Section 4: Disorders of Bone and Mineral Metabolism

BONE STRUCTURE AND METABOLISM

Bone is a dynamic tissue that is remodeled constantly throughout life. The arrangement of compact and cancellous bone provides strength and density suitable for both mobility and protection. In addition, bone provides a reservoir for calcium, magnesium, phosphorus, sodium, and other ions necessary for homeostatic functions. Bone also hosts and regulates hematopoiesis by providing niches for hematopoietic cell proliferation and differentiation. The skeleton is highly vascular and receives about 10% of the cardiac output. Remodeling of bone is accomplished by two distinct cell types: osteoblasts produce bone matrix, and osteoclasts resorb the matrix.

The extracellular components of bone consist of a solid mineral phase in close association with an organic matrix, of which 90–95% is type I collagen (Chap. 427). The noncollagenous portion of the organic matrix is heterogeneous and contains serum proteins such as albumin as well as many locally produced proteins, whose functions are incompletely understood. Those proteins include cell attachment/signaling proteins such as thrombospondin, osteopontin, and fibronectin; calcium-binding proteins such as matrix gla protein and osteocalcin; and proteoglycans such as biglycan and decorin. Some of the proteins organize collagen fibrils; others influence mineralization and binding of the mineral phase to the matrix.

The mineral phase is made up of calcium and phosphate and is best characterized as a poorly crystalline hydroxyapatite. The mineral phase of bone is deposited initially in intimate relation to the collagen fibrils and is found in specific locations in the “holes” between the collagen fibrils. This architectural arrangement of mineral and matrix results in a two-phase material well suited to withstand mechanical stresses. The organization of collagen influences the amount and type of mineral phase formed in bone. Although the primary structures of type I collagen in skin and bone tissues are similar, there are differences in posttranslational modifications and distribution of intermolecular cross-links. The holes in the packing structure of the collagen are larger in mineralized collagen of bone and dentin than in unmineralized collagens such as those in tendon. Single amino acid substitutions in the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chains of type I collagen disrupt the organization of bone in osteogenesis imperfecta. The severe skeletal fragility associated with this group of disorders highlights the importance of the fibrillar matrix in the structure of bone (Chap. 427).

Osteoblasts synthesize and secrete the organic matrix and regulate its mineralization. They are derived from cells of mesenchymal origin (Fig. 423-1A). Active osteoblasts are found on the surface of newly forming bone. As an osteoblast secretes matrix, which then is mineralized, the cell becomes an osteocyte, still connected with its blood supply through a series of canaliculi. Osteocytes account for the vast majority of the cells in bone. They are thought to be the mechanosensors in bone that communicate signals to surface osteoblasts and their progenitors through the canalicular network and thereby serve as master regulators of bone formation and resorption. Remarkably, osteocytes also secrete fibroblast growth factor 23 (FGF23), a major regulator of phosphate metabolism (see below). Mineralization of the matrix, both in trabecular bone and in osteones of compact cortical bone (Haversian systems), begins soon after the matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization). Although this mineralization takes advantage of the high concentrations of calcium and phosphate, already near saturation in serum, mineralization is a carefully regulated process that is dependent on the activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing inhibitors of mineralization.

Genetic studies in humans and mice have identified several key genes that control osteoblast development. Runx2 is a transcription factor expressed specifically in chondrocyte (cartilage cells) and osteoblast progenitors as well as in hypertrophic chondrocytes and mature osteoblasts. Runx2 regulates the expression of several important osteoblast proteins, including osterix (another transcription factor needed for osteoblast maturation), osteopontin, bone sialoprotein, type I collagen, osteocalcin, and receptor-activator of NFκB (RANK) ligand. Runx2 expression is regulated in part by bone morphogenic proteins (BMPs). Runx2-deficient mice are devoid of osteoblasts, whereas mice with a deletion of only one allele (Runx2 +/−) exhibit a delay in formation of the clavicles and some cranial bones. The latter abnormalities are similar to those in the human disorder cleidocranial dysplasia, which is also caused by heterozygous inactivating mutations in Runx2.

The paracrine signaling molecule, Indian hedgehog (Ihh), also plays a critical role in osteoblast development, as evidenced by Ihh-deficient mice that lack osteoblasts in the type of bone formed on a cartilage mold (endochondral ossification). Signals originating from members of the wnt (wingless-type mouse mammary tumor virus integration site) family of paracrine factors are also important for osteoblast proliferation and differentiation. Numerous other growth-regulatory factors affect osteoblast function, including the three closely related transforming growth factor βs, fibroblast growth factors (FGFs) 2 and 18, platelet-derived growth factor, and insulin-like growth factors (IGFs) I and II. Hormones such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25[OH]₂D) activate receptors expressed by osteoblasts to assure mineral homeostasis and influence a variety of bone cell functions.

Resorption of bone is carried out mainly by osteoclasts, multinucleated cells that are formed by fusion of cells derived from the common precursor of macrophages and osteoclasts. Thus, these cells derive from the hematopoietic lineage, quite different from the mesenchymal cells that become osteoblasts. Multiple factors that regulate osteoclast development have been identified (Fig. 423-1B). Factors produced by osteoblasts or marrow stromal cells allow osteoblasts to control osteoclast development and activity. Macrophage colony-stimulating factor (M-CSF) plays a critical role during several steps in the pathway and ultimately leads to fusion of osteoclast progenitor cells to form multinucleated, active osteoclasts. RANK ligand, a member of the tumor necrosis factor (TNF) family, is expressed on the surface of osteoblast progenitors and stromal fibroblasts. In a process involving cell-cell interactions, RANK ligand binds to the RANK receptor on osteoclast progenitors, stimulating osteoclast differentiation and activation. Alternatively, a soluble decoy receptor, referred to as osteoprotegerin, can bind RANK ligand and inhibit osteoclast differentiation. Several growth factors and cytokines (including interleukins 1, 6, and 11; TNF; and interferon γ) modulate osteoclast differentiation and function. Most hormones that influence osteoclast function do not target these cells directly but instead act on cells of the osteoblast lineage to increase production of M-CSF and RANK. Both PTH and 1,25(OH)₂D increase osteoclast number and activity by this indirect mechanism. Calcitonin, in contrast, binds to its receptor on the basal surface of osteoclasts and directly inhibits osteoclast function. Estradiol has multiple cellular targets in bone, including osteoclasts, immune cells, and osteoblasts; actions on all these cells serve to decrease osteoclast number and decrease bone resorption.

Osteoclast-mediated resorption of bone takes place in scalloped spaces (Howship’s lacunae) where the osteoclasts are attached through a specific α_vβ₃ integrin to components of the bone matrix such as osteopontin. The osteoclast forms a tight seal to the underlying matrix and secretes protons, chloride, and proteinases into a confined space that has been likened to an extracellular lysosome. The active osteoclast surface forms a ruffled border that contains a specialized proton pump ATPase that secretes acid and solubilizes the mineral phase. Carbonic anhydrase (type II isoenzyme) within the osteoclast generates the needed protons. The bone matrix is resorbed in the acid environment adjacent to the ruffled border by proteases, such as cathepsin K, that act at low pH.

In the embryo and the growing child, bone develops mostly by remodeling and replacing previously calcified cartilage (endochondral bone formation) or, in a few bones, is formed without a cartilage matrix (intramembranous bone formation). During endochondral bone formation, chondrocytes proliferate, secrete and mineralize a matrix, enlarge (hypertrophy), and then die, enlarging bone and providing the matrix and factors that stimulate endochondral bone formation. This program is regulated by both local factors, such as IGF-I and -II, Ihh, PTH-related peptide (PTHrP), and FGFs, and by systemic hormones, such as growth hormone, glucocorticoids, and estrogen.

New bone, whether formed in infants or in adults during repair, has a relatively high ratio of cells to matrix and is characterized by coarse fiber bundles of collagen that are interlaced and randomly dispersed (woven bone). In adults, the more mature bone is organized with fiber bundles regularly arranged in parallel or concentric sheets (lamellar bone). In long bones, deposition of lamellar bone in a concentric arrangement around blood vessels forms the Haversian systems. Growth in length of bones is dependent on proliferation of cartilage cells and the endochondral sequence at the growth plate. Growth in width and thickness is accomplished by formation of bone at the periosteal surface and by resorption at the endosteal surface, with the rate of formation exceeding that of resorption. In adults, after the growth plates of cartilage close, growth in length and endochondral bone formation cease except for some activity in the cartilage cells beneath the articular surface. Even in adults, however, remodeling of bone (within Haversian systems as well as along the surfaces of trabecular bone) continues throughout life. In adults, ~4% of the surface of trabecular bone (such as iliac crest) is involved in active resorption, whereas 10–15% of trabecular surfaces are covered with osteoid, unmineralized new bone formed by osteoblasts. Radioisotope studies indicate that as much as 18% of the total skeletal calcium is deposited and removed each year. Thus, bone is an active metabolizing tissue that requires an intact blood supply. The cycle of bone resorption and formation is a highly orchestrated process carried out by the basic multicellular unit, which is composed of a group of osteoclasts and osteoblasts (Fig. 423-2).

The response of bone to fractures, infection, and interruption of blood supply and to expanding lesions is relatively limited. Dead bone must be resorbed, and new bone must be formed, a process carried out in association with growth of new blood vessels into the involved area. In injuries that disrupt the organization of the tissue such as a fracture in which apposition of fragments is poor or when motion exists at the fracture site, progenitor stromal cells recapitulate the endochondral bone formation of early development and form cartilage that is replaced by bone and, variably, fibrous tissue. When there is good apposition with fixation and little motion at the fracture site, repair occurs predominantly by formation of new bone without other mediating tissue.

Remodeling of bone occurs along lines of force generated by mechanical stress. The signals from these mechanical stresses are sensed by osteocytes, which transmit signals to osteoclasts and osteoblasts or their precursors. One such signal made by osteocytes is sclerostin, an inhibitor of wnt signaling. Mechanical forces suppress sclerostin production and thus increase bone formation by osteoblasts. Expanding lesions in bone such as tumors induce resorption at the surface in contact with the tumor by producing ligands such as PTHrP that stimulate osteoclast differentiation and function. Even in a disorder as architecturally disruptive as Paget’s disease, remodeling is dictated by mechanical forces. Thus, bone plasticity reflects the interaction of cells with each other and with the environment.

Measurement of the products of osteoblast and osteoclast activity can assist in the diagnosis and management of bone diseases. Osteoblast activity can be assessed by measuring serum bone-specific alkaline phosphatase. Similarly, osteocalcin, a protein secreted from osteoblasts, is made virtually only by osteoblasts. Osteoclast activity can be assessed by measurement of products of collagen degradation. Collagen molecules are covalently linked to each other in the extracellular matrix through the formation of hydroxypyridinium cross-links (Chap. 427). After digestion by osteoclasts, these cross-linked peptides can be measured both in urine and in blood.

CALCIUM METABOLISM

Over 99% of the 1–2 kg of calcium present normally in the adult human body resides in the skeleton, where it provides mechanical stability and serves as a reservoir sometimes needed to maintain extracellular fluid (ECF) calcium concentration (Fig. 423-3). Skeletal calcium accretion first becomes significant during the third trimester of fetal life, accelerates throughout childhood and adolescence, reaches a peak in early adulthood, and gradually declines thereafter at rates that rarely exceed 1–2% per year. These slow changes in total skeletal calcium content contrast with relatively high daily rates of closely matched fluxes of calcium into and out of bone (~250–500 mg each), a process mediated by coupled osteoblastic and osteoclastic activity. Another 0.5–1% of skeletal calcium is freely exchangeable (e.g., in chemical equilibrium) with that in the ECF.

The concentration of ionized calcium in the ECF must be maintained within a narrow range because of the critical role calcium plays in a wide array of cellular functions, especially those involved in neuromuscular activity, secretion, and signal transduction. Intracellular cytosolic free calcium levels are ~100 nmol/L and are 10,000-fold lower than ionized calcium concentrations in the blood and ECF (1.1–1.3 mmol/L). Cytosolic calcium does not play the structural role played by extracellular calcium; instead, it serves a signaling function. The steep chemical gradient of calcium from outside to inside the cell promotes rapid calcium influx through various membrane calcium channels that can be activated by hormones, metabolites, or neurotransmitters, swiftly changing cellular function. In blood, total calcium concentration is normally 2.2–2.6 mM (8.5–10.5 mg/dL), of which ~50% is ionized. The remainder is bound ionically to negatively charged proteins (predominantly albumin and immunoglobulins) or loosely complexed with phosphate, citrate, sulfate, or other anions. Alterations in serum protein concentrations directly affect the total blood calcium concentration even if the ionized calcium concentration remains normal. An algorithm to correct for protein changes adjusts the total serum calcium (in mg/dL) upward by 0.8 times the deficit in serum albumin (g/dL) or by 0.5 times the deficit in serum immunoglobulin (in g/dL). Such corrections provide only rough approximations of actual free calcium concentrations, however, and may be misleading, particularly during acute illness. Acidosis also alters ionized calcium by reducing its association with proteins. The best practice is to measure blood ionized calcium directly by a method that employs calcium-selective electrodes in acute settings during which calcium abnormalities might occur.

Control of the ionized calcium concentration in the ECF ordinarily is accomplished by adjusting the rates of calcium movement across intestinal and renal epithelia. These adjustments are mediated mainly via changes in blood levels of the hormones, PTH and 1,25(OH)₂D. Blood ionized calcium directly suppresses PTH secretion by activating calcium-sensing receptors (CaSRs) in parathyroid cells. Also, ionized calcium indirectly affects PTH secretion by lowering 1,25(OH)₂D production. This active vitamin D metabolite inhibits PTH production by an incompletely understood mechanism of negative feedback (Chap. 424).

Normal dietary calcium intake in the United States varies widely, ranging from 10–37 mmol/d (400–1500 mg/d). An Institute of Medicine report recommends a daily allowance of 25–30 mmol (1000–1200 mg) for most adults. Intestinal absorption of ingested calcium involves both active (transcellular) and passive (paracellular) mechanisms. Passive calcium absorption is nonsaturable and approximates 5% of daily calcium intake, whereas active absorption involves apical calcium entry via specific ion channels (TRPV5 and TRPV6), whose expression is controlled principally by 1,25(OH)₂D, and normally ranges from 20 to 70%. Active calcium transport occurs mainly in the proximal small bowel (duodenum and proximal jejunum), although some active calcium absorption occurs in most segments of the small intestine. Optimal rates of calcium absorption require gastric acid. This is especially true for weakly dissociable calcium supplements such as calcium carbonate. In fact, large boluses of calcium carbonate are poorly absorbed because of their neutralizing effect on gastric acid. In achlorhydric subjects and for those taking drugs that inhibit gastric acid secretion, supplements should be taken with meals to optimize their absorption. Use of calcium citrate may be preferable in these circumstances. Calcium absorption may also be blunted in disease states such as pancreatic or biliary insufficiency, in which ingested calcium remains bound to unabsorbed fatty acids or other food constituents. At high levels of calcium intake, synthesis of 1,25(OH)₂D is reduced; this decreases the rate of active intestinal calcium absorption. The opposite occurs with dietary calcium restriction. Some calcium, ~2.5–5 mmol/d (100–200 mg/d), is excreted as an obligate component of intestinal secretions and is not regulated by calciotropic hormones.

The feedback-controlled hormonal regulation of intestinal absorptive efficiency results in a relatively constant daily net calcium absorption of ~5–7.5 mmol/d (200–400 mg/d) despite large changes in daily dietary calcium intake. This daily load of absorbed calcium is excreted by the kidneys in a manner that is also tightly regulated by the concentration of ionized calcium in the blood. Approximately 8–10 g/d of calcium is filtered by the glomeruli, of which only 2–3% appears in the urine. Most filtered calcium (65%) is reabsorbed in the proximal tubules via a passive, paracellular route that is coupled to concomitant NaCl reabsorption and not specifically regulated. The cortical thick ascending limb of Henle’s loop (cTAL) reabsorbs roughly another 20% of filtered calcium, also via a paracellular mechanism. Calcium reabsorption in the cTAL requires a tight-junctional protein called paracellin-1 and is inhibited by increased blood concentrations of calcium or magnesium, acting via the CaSR, which is highly expressed on basolateral membranes in this nephron segment. Operation of the renal CaSR provides a mechanism, independent of those engaged directly by PTH or 1,25(OH)₂D, by which serum ionized calcium can control renal calcium reabsorption. Finally, ~10% of filtered calcium is reabsorbed in the distal convoluted tubules (DCTs) by a transcellular mechanism. Calcium enters the luminal surface of the cell through specific apical calcium channels (TRPV5), whose number is regulated. It then moves across the cell in association with a specific calcium-binding protein (calbindin-D28k) that buffers cytosolic calcium concentrations from the large mass of transported calcium. Ca²⁺-ATPases and Na⁺/Ca²⁺ exchangers actively extrude calcium across the basolateral surface and thereby maintain the transcellular calcium gradient. All these processes are stimulated directly or indirectly by PTH. The DCT is also the site of action of thiazide diuretics, which lower urinary calcium excretion by inducing sodium depletion and thereby augmenting proximal calcium reabsorption. Conversely, dietary sodium loads, or increased distal sodium delivery caused by loop diuretics or saline infusion, induce calciuresis.

The homeostatic mechanisms that normally maintain a constant serum ionized calcium concentration may fail at extremes of calcium intake or when the hormonal systems or organs involved are compromised. Thus, even with maximal activity of the vitamin D–dependent intestinal active transport system, sustained calcium intakes <5 mmol/d (<200 mg/d) cannot provide enough net calcium absorption to replace obligate losses via the intestine, the kidney, sweat, and other secretions. In this case, increased blood levels of PTH and 1,25(OH)₂D activate osteoclastic bone resorption to obtain needed calcium from bone, which leads to progressive bone loss and negative calcium balance. Increased PTH and 1,25(OH)₂D also enhance renal calcium reabsorption, and 1,25(OH)₂D enhances calcium absorption in the gut. At very high calcium intakes (>100 mmol/d [>4 g/d]), passive intestinal absorption continues to deliver calcium into the ECF despite maximally downregulated intestinal active transport and renal tubular calcium reabsorption. This can cause severe hypercalciuria, nephrocalcinosis, progressive renal failure, and hypercalcemia (e.g., “milk-alkali syndrome”). Deficiency or excess of PTH or vitamin D, intestinal disease, and renal failure represent other commonly encountered challenges to normal calcium homeostasis (Chap. 424).

PHOSPHORUS METABOLISM

Although 85% of the ~600 g of body phosphorus is present in bone mineral, phosphorus is also a major intracellular constituent both as the free anion(s) and as a component of numerous organophosphate compounds, including structural proteins, enzymes, transcription factors, carbohydrate and lipid intermediates, high-energy stores (adenosine triphosphate [ATP], creatine phosphate), and nucleic acids. Unlike calcium, phosphorus exists intracellularly at concentrations close to those present in ECF (e.g., 1–2 mmol/L). In cells and in the ECF, phosphorus exists in several forms, predominantly as H₂PO₄⁻ or NaHPO₄⁻, with perhaps 10% as HPO₄²⁻. This mixture of anions will be referred to here as “phosphate.” In serum, about 12% of phosphorus is bound to proteins. Concentrations of phosphates in blood and ECF generally are expressed in terms of elemental phosphorus, with the normal range in adults being 0.75–1.45 mmol/L (2.5–4.5 mg/dL). Because the volume of the intracellular fluid compartment is twice that of the ECF, measurements of ECF phosphate may not accurately reflect phosphate availability within cells that follows even modest shifts of phosphate from one compartment to the other.

Phosphate is widely available in foods and is absorbed efficiently (65%) by the small intestine even in the absence of vitamin D. However, phosphate absorptive efficiency may be enhanced (to 85–90%) via active transport mechanisms that are stimulated by 1,25(OH)₂D. These mechanisms involve activation of Na⁺/PO₄²⁻ co-transporters that move phosphate into intestinal cells against an unfavorable electrochemical gradient. Daily net intestinal phosphate absorption varies widely with the composition of the diet but is generally in the range of 500–1000 mg/d. Phosphate absorption can be inhibited by large doses of calcium salts or by sevelamer hydrochloride (Renagel), strategies commonly used to control levels of serum phosphate in renal failure. Aluminum hydroxide antacids also reduce phosphate absorption but are used less commonly because of the potential for aluminum toxicity. Low serum phosphate stimulates renal proximal tubular synthesis of 1,25(OH)₂D, perhaps by suppressing blood levels of FGF23 (see below).

Serum phosphate levels vary by as much as 50% on a normal day. This reflects the effect of food intake but also an underlying circadian rhythm that produces a nadir between 7:00 and 10:00 a.m. Carbohydrate administration, especially as IV dextrose solutions in fasting subjects, can decrease serum phosphate by >0.7 mmol/L (2 mg/dL) due to rapid uptake into and utilization by cells. A similar response is observed in the treatment of diabetic ketoacidosis and during metabolic or respiratory alkalosis. Because of this wide variation in serum phosphate, it is best to perform measurements in the basal, fasting state.

Control of serum phosphate is determined mainly by the rate of renal tubular reabsorption of the filtered load, which is ~4–6 g/d. Because intestinal phosphate absorption is highly efficient, urinary excretion is not constant but varies directly with dietary intake. The fractional excretion of phosphate (ratio of phosphate to creatinine clearance) is generally in the range of 10–15%. The proximal tubule is the principal site at which renal phosphate reabsorption is regulated. This is accomplished by changes in the levels of apical expression and activity of specific Na⁺/PO₄²⁻ co-transporters (NaPi-2a and NaPi-2c) in the proximal tubule. Levels of these transporters at the apical surface of these cells are reduced rapidly by PTH, a major hormonal regulator of renal phosphate excretion. FGF23 can impair phosphate reabsorption dramatically by a similar mechanism. Activating FGF23 mutations cause the rare disorder autosomal dominant hypophosphatemic rickets. In contrast to PTH, FGF23 also leads to reduced synthesis of 1,25(OH)₂D, which may worsen the resulting hypophosphatemia by lowering intestinal phosphate absorption. Renal reabsorption of phosphate is responsive to changes in dietary intake such that experimental dietary phosphate restriction leads to a dramatic lowering of urinary phosphate within hours, preceding any decline in serum phosphate (e.g., filtered load). This physiologic renal adaptation to changes in dietary phosphate availability occurs independently of PTH and may be mediated in part by changes in levels of serum FGF23. Findings in FGF23-knockout mice suggest that FGF23 normally acts to lower blood phosphate and 1,25(OH)₂D levels. In turn, elevation of blood phosphate increases blood levels of FGF23.

Renal phosphate reabsorption is impaired by hypocalcemia, hypomagnesemia, and severe hypophosphatemia. Phosphate clearance is enhanced by ECF volume expansion and impaired by dehydration. Phosphate retention is an important pathophysiologic feature of renal insufficiency (Chap. 335).

HYPOPHOSPHATEMIA

Causes

Hypophosphatemia can occur by one or more of three primary mechanisms: (1) inadequate intestinal phosphate absorption, (2) excessive renal phosphate excretion, and (3) rapid redistribution of phosphate from the ECF into bone or soft tissue (Table 423-1). Because phosphate is so abundant in foods, inadequate intestinal absorption is almost never observed now that aluminum hydroxide antacids, which bind phosphate in the gut, are no longer widely used. Fasting or starvation, however, may result in depletion of body phosphate and predispose to subsequent hypophosphatemia during refeeding, especially if this is accomplished with IV glucose alone.

Chronic hypophosphatemia usually signifies a persistent renal tubular phosphate-wasting disorder. Excessive activation of PTH/PTHrP receptors in the proximal tubule as a result of primary or secondary hyperparathyroidism or because of the PTHrP-mediated hypercalcemia syndrome in malignancy (Chap. 424) is among the more common causes of renal hypophosphatemia, especially because of the high prevalence of vitamin D deficiency in older Americans. Familial hypocalciuric hypercalcemia and Jansen’s chondrodystrophy are rare examples of genetic disorders in this category (Chap. 424).

Several genetic and acquired diseases cause PTH/PTHrP-independent tubular phosphate wasting with associated rickets and osteomalacia. All these diseases manifest severe hypophosphatemia; renal phosphate wasting, sometimes accompanied by aminoaciduria; inappropriately low blood levels of 1,25(OH)₂D; low-normal serum levels of calcium; and evidence of impaired cartilage or bone mineralization. Analysis of these diseases led to the discovery of the hormone FGF23, which is an important physiologic regulator of phosphate metabolism. FGF23 decreases phosphate reabsorption in the proximal tubule and also suppresses the 1α-hydroxylase responsible for synthesis of 1,25(OH)₂D. FGF23 is synthesized by cells of the osteoblast lineage, primarily osteocytes. High-phosphate diets increase FGF23 levels, and low-phosphate diets decrease them. Autosomal dominant hypophosphatemic rickets (ADHR) was the first disease linked to abnormalities in FGF23. ADHR results from activating mutations in the gene that encodes FGF23. These mutations alter a cleavage site that ordinarily allows for inactivation of intact FGF23. Several other genetic disorders exhibit elevated FGF23 and hypophosphatemia. The most common of these is X-linked hypophosphatemic rickets (XLH), which results from inactivating mutations in an endopeptidase termed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) that is expressed most abundantly on the surface of osteocytes and mature osteoblasts. Patients with XLH usually have high FGF23 levels, and ablation of the FGF23 gene reverses the hypophosphatemia found in the mouse version of XLH. How inactivation of PHEX leads to increased levels of FGF23 has not been determined. Two rare autosomal recessive hypophosphatemic syndromes associated with elevated FGF23 are due to inactivating mutations of dentin matrix protein-1 (DMP1) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), both of which normally are highly expressed in bone and regulate FGF23 production. An unusual hypophosphatemic disorder, tumor-induced osteomalacia (TIO), is an acquired disorder in which tumors, usually of mesenchymal origin and generally histologically benign, secrete FGF23 and/or other molecules that induce renal phosphate wasting. The hypophosphatemic syndrome resolves completely within hours to days after successful resection of the responsible tumor. Such tumors typically express large amounts of FGF23 mRNA, and patients with TIO usually exhibit elevations of FGF23 in their blood.

Dent’s disease is an X-linked recessive disorder caused by inactivating mutations in CLCN5, a chloride transporter expressed in endosomes of the proximal tubule; features include hypercalciuria, hypophosphatemia, and recurrent kidney stones. Renal phosphate wasting is common among poorly controlled diabetic patients and alcoholics, who therefore are at risk for iatrogenic hypophosphatemia when treated with insulin or IV glucose, respectively. Diuretics and certain other drugs and toxins can cause defective renal tubular phosphate reabsorption (Table 423-1).

In hospitalized patients, hypophosphatemia is often attributable to massive redistribution of phosphate from the ECF into cells. Insulin therapy for diabetic ketoacidosis is a paradigm for this phenomenon, in which the severity of the hypophosphatemia is related to the extent of antecedent depletion of phosphate and other electrolytes (Chap. 417). The hypophosphatemia is usually greatest at a point many hours after initiation of insulin therapy and is difficult to predict from baseline measurements of serum phosphate at the time of presentation, when prerenal azotemia can obscure significant phosphate depletion. Other factors that may contribute to such acute redistributive hypophosphatemia include antecedent starvation or malnutrition, administration of IV glucose without other nutrients, elevated blood catecholamines (endogenous or exogenous), respiratory alkalosis, and recovery from metabolic acidosis.

Hypophosphatemia also can occur transiently (over weeks to months) during the phase of accelerated net bone formation that follows parathyroidectomy for severe primary hyperparathyroidism or during treatment of vitamin D deficiency or lytic Paget’s disease. This is usually most prominent in patients who preoperatively have evidence of high bone turnover (e.g., high serum levels of alkaline phosphatase). Osteoblastic metastases can also lead to this syndrome.

Clinical and Laboratory Findings

The clinical manifestations of severe hypophosphatemia reflect a generalized defect in cellular energy metabolism because of ATP depletion, a shift from oxidative phosphorylation toward glycolysis, and associated tissue or organ dysfunction. Acute, severe hypophosphatemia occurs mainly or exclusively in hospitalized patients with underlying serious medical or surgical illness and preexisting phosphate depletion due to excessive urinary losses, severe malabsorption, or malnutrition. Chronic hypophosphatemia tends to be less severe, with a clinical presentation dominated by musculoskeletal complaints such as bone pain, osteomalacia, pseudofractures, and proximal muscle weakness or, in children, rickets and short stature.

Neuromuscular manifestations of severe hypophosphatemia are variable but may include muscle weakness, lethargy, confusion, disorientation, hallucinations, dysarthria, dysphagia, oculomotor palsies, anisocoria, nystagmus, ataxia, cerebellar tremor, ballismus, hyporeflexia, impaired sphincter control, distal sensory deficits, paresthesia, hyperesthesia, generalized or Guillain-Barré–like ascending paralysis, seizures, coma, and even death. Serious sequelae such as paralysis, confusion, and seizures are likely only at phosphate concentrations <0.25 mmol/L (<0.8 mg/dL). Rhabdomyolysis may develop during rapidly progressive hypophosphatemia. The diagnosis of hypophosphatemia-induced rhabdomyolysis may be overlooked, as up to 30% of patients with acute hypophosphatemia (<0.7 mM) have creatine phosphokinase elevations that peak 1–2 days after the nadir in serum phosphate, when the release of phosphate from injured myocytes may have led to a near normalization of circulating levels of phosphate.

Respiratory failure and cardiac dysfunction, which are reversible with phosphate treatment, may occur at serum phosphate levels of 0.5–0.8 mmol/L (1.5–2.5 mg/dL). Renal tubular defects, including tubular acidosis, glycosuria, and impaired reabsorption of sodium and calcium, may occur. Hematologic abnormalities correlate with reductions in intracellular ATP and 2,3-diphosphoglycerate and may include erythrocyte microspherocytosis and hemolysis; impaired oxyhemoglobin dissociation; defective leukocyte chemotaxis, phagocytosis, and bacterial killing; and platelet dysfunction with spontaneous gastrointestinal hemorrhage.

TREATMENT

HYPERPHOSPHATEMIA

Causes

When the filtered load of phosphate and glomerular filtration rate (GFR) are normal, control of serum phosphate levels is achieved by adjusting the rate at which phosphate is reabsorbed by the proximal tubular NaPi-2 co-transporters. The principal hormonal regulators of NaPi-2 activity are PTH and FGF23. Hyperphosphatemia, defined in adults as a fasting serum phosphate concentration >1.8 mmol/L (5.5 mg/dL), usually results from impaired glomerular filtration, hypoparathyroidism, excessive delivery of phosphate into the ECF (from bone, gut, or parenteral phosphate therapy), or a combination of these factors (Table 423-3). The upper limit of normal serum phosphate concentrations is higher in children and neonates (2.4 mmol/L [7 mg/dL]). It is useful to distinguish hyperphosphatemia caused by impaired renal phosphate excretion from that which results from excessive delivery of phosphate into the ECF (Table 423-3).

In chronic renal insufficiency, reduced GFR leads to phosphate retention. Hyperphosphatemia in turn further impairs renal synthesis of 1,25(OH)₂D, increases FGF23 levels, and stimulates PTH secretion and hypertrophy both directly and indirectly (by lowering blood ionized calcium levels). Thus, hyperphosphatemia is a major cause of the secondary hyperparathyroidism of renal failure and must be addressed early in the course of the disease (Chaps. 335 and 424).

Hypoparathyroidism leads to hyperphosphatemia via increased expression of NaPi-2 co-transporters in the proximal tubule. Hypoparathyroidism, or parathyroid suppression, has multiple potential causes, including autoimmune disease; developmental, surgical, or radiation-induced absence of functional parathyroid tissue; vitamin D intoxication or other causes of PTH-independent hypercalcemia; cellular PTH resistance (pseudohypoparathyroidism or hypomagnesemia); infiltrative disorders such as Wilson’s disease and hemochromatosis; and impaired PTH secretion caused by hypermagnesemia, severe hypomagnesemia, or activating mutations in the CaSR. Hypocalcemia may also contribute directly to impaired phosphate clearance, as calcium infusion can induce phosphaturia in hypoparathyroid subjects. Increased tubular phosphate reabsorption also occurs in acromegaly, during heparin administration, and in tumoral calcinosis. Tumoral calcinosis is caused by a rare group of genetic disorders in which FGF23 is processed in a way that leads to low levels of active FGF23 in the bloodstream. This may result from mutations in the FGF23 sequence or via inactivating mutations in the GALNT3 gene, which encodes a galactosaminyl transferase that normally adds sugar residues to FGF23 that slow its proteolysis. A similar syndrome results from FGF23 resistance due to inactivating mutations of the FGF23 co-receptor Klotho. These abnormalities cause elevated serum 1,25(OH)₂D, parathyroid suppression, increased intestinal calcium absorption, and focal hyperostosis with large, lobulated periarticular heterotopic ossifications (especially at shoulders or hips) and are accompanied by hyperphosphatemia. In some forms of tumoral calcinosis, serum phosphorus levels are normal.

When large amounts of phosphate are delivered rapidly into the ECF, hyperphosphatemia can occur despite normal renal function. Examples include overzealous IV phosphate therapy, oral or rectal administration of large amounts of phosphate-containing laxatives or enemas (especially in children), extensive soft tissue injury or necrosis (crush injuries, rhabdomyolysis, hyperthermia, fulminant hepatitis, cytotoxic chemotherapy), extensive hemolytic anemia, and transcellular phosphate shifts induced by severe metabolic or respiratory acidosis.

Clinical Findings

The clinical consequences of acute, severe hyperphosphatemia are due mainly to the formation of widespread calcium phosphate precipitates and resulting hypocalcemia. Thus, tetany, seizures, accelerated nephrocalcinosis (with renal failure, hyperkalemia, hyperuricemia, and metabolic acidosis), and pulmonary or cardiac calcifications (including development of acute heart block) may occur. The severity of these complications relates to the elevation of serum phosphate levels, which can reach concentrations as high as 7 mmol/L (20 mg/dL) in instances of massive soft tissue injury or tumor lysis syndrome.

TREATMENT

MAGNESIUM METABOLISM

Magnesium is the major intracellular divalent cation. Normal concentrations of extracellular magnesium and calcium are crucial for normal neuromuscular activity. Intracellular magnesium forms a key complex with ATP and is an important cofactor for a wide range of enzymes, transporters, and nucleic acids required for normal cellular function, replication, and energy metabolism. The concentration of magnesium in serum is closely regulated within the range of 0.7–1 mmol/L (1.5–2 meq/L; 1.7–2.4 mg/dL), of which 30% is protein-bound and another 15% is loosely complexed to phosphate and other anions. One-half of the 25 g (1000 mmol) of total body magnesium is located in bone, only one-half of which is insoluble in the mineral phase. Almost all extraskeletal magnesium is present within cells, where the total concentration is 5 mM, 95% of which is bound to proteins and other macromolecules. Because only 1% of body magnesium resides in the ECF, measurements of serum magnesium levels may not accurately reflect the level of total body magnesium stores.

Dietary magnesium content normally ranges from 6 to 15 mmol/d (140–360 mg/d), of which 30–40% is absorbed, mainly in the jejunum and ileum. Intestinal magnesium absorptive efficiency is stimulated by 1,25(OH)₂D and can reach 70% during magnesium deprivation. Urinary magnesium excretion normally matches net intestinal absorption and is ~4 mmol/d (100 mg/d). Regulation of serum magnesium concentrations is achieved mainly by control of renal magnesium reabsorption. Only 20% of filtered magnesium is reabsorbed in the proximal tubule, whereas 60% is reclaimed in the cTAL and another 5–10% in the DCT. Magnesium reabsorption in the cTAL occurs via a paracellular route that requires both a lumen-positive potential, created by NaCl reabsorption, and tight-junction proteins encoded by members of the Claudin gene family. Magnesium reabsorption in the cTAL is increased by PTH but inhibited by hypercalcemia or hypermagnesemia, both of which activate the CaSR in this nephron segment.

HYPOMAGNESEMIA

Causes

Hypomagnesemia usually signifies substantial depletion of body magnesium stores (0.5–1 mmol/kg). Hypomagnesemia can result from intestinal malabsorption; protracted vomiting, diarrhea, or intestinal drainage; defective renal tubular magnesium reabsorption; or rapid shifts of magnesium from the ECF into cells, bone, or third spaces (Table 423-4). Dietary magnesium deficiency is unlikely except possibly in the setting of alcoholism. A rare genetic disorder that causes selective intestinal magnesium malabsorption has been described (primary infantile hypomagnesemia). Another rare inherited disorder (hypomagnesemia with secondary hypocalcemia) is caused by mutations in the gene encoding TRPM6, a protein that, along with TRPM7, forms a channel important for both intestinal and distal-tubular renal transcellular magnesium transport. Malabsorptive states, often compounded by vitamin D deficiency, can critically limit magnesium absorption and produce hypomagnesemia despite the compensatory effects of secondary hyperparathyroidism and of hypocalcemia and hypomagnesemia to enhance cTAL magnesium reabsorption. Diarrhea or surgical drainage fluid may contain ≥5 mmol/L of magnesium. Proton pump inhibitors (omeprazole and others) may produce hypomagnesemia by an unknown mechanism that does not involve renal wasting of magnesium.

Several genetic magnesium-wasting syndromes have been described, including inactivating mutations of genes encoding the DCT NaCl co-transporter (Gitelman’s syndrome), proteins required for cTAL Na-K-2Cl transport (Bartter’s syndrome), claudin 16 or claudin 19 (autosomal recessive renal hypomagnesemia with hypercalciuria), a DCT Na⁺,K⁺-ATPase γ-subunit (autosomal dominant renal hypomagnesemia with hypocalciuria), DCT K⁺ channels (Kv1.1, Kir4.1), and a mitochondrial gene encoding a tRNA. Activating mutations of the CaSR can cause hypomagnesemia as well as hypocalcemia. ECF expansion, hypercalcemia, and severe phosphate depletion may impair magnesium reabsorption, as can various forms of renal injury, including those caused by drugs such as cisplatin, cyclosporine, aminoglycosides, and pentamidine as well as the epidermal growth factor (EGF) receptor inhibitory antibody, cetuximab (EGF action is required for normal DCT apical expression of TRPM6) (Table 423-4). A rising blood concentration of ethanol directly impairs tubular magnesium reabsorption, and persistent glycosuria with osmotic diuresis leads to magnesium wasting and probably contributes to the high frequency of hypomagnesemia in poorly controlled diabetic patients. Magnesium depletion is aggravated by metabolic acidosis, which causes intracellular losses as well.

Hypomagnesemia due to rapid shifts of magnesium from ECF into the intracellular compartment can occur during recovery from diabetic ketoacidosis, starvation, or respiratory acidosis. Less acute shifts may be seen during rapid bone formation after parathyroidectomy, with treatment of vitamin D deficiency, or with osteoblastic metastases. Large amounts of magnesium may be lost with acute pancreatitis, extensive burns, or protracted and severe sweating and during pregnancy and lactation.

Clinical and Laboratory Findings

Hypomagnesemia may cause generalized alterations in neuromuscular function, including tetany, tremor, seizures, muscle weakness, ataxia, nystagmus, vertigo, apathy, depression, irritability, delirium, and psychosis. Patients are usually asymptomatic when serum magnesium concentrations are >0.5 mmol/L (1 meq/L; 1.2 mg/dL), although the severity of symptoms may not correlate with serum magnesium levels. Cardiac arrhythmias may occur, including sinus tachycardia, other supraventricular tachycardias, and ventricular arrhythmias. Electrocardiographic abnormalities may include prolonged PR or QT intervals, T-wave flattening or inversion, and ST straightening. Sensitivity to digitalis toxicity may be enhanced.

Other electrolyte abnormalities often seen with hypomagnesemia, including hypocalcemia (with hypocalciuria) and hypokalemia, may not be easily corrected unless magnesium is administered as well. The hypocalcemia may be a result of concurrent vitamin D deficiency, although hypomagnesemia can cause impaired synthesis of 1,25(OH)₂D, cellular resistance to PTH, and, at very low serum magnesium (<0.4 mmol/L [0.8 meq/L; <1 mg/dL]), a defect in PTH secretion; these abnormalities are reversible with therapy.

TREATMENT

HYPERMAGNESEMIA

Causes

Hypermagnesemia is rarely seen in the absence of renal insufficiency, as normal kidneys can excrete large amounts (250 mmol/d) of magnesium. Mild hypermagnesemia due to excessive reabsorption in the cTAL occurs with CaSR mutations in familial hypocalciuric hypercalcemia and has been described in some patients with adrenal insufficiency, hypothyroidism, or hypothermia. Massive exogenous magnesium exposures, usually via the gastrointestinal tract, can overwhelm renal excretory capacity and cause life-threatening hypermagnesemia (Table 423-5). A notable example of this is prolonged retention of even normal amounts of magnesium-containing cathartics in patients with intestinal ileus, obstruction, or perforation. Extensive soft tissue injury or necrosis can also deliver large amounts of magnesium into the ECF in patients who have suffered trauma, shock, sepsis, cardiac arrest, or severe burns.

Clinical and Laboratory Findings

The most prominent clinical manifestations of hypermagnesemia are vasodilation and neuromuscular blockade, which may appear at serum magnesium concentrations >2 mmol/L (>4 meq/L; >4.8 mg/dL). Hypotension that is refractory to vasopressors or volume expansion may be an early sign. Nausea, lethargy, and weakness may progress to respiratory failure, paralysis, and coma, with hypoactive tendon reflexes, at serum magnesium levels >4 mmol/L. Other findings may include gastrointestinal hypomotility or ileus; facial flushing; pupillary dilation; paradoxical bradycardia; prolongation of PR, QRS, and QT intervals; heart block; and, at serum magnesium levels approaching 10 mmol/L, asystole.

Hypermagnesemia, acting via the CaSR, causes hypocalcemia and hypercalciuria due to both parathyroid suppression and impaired cTAL calcium reabsorption.

TREATMENT

VITAMIN D

SYNTHESIS AND METABOLISM

1,25-Dihydroxyvitamin D (1,25[OH]₂D) is the major steroid hormone involved in mineral ion homeostasis regulation. Vitamin D and its metabolites are hormones and hormone precursors rather than vitamins, since in the proper biologic setting, they can be synthesized endogenously (Fig. 423-4). In response to ultraviolet radiation of the skin, a photochemical cleavage results in the formation of vitamin D from 7-dehydrocholesterol. Cutaneous production of vitamin D is decreased by melanin and high solar protection factor sunblocks, which effectively impair skin penetration by ultraviolet light. The increased use of sunblocks in North America and Western Europe and a reduction in the magnitude of solar exposure of the general population over the last several decades has led to an increased reliance on dietary sources of vitamin D. In the United States and Canada, these sources largely consist of fortified cereals and dairy products, in addition to fish oils and egg yolks. Vitamin D from plant sources is in the form of vitamin D₂, whereas that from animal sources is vitamin D₃. These two forms have equivalent biologic activity and are activated equally well by the vitamin D hydroxylases in humans. Vitamin D enters the circulation, whether absorbed from the intestine or synthesized cutaneously, bound to vitamin D–binding protein, an α-globulin synthesized in the liver. Vitamin D is subsequently 25-hydroxylated in the liver by cytochrome P450–like enzymes in the mitochondria and microsomes. The activity of this hydroxylase is not tightly regulated, and the resultant metabolite, 25-hydroxyvitamin D (25[OH]D), is the major circulating and storage form of vitamin D. Approximately 88% of 25(OH)D circulates bound to the vitamin D–binding protein, 0.03% is free, and the rest circulates bound to albumin. The half-life of 25(OH)D is approximately 2–3 weeks; however, it is shortened dramatically when vitamin D–binding protein levels are reduced, as can occur with increased urinary losses in the nephrotic syndrome.

The second hydroxylation, required for the formation of the mature hormone, occurs in the kidney (Fig. 423-5). The 25-hydroxyvitamin D-1α-hydroxylase is a tightly regulated cytochrome P450–like mixed-function oxidase expressed in the proximal convoluted tubule cells of the kidney. PTH and hypophosphatemia are the major inducers of this microsomal enzyme, whereas calcium, FGF23, and the enzyme’s product, 1,25(OH)₂D, repress it. The 25-hydroxyvitamin D-1α-hydroxylase is also present in epidermal keratinocytes, but keratinocyte production of 1,25(OH)₂D is not thought to contribute to circulating levels of this hormone. In addition to being present in the trophoblastic layer of the placenta, the 1α-hydroxylase is produced by macrophages associated with granulomas and lymphomas. In these latter pathologic states, the activity of the enzyme is induced by interferon γ and TNF-α but is not regulated by calcium or 1,25(OH)₂D; therefore, hypercalcemia, associated with elevated levels of 1,25(OH)₂D, may be observed. Treatment of sarcoidosis-associated hypercalcemia with glucocorticoids, ketoconazole, or chloroquine reduces 1,25(OH)₂D production and effectively lowers serum calcium. In contrast, chloroquine has not been shown to lower the elevated serum 1,25(OH)₂D levels in patients with lymphoma.

The major pathway for inactivation of vitamin D metabolites is an additional hydroxylation step by the vitamin D 24-hydroxylase, an enzyme that is expressed in most tissues. 1,25(OH)₂D is the major inducer of this enzyme; therefore, this hormone promotes its own inactivation, thereby limiting its biologic effects. Mutations of the gene encoding this enzyme (CYP24A1) can lead to infantile hypercalcemia and, in those less severely affected, long-standing hypercalciuria, nephrocalcinosis, and nephrolithiasis.

Polar metabolites of 1,25(OH)₂D are secreted into the bile and reabsorbed via the enterohepatic circulation. Impairment of this recirculation, which is seen with diseases of the terminal ileum, leads to accelerated losses of vitamin D metabolites.

ACTIONS OF 1,25(OH)₂D

1,25(OH)₂D mediates its biologic effects by binding to a member of the nuclear receptor superfamily, the vitamin D receptor (VDR). This receptor belongs to the subfamily that includes the thyroid hormone receptors, the retinoid receptors, and the peroxisome proliferator–activated receptors; however, in contrast to the other members of this subfamily, only one VDR isoform has been isolated. The VDR binds to target DNA sequences as a heterodimer with the retinoid X receptor, recruiting a series of coactivators that modify chromatin and approximate the VDR to the basal transcriptional apparatus, resulting in the induction of target gene expression. The mechanism of transcriptional repression by the VDR varies with different target genes but has been shown to involve either interference with the action of activating transcription factors or the recruitment of novel proteins to the VDR complex, resulting in transcriptional repression.

The affinity of the VDR for 1,25(OH)₂D is approximately three orders of magnitude higher than that for other vitamin D metabolites. In normal physiologic circumstances, these other metabolites are not thought to stimulate receptor-dependent actions. However, in states of vitamin D toxicity, the markedly elevated levels of 25(OH)D may lead to hypercalcemia by interacting directly with the VDR and by displacing 1,25(OH)₂D from vitamin D–binding protein, resulting in increased bioavailability of the active hormone.

The VDR is expressed in a wide range of cells and tissues. The molecular actions of 1,25(OH)₂D have been studied most extensively in tissues involved in the regulation of mineral ion homeostasis. This hormone is a major inducer of calbindin 9K, a calcium-binding protein expressed in the intestine, which is thought to play an important role in the active transport of calcium across the enterocyte. The two major calcium transporters expressed by intestinal epithelia, TRPV5 and TRPV6 (transient receptor potential vanilloid), are also vitamin D responsive. By inducing the expression of these and other genes in the small intestine, 1,25(OH)₂D increases the efficiency of intestinal calcium absorption, and it also has been shown to have several important actions in the skeleton. The VDR is expressed in osteoblasts and regulates the expression of several genes in this cell. These genes include the bone matrix proteins osteocalcin and osteopontin, which are upregulated by 1,25(OH)₂D, in addition to type I collagen, which is transcriptionally repressed by 1,25(OH)₂D. Both 1,25(OH)₂D and PTH induce the expression of RANK ligand, which promotes osteoclast differentiation and increases osteoclast activity, by binding to RANK on osteoclast progenitors and mature osteoclasts. This is the mechanism by which 1,25(OH)₂D induces bone resorption. However, the skeletal features associated with VDR-knockout mice (rickets, osteomalacia) are largely corrected by increasing calcium and phosphorus intake, underscoring the importance of vitamin D action in the gut.

The VDR is expressed in the parathyroid gland, and 1,25(OH)₂D has been shown to have antiproliferative effects on parathyroid cells and to suppress the transcription of the PTH gene. These effects of 1,25(OH)₂D on the parathyroid gland are an important part of the rationale for current therapies directed at preventing and treating hyperparathyroidism associated with renal insufficiency.

The VDR is also expressed in tissues and organs that do not play a role in mineral ion homeostasis. Notable in this respect is the observation that 1,25(OH)₂D has an antiproliferative effect on several cell types, including keratinocytes, breast cancer cells, and prostate cancer cells. The effects of 1,25(OH)₂D and the VDR on keratinocytes are particularly intriguing. Alopecia is seen in humans and mice with mutant VDRs but is not a feature of vitamin D deficiency; thus, the effects of the VDR on the hair follicle are ligand-independent.

VITAMIN D DEFICIENCY

The mounting concern about the relationship between solar exposure and the development of skin cancer has led to increased reliance on dietary sources of vitamin D. Although the prevalence of vitamin D deficiency varies, the third National Health and Nutrition Examination Survey (NHANES III) revealed that vitamin D deficiency is prevalent throughout the United States. The clinical syndrome of vitamin D deficiency can be a result of deficient production of vitamin D in the skin, lack of dietary intake, accelerated losses of vitamin D, impaired vitamin D activation, or resistance to the biologic effects of 1,25(OH)₂D (Table 423-6). The elderly and nursing home residents are particularly at risk for vitamin D deficiency, since both the efficiency of vitamin D synthesis in the skin and the absorption of vitamin D from the intestine decline with age. Similarly, intestinal malabsorption of dietary fats and short bowel syndrome, including that associated with intestinal bypass surgery, can lead to vitamin D deficiency. This is further exacerbated in the presence of terminal ileal disease, which results in impaired enterohepatic circulation of vitamin D metabolites. In addition to intestinal diseases, accelerated inactivation of vitamin D metabolites can be seen with drugs that induce hepatic cytochrome P450 mixed-function oxidases such as barbiturates, phenytoin, and rifampin. Impaired 25-hydroxylation, associated with severe liver disease or isoniazid, is an uncommon cause of vitamin D deficiency. A mutation in the gene responsible for 25-hydroxylation has been identified in one kindred. Impaired 1α-hydroxylation is prevalent in the population with profound renal dysfunction due to an increase in circulating FGF23 levels and a decrease in functional renal mass. Thus, therapeutic interventions should be considered in patients whose creatinine clearance is <0.5 mL/s (30 mL/min). Mutations in the renal 1α-hydroxylase are the basis for the genetic disorder, pseudovitamin D–deficiency rickets. This autosomal recessive disorder presents with the syndrome of vitamin D deficiency in the first year of life. Patients present with growth retardation, rickets, and hypocalcemic seizures. Serum 1,25(OH)₂D levels are low despite normal 25(OH)D levels and elevated PTH levels. Treatment with vitamin D metabolites that do not require 1α-hydroxylation results in disease remission, although lifelong therapy is required. A second autosomal recessive disorder, hereditary vitamin D–resistant rickets, a consequence of vitamin D receptor mutations, is a greater therapeutic challenge. These patients present in a similar fashion during the first year of life, but alopecia often accompanies the disorder, demonstrating a functional role of the VDR in postnatal hair regeneration. Serum levels of 1,25(OH)₂D are dramatically elevated in these individuals both because of increased production due to stimulation of 1α-hydroxylase activity as a consequence of secondary hyperparathyroidism and because of impaired inactivation, since induction of the 24-hydroxylase by 1,25(OH)₂D requires an intact VDR. Because the receptor mutation results in hormone resistance, daily calcium and phosphorus infusions may be required to bypass the defect in intestinal mineral ion absorption.

Regardless of the cause, the clinical manifestations of vitamin D deficiency are largely a consequence of impaired intestinal calcium absorption. Mild to moderate vitamin D deficiency is asymptomatic, whereas long-standing vitamin D deficiency results in hypocalcemia accompanied by secondary hyperparathyroidism, impaired mineralization of the skeleton (osteopenia on x-ray or decreased bone mineral density), and proximal myopathy. Vitamin D deficiency also has been shown to be associated with an increase in overall mortality, including cardiovascular causes. In the absence of an intercurrent illness, the hypocalcemia associated with long-standing vitamin D deficiency rarely presents with acute symptoms of hypocalcemia such as numbness, tingling, and seizures. However, the concurrent development of hypomagnesemia, which impairs parathyroid function, or the administration of potent bisphosphonates, which impair bone resorption, can lead to acute symptomatic hypocalcemia in vitamin D–deficient individuals.

Rickets and Osteomalacia

In children, before epiphyseal fusion, vitamin D deficiency results in growth retardation associated with an expansion of the growth plate known as rickets. Three layers of chondrocytes are present in the normal growth plate: the reserve zone, the proliferating zone, and the hypertrophic zone. Rickets associated with impaired vitamin D action is characterized by expansion of the hypertrophic chondrocyte layer. The proliferation and differentiation of the chondrocytes in the rachitic growth plate are normal, and the expansion of the growth plate is a consequence of impaired apoptosis of the late hypertrophic chondrocytes, an event that precedes replacement of these cells by osteoblasts during endochondral bone formation. Investigations in murine models demonstrate that hypophosphatemia, which in vitamin D deficiency is a consequence of secondary hyperparathyroidism, is a key etiologic factor in the development of the rachitic growth plate.

The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia. Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment.

Although vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone. Calcium deficiency without vitamin D deficiency, the disorders of vitamin D metabolism previously discussed, and hypophosphatemia can all lead to inefficient mineralization. Even in the presence of normal calcium and phosphate levels, chronic acidosis and drugs such as bisphosphonates can lead to osteomalacia. The inorganic calcium/phosphate mineral phase of bone cannot form at low pH, and bisphosphonates bind to and prevent mineral crystal growth. Because alkaline phosphatase is necessary for normal mineral deposition, probably because the enzyme can hydrolyze inhibitors of mineralization such as inorganic pyrophosphate, genetic inactivation of the alkaline phosphatase gene (hereditary hypophosphatasia) also can lead to osteomalacia in the setting of normal calcium and phosphate levels.

Diagnosis of Vitamin D Deficiency, Rickets, and Osteomalacia

The most specific screening test for vitamin D deficiency in otherwise healthy individuals is a serum 25(OH)D level. Although the normal ranges vary, levels of 25(OH)D <37 nmol/L (<15 ng/mL) are associated with increasing PTH levels and lower bone density. The Institute of Medicine has defined vitamin D sufficiency as a vitamin D level >50 nmol/L (>20 ng/mL), although higher levels may be required to optimize intestinal calcium absorption in the elderly and those with underlying disease states. Vitamin D deficiency leads to impaired intestinal absorption of calcium, resulting in decreased serum total and ionized calcium values. This hypocalcemia results in secondary hyperparathyroidism, a homeostatic response that initially maintains serum calcium levels at the expense of the skeleton. Due to the PTH-induced increase in bone turnover, alkaline phosphatase levels are often increased. In addition to increasing bone resorption, PTH decreases urinary calcium excretion while promoting phosphaturia. This results in hypophosphatemia, which exacerbates the mineralization defect in the skeleton. With prolonged vitamin D deficiency resulting in osteomalacia, calcium stores in the skeleton become relatively inaccessible, since osteoclasts cannot resorb unmineralized osteoid, and frank hypocalcemia ensues. Because PTH is a major stimulus for the renal 25(OH)D 1α-hydroxylase, there is increased synthesis of the active hormone, 1,25(OH)₂D. Paradoxically, levels of this hormone are often normal in severe vitamin D deficiency. Therefore, measurements of 1,25(OH)₂D are not accurate reflections of vitamin D stores and should not be used to diagnose vitamin D deficiency in patients with normal renal function.

Radiologic features of vitamin D deficiency in children include a widened, expanded growth plate that is characteristic of rickets. These findings not only are apparent in the long bones but also are present at the costochondral junction, where the expansion of the growth plate leads to swellings known as the “rachitic rosary.” Impairment of intramembranous bone mineralization leads to delayed fusion of the calvarial sutures and a decrease in the radiopacity of cortical bone in the long bones. If vitamin D deficiency occurs after epiphyseal fusion, the main radiologic finding is a decrease in cortical thickness and relative radiolucency of the skeleton. A specific radiologic feature of osteomalacia, whether associated with phosphate wasting or vitamin D deficiency, is pseudofractures, or Looser’s zones. These are radiolucent lines that occur where large arteries are in contact with the underlying skeletal elements; it is thought that the arterial pulsations lead to the radiolucencies. As a result, these pseudofractures are usually a few millimeters wide, are several centimeters long, and are seen particularly in the scapula, the pelvis, and the femoral neck.

TREATMENT

INTRODUCTION

The four parathyroid glands are located posterior to the thyroid gland. They produce parathyroid hormone (PTH), which is the primary regulator of calcium physiology. PTH acts directly on bone, where it induces calcium release; on the kidney, where it enhances calcium reabsorption in the distal tubules; and in the proximal renal tubules, where it synthesizes 1,25-dihydroxyvitamin D (1,25[OH]₂D), a hormone that increases gastrointestinal calcium absorption. Serum PTH levels are tightly regulated by a negative feedback loop. Calcium, acting through the calcium-sensing receptor, and vitamin D, acting through its nuclear receptor, reduce PTH release and synthesis. Additional evidence indicates that fibroblast growth factor 23 (FGF23), a phosphaturic hormone, can suppress PTH secretion. Understanding the hormonal pathways that regulate calcium levels and bone metabolism is essential for effective diagnosis and management of a wide array of hyper- and hypocalcemic disorders.

Hyperparathyroidism, characterized by excess production of PTH, is a common cause of hypercalcemia and is usually the result of autonomously functioning adenomas or hyperplasia. Surgery for this disorder is highly effective and has been shown to reverse some of the deleterious effects of long-standing PTH excess on bone density. Humoral hypercalcemia of malignancy is also common and is usually due to the overproduction of parathyroid hormone–related peptide (PTHrP) by cancer cells. The similarities in the biochemical characteristics of hyperparathyroidism and humoral hypercalcemia of malignancy, first noted by Albright in 1941, are now known to reflect the actions of PTH and PTHrP through the same G protein–coupled PTH/PTHrP receptor.

The genetic basis of multiple endocrine neoplasia (MEN) types 1 and 2, familial hypocalciuric hypercalcemia (FHH), different forms of pseudohypoparathyroidism, Jansen’s syndrome, disorders of vitamin D synthesis and action, and the molecular events associated with parathyroid gland neoplasia have provided new insights into the regulation of calcium homeostasis. PTH and possibly some of its analogues are promising therapeutic agents for the treatment of postmenopausal or senile osteoporosis, and calcimimetic agents, which activate the calcium-sensing receptor, have provided new approaches for PTH suppression.

PARATHYROID HORMONE

PHYSIOLOGY

The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. The hormone acts directly on bone and kidney and indirectly on the intestine through its effects on synthesis of 1,25(OH)₂D to increase serum ­calcium concentrations; in turn, PTH production is closely regulated by the concentration of serum ionized calcium. This feedback system is the critical homeostatic mechanism for maintenance of ECF calcium. Any tendency toward hypocalcemia, as might be induced by calcium- or vitamin D–deficient diets, is counteracted by an increased secretion of PTH. This in turn (1) increases the rate of dissolution of bone mineral, thereby increasing the flow of calcium from bone into blood; (2) reduces the renal clearance of calcium, returning more of the calcium and phosphate filtered at the glomerulus into ECF; and (3) increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH)₂D. Immediate control of blood calcium is due to PTH effects on bone and, to a lesser extent, on renal calcium clearance. Maintenance of steady-state calcium balance, on the other hand, probably results from the effects of 1,25(OH)₂D on calcium absorption (Chap. 423). The renal actions of the hormone are exerted at multiple sites and include inhibition of phosphate transport (proximal tubule), augmentation of calcium reabsorption (distal tubule), and stimulation of the renal 25(OH)D-1α-hydroxylase. As much as 12 mmol (500 mg) of calcium is transferred between the ECF and bone each day (a large amount in relation to the total ECF calcium pool), and PTH has a major effect on this transfer. The homeostatic role of the hormone can preserve calcium concentration in blood at the cost of bone demineralization.

PTH has multiple actions on bone, some direct and some indirect. PTH-mediated changes in bone calcium release can be seen within minutes. The chronic effects of PTH are to increase the number of bone cells, both osteoblasts and osteoclasts, and to increase the remodeling of bone; these effects are apparent within hours after the hormone is given and persist for hours after PTH is withdrawn. Continuous exposure to elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast-mediated bone resorption. However, the intermittent administration of PTH, elevating hormone levels for 1–2 h each day, leads to a net stimulation of bone formation rather than bone breakdown. Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. PTH (1–34) as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.

Osteoblasts (or stromal cell precursors), which have PTH/PTHrP receptors, are crucial to this bone-forming effect of PTH; osteoclasts, which mediate bone breakdown, lack such receptors. PTH-mediated stimulation of osteoclasts is indirect, acting in part through cytokines released from osteoblasts to activate osteoclasts; in experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone (Chap. 423).

STRUCTURE

PTH is an 84-amino-acid single-chain peptide. The amino-terminal portion, PTH (1–34), is highly conserved and is critical for the biologic actions of the molecule. Modified synthetic fragments of the amino-terminal sequence as small as PTH (1–11) are sufficient to activate the PTH/PTHrP receptor (see below). The carboxyl-terminal region of the full-length PTH (1–84) molecule also can bind to a separate binding protein/receptor (cPTH-R), but this receptor has been incompletely characterized. Fragments shortened at the amino-terminus possibly by binding to cPTH-R can reduce, directly or indirectly, some of the biologic actions of full-length PTH (1–84) and of PTH (1–34).

BIOSYNTHESIS, SECRETION, AND METABOLISM

Synthesis

Parathyroid cells have multiple methods of adapting to increased needs for PTH production. Most rapid (within minutes) is secretion of preformed hormone in response to hypocalcemia. Second, within hours, PTH mRNA expression is induced by sustained hypocalcemia. Finally, protracted challenge leads within days to cellular replication to increase parathyroid gland mass.

PTH is initially synthesized as a larger molecule (preproparathyroid hormone, consisting of 115 amino acids). After a first cleavage step to remove the “pre” sequence of 25 amino acid residues, a second cleavage step removes the “pro” sequence of 6 amino acid residues before secretion of the mature peptide comprising 84 residues. Mutations in the preprotein region of the gene can cause hypoparathyroidism by interfering with hormone synthesis, transport, or secretion.

Transcriptional suppression of the PTH gene by calcium is nearly maximal at physiologic calcium concentrations. Hypocalcemia increases transcriptional activity within hours. 1,25(OH)₂D strongly suppresses PTH gene transcription. In patients with renal failure, IV administration of supraphysiologic levels of 1,25(OH)₂D or analogues of this active metabolite can dramatically suppress PTH overproduction, which is sometimes difficult to control due to severe secondary hyperparathyroidism. Regulation of proteolytic destruction of preformed hormone (posttranslational regulation of hormone production) is an important mechanism for mediating rapid (within minutes) changes in hormone availability. High calcium increases and low calcium inhibit the proteolytic destruction of stored hormone.

Regulation of PTH Secretion

PTH secretion increases steeply to a maximum value of about five times the basal rate of secretion as the ­calcium concentration falls from normal to the range of 1.9–2.0 mmol/L (7.6–8.0 mg/dL; measured as total calcium). However, the ionized fraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion (see below).

ECF calcium controls PTH secretion by interaction with a calcium-sensing receptor (CaSR), a G protein–coupled receptor (GPCR) for which Ca²⁺ ions act as the primary ligand (see below). This receptor is a member of a distinctive subgroup of the GPCR superfamily that mediates its actions through the alpha-subunits of two related signaling G proteins, namely Gq and G11, and is characterized by a large extracellular domain suitable for “clamping” the small-molecule ligand. Stimulation of the CaSR by high calcium levels suppresses PTH secretion. The CaSR is present in parathyroid glands and the calcitonin-secreting cells of the thyroid (C cells), as well as in multiple other sites, including brain and kidney. Genetic evidence has revealed a key biologic role for the CaSR in parathyroid gland responsiveness to calcium and in renal calcium clearance. Heterozygous loss-of-function mutations in CaSR cause the syndrome of FHH, in which the blood calcium abnormality resembles that observed in hyperparathyroidism but with hypocalciuria; two more recently defined variants of FHH, FHH2 and FHH3, are caused either by heterozygous mutations in G11, one of the signaling proteins downstream of the CaSR, or by heterozygous mutations in AP2S1. Homozygous loss-of-function mutations in the CaSR are the cause of severe neonatal hyperparathyroidism, a disorder that can be lethal if not treated within the first days of life. On the other hand, heterozygous gain-of-function mutations cause a form of hypocalcemia resembling hypoparathyroidism (see below).

Metabolism

The secreted form of PTH is indistinguishable by immunologic criteria and by molecular size from the 84-amino-acid peptide (PTH[1–84]) extracted from glands. However, much of the immunoreactive material found in the circulation is smaller than the extracted or secreted hormone. The principal circulating fragments of immunoreactive hormone lack a portion of the critical amino-terminal sequence required for biologic activity and, hence, are biologically inactive fragments (so-called middle and carboxyl-terminal fragments). Much of the proteolysis of the hormone occurs in the liver and kidney. Peripheral metabolism of PTH does not appear to be regulated by physiologic states (high versus low calcium, etc.); hence, peripheral metabolism of hormone, although responsible for rapid clearance of secreted hormone, appears to be a high-capacity, metabolically invariant catabolic process.

The rate of clearance of the secreted 84-amino-acid peptide from blood is more rapid than the rate of clearance of the biologically inactive fragment(s) corresponding to the middle and carboxyl-terminal regions of PTH. Consequently, the interpretation of results obtained with earlier PTH radioimmunoassays was influenced by the nature of the peptide fragments detected by the antibodies.

Although the problems inherent in PTH measurements have been largely circumvented by use of double-antibody immunometric assays, it is now known that some of these assays detect, besides the intact molecule, large amino-terminally truncated forms of PTH, which are present in normal and uremic individuals in addition to PTH(1–84). The concentration of these fragments relative to that of intact PTH(1–84) is higher with induced hypercalcemia than in eucalcemic or hypocalcemic conditions and is higher in patients with impaired renal function. PTH(7–84) has been identified as a major component of these amino-terminally truncated fragments. Growing evidence suggests that the PTH(7–84) (and probably related amino-terminally truncated fragments) can act, through yet undefined mechanisms, as an inhibitor of PTH action and may be of clinical significance, particularly in patients with chronic kidney disease. In this group of patients, efforts to prevent secondary hyperparathyroidism by a variety of measures (vitamin D analogues, higher calcium intake, higher dialysate calcium, phosphate-lowering strategies, and calcimetic drugs) can lead to oversuppression of the parathyroid glands since some amino-terminally truncated PTH fragments, such as PTH(7–84), react in many immunometric PTH assays (now termed second-generation assays; see below under “Diagnosis”), thus overestimating the levels of biologically active, intact PTH. Such excessive parathyroid gland suppression in chronic kidney disease can lead to adynamic bone disease (see below), which has been associated with further impaired growth in children and increased bone fracture rates in adults, and can furthermore lead to significant hypercalcemia. The measurement of PTH with newer third-generation immunoassays, which use detection antibodies directed against extreme amino-terminal PTH epitopes and thus detect only full-length PTH(1–84), may provide some advantage to prevent bone disease in chronic kidney disease.

PARATHYROID HORMONE–RELATED PROTEIN (PTHrP)

PTHrP is responsible for most instances of humoral hypercalcemia of malignancy (Chap. 121), a syndrome that resembles primary hyperparathyroidism but without elevated PTH levels. Most cell types normally produce PTHrP, including brain, pancreas, heart, lung, mammary tissue, placenta, endothelial cells, and smooth muscle. In fetal animals, PTHrP directs transplacental calcium transfer, and high concentrations of PTHrP are produced in mammary tissue and secreted into milk, but the biologic significance of the very high concentrations of this hormone in breast milk is unknown. PTHrP also plays an essential role in endochondral bone formation and in branching morphogenesis of the breast, and possibly in uterine contraction and other biologic functions.

PTH and PTHrP, although products of different genes, exhibit considerable functional and structural homology (Fig. 424-1) and have evolved from a shared ancestral gene. The structure of the gene encoding human PTHrP, however, is more complex than that of PTH, containing multiple additional exons, which can undergo alternate splicing patterns during formation of the mature mRNA. Protein products of 139, 141, and 173 amino acids are produced, and other molecular forms may result from tissue-specific degradation at accessible internal cleavage sites. The biologic roles of these various molecular species and the nature of the circulating forms of PTHrP are unclear. In fact, it is uncertain whether PTHrP circulates at any significant level in adults. As a paracrine factor, PTHrP may be produced, act, and be destroyed locally within tissues. In adults, PTHrP appears to have little influence on calcium homeostasis, except in disease states, when large tumors, especially of the squamous cell type as well as renal cell carcinomas, lead to massive overproduction of the hormone and hypercalcemia.

PTH AND PTHrP HORMONE ACTION

Both PTH and PTHrP bind to and activate the PTH/PTHrP receptor. The PTH/PTHrP receptor (also known as the PTH-1 receptor, PTH1R) belongs to a subfamily of GPCRs that includes the receptors for calcitonin, glucagon, secretin, vasoactive intestinal peptide, and other peptides. Although both ligands activate the PTH1R, the two peptides induce distinct responses in the receptor, which explains how a single receptor without isoforms can serve two biologic roles. The extracellular regions of the receptor are involved in hormone binding, and the intracellular domains, after hormone activation, bind G protein subunits to transduce hormone signaling into cellular responses through the stimulation of second messenger formation. A second receptor that binds PTH, originally termed the PTH-2 receptor (PTH2R), is primarily expressed in brain, pancreas, and testis. Different mammalian PTH1Rs respond equivalently to PTH and PTHrP, at least when tested with traditional assays, whereas only the human PTH2R responds efficiently to PTH (but not to PTHrP). PTH2Rs from other species show little or no stimulation of second-messenger formation in response to PTH or PTHrP. The endogenous ligand of the PTH2R was shown to be a hypothalamic peptide referred to as tubular infundibular peptide of 39 residues, TIP39, that is distantly related to PTH and PTHrP. The PTH1R and the PTH2R can be traced backward in evolutionary time to fish; in fact, the zebrafish genome contains, in addition to the PTH1R and the PTH2R orthologs, a third receptor, the PTH3R, that is more closely related to the fish PTH1R than to the fish PTH2R. The evolutionary conservation of structure and function suggests important biologic roles for these receptors, even in fish, which lack discrete parathyroid glands but produce two molecules that are closely related to mammalian PTH.

Studies using the cloned PTH1R confirm that it can be coupled to more than one G protein and second-messenger pathway, apparently explaining the multiplicity of pathways stimulated by PTH. Activation of protein kinases (A and C) and calcium transport channels is associated with a variety of hormone-specific tissue responses. These responses include inhibition of phosphate and bicarbonate transport, stimulation of calcium transport, and activation of renal 1α-hydroxylase in the kidney. The responses in bone include effects on collagen synthesis, alkaline phosphatase, ornithine decarboxylase, citrate decarboxylase, and glucose-6-phosphate dehydrogenase activities; phospholipid synthesis; and calcium and phosphate transport. Ultimately, these biochemical events lead to an integrated hormonal response in bone turnover and calcium homeostasis. PTH also activates Na⁺/Ca²⁺ exchangers at renal distal tubular sites and stimulates translocation of preformed calcium transport channels, moving them from the interior to the apical surface to increase tubular uptake of calcium. PTH-dependent stimulation of phosphate excretion (reducing reabsorption—the opposite effect from actions on calcium in the kidney) involves the downregulation of two sodium-dependent phosphate co-transporters, NPT2a and NPT2c, and their expression at the apical membrane, thereby reducing phosphate reabsorption in the proximal renal tubules. Similar mechanisms may be involved in other renal tubular transporters that are influenced by PTH. Recent studies reaffirm the critical linkage of blood phosphate lowering to net calcium entry into blood by PTH action and emphasize the participation of bone cells other than osteoclasts in the rapid calcium-elevating actions of PTH.

PTHrP exerts important developmental influences on fetal bone development and in adult physiology. A homozygous ablation of the gene encoding PTHrP (or disruption of the PTH1R gene) in mice causes a lethal phenotype in which animals are born with pronounced acceleration of chondrocyte maturation that resembles a lethal form of chondrodysplasia in humans that is caused by homozygous or compound heterozygous, inactivating PTH1R mutations (Fig. 424-2). Heterozygous PTH1R mutations in humans furthermore can be a cause of delayed tooth eruption, and mice that are heterozygous for ablation of the PTHrP gene display reduced mineral density consistent with osteoporosis. Experiments with these mouse models point to a hitherto unappreciated role of PTHrP as a paracrine/autocrine factor that modulates bone metabolism in adults as well as during bone development.

CALCITONIN

(See also Chap. 408) Calcitonin is a hypocalcemic peptide hormone that in several mammalian species acts as an indirect antagonist to the calcemic actions of PTH. Calcitonin seems to be of limited physiologic significance in humans, at least with regard to calcium homeostasis. It is of medical significance because of its role as a tumor marker in sporadic and hereditary cases of medullary carcinoma and its medical use as an adjunctive treatment in severe hypercalcemia and in Paget’s disease of bone.

The hypocalcemic activity of calcitonin is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance. These effects are mediated by receptors on osteoclasts and renal tubular cells. Calcitonin exerts additional effects through receptors present in the brain, the gastrointestinal tract, and the immune system. The hormone, for example, exerts analgesic effects directly on cells in the hypothalamus and related structures, possibly by interacting with receptors for related peptide hormones such as calcitonin gene–related peptide (CGRP) or amylin. Both of these ligands have specific high-affinity receptors that share considerable structural similarity with the PTH1R and can also bind to and activate calcitonin receptors. The calcitonin receptor shares considerable structural similarity with the PTH1R.

The thyroid is the major source of the hormone, and the cells involved in calcitonin synthesis arise from neural crest tissue. During embryogenesis, these cells migrate into the ultimobranchial body, derived from the last branchial pouch. In submammalian vertebrates, the ultimobranchial body constitutes a discrete organ, anatomically separate from the thyroid gland; in mammals, the ultimobranchial gland fuses with and is incorporated into the thyroid gland.

The naturally occurring calcitonins consist of a peptide chain of 32 amino acids. There is considerable sequence variability among species. Calcitonin from salmon, which is used therapeutically, is 10–100 times more potent than mammalian forms in lowering serum calcium.

There are two calcitonin genes, α and β; the transcriptional control of these genes is complex. Two different mRNA molecules are transcribed from the α gene; one is translated into the precursor for calcitonin, and the other message is translated into an alternative product, CGRP. CGRP is synthesized wherever the calcitonin mRNA is expressed (e.g., in medullary carcinoma of the thyroid). The β, or CGRP-2, gene is transcribed into the mRNA for CGRP in the central nervous system (CNS); this gene does not produce calcitonin, however. CGRP has cardiovascular actions and may serve as a neurotransmitter or play a developmental role in the CNS.

The circulating level of calcitonin in humans is lower than that in many other species. In humans, even extreme variations in calcitonin production do not change calcium and phosphate metabolism; no definite effects are attributable to calcitonin deficiency (totally thyroidectomized patients receiving only replacement thyroxine) or excess (patients with medullary carcinoma of the thyroid, a calcitonin-secreting tumor) (Chap. 408). Calcitonin has been a useful pharmacologic agent to suppress bone resorption in Paget’s disease (Chap. 426e) and osteoporosis (Chap. 425) and in the treatment of hypercalcemia of malignancy (see below). However, bisphosphonates are usually more effective, and the physiologic role, if any, of calcitonin in humans is uncertain. On the other hand, ablation of the calcitonin gene (combined because of the close proximity with ablation of the CGRP gene) in mice leads to reduced bone mineral density, suggesting that its ­biologic role in mammals is still not fully understood.

HYPERCALCEMIA

(See also Chap. 65) Hypercalcemia can be a manifestation of a serious illness such as malignancy or can be detected coincidentally by laboratory testing in a patient with no obvious illness. The number of patients recognized with asymptomatic hypercalcemia, usually hyperparathyroidism, increased in the late twentieth century.

Whenever hypercalcemia is confirmed, a definitive diagnosis must be established. Although hyperparathyroidism, a frequent cause of asymptomatic hypercalcemia, is a chronic disorder in which manifestations, if any, may be expressed only after months or years, hypercalcemia can also be the earliest manifestation of malignancy, the second most common cause of hypercalcemia in the adult. The causes of hypercalcemia are numerous (Table 424-1), but hyperparathyroidism and cancer account for 90% of all cases.

Before undertaking a diagnostic workup, it is essential to be sure that true hypercalcemia, not a false-positive laboratory test, is present. A false-positive diagnosis of hypercalcemia is usually the result of inadvertent hemoconcentration during blood collection or elevation in serum proteins such as albumin. Hypercalcemia is a chronic problem, and it is cost-effective to obtain several serum calcium measurements; these tests need not be in the fasting state.

Clinical features are helpful in differential diagnosis. Hypercalcemia in an adult who is asymptomatic is usually due to primary hyperparathyroidism. In malignancy-associated hypercalcemia, the disease is usually not occult; rather, symptoms of malignancy bring the patient to the physician, and hypercalcemia is discovered during the evaluation. In such patients, the interval between detection of hypercalcemia and death, especially without vigorous treatment, is often <6 months. Accordingly, if an asymptomatic individual has had hypercalcemia or some manifestation of hypercalcemia such as kidney stones for more than 1 or 2 years, it is unlikely that malignancy is the cause. Nevertheless, differentiating primary hyperparathyroidism from occult malignancy can occasionally be difficult, and careful evaluation is required, particularly when the duration of the hypercalcemia is unknown. Hypercalcemia not due to hyperparathyroidism or malignancy can result from excessive vitamin D action, impaired metabolism of 1,25(OH)2D, high bone turnover from any of several causes, or renal failure (Table 424-1). Dietary history and a history of ingestion of vitamins or drugs are often helpful in diagnosing some of the less frequent causes. Immunometric PTH assays serve as the principal laboratory test in establishing the diagnosis.

Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urine output, a short QT interval in the electrocardiogram, and, in some patients, cardiac arrhythmias. There is a variable relation from one patient to the next between the severity of hypercalcemia and the symptoms. Generally, symptoms are more common at calcium levels >2.9–3.0 mmol/L (11.6–12.0 mg/dL), but some patients, even at this level, are asymptomatic. When the calcium level is >3.2 mmol/L (12.8 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal excretion. Severe hypercalcemia, usually defined as ≥3.7–4.5 mmol/L (14.8–18.0 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.

Acute management of the hypercalcemia is usually successful. The type of treatment is based on the severity of the hypercalcemia and the nature of associated symptoms, as outlined below.

PRIMARY HYPERPARATHYROIDISM

Natural History and Incidence

Primary hyperparathyroidism is a generalized disorder of calcium, phosphate, and bone metabolism due to an increased secretion of PTH. The elevation of circulating hormone usually leads to hypercalcemia and hypophosphatemia. There is great variation in the manifestations. Patients may present with ­multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers, mental changes, and, less frequently, extensive bone resorption. However, with greater awareness of the disease and wider use of multiphasic screening tests, including measurements of blood calcium, the diagnosis is frequently made in patients who have no symptoms and minimal, if any, signs of the disease other than hypercalcemia and elevated levels of PTH. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime. This milder form of the disease is usually termed asymptomatic hyperparathyroidism. Rarely, hyperparathyroidism develops or worsens abruptly and causes severe complications such as marked dehydration and coma, so-called hypercalcemic parathyroid crisis.

The annual incidence of the disease is calculated to be as high as 0.2% in patients >60, with an estimated prevalence, including undiscovered asymptomatic patients, of ≥1%; some reports suggest the incidence may be declining. If confirmed, these changing estimates may reflect less frequent routine testing of serum calcium in recent years, earlier overestimates in incidence, or unknown factors. The disease has a peak incidence between the third and fifth decades but occurs in young children and in the elderly.

Etiology

Parathyroid tumors are most often encountered as isolated adenomas without other endocrinopathy. They may also arise in hereditary syndromes such as MEN syndromes. Parathyroid tumors may also arise as secondary to underlying disease (excessive stimulation in secondary hyperparathyroidism, especially chronic renal failure) or after other forms of excessive stimulation such as lithium therapy. These etiologies are discussed below.

SOLITARY ADENOMAS

A single abnormal gland is the cause in ~80% of patients; the abnormality in the gland is usually a benign neoplasm or adenoma and rarely a parathyroid carcinoma. Some surgeons and pathologists report that the enlargement of multiple glands is common; double adenomas are reported. In ~15% of patients, all glands are hyperfunctioning; chief cell parathyroid hyperplasia is usually hereditary and frequently associated with other endocrine abnormalities.

HEREDITARY SYNDROMES AND MULTIPLE PARATHYROID TUMORS

Hereditary hyperparathyroidism can occur without other endocrine abnormalities but is usually part of a multiple endocrine neoplasia (MEN) syndrome (Chap. 408). MEN 1 (Wermer’s syndrome) consists of hyperparathyroidism and tumors of the pituitary and pancreas, often associated with gastric hypersecretion and peptic ulcer disease (Zollinger-Ellison syndrome). MEN 2A is characterized by pheochromocytoma and medullary carcinoma of the thyroid, as well as hyperparathyroidism; MEN 2B has additional associated features such as multiple neuromas but usually lacks hyperparathyroidism. Each of these MEN syndromes is transmitted in an apparent autosomal dominant manner, although, as noted below, the genetic basis of MEN 1 involves biallelic loss of a tumor suppressor.

The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in families with parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors. This disorder is caused by mutations in CDC73 (HRPT2), and mutations in this gene are also observed in parathyroid cancers. Some kindreds exhibit hereditary hyperparathyroidism without other endocrinopathies. This disorder is often termed nonsyndromic familial isolated hyperparathyroidism (FIHP). There is speculation that these families may be examples of variable expression of the other syndromes such as MEN 1, MEN 2, or the HPT-JT syndrome, but they may also have distinctive, still unidentified genetic causes.

Pathology

Adenomas are most often located in the inferior parathyroid glands, but in 6–10% of patients, parathyroid adenomas may be located in the thymus, the thyroid, the pericardium, or behind the esophagus. Adenomas are usually 0.5–5 g in size but may be as large as 10–20 g (normal glands weigh 25 mg on average). Chief cells are predominant in both hyperplasia and adenoma. With chief cell hyperplasia, the enlargement may be so asymmetric that some involved glands appear grossly normal. If generalized hyperplasia is present, however, histologic examination reveals a uniform pattern of chief cells and disappearance of fat even in the absence of an increase in gland weight. Thus, microscopic examination of biopsy specimens of several glands is essential to interpret findings at surgery.

Parathyroid carcinoma is often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule. Recurrent parathyroid carcinoma is usually slow-growing with local spread in the neck, and surgical correction of recurrent disease may be feasible. Occasionally, however, parathyroid carcinoma is more aggressive, with distant metastases (lung, liver, and bone) found at the time of initial operation. It may be difficult to appreciate initially that a primary tumor is carcinoma; increased numbers of mitotic figures and increased fibrosis of the gland stroma may precede invasion. The diagnosis of carcinoma is often made in retrospect. Hyperparathyroidism from a parathyroid carcinoma may be indistinguishable from other forms of primary hyperparathyroidism but is usually more severe clinically. A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with care to avoid capsular rupture. Recent findings concerning the genetic basis of parathyroid carcinoma (distinct from that of benign adenomas) indicate the need, in these kindreds, for family screening (see below).

GENETIC DEFECTS ASSOCIATED WITH HYPERPARATHYROIDISM

As in many other types of neoplasia, two fundamental types of genetic defects have been identified in parathyroid gland tumors: (1) overactivity of protooncogenes and (2) loss of function of tumor-suppressor genes. The former, by definition, can lead to uncontrolled cellular growth and function by activation (gain-of-function mutation) of a single allele of the responsible gene, whereas the latter requires loss of function of both allelic copies. Biallelic loss of function of a tumor-suppressor gene is usually characterized by a germline defect (all cells) and an additional somatic deletion/mutation in the tumor (Fig. 424-3).

Mutations in the MEN1 gene locus, encoding the protein MENIN, on chromosome 11q13 are responsible for causing MEN 1; the normal allele of this gene fits the definition of a tumor-suppressor gene. Inheritance of one mutated allele in this hereditary syndrome, followed by loss of the other allele via somatic cell mutation, leads to monoclonal expansion and tumor development. Also, in ~15–20% of sporadic parathyroid adenomas, both alleles of the MEN1 locus on chromosome 11 are somatically deleted, implying that the same defect responsible for MEN 1 can also cause the sporadic disease (Fig. 424-3A). Consistent with the Knudson hypothesis for two-step neoplasia in certain inherited cancer syndromes (Chap. 101e), the earlier onset of hyperparathyroidism in the hereditary syndromes reflects the need for only one mutational event to trigger the monoclonal outgrowth. In sporadic adenomas, typically occurring later in life, two different somatic events must occur before the MEN1 gene is silenced.

Other presumptive anti-oncogenes involved in hyperparathyroidism include a still unidentified gene mapped to chromosome 1p seen in 40% of sporadic parathyroid adenomas and a gene mapped to chromosome Xp11 in patients with secondary hyperparathyroidism and renal failure, who progressed to “tertiary” hyperparathyroidism, now known to reflect monoclonal outgrowths within previously hyperplastic glands.

A more complex pattern, still incompletely resolved, arises with genetic defects and carcinoma of the parathyroids. This appears to be due to biallelic loss of a functioning copy of a gene, HRPT2 (or CDC73), originally identified as the cause of the HPT-JT syndrome. Several inactivating mutations have been identified in HRPT2 (located on chromosome 1q21-31), which encodes a 531-amino-acid protein called parafibromin. The responsible genetic mutations in HRPT2 appear to be necessary, but not sufficient, for parathyroid cancer.

In general, the detection of additional genetic defects in these parathyroid tumor–related syndromes and the variations seen in ­phenotypic expression/penetrance indicate the multiplicity of the genetic factors responsible. Nonetheless, the ability to detect the presence of the major genetic contributors has greatly aided a more informed management of family members of patients identified in the hereditary syndromes such as MEN 1, MEN 2, and HPT-JT.

An important contribution from studies on the genetic origin of parathyroid carcinoma has been the realization that the mutations involve a different pathway than that involved with the benign gland enlargements. Unlike the pathogenesis of genetic alterations seen in colon cancer, where lesions evolve from benign adenomas to malignant disease by progressive genetic changes, the alterations commonly seen in most parathyroid cancers (HRPT2 mutations) are infrequently seen in sporadic parathyroid adenomas.

Abnormalities at the Rb gene were the first to be noted in parathyroid cancer. The Rb gene, a tumor-suppressor gene located on chromosome 13q14, was initially associated with retinoblastoma but has since been implicated in other neoplasias, including parathyroid carcinoma. Early studies implicated allelic deletions of the Rb gene in many parathyroid carcinomas and decreased or absent expression of the Rb protein. However, because there are often large deletions in chromosome 13 that include many genes in addition to the Rb locus (with similar findings in some pituitary carcinomas), it remains possible that other tumor-suppressor genes on chromosome 13 may be playing a role in parathyroid carcinoma.

Study of the parathyroid cancers found in some patients with the HPT-JT syndrome has led to identification of a much larger role for mutations in the HRPT2 gene in most parathyroid carcinomas, including those that arise sporadically, without apparent association with the HPT-JT syndrome. Mutations in the coding region have been identified in 75–80% of all parathyroid cancers analyzed, leading to the conclusion that, with addition of presumed mutations in the noncoding regions, this genetic defect may be seen in essentially all parathyroid carcinomas. Of special importance was the discovery that, in some sporadic parathyroid cancers, germline mutations have been found; this, in turn, has led to careful investigation of the families of these patients and a new clinical indication for genetic testing in this setting.

Hypercalcemia occurring in family members (who are also found to have the germline mutations) can lead to the finding, at parathyroid surgery, of premalignant parathyroid tumors.

Overall, it seems there are multiple factors in parathyroid cancer, in addition to the HRPT2 and Rb gene, although the HRPT2 gene mutation is the most invariant abnormality. RET encodes a tyrosine kinase type receptor; specific inherited germline mutations lead to a constitutive activation of the receptor, thereby explaining the autosomal dominant mode of transmission and the relatively early onset of neoplasia. In the MEN 2 syndrome, the RET protooncogene may be responsible for the earliest disorder detected, the polyclonal disorder (C cell hyperplasia, which then is transformed into a clonal outgrowth—a medullary carcinoma with the participation of other, still uncharacterized genetic defects).

In some parathyroid adenomas, activation of a protooncogene has been identified (Fig. 424-3B). A reciprocal translocation involving chromosome 11 has been identified that juxtaposes the PTH gene ­promoter upstream of a gene product termed PRAD-1, encoding a cyclin D protein that plays a key role in normal cell division. This translocation plus other mechanisms that cause an equivalent overexpression of cyclin D1 are found in 20–40% of parathyroid adenomas.

Mouse models have confirmed the role of several of the major identified genetic defects in parathyroid disease and the MEN syndromes. Loss of the MEN1 gene locus or overexpression of the PRAD-1 protooncogene or the mutated RET protooncogene have been analyzed by genetic manipulation in mice, with the expected onset of parathyroid tumors or medullary carcinoma, respectively.

Signs and Symptoms

Many patients with hyperparathyroidism are asymptomatic. Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970. With earlier detection, renal complications occur in <20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients, repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.

The distinctive bone manifestation of hyperparathyroidism is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago. Histologically, the pathognomonic features are an increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship’s lacunae) and a replacement of the normal cellular and marrow elements by fibrous tissue. X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption). In recent years, osteitis fibrosa cystica is very rare in primary hyperparathyroidism, probably due to the earlier detection of the disease.

Dual-energy x-ray absorptiometry (DEXA) of the spine provides reproducible quantitative estimates (within a few percent) of spinal bone density. Similarly, bone density in the extremities can be quantified by densitometry of the hip or of the distal radius at a site chosen to be primarily cortical. Computed tomography (CT) is a very sensitive technique for estimating spinal bone density, but reproducibility of standard CT is no better than 5%. Newer CT techniques (spiral, “extreme” CT) are more reproducible but are currently available in a limited number of medical centers. Cortical bone density is reduced while cancellous bone density, especially in the spine, is relatively preserved. In symptomatic patients, dysfunctions of the CNS, peripheral nerve and muscle, gastrointestinal tract, and joints also occur. It has been reported that severe neuropsychiatric manifestations may be reversed by parathyroidectomy. When present in symptomatic patients, neuromuscular manifestations may include proximal muscle weakness, easy fatigability, and atrophy of muscles and may be so striking as to suggest a primary neuromuscular disorder. The distinguishing feature is the complete regression of neuromuscular disease after surgical correction of the hyperparathyroidism.

Gastrointestinal manifestations are sometimes subtle and include vague abdominal complaints and disorders of the stomach and pancreas. Again, cause and effect are unclear. In MEN 1 patients with hyperparathyroidism, duodenal ulcer may be the result of associated pancreatic tumors that secrete excessive quantities of gastrin (Zollinger-Ellison syndrome). Pancreatitis has been reported in association with hyperparathyroidism, but the incidence and the mechanism are not established.

Much attention has been paid in recent years to the manifestations of and optimum management strategies for asymptomatic hyperparathyroidism. This is now the most prevalent form of the disease. Asymptomatic primary hyperparathyroidism is defined as biochemically confirmed hyperparathyroidism (elevated or inappropriately normal PTH levels despite hypercalcemia) with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such as features of renal or bone disease.

Three conferences on the topic have been held in the United States over the past two decades, with the most recent in 2008. The published proceedings include discussion of more subtle manifestations of disease, its natural history (without parathyroidectomy), and guidelines both for indications for surgery and medical monitoring in nonoperated patients.

Issues of concern include the potential for cardiovascular deterioration, the presence of subtle neuropsychiatric symptoms, and the longer-term status of skeletal integrity in patients not treated surgically. The current consensus is that medical monitoring rather than surgical correction of hyperparathyroidism may be justified in certain patients. The current recommendation is that patients who show mild disease, as defined by specific criteria (Table 424-2), can be safely followed under management guidelines (Table 424-3). There is, however, growing uncertainty about subtle disease manifestations and whether surgery is therefore indicated in most patients. Among the issues is the evidence of eventual (>8 years) deterioration in bone mineral density after a decade of relative stability. There is concern that this late-onset deterioration in bone density in nonoperated patients could contribute significantly to the well-known age-dependent fracture risk (osteoporosis). One study reported significant and sustained improvements in bone mineral density after successful parathyroidectomy, again raising the issue regarding benefits of surgery. Other randomized studies, however, did not report major gains after surgery.

Cardiovascular disease including left ventricular hypertrophy, cardiac functional defects, and endothelial dysfunction have been reported as reversible in European patients with more severe symptomatic disease after surgery, leading to numerous studies of these cardiovascular features in those with milder disease. There are reports of endothelial dysfunction in patients with mild asymptomatic hyperparathyroidism, but the expert panels concluded that more observation is needed, especially regarding whether there is reversibility with surgery.

A topic of considerable interest and some debate is assessment of neuropsychiatric status and health-related quality of life (QOL) status in hyperparathyroid patients both before surgery and in response to parathyroidectomy. Several observational studies suggest considerable improvements in symptom score after surgery. Randomized studies of surgery versus observation, however, have yielded inconclusive results, especially regarding benefits of surgery. Most studies report that hyperparathyroidism is associated with increased neuropsychiatric symptoms, so the issue remains a significant factor in decisions regarding the impact of surgery in this disease.

DIAGNOSIS

The diagnosis is typically made by detecting an elevated immunoreactive PTH level in a patient with asymptomatic hypercalcemia (see “Differential Diagnosis: Special Tests,” below). Serum phosphate is usually low but may be normal, especially if renal failure has developed.

Several modifications in PTH assays have been introduced in efforts to improve their utility in light of information about metabolism of PTH (as discussed above). First-generation assays were based on displacement of radiolabeled PTH from antibodies that reacted with PTH (often also PTH fragments). Double-antibody or immunometric assays (one antibody that is usually directed against the carboxyl-terminal portion of intact PTH to capture the hormone and a second radio- or enzyme-labeled antibody that is usually directed against the amino-terminal portion of intact PTH) greatly improved the diagnostic discrimination of the tests by eliminating interference from circulating biologically inactive fragments, detected by the original first-generation assays. Double-antibody assays are now referred to as second-generation. Such PTH assays have in some centers and testing laboratories been replaced by third-generation assays after it was discovered that large PTH fragments, devoid of only the extreme amino-terminal portion of the PTH molecule, are also present in blood and are detected, incorrectly, as intact PTH. These amino-terminally truncated PTH fragments were prevented from registering in the newer third-generation assays by use of a detection antibody directed against the extreme amino-terminal epitope. These assays may be useful for clinical research studies as in management of chronic renal disease, but the consensus is that either second- or third-generation assays are useful in the diagnosis of primary hyperparathyroidism and for the diagnosis of high-turnover bone disease in chronic kidney disease.

Many tests based on renal responses to excess PTH (renal calcium and phosphate clearance; blood phosphate, chloride, magnesium; urinary or nephrogenous cyclic AMP [cAMP]) were used in earlier decades. These tests have low specificity for hyperparathyroidism and are therefore not cost-effective; they have been replaced by PTH immunometric assays combined with simultaneous blood calcium measurements (Fig. 424-4).

TREATMENT

OTHER PARATHYROID-RELATED CAUSES OF HYPERCALCEMIA

Lithium Therapy

Lithium, used in the management of bipolar depression and other psychiatric disorders, causes hypercalcemia in ~10% of treated patients. The hypercalcemia is dependent on continued lithium treatment, remitting and recurring when lithium is stopped and restarted. The parathyroid adenomas reported in some hypercalcemic patients with lithium therapy may reflect the presence of an independently occurring parathyroid tumor; a permanent effect of lithium on parathyroid gland growth need not be implicated as most patients have complete reversal of hypercalcemia when lithium is stopped. However, long-standing stimulation of parathyroid cell replication by lithium may predispose to development of adenomas (as is documented in secondary hyperparathyroidism and renal failure).

At the levels achieved in blood in treated patients, lithium can be shown in vitro to shift the PTH secretion curve to the right in response to calcium; i.e., higher calcium levels are required to lower PTH secretion, probably acting at the calcium sensor (see below). This effect can cause elevated PTH levels and consequent hypercalcemia in otherwise normal individuals. Fortunately, there are usually alternative medications for the underlying psychiatric illness. Parathyroid surgery should not be recommended unless hypercalcemia and elevated PTH levels persist after lithium is discontinued.

GENETIC DISORDERS CAUSING HYPERPARATHYROID-LIKE SYNDROMES

Familial Hypocalciuric Hypercalcemia

FHH (also called familial benign hypercalcemia) is inherited as an autosomal dominant trait. Affected individuals are discovered because of asymptomatic hypercalcemia. Most cases of FHH (FHH1) are caused by an inactivating mutation in a single allele of the CaSR (see below), leading to inappropriately normal or even increased secretion of PTH, whereas another hypercalcemic disorder, namely the exceedingly rare Jansen’s disease, is caused by a constitutively active PTH/PTHrP receptor in target tissues. Neither FHH1 nor Jansen’s disease, however, is a growth disorder of the parathyroids. Other forms of FHH are caused either by heterozygous mutations in GNA11 (encoding G11), one of the signaling proteins downstream of the CaSR (FHH2), or by mutations in AP2S1 (FHH3).

The pathophysiology of FHH1 is now understood. The primary defect is abnormal sensing of the blood calcium by the parathyroid gland and renal tubule, causing inappropriate secretion of PTH and excessive reabsorption of calcium in the distal renal tubules. The CaSR is a member of the third family of GPCRs (type C or type III). The receptor responds to increased ECF calcium concentration by suppressing PTH secretion through second-messenger signaling involving the G protein alpha-subunits G11 and Gq, thereby providing ­negative-feedback regulation of PTH secretion. Many different inactivating CaSR mutations have been identified in patients with FHH1. These mutations lower the capacity of the sensor to bind calcium, and the mutant receptors function as though blood calcium levels were low; excessive secretion of PTH occurs from an otherwise normal gland. Approximately two-thirds of patients with FHH have mutations within the protein-coding region of the CaSR gene. The remaining one-third of kindreds may have mutations in the promoter of the CaSR gene or are caused by mutations in other genes.

Even before elucidation of the pathophysiology of FHH, abundant clinical evidence served to separate the disorder from primary hyperparathyroidism; these clinical features are still useful in differential diagnosis. Patients with primary hyperparathyroidism have <99% renal calcium reabsorption, whereas most patients with FHH have >99% reabsorption. The hypercalcemia in FHH is often detectable in affected members of the kindreds in the first decade of life, whereas hypercalcemia rarely occurs in patients with primary hyperparathyroidism or the MEN syndromes who are age <10 years. PTH may be elevated in the different forms of FHH, but the values are usually normal or lower for the same degree of calcium elevation than is observed in patients with primary hyperparathyroidism. Parathyroid surgery performed in a few patients with FHH before the nature of the syndrome was understood led to permanent hypoparathyroidism; nevertheless, hypocalciuria persisted, establishing that hypocalciuria is not PTH-dependent (now known to be due to the abnormal CaSR in the kidney).

Few clinical signs or symptoms are present in patients with FHH, whereas other endocrine abnormalities are not. Most patients are detected as a result of family screening after hypercalcemia is detected in a proband. In those patients inadvertently operated upon for primary hyperparathyroidism, the parathyroids appeared normal or moderately hyperplastic. Parathyroid surgery is not appropriate, nor, in view of the lack of symptoms, does medical treatment seem needed to lower the calcium. One striking exception to the rule against parathyroid surgery in this syndrome is the occurrence, usually in consanguineous marriages (due to the rarity of the gene mutation), of a homozygous or compound heterozygote state, resulting in severe impairment of CaSR function. In this condition, neonatal severe hypercalcemia, total parathyroidectomy is mandatory, but calcimetics have been used as a temporary measure. Rare but well-documented cases of acquired hypocalciuric hypercalcemia are reported due to antibodies against the CaSR. They appear to be a complication of an underlying autoimmune disorder and respond to therapies directed against the underlying disorder.

Jansen’s Disease

Activating mutations in the PTH/PTHrP receptor (PTH1R) have been identified as the cause of this rare autosomal ­dominant syndrome. Because the mutations lead to constitutive ­activation of receptor function, one abnormal copy of the mutant receptor is sufficient to cause the disease, thereby accounting for its dominant mode of transmission. The disorder leads to short-limbed dwarfism due to abnormal regulation of chondrocyte maturation in the growth plates of the bone that are formed through the endochondral process. In adult life, there are numerous abnormalities in bone, including multiple cystic resorptive areas resembling those seen in severe hyperparathyroidism. Hypercalcemia and hypophosphatemia with undetectable or low PTH levels are typically observed. The pathogenesis of the growth plate abnormalities in Jansen’s disease has been confirmed by transgenic experiments in which targeted expression of the mutant PTH/PTHrP receptor to the proliferating chondrocyte layer of growth plate emulated several features of the human disorder. Some of these genetic mutations in the parathyroid gland or PTH target cells that affect Ca²⁺ metabolism are illustrated in Fig. 424-5.

MALIGNANCY-RELATED HYPERCALCEMIA

Clinical Syndromes and Mechanisms of Hypercalcemia

Hypercalcemia due to malignancy is common (occurring in as many as 20% of cancer patients, especially with certain types of tumor such as lung carcinoma), often severe and difficult to manage, and, on rare occasions, difficult to distinguish from primary hyperparathyroidism. Although malignancy is often clinically obvious or readily detectable by medical history, hypercalcemia can occasionally be due to an occult tumor. Previously, hypercalcemia associated with malignancy was thought to be due to local invasion and destruction of bone by tumor cells; many cases are now known to result from the elaboration by the malignant cells of humoral mediators of hypercalcemia. PTHrP is the responsible humoral agent in most solid tumors that cause hypercalcemia.

The histologic character of the tumor is more important than the extent of skeletal metastases in predicting hypercalcemia. Small-cell carcinoma (oat cell) and adenocarcinoma of the lung, although the most common lung tumors associated with skeletal metastases, rarely cause hypercalcemia. By contrast, many patients with squamous cell carcinoma of the lung develop hypercalcemia. Histologic studies of bone in patients with squamous cell or epidermoid carcinoma of the lung, in sites invaded by tumor as well as areas remote from tumor invasion, reveal increased bone resorption.

Two main mechanisms of hypercalcemia are operative in cancer hypercalcemia. Many solid tumors associated with hypercalcemia, particularly squamous cell and renal tumors, produce and secrete PTHrP that causes increased bone resorption and mediate the hypercalcemia through systemic actions on the skeleton. Alternatively, direct bone marrow invasion occurs with hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. Lymphokines and cytokines (including PTHrP) produced by cells involved in the marrow response to the tumors promote resorption of bone through local destruction. Several hormones, hormone analogues, cytokines, and growth factors have been implicated as the result of clinical assays, in vitro tests, or chemical isolation. The etiologic ­factor produced by activated normal lymphocytes and by myeloma and lymphoma cells, originally termed osteoclast activation factor, now appears to represent the biologic action of several different cytokines, probably interleukin 1 and lymphotoxin or tumor necrosis factor (TNF). In some lymphomas, there is a third mechanism, caused by an increased blood level of 1,25(OH)₂D, produced by the abnormal lymphocytes.

In the more common mechanism, usually termed humoral hypercalcemia of malignancy, solid tumors (cancers of the lung and kidney, in particular), in which bone metastases are absent, minimal, or not detectable clinically, secrete PTHrP measurable by immunoassay. Secretion by the tumors of the PTH-like factor, PTHrP, activates the PTH1R, resulting in a pathophysiology closely resembling hyperparathyroidism, but with normal or suppressed PTH levels. The clinical picture resembles primary hyperparathyroidism (hypophosphatemia accompanies hypercalcemia), and elimination or regression of the primary tumor leads to disappearance of the hypercalcemia.

As in hyperparathyroidism, patients with the humoral hypercalcemia of malignancy have elevated urinary nephrogenous cAMP excretion, hypophosphatemia, and increased urinary phosphate clearance. However, in humoral hypercalcemia of malignancy, immunoreactive PTH is undetectable or suppressed, making the differential diagnosis easier. Other features of the disorder differ from those of true hyperparathyroidism. Although the biologic actions of PTH and PTHrP are exerted through the same receptor, subtle differences in receptor activation by the two ligands must account for some of the discordance in pathophysiology, when an excess of one or the other peptide occurs. Other cytokines elaborated by the malignancy may contribute to the variations from hyperparathyroidism in these patients as well. Patients with humoral hypercalcemia of malignancy may have low to normal levels of 1,25(OH)₂D instead of elevated levels as in true hyperparathyroidism. In some patients with the humoral hypercalcemia of malignancy, osteoclastic resorption is unaccompanied by an osteoblastic or bone-forming response, implying inhibition of the normal coupling of bone formation and resorption.

Several different assays (single- or double-antibody, different epitopes) have been developed to detect PTHrP. Most data indicate that circulating PTHrP levels are undetectable (or low) in normal individuals except perhaps in pregnancy (high in human milk) and elevated in most cancer patients with the humoral syndrome. The etiologic mechanisms in cancer hypercalcemia may be multiple in the same patient. For example, in breast carcinoma (metastatic to bone) and in a distinctive type of T cell lymphoma/leukemia initiated by human T cell lymphotropic virus I, hypercalcemia is caused by direct local lysis of bone as well as by a humoral mechanism involving excess production of PTHrP. Hyperparathyroidism has been reported to coexist with the humoral cancer syndrome, and rarely, ectopic hyperparathyroidism due to tumor elaboration of true PTH is reported.

Diagnostic Issues

Levels of PTH measured by the double-antibody technique are undetectable or extremely low in tumor hypercalcemia, as would be expected with the mediation of the hypercalcemia by a factor other than PTH (the hypercalcemia suppresses the normal parathyroid glands). In a patient with minimal symptoms referred for hypercalcemia, low or undetectable PTH levels would focus attention on a possible occult malignancy (except for very rare cases of ectopic hyperparathyroidism).

Ordinarily, the diagnosis of cancer hypercalcemia is not difficult because tumor symptoms are prominent when hypercalcemia is detected. Indeed, hypercalcemia may be noted incidentally during the workup of a patient with known or suspected malignancy. Clinical suspicion that malignancy is the cause of the hypercalcemia is heightened when there are other signs or symptoms of a paraneoplastic process such as weight loss, fatigue, muscle weakness, or unexplained skin rash, or when symptoms specific for a particular tumor are present. Squamous cell tumors are most frequently associated with hypercalcemia, particularly tumors of the lung, kidney, head and neck, and urogenital tract. Radiologic examinations can focus on these areas when clinical evidence is unclear. Bone scans with technetium-labeled bisphosphonate are useful for detection of osteolytic metastases; the sensitivity is high, but specificity is low; results must be confirmed by conventional x-rays to be certain that areas of increased uptake are due to osteolytic metastases per se. Bone marrow biopsies are helpful in patients with anemia or abnormal peripheral blood smears.

TREATMENT

VITAMIN D–RELATED HYPERCALCEMIA

Hypercalcemia caused by vitamin D can be due to excessive ingestion or abnormal metabolism of the vitamin. Abnormal metabolism of the vitamin is usually acquired in association with a widespread granulomatous disorder. Vitamin D metabolism is carefully regulated, particularly the activity of renal 1α-hydroxylase, the enzyme responsible for the production of 1,25(OH)₂D (Chap. 423). The regulation of 1α-hydroxylase and the normal feedback suppression by 1,25(OH)₂D seem to work less well in infants than in adults and to operate poorly, if at all, in sites other than the renal tubule; these phenomena may explain the occurrence of hypercalcemia secondary to excessive 1,25(OH)₂D production in infants with Williams’ syndrome (see below) and in adults with sarcoidosis or lymphoma.

Vitamin D Intoxication

Chronic ingestion of 40–100 times the normal physiologic requirement of vitamin D (amounts >40,000–100,000 U/d) is usually required to produce significant hypercalcemia in otherwise healthy individuals. The stated upper limit of safe dietary intake is 2000 U/d (50 μg/d) in adults because of concerns about potential toxic effects of cumulative supraphysiologic doses. These recommendations are now regarded as too restrictive, because some estimates are that in elderly individuals in northern latitudes, 2000 U/d or more may be necessary to avoid vitamin D insufficiency.

Hypercalcemia in vitamin D intoxication is due to an excessive biologic action of the vitamin, perhaps the consequence of increased levels of 25(OH)D rather than merely increased levels of the active metabolite 1,25(OH)₂D (the latter may not be elevated in vitamin D intoxication). 25(OH)D has definite, if low, biologic activity in the intestine and bone. The production of 25(OH)D is less tightly regulated than is the production of 1,25(OH)₂D. Hence concentrations of 25(OH)D are elevated several-fold in patients with excess vitamin D intake.

The diagnosis is substantiated by documenting elevated levels of 25(OH)D >100 mg/mL. Hypercalcemia is usually controlled by restriction of dietary calcium intake and appropriate attention to hydration. These measures, plus discontinuation of vitamin D, usually lead to resolution of hypercalcemia. However, vitamin D stores in fat may be substantial, and vitamin D intoxication may persist for weeks after vitamin D ingestion is terminated. Such patients are responsive to glucocorticoids, which in doses of 100 mg/d of hydrocortisone or its equivalent usually return serum calcium levels to normal over several days; severe intoxication may require intensive therapy.

Sarcoidosis and Other Granulomatous Diseases

In patients with sarcoidosis and other granulomatous diseases, such as tuberculosis and fungal infections, excess 1,25(OH)₂D is synthesized in macrophages or other cells in the granulomas. Indeed, increased 1,25(OH)₂D levels have been reported in anephric patients with sarcoidosis and hypercalcemia. Macrophages obtained from granulomatous tissue convert 25(OH)D to 1,25(OH)₂D at an increased rate. There is a positive correlation in patients with sarcoidosis between 25(OH)D levels (reflecting vitamin D intake) and the circulating concentrations of 1,25(OH)₂D, whereas normally there is no increase in 1,25(OH)₂D with increasing 25(OH)D levels due to multiple feedback controls on renal 1α-hydroxylase (Chap. 423). The usual regulation of active metabolite production by calcium and phosphate or by PTH does not operate in these patients. Clearance of 1,25(OH)₂D from blood may be decreased in sarcoidosis as well. PTH levels are usually low and 1,25(OH)₂D levels are elevated, but primary hyperparathyroidism and sarcoidosis may coexist in some patients.

Management of the hypercalcemia can often be accomplished by avoiding excessive sunlight exposure and limiting vitamin D and calcium intake. Presumably, however, the abnormal sensitivity to vitamin D and abnormal regulation of 1,25(OH)₂D synthesis will persist as long as the disease is active. Alternatively, glucocorticoids in the equivalent of 100 mg/d of hydrocortisone or equivalent doses of glucocorticoids may help control hypercalcemia. Glucocorticoids appear to act by blocking excessive production of 1,25(OH)₂D, as well as the response to it in target organs.

Idiopathic Hypercalcemia of Infancy

This rare disorder, usually referred to as Williams’ syndrome, is an autosomal dominant disorder characterized by multiple congenital development defects, including supravalvular aortic stenosis, mental retardation, and an elfin facies, in association with hypercalcemia due to abnormal sensitivity to vitamin D. The hypercalcemia associated with the syndrome was first recognized in England after fortification of milk with vitamin D. The cardiac and developmental abnormalities were independently described, but the connection between these defects and hypercalcemia were not described until later. Levels of 1,25(OH)₂D can be elevated, ranging from 46 to 120 nmol/L (150–500 pg/mL). The mechanism of the abnormal sensitivity to vitamin D and of the increased circulating levels of 1,25(OH)₂D is still unclear. Studies suggest that genetic mutations involving microdeletions at the elastin locus and perhaps other genes on chromosome 7 may play a role in the pathogenesis. Another cause of hypercalcemia in infants and young children is a 24-hydroxylase deficiency that impairs metabolism of 1,25(OH)₂D.

HYPERCALCEMIA ASSOCIATED WITH HIGH BONE TURNOVER

Hyperthyroidism

As many as 20% of hyperthyroid patients have high-normal or mildly elevated serum calcium concentrations; hypercalciuria is even more common. The hypercalcemia is due to increased bone turnover, with bone resorption exceeding bone formation. Severe calcium elevations are not typical, and the presence of such suggests a concomitant disease such as hyperparathyroidism. Usually, the diagnosis is obvious, but signs of hyperthyroidism may occasionally be occult, particularly in the elderly (Chap. 405). Hypercalcemia is managed by treatment of the hyperthyroidism. Reports that thyroid-stimulating hormone (TSH) itself normally has a bone-protective effect suggest that suppressed TSH levels also play a role in hypercalcemia.

Immobilization

Immobilization is a rare cause of hypercalcemia in adults in the absence of an associated disease but may cause hypercalcemia in children and adolescents, particularly after spinal cord injury and paraplegia or quadriplegia. With resumption of ambulation, the hypercalcemia in children usually returns to normal.

The mechanism appears to involve a disproportion between bone formation and bone resorption; the former decreased and the latter increased. Hypercalciuria and increased mobilization of skeletal calcium can develop in normal volunteers subjected to extensive bed rest, although hypercalcemia is unusual. Immobilization of an adult with a disease associated with high bone turnover, however, such as Paget’s disease, may cause hypercalcemia.

Thiazides

Administration of benzothiadiazines (thiazides) can cause hypercalcemia in patients with high rates of bone turnover. Traditionally, thiazides are associated with aggravation of hypercalcemia in primary hyperparathyroidism, but this effect can be seen in other high-bone-turnover states as well. The mechanism of thiazide action is complex. Chronic thiazide administration leads to reduction in urinary calcium; the hypocalciuric effect appears to reflect the enhancement of proximal tubular resorption of sodium and calcium in response to sodium depletion. Some of this renal effect is due to augmentation of PTH action and is more pronounced in individuals with intact PTH secretion. However, thiazides cause hypocalciuria in hypoparathyroid patients on high-dose vitamin D and oral calcium replacement if sodium intake is restricted. This finding is the rationale for the use of thiazides as an adjunct to therapy in hypoparathyroid patients, as discussed below. Thiazide administration to normal individuals causes a transient increase in blood calcium (usually within the high-normal range) that reverts to preexisting levels after a week or more of continued administration. If hormonal function and calcium and bone metabolism are normal, homeostatic controls are reset to counteract the calcium-elevating effect of the thiazides. In the presence of hyperparathyroidism or increased bone turnover from another cause, homeostatic mechanisms are ineffective. The abnormal effects of the thiazide on calcium metabolism disappear within days of cessation of the drug.

Vitamin A Intoxication

Vitamin A intoxication is a rare cause of hypercalcemia and is most commonly a side effect of dietary faddism (Chap. 96e). Calcium levels can be elevated into the 3–3.5-mmol/L (12–14 mg/dL) range after the ingestion of 50,000–100,000 units of vitamin A daily (10–20 times the minimum daily requirement). Typical features of severe hypercalcemia include fatigue, anorexia, and, in some, severe muscle and bone pain. Excess vitamin A intake is presumed to increase bone resorption.

The diagnosis can be established by history and by measurement of vitamin A levels in serum. Occasionally, skeletal x-rays reveal periosteal calcifications, particularly in the hands. Withdrawal of the vitamin is usually associated with prompt disappearance of the hypercalcemia and reversal of the skeletal changes. As in vitamin D intoxication, administration of 100 mg/d of hydrocortisone or its equivalent leads to a rapid return of the serum calcium to normal.

HYPERCALCEMIA ASSOCIATED WITH RENAL FAILURE

Severe Secondary Hyperparathyroidism

The pathogenesis of secondary hyperparathyroidism in chronic kidney disease is incompletely understood. Resistance to the normal level of PTH is a major factor contributing to the development of hypocalcemia, which, in turn, is a stimulus to parathyroid gland enlargement. However, recent findings have indicated that an increase of FGF23 production by osteocytes (and possibly osteoblasts) in bone occurs well before an elevation in PTH is detected. FGF23 is a potent inhibitor of the renal 1-alpha hydroxylase, and the FGF23-dependent reduction in 1,25(OH)₂ vitamin D seems to be an important stimulus for the development of secondary hyperparathyroidism.

Secondary hyperparathyroidism occurs not only in patients with renal failure but also in those with osteomalacia due to multiple causes (Chap. 423), including deficiency of vitamin D action and pseudohypoparathyroidism (deficient response to PTH downstream of PTHR1). For both disorders, hypocalcemia seems to be the common denominator in initiating the development of secondary hyperparathyroidism. Primary (1°) and secondary (2°) hyperparathyroidism can be distinguished conceptually by the autonomous growth of the parathyroid glands in primary hyperparathyroidism (presumably irreversible) and the adaptive response of the parathyroids in secondary hyperparathyroidism (typically reversible). In fact, reversal over weeks from an abnormal pattern of secretion, presumably accompanied by involution of parathyroid gland mass to normal, occurs in patients with osteomalacia who have been treated effectively with calcium and vitamin D. However, it is now recognized that a true clonal outgrowth (irreversible) can arise in long-standing, inadequately treated chronic kidney disease (e.g., tertiary [3°] hyperparathyroidism; see below).

Patients with secondary hyperparathyroidism may develop bone pain, ectopic calcification, and pruritus. The bone disease seen in patients with secondary hyperparathyroidism and chronic kidney disease is termed renal osteodystrophy and affects primarily bone turnover. However, osteomalacia is frequently encountered as well and may be related to the circulating levels of FGF23.

Two other skeletal disorders have been frequently associated in the past with chronic kidney disease (CKD) patients treated by long-term dialysis, who received aluminum-containing phosphate binders. Aluminum deposition in bone (see below) leads to an osteomalacia-like picture. The other entity is a low-turnover bone disease termed “aplastic” or “adynamic” bone disease; PTH levels are lower than typically observed in CKD patients with secondary hyperparathyroidism. It is believed that the condition is caused, at least in part, by excessive PTH suppression, which may be even greater than previously appreciated in light of evidence that some of the immunoreactive PTH detected by most commercially available PTH assays is not the full-length biologically active molecule (as discussed above) but may consist of amino-terminally truncated fragments that do not activate the PTH1R.

TREATMENT

Aluminum Intoxication

Aluminum intoxication (and often hypercalcemia as a complication of medical treatment) in the past occurred in patients on chronic dialysis; manifestations included acute dementia and unresponsive and severe osteomalacia. Bone pain, multiple nonhealing fractures, particularly of the ribs and pelvis, and a proximal myopathy occur. Hypercalcemia develops when these patients are treated with vitamin D or calcitriol because of impaired skeletal responsiveness. Aluminum is present at the site of osteoid mineralization, osteoblastic activity is minimal, and calcium incorporation into the skeleton is impaired. The disorder is now rare because of the avoidance of aluminum-containing antacids or aluminum excess in the dialysis regimen (Chap. 429).

Milk-Alkali Syndrome

The milk-alkali syndrome is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. It is much less frequent since proton pump inhibitors and other treatments became available for peptic ulcer disease. For a time, the increased use of calcium carbonate in the management of secondary hyperparathyroidism led to reappearance of the syndrome. Several clinical presentations—acute, subacute, and chronic—have been described, all of which feature hypercalcemia, alkalosis, and renal failure. The chronic form of the disease, termed Burnett’s syndrome, is associated with irreversible renal damage. The acute syndromes reverse if the excess calcium and absorbable alkali are stopped.

Individual susceptibility is important in the pathogenesis, because some patients are treated with calcium carbonate and alkali regimens without developing the syndrome. One variable is the fractional calcium absorption as a function of calcium intake. Some individuals absorb a high fraction of calcium, even with intakes ≥2 g of elemental calcium per day, instead of reducing calcium absorption with high intake, as occurs in most normal individuals. Resultant mild hypercalcemia after meals in such patients is postulated to contribute to the generation of alkalosis. Development of hypercalcemia causes increased sodium excretion and some depletion of total-body water. These phenomena and perhaps some suppression of endogenous PTH secretion due to mild hypercalcemia lead to increased bicarbonate resorption and to alkalosis in the face of continued calcium carbonate ingestion. Alkalosis per se selectively enhances calcium resorption in the distal nephron, thus aggravating the hypercalcemia. The cycle of mild hypercalcemia → bicarbonate retention → alkalosis → renal calcium retention → severe hypercalcemia perpetuates and aggravates hypercalcemia and alkalosis as long as calcium and absorbable alkali are ingested.

DIFFERENTIAL DIAGNOSIS: SPECIAL TESTS

Differential diagnosis of hypercalcemia is best achieved by using clinical criteria, but immunometric assays to measure PTH are especially useful in distinguishing among major causes (Fig. 424-6). The clinical features that deserve emphasis are the presence or absence of symptoms or signs of disease and evidence of chronicity. If one discounts fatigue or depression, >90% of patients with primary hyperparathyroidism have asymptomatic hypercalcemia; symptoms of malignancy are usually present in cancer-associated hypercalcemia. Disorders other than hyperparathyroidism and malignancy cause <10% of cases of hypercalcemia, and some of the nonparathyroid causes are associated with clear-cut manifestations such as renal failure.

Hyperparathyroidism is the likely diagnosis in patients with chronic hypercalcemia. If hypercalcemia has been manifest for >1 year, malignancy can usually be excluded as the cause. A striking feature of malignancy-associated hypercalcemia is the rapidity of the course, whereby signs and symptoms of the underlying malignancy are evident within months of the detection of hypercalcemia. Although clinical considerations are helpful in arriving at the correct diagnosis of the cause of hypercalcemia, appropriate laboratory testing is essential for definitive diagnosis. The immunoassay for PTH usually separates hyperparathyroidism from all other causes of hypercalcemia (exceptions are very rare reports of ectopic production of excess PTH by nonparathyroid tumors). Patients with hyperparathyroidism have elevated PTH levels despite hypercalcemia, whereas patients with malignancy and the other causes of hypercalcemia (except for disorders mediated by PTH such as lithium-induced hypercalcemia) have levels of hormone below normal or undetectable levels. Assays based on the double-antibody method for PTH exhibit very high sensitivity (especially if serum calcium is simultaneously evaluated) and specificity for the diagnosis of primary hyperparathyroidism (Fig. 424-4).

In summary, PTH values are elevated in >90% of parathyroid-related causes of hypercalcemia, undetectable or low in malignancy-related hypercalcemia, and undetectable or normal in vitamin D–related and high-bone-turnover causes of hypercalcemia. In view of the specificity of the PTH immunoassay and the high frequency of hyperparathyroidism in hypercalcemic patients, it is cost-effective to measure the PTH level in all hypercalcemic patients unless malignancy or a specific nonparathyroid disease is obvious. False-positive PTH assay results are rare. Immunoassays for PTHrP are helpful in diagnosing certain types of malignancy-associated hypercalcemia. Although FHH is parathyroid-related, the disease should be managed distinctively from hyperparathyroidism. Clinical features and the low urinary calcium excretion can help make the distinction. Because the incidence of malignancy and hyperparathyroidism both increase with age, they can coexist as two independent causes of hypercalcemia.

1,25(OH)₂D levels are elevated in many (but not all) patients with primary hyperparathyroidism. In other disorders associated with hypercalcemia, concentrations of 1,25(OH)₂D are low or, at the most, normal. However, this test is of low specificity and is not cost-effective, as not all patients with hyperparathyroidism have elevated 1,25(OH)₂D levels and not all nonparathyroid hypercalcemic patients have suppressed 1,25(OH)₂D. Measurement of 1,25(OH)₂D is, however, critically valuable in establishing the cause of hypercalcemia in sarcoidosis and certain lymphomas.

A useful general approach is outlined in Fig. 424-6. If the patient is asymptomatic and there is evidence of chronicity to the hypercalcemia, hyperparathyroidism is almost certainly the cause. If PTH levels (usually measured at least twice) are elevated, the clinical impression is confirmed and little additional evaluation is necessary. If there is only a short history or no data as to the duration of the hypercalcemia, occult malignancy must be considered; if the PTH levels are not elevated, then a thorough workup must be undertaken for malignancy, including chest x-ray, CT of chest and abdomen, and bone scan. Immunoassays for PTHrP may be especially useful in such situations. Attention should also be paid to clues for underlying hematologic disorders such as anemia, increased plasma globulin, and abnormal serum immunoelectrophoresis; bone scans can be negative in some patients with metastases such as in multiple myeloma. Finally, if a patient with chronic hypercalcemia is asymptomatic and malignancy therefore seems unlikely on clinical grounds, but PTH values are not elevated, it is useful to search for other chronic causes of hypercalcemia such as occult sarcoidosis. A careful history of dietary supplements and drug use may suggest intoxication with vitamin D or vitamin A or the use of thiazides.

TREATMENT

HYPOCALCEMIA

(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).

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.

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 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.

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.

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.

PTH ABSENT

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 manifestations such as choreoathetotic movements and dystonia.

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).

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).

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.

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 microdeletions 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, TBX1. Deletions of the orthologous mouse gene show a phenotype similar to the human syndrome.

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.

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.

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 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.

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.

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 hypoparathyroidism has been described in males, and the defect has been localized to chromosome Xq26-q27, perhaps involving the SOX3 gene.

Abnormalities in the CaSR are detected in three distinctive hypocalcemic disorders. All are rare, but more than 10 different gain-of-function 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.

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.

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 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 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.

TREATMENT

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.

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.

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 supranormal may precede restoration of normal serum calcium by several days.

TREATMENT

PTH INEFFECTIVE

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.

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).

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, 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.

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.

TREATMENT

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 causes osteomalacia.

Treatment involves adequate replacement with vitamin D and calcium 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.

Defective Vitamin D Metabolism

ANTICONVULSANT THERAPY

Anti-convulsant 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.

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.

Clinical features include hypocalcemia, often with tetany or convulsions, 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).

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.

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 G_sα subunit of the adenylate cyclase enzyme. Using these criteria, there are four types: PHP types Ia and Ib; pseudopseudohypoparathyroidism (PPHP), and PHP-II.

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 G_sα 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_sα activity. PHP-Ic, sometimes listed as a third form of PHP-I, is really a variant of PHP-Ia, although the mutant G_sα shows normal activity in certain in vitro assays.

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.

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 (G_sα), 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 G_sα activity in erythrocytes or other cells.

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 G_sα 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 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_sα allele from the female causes much reduced G_sα 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.

Imprinting is tissue selective. Paternal G_sα 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_sα haploinsufficiency during embryonic or postnatal development.

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 G_sα appears to be expressed exclusively from the maternal allele—to PTH resistance.

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 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.

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.

TREATMENT

PTH OVERWHELMED

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.

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.

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

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.

DIFFERENTIAL DIAGNOSIS OF HYPOCALCEMIA

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.

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.

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.

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.

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 ineffective due to associated abnormalities in vitamin D action. Assays for 25(OH)D can be helpful. Low or low-normal 25(OH)D indicates vitamin D deficiency due to lack of sunlight, inadequate vitamin D intake, or intestinal malabsorption. Recognition that mild hypocalcemia, rickets, and hypophosphatemia are due to anticonvulsant therapy is made by history.

TREATMENT

INTRODUCTION

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 associated with bone demineralization. Its chief clinical manifestations are 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.

DEFINITION

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 with deterioration in skeletal microarchitecture. The World Health Organization (WHO) operationally defines osteoporosis as a bone density that falls 2.5 standard deviations (SD) below the mean for young healthy adults of the same sex—also referred to as a T-score of –2.5. Postmenopausal women who fall at the lower end of the young normal range (a T-score <–1.0) are defined as having low bone density and are also at increased risk of osteoporosis. Although risk is lower in this group, more than 50% of fractures among postmenopausal women, including hip fractures, occur in this group with low bone density, because the number of individuals in this category is so much larger than that in the osteoporosis range. As a result, there are ongoing 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 the “diagnostic” criterion for osteoporosis.

EPIDEMIOLOGY

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.

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 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. 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.

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 diseases associated with malabsorption. Chronic diseases that increase 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.

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.

PATHOPHYSIOLOGY

BONE REMODELING

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 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 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 osteoporosis-pseudoglioma 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.

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 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.

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 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.

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 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 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 changes in microstructure of bone tissue, including increased cortical porosity and reduced cortical thickness.

CALCIUM NUTRITION

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 remodeling sites combine to accelerate loss of bone tissue.

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.

VITAMIN D

(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-hydroxy-vitamin 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 ultra-violet-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. 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.

ESTROGEN STATUS

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.

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, 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.

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.

PHYSICAL ACTIVITY

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.

CHRONIC DISEASE

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.

MEDICATIONS

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.

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.

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.

CIGARETTE CONSUMPTION

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).

MEASUREMENT OF BONE MASS

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 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 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 and the hip, but is rarely used clinically, in part because of higher radiation 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.

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.

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).

WHEN TO MEASURE BONE MASS

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.

WHEN TO TREAT BASED ON BONE MASS RESULTS

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 fracture over a 5- or 10-year period. Treatment threshold depends on cost-effectiveness analyses but probably is ~1% per year of risk in the United States.

APPROACH TO PATIENT

BONE BIOPSY

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.

BIOCHEMICAL MARKERS

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 resorption may help in the prediction of fracture risk, independently of bone density, particularly in older individuals. In women ≥65 years, when bone density results are greater than the usual treatment thresholds noted above, a high level of bone resorption should prompt consideration of treatment. The primary use of biochemical markers is for monitoring the response to treatment. With the introduction of antiresorptive therapeutic agents, bone remodeling declines rapidly, with the fall in resorption occurring earlier than the fall in formation. Inhibition of bone resorption is maximal within 3 months or so. Thus, measurement of bone resorption (C-telopeptide [CTX] is the preferred marker) before initiating therapy and 3–6 months after starting therapy provides an earlier estimate of patient response than does bone densitometry. A decline in resorptive markers can be ascertained after treatment with potent antiresorptive agents such as bisphosphonates, denosumab, or standard-dose estrogen; this effect is less marked after treatment with weaker agents such as raloxifene or intranasal calcitonin. A biochemical marker response to therapy is particularly useful for asymptomatic patients and may help ensure long-term adherence to treatment. Bone turnover markers are also useful in monitoring the effects of osteoanabolic agents such as 1-34hPTH, or teriparatide, which rapidly increases bone formation (P1NP is preferred, but osteocalcin is a reasonable alternative) and later bone resorption. The recent suggestion of “drug holidays” (see below) has created another use for biochemical markers, allowing evaluation of the off effect of drugs such as bisphosphonates.

TREATMENT

GLUCOCORTICOID-INDUCED OSTEOPOROSIS

Osteoporotic fractures are a well-characterized consequence of the hypercortisolism associated with Cushing’s syndrome. However, the therapeutic use of glucocorticoids is by far the most common form of glucocorticoid-induced osteoporosis. Glucocorticoids are used widely in the treatment of a variety of disorders, including chronic lung disorders, rheumatoid arthritis and other connective tissue diseases, inflammatory bowel disease, and after transplantation. Osteoporosis and related fractures are serious side effects of chronic glucocorticoid therapy. Because the effects of glucocorticoids on the skeleton are often superimposed on the consequences of aging and menopause, it is not surprising that women and the elderly are most frequently affected. The skeletal response to steroids is remarkably heterogeneous, however, and even young, growing individuals treated with glucocorticoids can present with fractures.

The risk of fractures depends on the dose and duration of glucocorticoid therapy, although recent data suggest that there may be no completely safe dose. Bone loss is more rapid during the early months of treatment, and trabecular bone is affected more severely than cortical bone. As a result, fractures have been shown to increase within 3 months of steroid treatment. There is an increase in fracture risk in both the axial skeleton and the appendicular skeleton, including risk of hip fracture. Bone loss can occur with any route of steroid administration, including high-dose inhaled glucocorticoids and intraarticular injections. Alternate-day delivery does not appear to ameliorate the skeletal effects of glucocorticoids.

PATHOPHYSIOLOGY

Glucocorticoids increase bone loss by multiple mechanisms, including (1) inhibition of osteoblast function and an increase in osteoblast apoptosis, resulting in impaired synthesis of new bone; (2) stimulation of bone resorption, probably as a secondary effect; (3) impairment of the absorption of calcium across the intestine, probably by a vitamin D–independent effect; (4) increase of urinary calcium loss and perhaps induction of some degree of secondary hyperparathyroidism; (5) reduction of adrenal androgens and suppression of ovarian and testicular secretion of estrogens and androgens; and (6) induction of glucocorticoid myopathy, which may exacerbate effects on skeletal and calcium homeostasis as well as increase the risk of falls.

EVALUATION OF THE PATIENT

Because of the prevalence of glucocorticoid-induced bone loss, it is important to evaluate the status of the skeleton in all patients starting or already receiving long-term glucocorticoid therapy. Modifiable risk factors should be identified, including those for falls. Examination should include testing of height and muscle strength. Laboratory evaluation should include an assessment of 24-h urinary calcium. All patients on long-term (>3 months) glucocorticoids should have measurement of bone mass at both the spine and the hip using DXA. If only one skeletal site can be measured, it is best to assess the spine in individuals <60 years and the hip in those >60 years.

PREVENTION

Bone loss caused by glucocorticoids can be prevented and the risk of fractures significantly reduced. Strategies must include using the lowest dose of glucocorticoid for disease management. Topical and inhaled routes of administration are preferred, where appropriate. Risk factor reduction is important, including smoking cessation, limitation of alcohol consumption, and participation in weight-bearing exercise, when appropriate. All patients should receive an adequate calcium and vitamin D intake from the diet or from supplements.

TREATMENT

PAGET’S DISEASE OF BONE

Paget’s disease is a localized bone-remodeling disorder that affects widespread, noncontiguous areas of the skeleton. The pathologic process is initiated by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new bone formation, resulting in a structurally disorganized mosaic of woven and lamellar bone. Pagetic bone is expanded, less compact, and more vascular; thus, it is more susceptible to deformities and fractures. Although most patients are asymptomatic, symptoms resulting directly from bony involvement (bone pain, secondary arthritis, fractures) or secondarily from the expansion of bone causing compression of surrounding neural tissue are not uncommon.

Epidemiology

There is a marked geographic variation in the frequency of Paget’s disease, with high prevalence in Western Europe (Great Britain, France, and Germany, but not Switzerland or Scandinavia) and among those who have immigrated to Australia, New Zealand, South Africa, and North and South America. The disease is rare in native populations of the Americas, Africa, Asia, and the Middle East; when it does occur, the affected subjects usually have evidence of European ancestry, supporting the migration theory. For unclear reasons, the prevalence and severity of Paget’s disease are decreasing, and the age of diagnosis is increasing.

The prevalence is greater in males and increases with age. Autopsy series reveal Paget’s disease in about 3% of those over age 40. Prevalence of positive skeletal radiographs in patients over age 55 is 2.5% for men and 1.6% for women. Elevated alkaline phosphatase (ALP) levels in asymptomatic patients have an age-adjusted incidence of 12.7 and 7 per 100,000 person-years in men and women, respectively.

Etiology

The etiology of Paget’s disease of bone remains unknown, but evidence supports both genetic and viral etiologies. A positive family history is found in 15–25% of patients and, when present, raises the prevalence of the disease seven- to tenfold among first-degree relatives.

A clear genetic basis has been established for several rare familial bone disorders that clinically and radiographically resemble Paget’s disease but have more severe presentation and earlier onset. A homozygous deletion of the TNFRSF11B gene, which encodes osteoprotegrin (Fig. 426e-1), causes juvenile Paget’s disease, also known as familial idiopathic hyperphosphatasia, a disorder characterized by uncontrolled osteoclastic differentiation and resorption. Familial patterns of disease in several large kindred are consistent with an autosomal dominant pattern of inheritance with variable penetrance. Familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset Paget’s disease are associated with mutations in TNFRSF11A gene, which encodes RANK (receptor activator of nuclear factor-κB), a member of the tumor necrosis factor superfamily critical for osteoclast differentiation (Fig. 426e-1). Finally, mutations in the gene for valosin-containing protein cause a rare syndrome with autosomal dominant inheritance and variable penetrance known as inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD). The role of genetic factors is less clear in the more common form of late-onset Paget’s disease. Although a few families with mutations in the gene encoding RANK have been reported, the most common mutations identified in familial and sporadic cases of Paget’s disease have been in the SQSTM1 gene (sequestasome-1 or p62 protein) in the C-terminal ubiquitin-binding domain. The p62 protein is involved in nuclear factor κB (NF-κB) signaling and regulates osteoclastic differentiation. The phenotypic variability in patients with SQSTM1 mutations suggests that additional factors, such as other genetic influences or viral infection, may influence clinical expression of the disease.

Several lines of evidence suggest that a viral infection may contribute to the clinical manifestations of Paget’s disease, including (1) the presence of cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles and respiratory syncytial virus) in pagetic osteoclasts and (2) viral mRNA in precursor and mature osteoclasts. The viral etiology is further supported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virus nucleocapsid or matrix genes. However, the viral etiology has been questioned by the inability to culture a live virus from pagetic bone and by failure to clone the full-length viral genes from material obtained from patients with Paget’s disease.

Pathophysiology

The principal abnormality in Paget’s disease is the increased number and activity of osteoclasts. Pagetic osteoclasts are large, increased 10- to 100-fold in number, and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal osteoclast). The overactive osteoclasts may create a sevenfold increase in resorptive surfaces and an erosion rate of 9 μg/d (normal is 1 μg/d). Several causes for the increased number and activity of pagetic osteoclasts have been identified: (1) osteoclastic precursors are hypersensitive to 1,25(OH)₂D₃; (2) osteoclasts are hyperresponsive to RANK ligand (RANKL), the osteoclast stimulatory factor that mediates the effects of most osteotropic factors on osteoclast formation; (3) marrow stromal cells from pagetic lesions have increased RANKL expression; (4) osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood of patients with active Paget’s disease and is overexpressed in pagetic osteoclasts; (5) expression of the protooncogene c-fos, which increases osteoclastic activity, is increased; and (6) the antiapoptotic oncogene Bcl-2 in pagetic bone is overexpressed. Numerous osteoblasts are recruited to active resorption sites and produce large amounts of new bone matrix. As a result, bone turnover is high, and bone mass is normal or increased, not reduced, unless there is concomitant deficiency of calcium and/or vitamin D.

The characteristic feature of Paget’s disease is increased bone resorption accompanied by accelerated bone formation. An initial osteolytic phase involves prominent bone resorption and marked hypervascularization. Radiographically, this manifests as an advancing lytic wedge, or “blade of grass” lesion. The second phase is a period of very active bone formation and resorption that replaces normal lamellar bone with haphazard (woven) bone. Fibrous connective tissue may replace normal bone marrow. In the final sclerotic phase, bone resorption declines progressively and leads to a hard, dense, less vascular pagetic or mosaic bone, which represents the so-called burned-out phase of Paget’s disease. All three phases may be present at the same time at different skeletal sites.

Clinical Manifestations

Diagnosis is often made in asymptomatic patients because they have elevated ALP levels on routine blood chemistry testing or an abnormality on a skeletal radiograph obtained for another indication. The skeletal sites most commonly involved are the pelvis, vertebral bodies, skull, femur, and tibia. Familial cases with an early presentation often have numerous active sites of skeletal involvement.

The most common presenting symptom is pain, which may result from increased bony vascularity, expanding lytic lesions, fractures, bowing, or other deformities. Bowing of the femur or tibia causes gait abnormalities and abnormal mechanical stresses with secondary osteoarthritis of the hip or knee joints. Long bone bowing also causes extremity pain by stretching the muscles attached to the bone softened by the pagetic process. Back pain results from enlarged pagetic vertebrae, vertebral compression fractures, spinal stenosis, degenerative changes of the joints, and altered body mechanics with kyphosis and forward tilt of the upper back. Rarely, spinal cord compression may result from bone enlargement or from the vascular steal syndrome. Skull involvement may cause headaches, symmetric or asymmetric enlargement of the parietal or frontal bones (frontal bossing), and increased head size. Cranial expansion may narrow cranial foramens and cause neurologic complications including hearing loss from cochlear nerve damage from temporal bone involvement, cranial nerve palsies, and softening of the base of the skull (platybasia) with the risk of brainstem compression. Pagetic involvement of the facial bones may cause facial deformity; loss of teeth and other dental conditions; and, rarely, airway compression.

Fractures are serious complications of Paget’s disease and usually occur in long bones at areas of active or advancing lytic lesions. Common fracture sites are the femoral shaft and subtrochanteric regions. Neoplasms arising from pagetic bone are rare (<0.5%). The incidence of sarcoma appears to be decreasing, possibly because of earlier, more effective treatment with potent antiresorptive agents. The majority of tumors are osteosarcomas, which usually present with new pain in a long-standing pagetic lesion. Osteoclast-rich benign giant cell tumors may arise in areas adjacent to pagetic bone, and they respond to glucocorticoid therapy.

Cardiovascular complications may occur in patients with involvement of large (15–35%) portions of the skeleton and a high degree of disease activity (ALP four times above normal). The extensive arteriovenous shunting and marked increases in blood flow through the vascular pagetic bone lead to a high-output state and cardiac enlargement. However, high-output heart failure is relatively rare and usually develops in patients with concomitant cardiac pathology. In addition, calcific aortic stenosis and diffuse vascular calcifications have been associated with Paget’s disease.

Diagnosis

The diagnosis may be suggested on clinical examination by the presence of an enlarged skull with frontal bossing, bowing of an extremity, or short stature with simian posturing. An extremity with an area of warmth and tenderness to palpation may suggest an underlying pagetic lesion. Other findings include bony deformity of the pelvis, skull, spine, and extremities; arthritic involvement of the joints adjacent to lesions; and leg-length discrepancy resulting from deformities of the long bones.

Paget’s disease is usually diagnosed from radiologic and biochemical abnormalities. Radiographic findings typical of Paget’s disease include enlargement or expansion of an entire bone or area of a long bone, cortical thickening, coarsening of trabecular markings, and typical lytic and sclerotic changes. Skull radiographs (Fig. 426e-2) reveal regions of “cotton wool,” or osteoporosis circumscripta, thickening of diploic areas, and enlargement and sclerosis of a portion or all of one or more skull bones. Vertebral cortical thickening of the superior and inferior end plates creates a “picture frame” vertebra. Diffuse radiodense enlargement of a vertebra is referred to as “ivory vertebra.” Pelvic radiographs may demonstrate disruption or fusion of the sacroiliac joints; porotic and radiodense lesions of the ilium with whorls of coarse trabeculation; thickened and sclerotic iliopectineal line (brim sign); and softening with protrusio acetabuli, with axial migration of the hips and functional flexion contracture. Radiographs of long bones reveal bowing deformity and typical pagetic changes of cortical thickening and expansion and areas of lucency and sclerosis (Fig. 426e-3). Radionuclide ^99mTc bone scans are less specific but are more sensitive than standard radiographs for identifying sites of active skeletal lesions. Although computed tomography (CT) and magnetic resonance imaging (MRI) studies are not necessary in most cases, CT may be useful for the assessment of possible fracture, and MRI is necessary to assess the possibility of sarcoma, giant cell tumor, or metastatic disease in pagetic bone. Definitive diagnosis of malignancy often requires bone biopsy.

Biochemical evaluation is useful in the diagnosis and management of Paget’s disease. The marked increase in bone turnover can be monitored using biochemical markers of bone formation and resorption. The parallel rise in markers of bone formation and resorption confirms the coupling of bone formation and resorption in Paget’s disease. The degree of bone marker elevation reflects the extent and severity of the disease. Patients with the highest elevation of ALP (10 × the upper limit of normal) typically have involvement of the skull and at least one other skeletal site. Lower values suggest less extensive involvement or a quiescent phase of the disease. For most patients, serum total ALP remains the test of choice both for diagnosis and assessing response to therapy. Occasionally, a symptomatic patient with evidence of progression at a single site may have a normal total ALP level but increased bone-specific ALP. For unclear reasons, serum osteocalcin, another marker of bone formation, is not always elevated and is not recommended for use in diagnosis or management of Paget’s disease. Bone resorption markers (serum or urine N-telopeptide or C-telopeptide measured in the blood or urine) are also elevated in active Paget’s disease and decrease more rapidly in response to therapy than does ALP.

Serum calcium and phosphate levels are normal in Paget’s disease. Immobilization of a patient with active Paget’s disease may rarely cause hypercalcemia and hypercalciuria and increase the risk for nephrolithiasis. However, the discovery of hypercalcemia, even in the presence of immobilization, should prompt a search for another cause of hypercalcemia. In contrast, hypocalcemia or mild secondary hyperparathyroidism may develop in Paget’s patients with very active bone formation and insufficient calcium and vitamin D intake, particularly during bisphosphonate therapy when bone resorption is rapidly suppressed and active bone formation continues. Therefore, adequate calcium and vitamin D intake should be instituted prior to administration of bisphosphonates.

TREATMENT

SCLEROSING BONE DISORDERS

OSTEOPETROSIS

Osteopetrosis refers to a group of disorders caused by severe impairment of osteoclast-mediated bone resorption. Other terms that are often used include marble bone disease, which captures the solid x-ray appearance of the involved skeleton, and Albers-Schonberg disease, which refers to the milder, adult form of osteopetrosis also known as autosomal dominant osteopetrosis type II. The major types of osteopetrosis include malignant (severe, infantile, autosomal recessive) osteopetrosis and benign (adult, autosomal dominant) osteopetrosis types I and II. A rare autosomal recessive intermediate form has a more benign prognosis. Autosomal recessive carbonic anhydrase (CA) II deficiency produces osteopetrosis of intermediate severity associated with renal tubular acidosis and cerebral calcification.

Etiology and Genetics

Naturally occurring and gene-knockout animal models with phenotypes similar to those of the human disorders have been used to explore the genetic basis of osteopetrosis. The primary defect in osteopetrosis is the loss of osteoclastic bone resorption and preservation of normal osteoblastic bone formation. Osteoprotegerin (OPG) is a soluble decoy receptor that binds osteoblast-derived RANK ligand, which mediates osteoclast differentiation and activation (Fig. 426e-1). Transgenic mice that overexpress OPG develop osteopetrosis, presumably by blocking RANK ligand. Mice deficient in RANK lack osteoclasts and develop severe osteopetrosis.

Recessive mutations of CA II prevent osteoclasts from generating an acid environment in the clear zone between its ruffled border and the adjacent mineral surface. Absence of CA II, therefore, impairs osteoclastic bone resorption. Other forms of human disease have less clear genetic defects. About one-half of the patients with malignant infantile osteopetrosis have a mutation in the TCIRG1 gene encoding the osteoclast-specific subunit of the vacuolar proton pump, which mediates the acidification of the interface between bone mineral and the osteoclast ruffled border. Mutations in the CICN7 chloride channel gene cause autosomal dominant osteopetrosis type II.

Clinical Presentation

The incidence of autosomal recessive severe (malignant) osteopetrosis ranges from 1 in 200,000 to 1 in 500,000 live births. As bone and cartilage fail to undergo modeling, paralysis of one or more cranial nerves may occur due to narrowing of the cranial foramens. Failure of skeletal modeling also results in inadequate marrow space, leading to extramedullary hematopoiesis with hypersplenism and pancytopenia. Hypocalcemia due to lack of osteoclastic bone resorption may occur in infants and young children. The untreated infantile disease is fatal, often before age 5.

Adult (benign) osteopetrosis is an autosomal dominant disease that is usually diagnosed by the discovery of typical skeletal changes in young adults who undergo radiologic evaluation of a fracture. The prevalence is 1 in 100,000 to 1 in 500,000 adults. The course is not always benign, because fractures may be accompanied by loss of vision, deafness, psychomotor delay, mandibular osteomyelitis, and other complications usually associated with the juvenile form. In some kindred, nonpenetrance results in skip generations, while in other families, severely affected children are born into families with benign disease. The milder form of the disease does not usually require treatment.

Radiography

Typically, there are generalized symmetric increases in bone mass with thickening of both cortical and trabecular bone. Diaphyses and metaphyses are broadened, and alternating sclerotic and lucent bands may be seen in the iliac crests, at the ends of long bones, and in vertebral bodies. The cranium is usually thickened, particularly at the base of the skull, and the paranasal and mastoid sinuses are underpneumatized.

Laboratory Findings

The only significant laboratory findings are elevated serum levels of osteoclast-derived tartrate-resistant acid phosphatase (TRAP) and the brain isoenzyme of creatine kinase. Serum calcium may be low in severe disease, and parathyroid hormone and 1,25-dihydroxyvitamin D levels may be elevated in response to hypocalcemia.

TREATMENT

PYKNODYSOSTOSIS

This is an autosomal recessive form of osteosclerosis that is believed to have affected the French impressionist painter Henri de Toulouse-Lautrec. The molecular basis involves mutations in the gene that encodes cathepsin K, a lysosomal metalloproteinase highly expressed in osteoclasts and important for bone-matrix degradation. Osteoclasts are present but do not function normally. Pyknodysostosis is a form of short-limb dwarfism that presents with frequent fractures but usually a normal life span. Clinical features include short stature; kyphoscoliosis and deformities of the chest; high arched palate; proptosis; blue sclerae; dysmorphic features including small face and chin, frontooccipital prominence, pointed beaked nose, large cranium, and obtuse mandibular angle; and small, square hands with hypoplastic nails. Radiographs demonstrate a generalized increase in bone density, but in contrast to osteopetrosis, the long bones are normally shaped. Separated cranial sutures, including the persistent patency of the anterior fontanel, are characteristic of the disorder. There may also be hypoplasia of the sinuses, mandible, distal clavicles, and terminal phalanges. Persistence of deciduous teeth and sclerosis of the calvarium and base of the skull are also common. Histologic evaluation shows normal cortical bone architecture with decreased osteoblastic and osteoclastic activities. Serum chemistries are normal, and unlike osteopetrosis, there is no anemia. There is no known treatment for this condition, and there are no reports of attempted bone marrow transplant.

PROGRESSIVE DIAPHYSEAL DYSPLASIA

Also known as Camurati-Engelmann disease, progressive diaphyseal dysplasia is an autosomal dominant disorder that is characterized radiographically by diaphyseal hyperostosis and a symmetric thickening and increased diameter of the endosteal and periosteal surfaces of the diaphyses of the long bones, particularly the femur and tibia, and, less often, the fibula, radius, and ulna. The genetic defect responsible for the disease has been localized to the area of chromosome 19q13.2 encoding tumor growth factor (TGF) β1. The mutation promotes activation of TGF-β1. The clinical severity is variable. The most common presenting symptoms are pain and tenderness of the involved areas, fatigue, muscle wasting, and gait disturbance. The weakness may be mistaken for muscular dystrophy. Characteristic body habitus includes thin limbs with little muscle mass yet prominent and palpable bones and, when the skull is involved, large head with prominent forehead and proptosis. Patients may also display signs of cranial nerve palsies, hydrocephalus, central hypogonadism, and Raynaud’s phenomenon. Radiographically, patchy progressive endosteal and periosteal new bone formation is observed along the diaphyses of the long bones. Bone scintigraphy shows increased radiotracer uptake in involved areas.

Treatment with low-dose glucocorticoids relieves bone pain and may reverse the abnormal bone formation. Intermittent bisphosphonate therapy has produced clinical improvement in a limited number of patients.

HYPEROSTOSIS CORTICALIS GENERALISATA

This is also known as van Buchem’s disease; it is an autosomal recessive disorder characterized by endosteal hyperostosis in which osteosclerosis involves the skull, mandible, clavicles, and ribs. The major manifestations are due to narrowed cranial foramens with neural compressions that may result in optic atrophy, facial paralysis, and deafness. Adults may have an enlarged mandible. Serum ALP levels may be elevated, which reflect the uncoupled bone remodeling with high osteoblastic formation rates and low osteoclastic resorption. As a result, there is increased accumulation of normal bone. Endosteal hyperostosis with syndactyly, known as sclerosteosis, is a more severe form. The genetic defects for both sclerosteosis and van Buchem’s disease have been assigned to the same region of the chromosome 17q12-q21. It is possible that both conditions may have deactivating mutations in the BEER (bone-expressed equilibrium regulator) gene.

MELORHEOSTOSIS

Melorheostosis (Greek, “flowing hyperostosis”) may occur sporadically or follow a pattern consistent with an autosomal recessive disorder. The major manifestation is progressive linear hyperostosis in one or more bones of one limb, usually a lower extremity. The name comes from the radiographic appearance of the involved bone, which resembles melted wax that has dripped down a candle. Symptoms appear during childhood as pain or stiffness in the area of sclerotic bone. There may be associated ectopic soft tissue masses, composed of cartilage or osseous tissue, and skin changes overlying the involved bone, consisting of scleroderma-like areas and hypertrichosis. The disease does not progress in adults, but pain and stiffness may persist. Laboratory tests are unremarkable. No specific etiology is known. There is no specific treatment. Surgical interventions to correct contractures are often unsuccessful.

OSTEOPOIKILOSIS

The literal translation of osteopoikilosis is “spotted bones”; it is a benign autosomal dominant condition in which numerous small, variably shaped (usually round or oval) foci of bony sclerosis are seen in the epiphyses and adjacent metaphyses. The lesions may involve any bone except the skull, ribs, and vertebrae. They may be misidentified as metastatic lesions. The main differentiating points are that bony lesions of osteopoikilosis are stable over time and do not accumulate radionucleotide on bone scanning. In some kindred, osteopoikilosis is associated with connective tissue nevi known as dermatofibrosis lenticularis disseminata, also known as Buschke-Ollendorff syndrome. Histologic inspection reveals thickened but otherwise normal trabeculae and islands of normal cortical bone. No treatment is indicated.

HEPATITIS C–ASSOCIATED OSTEOSCLEROSIS

Hepatitis C–associated osteosclerosis (HCAO) is a rare acquired diffuse osteosclerosis in adults with prior hepatitis C infection. After a latent period of several years, patients develop diffuse appendicular bone pain and a generalized increase in bone mass with elevated serum ALP. Bone biopsy and histomorphometry reveal increased rates of bone formation, decreased bone resorption with a marked decrease in osteoclasts, and dense lamellar bone. One patient had increased serum OPG levels, and bone biopsy showed large numbers of osteoblasts positive for OPG and reduced osteoclast number. Empirical therapy includes pain control, and there may be beneficial response to bisphosphonate. Long-term antiviral therapy may reverse the bone disease.

DISORDERS ASSOCIATED WITH DEFECTIVE MINERALIZATION

HYPOPHOSPHATASIA

This is a rare inherited disorder that presents as rickets in infants and children or osteomalacia in adults with paradoxically low serum levels of ALP. The frequency of the severe neonatal and infantile forms is about 1 in 100,000 live births in Canada, where the disease is most common because of its high prevalence among Mennonites and Hutterites. It is rare in African Americans. The severity of the disease is remarkably variable, ranging from intrauterine death associated with profound skeletal hypomineralization at one extreme to premature tooth loss as the only manifestation in some adults. Severe cases are inherited in an autosomal recessive manner, but the genetic patterns are less clear for the milder forms. The disease is caused by a deficiency of tissue nonspecific (bone/liver/kidney) ALP (TNSALP), which, although ubiquitous, results only in bone abnormalities. Protein levels and functions of the other ALP isozymes (germ cell, intestinal, placental) are normal. Defective ALP permits accumulation of its major naturally occurring substrates including phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal 5′-phosphate (PLP). The accumulation of PPi interferes with mineralization through its action as a potent inhibitor of hydroxyapatite crystal growth.

Perinatal hypophosphatasia becomes manifest during pregnancy and is often complicated by polyhydramnios and intrauterine death. The infantile form becomes clinically apparent before the age of 6 months with failure to thrive, rachitic deformities, functional craniosynostosis despite widely open fontanels (which are actually hypomineralized areas of the calvarium), raised intracranial pressure, and flail chest with predisposition to pneumonia. Hypercalcemia and hypercalciuria are common. This form has a mortality rate of about 50%. Prognosis seems to improve for the children who survive infancy. Childhood hypophosphatasia has variable clinical presentation. Premature loss of deciduous teeth (before age 5) is the hallmark of the disease. Rickets causes delayed walking with waddling gait, short stature, and dolichocephalic skull with frontal bossing. The disease often improves during puberty but may recur in adult life. Adult hypophosphatasia presents during middle age with painful, poorly healing metatarsal stress fractures or thigh pain due to femoral pseudofractures.

Laboratory investigation reveals low ALP levels and normal or elevated levels of serum calcium and phosphorus despite clinical and radiologic evidence of rickets or osteomalacia. Serum parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels are normal. The elevation of PLP is specific for the disease and may even be present in asymptomatic parents of severely affected children. Because vitamin B₆ increases PLP levels, vitamin B₆ supplements should be discontinued 1 week before testing. Clinical testing is available to detect loss-of-function mutation(s) within the ALPL gene that encodes TNSALP.

There is no established medical therapy. In contrast to other forms of rickets and osteomalacia, calcium and vitamin D supplementation should be avoided because they may aggravate hypercalcemia and hypercalciuria. A low-calcium diet, glucocorticoids, and calcitonin have been used in a small number of patients with variable responses. Because fracture healing is poor, placement of intramedullary rods is best for acute fracture repair and for prophylactic prevention of fractures.

AXIAL OSTEOMALACIA

This is a rare disorder characterized by defective skeletal mineralization despite normal serum calcium and phosphate levels. Clinically, the disorder presents in middle-aged or elderly men with chronic axial skeletal discomfort. Cervical spine pain may also be present. Radiographic findings are mainly osteosclerosis due to coarsened trabecular patterns typical of osteomalacia. Spine, pelvis, and ribs are most commonly affected. Histologic changes show defective mineralization and flat, inactive osteoblasts. The primary defect appears to be an acquired defect in osteoblast function. The course is benign, and there is no established treatment. Calcium and vitamin D therapies are not effective.

FIBROGENESIS IMPERFECTA OSSIUM

This is a rare condition of unknown etiology. It presents in both sexes; in middle age or later; and with progressive, intractable skeletal pain and fractures; worsening immobilization; and a debilitating course. Radiographic evaluation reveals generalized osteomalacia, osteopenia, and occasional pseudofractures. Histologic features include a tangled pattern of collagen fibrils with abundant osteoblasts and osteoclasts. There is no effective treatment. Spontaneous remission has been reported in a small number of patients. Calcium and vitamin D have not been beneficial.

FIBROUS DYSPLASIA AND McCUNE-ALBRIGHT SYNDROME

Fibrous dysplasia is a sporadic disorder characterized by the presence of one (monostotic) or more (polyostotic) expanding fibrous skeletal lesions composed of bone-forming mesenchyme. The association of the polyostotic form with café au lait spots and hyperfunction of an endocrine system such as pseudoprecocious puberty of ovarian origin is known as McCune-Albright syndrome (MAS). A spectrum of the phenotypes is caused by activating mutations in the GNAS1 gene, which encodes the α subunit of the stimulatory G protein (G_sα). As the postzygotic mutations occur at different stages of early development, the extent and type of tissue affected are variable and explain the mosaic pattern of skin and bone changes. GTP binding activates the G_sα regulatory protein and mutations in regions of G_sα that selectively inhibit GTPase activity, which results in constitutive stimulation of the cyclic AMP–protein kinase A signal transduction pathway. Such mutations of the G_sα protein–coupled receptor may cause autonomous function in bone (parathyroid hormone receptor); skin (melanocyte-stimulating hormone receptor); and various endocrine glands including ovary (follicle-stimulating hormone receptor), thyroid (thyroid-stimulating hormone receptor), adrenal (adrenocorticotropic hormone receptor), and pituitary (growth hormone–releasing hormone receptor). The skeletal lesions are composed largely of mesenchymal cells that do not differentiate into osteoblasts, resulting in the formation of imperfect bone. In some areas of bone, fibroblast-like cells develop features of osteoblasts in that they produce extracellular matrix that organizes into woven bone. Calcification may occur in some areas. In other areas, cells have features of chondrocytes and produce cartilage-like extracellular matrix.

Clinical Presentation

Fibrous dysplasia occurs with equal frequency in both sexes, whereas MAS with precocious puberty is more common (10:1) in girls. The monostotic form is the most common and is usually diagnosed in patients between 20 and 30 years of age without associated skin lesions. The polyostotic form typically manifests in children <10 years old and may progress with age. Early-onset disease is generally more severe. Lesions may become quiescent in puberty and progress during pregnancy or with estrogen therapy. In polyostotic fibrous dysplasia, the lesions most commonly involve the maxilla and other craniofacial bones, ribs, and metaphyseal or diaphyseal portions of the proximal femur or tibia. Expanding bone lesions may cause pain, deformity, fractures, and nerve entrapment. Sarcomatous degeneration involving the facial bones or femur is infrequent (<1%). The risk of malignant transformation is increased by radiation, which has proven to be ineffective treatment. In rare patients with widespread lesions, renal phosphate wasting and hypophosphatemia may cause rickets or osteomalacia. Hypophosphatemia may be due to production of a phosphaturic factor by the abnormal fibrous tissue.

MAS patients may have café au lait spots, which are flat, hyperpigmented skin lesions that have rough borders (“coast of Maine”) in contrast to the café au lait lesions of neurofibromatosis that have smooth borders (“coast of California”). The most common endocrinopathy is isosexual pseudoprecocious puberty in girls. Other less common endocrine disorders include thyrotoxicosis, Cushing’s syndrome, acromegaly, hyperparathyroidism, hyperprolactinemia, and pseudoprecocious puberty in boys.

Radiographic Findings

In long bones, the fibrous dysplastic lesions are typically well-defined, radiolucent areas with thin cortices and a ground-glass appearance. Lesions may be lobulated with trabeculated areas of radiolucency (Fig. 426e-4). Involvement of facial bones usually presents as radiodense lesions, which may create a leonine appearance (leontiasis osea). Expansile cranial lesions may narrow foramens and cause optic lesions, reduce hearing, and create other manifestations of cranial nerve compression.

Laboratory Results

Serum ALP is occasionally elevated but calcium, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxy-vitamin D levels are normal. Patients with extensive polyostotic lesions may have hypophosphatemia, hyperphosphaturia, and osteomalacia. The hypophosphatemia and phosphaturia are directly related to the levels of fibroblast growth factor 23 (FGF23). Biochemical markers of bone turnover may be elevated.

TREATMENT

OTHER DYSPLASIAS OF BONE AND CARTILAGE

PACHYDERMOPERIOSTOSIS

Pachydermoperiostosis, or hypertrophic osteoarthropathy (primary or idiopathic), is an autosomal dominant disorder characterized by periosteal new bone formation that involves the distal extremities. The lesions present as clubbing of the digits and hyperhidrosis and thickening of the skin, primarily of the face and forehead. The changes usually appear during adolescence, progress over the next decade, and then become quiescent. During the active phase, progressive enlargement of the hands and feet produces a paw-like appearance, which may be mistaken for acromegaly. Arthralgias, pseudogout, and limited mobility may also occur. The disorder must be differentiated from secondary hypertrophic osteopathy that develops during the course of serious pulmonary disorders. The two conditions can be differentiated by standard radiography of the digits in which secondary pachydermoperiostosis has exuberant periosteal new bone formation and a smooth and undulating surface. In contrast, primary hypertrophic osteopathy has an irregular periosteal surface.

There are no diagnostic blood or urine tests. Synovial fluid does not have an inflammatory profile. There is no specific therapy, although a limited experience with colchicine suggests some benefit in controlling the arthralgias.

OSTEOCHONDRODYSPLASIAS

These include several hundred heritable disorders of connective tissue. These primary abnormalities of cartilage manifest as disturbances in cartilage and bone growth. Selected growth-plate chondrodysplasias are described here. For discussion of chondrodysplasias, see Chap. 427.

Achondrodysplasia

This is a relatively common form of short-limb dwarfism that occurs in 1 in 15,000 to 1 in 40,000 live births. The disease is caused by a mutation of the fibroblast growth facto