InternalMed_Harrison

InternalMed_Harrison. The various therapies for hypercalcemia are listed in Table 424-4. The choice depends on the underlying disease, the severity of the hypercalcemia, the serum inorganic phosphate level, and the renal, hepatic, and bone marrow function. Mild hypercalcemia (≤3 mmol/L [12 mg/dL]) can usually be managed by hydration. Severe hypercalcemia (≥3.7 mmol/L [15 mg/dL]) requires rapid correction. Calcitonin should be given for its rapid, albeit short-lived, blockade of bone resorption, and IV pamidronate or zoledronate should be administered, although its onset of action is delayed for 1–2 days. In addition, for the first 24–48 h, aggressive sodium-calcium diuresis with IV saline should be given and, following rehydration, large doses of furosemide or ethacrynic acid, but only if appropriate monitoring is available and cardiac and renal function are adequate. Intermediate degrees of hypercalcemia between 3 and 3.7 mmol/L (12 and 15 mg/dL) should be approached with vigorous hydration and then the


InternalMed_Harrison

InternalMed_Harrison. is available and cardiac and renal function are adequate. Intermediate degrees of hypercalcemia between 3 and 3.7 mmol/L (12 and 15 mg/dL) should be approached with vigorous hydration and then the most appropriate selection for the patient of the combinations used with severe hypercalcemia.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 65) PATHOPHYSIOLOGY OF HYPOCALCEMIA: CLASSIFICATION BASED ON MECHANISM Chronic hypocalcemia is less common than hypercalcemia; causes include chronic renal failure, hereditary and acquired hypoparathyroidism, vitamin D deficiency, pseudohypoparathyroidism, and hypomagnesemia (Table 424-5).


InternalMed_Harrison

InternalMed_Harrison. Acute rather than chronic hypocalcemia is seen in critically ill patients or as a consequence of certain medications and often does not require specific treatment. Transient hypocalcemia is seen with severe sepsis, burns, acute kidney injury, and extensive transfusions with citrated blood. Although as many as one-half of patients in an intensive care setting are reported to have calcium concentrations of <2.1 mmol/L (8.5 mg/dL), most do not have a reduction in ionized calcium. Patients with severe sepsis may have a decrease in ionized calcium (true hypocalcemia), but in other severely ill individuals, hypoalbuminemia is the primary cause of the reduced total calcium concentration. Alkalosis increases calcium binding to proteins, and in this setting, direct measurements of ionized calcium should be made.


InternalMed_Harrison

InternalMed_Harrison. Medications such as protamine, heparin, and glucagon may cause transient hypocalcemia. These forms of hypocalcemia are usually not associated with tetany and resolve with improvement in the overall medical condition. The hypocalcemia after repeated transfusions of citrated blood usually resolves quickly. Patients with acute pancreatitis have hypocalcemia that persists during the acute inflammation and varies in degree with disease severity. The cause of hypocalcemia remains unclear. PTH values are ↓ Dietary intake or sunlight Vitamin D–dependent rickets type II Defective metabolism: Pseudohypoparathyroidism Anticonvulsant therapy Vitamin D–dependent rickets reported to be low, normal, or elevated, and both resistance to PTH and impaired PTH secretion have been postulated. Occasionally, a chronic low total calcium and low ionized calcium concentration are detected in an elderly patient without obvious cause and with a paucity of symptoms; the pathogenesis is unclear.


InternalMed_Harrison

InternalMed_Harrison. Chronic hypocalcemia, however, is usually symptomatic and requires treatment. Neuromuscular and neurologic manifestations of chronic hypocalcemia include muscle spasms, carpopedal spasm, facial grimacing, and, in extreme cases, laryngeal spasm and convulsions. Respiratory arrest may occur. Increased intracranial pressure occurs in some patients with long-standing hypocalcemia, often in association with papilledema. Mental changes include irritability, depression, and psychosis. The QT interval on the electrocardiogram is prolonged, in contrast to its shortening with hypercalcemia. Arrhythmias occur, and digitalis effectiveness may be reduced. Intestinal cramps and chronic malabsorption may occur. Chvostek’s or Trousseau’s sign can be used to confirm latent tetany.


InternalMed_Harrison

InternalMed_Harrison. The classification of hypocalcemia shown in Table 424-5 is based on an organizationally useful premise that PTH is responsible for minute-to-minute regulation of plasma calcium concentration and, therefore, that the occurrence of hypocalcemia must mean a failure of the homeostatic action of PTH. Failure of the PTH response can occur if there is hereditary or acquired parathyroid gland failure, if PTH is ineffective in target organs, or if the action of the hormone is overwhelmed by the loss of calcium from the ECF at a rate faster than it can be replaced.


InternalMed_Harrison

InternalMed_Harrison. Whether hereditary or acquired, hypoparathyroidism has a number of common components. Symptoms of untreated hypocalcemia are shared by both types of hypoparathyroidism, although the onset of hereditary hypoparathyroidism can be more gradual and associated with other developmental defects. Basal ganglia calcification and extrapyramidal syndromes are more common and earlier in onset in hereditary hypoparathyroidism. In previous decades, acquired hypoparathyroidism secondary to surgery in the neck was more common than hereditary hypoparathyroidism, but the frequency of surgically induced parathyroid failure has diminished as a result of improved surgical techniques that spare the parathyroid glands and increased use of nonsurgical therapy for hyperthyroidism. Pseudohypoparathyroidism, an example of ineffective PTH action rather than a failure of parathyroid gland production, may share several features with hypoparathyroidism, including extraosseous calcification and extrapyramidal


InternalMed_Harrison

InternalMed_Harrison. an example of ineffective PTH action rather than a failure of parathyroid gland production, may share several features with hypoparathyroidism, including extraosseous calcification and extrapyramidal manifestations such as choreoathetotic movements and dystonia.


InternalMed_Harrison

InternalMed_Harrison. Papilledema and raised intracranial pressure may occur in both hereditary and acquired hypoparathyroidism, as do chronic changes in fingernails and hair and lenticular cataracts, the latter usually reversible with treatment of hypocalcemia. Certain skin manifestations, including alopecia and candidiasis, are characteristic of hereditary hypoparathyroidism associated with autoimmune polyglandular failure (Chap. 408).


InternalMed_Harrison

InternalMed_Harrison. Hypocalcemia associated with hypomagnesemia is associated with both deficient PTH release and impaired responsiveness to the hormone. Patients with hypocalcemia secondary to hypomagnesemia have absent or low levels of circulating PTH, indicative of diminished hormone release despite a maximum physiologic stimulus by hypocalcemia. Plasma PTH levels return to normal with correction of the hypomagnesemia. Thus hypoparathyroidism with low levels of PTH in blood can be due to hereditary gland failure, acquired gland failure, or acute but reversible gland dysfunction (hypomagnesemia).


InternalMed_Harrison

InternalMed_Harrison. Genetic Abnormalities and Hereditary Hypoparathyroidism Hereditary hypoparathyroidism can occur as an isolated entity without other endocrine or dermatologic manifestations. More typically, it occurs in association with other abnormalities such as defective development of the thymus or failure of other endocrine organs such as the adrenal, thyroid, or ovary (Chap. 408). Hereditary hypoparathyroidism is often manifest within the first decade but may appear later. Genetic defects associated with hypoparathyroidism serve to illuminate the complexity of organ development, hormonal biosynthesis and secretion, and tissue-specific patterns of endocrine effector function (Fig. 424-5). Often, hypoparathyroidism is isolated, signifying a highly specific functional disturbance. When hypoparathyroidism is associated with other developmental or organ defects, treatment of the hypocalcemia can still be effective.


InternalMed_Harrison

InternalMed_Harrison. A form of hypoparathyroidism associated with defective development of both the thymus and the parathyroid glands is termed the DiGeorge syndrome, or the velocardiofacial syndrome. Congenital cardiovascular, facial, and other developmental defects are present, and patients may die in early childhood with severe infections, hypocalcemia and seizures, or cardiovascular complications. Patients can survive into adulthood, and milder, incomplete forms occur. Most cases are sporadic, but an autosomal dominant form involving micro-deletions of chromosome 22q11.2 has been described. Smaller deletions in chromosome 22 are seen in incomplete forms of the DiGeorge syndrome, appearing in childhood or adolescence, that are manifest primarily by parathyroid gland failure. The chromosome 22 defect is now termed DSG1; more recently, a defect in chromosome 10p is also recognized—now called DSG2. The phenotypes seem similar. Studies on the chromosome 22 defect have pinpointed a transcription factor,


InternalMed_Harrison

InternalMed_Harrison. now termed DSG1; more recently, a defect in chromosome 10p is also recognized—now called DSG2. The phenotypes seem similar. Studies on the chromosome 22 defect have pinpointed a transcription factor, TBX1. Deletions of the orthologous mouse gene show a phenotype similar to the human syndrome.


InternalMed_Harrison

InternalMed_Harrison. Another autosomal dominant developmental defect, featuring hypoparathyroidism, deafness, and renal dysplasia (HDR), has been studied at the genetic level. Cytogenetic abnormalities in some, but not all kindreds, point to translocation defects on chromosome 10, as in DiGeorge syndrome. However, the lack of immunodeficiency and heart defects distinguishes the two syndromes. Mouse models, as well as deletional analysis in some HDR patients, has identified the transcription factor GATA3, which is important in embryonic development and is expressed in developing kidney, ear structures, and the parathyroids.


InternalMed_Harrison

InternalMed_Harrison. Another pair of linked developmental disorders involving the parathyroids is recognized. Kenney-Caffey syndrome type I features hypoparathyroidism, short stature, osteosclerosis, and thick cortical bones. A defect seen in Middle Eastern patients, particularly in Saudi Arabia, termed Sanjad-Sakati syndrome, also exhibits growth failure and other dysmorphic features. This syndrome, which is clearly autosomal recessive, involves a gene on chromosome 1q42-q43. Both syndromes apparently involve a chaperone protein, called TBCE, relevant to tubulin function. Recently, a defect in FAM111A was identified as the cause of Kenney-Caffey syndrome type 2.


InternalMed_Harrison

InternalMed_Harrison. Hypoparathyroidism can occur in association with a complex hereditary autoimmune syndrome involving failure of the adrenals, the ovaries, the immune system, and the parathyroids in association 2483 with recurrent mucocutaneous candidiasis, alopecia, vitiligo, and pernicious anemia (Chap. 408). The responsible gene on chromosome 21q22.3 has been identified. The protein product, which resembles a transcription factor, has been termed the autoimmune regulator, or AIRE. A stop codon mutation occurs in many Finnish families with the disorder, commonly referred to as polyglandular autoimmune type 1 deficiency, whereas another AIRE mutation (Y85C) is typically observed in Jews of Iraqi and Iranian descent.


InternalMed_Harrison

InternalMed_Harrison. Hypoparathyroidism is seen in two disorders associated with mitochondrial dysfunction and myopathy, one termed the Kearns-Sayre syndrome (KSS), with ophthalmoplegia and pigmentary retinopathy, and the other termed the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Mutations or deletions in mitochondrial genes have been identified.


InternalMed_Harrison

InternalMed_Harrison. Several forms of hypoparathyroidism, each rare in frequency, are seen as isolated defects; the genetic mechanisms are varied. The inheritance includes autosomal dominant, autosomal recessive, and X-linked modes. Three separate autosomal defects involving the parathyroid gene have been recognized: one is dominant and the other two are recessive. The dominant form has a point mutation in the signal sequence, a critical region involved in intracellular transport of the hormone precursor. An Arg for Cys mutation interferes with processing of the precursor and is believed to trigger an apoptotic cellular response, hence acting as a dominant negative. The other two forms are recessive. One point mutation also blocks cleavage of the PTH precursor but requires both alleles to cause hypoparathyroidism. The third involves a single-nucleotide base change that results in an exon splicing defect; the lost exon contains the promoter—hence, the gene is silenced. An X-linked recessive form of


InternalMed_Harrison

InternalMed_Harrison. The third involves a single-nucleotide base change that results in an exon splicing defect; the lost exon contains the promoter—hence, the gene is silenced. An X-linked recessive form of hypoparathyroidism has been described in males, and the defect has been localized to chromosome Xq26-q27, perhaps involving the SOX3 gene.


InternalMed_Harrison

InternalMed_Harrison. Abnormalities in the CaSR are detected in three distinctive hypocalcemic disorders. All are rare, but more than 10 different gain-offunction mutations have been found in one form of hypocalcemia termed autosomal dominant hypocalcemic hypercalciuria (ADHH). The receptor senses the ambient calcium level as excessive and suppresses PTH secretion, leading to hypocalcemia. The hypocalcemia is aggravated by constitutive receptor activity in the renal tubule causing excretion of inappropriate amounts of calcium. Recognition of the syndrome is important because efforts to treat the hypocalcemia with vitamin D analogues and increased oral calcium exacerbate the already excessive urinary calcium excretion (several grams or more per 24 h), leading to irreversible renal damage from stones and ectopic calcification.


InternalMed_Harrison

InternalMed_Harrison. Other causes of isolated hypoparathyroidism include homozygous, inactivating mutations in the parathyroid-specific transcription factor GCM2, which lead to an autosomal recessive form of the disease, or heterozygous point mutations in GCM2, which have a dominant negative effect on the wild-type protein and thus lead to an autosomal dominant form of hypoparathyroidism. Furthermore, heterozygous mutations in G11, one of the two signaling proteins downstream of the CaSR, have been identified as a cause of autosomal dominant hypoparathyroidism.


InternalMed_Harrison

InternalMed_Harrison. Bartter’s syndrome is a group of disorders associated with disturbances in electrolyte and acid/base balance, sometimes with nephrocalcinosis and other features. Several types of ion channels or transporters are involved. Curiously, Bartter’s syndrome type V has the electrolyte and pH disturbances seen in the other syndromes but appears to be due to a gain of function in the CaSR. The defect may be more severe than in ADHH and explains the additional features seen beyond hypocalcemia and hypercalciuria. As with autoimmune disorders that block the CaSR (discussed above under hypercalcemic conditions), there are autoantibodies that at least transiently activate the CaSR, leading to suppressed PTH secretion and hypocalcemia. This disorder may wax and wane. Acquired Hypoparathyroidism Acquired chronic hypoparathyroidism is usually the result of inadvertent surgical removal of all the parathyroid


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Parathyroid Gland and Calcium Homeostasis 2484 glands; in some instances, not all the tissue is removed, but the remainder undergoes vascular supply compromise secondary to fibrotic changes in the neck after surgery. In the past, the most frequent cause of acquired hypoparathyroidism was surgery for hyperthyroidism. Hypoparathyroidism now usually occurs after surgery for hyperparathyroidism when the surgeon, facing the dilemma of removing too little tissue and thus not curing the hyperparathyroidism, removes too much. Parathyroid function may not be totally absent in all patients with postoperative hypoparathyroidism. Rare causes of acquired chronic hypoparathyroidism include radiation-induced damage subsequent to radioiodine therapy of hyperthyroidism and glandular damage in patients with hemochromatosis or hemosiderosis after repeated blood transfusions. Infection may involve one or more of the parathyroids but usually does not cause hypoparathyroidism because all


InternalMed_Harrison

InternalMed_Harrison. in patients with hemochromatosis or hemosiderosis after repeated blood transfusions. Infection may involve one or more of the parathyroids but usually does not cause hypoparathyroidism because all four glands are rarely involved. Transient hypoparathyroidism is frequent following surgery for hyperparathyroidism. After a variable period of hypoparathyroidism, normal parathyroid function may return due to hyperplasia or recovery of remaining tissue. Occasionally, recovery occurs months after surgery.


InternalMed_Harrison

InternalMed_Harrison. Treatment involves replacement with vitamin D or 1,25(OH)2D (calcitriol) combined with a high oral calcium intake. In most patients, blood calcium and phosphate levels are satisfactorily regulated, but some patients show resistance and a brittleness, with a tendency to alternate between hypocalcemia and hypercalcemia. For many patients, vitamin D in doses of 40,000–120,000 U/d (1–3 mg/d) combined with ≥1 g elemental calcium is satisfactory. The wide dosage range reflects the variation encountered from patient to patient; precise regulation of each patient is required. Compared to typical daily requirements in euparathyroid patients of 200 U/d (or in older patients as high as 800 U/d), the high dose of vitamin D (as much as 100-fold higher) reflects the reduced conversion of vitamin D to 1,25(OH)2D. Many physicians now use 0.5–1 μg of calcitriol in management of such patients, especially if they are difficult to control. Because of its storage in fat, when vitamin D is withdrawn, weeks


InternalMed_Harrison

InternalMed_Harrison. Many physicians now use 0.5–1 μg of calcitriol in management of such patients, especially if they are difficult to control. Because of its storage in fat, when vitamin D is withdrawn, weeks are required for the disappearance of the biologic effects, compared with a few days for calcitriol, which has a rapid turnover.


InternalMed_Harrison

InternalMed_Harrison. Oral calcium and vitamin D restore the overall calcium-phosphate balance but do not reverse the lowered urinary calcium reabsorption typical of hypoparathyroidism. Therefore, care must be taken to avoid excessive urinary calcium excretion after vitamin D and calcium replacement therapy; otherwise, nephrocalcinosis and kidney stones can develop, and the risk of CKD is increased. Thiazide diuretics lower urine calcium by as much as 100 mg/d in hypoparathyroid patients on vitamin D, provided they are maintained on a low-sodium diet. Use of thiazides seems to be of benefit in mitigating hypercalciuria and easing the daily management of these patients. There are now trials of parenterally administered PTH (either PTH[1–34] or PTH[1–84]) in patients with hypoparathyroidism providing greater ease of maintaining serum calcium and reducing urinary calcium excretion (desirable to protect any renal damage). However, PTH therapy for the treatment of hypoparathyroidism is not approved as of yet.


InternalMed_Harrison

InternalMed_Harrison. Hypomagnesemia Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L) is associated with hypocalcemia (Chap. 423). Restoration of the total-body magnesium deficit leads to rapid reversal of hypocalcemia. There are at least two causes of the hypocalcemia—impaired PTH secretion and reduced responsiveness to PTH. For further discussion of causes and treatment of hypomagnesemia, see Chap. 423.


InternalMed_Harrison

InternalMed_Harrison. The effects of magnesium on PTH secretion are similar to those of calcium; hypermagnesemia suppresses and hypomagnesemia stimulates PTH secretion. The effects of magnesium on PTH secretion are normally of little significance, however, because the calcium effects dominate. Greater change in magnesium than in calcium is needed to influence hormone secretion. Nonetheless, hypomagnesemia might be expected to increase hormone secretion. It is therefore surprising to find that severe hypomagnesemia is associated with blunted secretion of PTH. The explanation for the paradox is that severe, chronic hypomagnesemia leads to intracellular magnesium deficiency, which interferes with secretion and peripheral responses to PTH. The mechanism of the cellular abnormalities caused by hypomagnesemia is unknown, although effects on adenylate cyclase (for which magnesium is a cofactor) have been proposed.


InternalMed_Harrison

InternalMed_Harrison. PTH levels are undetectable or inappropriately low in severe hypomagnesemia despite the stimulus of severe hypocalcemia, and acute repletion of magnesium leads to a rapid increase in PTH level. Serum phosphate levels are often not elevated, in contrast to the situation with acquired or idiopathic hypoparathyroidism, probably because phosphate deficiency is often seen in hypomagnesmia (Chap. 393). Diminished peripheral responsiveness to PTH also occurs in some patients, as documented by subnormal response in urinary phosphorus and urinary cAMP excretion after administration of exogenous PTH to patients who are hypocalcemic and hypomagnesemic. Both blunted PTH secretion and lack of renal response to administered PTH can occur in the same patient. When acute magnesium repletion is undertaken, the restoration of PTH levels to normal or supra-normal may precede restoration of normal serum calcium by several days.


InternalMed_Harrison

InternalMed_Harrison. Repletion of magnesium cures the condition. Repletion should be parenteral. Attention must be given to restoring the intracellular deficit, which may be considerable. After IV magnesium administration, serum magnesium may return transiently to the normal range, but unless replacement therapy is adequate, serum magnesium will again fall. If the cause of the hypomagnesemia is renal magnesium wasting, magnesium may have to be given long-term to prevent recurrence (Chap. 423).


InternalMed_Harrison

InternalMed_Harrison. PTH is not sufficiently active to fully prevent hypocalcemia (although retaining phosphaturic activity, for example). This problem occurs when the PTH1R–signaling protein complex is defective (as in the different forms of pseudohypoparathyroidism [PHP], discussed below); when PTH action to promote calcium absorption from the diet via the synthesis of 1,25(OH)2D is insufficient because of vitamin D deficiency or because vitamin D is ineffective (defects in vitamin D receptor or vitamin D synthesis); or in CKD in which the calcium-elevating action of PTH is impaired. Typically, hypophosphatemia is more severe than hypocalcemia in vitamin D deficiency states because of the increased secretion of PTH, which, although only partly effective in elevating blood calcium, is readily capable of promoting urinary phosphate excretion.


InternalMed_Harrison

InternalMed_Harrison. PHP, on the other hand, has a pathophysiology that is different from the other disorders of ineffective PTH action. PHP resembles hypoparathyroidism (in which PTH synthesis is deficient) and is manifested by hypocalcemia and hyperphosphatemia, yet elevated PTH levels. The cause of the disorder is defective PTH-dependent activation of the stimulatory G protein complex or the downstream effector protein kinase A, resulting in failure of PTH to increase intracellular cAMP or to respond to elevated cAMP levels (see below).


InternalMed_Harrison

InternalMed_Harrison. Chronic Kidney Disease Improved medical management of CKD now allows many patients to survive for decades and hence allows time enough to develop features of renal osteodystrophy, which must be controlled to avoid additional morbidity. Impaired production of 1,25(OH)2D is now thought to be the principal factor that causes calcium deficiency, secondary hyperparathyroidism, and bone disease; hyperphosphatemia typically occurs only in the later stages of the disease. Low levels of 1,25(OH)2D due to increased FGF23 production in bone are critical in the development of hypocalcemia. The uremic state also causes impairment of intestinal absorption by mechanisms other than defects in vitamin D metabolism. Nonetheless, treatment with supraphysiologic amounts of vitamin D or calcitriol can correct the impaired calcium absorption. Because increased FGF23 levels are seen even in early stages of CKD and have been reported to correlate with increased mortality and left ventricular hypertrophy,


InternalMed_Harrison

InternalMed_Harrison. the impaired calcium absorption. Because increased FGF23 levels are seen even in early stages of CKD and have been reported to correlate with increased mortality and left ventricular hypertrophy, there is current interest in approaches to lower intestinal phosphate absorption early during the course of kidney disease and to thereby lower FGF23 levels. However, there is concern as to whether vitamin D supplementation increases the circulating FGF23 levels in CKD patients. Although vitamin D analogs improve survival in this patient population, it is notable that there are often dramatic elevations of FGF23.


InternalMed_Harrison

InternalMed_Harrison. Hyperphosphatemia in CKD lowers blood calcium levels by several mechanisms, including extraosseous deposition of calcium and phosphate, impairment of the bone-resorbing action of PTH, and reduction in 1,25(OH)2D production by remaining renal tissue.


InternalMed_Harrison

InternalMed_Harrison. Therapy of CKD (Chap. 335) involves appropriate management of patients prior to dialysis and adjustment of regimens once dialysis is initiated. Attention should be paid to restriction of phosphate in the diet; avoidance of aluminum-containing phosphate-binding antacids to prevent the problem of aluminum intoxication; provision of an adequate calcium intake by mouth, usually 1–2 g/d; and supplementation with 0.25–1 μg/d calcitriol or other activated forms of vitamin D. Each patient must be monitored closely. The aim of therapy is to restore normal calcium balance to prevent osteomalacia and severe secondary hyperparathyroidism (it is usually recommended to maintain PTH levels between 100 and 300 pg/ mL) and, in light of evidence of genetic changes and monoclonal outgrowths of parathyroid glands in CKD patients, to prevent secondary hyperparathyroidism from becoming autonomous hyperparathyroidism. Reduction of hyperphosphatemia and restoration of normal intestinal calcium absorption by


InternalMed_Harrison

InternalMed_Harrison. in CKD patients, to prevent secondary hyperparathyroidism from becoming autonomous hyperparathyroidism. Reduction of hyperphosphatemia and restoration of normal intestinal calcium absorption by calcitriol can improve blood calcium levels and reduce the manifestations of secondary hyperparathyroidism. Because adynamic bone disease can occur in association with low PTH levels, it is important to avoid excessive suppression of the parathyroid glands while recognizing the beneficial effects of controlling the secondary hyperparathyroidism. These patients should probably be closely monitored with PTH assays that detect only the full-length PTH(1–84) to ensure that biologically active PTH and not inactive, inhibitory PTH fragments are measured. Use of phosphate-binding agents such as sevelamer is approved only in end-stage renal disease, but it may be necessary to initiate such treatment much earlier during the course of kidney disease to prevent the increase in FGF23 and its “off-target”


InternalMed_Harrison

InternalMed_Harrison. is approved only in end-stage renal disease, but it may be necessary to initiate such treatment much earlier during the course of kidney disease to prevent the increase in FGF23 and its “off-target” effects.


InternalMed_Harrison

InternalMed_Harrison. Vitamin D Deficiency due to Inadequate Diet and/or Sunlight Vitamin D deficiency due to inadequate intake of dairy products enriched with vitamin D, lack of vitamin supplementation, and reduced sunlight exposure in the elderly, particularly during winter in northern latitudes, is more common in the United States than previously recognized. Biopsies of bone in elderly patients with hip fracture (documenting osteomalacia) and abnormal levels of vitamin D metabolites, PTH, calcium, and phosphate indicate that vitamin D deficiency may occur in as many as 25% of elderly patients, particularly in northern latitudes in the United States. Concentrations of 25(OH)D are low or low-normal in these patients. Quantitative histomorphometric analysis of bone biopsy specimens from such individuals reveals widened osteoid seams consistent with osteomalacia (Chap. 423). PTH hypersecretion compensates for the tendency for the blood calcium to fall but also increases renal phosphate excretion and thus


InternalMed_Harrison

InternalMed_Harrison. widened osteoid seams consistent with osteomalacia (Chap. 423). PTH hypersecretion compensates for the tendency for the blood calcium to fall but also increases renal phosphate excretion and thus causes osteomalacia.


InternalMed_Harrison

InternalMed_Harrison. Treatment involves adequate replacement with vitamin D and cal-2485 cium until the deficiencies are corrected. Severe hypocalcemia rarely occurs in moderately severe vitamin D deficiency of the elderly, but vitamin D deficiency must be considered in the differential diagnosis of mild hypocalcemia. Mild hypocalcemia, secondary hyperparathyroidism, severe hypophosphatemia, and a variety of nutritional deficiencies occur with gastrointestinal diseases. Hepatocellular dysfunction can lead to reduction in 25(OH)D levels, as in portal or biliary cirrhosis of the liver, and malabsorption of vitamin D and its metabolites, including 1,25(OH)2D, may occur in a variety of bowel diseases, hereditary or acquired. Hypocalcemia itself can lead to steatorrhea, due to deficient production of pancreatic enzymes and bile salts. Depending on the disorder, vitamin D or its metabolites can be given parenterally, guaranteeing adequate blood levels of active metabolites.


InternalMed_Harrison

InternalMed_Harrison. Defective Vitamin D Metabolism • anticonvulSant tHerapy Anticonvulsant therapy with any of several agents induces acquired vitamin D deficiency by increasing the conversion of vitamin D to inactive compounds and/or causing resistance to its action. The more marginal the vitamin D intake in the diet, the more likely that anticonvulsant therapy will lead to abnormal mineral and bone metabolism.


InternalMed_Harrison

InternalMed_Harrison. vitamin d–dependent ricKetS type i Vitamin D–dependent rickets type I, previously termed pseudo-vitamin D–resistant rickets, differs from true vitamin D–resistant rickets (vitamin D–dependent rickets type II, see below) in that it is typically less severe and the biochemical and radiographic abnormalities can be reversed with appropriate doses of the vitamin’s active metabolite, 1,25(OH)2D. Physiologic amounts of calcitriol cure the disease (Chap. 423). This finding fits with the pathophysiology of the disorder, which is autosomal recessive, and is now known to be caused by mutations in the gene encoding 25(OH) D-1α-hydroxylase. Both alleles are inactivated in affected patients, and compound heterozygotes, harboring distinct mutations, are common.


InternalMed_Harrison

InternalMed_Harrison. Clinical features include hypocalcemia, often with tetany or con vulsions, hypophosphatemia, secondary hyperparathyroidism, and osteomalacia, often associated with skeletal deformities and increased alkaline phosphatase. Treatment involves physiologic replacement doses of 1,25(OH)2D (Chap. 423). vitamin d–dependent ricKetS type ii Vitamin D–dependent rickets type II results from end-organ resistance to the active metabolite 1,25(OH)2D. The clinical features resemble those of the type I disorder and include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets but also partial or total alopecia. Plasma levels of 1,25(OH)2D are elevated, in keeping with the refractoriness of the end organs. This disorder is caused by mutations in the gene encoding the vitamin D receptor; treatment is difficult and requires regular, usually nocturnal calcium infusions, which dramatically improve growth but do not restore hair growth (Chap. 423).


InternalMed_Harrison

InternalMed_Harrison. Pseudohypoparathyroidism PHP refers to a group of distinct inherited disorders. Patients affected by PHP type Ia (PHP-Ia) are characterized by symptoms and signs of hypocalcemia in association with distinctive skeletal and developmental defects. The hypocalcemia is due to a deficient response to PTH, which is probably restricted to the proximal renal tubules. Hyperplasia of the parathyroids, a response to hormone-resistant hypocalcemia, causes elevation of PTH levels. Studies, both clinical and basic, have clarified some aspects of these disorders, including the variable clinical spectrum, the pathophysiology, the genetic defects, and their mode of inheritance.


InternalMed_Harrison

InternalMed_Harrison. A working classification of the various forms of PHP is given in Table 424-6. The classification scheme is based on the signs of ineffective PTH action (low calcium and high phosphate), low or normal urinary cAMP response to exogenous PTH, the presence or absence of Albright’s hereditary osteodystrophy (AHO), and assays to measure the concentration of the Gsα subunit of the adenylate cyclase enzyme. Using these criteria, there are four types: PHP types Ia and Ib; pseudopseudohypoparathyroidism (PPHP), and PHP-II. Disorders of the Parathyroid Gland and Calcium Homeostasis PHP-Ia Yes ↓↑ Yes Yes PPHP No Normal Normal Yes Yes PHP-Ib Yes ↓↑ No No PHP-II Yes Normal ↑ No No Acrodysostosis with Yes Normal (but ↓↑ No Yes phosphaturic response) Abbreviations: ↓, decreased; ↑, increased; AHO, Albright’s hereditary osteodystrophy; PTH, parathyroid hormone.


InternalMed_Harrison

InternalMed_Harrison. pHp-ia and pHp-iB Individuals with PHP-I, the most common of the disorders, show a deficient urinary cAMP response to administration of exogenous PTH. Patients with PHP-I are divided into type Ia and type Ib. Patients with PHP-Ia show evidence for AHO and reduced amounts of Gsα protein/activity, as determined in readily accessible tissues such as erythrocytes, lymphocytes, and fibroblasts. Patients with PHP-Ib typically lack evidence for AHO and they have normal G α activity. PHP-Ic, sometimes listed as a third form of PHP-I, is really sa variant of PHP-Ia, although the mutant G α shows normal activity in certain in vitro assays. s


InternalMed_Harrison

InternalMed_Harrison. Most patients who have PHP-Ia reveal characteristic features of AHO, which consist of short stature, round face, obesity, skeletal anomalies (brachydactyly), intellectual impairment, and/or heterotopic calcifications. Patients have low calcium and high phosphate levels, as with true hypoparathyroidism. PTH levels, however, are elevated, reflecting resistance to hormone action. Amorphous deposits of calcium and phosphate are found in the basal ganglia in about one-half of patients. The defects in metacarpal and metatarsal bones are sometimes accompanied by short phalanges as well, possibly reflecting premature closing of the epiphyses. The typical findings are short fourth and fifth metacarpals and metatarsals. The defects are usually bilateral. Exostoses and radius curvus are frequent.


InternalMed_Harrison

InternalMed_Harrison. Inheritance and Genetic Defects Multiple defects at the GNAS locus have now been identified in PHP-Ia, PHP-Ib, and PPHP patients. This gene, which is located on chromosome 20q13.3, encodes the α-subunit of the stimulatory G protein (Gsα), among other products (see below). Mutations include abnormalities in splice junctions associated with deficient mRNA production, point mutations, insertions, and/or deletion that all result in a protein with defective function resulting in a 50% reduction of Gsα activity in erythrocytes or other cells.


InternalMed_Harrison

InternalMed_Harrison. Detailed analyses of disease transmission in affected kindreds have clarified many features of PHP-Ia, PPHP, and PHP-Ib (Fig. 424-7). The former two entities, often traced through multiple generations, have an inheritance pattern consistent with genetic imprinting. The phenomenon of gene imprinting, involving methylation of genetic loci, independent of any mutation, impairs transcription from either the maternal or the paternal allele (Chap. 82). The Gsα transcript is biallelically expressed in most tissues; expression from paternal allele is silenced through as-of-yet unknown mechanisms in some tissues including the proximal renal tubules and the thyroid; consequently, inheritance of a defective paternal allele has no implications with regard to hormonal function. Thus, females affected by either PHP-Ia or PPHP will have offspring with PHP-Ia, if these children inherit the allele carrying the GNAS mutation; in contrast, if the mutant allele is inherited from a male affected by either


InternalMed_Harrison

InternalMed_Harrison. either PHP-Ia or PPHP will have offspring with PHP-Ia, if these children inherit the allele carrying the GNAS mutation; in contrast, if the mutant allele is inherited from a male affected by either disorder, the offspring will exhibit PPHP. Consistent with these data in humans, gene-ablation studies in mice have shown that inheritance of the mutant G α allele from the female causes much reduced Gsα protein in renal cortex, hypocalcemia, and resistance to PTH. Offspring inheriting the mutant allele from the male showed no evidence of PTH resistance or hypocalcemia.


InternalMed_Harrison

InternalMed_Harrison. Imprinting is tissue selective. Paternal Gsα expression is not silenced in most tissues. It seems likely, therefore, that the AHO phenotype recognized in PPHP as well as PHP-Ia reflects G α haploinsufficiency during embryonic or postnatal development. s The complex mechanisms that control the GNAS gene contribute to challenges involved in unraveling the pathogenesis of these disorders, especially that of PHP-Ib. Much intensive work with families in which multiple members are affected by PHP-Ib, as well as studies of the complex regulation of the GNAS gene locus, have now shown that PHP-Ib is caused by microdeletions within or upstream of the GNAS locus, which are associated with a loss of DNA methylation at one or several loci of the maternal allele (Table 424-6). These abnormalities in methylation silence the expression of the gene. This leads in the proximal renal tubules—where Gsα appears to be expressed exclusively from the maternal allele—to PTH resistance.


InternalMed_Harrison

InternalMed_Harrison. PHP-Ib, lacking the AHO phenotype in most instances, shares with PHP-Ia the hypocalcemia and hyperphosphatemia caused by PTH resistance, and thus the blunted urinary cAMP response to administered PTH, a standard test to assess the presence or absence of hormone resistance (Table 424-6). Furthermore, these endocrine abnormalities become apparent only if the disease-causing mutation is inherited maternally. Bone responsiveness may be excessive rather than blunted in PHP-Ib (and in PHP-Ia) patients, based on case reports that have emphasized an osteitis fibrosa–like pattern in several PHP-Ib patients. PHP-II refers to patients with hypocalcemia and hyperphosphatemia, who have a normal urinary cAMP but an impaired urinary phosphaturic


InternalMed_Harrison

InternalMed_Harrison. PHP-II refers to patients with hypocalcemia and hyperphosphatemia, who have a normal urinary cAMP but an impaired urinary phosphaturic FIGURE 424-7 Paternal imprinting of renal parathyroid hormone (PTH) resistance. An impaired excretion of urinary cyclic AMP and phosphate is observed in patients with pseudohypoparathyroidism type Ia (PHP-Ia). In the renal cortex, there is selective silencing of paternal Gsα expression. The disease becomes manifest only in patients who inherit the defective gene from an obligate female carrier (left). If the genetic defect is inherited from an obligate male gene carrier, there is no biochemical abnormality; administration of PTH causes an appropriate increase in the urinary cyclic AMP and phosphate concentration (pseudo-PHP [PPHP]; right). Both patterns of inheritance lead to Albright’s hereditary osteodystrophy (AHO), perhaps because of haplotype insufficiency—i.e., both copies of G α must be active for normal bone development.


InternalMed_Harrison

InternalMed_Harrison. response to PTH. In a PHP-II variant, referred to as acrodysostosis with hormonal resistance (ADOHR), patients have a defect in the regulatory subunit of PKA (PRKAR1A) that mediates the response to PTH distal to cAMP production. Acrodysostosis without hormonal resistance is caused by mutations in the cAMP-selective phosphodiesterase 4 (ADOP4). It remains unclear why the PTH-resistance in some patients, labeled as PHP-II without bony abnormalities, resolves upon treatment with vitamin D supplements.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of these hormone-resistant states can usually be made without difficulty when there is a positive family history for features of AHO, in association with the signs and symptoms of hypocalcemia. In both categories—PHP-Ia and PHP-Ib—serum PTH levels are elevated, particularly when patients are hypocalcemic. However, patients with PHP-Ib or PHP-II without acrodysostosis present only with hypocalcemia and high PTH levels, as evidence for hormone resistance. In PHP-Ia and PHP-Ib, the response of urinary cAMP to the administration of exogenous PTH is blunted. The diagnosis of PHP-II, in the absence of acrodysostosis, is more complex, and vitamin D deficiency must be excluded before such a diagnosis can be entertained.


InternalMed_Harrison

InternalMed_Harrison. Treatment of PHP is similar to that of hypoparathyroidism, except that calcium and vitamin D doses are usually higher. Patients with PHP show no PTH-resistance in the distal tubules—hence, urinary calcium clearance is typically reduced, and they are not at risk of developing nephrocalcinosis as are patients with true hypoparathyroidism, unless overtreatment occurs, for example, after the completion of pubertal development and skeletal mutation, when calcium and 1,25(OH)2D treatment should be reduced. Variability in response makes it necessary to establish the optimal regimen for each patient, based on maintaining appropriate blood calcium level and urinary calcium excretion and keeping the PTH level within or slightly above the normal range.


InternalMed_Harrison

InternalMed_Harrison. Occasionally, loss of calcium from the ECF is so severe that PTH cannot compensate. Such situations include acute pancreatitis and severe, acute hyperphosphatemia, often in association with renal failure, conditions in which there is rapid efflux of calcium from the ECF. Severe hypocalcemia can occur quickly; PTH rises in response to hypocalcemia but does not return blood calcium to normal.


InternalMed_Harrison

InternalMed_Harrison. Severe, Acute Hyperphosphatemia Severe hyperphosphatemia is associated with extensive tissue damage or cell destruction (Chap. 423). The combination of increased release of phosphate from muscle and impaired ability to excrete phosphorus because of renal failure causes moderate to severe hyperphosphatemia, the latter causing calcium loss from the blood and mild to moderate hypocalcemia. Hypocalcemia is usually reversed with tissue repair and restoration of renal function as phosphorus and creatinine values return to normal. There may even be a mild hypercalcemic period in the oliguric phase of renal function recovery. This sequence, severe hypocalcemia followed by mild hypercalcemia, reflects widespread deposition of calcium in muscle and subsequent redistribution of some of the calcium to the ECF after phosphate levels return to normal.


InternalMed_Harrison

InternalMed_Harrison. Other causes of hyperphosphatemia include hypothermia, massive hepatic failure, and hematologic malignancies, either because of high cell turnover of malignancy or because of cell destruction by chemotherapy. TREATmEnT severe, acute HyperpHospHatemia Treatment is directed toward lowering of blood phosphate by the administration of phosphate-binding antacids or dialysis, often needed for the management of CKD. Although calcium replacement may be necessary if hypocalcemia is severe and symptomatic, calcium administration during the hyperphosphatemic period tends to increase extraosseous calcium deposition and aggravate tissue 2487 damage. The levels of 1,25(OH)2D may be low during the hyperphosphatemic phase and return to normal during the oliguric phase of recovery.


InternalMed_Harrison

InternalMed_Harrison. Osteitis Fibrosa after Parathyroidectomy Severe hypocalcemia after parathyroid surgery is rare now that osteitis fibrosa cystica is an infrequent manifestation of hyperparathyroidism. When osteitis fibrosa cystica is severe, however, bone mineral deficits can be large. After parathyroidectomy, hypocalcemia can persist for days if calcium replacement is inadequate. Treatment may require parenteral administration of calcium; addition of calcitriol and oral calcium supplementation is sometimes needed for weeks to a month or two until bone defects are filled (which, of course, is of therapeutic benefit in the skeleton), making it possible to discontinue parenteral calcium and/or reduce the amount.


InternalMed_Harrison

InternalMed_Harrison. Care must be taken to ensure that true hypocalcemia is present; in addition, acute transient hypocalcemia can be a manifestation of a variety of severe, acute illnesses, as discussed above. Chronic hypocalcemia, however, can usually be ascribed to a few disorders associated with absent or ineffective PTH. Important clinical criteria include the duration of the illness, signs or symptoms of associated disorders, and the presence of features that suggest a hereditary abnormality. A nutritional history can be helpful in recognizing a low intake of vitamin D and calcium in the elderly, and a history of excessive alcohol intake may suggest magnesium deficiency.


InternalMed_Harrison

InternalMed_Harrison. Hypoparathyroidism and PHP are typically lifelong illnesses, usually (but not always) appearing by adolescence; hence, a recent onset of hypocalcemia in an adult is more likely due to nutritional deficiencies, renal failure, or intestinal disorders that result in deficient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with a delayed onset of postoperative hypoparathyroidism. A history of seizure disorder raises the issue of anticonvulsive medication. Developmental defects may point to the diagnosis of PHP. Rickets and a variety of neuromuscular syndromes and deformities may indicate ineffective vitamin D action, either due to defects in vitamin D metabolism or to vitamin D deficiency.


InternalMed_Harrison

InternalMed_Harrison. A pattern of low calcium with high phosphorus in the absence of renal failure or massive tissue destruction almost invariably means hypoparathyroidism or PHP. A low calcium and low phosphorus pattern points to absent or ineffective vitamin D, thereby impairing the action of PTH on calcium metabolism (but not phosphate clearance). The relative ineffectiveness of PTH in calcium homeostasis in vitamin D deficiency, anticonvulsant therapy, gastrointestinal disorders, and hereditary defects in vitamin D metabolism leads to secondary hyperparathyroidism as a compensation. The excess PTH on renal tubule phosphate transport accounts for renal phosphate wasting and hypophosphatemia.


InternalMed_Harrison

InternalMed_Harrison. Exceptions to these patterns may occur. Most forms of hypomagnesemia are due to long-standing nutritional deficiency as seen in chronic alcoholics. Despite the fact that the hypocalcemia is principally due to an acute absence of PTH, phosphate levels are usually low, rather than elevated, as in hypoparathyroidism. Chronic renal failure is often associated with hypocalcemia and hyperphosphatemia, despite secondary hyperparathyroidism.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis is usually established by application of the PTH immunoassay, tests for vitamin D metabolites, and measurements of the urinary cAMP response to exogenous PTH. In hereditary and acquired hypoparathyroidism and in severe hypomagnesemia, PTH is either undetectable or inappropriately in the normal range (Fig. 424-4). This finding in a hypocalcemic patient is supportive of hypoparathyroidism, as distinct from ineffective PTH action, in which even mild hypocalcemia is associated with elevated PTH levels. Hence a failure to detect elevated PTH levels establishes the diagnosis of hypoparathyroidism; elevated levels suggest the presence of secondary hyperparathyroidism, as found in many of the situations in which the hormone is


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Parathyroid Gland and Calcium Homeostasis 2488 ineffective due to associated abnormalities in vitamin D action. Assays –2.5. Postmenopausal women who fall at the lower end of the young for 25(OH)D can be helpful. Low or low-normal 25(OH)D indicates normal range (a T-score <–1.0) are defined as having low bone density vitamin D deficiency due to lack of sunlight, inadequate vitamin D and are also at increased risk of osteoporosis. Although risk is lower intake, or intestinal malabsorption. Recognition that mild hypocalce-in this group, more than 50% of fractures among postmenopausal mia, rickets, and hypophosphatemia are due to anticonvulsant therapy women, including hip fractures, occur in this group with low bone is made by history. density, because the number of individuals in this category is so much larger than that in the osteoporosis range. As a result, there are ongo- ing attempts to identify individuals within the low bone density range who are at high risk of


InternalMed_Harrison

InternalMed_Harrison. in this category is so much larger than that in the osteoporosis range. As a result, there are ongo- ing attempts to identify individuals within the low bone density range who are at high risk of fracture and might benefit from pharmacologic intervention. Furthermore, some have advocated using fracture risk as


InternalMed_Harrison

InternalMed_Harrison. The management of hypoparathyroidism, PHP, chronic renal failure, and hereditary defects in vitamin D metabolism involves the use of vitamin D or vitamin D metabolites and calcium supplementation. Vitamin D itself is the least expensive form of vitamin D replacement and is frequently used in the management of uncomplicated hypoparathyroidism and some disorders associated with ineffective vitamin D action. When vitamin D is used prophylactically, as in the elderly or in those with chronic anticonvulsant therapy, there is a wider margin of safety than with the more potent metabolites. However, most of the conditions in which vitamin D is administered chronically for hypocalcemia require amounts 50–100 times the daily replacement dose because the formation of 1,25(OH)2D is deficient. In such situations, vitamin D is no safer than the active metabolite because intoxication can occur with high-dose therapy (because of storage in fat). Calcitriol is more rapid in onset of action and also


InternalMed_Harrison

InternalMed_Harrison. situations, vitamin D is no safer than the active metabolite because intoxication can occur with high-dose therapy (because of storage in fat). Calcitriol is more rapid in onset of action and also has a short biologic half-life.


InternalMed_Harrison

InternalMed_Harrison. Vitamin D (at least 1000 U/d [2–3 μg/d] [higher levels required in older persons]) or calcitriol (0.25–1 μg/d) is required to prevent rickets in normal individuals. In contrast, 40,000–120,000 U (1–3 mg) of vitamin D2 or D3 is typically required in hypoparathyroidism. The dose of calcitriol is unchanged in hypoparathyroidism, because the defect is in hydroxylation by the 25(OH)D-1α-hydroxylase. Calcitriol is also used in disorders of 25(OH)D-1α-hydroxylase; vitamin D receptor defects are much more difficult to treat.


InternalMed_Harrison

InternalMed_Harrison. Patients with hypoparathyroidism should be given 2–3 g of elemental calcium PO each day. The two agents, vitamin D or calcitriol and oral calcium, can be varied independently. Urinary calcium excretion needs to be monitored carefully. If hypocalcemia alternates with episodes of hypercalcemia in high-brittleness patients with hypoparathyroidism, administration of calcitriol and use of thiazides, as discussed above, may make management easier. Clinical trials with PTH(1–34) or PTH(1–84) are promising, but these alternative treatments have not yet been approved. the “diagnostic” criterion for osteoporosis.


InternalMed_Harrison

InternalMed_Harrison. the “diagnostic” criterion for osteoporosis. In the United States, as many as 9 million adults have osteoporosis (T-score <–2.5 in either spine or hip), and an additional 48 million individuals have bone mass levels that put them at increased risk of developing osteoporosis (e.g., bone mass T-score <–1.0). Osteoporosis occurs more frequently with increasing age as bone tissue is lost progressively. In women, the loss of ovarian function at menopause (typically about age 50) precipitates rapid bone loss so that most women meet the diagnostic criterion for osteoporosis by age 70–80. As the population continues to age, the number of individuals with osteoporosis and fractures will also continue to increase, despite a recognized reduction in age-specific risk. It is estimated that about 2 million fractures occur each year in the United States as a consequence of osteoporosis, and that number is expected to increase as the population continues to age.


InternalMed_Harrison

InternalMed_Harrison. The epidemiology of fractures follows the trend for loss of bone density, with exponential increases in both hip and vertebral fractures with age. Fractures of the distal radius have a somewhat different epidemiology, increasing in frequency before age 50 and plateauing by age 60, with only a modest age-related increase thereafter. In contrast, incidence rates for hip fractures double every 5 years after age 70 (Fig. 425-1). This distinct epidemiology may be related to the way the elderly fall as they age, with fewer falls on an outstretched hand and more falls directly on the hip. About 300,000 hip fractures occur each year in the United States, most of which require hospital admission and surgical intervention. The probability that a 50-year-old white individual will have a hip fracture during his or her lifetime is 14% for women and 5% for men; the risk for African Americans is lower (about one-half those rates), and the risk for Asians is roughly equal to that for whites. Hip


InternalMed_Harrison

InternalMed_Harrison. during his or her lifetime is 14% for women and 5% for men; the risk for African Americans is lower (about one-half those rates), and the risk for Asians is roughly equal to that for whites. Hip fractures are associated with a high incidence of deep vein thrombosis and pulmonary embolism (20–50%) and a mortality rate between 5 and 20% during the year after surgery.


InternalMed_Harrison

InternalMed_Harrison. osteoporosis Robert Lindsay, Felicia Cosman Osteoporosis, a condition characterized by decreased bone strength, is prevalent among postmenopausal women but also occurs in men and women with underlying conditions or major risk factors associ-ated with bone demineralization. Its chief clinical manifestations are 425 Incidence/100,000 person-year 3,000 2,000 1,000 vertebral and hip fractures, although fractures can occur at almost any skeletal site. Osteoporosis affects almost 10 million individuals in the United States, but only a small proportion are diagnosed and treated. Osteoporosis is defined as a reduction in the strength of bone that leads to an increased risk of fractures. Loss of bone tissue is associated


InternalMed_Harrison

InternalMed_Harrison. Osteoporosis is defined as a reduction in the strength of bone that leads to an increased risk of fractures. Loss of bone tissue is associated Age group, year with deterioration in skeletal microarchitecture. The World Health Organization (WHO) operationally defines osteoporosis as a bone FIGURE 425-1 Epidemiology of vertebral, hip, and Colles’ fracdensity that falls 2.5 standard deviations (SD) below the mean for tures with age. (Adapted from C Cooper, LJ Melton III: Trends Endocrinol young healthy adults of the same sex—also referred to as a T-score of Metab 3:224, 1992; with permission.) FIGURE 425-2 Lateral spine x-ray showing severe osteopenia and a severe wedge-type deformity (severe anterior compression). There is also significant morbidity, with about 20–40% of survivors requiring long-term care, and many who are unable to function as they did before the fracture.


InternalMed_Harrison

InternalMed_Harrison. There is also significant morbidity, with about 20–40% of survivors requiring long-term care, and many who are unable to function as they did before the fracture. There are about 550,000 vertebral crush fractures per year in the United States. Only a fraction (estimated to be one-third) of them are recognized clinically, because many are relatively asymptomatic and are identified incidentally during radiography for other purposes (Fig. 425-2). Vertebral fractures rarely require hospitalization but are associated with long-term morbidity and a slight increase in mortality rates, primarily related to pulmonary disease. Multiple vertebral fractures lead to height loss (often of several inches), kyphosis, and secondary pain and discomfort related to altered biomechanics of the back. Thoracic fractures can be associated with restrictive lung disease, whereas lumbar fractures are associated with abdominal symptoms that include distention, early satiety, and constipation.


InternalMed_Harrison

InternalMed_Harrison. Approximately 400,000 wrist fractures and 135,000 pelvic fractures occur in the United States each year. Fractures of the humerus and other bones (estimated to be about 675,000 per year) also occur with osteoporosis; this is not surprising in light of the fact that bone loss is a systemic phenomenon. Although some fractures result from major trauma, the threshold for fracture is reduced for an osteoporotic bone (Fig. 425-3). In addition to bone density, there are a number of risk factors for fracture; the common ones are summarized in Table 425-1 Age, prior fractures (especially recent fractures), a family history of osteoporosis-related fractures, low body weight, smoking, and excessive alcohol use are all independent predictors of fracture. Chronic diseases with inflammatory components that increase skeletal remodeling such as rheumatoid arthritis, increase the risk of osteoporosis, as do FIGURE 425-3 Factors leading to osteoporotic fractures.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 425-3 Factors leading to osteoporotic fractures. diseases associated with malabsorption. Chronic diseases that increase 2489 the risk of falling or frailty, including dementia, Parkinson’s disease, and multiple sclerosis, also increase fracture risk. In the United States and Europe, osteoporosis-related fractures are more common among women than men, presumably due to a lower peak bone mass as well as postmenopausal bone loss in women. However, this sex difference in bone density and age-related increase in hip fractures is not as apparent in some other cultures, possibly due to genetics, physical activity level, or diet.


InternalMed_Harrison

InternalMed_Harrison. Fractures are themselves risk factors for future fractures (Table 425-1). Vertebral fractures increase the risk of other vertebral fractures as well as fractures of the peripheral skeleton such as the hip and wrist. Wrist fractures also increase the risk of vertebral and hip fractures. The risk for subsequent fractures is particularly high in the first several years after the first fracture, and the risk wanes considerably thereafter. Consequently, among individuals over age 50, any fracture should be considered as potentially related to osteoporosis regardless of the circumstances of the fracture. Osteoporotic bone is more likely to fracture than normal bone at any level of trauma, and a fracture in a person over 50 should trigger evaluation for osteoporosis. This often does not occur because postfracture care is not always well coordinated.


InternalMed_Harrison

InternalMed_Harrison. Osteoporosis results from bone loss due to age-related changes in bone remodeling as well as extrinsic and intrinsic factors that exaggerate this process. These changes may be superimposed on a low peak bone mass. Consequently, understanding the bone remodeling process is fundamental to understanding the pathophysiology of osteoporosis (Chap. 423). During growth, the skeleton increases in size by linear growth and by apposition of new bone tissue on the outer surfaces of the cortex (Fig. 425-4). The latter process is called modeling, a process that also allows the long bones to adapt in shape to the stresses placed on them. Increased sex hormone production at puberty is required for skeletal maturation, which reaches maximum mass and density in early adulthood. It is around puberty that the sexual dimorphism in skeletal size becomes obvious, although true bone density remains similar between the sexes. Nutrition and lifestyle also play an important role in growth, although genetic


InternalMed_Harrison

InternalMed_Harrison. the sexual dimorphism in skeletal size becomes obvious, although true bone density remains similar between the sexes. Nutrition and lifestyle also play an important role in growth, although genetic factors primarily determine peak skeletal mass and density. Numerous genes control skeletal growth, peak bone mass, and body size, as well as skeletal structure and density. Heritability estimates of 50–80% for bone density and size have been derived on the basis of twin studies. Although peak bone mass is often lower among individuals with a family history of osteoporosis, association studies of candidate genes (vitamin D receptor; type I collagen, the estrogen receptor [ER], and interleukin 6 [IL-6]; and insulin-like growth factor I [IGF-I]) and bone mass, bone turnover, and fracture prevalence have been inconsistent. Linkage studies suggest that a genetic locus on chromosome 11 is associated with high bone mass. Families with high bone mass and without much apparent age-related bone loss


InternalMed_Harrison

InternalMed_Harrison. have been inconsistent. Linkage studies suggest that a genetic locus on chromosome 11 is associated with high bone mass. Families with high bone mass and without much apparent age-related bone loss have been shown to have a point mutation in LRP5, a low-density lipoprotein receptor–related protein. The role of this gene in the general population is not clear, although a nonfunctional mutation results in osteoporosispseudoglioma syndrome, and LRP5 signaling appears to be important in controlling bone formation. LRP5 acts through the Wnt signaling pathway. With LRP5 and Wnt activation, beta-catenin is translocated to the nucleus, allowing stimulation of osteoblast formation, activation, and life span as well as suppression of osteoclast activity, thereby increasing bone formation. The osteocyte product, sclerostin, is a negative inhibitor of Wnt signaling.


InternalMed_Harrison

InternalMed_Harrison. Genome-wide scans for low bone mass suggest multiple genes are involved, many of which are also implicated in control of body size. In adults, bone remodeling, not modeling, is the principal metabolic skeletal process. Bone remodeling has two primary functions: (1) to repair microdamage within the skeleton to maintain skeletal strength and ensure the relative youth of the skeleton and (2) to supply calcium from the skeleton to maintain serum calcium. Remodeling may be activated by microdamage to bone as a result of excessive or accumulated stress. Acute demands for calcium involve 2490 TAblE 425-1 ConDiTionS, DiSEASES, AnD mEDiCATionS THAT ConTRibuTE To oSTEoPoRoSiS AnD fRACTuRES Parental history of hip fracture Porphyria Riley-Day syndrome


InternalMed_Harrison

InternalMed_Harrison. Parental history of hip fracture Porphyria Riley-Day syndrome Thiazolidinediones (such as pioglitazone and rosiglitazone) osteoclast-mediated resorption as well as calcium transport by osteocytes. Chronic demands for calcium result in secondary hyperparathyroidism, increased bone remodeling, and overall loss of bone tissue.


InternalMed_Harrison

InternalMed_Harrison. Bone remodeling also is regulated by several circulating hormones, including estrogens, androgens, vitamin D, and parathyroid hormone (PTH), as well as locally produced growth factors such as IGF-I and immunoreactive growth hormone II (IGH-II), transforming growth factor β (TGF-β), parathyroid hormone–related peptide (PTHrP), interleukins (ILs), prostaglandins, and members of the tumor necrosis factor (TNF) superfamily. These factors primarily modulate the rate at which new remodeling sites are activated, a process that results initially in bone resorption by osteoclasts, followed by a period of repair during which new bone tissue is synthesized by osteoblasts. The cytokine responsible for communication between the osteoblasts, other marrow cells, and osteoclasts is RANK ligand (RANKL; receptor activator of nuclear factor-κB [NF-κB]). RANKL, a member of the TNF family, is secreted by osteoblasts and certain cells of the immune system (Chap. 423). The osteoclast receptor for this


InternalMed_Harrison

InternalMed_Harrison. receptor activator of nuclear factor-κB [NF-κB]). RANKL, a member of the TNF family, is secreted by osteoblasts and certain cells of the immune system (Chap. 423). The osteoclast receptor for this protein is referred to as RANK. Activation of RANK by RANKL is a final common path in osteoclast development, activation, and life span. A humoral decoy for RANKL, also secreted by osteoblasts, is osteoprotegerin (Fig. 425-5). Modulation of osteoclast recruitment and activity appears to be related to the interplay among these three factors. It appears that estrogens are pivotal in modulating secretion of osteoprotegerin (OPG) and perhaps also RANKL. Additional influences include nutrition (particularly calcium intake) and physical activity level.


InternalMed_Harrison

InternalMed_Harrison. In young adults, resorbed bone is replaced by an equal amount of new bone tissue. Thus, the mass of the skeleton remains constant after peak bone mass is achieved in adulthood. After age 30–45, however, the resorption and formation processes become imbalanced, and resorption exceeds formation. This imbalance may begin at different ages and varies at different skeletal sites; it becomes exaggerated in women after menopause. Excessive bone loss can be due to an increase in osteoclastic activity and/or a decrease in osteoblastic activity. In addition, an increase in remodeling activation frequency, and thus the number of remodeling sites, can magnify the small imbalance seen at each remodeling unit. Increased recruitment of bone remodeling sites produces a reversible reduction in bone tissue but also can result in permanent loss of tissue and disrupted skeletal architecture. In trabecular bone, if the osteoclasts penetrate trabeculae, they leave no template for new bone formation to


InternalMed_Harrison

InternalMed_Harrison. but also can result in permanent loss of tissue and disrupted skeletal architecture. In trabecular bone, if the osteoclasts penetrate trabeculae, they leave no template for new bone formation to occur, and, consequently, rapid bone loss ensues and cancellous connectivity becomes impaired. A higher number of remodeling sites increases the likelihood of this event. In cortical bone, increased activation of remodeling creates more porous bone. The effect of this increased porosity on cortical bone strength may be modest if the overall diameter of the bone is not changed. However, decreased apposition of new bone on the periosteal surface coupled with increased endocortical resorption of bone decreases the biomechanical strength of long bones. Even a slight exaggeration in normal bone loss increases the risk of osteoporosis-related fractures because of the architectural changes that occur, and osteoporosis is primarily a disease of disordered skeletal architecture. The main clinically


InternalMed_Harrison

InternalMed_Harrison. increases the risk of osteoporosis-related fractures because of the architectural changes that occur, and osteoporosis is primarily a disease of disordered skeletal architecture. The main clinically available tool (dual-energy x-ray absorptiometry) measures mass not architecture. Emerging data from high-resolution peripheral quantitative computed tomography (CT) scans suggest that aging is associated with


InternalMed_Harrison

InternalMed_Harrison. Source: From the 2014 National Osteoporosis Foundation Clinician’s Guide to the Prevention and changes in microstructure of bone tissue, including increased Treatment of Osteoporosis. © National Osteoporosis Foundation. cortical porosity and reduced cortical thickness.


InternalMed_Harrison

InternalMed_Harrison. cortical porosity and reduced cortical thickness. FIGURE 425-4 Mechanism of bone remodeling. The basic molecular unit (BMU) moves along the trabecular surface at a rate of about 10 μm/d. The figure depicts remodeling over ~120 days. A. Origination of BMU-lining cells contracts to expose collagen and attract preosteoclasts. B. Osteoclasts fuse into multinucleated cells that resorb a cavity. Mononuclear cells continue resorption, and preosteoblasts are stimulated to proliferate. C. Osteoblasts align at bottom of cavity and start forming osteoid (black). D. Osteoblasts continue formation and mineralization. Previous osteoid starts to mineralize (horizontal lines). E. Osteoblasts begin to flatten. F. Osteoblasts turn into lining cells; bone remodeling at initial surface (left of drawing) is now complete, but BMU is still advancing (to the right). (Adapted from SM Ott, in JP Bilezikian et al [eds]: Principles of Bone Biology, vol. 18. San Diego, Academic Press, 1996, pp 231–241.)


InternalMed_Harrison

InternalMed_Harrison. Peak bone mass may be impaired by inadequate calcium intake during growth among other nutritional factors (calories, protein, and other minerals), leading to increased risk of osteoporosis later in life. During the adult phase of life, insufficient calcium intake contributes to relative secondary hyperparathyroidism and an increase in the rate of bone remodeling to maintain normal serum calcium levels. PTH stimulates the hydroxylation of vitamin D in the kidney, leading to increased levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] and enhanced gastrointestinal calcium absorption. PTH also reduces renal calcium loss. Although these are all appropriate compensatory homeostatic responses for adjusting calcium economy, the long-term effects are detrimental to the skeleton because the increased remodeling rates and the ongoing imbalance between resorption and formation at remodel-2491 ing sites combine to accelerate loss of bone tissue.


InternalMed_Harrison

InternalMed_Harrison. Total daily calcium intakes <400 mg are detrimental to the skeleton, and intakes in the range of 600–800 mg, which is about the average intake among adults in the United States, are also probably suboptimal. The recommended daily required intake of 1000–1200 mg for adults accommodates population heterogeneity in controlling calcium balance (Chap. 95e). Such intakes should preferentially come from dietary sources, and supplements should be used only when dietary intakes fall short. The supplement should contain enough calcium to bring total intake to about 1200 mg/d.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 423) Severe vitamin D deficiency causes rickets in children and osteomalacia in adults. However, there is accumulating evidence that vitamin D insufficiency may be more prevalent than previously thought, particularly among individuals at increased risk such as the elderly; those living in northern latitudes; and individuals with poor nutrition, malabsorption, or chronic liver or renal disease. Dark-skinned individuals are also at high risk of vitamin D deficiency. There is controversy regarding optimal levels of serum 25-hydroxyvitamin D [25(OH)D], with some advocating levels >20 ng/mL and others advocating optimal targets >75 nmol/L (30 ng/mL). To achieve this level for most adults requires an intake of 800–1000 units/d, particularly in individuals who avoid sunlight or routinely use ultraviolet-blocking lotions. Vitamin D insufficiency leads to compensatory secondary hyperparathyroidism and is an important risk factor for osteoporosis and fractures. Some studies have


InternalMed_Harrison

InternalMed_Harrison. use ultraviolet-blocking lotions. Vitamin D insufficiency leads to compensatory secondary hyperparathyroidism and is an important risk factor for osteoporosis and fractures. Some studies have shown that >50% of inpatients on a general medical service exhibit biochemical features of vitamin D deficiency, including increased levels of PTH and alkaline phosphatase and lower levels of ionized calcium. In women living in northern latitudes, vitamin D levels decline during the winter months. This is associated with seasonal bone loss, reflecting increased bone turnover. Even among healthy ambulatory individuals, mild vitamin D deficiency is increasing in prevalence, in part due to decreased exposure to sunlight coupled with increased use of potent sunscreens.


InternalMed_Harrison

InternalMed_Harrison. Treatment with vitamin D can return levels to normal and prevent the associated increase in bone remodeling, bone loss, and fractures. Improved muscle function and gait associated with reduced falls and fracture rates also have been documented among individuals in northern latitudes who have greater vitamin D intake and higher 25(OH)D levels (see below). Vitamin D adequacy also may affect risk and/or severity of other diseases, including cancers (colorectal, prostate, and breast), autoimmune diseases, and diabetes; however, many observational studies suggesting these potential extraskeletal benefits have not been confirmed with randomized controlled trials.


InternalMed_Harrison

InternalMed_Harrison. Estrogen deficiency probably causes bone loss by two distinct but interrelated mechanisms: (1) activation of new bone remodeling sites and (2) exaggeration of the imbalance between bone formation and resorption. The change in activation frequency causes a transient bone loss until a new steady state between resorption and formation is achieved. The remodeling imbalance, however, results in a permanent decrement in mass. In addition, the very presence of more remodeling sites in the skeleton increases the probability that trabeculae will be penetrated, eliminating the template on which new bone can be formed and accelerating the loss of bony tissue.


InternalMed_Harrison

InternalMed_Harrison. The most common estrogen-deficient state is the cessation of ovarian function at the time of menopause, which occurs on average at age 51 (Chap. 413). Thus, with current life expectancy, an average woman will spend about 30 years without an ovarian supply of estrogen. The mechanism by which estrogen deficiency causes bone loss is summarized in Fig. 425-5. Marrow cells (macrophages, monocytes, osteoclast precursors, mast cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts) express ERs α and β. Loss of estrogen increases production of RANKL and may reduce production of OPG, increasing osteoclast recruitment. Estrogen also may play an important role in determining the life span of bone cells by controlling the rate of apoptosis. Thus,


InternalMed_Harrison

InternalMed_Harrison. CFU-GM Activated T lymphocytes Activated synovial fibroblasts Activated dendritic cells RANKL RANK OPG Preosteoclast Multinucleated osteoclast Activated osteoclast Bone T Osteoblasts or bone marrow stromal cells Proresorptive and calciotropic factors 1,25(OH)2 vitamin D3. PTH, PTHrP, PGE2, IL-1, IL-6, TNF, prolactin, corticosteroids, oncostatin M, LIF M-CSF AApoptotic osteoclast T Anabolic or anti-resorptive factors Estrogens, calcitonin, BMP 2/4, TGF-˜, TPO, IL-17, PDGF, calcium M-CSF B


InternalMed_Harrison

InternalMed_Harrison. FIGURE 425-5 Hormonal control of bone resorption. A. Proresorptive and calciotropic factors. B. Anabolic and antiosteoclastic factors. RANK ligand (RANKL) expression is induced in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It binds to membrane-bound receptor RANK to promote osteoclast differentiation, activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by factors that block bone catabolism and promote anabolic effects. OPG binds and neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of preexisting osteoclasts. CFU-GM, colony-forming units, granulocyte macrophage; IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; OPG-L, osteoprotegerin-ligand; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor nuclear factor-κB; TGF-β, transforming growth factor β; TNF, tumor


InternalMed_Harrison

InternalMed_Harrison. PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor nuclear factor-κB; TGF-β, transforming growth factor β; TNF, tumor necrosis factor; TPO, thrombospondin. (From WJ Boyle et al: Nature 423: 337, 2003.) in situations of estrogen deprivation, the life span of osteoblasts may be decreased, whereas the longevity and activity of osteoclasts are increased. The rate and duration of bone loss after menopause are heterogeneous and unpredictable. Once surfaces are lost in cancellous bone, the rate of bone loss must decline. In cortical bone, loss is slower but continues for a longer time period.


InternalMed_Harrison

InternalMed_Harrison. Because remodeling is initiated at the surface of bone, it follows that trabecular bone—which has a considerably larger surface area (80% of the total) than cortical bone—will be affected preferentially by estrogen deficiency. Fractures occur earliest at sites where trabecular bone contributes most to bone strength; consequently, vertebral fractures are the most common early consequence of estrogen deficiency.


InternalMed_Harrison

InternalMed_Harrison. Inactivity, such as prolonged bed rest or paralysis, results in significant bone loss. Concordantly, athletes have higher bone mass than does the general population. These changes in skeletal mass are most marked when the stimulus begins during growth and before the age of puberty. Adults are less capable than children of increasing bone mass after restoration of physical activity. Epidemiologic data support the beneficial effects on the skeleton of chronic high levels of physical activity. Fracture risk is lower in rural communities and in countries where physical activity is maintained into old age. However, when exercise is initiated during adult life, the effects of moderate exercise on the skeleton are modest, with a bone mass increase of 1–2% in short-term studies of <2 years in duration. It is argued that more active individuals are less likely to fall and are more capable of protecting themselves upon falling, thereby reducing fracture risk.


InternalMed_Harrison

InternalMed_Harrison. Various genetic and acquired diseases are associated with an increase in the risk of osteoporosis (Table 425-1). Mechanisms that contribute to bone loss are unique for each disease and typically result from multiple factors, including nutrition, reduced physical activity levels, and factors that affect rates of bone remodeling. In most, but not all, circumstances the primary diagnosis is made before osteoporosis presents clinically.


InternalMed_Harrison

InternalMed_Harrison. A large number of medications used in clinical practice have potentially detrimental effects on the skeleton (Table 425-1). Glucocorticoids are the most common cause of medication-induced osteoporosis. It is often not possible to determine the extent to which osteoporosis is related to glucocorticoids or to other factors, because treatment is superimposed on the effects of the primary disease, which in itself may be associated with bone loss (e.g., rheumatoid arthritis). Excessive doses of thyroid hormone can accelerate bone remodeling and result in bone loss.


InternalMed_Harrison

InternalMed_Harrison. Other medications have less detrimental effects on the skeleton than pharmacologic doses of glucocorticoids. Anticonvulsants are thought to increase the risk of osteoporosis, although many affected individuals have concomitant insufficiency of 1,25(OH)2D, as some anticonvulsants induce the cytochrome P450 system and vitamin D metabolism. Patients undergoing transplantation are at high risk for rapid bone loss and fracture not only from glucocorticoids but also from treatment with other immunosuppressants such as cyclosporine and tacrolimus (FK506). In addition, these patients often have underlying metabolic abnormalities, such as hepatic or renal failure, that predispose to bone loss.


InternalMed_Harrison

InternalMed_Harrison. Aromatase inhibitors, which potently block the aromatase enzyme that converts androgens and other adrenal precursors to estrogen, reduce circulating postmenopausal estrogen levels dramatically. These agents, which are used in various stages for breast cancer treatment, also have been shown to have a detrimental effect on bone density and risk of fracture. More recently a variety of agents have been implicated in increased bone loss and fractures. These include selective serotonin reuptake inhibitors, proton pump inhibitors, and thiazolidinediones. It is difficult in some cases to separate the risk accrued by the underlying disease from that attributable to the medication. For example, both depression and diabetes are risk factors for fracture by themselves.


InternalMed_Harrison

InternalMed_Harrison. The use of cigarettes over a long period has detrimental effects on bone mass. These effects may be mediated directly by toxic effects on osteoblasts or indirectly by modifying estrogen metabolism. On average, cigarette smokers reach menopause 1–2 years earlier than the general population. Cigarette smoking also produces secondary effects that can modulate skeletal status, including intercurrent respiratory and other illnesses, frailty, decreased exercise, poor nutrition, and the need for additional medications (e.g., glucocorticoids for lung disease).


InternalMed_Harrison

InternalMed_Harrison. Several noninvasive techniques are available for estimating skeletal mass or density. They include dual-energy x-ray absorptiometry (DXA), single-energy x-ray absorptiometry (SXA), quantitative CT, and ultrasound (US). DXA is a highly accurate x-ray technique that has become the standard for measuring bone density. Although it can be used for measurement in any skeletal site, clinical determinations usually are made of the lumbar spine and hip. DXA also can be used to measure body composition. In the DXA technique, two x-ray energies are used to estimate the area of mineralized tissue, and the mineral content is divided by the area, which partially corrects for body size. However, this correction is only partial because DXA is a two-dimensional scanning technique and cannot estimate the depth or posteroanterior length of the bone. Thus, small slim people tend to have lower than average bone mineral density (BMD), a feature that is important in interpreting BMD measurements when


InternalMed_Harrison

InternalMed_Harrison. the depth or posteroanterior length of the bone. Thus, small slim people tend to have lower than average bone mineral density (BMD), a feature that is important in interpreting BMD measurements when performed in young adults, and something that must be taken into account at any age. Bone spurs, which are common in osteoarthritis, tend to falsely increase bone density of the spine and are a particular problem in measuring the spine in older individuals. Because DXA instrumentation is provided by several different manufacturers, the output varies in absolute terms. Consequently, it has become standard practice to relate the results to “normal” values by using T-scores (a T-score of 1 equals 1 SD), which compare individual results to those in a young population that is matched for race and sex. Z-scores (also measured in SD) compare individual results to those of an age-matched population that also is matched for race and sex. Thus, a 60-year-old woman with a Z-score of –1 (1 SD below


InternalMed_Harrison

InternalMed_Harrison. sex. Z-scores (also measured in SD) compare individual results to those of an age-matched population that also is matched for race and sex. Thus, a 60-year-old woman with a Z-score of –1 (1 SD below mean for age) has a T-score of –2.5 (2.5 SD below mean for a young control group) (Fig. 425-6). A T-score below –2.5 in the lumbar spine, femoral neck, or total hip has been defined as a diagnosis of osteoporosis. As noted above, because more than 50% of fractures occur in individuals with low bone mass rather than BMD osteoporosis, attempts are ongoing to redefine the disease as a fracture risk rather than a specific BMD. Consistent with this concept, fractures of the spine and hip that occur in the absence of major trauma would be considered to be sufficient to diagnose osteoporosis, regardless of BMD. Fractures of other sites, such as pelvis, proximal humerus, and wrist, would be tantamount to an osteoporosis diagnosis in the presence of low BMD. CT can also be used to measure the spine


InternalMed_Harrison

InternalMed_Harrison. of BMD. Fractures of other sites, such as pelvis, proximal humerus, and wrist, would be tantamount to an osteoporosis diagnosis in the presence of low BMD. CT can also be used to measure the spine and the


InternalMed_Harrison

InternalMed_Harrison. T-Score = –2.5 Z-Score=-1 FIGURE 425-6 Relationship between Z-scores and T-scores in a 60-year-old woman. BMD, bone mineral density; SD, standard deviation. hip, but is rarely used clinically, in part because of higher radiation 2493 exposure and cost, in addition to a lesser body of data confirming its ability to predict fracture risk, compared with BMD by DXA. High-resolution peripheral CT is used to measure bone in the forearm or tibia as a research tool to noninvasively provide some measure of skeletal architecture. Magnetic resonance imaging (MRI) can also be used in research settings to obtain some architectural information on the forearm and perhaps the hip.


InternalMed_Harrison

InternalMed_Harrison. DXA equipment can also be used to obtain lateral images of the spine, from T4 through L4, a technique called vertebral fracture assessment (VFA). Although not as definitive as radiography, it is a useful screening tool when height loss, back pain, or postural change suggests the presence of an undiagnosed vertebral fracture. Furthermore, because vertebral fractures are so prevalent with advancing age, screening vertebral imaging is recommended in women and men with low bone mass (T-score <1) by age 70 and 80, respectively. US is used to measure bone mass by calculating the attenuation of the signal as it passes through bone or the speed with which it traverses the bone. It is unclear whether US assesses properties of bone other than mass (e.g., quality), but this is a potential advantage of the technique. Because of its relatively low cost and mobility, US is amenable for use as a screening procedure in stores or at health fairs.


InternalMed_Harrison

InternalMed_Harrison. All of these techniques for measuring BMD have been approved by the U.S. Food and Drug Administration (FDA) on the basis of their capacity to predict fracture risk. The hip is the preferred site of measurement in most individuals, because it predicts the risk of hip fracture, the most important consequence of osteoporosis, better than any other bone density measurement site. When hip measurements are performed by DXA, the spine can be measured at the same time. In younger individuals such as perimenopausal or early postmenopausal women, spine measurements may be the most sensitive indicator of bone loss. A risk assessment tool (FRAX) incorporates femoral neck BMD to assess 10-year fracture risk (see below).


InternalMed_Harrison

InternalMed_Harrison. Clinical guidelines have been developed for the use of bone densitometry in clinical practice. The original National Osteoporosis Foundation guidelines recommend bone mass measurements in postmenopausal women, assuming they have one or more risk factors for osteoporosis in addition to age, sex, and estrogen deficiency. The guidelines further recommend that bone mass measurement be considered in all women by age 65, a position ratified by the U.S. Preventive Health Services Task Force. Criteria approved for Medicare reimbursement of BMD are summarized in Table 425-2.


InternalMed_Harrison

InternalMed_Harrison. Most guidelines suggest that patients be considered for treatment when BMD is >2.5 SD below the mean value for young adults (T-score ≤–2.5), in either spine, total hip, or femoral neck. Treatment also should also be considered in postmenopausal women with fracture risk factors even if BMD is not in the osteoporosis range. Risk factors (age, prior fracture, family history of hip fracture, low body weight, cigarette consumption, excessive alcohol use, steroid use, and rheumatoid arthritis) can be combined with BMD to assess the likelihood of a Consider BMD testing in the following individuals: • Women age 65 and older and men age 70 and older, regardless of clinical • Younger postmenopausal women, women in the menopausal transition and men age 50–69 with clinical risk factors for fracture


InternalMed_Harrison

InternalMed_Harrison. Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥5 mg prednisone or equivalent for ≥3 months) associated with low bone mass or bone loss Source: From the 2014 National Osteoporosis Foundation Clinician’s Guide to the Prevention and Treatment of Osteoporosis. © National Osteoporosis Foundation. 2494 fracture over a 5or 10-year period. Treatment threshold depends on cost-effectiveness analyses but probably is ~1% per year of risk in the United States. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: The perimenopausal transition is a good opportunity to initiate a discussion about risk factors for osteoporosis and consideration of indications for a BMD test. A careful history and physical examination should be performed to identify risk factors for osteoporosis. A low Z-score increases the suspicion of a secondary disease. Height loss >2.5–3.8 cm (>1–1.5 in.) is an indication for VFA by DXA or radiography to rule out asymptomatic vertebral fractures, as is the presence of significant kyphosis or back pain, particularly if it began after menopause. In appropriate individuals, screening BMD and screening vertebral imaging should be recommended as above, even in the absence of any specific risk factors (Table 425-3). For patients who present with fractures, it is important to ensure that the fractures are not caused by an underlying malignancy. Usually this is clear on routine radiography, but on occasion, CT, MRI, or radionuclide scans may be necessary.


InternalMed_Harrison

InternalMed_Harrison. There is no established algorithm for the evaluation of women who present with osteoporosis. A general evaluation that includes complete blood count, serum and 24-h urine calcium, renal and hepatic function tests, and a 25(OH)D level is useful for identifying selected secondary causes of low bone mass, particularly for women with fractures or very low Z-scores. An elevated serum calcium level suggests hyperparathyroidism or malignancy, whereas a reduced serum calcium level may reflect malnutrition and osteomalacia. In the presence of hypercalcemia, a serum PTH level differentiates between hyperparathyroidism (PTH↑) and malignancy (PTH↓), and a high PTHrP level can help document the presence of humoral hypercalcemia of malignancy (Chap. 424). A low urine calcium (<50 mg/24 h) suggests osteomalacia, malnutrition, or malabsorption; a high urine calcium (>300 mg/24 h) is indicative of hypercalciuria and must be investigated further. Hypercalciuria occurs primarily in three situations: (1)


InternalMed_Harrison

InternalMed_Harrison. malnutrition, or malabsorption; a high urine calcium (>300 mg/24 h) is indicative of hypercalciuria and must be investigated further. Hypercalciuria occurs primarily in three situations: (1) a renal calcium leak, which is more common in males with osteoporosis; (2) absorptive hypercalciuria, which can be idiopathic or associated with increased 1,25(OH)2D in granulomatous disease; or (3) hematologic malignancies or conditions associated with excessive bone turnover such as Paget’s disease, hyperparathyroidism, and hyperthyroidism. Renal hypercalciuria is treated with thiazide diuretics, which lower urine calcium and help improve calcium economy.


InternalMed_Harrison

InternalMed_Harrison. Individuals who have osteoporosis-related fractures or bone density in the osteoporotic range should have a measurement of serum 25(OH)D level, because the intake of vitamin D required to achieve a target level >20–30 ng/mL is highly variable. Vitamin D levels should be optimized in all individuals being treated for Consider vertebral imaging tests in the following individuals: mineral density (BMD) T-score is –1.0 or below In women age 65–69 and men age 75–79 if BMD T-score is –1.5 or below In postmenopausal women age 50–64 and men age 50–69 with specific risk factors: º Historical height loss of 1.5 in. or more (4 cm) º Prospective height loss of 0.8 in. or more (2 cm) Source: From the 2014 National Osteoporosis Foundation Clinician’s Guide to the Prevention and Treatment of Osteoporosis. © National Osteoporosis Foundation. osteoporosis. Hyperthyroidism should be evaluated by measuring thyroid-stimulating hormone (TSH).


InternalMed_Harrison

InternalMed_Harrison. When there is clinical suspicion of Cushing’s syndrome, urinary free cortisol levels or a fasting serum cortisol should be measured after overnight dexamethasone. When bowel disease, malabsorption, or malnutrition is suspected, serum albumin, cholesterol, and a complete blood count should be checked. Asymptomatic malabsorption may be heralded by anemia (macrocytic—vitamin B12 or folate deficiency; microcytic—iron deficiency) or low serum cholesterol or urinary calcium levels. If these or other features suggest malabsorption, further evaluation is required. Asymptomatic celiac disease with selective malabsorption is being found with increasing frequency; the diagnosis can be made by testing for antigliadin, antiendomysial, or transglutaminase antibodies but may require endoscopic biopsy. A trial of a gluten-free diet can be confirmatory (Chap. 349). When osteoporosis is found associated with symptoms of rash, multiple allergies, diarrhea, or flushing, mastocytosis should be excluded by


InternalMed_Harrison

InternalMed_Harrison. trial of a gluten-free diet can be confirmatory (Chap. 349). When osteoporosis is found associated with symptoms of rash, multiple allergies, diarrhea, or flushing, mastocytosis should be excluded by using 24-h urine histamine collection or serum tryptase.


InternalMed_Harrison

InternalMed_Harrison. Myeloma can masquerade as generalized osteoporosis, although it more commonly presents with bone pain and characteristic “punched-out” lesions on radiography. Serum and urine electrophoresis and or serum free light chains are required to exclude this diagnosis. More commonly, a monoclonal gammopathy of unclear significance (MGUS) is found, and the patient is subsequently monitored to ensure that this is not an incipient myeloma. Approximately 1% of patients with MGUS progress to myeloma each year. A bone marrow biopsy may be required to rule out myeloma (in patients with equivocal electrophoretic results) and also can be used to exclude mastocytosis, leukemia, and other marrow infiltrative disorders such as Gaucher’s disease. MGUS syndromes, although benign, may also be associated with reduced bone mass and elevated bone turnover.


InternalMed_Harrison

InternalMed_Harrison. Tetracycline labeling of the skeleton allows determination of the rate of remodeling as well as evaluation for other metabolic bone diseases. The current use of BMD tests, in combination with hormonal evaluation and biochemical markers of bone remodeling, has largely replaced the clinical use of bone biopsy, although it remains an important tool in clinical research and assessment of mechanism of action of medication for osteoporosis. Several biochemical tests are available that provide an index of the overall rate of bone remodeling (Table 425-4). Biochemical markers usually are characterized as those related primarily to bone formation or bone resorption. These tests measure the overall state of bone remodeling at a single point in time. Clinical use of these tests has been hampered by biologic variability (in part related to circadian rhythm) as well as analytic variability, although the latter is improving. Biochemical markers of bone turnover may: