TABLE IV-114 Risk Factors for Active Tuberculosis Among Persons Who Have Been Infected With Tubercle Bacilli 34 page

X-74 and X-75. The answers are D and C, respectively. (Chap. 352) Hypophosphatemia results from one of three mechanisms: inadequate intestinal phosphate absorption, excessive renal phosphate excretion, and rapid redistribution of phosphate from the extracellular space into bone or soft tissue. Inadequate intestinal absorption is rare since antacids containing aluminum hydroxide are no longer commonly prescribed. Malnutrition from fasting or starvation may result in depletion of phosphate. This is also commonly seen in alcoholism. In hospitalized patients, redistribution is the main cause. Insulin promotes phosphate entry into cells along with glucose. When nutrition is initiated, refeeding further increases redistribution of phosphate into cells and is more pronounced when IV glucose is used alone. Sepsis may cause destruction of cells and metabolic acidosis, resulting in a net shift of phosphate from the extracellular space into cells. Renal failure is associated with hyperphosphatemia, not hypophosphatemia, and initial prerenal azotemia, such as in this presentation, can obscure underlying phosphate depletion.

The approach to treating hypophosphatemia should take into account several factors, including the likelihood (and magnitude) of underlying phosphate depletion, renal function, serum calcium levels, and the concurrent administration of parenteral glucose. In addition, the treating physician should assess the patient for complications of hypophosphatemia, which can include neuromuscular weakness, cardiac dysfunction, hemolysis, and platelet dysfunction. Severe hypophosphatemia generally occurs when the serum concentration falls below 2 mg/dL (<0.75 mmol/L). This becomes particularly dangerous when there is underlying chronic phosphate depletion. However, there is no simple formula to determine the body’s phosphate needs from measurement of the serum phosphate levels because most phosphate is intracellular. It is generally recommended to use oral phosphate repletion when the serum phosphate

levels are greater than 1.5–2.5 mg/dL (0.5–0.8 mmol/L). The dose of oral phosphate is 750–2000 mg daily of elemental phosphate given in divided doses. More severe hypophosphatemia as in the case presented requires intravenous repletion. Intravenous phosphate repletion is given as neutral mixtures of sodium and potassium phosphate salts at doses of 0.2–0.8 mmol/kg given over 6 hours. Table X-75 outlines the total dose and recommended infusion rates for a range of phosphate levels. In this patient with a level of 1.0 mg/dL, the recommended infusion rate is 8 mmol/h over 6 hours for a total dose of 48 mmol. Until the underlying hypophosphatemia is corrected, one should measure phosphate and calcium levels every 6 hours. The infusion should be stopped if the calcium phosphate product rises to higher than 50 to decrease the risk of heterotopic calcification. Alternatively, if hypocalcemia is present coincident with the hypophosphatemia, it is important to correct the calcium prior to administering phosphate.

TABLE X-75 Intravenous Therapy for Hypophosphatemia

X-76. The answer is E. (Chap. 352) Magnesium sulfate is first-line therapy for seizures associated with eclampsia of pregnancy. A pregnant woman presenting with seizures and hypertension is initially treated with a bolus of magnesium sulfate at a dose of approximately 4 g followed by a continuous infusion at 1 g/h. While definitive treatment of eclampsia is delivery of the baby, ongoing therapy with magnesium sulfate for 24 hours following the last seizure is recommended. Patients should be monitored throughout the infusion for signs of hypermagnesemia, and levels should be measured at least every 6 hours. The usual magnesium concentration is 0.7–1 mmol/L (1.5–2 meq/L), and the desired

level for treatment of preeclampsia is usually 1.7–3.5 mmol/L, although signs and symptoms of hypermagnesemia can develop with levels of 2 mmol/L or higher. The initial signs of hypermagnesemia include prolongation of the QRS complex, depression of deep tendon reflexes, and hypotension that is refractory to vasopressors. At concentrations greater than 4 mmol/L, nausea, lethargy, and weakness can appear and progress to paralysis and respiratory failure. The symptoms become increasingly severe, and asystole occurs when levels approach 10 mmol/L.

X-77. The answer is B. (Chap. 352) Vitamin D deficiency is highly prevalent in the United States and is most common in older individuals who are hospitalized or institutionalized. Vitamin D deficiency can occur as a result of inadequate dietary intake, decreased production in the skin, decreased intestinal absorption, accelerated losses, or impaired vitamin D activation in the liver or kidney. Clinically, vitamin D deficiency in older individuals is most often silent. Often practitioners fail to consider vitamin D deficiency until a patient has been diagnosed with osteoporosis or suffered a fracture. However, some individuals can experience diffuse muscle and bone pain. When assessing vitamin D levels, the appropriate test is 25-hydroxy vitamin D [25(OH)D] levels. Optimal 25(OH)D levels are greater than 80 nmol/L (32 ng/mL); however, an individual is not considered deficient until the level is less than 37 nmol/L (15 ng/mL). When the 25(OH)D level falls below this level, parathyroid hormone (PTH) may rise, and it is also associated with a lower bone density. Vitamin D deficiency leads to decreased intestinal absorption of calcium with resultant hypocalcemia and secondary hyperparathyroidism. In response to this, there is higher bone turnover, which can be associated with an increase in alkaline phosphatase levels. In addition, elevated PTH stimulates renal conversion of 25-hydroxy vitamin D to 1,25-hydroxy vitamin D, the activated form of vitamin D. Thus, even in the face of severe vitamin D deficiency, the activated 1,25(OH)D levels may be normal and do not accurately reflect vitamin D stores. Thus, 1,25(OH)D should not be used to make a diagnosis of vitamin D deficiency. While vitamin D deficiency may be associated with abnormalities in PTH, alkaline phosphatase, and calcium levels, these biochemical abnormalities are seen in many other diseases and are neither sensitive nor specific for the diagnosis of vitamin D deficiency.

X-78. The answer is A. (Chap. 353) Granulomatous disorders including sarcoidosis, tuberculosis, and fungal infections can be associated with hypercalcemia-caused increased synthesis of 1,25-hydroxy vitamin D by macrophages within the granulomas. This process bypasses the normal feedback mechanisms, and elevated levels of both 25-hydroxy and 1,25-hydroxy vitamin can be seen. This does not normally occur as 1,25-hydroxy-vitamin D levels are normally tightly controlled through feedback mechanisms on renal 1-hydroxylase, the primary producer of activated vitamin D in normal circumstances. In addition, the normal feedback provided by parathyroid hormone concentrations is also bypassed and the PTH level may be low.

X-79. The answer is D. (Chap. 353) This patient demonstrates evidence of tertiary hyper-

parathyroidism, with inappropriate elevations in parathyroid hormone despite increases in calcium and phosphate. In addition, the patient is demonstrating clinical evidence of disease including bony pain and ectopic calcification. Tertiary hyperparathyroidism most commonly develops in individuals with long­standing renal failure who have been non-adherent to therapy. In this case scenario, the hypoxemia and ground-glass infiltrates on chest CT represent ectopic calcification of the lungs. This can be difficult to identify with typical imaging, and a technetium-99 bone scan will show increased uptake in the lungs. Treatment of tertiary hyperparathyroidism with severe clinical manifestations requires

parathyroidectomy.

X-80. The answer is B. (Chap. 353) Hypocalcemia can be a life-threatening consequence of thyroidectomy if the parathyroid glands are inadvertently removed during the surgery, as the four parathyroid glands are located immediately posterior to the thyroid gland. This is an infrequent occurrence currently as the parathyroid glands can be better identified both before and during surgery. However, hypoparathyroidism may occur even if the parathyroid glands are not removed by thyroidectomy due to devascularization or trauma to the parathyroid glands. Hypocalcemia following removal of the parathyroid glands may begin any time during the first 24–72 hours, and monitoring of serial calcium levels is recommended for the first 72 hours. The earliest symptoms of hypocalcemia are typically circumoral paresthesias and paresthesias with a “pins-and-needles” sensation in the fingers and toes. The development of carpal spasms upon inflation of the blood pressure cuff is a classic sign of hypocalcemia and is known as Trousseau sign. Chvostek sign is the other classic sign of hypocalcemia and is elicited by tapping the facial nerve in the preauricular area causing spasm of the facial muscles. A prolongation of the QT interval on ECG suggests life-threatening hypocalcemia that may progress to fatal arrhythmia, and treatment should not be delayed for serum testing to occur in a patient with a known cause of hypocalcemia. Immediate treatment with IV calcium should be initiated. Maintenance therapy with calcitriol and vitamin D is necessary for ongoing treatment of acquired hypoparathyroidism. Alternatively, surgeons may implant parathyroid tissue into the soft tissue of the forearm, if it is thought that the parathyroid glands will be removed. Hypomagnesemia can cause hypocalcemia by suppressing parathyroid hormone release despite the presence of hypocalcemia. However, in this patient, hypomagnesemia is not suspected after thyroidectomy, and magnesium administration is not indicated. Benztropine is a centrally acting anticholinergic medication that is used in the treatment of dystonic reactions that can occur after taking centrally acting antiemetic medications with dopaminergic activity, such as metoclopramide or Compazine. Dystonic reactions involve focal spasms of the face, neck, and extremities. While this patient has taken a medication (morphine) that can cause a dystonic reaction, the spasms that she is experiencing are more consistent with tetanic contractions of hypocalcemia than dystonic reactions. Finally, measurement of forced vital capacity is most commonly used as a measurement of disease severity in myasthenia gravis or Guillain-Barré syndrome. Muscle weakness is a typical presenting feature but not paresthesias.

X-81. The answer is E. (Chap. 353) Malignancy can cause hypercalcemia by several different mechanisms, including metastasis to bone, cytokine stimulation of bone turnover, and production of a protein structurally similar to parathyroid hormone by the tumor. This protein is called parathyroid hormone–related peptide (PTHrp) and acts at the same receptors as parathyroid hormone (PTH). Squamous cell carcinoma of the lung is the most common tumor associated with the production of PTHrp. Serum calcium levels can become quite high in malignancy because of unregulated production of PTHrp that is outside of the negative feedback control that normally results in the setting of hyper-calcemia. PTH hormone levels should be quite low or undetectable in this setting. When hypercalcemia is severe (>15 mg/dL), symptoms frequently include dehydration and altered mental status. The electrocardiogram may show a shortened QTc interval. Initial therapy includes large-volume fluid administration to reverse the dehydration that results from hypercalciuria. In addition, furosemide is added to promote further calciuria. If the calcium remains elevated, as in this patient, additional measures should be undertaken to decrease the serum calcium. Calcitonin has a rapid onset of action with a decrease in serum calcium seen within hours. However, tachyphylaxis develops, and the

duration of benefit is limited. Pamidronate is a bisphosphonate that is useful for the hypercalcemia of malignancy. It decreases serum calcium by preventing bone resorption and release of calcium from the bone. After IV administration, the onset of action of pamidronate is 1–2 days with a duration of action of at least 2 weeks. Thus, in this patient with ongoing severe symptomatic hypercalcemia, addition of both calcitonin and pamidronate is the best treatment. The patient should continue to receive IV fluids and furosemide. The addition of a thiazide diuretic is contraindicated because thiazides cause increased calcium resorption in the kidney and would worsen hypercalcemia.

X-82. The answer is B. (Chap. 353) Hyperparathyroidism is the most common cause of hyper-calcemia and is the most likely cause in an adult who is asymptomatic. Cancer is the second most common cause of hypercalcemia but usually is associated with symptomatic hypercalcemia. In addition, there are frequently symptoms from the malignancy itself that dominate the clinical picture. Primary hyperparathyroidism results from autonomous secretion of parathyroid hormone (PTH) that is no longer regulated by serum calcium levels, usually related to the development of parathyroid adenomas. Most patients are asymptomatic or have minimal symptoms at the time of diagnosis. When present, symptoms include recurrent nephrolithiasis, peptic ulcers, dehydration, constipation, and altered mental status. Laboratory studies show elevated serum calcium with decreased serum phosphate. Diagnosis can be confirmed with measurement of parathyroid hormone levels. Surgical removal of autonomous adenomas is generally curative, but not all patients need to be treated surgically. It is recommended that individuals below age 50 undergo primary surgical resection. However, in those above 50 years, a cautious approach with frequent laboratory monitoring is often used. Surgery can then be undertaken if a patient develops symptomatic or worsening hypercalcemia or complications such as osteopenia. Breast cancer is a frequent cause of hypercalcemia because of metastatic disease to the bone. In this patient who has received routine mammography as part of age-appropriate cancer screening and is asymptomatic, this would be unlikely. Multiple myeloma is another malignancy frequently associated with hypercalcemia that is thought to be due to the production of cytokines and humoral mediators by the tumor. Multiple myeloma should not present with isolated hypercalcemia and is associated with anemia and elevations in creatinine.

Approximately 20% of individuals with hyperthyroidism develop hypercalcemia related to increased bone turnover. This patient exhibits no signs or symptoms of hyper-thyroidism, making the diagnosis unlikely. Vitamin D intoxication is a rare cause of hypercalcemia. An individual must ingest 40–100 times the recommended daily amount in order to develop hypercalcemia. Because vitamin D acts to increase both calcium and phosphate absorption from the intestine, serum levels of both minerals would be elevated, which is not seen in this case.

X-83. The answer is B. (Chap. 353) Parathyroid hormone (PTH) is produced by the four small parathyroid glands that lie posterior to the thyroid gland and is the primary hormone responsible for regulating serum calcium and phosphate balance. PTH secretion is tightly regulated with negative feedback to the parathyroid glands by serum calcium and vitamin D levels. PTH primarily affects serum calcium and phosphate levels through its action in the bone and the kidney. In the bone, PTH increases bone remodeling through its actions on the osteoblasts and osteoclasts. It directly stimulates osteoblasts to increase bone formation, and this action of PTH has been utilized in the treatment of osteoporosis. Its action on osteoclasts, however, is indirect and likely is mediated through its actions on the osteoblasts. The osteoclast has no receptors for PTH. It has been hypothesized that cytokines produced by osteoblasts are responsible for increased osteoclastic activity that is seen after PTH administration, as

PTH fails to have an effect on osteoclasts in the absence of osteoblasts. The net effect of PTH on the bone is to increase bone remodeling. Ultimately, this leads to an increase in serum calcium, an effect that can be seen within hours of drug administration. In the kidney, PTH acts to increase calcium reabsorption while increasing phosphate excretion. At the proximal tubule, PTH acts to decrease phosphate transport, thus facilitating its excretion. Calcium reabsorption is increased by the action of PTH on the distal tubule. A final action of PTH in the kidney is to increase the production of 1,25-hydroxycholecalciferol, the activated form of vitamin D, through stimulation of 1-α-hydroxylase. Activated vitamin D then helps to increase calcium levels by increasing intestinal absorption of both calcium and phosphate.

X-84. The answer is B. (Chap. 354) Osteoporosis refers to a chronic condition characterized by decreased bone strength and frequently manifests as vertebral and hip fractures. In the Unites States, about 8 million women have osteoporosis compared to about 2 million men, for a ratio between men and women of 4 to 1. An additional 18 million individuals are estimated to have osteopenia. The risk of osteoporosis increases with advancing age and rapidly worsens following menopause in women. Most women meet the diagnostic criteria for osteoporosis between the ages of 70 and 80. White women have an increased risk for osteoporosis when compared to African-American women. The epidemiology for bone fractures follows the epidemiology for osteoporosis. Fractures of the distal radius (Colles’ fracture) increases up to age 50 and plateaus by age 60, and there is only a modest increase in risk thereafter. This is contrasted with the risk of hip fractures. Incidence rates for hip fractures double every 5 years after the age of 70. This change in fracture pattern is not entirely due to osteoporosis, but is also related to the fact that fewer falls in the elderly occur onto an outstretched arm and are more likely to occur directly onto the hip. Black women experience hip fractures at approximately half the rate as white women. The mortality rate in the year following a hip fracture is 5– 20%. Vertebral fractures are also common manifestations of osteoporosis. While most are found incidentally on chest radiograph, severe cases can lead to height loss, pulmonary restriction, and respiratory morbidity.

X-85. The answer is C. (Chap. 354) There are multiple risks for osteoporotic bone fractures that can be either modifiable or nonmodifiable. These are outlined in Table X-85. Non-modifiable risk factors include a previous history of fracture as an adult, female sex, white race, dementia, advanced age, and history of fracture (but not osteoporosis) in a first-degree relative. Risk factors that are potentially modifiable include body weight less than 58 kg (127 lb), low calcium intake, alcoholism, impaired eyesight, recurrent falls, inadequate physical activity, poor health, and estrogen deficiency including menopause prior to age 45 or prolonged premenstrual amenorrhea. Current cigarette smoking is a risk factor for osteoporosis-related fracture while a prior history of cigarette use is not.

TABLE X-85 Risk Factors for Osteoporosis Fracture

X-86. The answer is C. (Chap. 354) A variety of diseases in adults increase the risk of osteoporosis. First, diseases that lead to estrogen deficiency or hypogonadism can lead to osteoporosis. This would include Turner’s syndrome, Klinefelter’s syndrome, and hyperprolactinemia, among others. A wide range of endocrine disorders can also lead to abnormal bone metabolism, especially hyperparathyroidism and thyrotoxicosis. Poor nutrition and gastrointestinal disorders increase the likelihood of developing osteoporosis. Anorexia nervosa causes both hypogonadism and poor nutritional status. Malabsorption syndromes lead to decreased intake of calcium and vitamin D, which are essential to good bone health. Chronic obstructive pulmonary disease also has a high prevalence of osteoporosis, which is may be related to a chronic inflammatory state with high bone turnover that is exacerbated by frequent corticosteroid use, frequent vitamin D deficiency, and low activity states. Other broad categories of disease that can lead to osteoporosis include rheumatologic disorders, hematologic malignancies, and some inherited disorders such as osteogenesis imperfecta, Marfan’s syndrome, and porphyria, among many others. It is well known that immobilization, pregnancy, and lactation can lead to osteoporosis as well.

X-87. The answer is B. (Chap. 354) Osteoporosis is a common disease affecting 8 million women and 2 million men in the United States. It is most common in postmenopausal women, but the incidence is also increasing in men. Estrogen loss probably causes bone loss by activation of bone remodeling sites and exaggeration of the imbalance between bone formation and resorption. Osteoporosis is diagnosed by bone mineral density scan. Dual-energy x-ray absorptiometry (DXA) is the most accurate test for

measuring bone mineral density. Clinical determinations of bone density are most commonly measured at the lumbar spine and hip. In the DXA technique, two x-ray energies are used to measure the area of the mineralized tissues and compared to gender- and race-matched normative values. The T-score compares an individual’s results to a young population, whereas the Z-score compares the individual’s results to an age-matched population. Osteoporosis is diagnosed when the T-score is –2.5 SD in the lumbar spine, femoral neck, or total hip. An evaluation for secondary causes of osteoporosis should be considered in individuals presenting with osteoporotic fractures at a young age and those who have very low Z-scores. Initial evaluation should include serum and 24-hour urine calcium levels, renal function panel, hepatic function panel, serum phosphorous level, and vitamin D levels. Other endocrine abnormalities including hyperthyroidism and hyperparathyroidism should be evaluated, and urinary cortisol levels should be checked if there is a clinical suspicion for Cushing’s syndrome. Follicle-stimulating hormone and luteinizing hormone levels would be elevated but are not useful in this individual, as she presents with a known perimenopausal state.

X-88. The answer is C. (Chap. 354) Determination of when to initiate screening for osteoporosis with bone densitometry testing can be complicated by multiple factors. In general, most women do not require screening for osteoporosis until after completion of menopause unless there have been unexplained fractures or other risk factors that would suggest osteoporosis. There is no benefit to initiating screening for osteoporosis in the perimenopausal period. Indeed most expert recommendations do not recommend routine screening for osteoporosis until age 65 or older unless risk factors are present. Risk factors for osteoporosis include advanced age, current cigarette smoking, low body weight (<57.7 kg), family history of hip fracture, and long-term glucocorticoid use. Inhaled glucocorticoids may cause increased loss of bone density, but as this patient is on a low dose of inhaled fluticasone and is not estrogen deficient, bone mineral densitometry cannot be recommended at this time. The risk of osteoporosis related to inhaled glucocorticoids is not well defined, but most studies suggest that the risk is relatively low. Delaying childbearing until the fourth and fifth decade does increase the risk of osteoporosis but does not cause early onset of osteoporosis prior to completion of menopause. The patient’s family history of menopause likewise does not require early screening for osteoporosis.

X-89. The answer is D. (Chap. 354) Osteoporosis is defined as a reduction of bone mass or density or the presence of a fragility fracture. Operationally, the World Health Organization (WHO) defines osteoporosis as a bone density more than 2.5 SD less than the mean for young healthy adults of the same race and sex. Dual-energy x-ray absorptiometry (DXA) is the most widely used study to determine bone density. Bone density is expressed as a T-score, that is, the SD below the mean of young adults of the same race and gender. A T-score higher than 2.5 characterizes osteoporosis, and a T-score less than 1 identifies patients at risk of osteoporosis. The Z-score compares individuals with those in an age-, race-, and gender-matched population.

X-90. The answer is E. (Chap. 354) Multiple treatment choices are available to prevent fractures and reverse bone loss in osteoporosis, and the side-effect profiles should be carefully considered when making the appropriate choice for this patient. Risedronate belongs to a family of drugs called bisphosphonates. Bisphosphonates act to inhibit osteoclast activity to decrease bone resorption and increase bone mass. Alendronate, risedronate, and ibandronate are approved for the treatment of postmenopausal osteoporosis, and alendronate and risedronate are also approved for the treatment of

steroid-induced osteoporosis and osteoporosis in men. In clinical trials, risedronate decreases the risk of hip and vertebral fracture in women with osteoporosis by about 40% over 3 years. However, risedronate is not effective in decreasing hip fracture in women over the age of 80 without proven osteoporosis. The major side effect of bisphosphonate compounds taken orally is esophagitis. These drugs should be taken with a full glass of water, and the patient should remain upright for 30 minutes after taking the drug. There is also some concern about increased risk of osteonecrosis of the jaw in individuals treated with high doses of IV bisphosphonates or treated with oral therapy for prolonged periods, but in this patient with severe osteoporosis and a recent fracture, the benefits outweigh potential risks. Estrogens are also effective in preventing and treating osteoporosis. Epidemiologic data indicate that women taking estrogen have a 50% decreased risk of hip fracture. Raloxifene is a selective estrogen receptor modulator (SERM). The effect of raloxifene on bone density is somewhat less than that of estrogen, but it does decrease the risk of vertebral fracture by 30–50%. However, both drugs are contraindicated in this patient because of the recent occurrence of venous thromboembolic disease. Both estrogen and SERMs increase the risk of DVT and pulmonary embolus several-fold. If estrogen is to be used, it should be used in combination with a progestin compound in women with an intact uterus to decrease the risk of uterine cancer associated with unopposed estrogen stimulation. Both calcium and vitamin D supplementation are recommended as supplemental therapy, but given the degree of osteoporosis are inadequate alone. Calcitonin is available as an intranasal spray and produces small increases in bone density, but it has no proven effectiveness on the prevention of fractures.

X-91 and X-92. The answers are B and C, respectively. (Chap. 355) The most likely diagnosis in this case is Paget’s disease. A normal level of γ-glutamyl transferase localizes the cause of the elevated alkaline phosphatase to the bone. Thus, diseases of the liver and biliary tree are excluded. While both vertebral osteomyelitis and Paget’s disease could cause elevations in alkaline phosphatase, the patient has no symptoms of systemic illness that one would typically expect with vertebral osteomyelitis. Paget’s disease is a common dysplasia of the bone associated with localized bone remodeling that can affect numerous discreet areas of the skeleton. This disorder is relatively common. In autopsy series, Paget’s lesions can be demonstrated in about 3% of individuals older than 40 years of age, although clinical manifestations of the disease are far less common. Diagnosis is most often made in individuals with asymptomatic elevations of alkaline phosphatase or through characteristic radiographic changes in individuals who underwent biochemical or radiographic testing for other reasons. In symptomatic individuals, localized pain is most commonly seen. The bones most often affected include the femur, skull, pelvis, vertebral bodies, and tibia, and the specific symptoms depend on the location of the Paget’s lesion. When the vertebral bodies are involved, back pain can result from enlarged vertebrae, compression fractures of the spine, and spinal stenosis. In rare instances, spinal cord compression can occur. In this scenario, it is possible that the patient’s back pain is due to undiagnosed Paget’s disease. Diagnosis is typically made based on typical findings on radiographs and biochemical testing. Radiographs may demonstrate the enlargement or expansion of an entire bone, cortical thickening, coarsening of the trabecular markings, and both lytic and sclerotic changes. Characteristic findings of the vertebrae include cortical thickening of the superior and inferior endplates, creating a “picture frame” vertebra. If a vertebra is diffusely enlarged, the radiodensity created is known as an “ivory vertebra.” An elevation in alkaline phosphatase is the classic finding in Paget’s disease and is the test of choice for both diagnosis and assessing response to therapy. Serum osteocalcin, a marker of bone formation, is not always elevated in Paget’s disease for unknown reasons and is not recommended for either diagnosis or response to therapy. Serum or urine N-telopeptide or C-telopeptide are also bone

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