Primary & Secondary Hyperparathyroidism
Primary hyperparathyroidism is due to excessive production and release of PTH by the parathyroid glands. The prevalence of hyperparathyroidism is approximately 1:1000 in the United States, and the incidence of the disease increases with age. The patient group most frequently affected is postmenopausal women.
Primary hyperparathyroidism may be caused by any of the following: adenoma, hyperplasia, or carcinoma (Table 17–1). Chief cell adenomas are the most common cause, accounting for almost 85% of all cases. The vast majority of parathyroid adenomas occur sporadically and are solitary.
Table 17–1Causes of primary hyperparathyroidism. ||Download (.pdf) Table 17–1 Causes of primary hyperparathyroidism.
|Solitary adenomas ||80–85% |
|Hyperplasia ||10% |
|Multiple adenomas ||≈2% |
|Carcinoma ||≈2–5% |
Parathyroid hyperplasia refers to an enlargement or abnormality of all four glands. In atypical forms of hyperplasia, only one gland may be enlarged, but the other three glands typically show at least slight microscopic abnormalities such as increased cellularity and reduced fat content. The distinction between hyperplasia and multiple adenomas is challenging and usually requires the examination of all four glands. Key characteristics for judging whether a gland is normal or not are its size, weight, and histologic features.
Parathyroid hyperplasia may be part of the autosomal dominant multiple endocrine neoplasia (MEN) syndromes (Table 17–2). In patients with MEN-1, caused by mutations in the MEN1 gene, which encodes the protein menin, there is high penetrance of hyperparathyroidism, affecting as many as 95% of patients. When their glands are examined microscopically, there are usually abnormalities in all four glands. Recurrent hyperparathyroidism, even after initially successful surgery, is common in these patients. Hyperparathyroidism also occurs in MEN-2A, although at a much lower frequency (about 20%). Familial hyperparathyroidism, without other features of MEN syndromes, characteristically involves all four glands, but there is often asynchrony in the presentation of the hyperparathyroidism. Kindreds with isolated hyperparathyroidism and mutations in menin are considered to be allelic variants of MEN-1. The hyperparathyroidism-jaw tumor syndrome and familial isolated hyperparathyroidism are causes of autosomal dominant hyperparathyroidism. The former often includes ossifying fibromas of the jaw and renal tumors and is caused by inactivating germline mutations in the HRPT2 gene that encodes the protein parafibromin.
Table 17–2Clinical features of multiple endocrine neoplasia syndromes. ||Download (.pdf) Table 17–2 Clinical features of multiple endocrine neoplasia syndromes.
Benign parathyroid tumors (very common)
Pancreatic tumors (benign or malignant)
Other tumors: lipomas, carcinoids, adrenal and thyroid adenomas
Medullary carcinoma of the thyroid
Pheochromocytoma (benign or malignant)
Parathyroid carcinoma is a rare malignancy, but the diagnosis should be considered in a patient with severe hypercalcemia and a palpable cervical mass. At surgery, cancers are firmer than adenomas and more likely to be attached to adjacent structures. It is sometimes difficult to distinguish parathyroid carcinomas from adenomas on histopathologic grounds. Vascular or capsular invasion by tumor cells is a good indicator of malignancy, but these features are not always present. In many cases, local recurrences or distant metastases to liver, lung, or bone are the clinical findings that support this diagnosis. Approximately 20% of patients with the hyperparathyroidism-jaw tumor syndrome and germline mutations in the HRPT2 gene (described above) develop parathyroid cancer. Furthermore, mutations in HRPT2 have also been found in familial isolated hyperparathyroidism and in sporadic parathyroid cancers. The normal cellular function of parafibromin is unknown.
Secondary hyperparathyroidism implies diffuse glandular hyperplasia resulting from a defect outside the parathyroids. Secondary hyperparathyroidism in patients with normal kidney function may be observed in patients with severe calcium and vitamin D deficiency states (see below). In patients with chronic kidney disease, there are many causative factors that contribute to the often dramatic enlargement of the parathyroid glands. These include decreased 1,25-(OH)2D production, reduced intestinal calcium absorption, skeletal resistance to PTH, and renal phosphate retention.
PTH secretion in primary hyperparathyroidism is excessive given the level of the serum calcium. At the cellular level, there is both increased cell mass and a secretory defect. The latter is characterized by reduced sensitivity of PTH secretion to suppression by the elevated serum calcium concentration. This qualitative regulatory defect is more common than truly autonomous secretion. Thus, parathyroid glands from patients with primary hyperparathyroidism are typically enlarged and, in vitro, demonstrate a “shift to the right” in their calcium setpoint for secretion (Figure 17–15). How these two defects interact in the pathogenesis of the disease remains to be fully elucidated.
PTH secretion in vitro from human parathyroid cells from patients with parathyroid adenomas and hyperplasia. The set-point for secretion is the calcium concentration at which PTH release is suppressed by 50%. This is shifted to the right in the majority of parathyroid adenomas compared to normal tissues, in which the set-point is approximately 1.0 mmol/L ionized calcium. (Redrawn, with permission, from Brown EM et al. Dispersed cells prepared from human parathyroid glands: distinct calcium sensitivity of adenomas vs primary hyperplasia. J Clin Endocrinol Metab. 1978;46:267.)
The genetic defects responsible for primary hyperparathyroidism have received considerable attention. Genes that regulate the cell cycle are thought to be important in the pathogenesis of a significant subset of parathyroid tumors. The PRAD1 gene (parathyroid rearrangement adenoma), whose product is a D1 cyclin, has been implicated in parathyroid tumor development and also in the pathogenesis of several malignant tumors (B-cell lymphomas, breast and lung cancers, and squamous cell cancers of the head and neck). Cyclins are cell cycle regulatory proteins. The PRAD1 gene is located on the long arm of chromosome 11, as is the gene encoding for PTH. Analysis of parathyroid tumor DNA suggests that a chromosome inversion event occurred, which led to juxtaposition of the 5-regulatory domain of the PTH gene upstream to the PRAD1 gene (Figure 17–16). Because regulatory sequences in the PTH gene are responsible for its cell-specific transcription, this inversion was initially postulated to lead to a parathyroid cell-specific overproduction of the PRAD1 gene product. Excessive cyclin would enhance the proliferative potential of the cells bearing this inversion and, given sufficient time, could induce PTH excess. A transgenic mouse model in which cyclin D1 is overexpressed in parathyroid tissue under the control of the PTH gene promoter provides proof for this pathogenetic mechanism of primary hyperparathyroidism.
Proposed genetic rearrangement of chromosome 11 in a subset of sporadic parathyroid adenomas. An inversion of DNA sequence near the centromere of chromosome 11 places the 5′-regulatory region of the PTH gene (also on chromosome 11) adjacent to the PRAD1 gene, whose product is involved in cell cycle control. This places the PRAD1 gene under the control of PTH regulatory sequences, which would be predicted to be highly active in parathyroid cells. (Redrawn, with permission, from Arnold A. Molecular genetics of parathyroid gland neoplasia. J Clin Endocrinol Metab. 1993;77:1109.)
The gene responsible for MEN-1, which produces the protein product menin, was identified in 1997. It is thought to function as a tumor suppressor gene. In keeping with the “two-hit” hypothesis of oncogenesis, patients with MEN-1 inherit an abnormal or inactivated MEN1 allele from one parent. This germline defect is present in all cells. During postnatal life, the other MEN1 allele in a parathyroid cell, for example, undergoes spontaneous mutation or deletion. If this second mutation confers a growth advantage on the descendant cells, there is clonal outgrowth of cells bearing the second mutation, and eventually a tumor results. In approximately 25% of nonfamilial benign parathyroid adenomas, there is allelic loss of DNA from chromosome 11, where the MEN1 gene is located.
Menin localizes to the nucleus, where it binds to the transcription factor JunD in vitro and suppresses transcription. The role of menin in normal physiology and the mechanisms by which it promotes tumor formation in the pituitary, pancreas, and parathyroid glands are unknown. Mice with targeted deletion of both genes encoding the murine menin homologues (or Men1) die in utero. Mice that are heterozygous for Men1 deletion survive but develop tumors in their pancreatic islets, adrenal cortices, and parathyroid, thyroid, and pituitary glands as they age, serving as a model for the MEN-1 syndrome.
Genetic testing is available to detect mutations in the MEN1 gene so that appropriate case management and genetic counseling can be done.
Hyperparathyroidism in MEN-2A is caused by mutations in the RET protein. RET clearly plays an important role in the pathogenesis of the other endocrine tumors in these syndromes as well as in familial medullary carcinoma of the thyroid (see below). How RET mutations alter parathyroid cell growth or PTH secretion has not been elucidated.
Hyperparathyroidism may present in a variety of ways. Patients with this disease may be asymptomatic, and their diagnosis is made by screening laboratory tests. Other patients may have skeletal complications or nephrolithiasis. Because calcium affects the functioning of nearly every organ system, the symptoms and signs of hypercalcemia are protean (Table 17–3). Depending on the nature of the complaints, the patient with primary hyperparathyroidism may be suspected of having a psychiatric disorder, a malignancy, or, less commonly, a granulomatous disease such as tuberculosis or sarcoidosis.
Table 17–3Symptoms and signs of primary hyperparathyroidism. ||Download (.pdf) Table 17–3 Symptoms and signs of primary hyperparathyroidism.
|Systemic ||Ocular ||Skeletal and rheumatologic |
|Weakness ||Band keratopathy ||Osteopenia |
|Easy fatigue ||Cardiac ||Pathologic fractures |
|Weight loss ||Shortened QT interval ||Brown tumors of bone |
|Anemia ||Hypertension ||Bone pain |
|Anorexia ||Renal ||Gout |
|Pruritus ||Stones ||Pseudogout |
|Ectopic calcifications ||Polyuria, polydipsia ||Chondrocalcinosis |
|Neuropsychiatric and neuromuscular ||Metabolic acidosis ||Osteitis fibrosa cystica |
|Depression ||Concentrating defects ||GI |
|Poor concentration ||Nephrocalcinosis ||Peptic ulcer disease |
|Memory deficits || ||Pancreatitis |
|Peripheral sensory neuropathy || ||Constipation |
|Motor neuropathy || ||Nausea |
|Proximal and generalized muscle weakness || ||Vomiting |
Primary hyperparathyroidism is a chronic disorder in which longstanding PTH excess and hypercalcemia may produce increasing symptomatology, especially symptoms from renal stones or low bone mass. Recurrent stones containing calcium phosphate or calcium oxalate occur in 10–15% of patients with primary hyperparathyroidism. Nephrolithiasis may be complicated by urinary outflow tract obstruction, infection, and progressive renal insufficiency. Patients with significant PTH excess may experience increased bone turnover and progressive loss of bone mass, especially in postmenopausal women. This is reflected in subperiosteal resorption, osteoporosis (particularly of cortical bone), and even pathologic fractures.
A sizable proportion of patients with primary hyperparathyroidism, however, are asymptomatic. These patients may experience no clinical deterioration if their hyperparathyroidism is monitored rather than treated surgically. Because it is difficult to identify these patients with certainty when the diagnosis of hyperparathyroidism is made, regular follow-up is mandatory. Recent studies indicate that bone mass may deteriorate significantly, especially at cortical sites (ie, hip, forearm) after conservative follow-up beyond 8–10 years. These observations have reopened the issue about the advisability of long-term medical observation in this condition. By comparison, patients with mild disease who undergo definitive parathyroid surgery will experience improvements in bone mass over time. These data raise the question as to how a presumed innocuous mild primary hyperparathyroidism may be deleterious to the skeleton.
Radiologic features of primary hyperparathyroidism are caused by the chronic effects of excess PTH on bone. These include subperiosteal resorption (evident most strikingly in the clavicles and distal phalanges), generalized low bone mass, and the classic but now rare brown tumors. Uncommonly, osteosclerosis may result from excessive PTH action on bone. Abdominal films or computed tomography may show nephrocalcinosis or nephrolithiasis.
The complete differential diagnosis of hypercalcemia should be considered in all patients with this abnormality (Table 17–4). Primary hyperparathyroidism accounts for most cases of hypercalcemia in the outpatient setting (>90%). The diagnosis of primary hyperparathyroidism is confirmed by at least two simultaneous measurements of calcium and intact PTH. An elevated or inappropriately normal PTH in the setting of hypercalcemia is the key feature in making the diagnosis of primary hyperparathyroidism—the most common cause of PTH-dependent hypercalcemia (Table 17–5).
Table 17–4Differential diagnosis of hypercalcemia. ||Download (.pdf) Table 17–4 Differential diagnosis of hypercalcemia.
Familial (benign) hypocalciuric hypercalcemia
Table 17–5Laboratory findings in hypercalcemia from various causes. ||Download (.pdf) Table 17–5 Laboratory findings in hypercalcemia from various causes.
| ||Serum Ca2+ ||Serum PO43− ||Intact PTH ||PTHrP ||Serum 1,25-(OH)2D ||Urine Ca2+ |
|Primary hyperparathyroidism ||↑ ||↓, N ||↑ ||N, Und ||N, ↑ ||N, ↑1 |
|Malignancy-associated hypercalcemia ||↑ ||↓, N ||Und ||↑2 ||N, ↓ ||↑ |
|Familial (benign) hypocalciuric hypercalcemia ||↑ ||N ||N, ↑3 ||Und ||N ||↓ |
|Vitamin D–dependent hypercalcemia ||↑ ||N, ↑ ||↓ ||Und ||N, ↑4 ||↑ |
Patients with secondary hyperparathyroidism may have normal or subnormal calcium levels (see below). If renal function is normal, serum phosphate is also often reduced, due to the phosphaturic effects of the high PTH levels. Although serum PTH is elevated, the demineralized state of the bone and the chronic vitamin D deficiency combine to produce a low filtered load of calcium. Hence, urinary calcium excretion is often quite low. The 25-(OH)D level is also low or undetectable in vitamin D deficiency resulting from a variety of causes.
Familial (Benign) Hypocalciuric Hypercalcemia
In patients with asymptomatic hypercalcemia, the diagnosis of familial (benign) hypocalciuric hypercalcemia should be considered. Individuals with this condition typically have an elevated serum calcium and magnesium, normal or mildly elevated PTH levels, and hypocalciuria (Table 17–5). This disorder is inherited in an autosomal dominant manner and is typically due to point mutations in one allele of the CaSR gene. In families with this form of benign hypercalcemia, there are rare occurrences of neonatal severe primary hyperparathyroidism. Infants with this form of hyperparathyroidism, usually the result of consanguinity, generally have inherited two copies of mutant CaSR genes.
The CaSR, a member of the G protein-coupled receptor superfamily, is highly expressed in the parathyroid gland and kidney. In the parathyroid, the molecule functions to detect changes in ambient serum calcium concentration and then adjust the rate of PTH secretion. In the kidney, the CaSR sets the level of urinary calcium excretion, based on its perception of the serum calcium concentration.
In familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, the ability to detect serum calcium is faulty in both the kidney and parathyroid. Familial hypocalciuric hypercalcemia is due to a partial reduction—and neonatal hyperparathyroidism to a marked reduction—in the ability to sense extracellular calcium. Parathyroid chief cells missense the serum calcium as “low,” and PTH secretion occurs when it should be suppressed (Figure 17–2). This produces inappropriately normal or slightly high PTH levels. In the kidney, serum calcium concentrations are also detected (inappropriately) as low, and calcium is retained. This produces the hypocalciuria typical of this condition. Depending on the mutant gene dosage, the clinical symptoms tend to be mild in familial hypocalciuric hypercalcemia and profound and life-threatening in neonatal severe hyperparathyroidism.
Patients with familial hypocalciuric hypercalcemia typically have lifelong asymptomatic elevations in serum calcium. However, they are not thought to suffer the consequences of end-organ dysfunction characteristic of long-standing hyperparathyroidism and hypercalcemia. These individuals are generally spared the nephrolithiasis, low bone mass, and renal dysfunction that can occur in patients with primary hyperparathyroidism. Individuals with familial hypocalciuric hypercalcemia do not benefit from parathyroidectomy. Their hypercalcemia does not remit with surgery unless a total parathyroidectomy is performed. Surgery is not recommended because the condition is benign.
In contrast, infants with neonatal severe hyperparathyroidism have marked hypercalcemia, dramatic elevations in serum PTH, bone demineralization at birth, hypotonia, and failure to thrive. These infants usually require total parathyroidectomy in the newborn period for survival.
In the asymptomatic hypercalcemic patient, a careful family history should be obtained in an effort to document hypercalcemia or the occurrence of failed parathyroidectomies in other family members. Simultaneous serum and urinary calcium and creatinine levels should be measured to rule out familial hypocalciuric hypercalcemia. In this condition, urinary calcium levels are typically low and almost always less than 100 mg/24 h (Table 17–5). The calcium-creatinine clearance ratio derived from 24-hour urine collections is often below 0.01 but can be as high as 0.02. The ratio is calculated as urine calcium (mg/dL) × serum creatinine (mg/dL)/serum calcium (mg/dL) × urine creatinine (mg/dL). Genetic testing for CaSR gene mutations is commercially available in several reference laboratories and is the best approach to achieving a definitive diagnosis.
What is the most common cause of primary hyperparathyroidism?
What is the occurrence of hyperparathyroidism in the multiple endocrine neoplasia syndromes?
In what conditions does secondary hyperparathyroidism occur? By what symptoms and signs is it distinguished from primary hyperparathyroidism?
What are the common symptoms and signs of primary hyperparathyroidism? How can primary hyperparathyroidism be distinguished from familial hypocalciuric hypercalcemia? What is the mechanism for this difference?
Hypercalcemia of Malignancy
Hypercalcemia occurs in approximately 10% of all malignancies. It is commonly seen in solid tumors, particularly squamous cell carcinomas (eg, lung, esophagus), renal carcinoma, and breast carcinoma. Hypercalcemia occurs in more than one third of patients with multiple myeloma but is unusual in lymphomas and leukemias.
Solid tumors usually produce hypercalcemia by secreting PTHrP, whose properties have been described previously. This is humoral hypercalcemia, which mimics primary hyperparathyroidism and results from a diffuse increase in bone resorption induced by high circulating levels of PTHrP. The syndrome is exacerbated by the ability of PTHrP to reduce renal excretion of calcium and the ability of hypercalcemia (acting via renal CaSRs) to blunt renal concentrating ability, which results in progressive dehydration.
Multiple myeloma produces hypercalcemia by a different mechanism; myeloma cells induce local bone resorption or osteolysis in the bone marrow, probably by releasing cytokines with bone-resorbing activity, such as interleukin-1 and tumor necrosis factor. Rarely, lymphomas produce hypercalcemia by secreting 1,25-(OH)2D.
Finally, even though many hypercalcemic patients have bone metastases, these may not contribute directly to the pathogenesis of hypercalcemia.
Unlike patients with primary hyperparathyroidism, who often are minimally symptomatic, patients with hypercalcemia of malignancy are typically very ill. Hypercalcemia typically occurs in advanced malignancy—the average survival of hypercalcemic patients is usually several weeks to months—and the tumor is almost invariably obvious on examination of the patient. In addition, hypercalcemia is often severe and symptomatic, with nausea, vomiting, dehydration, confusion, or coma. Biochemically, malignancy-associated hypercalcemia is characterized by a decreased serum phosphate and a suppressed level of intact PTH (Table 17–5). With most solid tumors, the serum level of PTHrP is increased. These findings, together with the differences in clinical presentation, usually make the differentiation of this syndrome from primary hyperparathyroidism relatively easy.
What tumors commonly result in hypercalcemia?
What are the mechanisms by which a tumor may cause hypercalcemia?
What are the clinical symptoms and signs of hypercalcemia of malignancy?
Hypoparathyroidism & Pseudohypoparathyroidism
The total serum calcium includes the ionized, protein bound, and complexed forms of calcium. It should be recognized, however, that symptoms of hypocalcemia occur only if the ionized fraction of calcium is reduced. Furthermore, only patients with low ionized calcium levels should be evaluated for the possibility of a hypocalcemic disorder.
A common cause of low serum total calcium is hypoalbuminemia. A low serum albumin lowers only the protein-bound, and not the ionized, calcium. Thus, such patients need not be evaluated for mineral disorders. To determine whether a hypoalbuminemic patient has a low ionized calcium, this parameter can be measured directly. If this laboratory test is not readily available, a reasonable alternative is to correct the serum total calcium for the low serum albumin. This is done by adjusting the serum total calcium upward by 0.8 mg/dL for each 1 g/dL reduction in serum albumin. This simple correction usually brings the adjusted serum total calcium into the normal range.
The differential diagnosis of a low ionized calcium is lengthy (Table 17–6). Hypocalcemia can result from reduced PTH secretion caused by hypoparathyroidism or hypomagnesemia. It can also be due to decreased end-organ responsiveness to PTH despite adequate or even excessive levels of the hormone; this is termed pseudohypoparathyroidism.
Table 17–6Differential diagnosis of hypocalcemia. ||Download (.pdf) Table 17–6 Differential diagnosis of hypocalcemia.
|Failure to secrete parathyroid hormone (PTH) |
|Hypoparathyroidism (see Table 17–7) |
|Resistance to PTH action |
|Pseudohypoparathyroidism (types 1a, 1b, 2) |
|Sepsis-associated hypocalcemia |
|Failure to secrete PTH and resistance to PTH action |
|Chronic magnesium depletion as a result of |
| Diarrhea, malabsorption |
| Alcoholism |
| Drugs: aminoglycoside antibiotics, loop diuretics, cisplatin, amphotericin B |
| Parenteral nutrition |
| Primary renal magnesium wasting |
|Failure to produce 1,25-(OH)2D |
|Vitamin D deficiency as a result of nutritional causes |
| Liver disease |
| Cholestasis |
| Small intestinal disorders producing malabsorption |
|Renal failure |
|Vitamin D–dependent rickets type 1: defective 1α-hydroxylase activity (very rare) |
|Tumor-induced osteomalacia |
|Resistance to 1, 25-(OH)2D action |
|Vitamin D–dependent rickets type 2: defect in vitamin D receptor (rare) |
|Vitamin D–dependent rickets type 3: overproduction of a hormone response element binding protein that interferes with binding of the vitamin D receptor-retinoic acid receptor heterodimer to target DNA |
|Acute challenges to the homeostatic mechanisms |
|Pancreatitis (formation of calcium salts in retroperitoneal fat) |
|Drug-induced (eg, EDTA, citrate, bisphosphonates, phosphate, foscarnet) |
|Liver transplantation (citrate is not metabolized, thereby forming calcium citrate complexes and lowering ionized calcium) |
|Hungry bone syndrome (increased deposition into demineralized bone) |
|Osteoblastic metastases (eg, breast or prostate cancer) |
|Tumor lysis syndrome (acute phosphate load released from tumor cells as a result of cytolytic therapy) |
All forms of hypoparathyroidism are uncommon (Table 17–7). Most cases are the result of inadvertent trauma to, removal of, or devascularization of the parathyroid glands during thyroid or parathyroid surgery. The incidence of postoperative hypoparathyroidism (range: 0.2–30%) depends on the extent of the antecedent surgery and the surgeon’s skill in identifying normal parathyroid tissue and preserving its blood supply. Postoperative hypocalcemia may be transient or permanent. Some patients may also be left with diminished parathyroid reserve.
Table 17–7Causes of hypoparathyroidism. ||Download (.pdf) Table 17–7 Causes of hypoparathyroidism.
Complication of thyroid, parathyroid or laryngeal surgery
Autoimmune polyendocrine failure syndrome type 1 (APS-1)
Secondary to magnesium depletion or hypermagnesemia
Post-131I therapy for Graves disease or thyroid cancer
Secondary to accumulation of iron (thalassemia, hemochromatosis) or copper (Wilson disease)
Genetic forms of hypoparathyroidism
DiGeorge or 22q deletion syndrome
Autosomal recessive or autosomal dominant mutations in pre-proPTH gene
Mutations in transcription factors involved in parathyroid development (eg, GCMB, GATA3)
Mitochondrial DNA mutations
Activating mutations of the CaSR
Acquired autoimmune syndrome caused by autoantibodies activating the calcium-sensing receptor (CaSR)
Tumor invasion (very rare)
A variety of causes other than postsurgical complications may produce an absolute or relative state of PTH deficiency (Table 17–7). These include autoimmune destruction, magnesium depletion, autosomal dominant or recessive or X-linked hypoparathyroidism, hypoparathyroidism resulting from activating mutations of the CaSR or stimulating antibodies directed against the CaSR (see below), and hypoparathyroidism resulting from iron overload or Wilson disease. Abnormal development of the glands resulting in varying degrees of severity of hypoparathyroidism is seen in the DiGeorge syndrome. This syndrome can present in infancy, childhood, or even adulthood and may be accompanied by defective cell-mediated immunity and other congenital anomalies (Table 17–7). Mutations in the gene for transcription factor GCMB (glial cell missing-B), which is essential in the development of the parathyroid glands, are linked to familial isolated hypoparathyroidism. Mutations in the transcription factor GATA3 cause abnormal otic vesicle, renal, and parathyroid gland development resulting in deafness, renal anomalies, and hypoparathyroidism.
There are two syndromes of autoimmune polyendocrine failure syndrome termed APS. Patients with APS-1 commonly have mucocutaneous candidiasis, Addison disease (adrenal insufficiency), and hypoparathyroidism and less commonly ovarian failure and thyroid dysfunction. Various components of APS-1 present by the teens or early 20s (Figure 17–17).
Cumulative incidence of three common manifestations of autoimmune polyglandular failure type 1 (APS-1) compared with age at onset in a cohort of 68 patients. The figures in parentheses reflect incidences at age 20. (Data plotted from Ahonen P et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED] in a series of 68 patients. N Engl J Med. 1990;322:1829.)
Autoantibodies to adrenal and parathyroid tissue are seen in most of these patients. Eventually, other endocrine glands may become involved (eg, gonads, thyroid, and pancreas). APS-1 is an autosomal recessive disorder due to mutations in the autoimmune regulator (AIRE) gene. AIRE is expressed normally in a subpopulation of epithelial cells in the thymus that are thought to be involved in negative selection of autoreactive T cells during clonal selection. These T-cell clones are involved in self-recognition, and the failure to delete these T-cell clones is thought to underlie the autoimmune destruction of the endocrine cells affected in APS-1.
APS-2 or Schmidt syndrome is characterized by hypothyroidism and adrenal insufficiency and does not involve the parathyroid glands (see Chapter 21).
The pathogenesis of hypoparathyroidism is straightforward. The mineral disturbance occurs because the amount of PTH released is inadequate to maintain normal serum calcium concentrations, mainly due to the loss of the renal calcium-conserving effects of PTH and the inability to generate 1,25-(OH)2D. Hypocalcemia results, and hyperphosphatemia is also observed because the proximal tubular effect of PTH to promote phosphate excretion is lost. Because PTH is required to stimulate the renal production of 1,25-(OH)2D, levels of 1,25-(OH)2D are low in patients with hypoparathyroidism. Hyperphosphatemia further suppresses 1,25-(OH)2D synthesis. Low 1,25-(OH)2D levels lead to reduced intestinal calcium absorption. In the absence of adequate 1,25-(OH)2D and PTH, the mobilization of calcium from bone is abnormal. Because PTH is deficient, urinary calcium excretion is often high, despite the hypocalcemia.
Magnesium depletion is a common cause of hypocalcemia. The pathogenesis of hypocalcemia in this clinical setting relates to a functional and reversible state of hypoparathyroidism. There is also decreased renal and skeletal responsiveness to PTH. Magnesium depletion may occur from a variety of causes, including chronic alcoholism, diarrhea, and drugs such as loop diuretics, aminoglycoside antibiotics, amphotericin B, and cisplatin (Table 17–6). Magnesium is required to maintain normal PTH secretory responses. Once body magnesium stores are replete, PTH levels rise appropriately in response to the hypocalcemia, and the mineral imbalance is corrected.
In pseudohypoparathyroidism, PTH levels are usually elevated, but the ability of target tissues (particularly kidney) to respond to the hormone is subnormal. In pseudohypoparathyroidism type 1, the ability of PTH to generate an increase in the second-messenger cAMP is reduced. In patients with type 1a, this is due to a deficiency in the cellular content of the α subunit of the stimulatory G protein (Gs-α), which couples the PTH receptor to the adenylyl cyclase enzyme. In patients with type 1b, Gs-α protein levels are normal, and in some cases there is altered regulation of the Gs-α gene transcription due to abnormal DNA methylation. In patients with pseudohypoparathyroidism type 2, urinary cAMP is normal but the phosphaturic response to infused PTH is reduced. The pathogenesis of this more rare form of PTH resistance remains obscure.
Patients with activating mutations of the CaSR typically present with autosomal dominant hypocalcemia and hypercalciuria. Both defects are due to overly sensitive CaSRs, which turn off PTH secretion and renal calcium reabsorption at subnormal serum calcium levels. These individuals rarely experience symptoms of their often mild hypocalcemia, but if given vitamin D, they are prone to develop marked hypercalciuria, nephrocalcinosis, and even renal failure.
The symptoms and signs of hypocalcemia are similar, regardless of the underlying cause (Table 17–8). Patients may be asymptomatic or may have latent or overt tetany. Tetany is defined as spontaneous tonic muscular contractions. Painful carpal spasms and laryngeal stridor are striking manifestations of tetany. Latent tetany may be demonstrated by testing for Chvostek and Trousseau signs. Chvostek sign is elicited by tapping on the facial nerve anterior to the ear. Twitching of the ipsilateral facial muscles indicates a positive test. A positive Trousseau sign is demonstrated by inflating the sphygmomanometer with the cuff around the arm above the systolic blood pressure for 3 min. In hypocalcemic individuals, this causes painful carpal muscle contractions and spasms (Figure 17–18). If hypocalcemia is severe and unrecognized, airway compromise, altered mental status, generalized seizures, and even death may occur.
Table 17–8Symptoms and signs of hypocalcemia. ||Download (.pdf) Table 17–8 Symptoms and signs of hypocalcemia.
|Systemic || |
|Neuromuscular || |
|Cardiac || |
|Ocular || |
|Dental || |
|Respiratory || |
Position of fingers in carpal spasm resulting from hypocalcemic tetany. (Redrawn, with permission, from Ganong WAF: Review of medical physiology, 16th ed. McGraw-Hill Companies, Inc, 1993.)
Chronic hypocalcemia can produce intracranial calcifications that have a predilection for the basal ganglia. These may be detectable by CT scanning, MRI, or skull radiographs. Chronic hypocalcemia may also enhance calcification of the lens and the formation of cataracts.
In addition to the symptoms and signs of hypocalcemia, patients with pseudohypoparathyroidism type 1a may have a constellation of features collectively known as Albright hereditary osteodystrophy. They include short stature, obesity, mental retardation, round facies, shortened fourth and fifth metacarpal and metatarsal bones, and subcutaneous ossifications. In considering the differential diagnosis of hypocalcemia, one must be guided by the clinical setting. A positive family history is very important in supporting a diagnosis of pseudohypoparathyroidism and other hereditary forms of hypoparathyroidism (Table 17–7). The patient with hypocalcemia, hyperphosphatemia, and a normal serum creatinine most likely has hypoparathyroidism. A history of neck surgery should be sought. There may be a long latent period before symptomatic hypocalcemia presents in postsurgical hypoparathyroidism. The physical examination can be helpful if it identifies signs of hypocalcemia, stigmata of Albright hereditary osteodystrophy, or other features of APS-1 (ie, vitiligo, mucocutaneous candidiasis, adrenal insufficiency). Patients with pseudohypoparathyroidism type 1a often have other endocrine abnormalities such as primary hypothyroidism or gonadal failure.
In the differential diagnosis of hypocalcemia, laboratory findings are extremely useful (Table 17–9). Serum phosphate is often (not invariably) elevated in hypoparathyroidism and pseudohypoparathyroidism. In magnesium depletion, serum phosphate is usually normal. In secondary hyperparathyroidism not due to renal failure, serum phosphate is typically low. Serum PTH levels are crucial in determining the cause of hypocalcemia. PTH is classically elevated in untreated pseudohypoparathyroidism but not in hypoparathyroidism or magnesium depletion. Intact PTH may be undetectable, low, or normal in patients with hypoparathyroidism depending on the parathyroid functional reserve. In patients with secondary hyperparathyroidism resulting from defects in the production or bioavailability of vitamin D, the clinical setting often suggests a problem with vitamin D (eg, regional enteritis, bowel resection, liver disease). The presence of a low 25-(OH)D level and an increased PTH confirms this diagnosis.
Table 17–9Laboratory findings in hypocalcemia. ||Download (.pdf) Table 17–9 Laboratory findings in hypocalcemia.
| ||Serum Ca2+ ||Serum PO43− ||Intact PTH ||25-(OH)D3 ||Urinary cAMP Response to PTH Infusion |
|Hypoparathyroidism ||↓ ||↑, N ||↓, N1 ||N ||N |
|Pseudohypoparathyroidism ||↓ ||↑, N ||↑ ||N ||↓2 |
|Magnesium depletion ||↓ ||N ||↓, N1 ||N ||N |
|Secondary hyperparathyroidism3 ||↓ ||N, ↓ ||↑ ||↓ ||N |
Measurement of serum magnesium is the first step in ruling out magnesium depletion as the cause of hypocalcemia and should be part of the initial evaluation. If urinary magnesium is inappropriately high relative to the serum magnesium, renal magnesium wasting is present. PTH levels in this setting are typically low or normal. Normal PTH levels, however, are inappropriate in the presence of hypocalcemia.
Patients with autoimmune hypoparathyroidism due to AIRE mutations can be suspected clinically by having at least two of the three features of the syndrome. Recent work indicates that autoantibodies to interferon-α or interferon-ω are present in more than 95% of patients with APS-1 and are an excellent screening test for the disorder.
The diagnosis of pseudohypoparathyroidism can be confirmed by infusing synthetic human PTH(1–34) and measuring urinary cAMP and phosphate responses. This maneuver is designed to prove that there is end-organ resistance to PTH and to determine whether the diagnosis is pseudohypoparathyroidism type 1 or type 2.
Hypoparathyroidism may vary in its severity and, therefore, in the need for therapy. In some patients with decreased parathyroid reserve, only situations of increased stress on the glands, such as pregnancy or lactation, induce hypocalcemia. In other patients, PTH deficiency is a chronic symptomatic disorder necessitating lifelong therapy with calcium supplements and vitamin D analogues. All patients so treated should have periodic monitoring of serum calcium, urinary calcium, and renal function. Patients with autoimmune hypoparathyroidism should also be examined regularly for the development of adrenal insufficiency as well as malabsorption, chronic hepatitis, keratitis, pernicious anemia, alopecia, vitiligo, and other nonendocrine complications of APS-1.
What are the causes of hypoparathyroidism?
What is the mechanism of pseudohypoparathyroidism?
What are the symptoms and signs of hypocalcemia?
How can laboratory studies be used to distinguish various causes of hypocalcemia?
Medullary Carcinoma of the Thyroid
Medullary carcinoma of the thyroid gland, a C-cell neoplasm, accounts for only 5–10% of all thyroid malignancies. Approximately 80% are sporadic and 20% are familial, occurring in autosomal dominant MEN-2A and MEN-2B and in non-MEN syndromes. In sporadic cases, the tumor is usually unilateral. In hereditary forms, however, tumors are often bilateral and multifocal. Germline activating mutations in the RET proto-oncogene on chromosome 10 are known to play a causal role in three forms of medullary carcinoma. These include cases of familial isolated medullary thyroid cancer, MEN-2A, and MEN-2B. Over half of sporadically occurring medullary thyroid carcinoma have a somatic mutation identical to that causing the familial syndromes; however, because the mutation is present only in the tumor and not in the genomic DNA, these cases are not heritable.
The growth pattern of medullary carcinoma is slow but progressive, and local invasion of adjacent structures is common. The tumor spreads hematogenously, with metastases typically to lymph nodes, bone, and lung. The clinical progression of this cancer is variable. Although there may be early metastases to cervical and mediastinal lymph nodes in as many as 70% of patients, the tumor still usually behaves in an indolent fashion. In a minority of cases, a more aggressive pattern of tumor growth has been noted. Early detection in high-risk individuals, such as those with a family history of medullary carcinoma or MEN-2A or MEN-2B, is crucial to prevent advanced disease and distant metastases. Overall survival is estimated to be 80% at 5 years and 60% at 10 years. Some studies suggest individuals who are younger than 40 years at the time of diagnosis may have higher survival rates than older individuals. The RET proto-oncogene mutation on codon 918 seen in nearly 95% of MEN-2B cases portends a worse prognosis.
Patients with MEN-2 develop medullary carcinoma at frequencies approaching 100%. In MEN-2A and MEN-B, the thyroid lesions are malignant. C-cell hyperplasia typically precedes the development of cancer, allowing for premalignancy detection and consideration of prophylactic thyroidectomy. The pheochromocytomas associated with either MEN-2A or MEN-2B are infrequently malignant. Hyperparathyroidism in MEN-2A, which is uncommon, is usually due to diffuse hyperplasia rather than malignancy of the parathyroids. Chronic hypercalcitoninemia as a result of the tumor may contribute to the pathogenesis of parathyroid hyperplasia. Parathyroid hyperplasia is rarely seen in patients with either MEN-2B or sporadic medullary carcinoma.
Sporadic medullary carcinoma occurs with about equal frequency in males and females and is typically found in patients older than 50 years. In MEN-2A or MEN-2B, the tumor occurs at a much younger age, often in childhood. In fact, medullary carcinoma in a patient younger than 40 years should suggest familial medullary carcinoma or MEN-2A or MEN-2B. Medullary carcinoma may present as a single nodule or as multiple thyroid nodules. Patients with sporadic medullary carcinoma often have palpable cervical lymphadenopathy.
Because C cells are neuroendocrine cells, these tumors have the capacity to release calcitonin and other hormones such as prostaglandins, serotonin, adrenocorticotropin, somatostatin, and calcitonin gene-related peptide. Serotonin, calcitonin, or the prostaglandins have been implicated in the pathogenesis of the secretory diarrhea observed in approximately 25% of patients with medullary carcinoma. If diarrhea is present, this usually indicates a large tumor burden or metastatic disease. Patients may also have flushing, which has been ascribed to the production by the tumor of substance P or calcitonin gene-related peptide, both of which are vasodilators.
In a patient suspected of having medullary carcinoma, a radionuclide thyroid scan may demonstrate one or more cold nodules. These nodules are solid on ultrasonography. Fine-needle aspiration biopsy shows the characteristic C-cell lesion with positive immuno-staining for calcitonin. Fine needle aspiration may be nondiagnostic in more than half of individuals with medullary thyroid carcinoma. Staining for calcitonin may improve diagnostic sensitivity; however, the diagnosis of medullary thyroid carcinoma may not be evident until examination of frozen section specimen slides during surgery or, later, of final pathological slides from the resected thyroid. The tumor has the propensity to contain large calcifications, which can be seen on x-ray films of the neck. Bone metastases may be lytic or sclerotic in their appearance, and pulmonary metastases may be surrounded by fibrotic reactions.
The most important laboratory test in determining the presence and extent of medullary carcinoma is the calcitonin level. Circulating calcitonin levels are typically elevated in most patients, and serum levels correlate with tumor burden. In C-cell hyperplasia, basal calcitonin may or may not be elevated. However, these patients usually demonstrate abnormal provocative testing. Intravenous calcium gluconate (2 mg/kg of elemental calcium) is injected over 1 minute, followed by pentagastrin (0.5 μg/kg) over 5 seconds. Provocative testing is based on the ability of calcium and the synthetic gastrin analogue pentagastrin to hyperstimulate calcitonin release in patients with increased C-cell mass resulting from either hyperplasia or carcinoma. An increase in serum calcitonin, more than twice the normal response, is considered abnormal. It must be borne in mind that false-positive provocative testing for calcitonin can occur. Provocative testing to detect C-cell hyperplasia (and hence elevation in serum calcitonin) in relatives of patients with medullary thyroid carcinoma has largely been replaced by genetic testing for germline mutations known to cause MEN or familial medullary thyroid carcinoma syndromes.
Serial calcitonin levels are a useful parameter for monitoring therapeutic responses in patients with medullary carcinoma or for diagnosing a recurrence, along with clinical examination and imaging procedures. Calcitonin levels usually reflect the extent of disease. If the tumor becomes less differentiated, calcitonin levels may no longer reflect tumor burden. Another useful tumor marker for medullary carcinoma is carcinoembryonic antigen (CEA). This antigen is frequently elevated in patients with medullary carcinoma and is present at all stages of the disease. Rapid increases in CEA predict a worse clinical course.
Surgery is the mainstay of therapy for patients with medullary thyroid carcinoma. Total thyroidectomy is advocated because the tumors are often multicentric. Patients should be monitored indefinitely for recurrences because these tumors may be very indolent. Indefinite monitoring is also required because individuals with presumed familial medullary thyroid carcinoma have developed pheochromocytoma or hyperparathyroidism long after their medullary thyroid carcinoma diagnosis and thus are eventually found to have MEN-2A rather than familial medullary thyroid carcinoma. All patients with medullary carcinoma of the thyroid, whether familial or sporadic, should be tested for RET oncogene mutations. This testing is commercially available and has supplanted calcitonin provocative testing. More than 95% of patients with MEN-2 have been found to harbor RET mutations. Sporadic cases of medullary carcinoma of the thyroid should also be tested to detect the occurrence of a new mutation for which other family members can then be screened. Properly performed DNA testing is essentially unambiguous in predicting gene carrier status and can be used prospectively to recommend prophylactic thyroidectomy in young patients and children with MEN-2 before the development of C-cell hyperplasia or frank carcinoma.
Patients with either MEN-2A or MEN-2B, even in the absence of symptoms, should undergo screening tests for the possibility of pheochromocytoma, while only patients with MEN-2A need to be screened for hyperparathyroidism before thyroid surgery. These tests include the determination of serum calcium and PTH together with plasma fractionated metanephrines and additional biochemical testing or imaging as needed. Pheochromocytomas may be clinically silent at the time medullary carcinoma is diagnosed, and they should be removed before thyroidectomy to prevent potentially serious surgical complications from uncontrolled catecholamine secretion. If hyperparathyroidism is present, it should be treated surgically at the time of thyroidectomy to avoid a second neck operation (Chapter 12).
How can you make the diagnosis of medullary carcinoma of the thyroid?
What is the treatment for medullary carcinoma?
Which patients are at high risk for medullary carcinoma?
Osteoporosis is defined as low bone mass. The bone is normal in composition but reduced in amount. Bone mass accrues rapidly throughout childhood and very rapidly in adolescence; half of adult bone mineral density is achieved during the teenage years (Figure 17–19). Peak bone mass is reached late in the third decade of life. Bone mass then remains relatively stable through the adult years, followed by a rapid loss of bone in women at the time of menopause. In the later stages of life, both men and women continue to lose bone, although at a slower rate than that seen at the time of menopause.
Bone mass in women as a function of age, demonstrating the potential effect of suboptimal nutrition and physical activity during the critical time of bone accrual in childhood and adolescence. (Redrawn, with permission, from Heaney RP et al. Peak bone mass. Osteo Int. 2000;11:985.)
Achieving maximum peak bone mass depends on optimal nutrition, physical activity, general health, and hormonal exposure throughout childhood and adolescence. Inadequacies in nutrition, weight-bearing exercise, and gonadal steroid exposure all have a negative impact on acquisition of peak bone mass. After bone growth is completed, the bone mass is determined by the level of peak bone mass that was attained and the subsequent rate of loss. Genetics are very important in determining bone mass. It has long been recognized that blacks have greater peak bone mass than whites or Asians and are relatively protected from osteoporosis. It now appears that, within the Caucasian population, more than half the variance in bone mass is genetically determined. However, a number of hormonal and environmental factors can reduce the genetically determined peak bone mass or hasten the loss of bone mineral and thus represent important risk factors for osteoporosis (Figure 17–19, Table 17–10).
Table 17–10Causes of osteoporosis.
The most important etiologic factor in osteoporosis is gonadal steroid deficiency. The estrogen deficiency that occurs after menopause accelerates loss of bone mass; postmenopausal women consistently have lower bone mass than men and a higher incidence of osteoporotic fractures. With respect to bone remodeling in men, testosterone serves some of the same functions as estrogen in women, but estradiol generated from the peripheral aromatization of testosterone is the critical gonadal steroid mediating the development and preservation of male bone mass. Hypogonadal men experience accelerated bone loss. Men on androgen deprivation therapy for prostate cancer are at increased risk for bone loss and fracture. Another important risk factor for bone loss is the use of corticosteroids or endogenous cortisol excess in Cushing syndrome. Glucocorticoid-induced osteoporosis is one of the most devastating complications of chronic therapy with these agents. Certain other medications, including excessive thyroid hormone, anticonvulsants, and chronic heparin therapy, immobilization, alcohol abuse, and smoking are also risk factors for osteoporosis. Diet is important as well. As discussed below, an adequate intake of calcium and vitamin D is necessary to build peak bone mass optimally and to minimize the rate of loss. Other dietary factors may also be important. Osteoporosis is most prevalent in Western societies, and it has been speculated that their increased dietary protein and sodium chloride intake, along with suboptimal potassium intake or related factors, may predispose to osteoporosis, perhaps via enhanced urinary calcium losses. Many additional disorders affecting the GI, hematologic, and connective tissue systems can contribute to the development of osteoporosis (Table 17–10).
Because bone remodeling involves the coupled resorption of bone by osteoclasts and the deposition of new bone by osteoblasts, bone loss could result from increased bone resorption, decreased bone formation, or a combination of both processes. Younger individuals with low bone mass typically have experienced low bone formation and insufficient bone accrual, while postmenopausal osteoporosis is the consequence of accelerated bone resorption. The urinary excretion of calcium and breakdown products of type 1 collagen (eg, N- and C-telopeptides) increases and osteoclast numbers and resorption surfaces are increased. The bone formation rate is also enhanced, with an increase in serum alkaline phosphatase and the serum level of the bone matrix protein osteocalcin, both reflecting increased osteoblastic activity. Bone formation, while increased, does not keep pace with bone resorption, and there is a net loss of bone mass at the time of menopause. This high-turnover state is the direct result of estrogen deficiency and can be reversed by estrogen replacement therapy.
The accelerated phase of estrogen-deficient bone loss begins immediately at the time of menopause (natural or surgical). It is most evident in trabecular bone, the compartment that is remodeled most rapidly. As much as 5–10% of spinal trabecular bone mineral is lost yearly in early postmenopausal women; osteoporotic fractures in such early post-menopausal women are often in the spine, a site of primarily trabecular bone. After 5–15 years, the rate of bone loss slows, so that after age 65, the annual rate of bone loss is similar in both sexes.
The cellular basis for the activation of bone resorption in the estrogen-deficient state is not fully understood but involves increased release of cytokines such as interleukin-6 from cells in the bone microenvironment in estrogen deficiency. These cytokines increase the expression of RANK-L and decrease the expression of OPG on stromal cells and osteoblasts. These critical changes together promote an imbalance in bone remodeling that favors increased osteoclastogenesis and bone resorption.
The pathogenesis of age-related bone loss is less certain. Bone mass is relatively stable in the fourth and fifth decades of life, accelerates for 5–10 years in women at the time of menopause, and then continues throughout life at a slower rate that is similar in men and women.
One important factor in the pathogenesis of age-related bone loss is a relative deficiency of calcium and 1,25-(OH)2D. The capacity of the intestine to absorb calcium diminishes with age. Because renal losses of calcium are obligatory, a decreased efficiency of calcium absorption means that dietary calcium intake must be increased to prevent negative calcium balance. It is estimated that about 1200 mg/d of elemental calcium is required to maintain calcium balance in people over age 65 (Table 17–11). American women in this age group typically ingest 500–600 mg of calcium daily; the calcium intakes in men are somewhat higher. In addition, older individuals may be deficient in vitamin D, further impairing their ability to absorb calcium. 25-(OH)D shows seasonal variability with lower levels and mild secondary hyperparathyroidism evident by the end of winter.
Table 17–11Recommended calcium and vitamin D intakes. ||Download (.pdf) Table 17–11 Recommended calcium and vitamin D intakes.
|Age ||Calcium (mg/d) ||Vitamin D (IU/d) |
|0–6 months ||200 ||400 |
|6–12 months ||260 ||400 |
|1–3 years ||700 ||600 |
|4–8 years ||1000 ||600 |
|9–13 years ||1300 ||600 |
|14–18 years ||1300 ||600 |
|19–30 years ||1000 ||600 |
|31–50 years ||1000 ||600 |
|51–70 years (women) ||1200 ||600 |
|51–70 years (men) ||1000 ||600 |
|70+ years ||1200 ||800 |
The PTH level increases with age due to changes in multiple organ systems with aging. There is a decrease in the mass of functioning renal tissue with age that could lead to decreased renal synthesis of 1,25-(OH)2D, which would directly release PTH secretion from its normal inhibition by 1,25-(OH)2D. The reduced 1,25-(OH)2D level decreases calcium absorption, exacerbating an intrinsic inability of the aging intestine to absorb calcium normally. Secondary hyperparathyroidism results from the dual effects of 1,25-(OH)2D deficiency on the parathyroid gland and the intestine. In addition, the responsiveness of the parathyroid gland to inhibition by calcium is reduced with aging. The hyperparathyroidism of aging may thus result from the combined effects of age on the kidney, intestine, and parathyroid glands.
Provision of a dietary supplement with adequate vitamin D reduces the rate of age-related bone loss and protects against fracture. This suggests that reduced calcium absorption and secondary hyperparathyroidism play significant roles in the pathogenesis of osteoporosis in the elderly. However, calcium and vitamin D supplements alone do not completely ameliorate fracture risk.
In secondary osteoporosis associated with glucocorticoid administration or alcoholism, there is a marked reduction in bone formation rates and serum osteocalcin levels. It is likely that glucocorticoids produce a devastating osteoporotic syndrome because of the rapid loss of bone that results from frankly depressed bone formation in the face of normal or even increased bone resorption. Additionally, glucocorticoids decrease intestinal calcium and vitamin D absorption and increase urine calcium losses.
The form of secondary osteoporosis associated with immobilization is another example of a resorptive state with marked uncoupling of bone resorption and bone formation and is characterized by hypercalciuria and suppression of PTH. When individuals with a high preexisting state of bone remodeling (eg, adolescents and patients with hyperthyroidism or Paget disease) are immobilized, bone resorption may be accelerated enough to produce hypercalcemia.
Osteoporosis is asymptomatic until it produces fractures and deformity. Typical osteoporotic fractures occur in the spine, the hip, and the wrist (Colles fracture). In women, wrist fractures increase in incidence at menopause and then stay relatively stable at this increased rate with age. The incidence of hip and vertebral fractures increases rapidly with aging in both men and women (Figure 17–20). The vertebral bodies may be crushed, resulting in loss of height, or may be wedged anteriorly, resulting in height loss and kyphosis. The dorsal kyphosis of elderly women (“dowager’s hump”) results from anterior wedging of multiple thoracic vertebrae. Spinal fractures may be acute and painful or may occur gradually and be manifested only as kyphosis or loss of height.
Age-specific incidence rates of wrist, hip, and vertebral fractures in men and women derived from Rochester, Minnesota data. (Redrawn, with permission, from Cooper C et al. Epidemiology of osteoporosis. Trends Endo Metab. 1992;3:224.)
The complication of osteoporosis with the highest morbidity and mortality is hip fracture. Hip fractures typically occur in the elderly, with a sharply rising incidence in both sexes after age 80 years. This is due to a variety of factors, including the tendency for a slower rate of bone loss in the cortical bone that makes up the hip compared with the predominantly trabecular bone of the spine as well as diminished motor and visual function with aging that result in more frequent falls. The personal and social costs of hip fracture are enormous. One third of American women who survive past age 80 years will suffer a hip fracture. The 6-month mortality rate is approximately 20%, much of it resulting from the complications of immobilizing frail persons in a hospital bed. The complications include pulmonary embolus and pneumonia. About half of elderly people with a hip fracture will never walk freely again. The long-term costs of chronic care for these persons are a major social concern.
The diagnosis of osteoporosis is sometimes made radiologically, but in general x-ray films are a poor diagnostic tool. A chest x-ray film will miss 30–50% of cases of spinal osteoporosis and, if overpenetrated, may lead to the diagnosis of osteoporosis in someone with a normal bone mass. The best way to diagnose osteoporosis is by measuring bone mineral density by dual-energy x-ray absorptiometry (DXA). The technique is precise, rapid, and inexpensive. The relationship between bone mineral density and fracture risk is a continuous one (ie, the lower the bone mineral density, the higher the fracture risk). Osteoporosis has been defined by the World Health Organization (WHO) as a bone mineral density value 2.5 standard deviations or more below the young adult normal value (ie, a T score of −2.5 or less). This cutoff was selected based on the observation that 16% of postmenopausal Caucasian women at age 50 years will have femoral neck bone density values below −2.5, and this population has a 16% lifetime risk of hip fracture. However, it should be remembered that there is no threshold at this value and that bone mineral density measurements need to be interpreted in light of other risk factors for fracture such as age and propensity for falls. An absolute 10-year fracture risk calculation algorithm (termed FRAX) has recently been developed by the WHO. The algorithm incorporates femoral neck bone mineral density values and several clinical risk factors to determine an individual’s 10-year probability of a major osteoporotic or hip fracture. The URL www.shef.ac.uk/FRAX/ provides access to the WHO absolute fracture risk calculator. This tool is useful for determining the need for treatment in addition to the bone density values themselves.
It is additionally important to realize that not all of the risk for fracture is captured by measurements of bone mineral density because the strength of bone is also a function of bone quality. Bone quality, determined by the microarchitecture of a bone, its mechanical strength, its material properties, and its ability to withstand stress, may be substantially different in two individuals with the same bone mineral density. Techniques to assess bone quality noninvasively are being actively investigated.
Elderly persons with osteoporosis are unlikely to sustain a hip fracture unless they fall. Risk factors for falling include muscle weakness, impaired vision, impaired balance, sedative use, and environmental factors. Therefore, strategies to prevent falls are an important part of the approach to the osteoporotic patient.
Individuals at risk for osteoporosis benefit from a total calcium intake of about 1200–1500 mg/d. This can be accomplished with dairy products or other calcium-rich foods, with calcium-fortified foods, or with a calcium supplement such as calcium carbonate or calcium citrate. Vitamin D should be provided in age-appropriate doses (600–800 IU/d). The serum level of 25-(OH)D that represents sufficiency remains controversial, with the Institute of Medicine recommending a level of 20 ng/mL, while many metabolic bone experts recommend a level of more than 32 ng/mL. The current recommended intakes for calcium and vitamin D are given in Table 17–11. Calcium supplementation in younger individuals may increase peak bone mass and decrease premenopausal bone loss, but its optimal role in this age group has not been determined. Estrogen replacement reduces bone loss, relieves hot flushes after menopause, and reduces fracture risk. It requires concomitant use of progestins in women who have not had a hysterectomy to prevent endometrial carcinoma and also increases the risk of breast cancer, stroke, myocardial infarction, and venous thromboembolism. The side-effect profile of estrogen has limited its use to short-term therapy at the time of menopause, typically in women suffering from hot flushes. Other antiresorptive agents available for treatment of osteoporosis include alendronate, risedronate, ibandronate, zoledronic acid, calcitonin, raloxifene, and denosumab. The first four agents are bisphosphonates that directly inhibit osteoclastic bone resorption. Given therapeutically, calcitonin decreases bone resorption and may protect against bone loss and vertebral fractures. Raloxifene, a selective estrogen response modulator, inhibits bone resorption as estrogen does. Raloxifene does not induce endometrial changes, and it has estrogen antagonist actions in breast cells that may appear to decrease the incidence of breast carcinoma in postmenopausal women. Denosumab is a monoclonal antibody to RANK ligand and inhibits osteoclast development and activation. The only agent currently available that can stimulate bone formation is parathyroid hormone (PTH1-34) (teriparatide). In contrast to the bone resorption that is caused by continuous elevations in PTH such as occur in hyperparathyroidism, a single daily injection of PTH stimulates bone formation and, to a lesser extent, bone resorption, resulting in net gains in bone density and decreased fracture risk.
What is the relative importance of hereditary versus environmental or hormonal factors in contributing to osteoporosis?
What are the risk factors for osteoporosis?
What are the symptoms and signs of osteoporosis?
What are the risk factors for fracture in a patient with osteoporosis?
What treatments can prevent bone loss?
Osteomalacia is defined as a defect in the mineralization of bone. When it occurs in young individuals, it also affects the mineralization of cartilage in the growth plate, a disorder called rickets. Osteomalacia can result from a deficiency of vitamin D, a deficiency of phosphate, an inherited deficiency in alkaline phosphatase (hypophosphatasia), or agents that have adverse effects on bone (Table 17–12). Surprisingly, dietary calcium deficiency rarely produces osteomalacia, although a few cases have been reported.
Table 17–12Causes of osteomalacia.
Vitamin D deficiency is becoming more common in the United States because of decreased sunlight exposure, increased use of sunscreens, and limited dietary sources of vitamin D. Individuals of dark-skinned ethnicities are particularly vulnerable because they have less cutaneous synthesis of vitamin D in response to sunlight. Fortified milk is the main food source of vitamin D, but at 100 IU/cup of milk, it can be difficult to achieve the daily recommended intake of 600–800 IU of vitamin D for adults. Some cereals and other foods have been also been fortified with vitamin D. In addition to insufficient intake, vitamin D deficiency can be the result of malabsorption of this fat-soluble vitamin. Severe rickets also occurs as part of three rare heritable disorders of vitamin D action: renal 1α-hydroxylase deficiency, in which vitamin D is not converted to 1,25-(OH)2D; mutant vitamin D receptors with reduced activity; and overproduction of a hormone response element binding protein that interferes with the activation (by the vitamin D receptor-retinoic acid receptor heterodimer) of vitamin D response elements on genes.
Phosphate deficiency with osteomalacia is usually caused by inherited or acquired renal phosphate wasting. Three hereditary forms of renal phosphate wasting include X-linked, autosomal dominant, or autosomal recessive hypophosphatemic rickets. Osteomalacia and hypophosphatemia can also result from tumors that are typically mesenchymal in origin and often located in the head and neck region. Many of these tumors overproduce FGF-23 (see above) and induce renal phosphate wasting and low 1,25-(OH)2D levels, eventually leading to osteomalacia. The FGF23 gene is mutated in kindreds with autosomal dominant hypophosphatemic rickets. Families with X-linked hypophosphatemic rickets have mutations in the PHEX gene, which encodes an endopeptidase, PHEX. This endopeptidase is involved in the production and degradation of FGF-23. In X-linked hypophosphatemic rickets, FGF-23 levels are elevated and appear to be responsible for the hypophosphatemic phenotype, although the exact role of PHEX in FGF-23 metabolism remains to be elucidated.
Vitamin D deficiency produces osteomalacia in stages. In the early stage, reduced calcium absorption produces secondary hyperparathyroidism, preventing hypocalcemia at the cost of increased renal phosphate excretion and hypophosphatemia. In later stages, hypocalcemia ensues, and hypophosphatemia progresses because of the combined effects of reduced absorption and the phosphaturic action of PTH. The poor delivery of minerals to bone (possibly coupled with the absence of direct effects of vitamin D on bone) impairs the mineralization of bone matrix. Since osteoblasts continue to synthesize bone matrix, unmineralized matrix or osteoid accumulates at bone-forming surfaces.
Patients with osteomalacia have bone pain, muscle weakness, and a waddling gait. Radiologically, they may have reduced bone mass, detectable by both x-ray and bone densitometry. The hallmark of the disorder, however, is the pseudofracture: local bone resorption that has the appearance of a nondisplaced fracture, classically in the pubic rami, clavicles, or scapulas. In children with rickets, the leg bones are bowed (osteomalacia means “softening of bones”), the costochondral junctions are enlarged (“rachitic rosary”), and the growth plates are widened and irregular, reflecting the increase in unmineralized cartilage that bends under the child’s weight, resulting in the bowing. Biochemically, the hallmarks of vitamin D–deficient osteomalacia are hypophosphatemia, hyperparathyroidism, variable hypocalcemia, and marked reductions in urinary calcium to less than 50 mg/d. The 25-(OH)D level is reduced, indicative of decreased body stores of vitamin D. In vitamin D deficiency and other forms of osteomalacia, the alkaline phosphatase level is increased.
Although the disorder can be suspected strongly on clinical grounds and the biochemical changes summarized previously are confirmatory, a firm diagnosis of osteomalacia requires either the radiologic appearance of rickets or pseudofractures or a characteristic bone biopsy. If bone is biopsied for quantitative histomorphometry, thickened osteoid seams and a reduction in the mineralization rate are found. Treatment with vitamin D or aggressive phosphate replacement in patients with renal phosphate wasting will reverse osteomalacia and heal rickets. In renal disease, and in the FGF-23–mediated disorders, calcitriol also must be provided to mineralize bone because in these disorders, endogenous synthesis is either absent (renal disease) or suppressed (FGF-23 disorders).
What are the causes of osteomalacia?
What are the two stages in which vitamin D deficiency produces osteomalacia?
What are the symptoms and signs of osteomalacia?