Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 58

Disorders of bone and bone mineral metabolism MONICA KOMOROSKI1, NASRIN AZAD2, AND PAULINE CAMACHO1* Loyola University Osteoporosis and Metabolic Bone Disease Center, Loyola University Medical Center, Maywood, IL, USA

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Edward Hines Jr. VA Hospital, Hines, IL, USA

CALCIUM AND PARATHYROID HORMONE DISORDERS Introduction Calcium is the third most abundant ion in the body and plays an important role regarding normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signaling (Liamis et al., 2009). Parathyroid hormone (PTH) is an important hormone involved in the regulation of calcium and phosphorus homeostasis. PTH is synthesized by the parathyroid glands and is then processed and stored in secretory granules as a mature 84 residue hormone. Once released, the circulating 84 amino acid protein has a short half-life of 2–4 minutes. It is through the effects of PTH that the serum calcium concentration is maintained within normal limits (Al Zahrani and Levine, 1997). Most of total-body calcium (99%) is in the form of hydroxyapatite in the skeleton, and the rest is in extracellular fluids and soft tissues. It is the extracellular concentration of ionized calcium that is the most important determinant of PTH secretion. The rate of PTH secretion is controlled by the interaction of extracellular calcium with specific calcium-sensing receptors present on the plasma membrane of the parathyroid cell. Hypocalcemia stimulates PTH synthesis and secretion. Hyperphosphatemia and severe hypomagnesemia also stimulate PTH secretion. PTH acts via direct and indirect mechanisms to increase serum calcium. Within minutes, PTH directly increases renal calcium reabsorption and decreases renal phosphorus reabsorption in the distal tubule. PTH also directly stimulates osteoclasts, leading to bone resorption. This process releases calcium and phosphorus from the bone into the circulation. PTH also increases 1a-hydroxylase activity in the kidney which converts

calcidiol to calcitriol, which in turn increases intestinal absorption of calcium and phosphorus. This process takes about 1–2 days. Overall, PTH acts to raise serum calcium concentrations and to lower serum phosphorous concentrations (Al Zahrani and Levine, 1997). Vitamin D is also important in the regulation of calcium. It is synthesized in the skin or can be obtained through dietary sources; it is carried in the bloodstream to the liver, where it is converted into calcidiol. Calcidiol can then be metabolized by the kidney, via 1ahydroxylase, to the biologically active form of vitamin D, calcitriol, which then acts throughout the body and essentially functions as a hormone. The most important function is exerted on the small intestine, where calcitriol regulates the intestinal reabsorption of calcium and, to a lesser degree, phosphorus. Calcitriol inhibits PTH secretion. In summary, the integrated actions of PTH and vitamin D on target tissues gives precise control of serum concentrations of calcium and phosphorous (Al Zahrani and Levine, 1997).

HYPERCALCEMIA Many disorders are associated with hypercalcemia. However, there are a limited number of mechanisms contributing to the hypercalcemia which include the following: increased bone resorption, increased gastrointestinal absorption of calcium, or decreased renal excretion of calcium.

Classification The most common causes of hypercalcemia are malignancy and primary hyperparathyroidism (Riggs, 2002). Hypercalcemic disorders can be divided into two major groups, PTH-mediated and non-PTH-mediated.

*Correspondence to: Pauline M. Camacho, MD, FACE, Associate Professor of Medicine, Program Director, Endocrinology Fellowship Program, Director, Loyola University Osteoporosis and Metabolic Bone Disease Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-0160, Fax: þ1-708-216-5936, E-mail: [email protected]

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PTH- mediated hypercalcemic disorders can be distinguished by an elevated or inappropriately normal PTH level in the setting of hypercalcemia. These include primary hyperparathyroidism (secondary to parathyroid adenoma or hyperplasia), lithium-associated hypercalcemia, and familial hypercalcemic hypocalciuria. NonPTH-mediated hypercalcemic disorders are characterized by a suppressed PTH in the setting of hypercalcemia. These include hypercalcemia of malignancy (secondary to bony metastases, PTHrP or other humoral factors), vitamin D intoxication (from ingestion of supraphysiologic doses of vitamin D or increased synthesis of calcitriol from macrophages in granulomatous disease), milkalkali syndrome, conditions associated with high bone turnover (including hyperthyroidism, immobilization, vitamin A intoxication), conditions associated with renal failure (tertiary hyperparathyroidism, aluminum intoxication, excessive calcium and vitamin D intake), and medications (thiazides and theophylline).

Clinical features Mild hypercalcemia may be asymptomatic or may be associated with vague, nonspecific symptoms such as fatigue, difficulty concentrating, personality changes, irritability, anxiety, and depression. Alterations in mental status, including progressive lethargy, confusion, and ultimately coma, are common in severe hypercalcemia, defined as serum calcium levels greater than 14 mg/dL or in acute hypercalcemia . Headache, elevated cerebrospinal fluid protein, and seizures may also occur in patients with hypercalcemia (Riggs, 2002). The kidney is the only route of calcium elimination. Hypercalcemia impairs glomerular filtration rate. As a result, the urinary concentrating ability is impaired which leads to dehydration. This further compromises renal calcium clearance.

Treatment The treatment of hypercalcemia includes medical and surgical strategies, and the severity and chronicity influence management. In all situations, drugs contributing to hypercalcemia should be discontinued. The goal of treatment in symptomatic hypercalcemia is to increase renal excretion of calcium in attempts to decrease serum calcium level. Intravenous fluids, preferably normal saline, should be administered at a rapid rate (200–300 cc/hour) to reverse intravascular volume contraction and to promote renal excretion of calcium. Loop diuretics can also be employed to reduce the risk of volume overload and to inhibit calcium resorption in the loop of Henle (Ariyan and Sosa, 2004). Calcitonin, administered subcutaneously, acts quickly (within 24–48 hours) to lower serum calcium and can be used in the

acute setting. Intravenous bisphosphonates may also be used to lower serum calcium but they may take up to 1 week to exert maximal effect. Some of the other treatments for hypercalcemia are dependent upon the etiology of the hypercalcemia. Parathyroidectomy is the recommended treatment for primary hyperparathyroidism. Glucocorticoids are effective in managing hypercalcemia secondary to sarcoidosis, where hypercalcemia stems from vitamin D toxicity. These agents inhibit the effects of vitamin D, reduce intestinal calcium absorption, and increase renal calcium excretion. Surgery, radiation, and/or chemotherapy are effective treatments in hypercalcemia related to malignancy.

PRIMARY HYPERPARATHYROIDISM Introduction Primary hyperparathyroidism (PHPT) is characterized by excessive secretion of parathyroid hormone (PTH) and consequent hypercalcemia. Before routine measurement of serum calcium concentration was available, PHPT was thought to be an uncommon metabolic disorder that was typically associated with pronounced metabolic bone disease and renal stones. PHPT is now a common metabolic disorder most often diagnosed after the incidental discovery of hypercalcemia in an asymptomatic patient. There has been a marked reduction in the classic signs and symptoms of primary hyperparathyroidism. Although PHPT can occur at any age, it is most common in the fifth and sixth decades. The disorder is also two to three times more common in women than in men, and this difference increases with age.

Etiology More than 80% of cases of primary hyperparathyroidism are secondary to a single parathyroid adenoma. Multiple adenomas are uncommon. Diffuse hyperplasia of all parathyroid glands account for 15–20% of cases. Half of these are part of a familial syndrome (multiple endocrine neoplasia I or IIb). Parathyroid cysts are uncommon and parathyroid carcinoma is very rare (0.5% of primary hyperparathyroidism) (Bilezikian et al., 2005).

Diagnosis Hypercalcemia is the biochemical hallmark of primary hyperparathyroidism and is an essential diagnostic criterion. Hypercalcemia may be mild or even intermittent in some patients, and PTH is either elevated or is inappropriately normal (Al Zahrani and Levine, 1997). The serum phosphate concentration is usually in the low or low normal range; there may be a mild hyperchloremic acidosis as well (Al Zahrani and Levine, 1997).

DISORDERS OF BONE AND BONE MINERAL METABOLISM

Clinical features Primary hyperparathyroidism (PHP) has been associated with skeletal, renal, gastrointestinal, cardiovascular, neuromuscular, and neuropsychiatric manifestations. Most of the following manifestations are seen in moderate and severe hyperparathyroidism. However, some skeletal, cardiovascular, and neuropsychiatric features have been described in mild hyperparathyroidism, which is the most common form seen today. The symptoms and signs of PHP are, in part, related to the degree of hypercalcemia.

Skeletal manifestations Osteitis fibrosa cystica is the classic bone disease of primary hyperparathyroidism but now occurs in < 10% of patients. Features include subperiosteal resorption (at the radial aspects of the middle phalanges or the distal phalanges), distal tapering of the clavicles, and a “salt and pepper” appearance of the skull. Bone cysts and brown tumors are locally destructive lesions that occur in more advanced stages of hyperparathyroid bone disease (Al Zahrani and Levine, 1997). Histologically, there is an increase in the number of osteoclasts, marrow fibrosis, and cystic lesions that may contain fibrous tissue. This condition is associated with bone pain and pathologic fractures. Osteoporosis, fractures, pseudogout (Geelhoed and Kelly, 1989), bone and joint pains are the other skeletal manifestations of primary hyperparathyroidism. These features have been described in mild PHPT. Unlike other disorders causing osteoporosis, hyperparathyroidism often results in cortical bone loss (Khan and Bilezikian, 2000). The most common site of skeletal involvement is the distal third of the radius, a site of cortical bone. The lumbar spine is made up mostly of cancellous bone and therefore is only minimally reduced. The hip region is a mixture of cortical and cancellous bone and bone density is intermediate between the radius and spine. Trabecular/cancellous bone mass and strength are relatively maintained in mild hyperparathyroidism. Therefore, one would expect the spine to be relatively resistant to fractures. The above densitometric profile though is not always seen in PHPT. In some patients, cancellous bone density of the lumbar spine can be substantially reduced (Khan and Bilezikian, 2000). Back pain and vertebral crush fractures can be a presenting feature of PHPT (Dauphine et al., 1975).

Renal manifestations Nephrolithiasis is the classic renal disease, which occurred in about 40% of cases but now occurs in about 15–20% of cases (Al Zahrani and Levine, 1997).

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Hypercalciuria has been implicated in the pathogenesis of nephrolithiasis. Nephrocalcinosis is the diffuse deposition of calcium and phosphate throughout the kidneys, which can also occur in patients with PHP. Nephrocalcinosis may be associated with stones but it is rare; progressive renal insufficiency, however, is not uncommon. Chronic hypercalcemia can compromise the renal concentrating ability, contributing to polyuria and as a result polydipsia.

Cardiovascular manifestations Studies have revealed the effects of hyperparathyroidism on the heart. The development of coronary artery disease has been associated with elevated calcium and PTH levels. Hypertension (HTN) is frequently seen in association with PHPT, even among those with mild disease. Left ventricular hypertrophy, independent of HTN, is also seen in association with PHPT in most but not all studies across a wide range of calcium levels (10.5–12 mg/ dL). PTH seems to increase intracellular levels of calcium that subsequently activates protein kinase C, thereby initiating hypertrophic processes such as protein synthesis. Hyperparathyroidism has been associated with diastolic filling impairment but not with systolic dysfunction (Andersson et al., 2004). Myocardial and valvular calcifications have clearly been demonstrated in PHPT patients with marked hypercalcemia but not in mild or moderate hypercalcemia. In patients with severe hypercalcemia (12.1 mg/dL or above), serum calcium levels correlated positively with T wave duration and negatively with QT interval. Studies from Scandinavia have documented an increased mortality from cardiovascular disease in severe and moderately severe PHPT. Several studies of patients with mild PHPT have not found an increased cardiovascular mortality (Silverberg et al., 2009).

Gastrointestinal manifestations Dyspepsia, nausea, and constipation all occur, probably as a consequence of hypercalcemia. There is probably no increase in peptic ulcer disease except in patients with multiple endocrine neoplasia (Silverberg, 2002; Bilezikian et al., 2005).

Neuromuscular and neuropsychiatric manifestations Hypercalcemia reduces neuromuscular excitability and may cause muscle weakness. Easy fatigability and muscle weakness are more common in hyperparathyroidism than in other hypercalcemic disorders (Riggs, 2002). Von Recklinghausen and Vical were the first to describe neuromuscular involvement in primary hyperparathyroidism. Primary hyperparathyroidism should be in the differential

868 M. KOMOROSKI ET AL. diagnosis of those presenting with symptoms consistent dramatic changes in biochemical status following surwith motor neuron disease (Delmont et al., 2001; gery responded less well to surgical intervention. One Carvalho et al., 2005). The clinical features of hyperparprospective study looked at patients with PHPT and athyroid myopathy include proximal muscle weakness evaluated them pre- and postoperatively with validated and wasting with preserved or even brisk reflexes and psychometric and neurocognitive testing to determine mild nonspecific myopathic features on electromyogram whether learning, memory, or concentration improved and muscle biopsy. Aside from hypercalcemia, vitamin D after parathyroidectomy. Analysis revealed that a spatial deficiency, chronic phosphate deficiency, or neuropathy learning deficit and delayed processing occurred in may contribute to myopathy (Riggs, 2002). Carpal tunnel patients with primary hyperparathyroidism and these syndrome has occasionally been associated with hyperimproved after parathyroidectomy. In addition, individparathyroidism (Palma, 1983). uals with a greater change in PTH were more likely to Calcium is critical to neurotransmitter function and improve in their learning efficiency postparathyroidecelevations in serum calcium have been postulated to have tomy and there were no differences in depressive sympeither a direct or indirect effect on cerebral function. toms or verbal memory in the pre- versus postoperative PTH is also elevated in the cerebrospinal fluid of patients groups (Roman et al., 2005). with hyperparathyroidism compared with controls, One study looked at 18 asymptomatic older (>50 although it is uncertain if this contributes to the neuroyears) patients with biochemically confirmed PHPT psychiatric manifestations. Neuropsychiatric manifestawho did not meet US National Institutes of Health tions of primary hyperparathyroidism range from subtle (NIH) consensus conference criteria for undergoing a personality changes to stupor and coma. Memory parathyroidectomy. They were randomly assigned to problems, dementia, confusion, delirium, and obtundaeither a surgical group (parathyroidectomy) or a control tion have been reported. In addition, psychotic behavior, group (observation). All patients were functionally simcatatonia, and mania have been described. A Creutzilar at baseline; all underwent functional testing which feldt–Jakob-like syndrome, manifesting with subacute included a 6 minute walk test at baseline/presurgery dementia and a gait disorder, has also been described and at 6 weeks and 6 months after surgery or baseline. in primary hyperparathyroidism (Chadenat et al., 2009). Six minute walk distance increased in the surgery Hyperparathyroidism has also rarely been associated group by 184 feet, a distance that is both significant with severe CNS dysfunction, including ataxia, internuc(p < 0.05) and clinically meaningful. The improvement lear ophthalmoplegia, corticospinal tract dysfunction, in 6 minute walk distance observed in the surgery group dysarthria, and dysphagia. suggests that parathyroidectomy can improve functional Classic neuromuscular and neuropsychiatric disease capacity, and hence the performance of activities of are rare in mild PHPT, although weakness and easy fatidaily living in asymptomatic, older PHPT patients gability remain common complaints. Other common (Morris et al., 2010). complaints include depression, cognitive impairment, Another study looked at the impact of parathyroidecloss of initiative, anxiety, irritability, sleep disturbances, tomy (PTX) on brain function and sleep in 18 “asympand somatization (Walker and Silverberg, 2007; tomatic” PHPT patients. These patients were randomly Silverberg et al., 2009). These nonspecific symptoms assigned to parathyroidectomy versus observation. may or may not improve with surgery (Silverberg, 2002) Functional magnetic resonance imaging (MRI) of the Data regarding the presence, extent, and reversibility brain, sleep assessment, and validated neuropsychologof psychological and cognitive features of primary ical battery were performed at baseline, 6 weeks, and 6 hyperparathyroidism (PHPT) are conflicting. Multiple months. This study revealed that decreased serum PTH trials have also shown variable results in terms of funclevels correlated with improved sleep and that parathytional/physical functioning. One study sought to clarify roidectomy decreased sleepiness (which correlated with the nature of cognitive and affective impairments in better performance on executive function) in patients PHPT and changes postparathyroidectomy. Of 111 with asymptomatic PHPT (Perrier et al., 2009). Another patients with PHPT who underwent neuropsychological nonrandomized study also revealed increased sleep disevaluation prior to parathyroidectomy, 68 returned for turbance and neurocognitive impairment in patients with an early postsurgical evaluation. In a subset of patients, PHPT, with improvement after parathyroidectomy assessment revealed a significant pattern of cognitive (Mittendorf et al., 2007). slowing, reductions in psychomotor speed, memory A large, controlled, multinational study randomized impairment, and depression prior to parathyroidectomy. 191 patients with asymptomatic mild hyperparathyroidism Postsurgical evaluations revealed a trend for improveto either parathyroidectomy or medical observation to ments on timed tests and depression but a decline in study the effects on morbidity, quality of life (QOL) memory. Older patients and the patients with more and psychiatric symptoms. The SF-36 and comprehensive

DISORDERS OF BONE AND BONE MINERAL METABOLISM 869 psychopathologic rating scale (CPRS) are validated and those who have persistent disease, those who are poor reliable methods that were used to assess symptoms. surgical candidates, and those who decline surgery. CPRS can be used to screen for the presence and severity The Third International Workshop on Primary Hyperof psychotic, mood, and neurotic disorders. At baseline, parathyroidism held in 2008 recommended surgery for the patients had significantly lower QOL and more psythe following situations: a calcium level more than chological symptoms, compared with age- and sex1 mg/dL above the upper limit of normal; creatinine matched healthy subjects. However, in this study, surgery clearance less than 60 mL/minute; age less than 50 years; did not provide consistent improvement over medical T score less than 2.5 at the spine, hip, and/or radius or observation in terms of psychological domains of funchistory of fragility fracture. For less severe bone disease, tioning or psychiatric symptoms (Bollerslev et al., antiresorptive therapy is an alternative to surgical 2007). A prospective study also revealed significantly intervention. A meta-analysis looking at the optimal mandecreased quality of life (assessed by a mental and agement of the skeletal consequences of mild primary physical functioning score) in the group with primary hyperparathyroidism (PHPT) revealed that surgical treathyperparathyroidism versus controls. Preoperative neuroment and antiresorptive therapies increase BMD in mild psychological symptoms were related to the serum calPHPT to a similar degree, and each represents a reasoncium levels. In this study, however, postoperative able option in a patient with mild PHPT and low BMD. health-related QOL improved significantly in addition Untreated subjects had significant bone loss; the rates to symptoms of depression and anxiety (Weber et al., of loss ranged from 0.6% to 1.0% per year. Analysis 2007). Another prospective randomized study looked at of studies reporting data beyond 2 years of follow-up 50 patients with mild asymptomatic hyperparathyroidism demonstrated stable increases in BMD after surgery and tried to determine if there was any benefit in terms of and stable BMD or slow loss (0.1–0.3%/year) in untreated BMD and also QOL. These 50 patients were randomly PHPT (Sankaran et al., 2010). assigned to parathyroidectomy or no parathyroidectomy Urinary calcium excretion> 400 mg/day is no longer and were evaluated at 6 months and at 1 year. This study an indication for surgery as it was in the 1990 and 2002 revealed a significant improvement in BMD at the hip and consensus panel guidelines. This is because urinary calspine and QOL (based on four QOL measures: bodily cium excretion has low precision and varies with age, pain, vitality, general health, and mental health) in patients sex, race, and dietary calcium intake and vitamin D status with mild asymptomatic PHPT who underwent a parathyas well as glomerular filtration rate. Moreover, urinary roidectomy (Ambrogini et al., 2007). calcium is only one of multiple risk factors affecting One case-control study revealed that at baseline, the development of kidney stones. The other risk factors women with PHPT had significantly higher symptom include urinary volume, oxalate levels, uric acid, pH, and scores for depression and anxiety than controls and citrate. In addition, a high urinary calcium is not associworse performance on tests of verbal memory and nonated with the development of stones in patients who have verbal abstraction. Depressive symptoms, nonverbal not yet formed stones (Silverberg et al., 2009). abstraction, and some aspects of verbal memory Some have argued that cardiovascular effects in mild improved after parathyroidectomy (Walker et al., 2009). PHPT should be included in the criteria for surgery referral. However, studies looking at cardiovascular manifestations in mild disease have been inconsistent. Also, studies looking at surgery and resolution of cardiovascular manifestations Management in mild PHPT have been inconsistent. HTN does not resolve Parathyroidectomy is the definitive therapy for primary after parathyroidectomy. Left ventricular hypertrophy hyperparathyroidism. The procedure is curative(LVH) has been found to regress after parathyroidectomy in > 90% of individuals in the hands of an experienced in some but not all studies. Also, several studies of patients parathyroid surgeon (Bilezikian, 2000). However, the with mild PHPT have not found an increased cardiovascular decision to operate on all patients with primary hypermortality (Silverberg et al., 2009). parathyroidism is controversial, especially in the setting Neuropsychiatric symptoms were not added as an of asymptomatic hyperparathyroidism. This is because a indication for parathyroidectomy because of inconsisnumber of prospective, nonrandomized studies have tent data on their precise nature, association with suggested that bone mineral density, renal function, underlying disease, and reversibility. In addition, these serum calcium, and PTH levels remain stable in the symptoms are difficult to quantify. The current NIH majority of asymptomatic patients during periods of guidelines for curative, surgical intervention of PHPT observation as long as 10 years. Bisphosphonates, exclude the 80% of patients with asymptomatic hyperhormone replacement therapy, and calcimimetics are parathyroid disease who have subjective neurobehaalternative options for those who have mild disease, vioral and physical symptoms affecting quality of life.

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Some have argued that neuromuscular and neuropsychiatric effects should be included in the criteria for surgery referral. However, studies looking at surgery and resolution of neuromuscular and neuropsychiatric manifestations have been inconsistent (Coker et al., 2005; Silverberg et al., 2009). Moreover, most studies looking at the reversibility of cognitive effects with surgery in mild hyperparathyroidism are suboptimal, limited by observational design, small sample sizes, inclusion of subjects with symptomatic hyperparathyroidism, lack of appropriate control groups, lack of objective testing, or short follow-up time. Others are suboptimal as a result of the nonspecific effects of surgery, selection bias, or confounding factors. Two major studies doing an extensive literature review have suggested improvement in quality of life after parathyroidectomy; psychiatric and cognitive benefits are more variable. Coker et al. (2005) did an electronic search reviewing prospective studies in which cognitive functioning was measured with formal neuropsychological (NP) testing and health-related quality of life (HRQL) was measured with valid and reliable instruments before and following parathyroidectomy for PHPT. Six small studies of cognitive functioning report inconsistent findings. Seven well-designed studies of HRQL report improvement across multiple domains following surgery. The authors concluded that formal NP testing and evaluation of HRQL are useful tools that may assist physicians in choosing whom to refer for parathyroidectomy. Roman and Sosa (2007) also performed a rigorous review of the most recent advances and studies that measured health-related quality of life, neurocognitive and psychiatric changes, as well as neurophysiologic imaging in patients with primary hyperparathyroidism undergoing parathyroidectomy. In studies conducted pre- and postparathyroidectomy, six studies have described improvements in health-related quality of life. Five studies included evaluations with validated psychiatric and cognitive tests in prospective case-control trials, but showed varied improvements in depression, memory, and concentration after parathyroidectomy.

HYPOCALCEMIA Classification Hypocalcemia can result from a failure to secrete PTH, altered responsiveness to PTH, a deficiency of vitamin D, or a resistance to vitamin D. Hypocalcemia may also occur secondary to abnormal magnesium metabolism or in clinical situations in which multiple factors (pancreatitis, sepsis, and critical illness) play contributing roles. Severe acute hypocalcemia most frequently occurs after thyroid or parathyroid surgery (Cooper and Gittoes, 2008).

Clinical features Most patients who have mild hypocalcemia are asymptomatic, but large or abrupt changes in ionized calcium may lead to symptoms (Moe, 2008). Most of the signs and symptoms of hypocalcemia occur secondary to increased neuromuscular excitability (Riggs, 2002). The increased neuromuscular reactivity manifest as hyperactive deep tendon reflexes, Chvostek’s and Trousseau’s signs (Moe, 2008). Chvostek’s sign refers to twitching or spasm of the facial muscles elicited by tapping on the facial nerve in front of the earlobe. Trousseau’s sign refers to the spasm of the outstretched hand that occurs after 3 minutes of inflating a blood pressure cuff 20 mmHg above the systolic blood pressure. Trousseau’s sign is more specific than Chvostek’s (Moe, 2008). Positive Trousseau’s sign can be seen in 4% and Chvostek’s sign in up to 25% of normal individuals. Clinically, the hallmark of severe hypocalcemia is tetany, a state of spontaneous tonic muscular contraction. Tetany originates in the peripheral nerve axon and is caused by spontaneous, irregular, repetitive nerve action potentials. The classic presentation is carpopedal spasm which is preceded by perioral and acral numbness. Opisthotonos may occur if spasms involve the trunk. Bronchospasm and laryngeal stridor may ultimately occur. Hypocalcemia may predispose to central nervous system effects, including irritability, anxiety, agitation, confusion, delirium, delusions, hallucinations, psychosis, depression, focal or generalized seizures, pseudotumor cerebri, papilledema, confusion, and organic brain syndrome. Longstanding hypocalcemia, even without neuromuscular symptoms, is associated with neuropsychiatric symptoms and occasionally raised intracranial pressure (Cooper and Gittoes, 2008). Chronic hypocalcemia in children may lead to mental retardation. The other signs and symptoms attributable to hypocalcemia occur secondary to deposition of calcium into soft tissues such as the pancreas (contributing to pancreatitis), the eyes (contributing to cataract formation), the basal ganglion (contributing to movement disorders such as chorea and parkinsonism).

Treatment Intravenous calcium gluconate is recommended in those presenting with acute hypocalcemia and neuromuscular irritability. In milder hypocalcemia, the treatment depends upon the underlying etiology. Vitamin D supplementation, in the form of cholecalciferol or ergocalciferol, is needed in vitamin D deficiency. Vitamin D supplementation, in the form of calcitriol, is needed in hypoparathyroidism since there is no conversion from inactive to active vitamin D without PTH (Cooper and Gittoes, 2008).

DISORDERS OF BONE AND BONE MINERAL METABOLISM

HYPOPARATHYROIDISM AND PSEUDOHYPOPARATHYROIDISM Hypoparathyroidism may be surgical, idiopathic, familial, autoimmune, infiltrative, or idiopathic. The hallmarks are hypocalcemia, hyperphosphatemia, and an inappropriately low or normal PTH, with a few exceptions. When PTH is normal, it is usually within the lower part of the reference range (Cooper and Gittoes, 2008). Hypoparathyroidism causes hypocalcemia because PTH secretion is inadequate; calcium cannot be mobilized from the bone or reabsorbed from the distal nephron; in addition, there is no activation of renal 1a-hydroxylase activity and as a result, there is insufficient 1,25dihydroxyvitamin D, which leads to decreased intestinal absorption of calcium (Shoback, 2008). The most common cause of hypoparathyroidism is surgery on the neck, with removal or destruction of the parathyroid glands. Tetany occurs 1–2 days postoperatively. Postoperatively, there may be impaired blood supply to the parathyroid gland, often referred to as stunning, which results in inadequate PTH secretion. However, PTH secretion may resolve when the gland recovers its blood supply. Because of this phenomenon, half of the patients with hypoparathyroidism after surgery will not need permanent treatment. Parathyroidectomy for primary hyperparathyroidism in those with severe hyperparathyroid bone disease may result in hypocalcemia. This phenomenon of “hungry bone syndrome” is because calcium and phosphate are avidly taken up by the bone and the parathyroids cannot compensate. This condition can be distinguished from the above based on elevated PTH and low phosphorus. Aside from surgery, destruction of the parathyroid glands may also occur secondary to an autoimmune or infiltrative process. Type I polyglandular autoimmune syndrome includes hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidasis. In this syndrome, hypoparathyroidism results from the formation of antibodies against the parathyroid glands and typically occurs about 5–9 years of age. This syndrome is also associated with adrenal insufficiency and mucocutaneous candidiasis. Hypoparathyroidism can also be caused by accumulation of iron (in hemochromatosis or transfusion-dependent thalassemia) or copper (in Wilson disease) in the parathyroid glands or metastatic infiltration of the parathyroid glands by tumor. Iodine 131 therapy for thyroid disease is a rare cause of hypoparathyroidism. Both hypomagnesemia and acute severe hypermagnesemia may be responsible for the development of functional hypoparathyroidism. They can impair release of PTH and lead to hypocalcemia; in addition, hypomagnesemia and hypermagnesemia can blunt the peripheral actions of PTH. Cisplatin, aminoglycosides, and amphotericin are

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the most common causes of drug-induced hypomagnesemia; loop diuretics can also contribute to hypomagnesemia. Long-term use of magnesium-containing drugs such as antacids and laxatives, in the setting of renal failure, are common causes of hypermagnesemia (Liamis et al., 2009). Hypoparathyroidism may also be secondary to genetic disorders of PTH biosynthesis and parathyroid gland development. Etiologies include PTH gene mutations, mutations or deletions in transcription factors and other regulators of the development of the parathyroid glands, and mitochondrial gene mutations. Features such as growth failure, congenital anomalies, hearing loss, or retardation point to a genetic disease (Shoback, 2008). Pseudohypoparathyroidism is the term used to describe a group of rare disorders characterized by hypocalcemia and hyperphosphatemia but elevated PTH, indicating unresponsiveness or resistance to PTH at the tissue level (Moe, 2008). The most common form of pseudohypoparathyroidism is type Ia, Albright’s hereditary osteodystrophy. This disease is characterized by short stature, round facies, obesity, mental retardation, brachydactyly, frontal bossing, and ectopic ossifications (Shoback, 2008).

Clinical manifestations The neurologic manifestations of hypoparathyroidism resulting from primary, secondary, or pseudohypoparathyroidism (parathyroid hormone-resistant syndromes) largely reflect hypocalcemia (refer to section on hypocalcemia). The duration, severity, and rate of development of hypocalcemia determine the clinical presentation. Hypoparathyroidism may present as reversible peripheral neuropathy (Goswami et al., 2002). Chronic hypoparathyroidism may present with extensive intracranial calcifications of the basal ganglia (Kowdley et al., 1999; Jabr et al., 2004; Mejdoubi and Zegermann, 2006); involvement of the basal ganglia may present as tetany and seizures in addition to parkinsonism and dementia (Verulashvili et al., 2006). Hypocalcemia secondary to hypoparathyroidism is a rare cause of reversible congestive heart failure; it must be considered in the differential diagnosis in someone presenting with heart failure that is not responding to traditional treatment; cardiac function improves after restoration of normocalcemia (Altunbas et al., 2003; Kazmi and Wall, 2007).

Treatment Hypermagnesemia and severe magnesium depletion should be ruled out first as these could cause reversible impairment of PTH secretion. Slightly low serum

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calcium levels with a detectable but inappropriately low PTH may indicate hypomagnesemia (Shoback, 2008). Severe magnesium depletion should be treated; dialysis may be indicated in hypermagnesemia. In all other situations of hypoparathyroidism, the only mechanism to increase serum calcium in hypoparathyroidism is via intestinal absorption. This is achieved by the administration of vitamin D (preferably the active form, calcitriol, because of its potency and its rapid onset of action) and oral calcium (Moe, 2008; Shoback, 2008). When parathyroid hormone is absent or nonfunctional, hypercalciuria may occur. Therefore, thiazide diuretics may be indicated to increase the renal tubular reabsorption of calcium, reducing hypercalciuria (Marx, 2000). Intravenous calcium therapy is only indicated in severe symptomatic hypocalcemia (i.e., seizures, laryngospasm, bronchospasm, significant electrocardiographic changes, cardiac failure, and altered mental status). If hyperphosphatemia is a problem, dietary restriction of phosphorus or phosphate binders are acceptable options (Shoback, 2008).

MAGNESIUM AND PHOSPHORUS DISORDERS Magnesium Some 66% of the total body stores of magnesium are in bone, 33% in the intracellular compartment, and 1% in the extracellular compartment. Magnesium homeostasis (in addition to calcium and phosphorus) is controlled by serum concentrations of the ion and regulating hormones (i.e., PTH) that act on three target organs: bone, intestine, and kidney. Severe hypomagnesemia stimulates PTH secretion which in turn increases bone resorption by multiple mechanisms. However, hypomagnesemia may also impair synthesis or secretion of PTH or contribute to end organ resistance to the action of PTH and contribute to worsening hypomagnesemia. Magnesium supplementation in this situation leads to a rapid rise in plasma PTH (Weisinger and Bellorin-Font, 1998). Dietary intake of magnesium is a critical determinant of magnesium levels (Dacey, 2001) as intestinal magnesium absorption is a passive process. Renal magnesium absorption involves both passive and active processes. Most absorption occurs in the proximal tubule and the thick ascending limb of the loop of Henle with only 5% occurring in the distal tubule.

CLASSIFICATION OF HYPOMAGNESEMIA Hypomagnesemia is very common. One study found that 7–12% of inpatients and 20% of ICU patients had hypomagnesemia. Hypomagnesemia is commonly associated with other electrolyte abnormalities including

hypokalemia (in up to 40–60%), hypocalcemia (Weisinger and Bellorin-Font, 1998), hyponatremia (Topf and Murray, 2003), and hypophosphatemia. The differential diagnosis of hypomagnesemia involves four main categories: (1) reduced intake secondary to starvation, alcohol abuse, or prolonged postoperative state; (2) acute intracellular shift of magnesium secondary to metabolic acidosis, insulin administration for DKA, hungry bone syndrome after parathyroidectomy, catecholamine excess states including alcohol withdrawal, and acute pancreatitis; pancreatitis can lead to hypomagnesemia because of sequestration of magnesium-rich fluid within the pancreas combined with losses through nasogastric suctioning and diarrhea; (3) reduced absorption which includes a specific gastrointestinal magnesium malabsorption syndrome (secondary to a rare inborn error of metabolism) or generalized malabsorption syndrome (secondary to extensive bowel resection), diffuse bowel disease and/or chronic diarrhea; (4) extrarenal factors that increase magnesuria which include drugs (diuretics, aminoglycosides, antibiotics, digoxin, cisplatin, amphotericin B, foscarnet, and ciclosporin), hormones (hyperaldosteronism, hyperthyroidism, and hypoparathyroidism, syndrome of inappropriate antidiuretic hormone secretion (SIADH)), hypercalcemia, hypophosphatemia, and alcohol ingestion. Any acute renal injury, particularly renal tubular injury, may promote wasting of magnesium (Dacey, 2001). There are also two congenital conditions associated with a primary renal tubular magnesium wasting. Both are characterized by hypokalemia, metabolic alkalosis, and normotension. Bartter’s syndrome is also characterized by hypercalciuria, nephrocalcinosis, and a tubular acidification defect; Gitelman’s syndrome is associated with hypocalciuria and a defect in the gene encoding for the thiazide-sensitive Na þ/Cl  cotransporter (Weisinger and Bellorin-Font, 1998). Hypomagnesemia may also be secondary to correction of chronic systemic acidosis, postobstructive nephropathy, renal transplantation, and the diuretic phase of acute tubular necrosis. Magnesium wasting in these clinical situations is due to tubular dysfunction in the recovering kidney. Diabetes mellitus is the most common cause of hypomagnesemia (Mouw et al., 2005), secondary to glycosuria and osmotic diuresis.

CLINICAL MANIFESTATIONS OF HYPOMAGNESEMIA Magnesium has a profound effect on neural excitability; the most characteristic signs and symptoms of magnesium deficiency are produced by neural and neuromuscular hyperexcitability. The neurologic manifestations of hypomagnesemia are similar to those of hypocalcemia and include hyperirritability with agitation, apathy,

DISORDERS OF BONE AND BONE MINERAL METABOLISM depression, delirium, confusion, convulsions, generalized muscle weakness, tremors of extremities and of the tongue, Chvostek’s sign, paresthesias, and tetany. A tetany syndrome has been described, which encompasses a constellation of clinical findings including muscle spasms, cramps, hyperarousal, hyperventilation, and asthenia in addition to Chvostek’s and Trousseau’s. Other features of this syndrome may include migraine attacks, transient ischemic attacks, sensorineural hearing loss, and convulsions (Galland, 1991). Other manifestations of hypomagnesemia include vertigo, nystagmus, myoclonus, and hyperreflexia. These signs and symptoms typically occur when serum magnesium is less than 0.8 mEq/L. Cortical blindness has also been associated with hypomagnesemia (Al-Tweigeri et al., 1999). Occasionally, focal neurologic signs may be seen in patients with hypomagnesemia. Magnesium is vital to carbohydrate metabolism. Magnesium influences glucose and insulin homeostasis, and hypomagnesemia is associated with the metabolic syndrome (Volpe, 2008). Hypomagnesemia could potentially increase the risk of atherosclerosis, since experimental magnesium deficiency has resulted in hypertriglyceridemia and hypercholesterolemia. Hypomagnesemia has cardiovascular effects. Hypomagnesemia enhances arterial sensitivity to vasoconstrictor agents, attenuates responses to vasodilators, promotes vasoconstriction and increases peripheral resistance, leading to hypertension (Sontia and Touyz, 2007). Hypomagnesemia is associated with a prolonged PR interval, prolonged QRS interval, T wave inversion, and the appearance of U waves (Topf and Murray, 2003). Hypomagnesemia has been implicated in severe ventricular arrhythmias, especially in the settings of acute ischemic heart disease, congestive heart failure, torsades de pointes, after cardiopulmonary bypass, in the acutely ill patient in the intensive care unit, and as a risk factor for developing coronary heart disease (Agus and Agus, 2001). Chronic hypomagnesemia has also been associated with a cardioskeletal mitochondrial myopathy. Persistent magnesium deficiency has been implicated as a risk factor for osteoporosis and osteomalacia, especially in patients with chronic alcoholism, diabetes mellitus, and malabsorption syndromes (Rude and Olerich, 1996).

TREATMENT The choice of route of magnesium repletion depends on the severity of the clinical findings. When convulsions occur in patients with hypomagnesemia, intravenous magnesium sulfate is required. However, an acute infusion of magnesium could decrease magnesium

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reabsorption in the loop of Henle, with most of the infused magnesium excreted in the urine. For this reason, oral replacement is usually preferred, especially in the symptom-free patients (Weisinger and BellorinFont, 1998).

Hypermagnesemia Magnesium is regulated by the kidneys. The kidney responds rapidly to elevated serum magnesium levels. Therefore, hypermagnesemia is uncommon and is primarily seen in the setting of renal failure with excessive magnesium intake. Excessive magnesium intake can occur by the oral, intravenous route or by means of enema. Massive oral ingestion can exceed renal excretory capacity, especially if there is underlying renal failure. Magnesium is found in over-the-counter antacids, in many laxatives, in enemas, and in herbal supplements. Severe hypermagnesemia has been described with accidental poisoning with Epsom salts, in laxative abusers, and in those receiving magnesium as catharsis for drug overdose. In addition, those with active gastrointestinal disease (including peptic ulcer disease, gastritis, colitis) can have enhanced magnesium absorption with subsequent hypermagnesemia. Substantial quantities of magnesium can also be absorbed from the large bowel following a magnesium enema. Intravenous magnesium is commonly used to decrease neuromuscular excitability in pregnant women with severe pre-eclampsia or eclampsia. Mild hypermagnesemia (defined as magnesium < 3 mEq/L) can occur in a variety of other clinic settings including some cases of primary hyperparathyroidism, familial hypocalciuric hypercalcemia, diabetic ketoacidosis, hypercatabolic states (such as in tumor lysis syndrome), lithium ingestion, milk-alkali syndrome, and adrenal insufficiency.

CLINICAL MANIFESTATIONS In contrast to hypomagnesemia, the neurologic manifestations of hypermagnesemia are characterized by nervous system depression (Riggs, 2002). Clinical manifestations of hypermagnesemia typically correlate with the degree of hypermagnesemia. Nausea, flushing, headache, lethargy, drowsiness, and diminished deep tendon reflexes may be seen with a plasma magnesium concentration of 4–6 mEq/L. Somnolence and absent deep tendon reflexes may be seen with a plasma concentration of 6–10 mEq/L. Hypermagnesemia at this level may also inhibit PTH secretion and lead to hypocalcemia. Muscular paralysis, which is the result of neuromuscular transmission blockade, is the predominant neurologic manifestation in severe hypermagnesemia. When the

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respiratory muscles are involved, subsequent hypoxia, hypercarbia, coma, and ultimately death ensues. Intracellular magnesium profoundly blocks several cardiac potassium channels which accounts for the cardiac manifestations. Hypotension, bradycardia, electrocardiographic features such as an increase in the PR interval, QRS duration and QT interval may be seen with a plasma concentration of 6–10 mEq/L. Further prolongation of the QT interval can lead to complete heart block and cardiac arrest.

TREATMENT The treatment in hypermagnesemia-induced arrhythmias is calcium; hemodialysis is indicated in symptomatic hypermagnesemia (characterized by refractory hypotension, mental obtundation, and respiratory arrest) (Hirose et al., 2002).

Congenital and acquired phosphorus disorders Approximately 85% of the total adult body store of phosphorus is contained in bone in the form of hydroxyapatite. Of the remainder, 14% is intracellular and only 1% is extracellular. Inorganic phosphorus is critical for numerous normal physiologic functions including skeletal development, mineral metabolism, energy transfer through mitochondrial metabolism, cell membrane phospholipid content and function, cell signaling, and even platelet aggregation. Between 60% and 70% of dietary phosphorus is absorbed by the gastrointestinal tract, in all segments. Phosphorus absorption depends on passive transport (related to the concentration in the intestinal lumen) and on active transport (stimulated by calcitriol). In the kidney, approximately 70–80% of the filtered load of phosphorus is reabsorbed in the proximal tubule, which serves as the primary regulated site of the kidney. The remaining approximately 20–30% is reabsorbed in the distal tubule. Vitamin D, 1,25 OH and PTH are key hormone players in phosphorus regulation. When serum phosphorus levels decrease, the kidneys secrete 1a-hydroxylase, increasing the conversion of inactive to active vitamin D (calcitriol), which in turn increases intestinal phosphorus absorption and decreases urinary phosphorus excretion. When serum phosphorus levels increase, PTH is increased which increases urinary excretion of phosphorus.

Hypophosphatemia CLASSIFICATION Hypophosphatemia is often graded as mild (phosphorus < 3.5 mg/dL), moderate (phosphorus < 2.5 mg/dL) or severe (phosphorus < 1 mg/dL). Hypophosphatemia

may occur secondary to internal redistribution of phosphorus from the extracellular fluid into the cell. Glycolysis leads to redistribution of phosphorus into the cell by formation of phosphorylated glucose compounds, with resultant hypophosphatemia. Glycolysis is stimulated in the following conditions: respiratory alkalosis secondary to hyperventilation, recovery from malnutrition, recovery from diabetic ketoacidosis, and insulin administration. Internal redistribution of phosphorus also occurs in parathyroidectomy for primary hyperparathyroidism. Phosphorus moves into the bone, contributing to hypophosphatemia (Weisinger and Bellorin-Font, 1998). Hypophosphatemia may also occur secondary to increased urinary excretion of phosphorus. This can occur in the following clinical conditions: primary hyperparathyroidism; secondary hyperparathyroidism in as a result of decreased vitamin D synthesis, or vitamin D resistance; familial disorders of vitamin D metabolism including vitamin D-dependent rickets and X-linked hypophosphatemic rickets; kidney transplant; malabsorption; renal tubular defects such as in Fanconi’s syndrome; alcohol abuse, and metabolic or respiratory acidosis (Weisinger and Bellorin-Font, 1998). Finally, hypophosphatemia can occur secondary to decreased intestinal absorption. This can occur in the following clinical conditions: severe dietary phosphorus restriction, antacid abuse, and chronic diarrhea. Vitamin D deficiency secondary to malabsorption of vitamin D that occurs with diarrhea may exacerbate hypophosphatemia by enhancing phosphaturia (Weisinger and BellorinFont, 1998). Pseudohypoparathyroidism encompasses a group of rare disorders characterized by hypocalcemia and hypophosphatemia but elevated PTH, indicating unresponsiveness to PTH at the tissue level.

CLINICAL MANIFESTATIONS Hypophosphatemia contributes to altered bone and mineral metabolism and disorders of the skeletal muscle, cardiac, respiratory, hematologic, and central nervous systems. Many of these manifestations are related to decreased intracellular adenosine triphosphate. Common skeletal/smooth muscle manifestations include myopathy, dysphagia, and ileus; respiratory failure occurs with respiratory muscle involvement; depressed cardiac contractility occurs with cardiac muscle involvement. Rhabdomyolysis may occur in severe hypophosphatemia, especially in alcoholics. Hematologic manifestations include hemolysis, thrombocytopenia, impaired phagocytosis, and granulocyte chemotaxis. Neurologic manifestations, secondary to tissue ischemia, include irritability, confusion/encephalopathy, and even coma.

DISORDERS OF BONE AND BONE MINERAL METABOLISM

TREATMENT Oral phosphorus is recommended in the treatment of hypophosphatemia. Intravenous phosphorus carries a high risk of severe hypocalcemia; however, intravenous phosphorus is indicated in severe symptomatic hypophosphatemia (Weisinger and Bellorin-Font, 1998).

Hyperphosphatemia CLASSIFICATION Hyperphosphatemia can occur from increased intestinal absorption, cellular release or rapid intracellular to extracellular shifts, or decreased renal excretion (Moe, 2008). Increased intestinal absorption is caused by large intake of phosphorus-containing laxatives or enemas, or by vitamin D overdose. Increased cellular release can occur in acute tumor lysis syndrome (most commonly after the initiation of cytotoxic therapy in patients with hematologic malignancies such as lymphoma, leukemia, and multiple myeloma (Liamis et al., 2009)), bowel infarction, rhabdomyolysis, hemolysis, hyperthermia, profound catabolic stress; these disorders can lead to renal injury further exacerbating hyperphosphatemia. Rapid cellular shifts can occur in acid–base disorders such as lactic acidosis, diabetic ketoacidosis, and respiratory acidosis (Weisinger and Bellorin-Font, 1998). Hypoparathyroidism, acromegaly, and thyrotoxicosis can also cause hyperphosphatemia by reducing urinary phosphorus excretion (Weisinger and Bellorin-Font, 1998). The kidneys respond rapidly to elevated phosphorus levels after dietary ingestion by excreting urinary phosphorus. Therefore, sustained hyperphosphatemia occurs predominantly in the setting of renal disease.

CLINICAL MANIFESTATIONS Acute hyperphosphatemia generally does not cause symptoms. It is the resultant hypocalcemia (which occurs when excess phosphorus complexes with calcium and deposits in the soft tissues) that contributes to symptoms. The calcium phosphate depositions also contribute to symptoms by impairing the proper function of the heart, kidneys, vasculature, and other soft tissues. Signs and symptoms include decreased mental status, seizures, dysrhythmia, weakness, cramps, hyperreflexia, tetany, anorexia, nausea, vomiting, decreased visual acuity, conjunctivitis, renal failure, and papular eruptions (Shiber and Mattu, 2002).

TREATMENT Hyperphosphatemia is best managed by treating the underlying disorder (i.e., administering intravenous fluids for rhabdomyolysis). No treatment is usually

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needed in the setting of normal renal function as hyperphosphatemia is self-resolving. Limiting dietary phosphate intake (by reducing protein intake) and blocking intestinal phosphate absorption with phosphate binders is indicated in mild persistent asymptomatic hyperphosphatemia in the setting of mild to moderate renal failure. Common oral phosphate binders include calcium carbonate, calcium acetate, and sevelamer (Moe, 2008). Hemodialysis may be required for severe hyperphosphatemia with symptomatic hypocalcemia (Shiber and Mattu, 2002).

OSTEOPOROSIS Introduction Osteoporosis is a skeletal disease in which reduced bone strength results in an increase in bone fragility and thus increases susceptibility to fractures. Bone strength takes into account not only bone mineral density (the amount of bone tissue) but also bone quality (the structure and material composition of bone) (Becker, 2008). Osteoporosis is defined by the World Health Organization in postmenopausal women as a bone mineral density 2.5 standard deviations below peak bone mass (the standard is the average bone density of a 20-year-old healthy female) as measured by dual energy X-ray absorptiometry (DXA). Bone quality includes other properties of bone including macroarchitecture (shape and geometry), microarchitecture (trabecular and cortical), matrix and mineral composition, as well as the degree of mineralization, microdamage accumulation, and the rate of bone turnover. These are not visualized on the DXA scan but do affect the structural and material properties of bone. These components must also be included in the algorithms of fracture detection. Fractures of the hip, vertebral body, and distal forearm are the typical osteoporotic fractures although there is an increased risk of almost any type of fracture. Worldwide, elderly people represent the fastest growing age group, and the yearly number of fractures is likely to rise substantially with continued aging of the population.

Etiology Low peak bone mass, excessive bone resorption, or inadequate bone formation are the major processes that lead to osteoporosis. Estrogen deficiency, calcium deficiency, vitamin D deficiency, and hyperparathyroidism are the major underlying etiologies (Becker, 2008). Other etiologies include hypercalciuria, hyperthyroidism, testosterone deficiency, hypercortisolism, and multiple myeloma.

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Clinical manifestations Osteoporosis is generally a silent disease until a fragility fracture occurs. There is a high frequency of spinal fractures secondary to osteoporosis. Most spinal fractures usually show no serious spinal canal compromise or spinal instability. Most spinal fractures resulting from osteoporosis usually do not manifest with immediate neurologic deficits but they may lead to a gradual collapse of the vertebrae, ultimately resulting in progressive kyphosis, prolonged back pain and/or paraparesis (Ito et al., 2002). In particular, fractures of the middle vertebral column can lead to retropulsion of vertebral body fragments with significant canal compromise and neurologic injury; surgical intervention may be indicated. It is important to assess a patient with an osteoporotic fracture for neurologic deterioration (Nguyen et al., 2003). The majority of osteoporotic, spinal cord compressive, vertebral fractures occurs at the thoracolumbar junction level (Blondel et al., 2009). Most of the neurologic symptoms may develop late and manifest as radiculopathy (Tezer et al., 2006); a decompression procedure may be indicated in certain cases. Burst fractures may occur after a fall in osteoporosis. A burst fracture is a type of traumatic spinal injury in which a vertebra breaks from a high-energy axial load, with pieces of vertebra shattering into surrounding tissues and sometimes the spinal canal. Immediate hospitalization is required, as such injuries may result in varying degrees of spinal cord injury with possible paralysis. A retrospective study was performed on the operative results following osteoporotic burst fractures with neurologic compromise; 70% of the fractures occurred at the thoracolumbar junction. All the patients were treated operatively with decompression and arthrodesis with a mean time to follow-up of 16 months. Neurologic recovery occurred in six of the 10 patients; however, significant disability secondary to pain was common (Nguyen et al., 2003). Despite surgical intervention and neurologic recovery, pain remains a persistent problem. Multiple thoracic fractures can result in restrictive lung disease, progressive back pain, and disabling kyphosis. Other sequelae include constipation, abdominal pain and distention, reduced appetite, premature satiety, and weight loss (Becker, 2008). Osteoporotic fractures of the sacrum have also been reported; the most common symptoms include sphincter dysfunction and lower limb paresthesias (Finiels et al., 2002). In summary, osteoporotic fractures may contribute to neurologic deficits, pain, and physical limitations. In addition, osteoporotic fractures can contribute to changes in lifestyle and appearance which can have

damaging psychological effects, including depression, loss of self-esteem, anxiety, fear, anger, and strained relationships with family and friends (Becker, 2008).

Treatment The major target of treatment is the inhibition of bone resorption by osteoclasts. The main class of antiresorptives currently in use are bisphosphonates; they decrease the numbers of vertebral and nonvertebral fractures. Estrogen, calcium, selective estrogen receptor modulators (SERMs) and calcitonin are other antiresorptives (Reid, 2008). A newer antiresorptive, denosumab, is a human monoclonal antibody that inhibits osteoclasticmediated bone resorption by binding to osteoblastproduced RANKL. By reducing RANKL binding to the osteoclast receptor RANK, bone resorption and turnover decrease. It has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis (Lewiecki, 2009). It has been approved for the treatment of postmenopausal women who have a high risk for osteoporotic fractures, including those with a history of fracture or multiple risk factors for fracture, or those who have failed or are intolerant to other osteoporosis therapy. Another target of treatment is bone formation. Recombinant teriparatide is the only agent in this category. Current limitations include limited length of treatment (2 years) and a high cost of therapy. Therefore, teriparatide is best reserved for the treatment of patients with osteoporosis at high risk of fracture, or for patients with osteoporosis who have unsatisfactory responses to or intolerance of other osteoporosis therapies (Blick et al., 2008).

PAGET’S DISEASE Introduction Paget’s disease is a metabolic bone disease characterized by increased and disorganized bone turnover which results in excessive and dense but structurally deficient and weak bones. Paget’s disease rarely occurs before 30 years of age. Paget’s disease may involve one (monostotic) or multiple bones (polyostotic). The monostotic form, found in 15% of patients, commonly affects the tibia, ilium, femur, and skull. The polyostotic form commonly affects the pelvis, spine, and skull. The hands, feet, ribs, and fibula are rarely involved (Hullar and Lustig, 2003). Highest prevalence occurs in the US, Germany, France, Austria, England, Australia, and New Zealand (Hullar and Lustig, 2003). Genetic and environmental factors have been implicated in the disease (Ralston, 2008).

DISORDERS OF BONE AND BONE MINERAL METABOLISM 877 the skull base is involved, platybasia may occur. PlatybaClinical manifestations sia is the malformation of the skull base, which may Symptomatic Paget’s is only seen in 15–20% of affected result in the forward displacement of the upper cervical individuals (Hullar and Lustig, 2003). Pain is the most vertebrae and bony impingement on the brainstem. Neucommon symptom. Pain may be secondary to direct rologic presentation varies secondary to the degree of pagetic involvement or osteoarthropathy. Pain in the compression and also the structures affected. The most extremities may be caused by expansion of bone with common symptoms are neck pain, often associated with involvement of the periosteum, whereas in the lumbar a headache and also signs and symptoms of spinal cord spine, pain may result from vertebral expansion or colcompression. Compression of the C2 root and the lapse as a result of microfractures. In contrast to pain greater occipital nerve leads to neck pain, oftentimes from degenerative joint disease, pagetic pain is typically spreading to the arms and accompanied by an occipital increased at night, when the limbs are warm, and upon headache. Spinal cord compression involves the upper weight bearing. The structural changes from disrupted cervical cord and may affect the motor tracts resulting bone architecture can interact with the mechanical in spastic paresis in the arms, legs or both; joint position requirements of the affected bone and/or the function and vibration sense (posterior column function) are comof adjacent organs and lead to various other complicamonly affected; pain and temperature sense (spinothalations, both structural and functional. mic tract) are rarely affected. Brain compression may Orthopedic complications are common; oncologic comalso occur in platybasia and may cause brainstem, craplications are rare. Involvement of the skull may result in nial nerve, and cerebellar deficits (Poncelet, 1999; Beer skull enlargement and pain. Enlargement of the skull can et al., 2006). Brainstem and cranial nerve deficits include lead to leontiasis ossea, making it difficult for the patient to sleep apnea, internuclear ophthalmoplegia, downbeat hold the head erect. Involvement of the spine may result in nystagmus, hoarseness, dysarthria, and dysphagia. Cerskeletal pain and altered posture, predominantly kyphosis. ebellar deficits lead to impaired coordination. VertebroInvolvement of the weight bearing long bones such as the basilar ischemia can be triggered by changing head tibia or fibula may lead to skeletal deformation, i.e., bowposition; symptoms include intermittent syncope, vering of the lower extremities. This deformation may result tigo, confusion or altered consciousness, weakness in abnormal mechanical stress on the bone and may lead to and visual disturbance (Beer et al., 2006). Syringomyelia fissure and compression fractures. In addition, the defor(Raubenheimer et al., 2002) and hydrocephalus (Meca mation may result in a gait disturbance which may acceleret al., 1997; Raubenheimer et al., 2002) have also been ate degenerative joint disease in the hip and/or the knee. reported. Cranial nerve deficits secondary to narrowing However, Paget’s disease itself may involve subchondral of the neural foramina have been described but are areas resulting in damage to cartilage and leading to osteuncommon. Optic foramen involvement may result in oarthritis. In addition to osteoarthritis /degenerative joint optic atrophy and papilledema. Ophthalmoplegia, anosdisease, acute gouty arthritis and other inflammatory mia, trigeminal neuralgia, and facial and bulbar palsy arthritides have been associated with Paget’s disease, have also been described (Bone, 2006). The spine is including rheumatoid arthritis, psoriatic arthritis, and the second most commonly affected site with Paget’s ankylosing spondylitis (Ankrom and Shapiro, 1998). disease. Pagetic involvement of the cervical and thoracic Neoplastic degeneration of pagetic bone, or osteosarcoma, spine is more commonly associated with neural sympmay also occur but it is rare (