Bone and Mineral Metabolism in Health and Disease

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.

FIGURE 423-1   Pathways regulating development of (A) osteoblasts and (B) osteoclasts. Hormones, cytokines, and growth factors that control cell proliferation and differentiation are shown above the arrows. Transcription factors and other markers specific for various stages of development are depicted below the arrows. BMPs, bone morphogenic proteins; IGFs, insulin-like growth factors; IL-1, interleukin 1; IL-6, interleukin 6; M-CSF, macrophage colony-stimulating factor; NFκB, nuclear factor κB; PTH, parathyroid hormone; PU-1, a monocyte- and B lymphocyte–specific ets family transcription factor; RANK ligand, receptor activator of NFκB ligand; Runx2, Runt-related transcription factor 2; TRAF, tumor necrosis factor receptor–associated factors; Vit D, vitamin D; wnts, wingless-type mouse mammary tumor virus integration site. (Modified from T Suda et al: Endocr Rev 20:345, 1999, with permission.)

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).

FIGURE 423-2   Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), which consists of a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of bone remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which eventually is mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone.

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.

FIGURE 423-3   Calcium homeostasis. Schematic illustration of calcium content of extracellular fluid (ECF) and bone as well as of diet and feces; magnitude of calcium flux per day as calculated by various methods is shown at sites of transport in intestine, kidney, and bone. Ranges of values shown are approximate and were chosen to illustrate certain points discussed in the text. In conditions of calcium balance, rates of calcium release from and uptake into bone are equal.

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 HPO₄^2–. 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⁺/PO₄^2– 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⁺/PO₄^2– 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.

Abbreviations: PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide.

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.

Severe hypophosphatemia (<0.75 mmol/L [<2 mg/dL]), particularly in the setting of underlying phosphate depletion, constitutes a dangerous electrolyte abnormality that should be corrected promptly. Unfortunately, the cumulative deficit in body phosphate cannot be predicted easily from knowledge of the circulating level of phosphate, and therapy must be approached empirically. The threshold for IV phosphate therapy and the dose administered should reflect consideration of renal function, the likely severity and duration of the underlying phosphate depletion, and the presence and severity of symptoms consistent with those of hypophosphatemia. In adults, phosphate may be safely administered IV as neutral mixtures of sodium or potassium phosphate salts at initial doses of 0.2–0.8 mmol/kg of elemental phosphorus over 6 h (e.g., 10–50 mmol over 6 h), with doses >20 mmol/6 h reserved for those who have serum levels <0.5 mmol/L (1.5 mg/dL) and normal renal function. A suggested approach is presented in Table 423-2. Serum levels of phosphate and calcium must be monitored closely (every 6–12 h) throughout treatment. It is necessary to avoid a serum calcium-phosphorus product >50 to reduce the risk of heterotopic calcification. Hypocalcemia, if present, should be corrected before administering IV phosphate. Less severe hypophosphatemia, in the range of 0.5–0.8 mmol/L (1.5–2.5 mg/dL), usually can be treated with oral phosphate in divided doses of 750–2000 mg/d as elemental phosphorus; higher doses can cause bloating and diarrhea.

Management of chronic hypophosphatemia requires knowledge of the cause(s) of the disorder. Hypophosphatemia related to the secondary hyperparathyroidism of vitamin D deficiency usually responds to treatment with vitamin D and calcium alone. XLH, ADHR, TIO, and related renal tubular disorders usually are managed with divided oral doses of phosphate, often with calcium and 1,25(OH)₂D supplements to bypass the block in renal 1,25(OH)₂D synthesis and prevent secondary hyperparathyroidism caused by suppression of ECF calcium levels. Thiazide diuretics may be used to prevent nephrocalcinosis in patients who are managed this way. Complete normalization of hypophosphatemia is generally not possible in these conditions. Optimal therapy for TIO is extirpation of the responsible tumor, which may be localized by radiographic skeletal survey or bone scan (many are located in bone) or by radionuclide scanning using sestamibi or labeled octreotide. Successful treatment of TIO-induced hypophosphatemia with octreotide has been reported in a small number of patients.

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.

Therapeutic options for management of severe hyperphosphatemia are limited. Volume expansion may enhance renal phosphate clearance. Aluminum hydroxide antacids or sevelamer may be helpful in chelating and limiting absorption of offending phosphate salts present in the intestine. Hemodialysis is the most effective therapeutic strategy and should be considered early in the course of severe hyperphosphatemia, especially in the setting of renal failure and symptomatic hypocalcemia.

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.

Abbreviations: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate antidiuretic hormone.

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.

Mild, asymptomatic hypomagnesemia may be treated with oral magnesium salts (MgCl₂, MgO, Mg[OH]₂) in divided doses totaling 20–30 mmol/d (40–60 meq/d). Diarrhea may occur with larger doses. More severe hypomagnesemia should be treated parenterally, preferably with IV MgCl₂, which can be administered safely as a continuous infusion of 50 mmol/d (100 meq Mg²⁺/d) if renal function is normal. If GFR is reduced, the infusion rate should be lowered by 50–75%. Use of IM MgSO₄ is discouraged; the injections are painful and provide relatively little magnesium (2 mL of 50% MgSO₄ supplies only 4 mmol). MgSO₄ may be given IV instead of MgCl₂, although the sulfate anions may bind calcium in serum and urine and aggravate hypocalcemia. Serum magnesium should be monitored at intervals of 12–24 h during therapy, which may continue for several days because of impaired renal conservation of magnesium (only 50–70% of the daily IV magnesium dose is retained) and delayed repletion of intracellular deficits, which may be as high as 1–1.5 mmol/kg (2–3 meq/kg).

It is important to consider the need for calcium, potassium, and phosphate supplementation in patients with hypomagnesemia. Vitamin D deficiency frequently coexists and should be treated with oral or parenteral vitamin D or 25(OH)D (but not with 1,25[OH]₂D, which may impair tubular magnesium reabsorption, possibly via PTH suppression). In severely hypomagnesemic patients with concomitant hypocalcemia and hypophosphatemia, administration of IV magnesium alone may worsen hypophosphatemia, provoking neuromuscular symptoms or rhabdomyolysis, due to rapid stimulation of PTH secretion. This is avoided by administering both calcium and magnesium.

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.

Successful treatment of hypermagnesemia generally involves identifying and interrupting the source of magnesium and employing measures to increase magnesium clearance from the ECF. Use of magnesium-free cathartics or enemas may be helpful in clearing ingested magnesium from the gastrointestinal tract. Vigorous IV hydration should be attempted, if appropriate. Hemodialysis is effective and may be required in patients with significant renal insufficiency. Calcium, administered IV in doses of 100–200 mg over 1–2 h, has been reported to provide temporary improvement in signs and symptoms of hypermagnesemia.

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

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