Bone Structure and Metabolism
Bone is a dynamic tissue that is remodeled constantly throughout life. The arrangement of compact and cancellous bone provides a 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. 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. 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. These 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 these 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 tendon. Single amino-acid substitutions in the helical portion of either the 1 (COL1A1) or 2 (COL1A2) chains of type I collagen disrupt the organization of bone in osteogenesis imperfecta. The severe skeletal fragility associated with these disorders highlights the importance of the fibrillar matrix in the structure of bone.
Osteoblasts synthesize and secrete the organic matrix. They are derived from cells of mesenchymal origin (Fig. 346-1A ). Active osteoblasts are found on the surface of newly forming bone. As an osteoblast secretes matrix, which is then mineralized, the cell becomes an osteocyte, still connected with its blood supply through a series of canaliculi. Osteocytes comprise 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. 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). While this mineralization takes advantage of the high concentrations of calcium and phosphate already near saturation in serum, mineralization is a carefully regulated process dependent on the activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing inhibitors of mineralization.
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Genetic studies in humans and mice have identified several key genes that control osteoblast development. Core-binding factor A1 (CBFA1, also called 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 NFB (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 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. Humans and mice missing a wnt-family co-receptor, LRP5 (lipoprotein receptor–related protein 5), have osteoporosis. Remarkably, humans with an overactive form of LPR5 have increased bone mass. Numerous other growth-regulatory factors affect osteoblast function, including the three closely related transforming growth factor s, 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 to 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. Multiple factors regulating osteoclast development have been identified (Fig. 346-1B ). 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 ) modulate osteoclast differentiation and function. Most hormones that influence osteoclast function do not directly target this cell but instead influence M-CSF and RANK ligand signaling by osteoblasts. Both PTH and 1,25(OH)2D increase osteoclast number and activity, whereas estrogen decreases 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.
Osteoclast-mediated resorption of bone takes place in scalloped spaces (Howship's lacunae) where the osteoclasts are attached through a specific v3 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 likened to an extracellular lysosome. The active osteoclast surface forms a ruffled border that contains a specialized proton-pump ATPase, which 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 that act at low pH, such as cathepsin K.
In the embryo and in the growing child, bone develops by remodeling and replacing previously calcified cartilage (endochondral bone formation) or is formed without a cartilage matrix (intramembranous bone formation). Chondrocytes proliferate, secrete and mineralize a matrix, enlarge (hypertrophy), and then die, thereby 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, parathyroid hormone–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 on 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 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 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 is covered with osteoid. 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, composed of a group of osteoclasts and osteoblasts (Fig. 346-2).
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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, the progenitor stromal cells differentiate into cells with functional capacities different from those of osteoblasts, and varying amounts of fibrous tissue and cartilage are formed. When there is good apposition with fixation and little motion at the fracture site, repair occurs predominantly by formation of new bone without other scar 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 or osteoblasts, or their precursors. A bowing deformity increases new bone formation at the concave surface and resorption at the convex surface, seemingly designed to produce the strongest mechanical structure. 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 crosslinks. 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. 346-3). 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.
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The concentration of ionized calcium in the ECF must be maintained within a narrow range because of the critical role it 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 concentration in the blood and ECF (1.1–1.3 mmol/L). This steep chemical gradient 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 parathyroid calcium-sensing receptors (CaSRs). Also, ionized calcium indirectly affects PTH secretion via effects on 1,25(OH)2D production. This active vitamin D metabolite inhibits PTH production by an incompletely understood mechanism of negative feedback.
Normal dietary calcium intake in the United States varies widely, ranging from 10–37 mmol/d (400–1500 mg/d). Many individuals, in an effort to prevent osteoporosis, routinely supplement this further with oral calcium salts to a total intake of 37–50 mmol/d (1500–2000 mg/d). 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 the active mechanism, controlled principally by 1,25(OH)2D, normally ranges from 20–70%. 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 upon gastric acid. In achlorhydric subjects or 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, which decreases the rate of active intestinal calcium absorption. The opposite occurs with dietary calcium restriction. Some calcium, ~2.5–5.0 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 are 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, whereby serum ionized calcium can control renal calcium reabsorption. Finally, ~10% of filtered calcium is reabsorbed in the distal convoluted tubules (DCT) by a transcellular mechanism. Calcium enters the luminal surface of the cell through specific apical calcium channels, 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 of 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. Conversely, dietary sodium loads, or increased distal sodium delivery caused by loop diuretics or saline infusion, reduce DCT calcium reabsorption.
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 less than5 mmol/d (less than 200 mg/d) cannot provide enough net calcium absorption to replace obligate losses via the intestine, kidney, sweat, or 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 [more than100 mmol/d; more than 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
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 (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 are generally expressed in terms of elemental phosphorus, 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 efficiently absorbed (65%) by the small intestine, even in the absence of vitamin D. On the other hand, phosphate absorptive efficiency may be further enhanced (to 85–90%) via active transport mechanisms that are stimulated by 1,25(OH)2D. These 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 according to 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 less commonly used because of the potential for aluminum toxicity. Low serum phosphate directly stimulates renal proximal tubular synthesis of 1,25(OH)2D.
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 and 10 A.M. Carbohydrate administration, especially as IV dextrose solutions in fasting subjects, can decrease serum phosphate by more than 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.
Hypophosphatemia
Causes
Hypophosphatemia can occur by one or more of three primary mechanisms: (1) inadequate intestinal phosphate absorption, (2) excessive renal phosphate excretion, or (3) rapid redistribution of phosphate from the ECF into bone or soft tissue (Table 346-1). 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 commonly 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.
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 apical expression and activity of a specific Na+/PO42– co-transporter (NaPi-2) in the proximal tubule. Apical expression of NaPi-2 is rapidly reduced by PTH, the major known hormonal regulator of renal phosphate excretion. FGF23 can dramatically impair phosphate reabsorption (see below). Activating FGF23 mutations cause the rare disorder autosomal dominant hypophosphatemic rickets. In contrast to PTH, this molecule 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. Findings in FGF23-knockout mice suggest that FGF23 normally acts to lower blood phosphate and 1,25(OH)2D levels. In turn, elevations 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
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Note: CSF, cerebrospinal fluid.
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Chronic hypophosphatemia usually signifies a persistent renal tubular phosphate-wasting disorder. Excessive activation of PTH/PTHrP receptors in the proximal tubule, because of primary or secondary hyperparathyroidism or because of the PTHrP-mediated hypercalcemia syndrome in malignancy, 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.
Several genetic and acquired diseases cause PTH/PTHrP-independent tubular phosphate wasting, with associated rickets and osteomalacia. All of these diseases manifest severe hypophosphatemia; renal phosphate wasting, sometimes accompanied by aminoaciduria; 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 has led to the discovery of a "new" hormone, FGF23, that is an important physiologic regulator of phosphate metabolism. FGF23 decreases phosphate reabsorption in the proximal tubule and also suppresses the 1-hydroxylase responsible for synthesis of 1,25(OH)2D. FGF23 is synthesized by cells of the osteoblast lineage. 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 encoding FGF23. The most common inherited cause of hypophosphatemia is X-linked hypophosphatemic rickets (XLHR), which results from inactivating mutations in an endopeptidase termed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) that is most abundantly expressed on the surface of 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 yet been determined. A third hypophosphatemic disorder, tumor-induced osteomalacia (TIO), is an acquired disorder in which tumors, usually of mesenchymal origin and generally histologically benign, secrete molecules that induce renal phosphate wasting. The hypophosphatemic syndrome resolves completely within hours to days following successful resection of the responsible tumor. Such tumors 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 diabetics 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 346-1).
In hospitalized patients, hypophosphatemia is often attributable to massive redistribution of phosphate from the ECF into cells. Insulin therapy of 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. 338). 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 can also occur transiently (over weeks to months) during the phase of accelerated net bone formation following 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, 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 death. Serious sequelae such as paralysis, confusion, and seizures are likely only at phosphate concentrations less than 0.25 mmol/L (less than 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 (less tahn0.7 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, 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.
Hypophosphatemia: Treatment
Severe hypophosphatemia [less tahn 0.75 mmol/L (less than 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 easily predicted 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 and 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 more than 20 mmol/6 h reserved for those who have serum levels less tahn 0.5 mmol/L (1.5 mg/dL) and normal renal function. A suggested approach is presented in Table 346-2. 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 more than 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), can usually be treated with oral phosphate in divided doses of 750–2000 mg/d, as elemental phosphorus; higher doses can cause bloating and diarrhea.
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Rates shown are calculated for a 70-kg person; levels of serum calcium and phosphorus must be measured every 6 to 12 h during therapy; infusions can be repeated to achieve stable serum phosphorus levels more than 0.8 mmol/L (more than 2.5 mg/dL); most formulations available in the United States provide 3 mmol/mL of sodium or potassium phosphate.
Management of chronic hypophosphatemia requires knowing 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. XLHR, ADHR, TIO, and related renal tubular disorders are usually 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 of 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
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-transporter. The principal hormonal regulator of NaPi-2 activity is PTH. Hyperphosphatemia, defined in adults as a fasting serum phosphate concentration more than 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 some combination of these factors (Table 346-3). 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 346-3).
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In chronic renal insufficiency, reduced GFR leads to phosphate retention. Hyperphosphatemia, in turn, further impairs renal synthesis of 1,25(OH)2D 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. 274 and 347).
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 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 hyperphosphaturia in hypoparathyroid subjects. Increased tubular phosphate reabsorption also occurs in acromegaly, during heparin administration, and in tumoral calcinosis. Tumoral calcinosis is a caused by a rare group of genetic disorders in which the FGF23 gene is either inactivated directly or in which FGF23 is processed in a way that leads to low levels of active FGF23 in the bloodstream. 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 rapidly delivered 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, or 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.
Hyperphosphatemia: Treatment
Therapeutic options for management of severe hyperphosphatemia are limited. Volume expansion may enhance renal phosphate clearance. Aluminum hydroxide antacids or sevalamer 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 0.7–1.0 mmol/L (1.5–2.0 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. Half of the 25 g (1000 mmol) of total body magnesium is located in bone, only 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 6–15 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-negative potential, created by NaCl reabsorption, and the tight-junction protein, paracellin-1. 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 346-4). Dietary magnesium deficiency is unlikely except possibly in the setting of alcoholism. A rare genetic disorder causing 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 renal 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.
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Note: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate anti-diuretic hormone.
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Several genetic magnesium-wasting syndromes are described, including inactivating mutations of genes encoding the DCT NaCl co-transporter (Gitelman syndrome), proteins required for cTAL Na-K-2Cl transport (Bartter syndrome), paracellin-1 (autosomal recessive renal hypomagnesemia with hypercalciuria), a DCT Na+,K+-ATPase -subunit (autosomal dominant renal hypomagnesemia with hypocalciuria), the FXYD2 -subunit of the distal tubular basolateral Na+,K+-ATPase, and a mitochondrial DNA gene encoding a mitochondrial tRNA. 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 (Table 346-4). A rising blood concentration of ethanol directly impairs tubular magnesium reabsorption, and persistent glycosuria with osmotic diuresis leads to magnesium wasting and likely contributes to the high frequency of hypomagnesemia in poorly controlled diabetics. 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, from starvation, or from 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, 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 more than 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 [more than 0.4 mmol/L (more than 0.8 meq/L; more than 1 mg/dL)], a defect in PTH secretion; these abnormalities are reversible with therapy.
Hypomagnesemia: Treatment
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 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
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 calcium-sensing receptor 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 346-5). 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.
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Clinical and Laboratory Findings
The most prominent clinical manifestations of hypermagnesemia are vasodilation and neuromuscular blockade, which may appear at serum magnesium concentrations more than2 mmol/L (more than4 meq/L; more than4.8 mg/dL). Hypotension, 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 more than 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.
Hypermagnesemia: Treatment
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. 346-4). 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 of 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 past 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 -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 dramatically shortened when vitamin D–binding protein levels are reduced, as can occur with increased urinary losses in the nephrotic syndrome.
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The second hydroxylation, required for the formation of the mature hormone, occurs in the kidney (Fig. 346-5). The 25-hydroxyvitamin D-1-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-1-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 1-hydroxylase is produced by macrophages associated with granulomata and lymphomas. In these latter pathologic states, the activity of the enzyme is induced by interferon and TNF- 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.
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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. Polar metabolites of 1,25(OH)2D are secreted into the bile and reabsorbed via the enterohepatic circulation. Impairment of this recirculation, 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. Under 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 most extensively studied 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 has also 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 parathyroid hormone 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 parathyroid hormone 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 346-6). 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 leads 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 infrequent cause of vitamin D deficiency. Impaired 1-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 less than0.5 mL/s (30 mL/min). Mutations in the renal 1-hydroxylase are the basis for the genetic disorder, pseudo-vitamin 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 1-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 1-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. Since the receptor mutation results in hormone resistance, daily calcium and phosphorus infusions may be required to bypass the defect in intestinal mineral ion absorption.
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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. 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, or 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, prior to 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.
Though 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. Since 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) can also 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. While the normal ranges vary, levels of 25(OH)D less than 37 nmol/L (less than 15 ng/mL) are associated with increasing PTH levels and lower bone density; optimal vitamin D levels are more than 62 nmol/L (more than 25 ng/mL). 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. Since PTH is a major stimulus for the renal 25(OH)D 1-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 an accurate reflection 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, characteristic of rickets. These findings are not only apparent in the long bones but are also 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 radio-opacity 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 (Fig. 346-6). 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, several centimeters long, and are seen particularly in the scapula, the pelvis, and the femoral neck
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Vitamin D Deficiency: Treatment
Daily intake of a multivitamin (400 IU) is often insufficient to prevent vitamin D deficiency. Based on the observation that 800 IU of vitamin D, with calcium supplementation, decreases the risk of hip fractures in elderly women, this higher dose is thought to be an appropriate daily intake for prevention of vitamin D deficiency in adults. The safety margin for vitamin D is large, and vitamin D toxicity is usually observed only in patients taking doses in the range of 40,000 IU daily. Treatment of vitamin D deficiency should be directed at the underlying disorder, if possible, and should also be tailored to the severity of the condition. Vitamin D should always be repleted in conjunction with calcium supplementation since most, if not all, of the consequences of vitamin D deficiency are a result of impaired mineral ion homeostasis. In patients in whom 1-hydroxylation is impaired, metabolites not requiring this activation step are the treatment of choice. These include 1,25(OH)2D3 [calcitriol (Rocaltrol), 0.25–0.5 g/d] and 1,25-dihydroxyvitamin D2 (Hectorol, 2.5–5 g/d). If the pathway required for activation of vitamin D is intact, severe vitamin D deficiency can be treated with pharmacologic repletion initially (50,000 IU weekly for 3–12 weeks), followed by maintenance therapy (800 IU daily). Pharmacologic doses may be required for maintenance therapy in patients who are taking medications, such as barbiturates or phenytoin, that accelerate metabolism of or cause resistance to 1,25(OH)2D. If intestinal malabsorption is a contributing factor, repletion can be performed with IM vitamin D (250,000 IU biannually). Calcium supplementation should include 1.5–2.0 g/d of elemental calcium. Normocalcemia is usually observed within 1 week of institution of therapy, although increases in PTH and alkaline phosphatase levels may persist for 3–6 months. The most efficacious methods to monitor treatment and resolution of vitamin D deficiency are serum and urinary calcium measurements. In patients who are vitamin D replete and taking adequate calcium supplementation, the 24-h urinary calcium excretion should be in the range of 100–250 mg/24 h. Lower levels suggest problems with adherence to the treatment regimen or with absorption of calcium or vitamin D supplements. Levels more than 250 mg/24 h predispose to nephrolithiasis and should lead to a reduction in vitamin D dosage and/or calcium supplementation.
