manifestations
The symptoms of hypocalcemia are primarily neuromuscular and are not usually evident until the serum calcium
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falls below approximately 8 mg/dL, and often considerably lower. Symptoms of mild hypocalcemia are nonspecific and include psychologic manifestations (irritability, mood changes, lassitude, depression) and neuromuscular symptoms (circumoral or acral paresthesias, muscle cramps [spasms], muscle weakness, and wasting). More severe symptoms are seen at extremely depressed serum calcium levels, 5.5 to 6 mg/dL, and include delirium, psychosis, tetany (including laryngeal stridor), seizures, and papilledema. Neuromuscular irritability can often be demonstrated by the twitching induced by tapping over the facial nerve just anterior to the ear. This maneuver results in contraction of the facial muscles around the lip (Chvostek sign). Another clinical test is compression of the upper arm by a blood pressure cuff with the pressure elevated above the systolic pressure. A positive response is spasm of the hand induced within 3 minutes (Trousseau sign). Myocardial dysfunction has been associated with acute and chronic hypocalcemia and there is a characteristic prolongation of the QT interval on electrocardiogram. Signs of chronic hypocalcemia include patchy hair loss, scaling of skin, atrophy, and brittleness of fingernails collectively referred to as ectodermal dysplasia, as well as dental enamel hypoplasia and cataracts. Calcification of the basal ganglia may occur and may lead to extrapyramidal movement disorders.
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TABLE 84.1 Causes of Hypocalcemia |
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Evaluation
Hypocalcemia is defined as a serum calcium level below 8.5 mg/dL. Because almost half of serum calcium is protein bound, reduction of serum albumin by 1 g/dL lowers the serum calcium by approximately 0.8 mg/dL. Thus, the serum calcium level must always be evaluated in the context of the serum albumin concentration; simultaneous evaluation of serum magnesium is also recommended. Measurement of the plasma parathyroid hormone (PTH) level is the first step in determining the etiology of true hypocalcemia. In hypoparathyroidism from any cause and in some cases of magnesium deficiency, plasma PTH is low or undetectable. In contrast, plasma PTH is elevated in renal failure, malabsorption, vitamin D deficiency, and pseudohypoparathyroidism. The interpretation and indications for determination of PTH levels are discussed below.
Hypoparathyroidism
The term “hypoparathyroidism” designates a group of conditions, all of which manifest hypocalcemia and hyperphosphatemia, and is thus a generic term for one of the many “hypoparathyroid disorders.” Hypoparathyroidism arises from a deficiency in either PTH production, a defect in the calcium sensing receptor or insensitivity to PTH as a result of post-receptor molecular defects (pseudohypoparathyroidism).
The most common cause of hypoparathyroidism is postsurgical hypoparathyroidism (1,2). Other causes of acquired hypoparathyroidism include autoimmune destruction (either as isolated hypoparathyroidism or as part of the Autoimmune Polyglandular Syndrome Type 1) and destruction by infiltration (sarcoidosis, Wilson disease, hemochromatosis, amyloidosis) (1).
The most common form of congenital hypoparathyroidism is autosomal dominant hypocalcemia, which is caused by mutations in the calcium sensing receptor gene, so that PTH secretion does not increase appropriately in response to hypocalcemia (3). Other rare forms of congenital hypoparathyroidism include Di George syndrome, in which thymic aplasia and cardiac malformations are also present (4), mutations in the signal sequence of the PTH gene (5), and mutations in the GCMB gene that encodes a transcription factor essential for parathyroid development (6).
Functional hypoparathyroidism can be caused by hypomagnesemia and by severe acute hypermagnesemia. Severe magnesium depletion leads to hypocalcemia through PTH resistance but can also impair PTH secretion (7). Severe hypermagnesemia also suppresses PTH secretion (8).
Pseudohypoparathyroidism (PHP) describes a group of disorders characterized by biochemical hypoparathyroidism (i.e., hypocalcemia and hyperphosphatemia), increased secretion of PTH, and target tissue unresponsiveness to the biological actions of PTH. Thus, biochemical hypoparathyroidism in PHP is because of PTH resistance rather than PTH deficiency. In addition to hypocalcemia and its manifestations, there are associated skeletal and developmental defects that result in short stature, shortening of the metacarpals and metatarsals, and round facies (collectively known as Albright hereditary osteodystrophy). The molecular basis of this syndrome is inactivating mutations or defective imprinting of the alpha subunit of the stimulatory G protein that transduces the signal from the cell surface receptor to intracellular effectors such as adenylyl cyclase (9). The stimulatory G protein couples a number of hormonal receptors, including those for PTH and TSH. For this reason, these patients exhibit multiple hormone resistances. The combination of hypocalcemia, hyperphosphatemia, an elevated level of PTH, and typical skeletal abnormalities is virtually diagnostic of PHP.
Because hypoparathyroidism is a collection of disorders and the underlying cause must be identified in order to select appropriate therapy, hypocalcemic individuals should be referred to an endocrinologist.
Postthyroidectomy Hypoparathyroidism
Hypoparathyroidism was, in the past era of frequent surgical therapy of thyroid diseases, a complication of
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thyroidectomy. The hypocalcemic state could become evident immediately after surgery but often took many years to develop, presumably because of slowly progressive interference with the blood supply to the parathyroids. Routine screening of serum calcium in patients who have had a thyroidectomy reveals many asymptomatic mildly hypocalcemic patients. Most of these individuals seem to need no therapy, but in view of the subtle neuromuscular changes that can result from hypocalcemia, careful consideration should always be given to this issue. Hypoparathyroidism is rare after radioiodide therapy of thyroid disease; only a very few cases have been reported.
Treatment of Postsurgical Hypoparathyroidism
A few patients with substantial residual PTH secretion can be managed solely by increasing dietary calcium by 1 to 2 g/day. However, most patients with hypoparathyroidism require both long-term calcium and vitamin D supplementation. Severely symptomatic patients should be hospitalized to receive intravenous calcium and for initiation of chronic therapy with oral calcium supplements and with vitamin D. Symptomatic patients who do not require hospitalization should also be prescribed calcium supplements and vitamin D. Calcium supplementation usually requires 1500 to 3000 milligrams per day of elemental calcium.
Because calcium gluconate and lactate contain only approximately 10% elemental calcium, 10 to 20 g of these salts are required daily; numerous tablets must be taken, and patient compliance is a common problem. Calcium carbonate contains approximately 40% elemental calcium, so fewer tablets are necessary, but this salt is insoluble at neutral pH and requires sufficient gastric acidity for absorption to occur. Calcium citrate (21% elemental calcium) is now available in 950-mg tablets and is probably the best choice (8 to 10 tablets a day). Every effort should be made to work out an acceptable, palatable, and economic program with a consistently available preparation for what is invariably lifelong therapy.
The second mainstay of therapy is vitamin D. The most commonly used preparation in the past has been ergocalciferol (vitamin D2, Calciferol). The dosage is usually 50,000 or 100,000 units daily, although higher doses may be necessary. The compound is available in 50,000-unit (1.25-mg) capsules. The sole advantage of ergocalciferol is cost; it is by far the least expensive form of vitamin D therapy. The disadvantage of ergocalciferol is that it takes several weeks to attain therapeutic levels and toxicity, should it occur, may last for many weeks or even months after discontinuation of therapy.
Another effective compound is 1,25-dihydroxyvitamin D3 (calcitriol, Rocaltrol), the natural active form of vitamin D. The dosage is 0.25 to 1.0 µg/day. This compound is more rapid in onset than ergocalciferol and dihydrotachysterol and has a shorter duration of effect, but has the disadvantage of even greater cost. Additionally, vitamin D toxicity can rapidly develop and thus the patient must be monitored at least every 3 months for serum calcium and twice yearly for urine calcium excretion.
Another vitamin D preparation is its synthetic analog dihydrotachysterol (Hytakerol). The dosage varies from 0.2 to 2 mg/day. The compound is available as tablets and as a solution. The advantage of therapy with dihydrotachysterol is more rapid onset of action than D2and more rapid reversal of toxicity on withdrawal of the drug. The only disadvantage of dihydrotachysterol is its relatively high cost and that it is intermittently unavailable.
In whatever form selected, vitamin D is given simultaneously with calcium tablets, with adjustments of dosage at weekly or biweekly intervals depending on the serum calcium level. The goal of therapy is a serum calcium concentration of 8.5 to 9.0 mg/dL. Hypercalcemia should be avoided. Once a stable level of serum calcium is reached (1 to 2 months), the patient can be monitored at monthly intervals and eventually every 3 to 4 months. Even on stable therapy, the patient should have semiannual measurement of urine calcium and creatinine. Hypercalciuria is the earliest sign of vitamin D intoxication. When 24-hour urine calcium exceeds 300 mg/day, vitamin D dosage should be reduced. The possibility of toxicity from hypercalcemia must always be kept in mind. Even mild hypercalcemia predisposes to nephrocalcinosis and nephrolithiasis in these patients.
Hypocalcemia from Causes Other than Parathyroid Disease
Other diseases associated with hypocalcemia include osteomalacia (vitamin D or phosphate deficiency) (see Osteomalacia) and variants of Fanconi syndrome (a spectrum of renal tubular abnormalities). Chapter 52 describes the hypocalcemia associated with renal failure.
HypercalcemiA
Because routine automated blood analyses include determinations of serum calcium, asymptomatic hypercalcemia is increasingly detected. Hypercalcemia, whether symptomatic, or asymptomatic, always requires investigation.
Causes
In an ambulatory setting, the most common cause of hypercalcemia (80% to 90% of cases) is hyperparathyroidism because of a single parathyroid adenoma (10).
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Malignancy, due to bony metastases, elaboration of a parathyroid hormone related protein (PTHrP), other osteoclast-activating cytokines, or production of calcitriol, is the most common cause of hypercalcemia in hospitalized patients (11,12). However, when hypercalcemia complicates malignancy it is usually not part of the initial presentation of the malignancy and often presents with associated ominous symptoms (e.g., weight loss and anorexia). Table 84.2 lists causes of hypercalcemia.
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TABLE 84.2 Causes of Hypercalcemia |
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TABLE 84.3 Symptoms and Signs of Hypercalcemia |
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Evaluation
Symptoms of hypercalcemia (Table 84.3) may be vague and difficult to interpret, especially when the serum calcium is only slightly to moderately elevated (10.5 to 12 mg/dL). More severe symptoms are experienced when the serum calcium level is higher or when hypercalcemia develops rapidly.
Since serum protein concentration and pH can effect total serum calcium measurements, ionized calcium should be measured in cases where serum protein or pH may be altered.
Measuring the plasma PTH concentration is the initial step in evaluating the underlying cause of hypercalcemia. In the cases of parathyroid mediated hypercalcemia, such as primary hyperparathyroidism, the plasma PTH will be elevated or inappropriately normal. In contrast, in hypercalcemia from other causes, the serum calcium concentration is elevated and PTH is suppressed.
Primary Hyperparathyroidism
The term primary hyperparathyroidism refers to autonomous hyperfunction of one or more parathyroid glands. Hypercalcemia is the hallmark of this disorder. Secondary hyperparathyroidism, on the other hand, is a physiologic or pathophysiologic homeostatic response to situations that lower blood calcium.
The most common cause of primary hyperparathyroidism is a solitary benign adenoma (85% of patients). In a small proportion of patients, more than one adenoma is present, and in the remainder, the cause is multigland hyperplasia. Carcinoma of the parathyroid is rare (less than 1% of patients). Hyperparathyroidism may be familial and may occur as part of the syndrome of multiple endocrine neoplasia.
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Diagnosis
Most cases are now detected by routine automated analysis of blood electrolytes. The symptoms (Table 84.3) or sequelae of hypercalcemia may also alert the clinician to the diagnosis, but unlike the situation in the past, symptomatic hyperparathyroidism is now a rarity, except for a history of kidney stones in perhaps 20% of cases (13). Once the diagnosis is suspected, however, the presence of hypercalcemia must be established beyond a doubt. Multiple determinations of serum calcium should be made. Because of spontaneous fluctuations of the serum calcium and because of analytic error, values that are only minimally elevated must be repeated several times. The resulting mean level should be used for diagnostic purposes, not the last—sometimes normal—value obtained.
Once hypercalcemia is established (greater than 10.5 mg/dL on multiple determinations), the next (or simultaneous) step is to measure plasma PTH. Once it is determined whether the hypercalcemia is parathyroid-mediated or nonparathyroid-mediated, then a targeted investigation of the likely causes of the hypercalcemia is performed (Table 84.3).
Other laboratory findings that support the diagnosis of hyperparathyroidism include low serum phosphorus concentration and, rarely, in severe cases with bone involvement, elevation of serum alkaline phosphatase activity. Other abnormalities in laboratory tests occur but are not useful for screening or in differential diagnosis because they occur nonspecifically. Patients with hypercalcemia, regardless of cause, usually show hypercalciuria, but hypercalciuria may also occur without hypercalcemia. Increased excretion of hydroxyproline-containing peptides occurs, as it does in other bone diseases.
In severe cases of long duration, radiographic studies of various bones reveal a variety of changes suggestive but not diagnostic of hyperparathyroidism. Demineralization (osteopenia) and subperiosteal resorption are most obvious in the clavicles and the distal phalanges, and the lamina dura of the teeth may be resorbed. Cystic changes occur in the skull and long bones (osteitis fibrosa cystica). Radiographic studies are not useful for screening purposes.
Parathyroid Hormone Assays
The development of the PTH assay was a significant breakthrough in the diagnosis of primary hyperparathyroidism and in distinguishing it from tumor-induced, PTHrp-mediated hypercalcemia. Double antibody immunoradiometric and immuno chemiluminescent assays that detect the “intact” PTH molecule, an 84 amino acid peptide referred to as PTH 1-84, have replaced older radioimmunoassays that measured the N and C terminal fragments of PTH. The “intact” PTH 1-84 assay is sensitive and is superior in detecting hyperparathyroidism; frankly elevated levels are seen in 85% to 90% of hyperparathyroid patients. In some patients, the values are not overtly elevated, although normal, they are inappropriately so in the setting of hypercalcemia. Moreover, the assays show a high degree of specificity and do not detect the PTH-like peptides produced by tumors. A limitation of the “intact” PTH assay is that it also detects the PTH 7-84 fragment, which is a biologically inactive fragment that circulates in excess in renal failure. Therefore, in patients with impaired renal function, an assay that measures only the whole, biologically active PTH 1-84 should be employed. These cyclase-activating PTH (CAP) assays measure the “whole” PTH molecule (also called biointact PTH assay) and may offer increased sensitivity for diagnosing primary hyperparathyroidism especially in renal failure (14).
Further Evaluation
Although most cases of hyperparathyroidism and of other hypercalcemic states can be diagnosed by the means described, the cause of occasional cases of hypercalcemia remains in doubt. In these patients, the steroid suppression test, a short course of prednisone therapy (30 to 40 mg/day for 10 to 14 days), may help diagnostically. The hypercalcemia of hyperparathyroidism does not respond to such therapy. Although only approximately half of cases of hypercalcemia because of malignancy respond, hypercalcemia from diseases that are not always apparent, such as sarcoidosis and vitamin D intoxication from endogenous conversion of precursors, respond consistently. Determinations of blood calcium should always be obtained for several consecutive days before and daily during such a test.
Having confirmed the presence of hypercalcemia and elevation of PTH and having excluded by appropriate means malignancy, impaired renal function, and other conditions listed in Table 84.3, the diagnosis of hyperparathyroidism is reasonably well established. However, the urinary excretion of calcium should be determined at this point because patients with benign familial hypocalciuric hypercalcemia (FHH) do not have hypercalciuria or other complications of hypercalcemia and do not need surgical intervention. The features of FHH (hypercalcemia, elevated PTH, and low urinary calcium clearance) are because of aberrant calcium sensing resulting from inactivating mutations in the calcium sensing receptor (3). In most cases of hyperparathyroidism, referral to an endocrinologist should be made if the diagnosis is in doubt or if surgery is contemplated.
Preoperative Localization of Parathyroid Adenoma
A variety of imaging methods have been used to localize a parathyroid adenoma, but none has been more successful
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than 99mtechnetium sestamibi imaging, which has 69% to 91% sensitivity and 98% specificity (15). Other techniques include ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and, in previously operated patients, selective venous sampling for PTH. The diagnosis of primary hyperparathyroidism is based on the appropriate biochemical findings; inability to demonstrate a parathyroid adenoma with imaging techniques does not rule out the diagnosis of hyperparathyroidism. Preoperative localization of parathyroid adenomas is indicated in two settings. The first is when a reoperation is indicated. Imaging may provide guidance to the surgeon when anatomical structures have been disrupted. The second indication is when a minimally invasive parathyroidectomy is being considered. In contrast to a traditional parathyroidectomy with bilateral neck exploration in which all four glands are inspected and the enlarged adenoma is removed, in the minimally invasive parathyroidectomy there is a focused removal of a single parathyroid that had been localized preoperatively. The development of a rapid PTH assay has allowed PTH measurements in the operating room while the patient is still under anesthesia. Within 5 minutes of removing the aberrant parathyroid, there should be a 50% reduction in the preoperative PTH level (16). Such measurements allow the surgeon to confirm that the correct parathyroid has been removed and that there are no additional adenomas.
Complications of Hyperparathyroidism
Nephrolithiasis
Renal calculus disease (nephrolithiasis) develops in up to 20% of patients and is related to the degree of hypercalcemia and hypercalciuria. Classic cases of hyperparathyroidism are no doubt at risk for progressive renal failure, but in minimal disease, this problem is not usually observed. Nonetheless, recurrent renal calculi are worth preventing. Therefore, in the patient with primary hyperparathyroidism who has nephrolithiasis or has a 24-hour urine calcium that exceeds 400 mg, parathyroidectomy is indicated.
Bone Disease
Loss of bone mineral is a well-known effect of hyperparathyroidism and is often termed “osteoporosis.” Successful parathyroidectomy results in rapid remineralization, especially of the lumbar spine and femoral neck with a mean postparathyroidectomy rise of 12% (17). In postmenopausal patients improvement in bone density may reach 20%. Patients with primary hyperparathyroidism should have bone density monitored yearly by dual-energy x-ray absorptiometry (DEXA) scan. If the patient is already osteoporotic, has sustained a fragility fracture, or if ongoing bone loss is observed with yearly monitoring, surgical intervention is indicated (18). Some studies have demonstrated that the use of oral bisphosphonates can prevent bone loss in patients with primary hyperparathyroidism (19, 20, 21); however, the gain in bone density seen with parathyroidectomy is far greater than the minimal changes seen with bisphosphonate therapy.
Hypertension and Cardiovascular Disease
Hyperparathyroidism has been associated with hypertension; left ventricular hypertrophy; arrhythmias; calcification of the coronary arteries, myocardium, and heart valves; and increased mortality rates. However, these observations represented the overt hypercalcemia of older series. In more recent studies, the cardiovascular death rate in minimal disease (serum calcium elevation not more than 1 mg/dL above the upper limits of normal) was reduced, as was the overall death rate (22). Clearly, the severity of the hyperparathyroidism accounts for these differences. However, the association of hypertension and hyperparathyroidism remains unclear, because successful parathyroidectomy does not improve hypertension in these cases.
Surgical versus Conservative Therapy
In diagnosed patients the main question is whether surgical intervention is warranted. A common dilemma in demonstrated hyperparathyroidism with mild hypercalcemia is the so-called asymptomatic patient (23). Some experts are convinced that 80% of patients are, in fact, asymptomatic (24). Others believe that nonspecific but real symptoms may be present in 90% of patients with mild to moderate hypercalcemia (17). This view is based on studies of preoperative and postoperative symptom questionnaires. A National Institutes of Health (NIH) Consensus Development Conference in 2002 (18) concluded that many patients older than 50 years of age could be safely followed without surgery and outlined a plan for those for whom surgery should be recommended. A study of the natural history of asymptomatic hyperparathyroidism is reassuring. Only 25% of patients without indication for surgery developed an indication during the 10-year study period (25). Most would agree that clearly symptomatic patients or those with major complications should seriously consider surgery as an option and that asymptomatic patients without complications can be followed safely most of the time (25,26).
The NIH Consensus Conference established and reiterated guidelines for consideration of surgical treatment: (a) serum calcium concentration greater than 1 mg/dL above the normal limit of serum calcium; (b) hypercalciuria, greater than 400 mg/24 hr; (c) nephrolithiasis, cystic bone disease, or overt neuromuscular disease; (d) markedly reduced bone density (T score of -2.5 or lower at any skeletal site); (e) reduced renal function as determined by creatinine clearance in the absence of other causes; and (f) age
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younger than 50 years; and (g) patients who cannot be reliably monitored (27).
If the decision is made to treat the patient surgically, referral to a surgeon experienced in parathyroid and thyroid exploration is essential. Parathyroidectomy is an operation in which the outcome is clearly related to the surgeon's experience. The most successful surgeons have performed 100 or more parathyroidectomies, often 25 to 50 per year (28). With an experienced surgeon, parathyroidectomy is curative in greater than 95% of the cases and the complications, including permanent hypoparathyroidism and recurrent laryngeal nerve damage, are less than 1%.
In experienced hands, an adenoma, if present, will be located and easily removed in approximately 98% of cases (28). Parathyroid hyperplasia, which accounts for 10% of cases of hyperparathyroidism, is usually identified easily. In such cases, the surgeon should be prepared to perform a nearly total parathyroidectomy. Second neck explorations are technically difficult and may result in unnecessary morbidity (e.g., damage to the recurrent laryngeal nerve). Accordingly, any hyperplastic parathyroid tissue that is left behind should be identified with clips. As an alternative, many surgeons are now removing all parathyroid tissue from the neck and transplanting a portion of one hyperplastic gland to an accessible location, usually a sternocleidomastoid muscle or into the forearm.
Medical Therapy
Medical therapy for primary hyperparathyroidism is indicated in patients who refuse surgery, who are not candidates for surgery, or who have had unsuccessful parathyroidectomy. In these individuals lifestyle modification should include (a) a normal diet with normal calcium content in foods but no calcium supplementation; (b) exercise, to avoid inactivity-induced bone resorption, which may worsen hypercalcemia; (c) adequate hydration since dehydration worsens hypercalcemia. Diuretics should be avoided if possible. For patients with low 25 hydroxy vitamin D levels a multiple vitamin per day is indicated.
Estrogen is an effective alternative to surgery for uncomplicated hyperparathyroidism, as shown by improvement in bone mineral density (29). The effect on serum calcium usually does not exceed 0.5 mg%. Because many patients with asymptomatic hyperparathyroidism are postmenopausal women, this approach has considerable appeal. Unfortunately, because of the risks now known to be associated with estrogen replacement, it is no longer recommended as a first line therapy.
Raloxifene, an estrogen receptor modulator, has also been shown to reduce serum calcium levels and markers of bone resorption in short-term studies (30).
Oral bisphosphonates do not alter serum calcium levels but do reduce bone resorption and bone loss associated with hyperparathyroidism (19, 20, 21).
Cinacalcet is a calcimimetic designed to bind to the calcium sensing receptor in the parathyroid cells, resulting in increased sensitivity of the parathyroid to circulating calcium and thus reducing PTH secretion. In a multicenter double-blind, placebo-controlled trial of 78 patients with primary hyperparathyroidism, those treated with cinacalcet had reduced serum calcium and PTH concentrations (31). Nearly 75% of patients achieved normocalcemia within weeks and the effects were maintained over the 52 weeks of the study. Longer-term studies have shown responses up to 3 years.
Monitoring
The 1 NIH guidelines recommend that patients with primary hyperparathyroidism without parathyroid surgery be monitored with serum calcium concentrations every 6 months, serum creatinine annually, and bone density of spine, hip, and forearm annually. Annual abdominal radiography, 24-hour urine calcium excretion and creatinine clearance, although recommended in older guidelines, are no longer considered necessary (18).
Treatment
The treatment of hypercalcemia due to hyperparathyroidism is discussed above (see Primary Hyperparathyroidism). Therapy to control hypercalcemia that results from a cause other than hyperparathyroidism is not commonly initiated in ambulatory patients. Most often the hypercalcemia or its underlying cause has required initial therapy in a hospital. However, when the acute symptoms of hypercalcemia have been controlled during hospitalization, long-term palliative therapy may be needed for the ambulatory patient.
Treatment of hypercalcemia of malignancy is usually begun in the hospital; the current drug of choice is the IV bisphosphonate, zoledronic acid (Zometa) (32). Once hypercalcemia is controlled, therapy may be continued on an ambulatory basis by administration of intravenous zoledronic acid, 5 mg over 15 minutes monthly. If this dosage is inadequate or if severe, symptomatic hypercalcemia (calcium above 13 mg/100 mL) occurs, the patient may need to be hospitalized again. Other drugs (e.g., glucocorticoids, mithramycin, calcitonin) that have been used in the treatment of malignancy are less effective or potentially more toxic than zoledronic acid and are prescribed less often today. In addition to medical therapy, avoiding dehydration and immobilization is critical to prevent worsening of hypercalcemia. If possible, the hypercalcemia of malignancy is best dealt with by an oncologist.
Glucocorticoids are often effective in lowering hypercalcemia caused by sarcoidosis and other granulomatous disorders that result in endogenous vitamin D intoxication. Treatment of hypercalcemia with oral phosphates is possible, but rarely used because of the risk of precipitation
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of calcium phosphate produces in tissues and vital organs. Often, partial control of hypercalcemia is sufficient to relieve symptoms; complete normalization of calcium level is often not necessary or achievable.
Osteomalacia
Osteomalacia is a disorder that is characterized by a defect in the mineralization of newly formed organic matrix of bone, known as osteoid, which leaves the bone soft and prone to fracture. In children, this mineralization defect, popularly known as rickets, involves cartilage at the epiphyseal growth plate and leads to widening of the ends of the long bones, growth retardation and skeletal deformities.
Causes
Table 84.4 lists the causes of osteomalacia. Defective mineralization in osteomalacia is due to lack of one or more factors necessary for mineralization: (a) newly formed osteoid must be of normal amount and quality; (b) normal amounts of calcium and phosphorus must be present in the extracellular fluid (associated disorders: vitamin D deficiency and primary renal tubular defects); (c) bioactivity of the alkaline phosphatase enzyme must be adequate (associated disorder: hypophosphatasia); (d) the pH at the site of calcification must be normal (associated disorder: renal tubular acidosis); (e) inhibitors of calcification must be absent (associated disorder: fluorosis or aluminum toxicity).
Vitamin D deficiency is the most common cause of osteomalacia. Vitamin D is essential for calcium and phosphorus metabolism, the critical elements in mineralization of bone. The major source of vitamin D (greater than 90%) is synthesis in skin exposed to sunlight. There are not many dietary sources that are rich in vitamin D; they include fatty fish oils, liver, and egg yolks. In the United States, milk and some other dairy products are supplemented with vitamin D, which has made dietary deficiencies less common. However, those who eat poorly and have minimal sunlight exposure, such as the frail elderly, are at risk for developing vitamin D deficiency and osteomalacia (33); dark-skinned individuals are at greater risk in this regard.
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TABLE 84.4 Causes of Osteomalacia |
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Osteomalacia because of malabsorption of vitamin D has been associated most commonly with celiac disease, postgastrectomy syndrome, intestinal bypass or resection, inflammatory bowel disease, and a variety of other intestinal disorders. Rarely, chronic hepatic or pancreatic disease may result in malabsorption of vitamin D as part of a generalized malabsorption of fat-soluble substances.
Osteomalacia associated with congenital or acquired renal disease may occur by a variety of mechanisms:
Osteomalacia as a result of dietary calcium deficiency is very rare; however, renal phosphate wasting is the second most common cause of osteomalacia.
A number of medications, with prolonged use, can cause osteomalacia, either indirectly because they inhibit vitamin D metabolism or directly because they inhibit mineralization of bone. These agents include anticonvulsants, lithium, fluoride, aluminum (historically, in dialysates), and cyclosporine (36). The first-generation bisphosphonates (e.g., etidronate), developed for treatment of osteoporosis and Paget disease, have been abandoned, except in rare instances, largely because they inhibit bone formation; the newer bisphosphonates do not.
Evaluation
History
The clinical presentation of adult osteomalacia is quite variable: Affected people can be asymptomatic or can present with nonspecific muscle and bone pain (pronounced
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in lower spine, pelvis, lower extremities), proximal muscle weakness, discomfort aggravated with movement and weight bearing, or unprovoked or minimally provoked fractures, especially of the ribs, vertebrae and long bones (37). The practitioner who suspects osteomalacia should ask questions about the amount of sun exposure (at least 15 minutes per day is necessary for optimal synthesis of vitamin D), the amount of calcium and vitamin D consumed in the diet (through vitamin preparations and fortified milk products), medications, and any history or symptoms of gastrointestinal or renal disease.
Physical Examination
Unlike the presentation in children, the physical examination in an adult may be unrevealing, although there may be objective evidence of weakness, especially of the proximal muscles. Also, there may be tenderness at the sites of otherwise inapparent fractures, typically in the lower spine, pelvis, and anterior tibias. The patient may exhibit a waddling gait.
Radiography
Radiologic studies, including films of symptomatic bones and joints, should be part of the initial examination. Commonly, cortical thinning and reduced bone density are seen. Looser lines, although not common, are diagnostic of osteomalacia; they are pseudofractures (“milkman fractures”) that occur typically in the femur, metatarsal bones, or pelvis, where they appear as symmetric, ribbon-like, radiolucent zones oriented perpendicular to the surface of the bone. Inadequate mineralization of osteoid and loss of trabeculae may lead to a concavity of the vertebral body referred to as codfish vertebrae.
Laboratory Studies
Laboratory findings in osteomalacia are largely dependent on the underlying cause. Initial tests should include measurement of serum calcium, phosphate, albumin, creatinine, urea nitrogen, alkaline phosphatase, and 25-hydroxyvitamin D. Patients with vitamin D deficiency exhibit hypophosphatemia, low normal or low serum calcium levels, low 25 hydroxyvitamin D levels (vitamin D sufficiency is defined as a serum level of 30 ng/mg or greater), evidence of secondary hyperparathyroidism, and elevated alkaline phosphatase activity. Patients with primary phosphate wasting have hypophosphatemia with increased phosphate clearance. Other tubular defects may also be present (e.g., aminoaciduria, glucosuria). Calcium and PTH levels are usually normal but alkaline phosphatase activity is typically elevated. In patients with a low alkaline phosphatase, hypophosphatasia should be considered. In one study of patients with osteomalacia, all patients had at least two abnormal tests when serum calcium, phosphate, and alkaline phosphatase were measured and radiographic findings were evaluated (38).
Bone Biopsy
In some instances, a tetracycline-labeled, iliac crest bone biopsy is obtained for bone histomorphometric studies to confirm the diagnosis. Bone biopsy reveals prominent features of osteomalacia with increased unmineralized bone or osteoid surface and an increased mineralization lag time as indicated by a reduced distance between the two tetracycline labels in the bone. Bone biopsy is diagnostic of osteomalacia but ordinarily does not need to be done unless the diagnosis cannot be made noninvasively. In such circumstances, the distinction that must be made is between osteomalacia and osteoporosis.
Treatment
The treatment of osteomalacia should target the underlying disorder and correction of hypophosphatemia, hypocalcemia, and vitamin D deficiency. There is no standardized replacement regimen for patients with vitamin D deficiency. Dosing depends on the cause of the deficiency and the severity of the disease. Pharmacologic vitamin D is available in several forms: D2 (ergocalciferol [calciferol]), 1,25 dihydroxyvitamin D3 (calcitriol [Rocaltrol]), the active form of the vitamin, and dihydrotachysterol (DHT [Hytakerol]), the synthetic analog of the vitamin. Nutritional deficiency of vitamin D can be treated with 50,000 IU of ergocalciferol (available in 50,000-U capsules) once or twice a week, orally or parenterally, until there is radiologically demonstrable healing of bone (usually by 6 to 12 months). Thereafter, the patient's diet should be supplemented by 400 to 800 International Units per day (the higher dose is advisable in the elderly).
Patients with malabsorption require higher oral doses of vitamin D, the equivalent of 50,000 to 100,000 International Units per day of ergocalciferol. Osteomalacia associated with liver disease should be treated with a form of vitamin D that is already 25 hydroxylated, such as calcidiol. Patients with hereditary hypophosphatemic rickets are treated with phosphate supplementation and calcitriol. The treatment of vitamin D deficiency in patients with renal disease is more complicated and may require oral and intravenous vitamin D treatment. For a full discussion, see Chapter 52. In addition to vitamin D supplementation, the diets of all patients should be enhanced by the addition of 1,000 to 1,200 mg of calcium per day. With each regimen the plasma calcium concentration, urinary calcium excretion, and bone density should be monitored. Increases in the urine calcium excretion and bone density indicate healing of the osteomalacia.
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Male Osteoporosis
Osteoporosis in men, as in women, is characterized by decreased bone mass and disruption of the normal architecture of bone. Osteoporosis in both men and women is a disease of bone loss. The disease results in decreases in trabecular bone (e.g., vertebrae) and in cortical bone (e.g., hips, long bones) that weaken the overall structural support of the skeleton, predisposing it to fracture. The World Health Organization (WHO) has defined osteoporosis as bone mineral density, as measured by bone densitometry (e.g., by DEXA scanning), more than 2.5 standard deviations below the gender-specific peak bone mass. Osteopenia is bone mineral density as measured by DEXA between 2.5 and 1.0 standard deviations below the gender-specific peak bone mass.
Epidemiology
More than 10 million people in the United States have osteoporosis, of whom more than 2 million are men (39). The most severe complication of osteoporosis in men is hip fracture. White men older than 50 years of age have lifetime risks of 6% and 5% for hip and vertebral fracture, respectively (40,41). The risks for African American men are less, probably because of their higher peak bone mass. With age, the risk of hip fracture for men increases (42, 43, 44). At age 80 years, the risk of hip fracture in men is one in six (17%) (45,46). Despite great improvements in surgical procedures and posthospital care and rehabilitation, the morbidity and mortality associated with hip fracture remain high, and are in fact higher in men than in women. Osteoporotic men are also at increased risk for vertebral fractures, which, with their potential for back pain, decreased mobility, and restrictive lung disease, are also significant contributors to morbidity.
Causes
Osteoporosis in men is caused primarily by the progressive loss of bone beginning at approximately 35 years of age, when the peak bone mass is achieved. The cause of such loss is unknown. In half the cases in men, osteoporosis is associated with a variety of predisposing disorders (Table 84.5), including endocrinopathies such as gonadal failure (see Chapter 85), hyperthyroidism (see Chapter 80), hyperparathyroidism (see Primary Hypoparathyroidism), and hyperadrenalism (see Chapter 81); malabsorption syndromes (such as celiac disease); malignant disease (e.g., myelomas); and administration of certain drugs (especially corticosteroids, possibly the leading cause of osteoporosis in men). Excessive alcohol consumption and smoking are a common cause of osteoporosis in men and are potentially modifiable (47). Genetic influences on the propensity to develop osteoporosis are poorly understood but probably reflect the interaction of multiple genes. Several well-defined genetic syndromes (osteogenesis imperfecta, Ehlers–Danlos syndrome, and Marfan syndrome) are associated with osteoporosis. The exact causes of age-related osteopenia in men are unknown but may include changes in endocrine function, nutritional status, and physical activity that accompany normal aging.
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TABLE 84.5 Causes of Male Osteoporosis |
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Evaluation
History
Osteoporotic men are usually asymptomatic until they fracture a bone. Fractures may be incurred after no apparent or minimal trauma, and loss of height after vertebral fracture is common. In a man with a recent fracture or evidence of osteoporosis, a focused medical history to detect secondary causes of osteoporosis is important and should include an exploration of the chronic use of predisposing medications. In younger men, secondary conditions
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should be even more diligently sought, as should a family history compatible with osteoporosis. A detailed history of alcohol use and cigarette smoking should be elicited.
Physical Examination
The patient's height and weight should be compared with his previous measurements. An examination of the spine (see Chapter 71) should be done with attention to spinal deformity and spinal tenderness, especially if the patient complains of backache or loss of height. A general examination, including a testicular examination, should be performed to seek secondary causes of osteoporosis.
Radiography
Routine radiographs of the skeleton are often unrevealing, because a loss of 30% or more of bone mass must occur before osteopenia can be appreciated. Thinning of bone is usually seen first in the vertebrae, the pelvis, and the femoral heads.
The diagnosis of osteoporosis is made or confirmed by measurement of bone mineral density by DEXA scan (see Chapter 103). Multiple sites, including hips, lumbar spine, and forearms, are scanned according to standardized protocols.
Laboratory Studies
In contrast to osteomalacia, levels of serum calcium, phosphate, and alkaline phosphatase are typically normal. As there is an identifiable underlying cause in 50% of men with osteoporosis, secondary causes should be considered; therefore, other tests (e.g., measurements of serum testosterone, thyroxine, thyroid-stimulating hormone, cortisol, PTH, 25 hydroxy vitamin D, urine calcium and creatinine, serum and urine protein electrophoresis, urinary free cortisol) may be indicated.
Bone Biopsies
The only reason to do a bone biopsy is if osteoporosis and osteomalacia cannot be distinguished on the basis of the evaluation described above (see also Osteomalacia).
Treatment
There are multiple approaches to treatment. Dietary interventions include calcium supplementation to bring total calcium consumption to 1200 to 1500 mg/day and vitamin D2 supplementation 800 International Units per day. These interventions are appropriate for all men at risk, including asymptomatic men older than 60 years of age and men taking corticosteroids or other osteoporosis-producing drugs chronically. Physical activity is important in maintaining bone mass. Resistance training and aerobic exercise, alone and in combination, have been effective in stabilizing bone density (48,49).
A number of drugs have been developed to increase bone mass, and one or more of them should be considered for all men with osteoporosis. Men with osteopenia may be treated by diet supplementation and exercise alone and monitored by DEXA scanning.
Bisphosphonates are the primary drugs used in the treatment of men with osteoporosis. They have been shown to be effective in eugonadal and hypogonadal men (50), as well as in men with glucocorticoid-induced bone loss (51,52). Therefore, bisphosphonates are indicated in men with idiopathic osteoporosis, in hypogonadal men with osteoporosis in which testosterone is not indicated or tolerated, and in men with glucocorticoid-induced bone loss. The treatment protocols are similar to those used in the treatment of women with osteoporosis (Chapter 103). A typical regimen is alendronate, 70 mg orally once a week or 10 mg/day. Alternatively, risedronate, a third-generation bisphosphonate, 35 mg a week or 5 mg/day, may be prescribed. Another oral bisphosphonate recently released is ibandronate which is administered 150 mg orally once a month (53).
Bisphosphonates should be taken in the morning, while in the upright position, with a full glass of water, 30 minutes (1 hour for ibandronate) before eating breakfast or taking other medications to avoid esophagitis, the major complication of these drugs. If the oral preparations cannot be tolerated, pamidronate or zoledronic acid, intravenously administered bisphosphonates, can be given (30 mg in saline, once every 3 months or 4 mg yearly respectively); however, these are not Food and Drug Administration (FDA)-approved for osteoporosis in men or women. Intravenous ibandronate has been recently approved by the Food and Drug Administration for treatment of osteoporosis and it is administered 3 mg every 3 months.
Because as many as 30% of men with osteoporosis have been found to be hypogonadal, the use of testosterone has been investigated for osteoporosis treatment (54). Many studies have demonstrated that testosterone replacement increases bone mineral density in men with hypogonadism. These studies showed efficacy of testosterone in men with primary and secondary hypogonadism and both congenital and acquired hypogonadism. Testosterone may be administered by injection, patch, gel, or orally (see Chapter 85). Since monitoring for the side effects of testosterone (prostate growth and carcinoma, hyperlipidemia, polycythemia) is critical, referral to an endocrinologist is indicated.
Calcitonin is an alternative for patients who cannot tolerate bisphosphonates. It is administered by nasal spray, one puff (200 IU) daily, alternating nostrils. The major adverse effects are rhinitis and epistaxis. Calcitonin may have an analgesic effect on bone pain. Calcitonin is not as
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potent as other available agents and is reserved for the patient with intolerance to other medications.
Hydrochlorothiazide has been reported to be effective in increasing bone density, but less so than bisphosphonates or calcitonin (55). It is particularly useful when the underlying reason for the reduced bone mass is hypercalciuria.
Teriparatide (parathyroid hormone) is a potent anabolic agent that builds bone in men and women (56). In a large trial of 437 men with osteoporosis treated with teriparatide (20 or 40 µg) or placebo, after just 11 months, there was a 6% to 9% increase in the bone mineral density in the spine and a 1.5% to 3% increase in the femoral neck compared to placebo (57). Teriparatide has been approved for men who have severe osteoporosis, are at high risk of fracture, or have failed other osteoporosis therapy. The benefits of therapy are weighed against the high cost of the medication (700 dollars per month), the need for daily subcutaneous injection, and concern about the theoretical risks of osteosarcoma.
Followup
The response to treatment of reduced bone density should be assessed by DEXA scan every 12 to 24 months. The use of serum and urine biomarkers of bone metabolism to assess response to therapy is less reliable than DEXA scanning and is not recommended. Patients receiving calcium and vitamin D supplementation should have serum calcium levels measured after 2 to 3 months, and then, if within normal limits, yearly thereafter to be sure that hypercalcemia does not develop. The use of testosterone and teriparatide requires special monitoring, usually by an endocrinologist.
Paget Disease Of Bone
Paget disease is a focal skeletal disorder characterized by rapid absorption and subsequent formation of bone.
Epidemiology
Most commonly, Paget disease is a disorder of older individuals that increases in frequency with increasing age (58). In the United States, it occurs in approximately 3% of Caucasians older than 55 years of age; it appears to be less common among African Americans, although additional data are required to be certain of this impression (59). In the elderly it occurs almost equally often in men and in women. The epidemiology of Paget disease is unusual because of its distinctive geographic distribution throughout the world. Paget disease occurs commonly in England, North America, Australia, New Zealand, France, and Germany. By contrast, it is uncommon in Switzerland and rare in Africa and throughout Asia, including China, India, and the Middle East (60). This information is important because it points to factors, both genetic and environmental, that are essential to the occurrence of the disorder.
Pathogenesis and Etiology
Normal bone remodeling depends on a coupled metabolic response of bone-forming osteoblasts and bone-resorbing osteoclasts. Paget disease is characterized by an initial phase of intense osteoclastic resorption followed by an increase in bone formation. As a result, the rate of bone remodeling is greatly enhanced, leading to the production of excessive, dense, but structurally deficient skeletal tissue. This weakened skeletal tissue is at risk for development of bony deformities and fracture. These changes are responsible for the signs and symptoms of the disease.
Paracrystalline nuclear inclusion bodies have been observed in osteoclasts from patients with Paget disease that are similar to the nuclear inclusions found in subjects with “slow virus” infections such as progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis (61). The inclusions have been identified, with the use of viral antisera, as nucleocapsids of the paramyxovirus family, with resemblance to both the measles and respiratory syncytial viruses (62). Both measles virus and respiratory syncytial virus nucleocapsids were identified in the same osteoclasts, suggesting the expression of antigen from an altered viral particle (63). However, attempts to isolate or pass an infectious agent from cultured surgical specimens or from cultured bone cells have been unsuccessful. There is also evidence from family studies for a genetic component to Paget disease; 14% to 25% of family members of patients with Paget disease will contract the disease (58,64,65). First-degree relatives of those with Paget disease have a sevenfold to 10-fold increased risk for developing Paget (65,66). In some families with Paget disease, mutations in the SQSTM1 gene have been identified, and in other family studies, genetic susceptibility loci on chromosome 18, 6, and 5 are implicated (66). Taken together, these finding suggest that Paget disease develops in individuals with a latent viral infection in osteoclasts with genetic susceptibility.
Evaluation
History
Early in the disease, patients are asymptomatic and are diagnosed only because a screening blood test has revealed an unexplained elevation of serum alkaline phosphatase activity or when pagetic lesions are incidentally discovered during imaging for another reason (seeRadiology).
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Chronic pain is the most common complaint of patients with Paget disease of bone. Resulting from either direct pagetic involvement or from osteoarthropathy, pain is the presenting complaint in two thirds of subjects older than 60 years of age (67). Bone pain or limitation of joint function points to the diagnosis in approximately 50% of patients with symptomatic Paget disease. Pagetic pain is typically increased at night and in the limbs with weight bearing (68). Pain in the extremities may result from expansion of bone with involvement of the periosteum. Lumbar spine pain may result from vertebral expansion, collapse, or microfractures. Facet enlargement, cord compression, or impingement of structures in the cauda equina or spinal nerve root may result in pain. The incidence of hip pain in Paget disease ranges from 30% to 50% (69). Pagetic coxopathy refers to involvement of both femur and acetabulum that may be associated with protrusio acetabuli.
Skeletal deformity in Paget disease is most common in the long bones, skull, and clavicle. Deformity of the tibia and femur is typically bowing, caused by enlarging and abnormal contouring of the rapidly remodeling bone. These deformities can result in gait disturbances and abnormal mechanical loads that predispose to pain and fracture. Hyperemia in the vascular pagetic bone results in warmth over the affected area. Involvement of the skull first leads to areas of radiolucency called osteoporosis circumscripta; later, there is skull enlargement in the frontal and occipital area.
Fractures are the most common complication of pagetic lesions. Most frequently seen in the femur, fractures are usually transverse and perpendicular to the cortex. Because of the vascular nature of Paget bone, fractures can be associated with substantial blood loss.
Neurologic symptoms and signs in Paget disease arise from three major sources. First, there can be a reduction in the size of neural foramina, leading to compression of the cranial nerves. Compression of the eighth cranial nerve causes deafness, one of the more common problems in patients with Paget disease, and occurs in more than one third of individuals with the disorder (70). Occasionally, various ocular and facial palsies also develop. Second, brainstem and cerebellar compression and/or hydrocephalus due to basilar invagination (so called platybasia) can occur. Third, spinal cord and nerve root compression occurs occasionally. Rarely, ischemic brain disease may occur secondary to a vascular steal syndrome resulting from increased vascularity of the cranial vault. Myelopathy due to ischemic myelitis has also been reported in the presence of highly vascularized and hypermetabolic bone in the vertebral column or as a consequence of compression of the spinal arteries (71). Spinal stenosis may occur, depending on the level of vertebral involvement; symptoms vary from radicular pain to numbness, paresthesia, and, finally, progressive paraparesis with bladder and bowel involvement.
Physical Examination
Physical examination is normal early in the disease but later may reveal structural deformities of bone (e.g., sabre shins, frontal bossing of the skull), hearing loss, or signs of nerve root compression. Active pagetic areas of bone are warm to palpation on exam.
Laboratory Evaluation
Patients are often diagnosed after a screening blood test has revealed elevated serum alkaline phosphatase activity with normal serum calcium, phosphate, and parathyroid hormone concentrations and normal liver function tests. The alkaline phosphatase can be identified by the laboratory as originating in bone. The level of serum alkaline phosphatase generally correlates with the activity of the disease.
Other biologic markers of bone metabolism may be increased in patients with Paget disease. The high rate of skeletal turnover during the resorptive and mixed stages of the disease has resulted in the development of multiple assays to measure disease activity. Metabolic markers of bone disease, in addition to alkaline phosphatase, include osteocalcin, procollagen type I C-terminal peptide, and newer assays of nonmetabolized collagen peptides, including N-telopeptides and pyridinoline crosslinks.
The level of serum osteocalcin, a protein produced by osteoblasts, tends to be increased in states of high bone turnover. Osteocalcin levels are frequently, but not always, increased in Paget disease. Procollagen type I C-terminal peptide, although not specific for bone collagen turnover, is increased when bone turnover is elevated, and a rapid decline in serum levels has been observed after treatment of Paget disease with calcitonin and bisphosphonates (72). Procollagen type I C-terminal peptide, measured in urine, is a highly sensitive assay for the determination of tissue type I collagen breakdown and, consequently, measurement of the rate of bone resorption (72,73). Because pyridinoline crosslink excretion is increased overnight, specimens are collected as second voided urines over a 2-hour period during the morning (e.g., 7 to 9 a.m.). The N-telopeptides and procollagen type I C-terminal peptide assays are believed to be the most sensitive markers of bone resorption and are readily available through commercial laboratories (74).
Radiology
The importance of radiologic evaluation in Paget disease cannot be underestimated. Only one third of patients have monostotic disease, with pelvic involvement in 72%, involvement of the lumbar spine in 58%, the thoracic spine in 45%, the femur in 55%, and the skull in 42% (75). The early radiologic lesions of Paget disease reflect severe
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localized osteolysis. These are typically “flame-shaped” osteolytic lesions that most commonly occur proximal to the distal epiphysis of a long bone. This resorptive lesion gradually progresses to the opposite end of the bone. As the disease evolves, an ingrowth of fibrovascular tissue and a high rate of bone remodeling may lead to deformity of the skull, enlarged dense vertebral bodies, and slowly progressive deformities of weight-bearing bones. Microfractures may occur on the convex side of the femur or tibia, increasing the degree of deformity and leading to the transverse or “banana” fracture that is typical of Paget disease. Pelvic involvement may be limited to the iliac and pubic rami but may involve the acetabulum or both the acetabulum and the femur, resulting in protrusio acetabuli.
For a complete evaluation, each patient should have a bone scan at the time of diagnosis to evaluate the extent of disease. Although scintigraphy is diagnostically less specific than radiography, bone scan identifies approximately 15% to 30% of lesions not visualized on radiographs (76). Alternatively, in 5% of cases the radiograph demonstrates diffuse Pagetic involvement (e.g., of the pelvis) whereas the bone scan reveals little uptake of the isotope. In this circumstance, the alkaline phosphatase level may be normal or only slightly elevated, reflecting lesions that are sclerotic, relatively inactive, or “burned out.”
Differentiating Paget disease from metastatic cancer may sometimes be difficult. Examination of previous laboratory studies and radiographs may be helpful. If the alkaline phosphatase and bony lesions were not present in the recent past, Paget disease is unlikely. Furthermore, spread of Paget disease to new sites is unusual, therefore, the development of new sites of radiographic involvement should raise suspicion of another process and bone biopsy should be considered.
Bone Biopsy
A bone biopsy is rarely needed to establish the diagnosis of Paget disease. However, a bone biopsy is indicated to rule out malignancy when mixed osteoblastic and osteolytic vertebral lesions are seen. The value of a vertebral needle biopsy is limited. An open biopsy of the involved bone is more likely to be diagnostic.
Complications
In addition to orthopedic and neurologic problems, a few rarer complications may occur.
High-output heart failure may develop if a third or more of the bones are diseased; in addition, calcific aortic stenosis, heart block, and left bundle branch block appear to be more common than in the general population (77).
Osteosarcoma is a dreaded but unusual complication, sometimes multicentric; the tumors usually are detected because the patient complains of increased localized pain, sometimes associated with swelling. Radiologically, either osteolytic or osteoblastic lesions may be seen; computed tomography–directed biopsy can often make the definitive diagnosis and distinguish the malignancy from benign giant cell tumor of bone, the incidence of which is also increased in Paget disease.
Increased incidences of primary hyperparathyroidism and hyperuricemia have been reported in patients with Paget disease (78). Urinary stones (see Chapter 51) have been reported in 13% of patients (79).
Treatment
Effective medical therapy for Paget disease has been available for more than 20 years. The availability of newer and more potent agents suggests that treatment should be pursued more aggressively, both to control the disease and to decrease the risk of future complications. Indications for treatment include symptoms of bone pain, headache from skull involvement, hypercalcemia from immobilization, and symptoms of nerve compression. In asymptomatic patients with involvement of the skull, spine, or weight-bearing bones, treatment is also recommended. A general guideline is to treat if the serum alkaline phosphatase concentration is more than two to three times normal. Elevations of alkaline phosphatase indicate either widespread disease or intense activity in a limited area. Such patients are at higher risk for future complications of their disease. Patients with skull involvement or monostotic disease of the tibia or femur should be treated since progression and complications are likely.
Bisphosphonates are the cornerstone of the treatment of Paget disease. Bisphosphonates bind to the surface of the hydroxyapatite crystal and decrease bone resorption by disrupting osteoclast recruitment and cellular activity. The effects of these agents may last several months or produce complete remission. Because it is less potent than newer agents and because it also inhibits bone mineralization, etidronate, the first agent widely used to treat Paget disease, is used currently only if subjects have limiting side effects with newer agents (80).
Alendronate, the first of the third-generation oral bisphosphonates, is approved for the treatment of Paget disease at an oral dose of 40 mg/day (5-, 10-, 35-, 40-, 70-mg tablets) for 6 months. In one study, the drug caused a 71% fall in alkaline phosphatase levels, compared with 44% in patients treated with etidronate; osteolytic lesions improved; and no impairment of bone formation was seen on biopsy after 6 months of therapy (80,81). Tiludronate (200 to 400 mg/day, available in 200-mg tablets) and risedronate (30 mg/day, available in 5-, 30-, and 35-mg tablets) are newer bisphosphonates approved for the treatment of Paget disease (82,83). They appear comparable to alendronate in potency; however, risedronate
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requires a shorter course of treatment (2 months) than alendronate (6 months). Treatment of Paget disease should always be accompanied by appropriate calcium and vitamin D supplementation (calcium 1,000 mg/day and vitamin D2 800 IU/day) to aid in the mineralization of newly formed bone and to prevent the theoretical risk of hypocalcemia related to bisphosphonate therapy. The most common side effects of oral bisphosphonates include epigastric pain, heartburn, and nausea due to esophagitis or gastritis. To avoid these symptoms, oral bisphosphonates must be taken alone on an empty stomach with an 8-ounce glass of water 30 to 60 minutes before breakfast or before taking other medications, and the patient must remain upright for 30 minutes after dosing.
Pamidronate, a potent second-generation bisphosphonate that can be administered intravenously, is useful in refractory disease, producing disease remission for up to 3 years in up to 90% of patients (84, 85, 86). After a series of initial infusions, maintenance infusions of pamidronate are then repeated at intervals based on the response of biochemical markers. Zoledronic acid, a potent, third-generation IV bisphosphonate administered as a single infusion, is also effective (87). Rare side effects of IV bisphosphonate therapy include a transient flu-like syndrome with leukopenia, anterior uveitis, episcleritis, ototoxicity, and jaw necrosis (88, 89, 90). Because the incidence of gastrointestinal (GI) side effects is less with IV bisphosphonates, these agents are an acceptable alternative treatment for patients who are unable to tolerate oral bisphosphonate therapy.
Calcitonin is an alternative treatment to bisphosphonate therapy, although it is less efficacious. The high doses used in subcutaneous administration often result in the development of nausea and transient flushing. Starting subcutaneous doses are in the range of 50 to 100 IU of salmon calcitonin or 50 IU of human calcitonin daily for 1 month; it is then continued three to 4 days per week thereafter (91). It also may be administered by intranasal spray in a dose of 200 to 400 IU daily. Nasal calcitonin causes less nausea, but 11% of patients develop rhinitis (92). Although prolonged remission may occur with calcitonin treatment, a partial or “plateau” response is more common: Biochemical abnormalities wane over a period of months but may not return to normal.
For patients with poor response to bisphosphonate or calcitonin therapy, second-line agents include gallium nitrate and plicamycin (Mithramycin). Gallium nitrate, a potent antiresorptive drug, is currently an experimental therapy for Paget disease (93). In a multicenter trial, gallium nitrate was administered in doses of 0.05, 0.25, and 0.5 mg/kg/day by subcutaneous injection in two 14-day cycles; cyclical low-dose subcutaneous administration may be effective for patients with advanced disease that has been resistant to other agents (94).
Surgery
There are several skeletal problems that may require surgical intervention, but only after careful planning with an orthopedist or neurosurgeon. The operations are often complicated by infection and hemorrhage, in part because of the hypervascularity of pagetic bone. For that reason bisphosphonate or calcitonin should be given for approximately 3 months before elective surgery, to decrease the risk of bleeding. To permit unhindered healing, however, it is best to stop treatment at the time of surgery and then resume it 8 weeks postoperatively.
Specific problems that may warrant surgical intervention include basilar invagination and hydrocephalus (which may require a ventricular shunt), nerve compression syndromes (sometimes reversible by medical therapy), degenerative disease of joints that may lead to joint replacement, and pathologic fractures that require fixation.
Specific References
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